{   "39865654": { "pmid": "39865654", "title": "PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery.", "sortKey": "2025-03-pbae-peg-based lipid", "pubDateYear": "2025", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Liu B, Sajiki Y, Littlefield N, Hu Y, Stuart WD, Sridharan A, Cui X, Siefert ME, Araki K, Ziady AG, Shi D, Whitsett JA, Maeda Y", "citation": "Molecular therapy : the journal of the American Society of Gene Therapy, 03 2025", "abstractText": "Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles (LNPs) provides a framework for treating various genetic and acquired disorders. However, LNPs that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought to determine whether poly(β-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination with 4A3-SC8/DOPE/cholesterol/DOTAP LNPs could deliver mRNA into different types of lung cells in vivo. PBAE-PEG/LNP was similar to Lipofectamine MessengerMAX followed by PBAE/LNP for mRNA transfection efficiency in HEK293T cells in vitro. PBAE-PEG/LNP administered by intravenous (IV) injection achieved 73% mRNA transfection efficiency into lung endothelial cells, while PBAE-PEG/LNP administered by intratracheal (IT) injection achieved 55% efficiency in lung alveolar type II (ATII) epithelial cells in mice in vivo. PBAE/LNP administered by IT injection were superior for specific delivery into lung airway club epithelial cells compared to PBAE-PEG/LNP. Lipofectamine MessengerMAX was inactive in vivo. 5-Methoxyuridine-modified mRNA was more efficient than unmodified mRNA in vivo but not in vitro. Our findings indicate that PBAE-PEG/LNP and PBAE/LNP can transfect multiple lung cell types in vivo, which can be applied in gene therapy targeting genetic lung diseases.", "pubmedLink": "" },   "39666855": { "pmid": "39666855", "title": "An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung.", "sortKey": "2024-12-an injury-induced me", "pubDateYear": "2024", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Jones DL, Morley MP, Li X, Ying Y, Zhao G, Schaefer SE, Rodriguez LR, Cardenas-Diaz FL, Li S, Zhou S, Chembazhi UV, Kim M, Shen C, Nottingham A, Lin SM, Cantu E, Diamond JM, Basil MC, Vaughan AE, Morrisey EE", "citation": "Science (New York, N.Y.), 12 2024", "abstractText": "Severe lung injury causes airway basal stem cells to migrate and outcompete alveolar stem cells, resulting in dysplastic repair. We found that this  stem cell collision  generates an injury-induced tissue niche containing keratin 5 epithelial cells and plastic Pdgfra mesenchymal cells. Single-cell analysis revealed that the injury-induced niche is governed by mesenchymal proliferation and Notch signaling, which suppressed Wnt/Fgf signaling in the injured niche. Conversely, loss of Notch signaling rewired alveolar signaling patterns to promote functional regeneration and gas exchange. Signaling patterns in injury-induced niches can differentiate fibrotic from degenerative human lung diseases through altering the direction of Wnt/Fgf signaling. Thus, we have identified an injury-induced niche in the lung with the ability to discriminate human lung disease phenotypes.", "pubmedLink": "" },   "39641142": { "pmid": "39641142", "title": "EMC3 is critical for CFTR function and calcium mobilization in the mouse intestinal epithelium.", "sortKey": "2025-01-emc3 is critical for", "pubDateYear": "2025", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Penrod S, Tang X, Moon C, Whitsett JA, Naren AP, Huang Y", "citation": "American journal of physiology. Gastrointestinal and liver physiology, 01 2025", "abstractText": "Membrane proteins, such as the cystic fibrosis transmembrane-conductance regulator (CFTR), play a crucial role in gastrointestinal functions and health. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins  processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3). EMC3 mice were viable but notably smaller compared with their wild-type littermates. Although the intestinal structure was generally maintained, EMC3 crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3 enteroids. CFTR-mediated organoid swelling in EMC3 mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC. We generated mice in which endoplasmic reticulum membrane protein complex (EMC) subunit 3 was deleted from intestinal epithelium cells and studied the molecular functions of EMC in vivo. Our findings demonstrate the importance of intestinal EMC in the biogenesis of membrane proteins in vivo, including CFTR, and highlight its critical role in maintaining intracellular calcium homeostasis and, consequently, in calcium-dependent functions in the intestine and beyond.", "pubmedLink": "" },   "39405113": { "pmid": "39405113", "title": "EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.", "sortKey": "2024-10-emc3 regulates traff", "pubDateYear": "2024", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Tang X, Wei W, Sun Y, Weaver TE, Nakayasu ES, Clair G, Snowball JM, Na CL, Apsley KS, Martin EP, Kotton DN, Alysandratos KD, Huo J, Molkentin JD, Gower WA, Lin X, Whitsett JA", "citation": "The Journal of clinical investigation, 10 2024", "abstractText": "The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including valosin containing protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T-expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking, respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing therapeutical targets for SFTPCI73T-associated interstitial lung disease.", "pubmedLink": "" },   "39271260": { "pmid": "39271260", "title": "Deep learning-based multimodal spatial transcriptomics analysis for cancer.", "sortKey": "2024-00-deep learning-based ", "pubDateYear": "2024", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Rajdeo P, Aronow B, Surya Prasath VB", "citation": "Advances in cancer research, 00 2024", "abstractText": "The advent of deep learning (DL) and multimodal spatial transcriptomics (ST) has revolutionized cancer research, offering unprecedented insights into tumor biology. This book chapter explores the integration of DL with ST to advance cancer diagnostics, treatment planning, and precision medicine. DL, a subset of artificial intelligence, employs neural networks to model complex patterns in vast datasets, significantly enhancing diagnostic and treatment applications. In oncology, convolutional neural networks excel in image classification, segmentation, and tumor volume analysis, essential for identifying tumors and optimizing radiotherapy. The chapter also delves into multimodal data analysis, which integrates genomic, proteomic, imaging, and clinical data to offer a holistic understanding of cancer biology. Leveraging diverse data sources, researchers can uncover intricate details of tumor heterogeneity, microenvironment interactions, and treatment responses. Examples include integrating MRI data with genomic profiles for accurate glioma grading and combining proteomic and clinical data to uncover drug resistance mechanisms. DL s integration with multimodal data enables comprehensive and actionable insights for cancer diagnosis and treatment. The synergy between DL models and multimodal data analysis enhances diagnostic accuracy, personalized treatment planning, and prognostic modeling. Notable applications include ST, which maps gene expression patterns within tissue contexts, providing critical insights into tumor heterogeneity and potential therapeutic targets. In summary, the integration of DL and multimodal ST represents a paradigm shift towards more precise and personalized oncology. This chapter elucidates the methodologies and applications of these advanced technologies, highlighting their transformative potential in cancer research and clinical practice.", "pubmedLink": "" },   "39189851": { "pmid": "39189851", "title": "Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.", "sortKey": "2024-08-toll-like receptor 9", "pubDateYear": "2024", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Trujillo G, Regueiro-Ren A, Liu C, Hu B, Sun Y, Ahangari F, Fiorini V, Ishikawa G, Al Jumaily K, Khoury J, McGovern J, Lee CJ, Peng XY, Pivarnik T, Sun H, Walia A, Woo S, Yu S, Antin-Ozerkis DE, Sauler M, Kaminski N, Herzog EL, Ryu C", "citation": "American journal of respiratory and critical care medicine, 08 2024", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).", "pubmedLink": "" },   "39149399": { "pmid": "39149399", "title": "Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.", "sortKey": "2024-08-alterations of the s", "pubDateYear": "2024", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Martin RA, Viggars MR, Sanford JA, Taylor ZW, Hansen JR, Clair GC, Adkins JN, Douglas CM, Esser KA", "citation": "bioRxiv : the preprint server for biology, 08 2024", "abstractText": "Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise.", "pubmedLink": "" },   "39090672": { "pmid": "39090672", "title": "MAMS: matrix and analysis metadata standards to facilitate harmonization and reproducibility of single-cell data.", "sortKey": "2024-08-mams: matrix and ana", "pubDateYear": "2024", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Sarfraz I, Wang Y, Shastry A, Teh WK, Sokolov A, Herb BR, Creasy HH, Virshup I, Dries R, Degatano K, Mahurkar A, Schnell DJ, Madrigal P, Hilton J, Gehlenborg N, Tickle T, Campbell JD", "citation": "Genome biology, 08 2024", "abstractText": "Many datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While biospecimen and experimental information is often captured, detailed metadata standards related to data matrices and analysis workflows are currently lacking. To address this, we develop the matrix and analysis metadata standards (MAMS) to serve as a resource for data centers, repositories, and tool developers. We define metadata fields for matrices and parameters commonly utilized in analytical workflows and developed the rmams package to extract MAMS from single-cell objects. Overall, MAMS promotes the harmonization, integration, and reproducibility of single-cell data across platforms.", "pubmedLink": "" },   "38948835": { "pmid": "38948835", "title": "Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease.", "sortKey": "2024-06-cell type-specific e", "pubDateYear": "2024", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Benjamin KJ, Sauler M, Poonyagariyagorn H, Neptune ER", "citation": "bioRxiv : the preprint server for biology, 06 2024", "abstractText": "The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung,  and , using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes for  and a subtype of alveolar epithelial type 2 cells for . In the context of disease, we further pinpoint  localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2) and  localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, finding  associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway s role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.", "pubmedLink": "" },   "38693267": { "pmid": "38693267", "title": "Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.", "sortKey": "2024-05-airway hillocks are ", "pubDateYear": "2024", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Lin B, Shah VS, Chernoff C, Sun J, Shipkovenska GG, Vinarsky V, Waghray A, Xu J, Leduc AD, Hintschich CA, Surve MV, Xu Y, Capen DE, Villoria J, Dou Z, Hariri LP, Rajagopal J", "citation": "Nature, 05 2024", "abstractText": "Airway hillocks are stratified epithelial structures of unknown function. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of  squamous metaplasia , which is long thought to be a precursor of lung cancer.", "pubmedLink": "" },   "38642558": { "pmid": "38642558", "title": "Generation of human alveolar epithelial type I cells from pluripotent stem cells.", "sortKey": "2024-05-generation of human ", "pubDateYear": "2024", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Burgess CL, Huang J, Bawa PS, Alysandratos KD, Minakin K, Ayers LJ, Morley MP, Babu A, Villacorta-Martin C, Yampolskaya M, Hinds A, Thapa BR, Wang F, Matschulat A, Mehta P, Morrisey EE, Varelas X, Kotton DN", "citation": "Cell stem cell, 05 2024", "abstractText": "Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s.", "pubmedLink": "" },   "38540357": { "pmid": "38540357", "title": "Single-Cell Transcriptomic Profiling Identifies Molecular Phenotypes of Newborn Human Lung Cells.", "sortKey": "2024-02-single-cell transcri", "pubDateYear": "2024", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Bhattacharya S, Myers JA, Baker C, Guo M, Danopoulos S, Myers JR, Bandyopadhyay G, Romas ST, Huyck HL, Misra RS, Dutra J, Holden-Wiltse J, McDavid AN, Ashton JM, Al Alam D, Potter SS, Whitsett JA, Xu Y, Pryhuber GS, Mariani TJ", "citation": "Genes, 02 2024", "abstractText": "While animal model studies have extensively defined the mechanisms controlling cell diversity in the developing mammalian lung, there exists a significant knowledge gap with regards to late-stage human lung development. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Transcriptomic profiling at the single-cell level created a cellular atlas of newborn human lungs. Frozen single-cell isolates obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository, were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Transcriptional interrogation of 5500 newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, immune cells and their gene signatures. Computational integration of data from newborn human cells and with 32,000 cells from postnatal days 1 through 10 mouse lungs generated by the LungMAP Cincinnati Research Center facilitated the identification of distinct cellular lineages among all the major cell types. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. Specifically, newborn human lung matrix fibroblasts could be separated into those representative of younger cells ( = 393), or older cells ( = 158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity.", "pubmedLink": "" },   "38529490": { "pmid": "38529490", "title": "An injury-induced tissue niche shaped by mesenchymal plasticity coordinates the regenerative and disease response in the lung.", "sortKey": "2024-02-an injury-induced ti", "pubDateYear": "2024", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Jones DL, Morley MP, Li X, Ying Y, Cardenas-Diaz FL, Li S, Zhou S, Schaefer SE, Chembazhi UV, Nottingham A, Lin S, Cantu E, Diamond JM, Basil MC, Vaughan AE, Morrisey EE", "citation": "bioRxiv : the preprint server for biology, 02 2024", "abstractText": "Severe lung injury causes basal stem cells to migrate and outcompete alveolar stem cells resulting in dysplastic repair and a loss of gas exchange function. This  stem cell collision  is part of a multistep process that is now revealed to generate an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and plastic Pdgfra+ mesenchymal cells. Temporal and spatial single cell analysis reveals that iTCHs are governed by mesenchymal proliferation and Notch signaling, which suppresses Wnt and Fgf signaling in iTCHs. Conversely, loss of Notch in iTCHs rewires alveolar signaling patterns to promote euplastic regeneration and gas exchange. The signaling patterns of iTCHs can differentially phenotype fibrotic from degenerative human lung diseases, through apposing flows of FGF and WNT signaling. These data reveal the emergence of an injury and disease associated iTCH in the lung and the ability of using iTCH specific signaling patterns to discriminate human lung disease phenotypes.", "pubmedLink": "" },   "38492572": { "pmid": "38492572", "title": "Lung repair and regeneration: Advanced models and insights into human disease.", "sortKey": "2024-04-lung repair and rege", "pubDateYear": "2024", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Basil MC, Alysandratos KD, Kotton DN, Morrisey EE", "citation": "Cell stem cell, 04 2024", "abstractText": "The respiratory system acts as both the primary site of gas exchange and an important sensor and barrier to the external environment. The increase in incidences of respiratory disease over the past decades has highlighted the importance of developing improved therapeutic approaches. This review will summarize recent research on the cellular complexity of the mammalian respiratory system with a focus on gas exchange and immunological defense functions of the lung. Different models of repair and regeneration will be discussed to help interpret human and animal data and spur the investigation of models and assays for future drug development.", "pubmedLink": "" },   "38488000": { "pmid": "38488000", "title": "TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.", "sortKey": "2024-01-tgf-β controls alve", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Callaway DA, Penkala IJ, Zhou S, Knowlton JJ, Cardenas-Diaz F, Babu A, Morley MP, Lopes M, Garcia BA, Morrisey EE", "citation": "The Journal of clinical investigation, 01 2024", "abstractText": "Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.", "pubmedLink": "" },   "38442187": { "pmid": "38442187", "title": "Bulk RNA sequencing of human pediatric lung cell populations reveals unique transcriptomic signature associated with postnatal pulmonary development.", "sortKey": "2024-05-bulk rna sequencing ", "pubDateYear": "2024", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Bandyopadhyay G, Jehrio MG, Baker C, Bhattacharya S, Misra RS, Huyck HL, Chu C, Myers JR, Ashton J, Polter S, Cochran M, Bushnell T, Dutra J, Katzman PJ, Deutsch GH, Mariani TJ, Pryhuber GS", "citation": "American journal of physiology. Lung cellular and molecular physiology, 05 2024", "abstractText": "Postnatal lung development results in an increasingly functional organ prepared for gas exchange and pathogenic challenges. It is achieved through cellular differentiation and migration. Changes in the tissue architecture during this development process are well-documented and increasing cellular diversity associated with it are reported in recent years. Despite recent progress, transcriptomic and molecular pathways associated with human postnatal lung development are yet to be fully understood. In this study, we investigated gene expression patterns associated with healthy pediatric lung development in four major enriched cell populations (epithelial, endothelial, and nonendothelial mesenchymal cells, along with lung leukocytes) from 1-day-old to 8-yr-old organ donors with no known lung disease. For analysis, we considered the donors in four age groups [less than 30 days old neonates, 30 days to < 1 yr old infants, toddlers (1 to < 2 yr), and children 2 yr and older] and assessed differentially expressed genes (DEG). We found increasing age-associated transcriptional changes in all four major cell types in pediatric lung. Transition from neonate to infant stage showed highest number of DEG compared with the number of DEG found during infant to toddler- or toddler to older children-transitions. Profiles of differential gene expression and further pathway enrichment analyses indicate functional epithelial cell maturation and increased capability of antigen presentation and chemokine-mediated communication. Our study provides a comprehensive reference of gene expression patterns during healthy pediatric lung development that will be useful in identifying and understanding aberrant gene expression patterns associated with early life respiratory diseases. This study presents postnatal transcriptomic changes in major cell populations in human lung, namely endothelial, epithelial, mesenchymal cells, and leukocytes. Although human postnatal lung development continues through early adulthood, our results demonstrate that greatest transcriptional changes occur in first few months of life during neonate to infant transition. These early transcriptional changes in lung parenchyma are particularly notable for functional maturation and activation of alveolar type II cell genes.", "pubmedLink": "" },   "38377991": { "pmid": "38377991", "title": "Stem cell migration drives lung repair in living mice.", "sortKey": "2024-04-stem cell migration ", "pubDateYear": "2024", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Chioccioli M, Liu S, Magruder S, Tata A, Borriello L, McDonough JE, Konkimalla A, Kim SH, Nouws J, Gonzalez DG, Traub B, Ye X, Yang T, Entenberg DR, Krishnaswamy S, Hendry CE, Kaminski N, Tata PR, Sauler M", "citation": "Developmental cell, 04 2024", "abstractText": "Tissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 cells (AT2s) act as stem cells to replenish both themselves and alveolar type 1 cells (AT1s); however, the complex orchestration of stem cell activity after injury is poorly understood. Here, we establish longitudinal imaging of AT2s in murine intact tissues ex vivo and in vivo in order to track their dynamic behavior over time. We discover that a large fraction of AT2s become motile following injury and provide direct evidence for their migration between alveolar units. High-resolution morphokinetic mapping of AT2s further uncovers the emergence of distinct motile phenotypes. Inhibition of AT2 migration via genetic depletion of ArpC3 leads to impaired regeneration of AT2s and AT1s in vivo. Together, our results establish a requirement for stem cell migration between alveolar units and identify properties of stem cell motility at high cellular resolution.", "pubmedLink": "" },   "38232136": { "pmid": "38232136", "title": "Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy.", "sortKey": "2024-01-splicing neoantigen ", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Li G, Mahajan S, Ma S, Jeffery ED, Zhang X, Bhattacharjee A, Venkatasubramanian M, Weirauch MT, Miraldi ER, Grimes HL, Sheynkman GM, Tilburgs T, Salomonis N", "citation": "Science translational medicine, 01 2024", "abstractText": "Immunotherapy has emerged as a crucial strategy to combat cancer by  reprogramming  a patient s own immune system. Although immunotherapy is typically reserved for patients with a high mutational burden, neoantigens produced from posttranscriptional regulation may provide an untapped reservoir of common immunogenic targets for new targeted therapies. To comprehensively define tumor-specific and likely immunogenic neoantigens from patient RNA-Seq, we developed Splicing Neo Antigen Finder (SNAF), an easy-to-use and open-source computational workflow to predict splicing-derived immunogenic MHC-bound peptides (T cell antigen) and unannotated transmembrane proteins with altered extracellular epitopes (B cell antigen). This workflow uses a highly accurate deep learning strategy for immunogenicity prediction (DeepImmuno) in conjunction with new algorithms to rank the tumor specificity of neoantigens (BayesTS) and to predict regulators of mis-splicing (RNA-SPRINT). T cell antigens from SNAF were frequently evidenced as HLA-presented peptides from mass spectrometry (MS) and predict response to immunotherapy in melanoma. Splicing neoantigen burden was attributed to coordinated splicing factor dysregulation. Shared splicing neoantigens were found in up to 90% of patients with melanoma, correlated to overall survival in multiple cancer cohorts, induced T cell reactivity, and were characterized by distinct cells of origin and amino acid preferences. In addition to T cell neoantigens, our B cell focused pipeline (SNAF-B) identified a new class of tumor-specific extracellular neoepitopes, which we termed ExNeoEpitopes. ExNeoEpitope full-length mRNA predictions were tumor specific and were validated using long-read isoform sequencing and in vitro transmembrane localization assays. Therefore, our systematic identification of splicing neoantigens revealed potential shared targets for therapy in heterogeneous cancers.", "pubmedLink": "" },   "38226623": { "pmid": "38226623", "title": "Human pluripotent stem cell modeling of alveolar type 2 cell dysfunction caused by ABCA3 mutations.", "sortKey": "2024-01-human pluripotent st", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Sun YL, Hennessey EE, Heins H, Yang P, Villacorta-Martin C, Kwan J, Gopalan K, James M, Emili A, Cole FS, Wambach JA, Kotton DN", "citation": "The Journal of clinical investigation, 01 2024", "abstractText": "Mutations in ATP-binding cassette A3 (ABCA3), a phospholipid transporter critical for surfactant homeostasis in pulmonary alveolar type II epithelial cells (AEC2s), are the most common genetic causes of childhood interstitial lung disease (chILD). Treatments for patients with pathological variants of ABCA3 mutations are limited, in part due to a lack of understanding of disease pathogenesis resulting from an inability to access primary AEC2s from affected children. Here, we report the generation of AEC2s from affected patient induced pluripotent stem cells (iPSCs) carrying homozygous versions of multiple ABCA3 mutations. We generated syngeneic CRISPR/Cas9 gene-corrected and uncorrected iPSCs and ABCA3-mutant knockin ABCA3:GFP fusion reporter lines for in vitro disease modeling. We observed an expected decreased capacity for surfactant secretion in ABCA3-mutant iPSC-derived AEC2s (iAEC2s), but we also found an unexpected epithelial-intrinsic aberrant phenotype in mutant iAEC2s, presenting as diminished progenitor potential, increased NFκB signaling, and the production of pro-inflammatory cytokines. The ABCA3:GFP fusion reporter permitted mutant-specific, quantifiable characterization of lamellar body size and ABCA3 protein trafficking, functional features that are perturbed depending on ABCA3 mutation type. Our disease model provides a platform for understanding ABCA3 mutation-mediated mechanisms of alveolar epithelial cell dysfunction that may trigger chILD pathogenesis.", "pubmedLink": "" },   "38212075": { "pmid": "38212075", "title": "Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs  models of mesothelioma.", "sortKey": "2024-01-single-cell transcri", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Obacz J, Valer JA, Nibhani R, Adams TS, Schupp JC, Veale N, Lewis-Wade A, Flint J, Hogan J, Aresu G, Coonar AS, Peryt A, Biffi G, Kaminski N, Francies H, Rassl DM, Garnett MJ, Rintoul RC, Marciniak SJ", "citation": "The European respiratory journal, 01 2024", "abstractText": "The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple  models of benign and malignant mesothelial cells, and characterise these through comparison with  transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation .", "pubmedLink": "" },   "38196613": { "pmid": "38196613", "title": "Unagi: Deep Generative Model for Deciphering Cellular Dynamics and In-Silico Drug Discovery in Complex Diseases.", "sortKey": "2023-12-unagi: deep generati", "pubDateYear": "2023", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Zheng Y, Schupp JC, Adams T, Clair G, Justet A, Ahangari F, Yan X, Hansen P, Carlon M, Cortesi E, Vermant M, Vos R, De Sadeleer LJ, Rosas IO, Pineda R, Sembrat J, Königshoff M, McDonough JE, Vanaudenaerde BM, Wuyts WA, Kaminski N, Ding J", "citation": "Research square, 12 2023", "abstractText": "Human diseases are characterized by intricate cellular dynamics. Single-cell sequencing provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in-silico drug interventions. Here, we introduce UNAGI, a deep generative neural network tailored to analyze time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modeling and discovery. When applied to a dataset from patients with Idiopathic Pulmonary Fibrosis (IPF), UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation via proteomics reveals the accuracy of UNAGI s cellular dynamics analyses, and the use of the Fibrotic Cocktail treated human Precision-cut Lung Slices confirms UNAGI s predictions that Nifedipine, an antihypertensive drug, may have antifibrotic effects on human tissues. UNAGI s versatility extends to other diseases, including a COVID dataset, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond IPF, amplifying its utility in the quest for therapeutic solutions across diverse pathological landscapes.", "pubmedLink": "" },   "38182591": { "pmid": "38182591", "title": "Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease.", "sortKey": "2024-01-airway epithelial ce", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Shiraishi K, Morley MP, Jones DL, Zhao G, Weiner AI, Basil MC, Cantu E, Ferguson LT, Oyster M, Babu A, Ying Y, Zhou S, Li S, Vaughan AE, Morrisey EE", "citation": "NPJ Regenerative medicine, 01 2024", "abstractText": "Maintenance of the cellular boundary between airway and alveolar compartments during homeostasis and after injury is essential to prohibit pathological plasticity which can reduce respiratory function. Lung injury and disease can induce either functional alveolar epithelial regeneration or dysplastic formation of keratinized epithelium which does not efficiently contribute to gas exchange. Here we show that Sox2 preserves airway cell identity and prevents fate changes into either functional alveolar tissue or pathological keratinization following lung injury. Loss of Sox2 in airway epithelium leads to a loss of airway epithelial identity with a commensurate gain in alveolar and basal cell identity, in part due to activation of Wnt signaling in secretory cells and increased Trp63 expression in intrapulmonary basal-like progenitors. In idiopathic pulmonary fibrosis, loss of SOX2 expression correlates with increased WNT signaling activity in dysplastic keratinized epithelium. SOX2-deficient dysplastic epithelial cells are also observed in COVID-19 damaged lungs. Thus, Sox2 provides a molecular barrier that suppresses airway epithelial plasticity to prevent acquisition of alveolar or basal cell identity after injury and help guide proper epithelial fate and regeneration.", "pubmedLink": "" },   "38156804": { "pmid": "38156804", "title": "Homozygous, Intragenic Tandem Duplication of  Causes Neonatal Respiratory Failure.", "sortKey": "2024-01-homozygous, intragen", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Wambach JA, Wegner DJ, Kitzmiller J, White FV, Heins HB, Yang P, Paul AJ, Granadillo JL, Eghtesady P, Kuklinski C, Turner T, Fairman K, Stone K, Wilson T, Breman A, Smith J, Schroeder MC, Neidich JA, Whitsett JA, Cole FS", "citation": "American journal of respiratory cell and molecular biology, 01 2024", "pubmedLink": "" },   "38084407": { "pmid": "38084407", "title": "Single-cell resolution of human airway epithelial cells exposed to bronchiolitis obliterans-associated chemicals.", "sortKey": "2024-02-single-cell resoluti", "pubDateYear": "2024", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Chu CY, Kim SY, Pryhuber GS, Mariani TJ, McGraw MD", "citation": "American journal of physiology. Lung cellular and molecular physiology, 02 2024", "abstractText": "Bronchiolitis obliterans (BO) is a fibrotic lung disease characterized by progressive luminal narrowing and obliteration of the small airways. In the nontransplant population, inhalation exposure to certain chemicals is associated with BO; however, the mechanisms contributing to disease induction remain poorly understood. This study s objective was to use single-cell RNA sequencing for the identification of transcriptomic signatures common to primary human airway epithelial cells after chemical exposure to BO-associated chemicals-diacetyl or nitrogen mustard-to help explain BO induction. Primary airway epithelial cells were cultured at air-liquid interface and exposed to diacetyl, nitrogen mustard, or control vapors. Cultures were dissociated and sequenced for single-cell RNA. Differential gene expression and functional pathway analyses were compared across exposures. In total, 75,663 single cells were captured and sequenced from all exposure conditions. Unbiased clustering identified 11 discrete phenotypes, including 5 basal, 2 ciliated, and 2 secretory cell clusters. With chemical exposure, the proportion of cells assigned to keratin 5+ basal cells decreased, whereas the proportion of cells aligned to secretory cell clusters increased compared with control exposures. Functional pathway analysis identified interferon signaling and antigen processing/presentation as pathways commonly upregulated after diacetyl or nitrogen mustard exposure in a ciliated cell cluster. Conversely, the response of airway basal cells differed significantly with upregulation of the unfolded protein response in diacetyl-exposed basal cells, not seen in nitrogen mustard-exposed cultures. These new insights provide early identification of airway epithelial signatures common to BO-associated chemical exposures. Bronchiolitis obliterans (BO) is a devastating fibrotic lung disease of the small airways, or bronchioles. This original manuscript uses single-cell RNA sequencing for identifying common signatures of chemically exposed airway epithelial cells in BO induction. Chemical exposure reduced the proportion of keratin 5+ basal cells while increasing the proportion of keratin 4+ suprabasal cells. Functional pathways contributory to these shifts differed significantly across exposures. These new results highlight similarities and differences in BO induction across exposures.", "pubmedLink": "" },   "38038158": { "pmid": "38038158", "title": "Noninvasive management of infants with SFTPC pathogenic variants.", "sortKey": "2024-02-noninvasive manageme", "pubDateYear": "2024", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Liptzin DR, McGraw MD, Stidham T, Wambach JA, Deterding RR", "citation": "Pediatric pulmonology, 02 2024", "pubmedLink": "" },   "38036307": { "pmid": "38036307", "title": "Towards personalized therapies for genetic disorders of surfactant dysfunction.", "sortKey": "2023-12-towards personalized", "pubDateYear": "2023", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Peers de Nieuwburgh M, Wambach JA, Griese M, Danhaive O", "citation": "Seminars in fetal & neonatal medicine, 12 2023", "abstractText": "Genetic disorders of surfactant dysfunction are a rare cause of chronic, progressive or refractory respiratory failure in term and preterm infants. This review explores genetic mechanisms underpinning surfactant dysfunction, highlighting specific surfactant-associated genes including SFTPB, SFTPC, ABCA3, and NKX2.1. Pathogenic variants in these genes contribute to a range of clinical presentations and courses, from neonatal hypoxemic respiratory failure to childhood interstitial lung disease and even adult-onset pulmonary fibrosis. This review emphasizes the importance of early recognition, thorough phenotype assessment, and assessment of variant functionality as essential prerequisites for treatments including lung transplantation. We explore emerging treatment options, including personalized pharmacological approaches and gene therapy strategies. In conclusion, this comprehensive review offers valuable insights into the pathogenic mechanisms of genetic disorders of surfactant dysfunction, genetic fundamentals, available and emerging therapeutic options, and underscores the need for further research to develop personalized therapies for affected infants and children.", "pubmedLink": "" },   "37876024": { "pmid": "37876024", "title": "CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia.", "sortKey": "2023-10-cxcl10 deficiency li", "pubDateYear": "2023", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Hirani DV, Thielen F, Mansouri S, Danopoulos S, Vohlen C, Haznedar-Karakaya P, Mohr J, Wilke R, Selle J, Grosch T, Mizik I, Odenthal M, Alvira CM, Kuiper-Makris C, Pryhuber GS, Pallasch C, van Koningsbruggen-Rietschel S, Al-Alam D, Seeger W, Savai R, Dötsch J, Alejandre Alcazar MA", "citation": "Inflammation and regeneration, 10 2023", "abstractText": "Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10) and wild-type mice to an experimental model of hyperoxia (85% O)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10 mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10 mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.", "pubmedLink": "" },   "37824216": { "pmid": "37824216", "title": "Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung.", "sortKey": "2023-11-functional pdgfra fi", "pubDateYear": "2023", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Trempus CS, Papas BN, Sifre MI, Bortner CD, Scappini E, Tucker CJ, Xu X, Johnson KL, Deterding LJ, Williams JG, Johnson DJ, Li JL, Sutton D, Ganta C, Mahapatra D, Arif M, Basu A, Pommerolle L, Cinar R, Perl AK, Garantziotis S", "citation": "JCI insight, 11 2023", "abstractText": "Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor α-positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast-supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.", "pubmedLink": "" },   "37786667": { "pmid": "37786667", "title": " joint cell segmentation and annotation for spatial transcriptomics with transferred graph embeddings.", "sortKey": "2023-09- joint cell segmenta", "pubDateYear": "2023", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Jin K, Zhang Z, Zhang K, Viggiani F, Callahan C, Tang J, Aronow BJ, Shu J", "citation": "bioRxiv : the preprint server for biology, 09 2023", "abstractText": "Single-cell spatial transcriptomics such as  hybridization or sequencing technologies can provide subcellular resolution that enables the identification of individual cell identities, locations, and a deep understanding of subcellular mechanisms. However, accurate segmentation and annotation that allows individual cell boundaries to be determined remains a major challenge that limits all the above and downstream insights. Current machine learning methods heavily rely on nuclei or cell body staining, resulting in the significant loss of both transcriptome depth and the limited ability to learn latent representations of spatial colocalization relationships. Here, we propose , a graph deep learning model that leverages transcript colocalization relationships for joint noise-aware cell segmentation and molecular annotation in 2D and 3D spatial transcriptomics data. Graph embeddings for the cell annotation are transferred as a component of multi-modal input for cell segmentation, which is employed to enrich gene relationships throughout the process. To evaluate performance, we benchmarked  with state-of-the-art methods and observed significant improvement in cell segmentation accuracies and numbers of detected transcripts across various spatial technologies and tissues. To streamline segmentation processes, we constructed expansive pre-trained models, which yield high segmentation accuracy in new data through transfer learning and self-distillation, demonstrating the generalizability of .", "pubmedLink": "" },   "37734036": { "pmid": "37734036", "title": "Prenatal FGFR2 Signaling via PI3K/AKT Specifies the PDGFRA Myofibroblast.", "sortKey": "2024-01-prenatal fgfr2 signa", "pubDateYear": "2024", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Riccetti MR, Green J, Taylor TJ, Perl AT", "citation": "American journal of respiratory cell and molecular biology, 01 2024", "abstractText": "It is well known that FGFR2 (fibroblast growth factor receptor 2) signaling is critical for proper lung development. Recent studies demonstrate that epithelial FGFR2 signaling during the saccular phase of lung development (sacculation) regulates alveolar type 1 (AT1) and AT2 cell differentiation. During sacculation, PDGFRA (platelet-derived growth factor receptor-α)-positive lung fibroblasts exist as three functional subtypes: contractile myofibroblasts, extracellular matrix-producing matrix fibroblasts, and lipofibroblasts. All three subtypes are required during alveolarization to establish a niche that supports AT2 epithelial cell self-renewal and AT1 epithelial cell differentiation. FGFR2 signaling directs myofibroblast differentiation in PDGFRA fibroblasts during alveolar reseptation after pneumonectomy. However, it remains unknown if FGFR2 signaling regulates PDGFRA myo-, matrix, or lipofibroblast differentiation during sacculation. In this study, FGFR2 signaling was inhibited by temporal expression of a secreted dominant-negative FGFR2b (dnFGFR2) by AT2 cells from embryonic day (E) 16.5 to E18.5. Fibroblast and epithelial differentiation were analyzed at E18.5 and postnatal days 7 and 21. At all time points, the number of myofibroblasts was reduced and the number of lipo-/matrix fibroblasts was increased. AT2 cells are increased and AT1 cells are reduced postnatally, but not at E18.5. Similarly, in organoids made with PDGFRA fibroblasts from dnFGFR2 lungs, increased AT2 cells and reduced AT1 cells were observed.  treatment of primary wild-type E16.5 adherent saccular lung fibroblasts with recombinant dnFGFR2b/c resulted in reduced myofibroblast contraction. Treatment with the PI3K/AKT activator 740 Y-P rescued the lack of myofibroblast differentiation caused by dnFGFR2b/2c. Moreover, treatment with the PI3K/AKT activator 740 Y-P rescued myofibroblast differentiation in E18.5 fibroblasts isolated from dnFGFR2 lungs.", "pubmedLink": "" },   "37733441": { "pmid": "37733441", "title": "Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis.", "sortKey": "2023-11-population-level sin", "pubDateYear": "2023", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Verweyen EL, Thakkar K, Dhakal S, Baker E, Chetal K, Schnell D, Canna S, Grom AA, Salomonis N, Schulert GS", "citation": "The Journal of clinical investigation, 11 2023", "abstractText": "Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.", "pubmedLink": "" },   "37625412": { "pmid": "37625412", "title": "Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice.", "sortKey": "2023-09-durable alveolar eng", "pubDateYear": "2023", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Herriges MJ, Yampolskaya M, Thapa BR, Lindstrom-Vautrin J, Wang F, Huang J, Na CL, Ma L, Montminy MM, Bawa P, Villacorta-Martin C, Mehta P, Kotton DN", "citation": "Cell stem cell, 09 2023", "abstractText": "Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells. After months in vivo, donor-derived cells retain their mature phenotypes, as characterized by single-cell RNA sequencing (scRNA-seq), histologic profiling, and functional assessment that demonstrates continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung s facultative progenitor and differentiated epithelial cell compartments with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy that can be utilized to better understand the mechanisms and utility of engraftment.", "pubmedLink": "" },   "37625411": { "pmid": "37625411", "title": "Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells.", "sortKey": "2023-09-airway stem cell rec", "pubDateYear": "2023", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Ma L, Thapa BR, Le Suer JA, Tilston-Lünel A, Herriges MJ, Berical A, Beermann ML, Wang F, Bawa PS, Kohn A, Ysasi AB, Kiyokawa H, Matte TM, Randell SH, Varelas X, Hawkins FJ, Kotton DN", "citation": "Cell stem cell, 09 2023", "abstractText": "Life-long reconstitution of a tissue s resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway transplantation of mouse or human primary and pluripotent stem cell (PSC)-derived airway basal cells (BCs). Murine primary or PSC-derived BCs transplanted into polidocanol-injured syngeneic recipients give rise for at least two years to progeny that stably display the morphologic, molecular, and functional phenotypes of airway epithelia. The engrafted basal-like cells retain extensive self-renewal potential, evident by the capacity to reconstitute the tracheal epithelium through seven generations of secondary transplantation. Using the same approach, human primary or PSC-derived BCs transplanted into NOD scid gamma (NSG) recipient mice similarly display multilineage airway epithelial differentiation in vivo. Our results may provide a step toward potential future syngeneic cell-based therapy for patients with diseases resulting from airway epithelial cell damage or dysfunction.", "pubmedLink": "" },   "37595582": { "pmid": "37595582", "title": "DOT1L regulates lung developmental epithelial cell fate and adult alveolar stem cell differentiation after acute injury.", "sortKey": "2023-09-dot1l regulates lung", "pubDateYear": "2023", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Li S, Liberti D, Zhou S, Ying Y, Kong J, Basil MC, Cardenas-Diaz FL, Shiraishi K, Morley MP, Morrisey EE", "citation": "Stem cell reports, 09 2023", "abstractText": "AT2 cells harbor alveolar stem cell activity in the lung and can self-renew and differentiate into AT1 cells during homeostasis and after injury. To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors. This screen identified DOT1L as a regulator of AT2 cell growth and differentiation. In vivo inactivation of Dot1l leads to precocious activation of both AT1 and AT2 gene expression during lung development and accelerated AT1 cell differentiation after acute lung injury. Single-cell transcriptome analysis reveals the presence of a new AT2 cell state upon loss of Dot1l, characterized by increased expression of oxidative phosphorylation genes and changes in expression of critical transcription and epigenetic factors. Taken together, these data demonstrate that Dot1l controls the rate of alveolar epithelial cell fate acquisition during development and regeneration after acute injury.", "pubmedLink": "" },   "37553579": { "pmid": "37553579", "title": "Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury.", "sortKey": "2023-08-loss of microrna-30a", "pubDateYear": "2023", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Grimm SL, Reddick S, Dong X, Leek C, Wang AX, Gutierrez MC, Hartig SM, Moorthy B, Coarfa C, Lingappan K", "citation": "Biology of sex differences, 08 2023", "abstractText": "Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.", "pubmedLink": "" },   "37534975": { "pmid": "37534975", "title": "Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.", "sortKey": "2023-10-chymotrypsin-like el", "pubDateYear": "2023", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Devine AJ, Smith NJ, Joshi R, Fan Q, Borchers MT, Clair GC, Adkins JN, Varisco BM", "citation": "Chronic obstructive pulmonary diseases (Miami, Fla.), 10 2023", "abstractText": "Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by alpha-1antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of  do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of the  gene in emphysema development in this genetic model of -deficiency following tracheal lipopolysaccharide (LPS), 10 months of cigarette smoke exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model we developed. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that -deficient mice developed more emphysema than wild type with escalating doses of LPS. In the LD-PPE model, deficient mice developed significant and progressive emphysema from which  & -deficient mice were protected. & deficient lungs had more matrix-associated proteins than deficientlungs but also had more leukocyte-associated proteases. With cigarette smoke exposure, -deficient mice had more emphysema than deficient mice but had less myeloperoxidase activity. -deficient mice had less age-related airspace simplification than AAT-deficient and were comparable to wild type. While CELA1 promotes inflammation-independent emphysema progression and its absence preserves the lung matrix in multiple models of AAT-deficient emphysema, for unclear reasons  deficiency is associated with increased emphysema with cigarette smoke. While anti-CELA1 therapies could potentially be used to prevent emphysema progression in AAT deficiency after smoking cessation, an understanding of why and how cigarette smoke exacerbates emphysema in  deficiency and whether AAT replacement therapy mitigates this effect is needed first.", "pubmedLink": "" },   "37516747": { "pmid": "37516747", "title": "Guided construction of single cell reference for human and mouse lung.", "sortKey": "2023-07-guided construction ", "pubDateYear": "2023", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Guo M, Morley MP, Jiang C, Wu Y, Li G, Du Y, Zhao S, Wagner A, Cakar AC, Kouril M, Jin K, Gaddis N, Kitzmiller JA, Stewart K, Basil MC, Lin SM, Ying Y, Babu A, Wikenheiser-Brokamp KA, Mun KS, Naren AP, Clair G, Adkins JN, Pryhuber GS, Misra RS, Aronow BJ, Tickle TL, Salomonis N, Sun X, Morrisey EE, Whitsett JA,  , Xu Y", "citation": "Nature communications, 07 2023", "abstractText": "Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.", "pubmedLink": "" },   "37489262": { "pmid": "37489262", "title": "New insights into the natural history of bronchopulmonary dysplasia from proteomics and multiplexed immunohistochemistry.", "sortKey": "2023-10-new insights into th", "pubDateYear": "2023", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Dylag AM, Misra RS, Bandyopadhyay G, Poole C, Huyck HL, Jehrio MG, Haak J, Deutsch GH, Dvorak C, Olson HM, Paurus V, Katzman PJ, Woo J, Purkerson JM, Adkins JN, Mariani TJ, Clair GC, Pryhuber GS", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2023", "abstractText": "Bronchopulmonary dysplasia (BPD) is a disease of prematurity related to the arrest of normal lung development. The objective of this study was to better understand how proteome modulation and cell-type shifts are noted in BPD pathology. Pediatric human donors aged 1-3 yr were classified based on history of prematurity and histopathology consistent with  healed  BPD (hBPD,  = 3) and  established  BPD (eBPD,  = 3) compared with respective full-term born ( = 6) age-matched term controls. Proteins were quantified by tandem mass spectroscopy with selected Western blot validations. Multiplexed immunofluorescence (MxIF) microscopy was performed on lung sections to enumerate cell types. Protein abundances and MxIF cell frequencies were compared among groups using ANOVA. Cell type and ontology enrichment were performed using an in-house tool and/or EnrichR. Proteomics detected 5,746 unique proteins, 186 upregulated and 534 downregulated, in eBPD versus control with fewer proteins differentially abundant in hBPD as compared with age-matched term controls. Cell-type enrichment suggested a loss of alveolar type I, alveolar type II, endothelial/capillary, and lymphatics, and an increase in smooth muscle and fibroblasts consistent with MxIF. Histochemistry and Western analysis also supported predictions of upregulated ferroptosis in eBPD versus control. Finally, several extracellular matrix components mapping to angiogenesis signaling pathways were altered in eBPD. Despite clear parsing by protein abundance, comparative MxIF analysis confirms phenotypic variability in BPD. This work provides the first demonstration of tandem mass spectrometry and multiplexed molecular analysis of human lung tissue for critical elucidation of BPD trajectory-defining factors into early childhood. We provide new insights into the natural history of bronchopulmonary dysplasia in donor human lungs after the neonatal intensive care unit hospitalization. This study provides new insights into how the proteome and histopathology of BPD changes in early childhood, uncovering novel pathways for future study.", "pubmedLink": "" },   "37483602": { "pmid": "37483602", "title": "Editorial: Global excellence in inflammatory diseases: North America 2021.", "sortKey": "2023-00-editorial: global ex", "pubDateYear": "2023", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Kusner LL, Misra RS, Lucas R", "citation": "Frontiers in immunology, 00 2023", "pubmedLink": "" },   "37468619": { "pmid": "37468619", "title": "Organ Mapping Antibody Panels: a community resource for standardized multiplexed tissue imaging.", "sortKey": "2023-08-organ mapping antibo", "pubDateYear": "2023", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Quardokus EM, Saunders DC, McDonough E, Hickey JW, Werlein C, Surrette C, Rajbhandari P, Casals AM, Tian H, Lowery L, Neumann EK, Björklund F, Neelakantan TV, Croteau J, Wiblin AE, Fisher J, Livengood AJ, Dowell KG, Silverstein JC, Spraggins JM, Pryhuber GS, Deutsch G, Ginty F, Nolan GP, Melov S, Jonigk D, Caldwell MA, Vlachos IS, Muller W, Gehlenborg N, Stockwell BR, Lundberg E, Snyder MP, Germain RN, Camarillo JM, Kelleher NL, Börner K, Radtke AJ", "citation": "Nature methods, 08 2023", "abstractText": "Multiplexed antibody-based imaging enables the detailed characterization of molecular and cellular organization in tissues. Advances in the field now allow high-parameter data collection (>60 targets); however, considerable expertise and capital are needed to construct the antibody panels employed by these methods. Organ mapping antibody panels are community-validated resources that save time and money, increase reproducibility, accelerate discovery and support the construction of a Human Reference Atlas.", "pubmedLink": "" },   "37463497": { "pmid": "37463497", "title": "Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.", "sortKey": "2023-09-single cell multiomi", "pubDateYear": "2023", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Guo M, Wikenheiser-Brokamp KA, Kitzmiller JA, Jiang C, Wang G, Wang A, Preissl S, Hou X, Buchanan J, Karolak JA, Miao Y, Frank DB, Zacharias WJ, Sun X, Xu Y, Gu M, Stankiewicz P, Kalinichenko VV, Wambach JA, Whitsett JA", "citation": "American journal of respiratory and critical care medicine, 09 2023", "abstractText": " Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown.  To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV.  We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA  hybridization to identify cell types and molecular networks influenced by  in ACDMPV lungs.  Pathogenic single-nucleotide variants and copy-number variant deletions involving the  gene locus in all subjects with ACDMPV ( = 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles for  in capillary ECs and pericytes were identified. Pathogenic variants involving the  gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV α 1 chain).  Distinct  gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.", "pubmedLink": "" },   "37311756": { "pmid": "37311756", "title": "Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme.", "sortKey": "2023-06-directed differentia", "pubDateYear": "2023", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Alber AB, Marquez HA, Ma L, Kwong G, Thapa BR, Villacorta-Martin C, Lindstrom-Vautrin J, Bawa P, Wang F, Luo Y, Ikonomou L, Shi W, Kotton DN", "citation": "Nature communications, 06 2023", "abstractText": "While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.", "pubmedLink": "" },   "37291214": { "pmid": "37291214", "title": "An integrated cell atlas of the lung in health and disease.", "sortKey": "2023-06-an integrated cell a", "pubDateYear": "2023", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Sikkema L, Ramírez-Suástegui C, Strobl DC, Gillett TE, Zappia L, Madissoon E, Markov NS, Zaragosi LE, Ji Y, Ansari M, Arguel MJ, Apperloo L, Banchero M, Bécavin C, Berg M, Chichelnitskiy E, Chung MI, Collin A, Gay ACA, Gote-Schniering J, Hooshiar Kashani B, Inecik K, Jain M, Kapellos TS, Kole TM, Leroy S, Mayr CH, Oliver AJ, von Papen M, Peter L, Taylor CJ, Walzthoeni T, Xu C, Bui LT, De Donno C, Dony L, Faiz A, Guo M, Gutierrez AJ, Heumos L, Huang N, Ibarra IL, Jackson ND, Kadur Lakshminarasimha Murthy P, Lotfollahi M, Tabib T, Talavera-López C, Travaglini KJ, Wilbrey-Clark A, Worlock KB, Yoshida M,  , van den Berge M, Bossé Y, Desai TJ, Eickelberg O, Kaminski N, Krasnow MA, Lafyatis R, Nikolic MZ, Powell JE, Rajagopal J, Rojas M, Rozenblatt-Rosen O, Seibold MA, Sheppard D, Shepherd DP, Sin DD, Timens W, Tsankov AM, Whitsett J, Xu Y, Banovich NE, Barbry P, Duong TE, Falk CS, Meyer KB, Kropski JA, Pe'er D, Schiller HB, Tata PR, Schultze JL, Teichmann SA, Misharin AV, Nawijn MC, Luecken MD, Theis FJ", "citation": "Nature medicine, 06 2023", "abstractText": "Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.", "pubmedLink": "" },   "37233732": { "pmid": "37233732", "title": "Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration.", "sortKey": "2023-05-atf3 defines a popul", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Niethamer TK, Levin LI, Morley MP, Babu A, Zhou S, Morrisey EE", "citation": "eLife, 05 2023", "abstractText": "Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection.  expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases the expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.", "pubmedLink": "" },   "37163604": { "pmid": "37163604", "title": "Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells.", "sortKey": "2023-05-single-cell multiomi", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Olatoke T, Wagner A, Astrinidis A, Zhang EY, Guo M, Zhang AG, Mattam U, Kopras EJ, Gupta N, Smith EP, Karbowniczek M, Markiewski MM, Wikenheiser-Brokamp KA, Whitsett JA, McCormack FX, Xu Y, Yu JJ", "citation": "Science advances, 05 2023", "abstractText": "Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry  mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy. Although the genetic basis of LAM is known, mechanisms underlying LAM pathogenesis remain elusive. We integrated single-cell RNA sequencing and single-nuclei ATAC-seq of LAM lungs to construct a gene regulatory network controlling the transcriptional program of LAM cells. We identified activation of uterine-specific HOX-PBX transcriptional programs in pulmonary LAM cells as regulators of cell survival depending upon HOXD11-PBX1 dimerization. Accordingly, blockage of HOXD11-PBX1 dimerization by HXR9 suppressed LAM cell survival in vitro and in vivo. PBX1 regulated STAT1/3, increased the expression of antiapoptotic genes, and promoted LAM cell survival in vitro. The HOX-PBX gene network provides promising targets for treatment of LAM/TSC mTORC1-hyperactive cancers.", "pubmedLink": "" },   "37119134": { "pmid": "37119134", "title": "Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1.", "sortKey": "2023-05-temporal and spatial", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Cardenas-Diaz FL, Liberti DC, Leach JP, Babu A, Barasch J, Shen T, Diaz-Miranda MA, Zhou S, Ying Y, Callaway DA, Morley MP, Morrisey EE", "citation": "Cell reports, 05 2023", "abstractText": "Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single-cell transcriptomics, software-guided segmentation of tissue damage, and in vivo mouse lineage tracing, we identified the grainyhead transcription factor cellular promoter 2-like 1 (Tfcp2l1) as a regulator of this regenerative process. Tfcp2l1 loss in adult AT2 cells inhibits self-renewal and enhances AT2-AT1 differentiation during tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute injury phase. Tfcp2l1 temporally regulates AT2 self-renewal and differentiation in alveolar regions undergoing active regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics across the AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells. Organoid modeling shows that Tfcp2l1 regulation of interleukin-1 (IL-1) receptor expression controlled these cell fate dynamics. These findings highlight the critical role Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation during alveolar regeneration.", "pubmedLink": "" },   "37097893": { "pmid": "37097893", "title": "pyInfinityFlow: optimized imputation and analysis of high-dimensional flow cytometry data for millions of cells.", "sortKey": "2023-05-pyinfinityflow: opti", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Ferchen K, Salomonis N, Grimes HL", "citation": "Bioinformatics (Oxford, England), 05 2023", "abstractText": "While conventional flow cytometry is limited to dozens of markers, new experimental and computational strategies, such as Infinity Flow, allow for the generation and imputation of hundreds of cell surface protein markers in millions of cells. Here, we describe an end-to-end analysis workflow for Infinity Flow data in Python.", "pubmedLink": "" },   "37086403": { "pmid": "37086403", "title": "Emergence of division of labor in tissues through cell interactions and spatial cues.", "sortKey": "2023-05-emergence of divisio", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Adler M, Moriel N, Goeva A, Avraham-Davidi I, Mages S, Adams TS, Kaminski N, Macosko EZ, Regev A, Medzhitov R, Nitzan M", "citation": "Cell reports, 05 2023", "abstractText": "Most cell types in multicellular organisms can perform multiple functions. However, not all functions can be optimally performed simultaneously by the same cells. Functions incompatible at the level of individual cells can be performed at the cell population level, where cells divide labor and specialize in different functions. Division of labor can arise due to instruction by tissue environment or through self-organization. Here, we develop a computational framework to investigate the contribution of these mechanisms to division of labor within a cell-type population. By optimizing collective cellular task performance under trade-offs, we find that distinguishable expression patterns can emerge from cell-cell interactions versus instructive signals. We propose a method to construct ligand-receptor networks between specialist cells and use it to infer division-of-labor mechanisms from single-cell RNA sequencing (RNA-seq) and spatial transcriptomics data of stromal, epithelial, and immune cells. Our framework can be used to characterize the complexity of cell interactions within tissues.", "pubmedLink": "" },   "37074178": { "pmid": "37074178", "title": "Generation and Functional Analysis of Defective Viral Genomes during SARS-CoV-2 Infection.", "sortKey": "2023-06-generation and funct", "pubDateYear": "2023", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Zhou T, Gilliam NJ, Li S, Spandau S, Osborn RM, Connor S, Anderson CS, Mariani TJ, Thakar J, Dewhurst S, Mathews DH, Huang L, Sun Y", "citation": "mBio, 06 2023", "abstractText": "Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from transcriptome sequencing (RNA-seq) data sets of  infections and autopsy lung tissues of COVID-19 patients. Four genomic hot spots were identified for DVG recombination, and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single-cell RNA-seq analysis indicated the interferon (IFN) stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the next-generation sequencing (NGS) data set from a published cohort study and observed a significantly higher amount and frequency of DVG in symptomatic patients than those in asymptomatic patients. Finally, we observed exceptionally diverse DVG populations in one immunosuppressive patient up to 140 days after the first positive test of COVID-19, suggesting for the first time an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and into how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection.  Defective viral genomes (DVGs) are generated ubiquitously in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide the potential for them to be used in novel antiviral therapies and vaccine development. SARS-CoV-2 DVGs are generated through the recombination of two discontinuous genomic fragments by viral polymerase complex, and this recombination is also one of the major mechanisms for the emergence of new coronaviruses. Focusing on the generation and function of SARS-CoV-2 DVGs, these studies identify new hot spots for nonhomologous recombination and strongly suggest that the secondary structures within viral genomes mediate the recombination. Furthermore, these studies provide the first evidence for IFN stimulation activity of  DVGs during natural SARS-CoV-2 infection. These findings set up the foundation for further mechanism studies of SARS-CoV-2 recombination and provide evidence to harness the immunostimulatory potential of DVGs in the development of a vaccine and antivirals for SARS-CoV-2.", "pubmedLink": "" },   "37067057": { "pmid": "37067057", "title": "FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung.", "sortKey": "2023-05-foxa2 cooperates wit", "pubDateYear": "2023", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Tomoshige K, Stuart WD, Fink-Baldauf IM, Ito M, Tsuchiya T, Nagayasu T, Yamatsuji T, Okada M, Fukazawa T, Guo M, Maeda Y", "citation": "Cancer research, 05 2023", "abstractText": "The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation.", "pubmedLink": "" },   "36945543": { "pmid": "36945543", "title": "Matrix and analysis metadata standards (MAMS) to facilitate harmonization and reproducibility of single-cell data.", "sortKey": "2023-03-matrix and analysis ", "pubDateYear": "2023", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Wang Y, Sarfraz I, Teh WK, Sokolov A, Herb BR, Creasy HH, Virshup I, Dries R, Degatano K, Mahurkar A, Schnell DJ, Madrigal P, Hilton J, Gehlenborg N, Tickle T, Campbell JD", "citation": "bioRxiv : the preprint server for biology, 03 2023", "abstractText": "A large number of genomic and imaging datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While much effort has been devoted to capturing information related to biospecimen information and experimental procedures, the metadata standards that describe data matrices and the analysis workflows that produced them are relatively lacking. Detailed metadata schema related to data analysis are needed to facilitate sharing and interoperability across groups and to promote data provenance for reproducibility. To address this need, we developed the Matrix and Analysis Metadata Standards (MAMS) to serve as a resource for data coordinating centers and tool developers. We first curated several simple and complex  use cases  to characterize the types of feature-observation matrices (FOMs), annotations, and analysis metadata produced in different workflows. Based on these use cases, metadata fields were defined to describe the data contained within each matrix including those related to processing, modality, and subsets. Suggested terms were created for the majority of fields to aid in harmonization of metadata terms across groups. Additional provenance metadata fields were also defined to describe the software and workflows that produced each FOM. Finally, we developed a simple list-like schema that can be used to store MAMS information and implemented in multiple formats. Overall, MAMS can be used as a guide to harmonize analysis-related metadata which will ultimately facilitate integration of datasets across tools and consortia. MAMS specifications, use cases, and examples can be found at https://github.com/single-cell-mams/mams/.", "pubmedLink": "" },   "36879800": { "pmid": "36879800", "title": "Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth.", "sortKey": "2023-03-developmental divers", "pubDateYear": "2023", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Zanini F, Che X, Knutsen C, Liu M, Suresh NE, Domingo-Gonzalez R, Dou SH, Zhang D, Pryhuber GS, Jones RC, Quake SR, Cornfield DN, Alvira CM", "citation": "iScience, 03 2023", "abstractText": "At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life. Although subtype speciation was evident at birth, immature lung EC exhibited transcriptomes distinct from mature counterparts, which progressed dynamically over time. Gradual, temporal changes in aerocyte capillary EC (CAP2) contrasted with more marked alterations in general capillary EC (CAP1) phenotype, including distinct CAP1 present only in the early alveolar lung expressing , a paternally imprinted transcription factor. Hyperoxia, an injury that impairs angiogenesis induced both common and unique endothelial gene signatures, dysregulated capillary EC crosstalk, and suppressed CAP1 proliferation while stimulating venous EC proliferation. These data highlight the diversity, transcriptomic evolution, and pleiotropic responses to injury of immature lung EC, possessing broad implications for lung development and injury across the lifespan.", "pubmedLink": "" },   "36870331": { "pmid": "36870331", "title": "Biophysical forces mediated by respiration maintain lung alveolar epithelial cell fate.", "sortKey": "2023-03-biophysical forces m", "pubDateYear": "2023", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Shiraishi K, Shah PP, Morley MP, Loebel C, Santini GT, Katzen J, Basil MC, Lin SM, Planer JD, Cantu E, Jones DL, Nottingham AN, Li S, Cardenas-Diaz FL, Zhou S, Burdick JA, Jain R, Morrisey EE", "citation": "Cell, 03 2023", "abstractText": "Lungs undergo mechanical strain during breathing, but how these biophysical forces affect cell fate and tissue homeostasis are unclear. We show that biophysical forces through normal respiratory motion actively maintain alveolar type 1 (AT1) cell identity and restrict these cells from reprogramming into AT2 cells in the adult lung. AT1 cell fate is maintained at homeostasis by Cdc42- and Ptk2-mediated actin remodeling and cytoskeletal strain, and inactivation of these pathways causes a rapid reprogramming into the AT2 cell fate. This plasticity induces chromatin reorganization and changes in nuclear lamina-chromatin interactions, which can discriminate AT1 and AT2 cell identity. Unloading the biophysical forces of breathing movements leads to AT1-AT2 cell reprogramming, revealing that normal respiration is essential to maintain alveolar epithelial cell fate. These data demonstrate the integral function of mechanotransduction in maintaining lung cell fate and identifies the AT1 cell as an important mechanosensor in the alveolar niche.", "pubmedLink": "" },   "36865303": { "pmid": "36865303", "title": "CELA1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.", "sortKey": "2023-02-cela1 mediates progr", "pubDateYear": "2023", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Devine AJ, Smith NJ, Joshi R, Fan Q, Borchers MT, Clair GC, Adkins JN, Varisco BM", "citation": "Research square, 02 2023", "abstractText": " (  ) is a serine protease that is neutralized by α1-antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of  do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of  in emphysema development in this genetic model of  -deficiency following tracheal lipopolysacharide (LPS), 8 months of cigarette smoke (CS) exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that    mice developed more emphysema than wild type with LPS. In the LD-PPE model,   mice developed progressive emphysema from which     mice were protected. In the CS model,     mice had worse emphysema than   , and in the aging model, 72-75 week-old     mice had less emphysema than   mice. Proteomic analysis of   vs. wildtype lungs in the LD-PPE model showed reduced amounts of AAT proteins and increased amounts of proteins related to Rho and Rac1 GTPases and protein oxidation. Similar analysis of     vs.   lungs showed differences in neutrophil degranulation, elastin fiber synthesis, and glutathione metabolism. Thus,  prevents post-injury emphysema progression in  -deficiency, but it has no effect and potentially worsens emphysema in response to chronic inflammation and injury. Prior to developing anti-CELA1 therapies for AAT-deficient emphysema, an understanding of why and how CS exacerbates emphysema in  deficiency is needed.", "pubmedLink": "" },   "36864068": { "pmid": "36864068", "title": "Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.", "sortKey": "2023-03-insights into pulmon", "pubDateYear": "2023", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Uehara Y, Tanaka Y, Zhao S, Nikolaidis NM, Pitstick LB, Wu H, Yu JJ, Zhang E, Hasegawa Y, Noel JG, Gardner JC, Kopras EJ, Haffey WD, Greis KD, Guo J, Woods JC, Wikenheiser-Brokamp KA, Kyle JE, Ansong C, Teitelbaum SL, Inoue Y, Altinişik G, Xu Y, McCormack FX", "citation": "Nature communications, 03 2023", "abstractText": "Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.", "pubmedLink": "" },   "36827401": { "pmid": "36827401", "title": "Preparation of noninfectious scRNAseq samples from SARS-CoV-2-infected epithelial cells.", "sortKey": "2023-00-preparation of nonin", "pubDateYear": "2023", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Osborn RM, Leach J, Zanche M, Ashton JM, Chu C, Thakar J, Dewhurst S, Rosenberger S, Pavelka M, Pryhuber GS, Mariani TJ, Anderson CS", "citation": "PloS one, 00 2023", "abstractText": "Coronavirus disease (COVID-19) is an infectious disease caused by the SARS coronavirus 2 (SARS-CoV-2) virus. Direct assessment, detection, and quantitative analysis using high throughput methods like single-cell RNA sequencing (scRNAseq) is imperative to understanding the host response to SARS-CoV-2. One barrier to studying SARS-CoV-2 in the laboratory setting is the requirement to process virus-infected cell cultures, and potentially infectious materials derived therefrom, under Biosafety Level 3 (BSL-3) containment. However, there are only 190 BSL3 laboratory facilities registered with the U.S. Federal Select Agent Program, as of 2020, and only a subset of these are outfitted with the equipment needed to perform high-throughput molecular assays. Here, we describe a method for preparing non-hazardous RNA samples from SARS-CoV-2 infected cells, that enables scRNAseq analyses to be conducted safely in a BSL2 facility-thereby making molecular assays of SARS-CoV-2 cells accessible to a much larger community of researchers. Briefly, we infected African green monkey kidney epithelial cells (Vero-E6) with SARS-CoV-2 for 96 hours, trypsin-dissociated the cells, and inactivated them with methanol-acetone in a single-cell suspension. Fixed cells were tested for the presence of infectious SARS-CoV-2 virions using the Tissue Culture Infectious Dose Assay (TCID50), and also tested for viability using flow cytometry. We then tested the dissociation and methanol-acetone inactivation method on primary human lung epithelial cells that had been differentiated on an air-liquid interface. Finally, we performed scRNAseq quality control analysis on the resulting cell populations to evaluate the effects of our virus inactivation and sample preparation protocol on the quality of the cDNA produced. We found that methanol-acetone inactivated SARS-CoV-2, fixed the lung epithelial cells, and could be used to obtain noninfectious, high-quality cDNA libraries. This methodology makes investigating SARS-CoV-2, and related high-containment RNA viruses at a single-cell level more accessible to an expanded community of researchers.", "pubmedLink": "" },   "36813173": { "pmid": "36813173", "title": "Influence of the irradiated pulmonary microenvironment on macrophage and T cell dynamics.", "sortKey": "2023-06-influence of the irr", "pubDateYear": "2023", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Groves AM, Misra R, Clair G, Hernady E, Olson H, Orton D, Finkelstein J, Marples B, Johnston CJ", "citation": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 06 2023", "abstractText": "The lung is sensitive to radiation, increasing normal tissue toxicity risks following radiation therapy. Adverse outcomes include pneumonitis and pulmonary fibrosis, which result from dysregulated intercellular communication within the pulmonary microenvironment. Although macrophages are implicated in these pathogenic outcomes, the impact of their microenvironment is not well understood.", "pubmedLink": "" },   "36738870": { "pmid": "36738870", "title": "Informative missingness: What can we learn from patterns in missing laboratory data in the electronic health record?", "sortKey": "2023-03-informative missingn", "pubDateYear": "2023", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Tan ALM, Getzen EJ, Hutch MR, Strasser ZH, Gutiérrez-Sacristán A, Le TT, Dagliati A, Morris M, Hanauer DA, Moal B, Bonzel CL, Yuan W, Chiudinelli L, Das P, Zhang HG, Aronow BJ, Avillach P, Brat GA, Cai T, Hong C, La Cava WG, Hooi Will Loh H, Luo Y, Murphy SN, Yuan Hgiam K, Omenn GS, Patel LP, Jebathilagam Samayamuthu M, Shriver ER, Shakeri Hossein Abad Z, Tan BWL, Visweswaran S, Wang X, Weber GM, Xia Z, Verdy B,  , Long Q, Mowery DL, Holmes JH", "citation": "Journal of biomedical informatics, 03 2023", "abstractText": "In electronic health records, patterns of missing laboratory test results could capture patients  course of disease as well as ​​reflect clinician s concerns or worries for possible conditions. These patterns are often understudied and overlooked. This study aims to identify informative patterns of missingness among laboratory data collected across 15 healthcare system sites in three countries for COVID-19 inpatients.", "pubmedLink": "" },   "36711505": { "pmid": "36711505", "title": "Generation of human alveolar epithelial type I cells from pluripotent stem cells.", "sortKey": "2023-01-generation of human ", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Burgess CL, Huang J, Bawa P, Alysandratos KD, Minakin K, Morley MP, Babu A, Villacorta-Martin C, Hinds A, Thapa BR, Wang F, Matschulat AM, Morrisey EE, Varelas X, Kotton DN", "citation": "bioRxiv : the preprint server for biology, 01 2023", "abstractText": "In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients.", "pubmedLink": "" },   "36697445": { "pmid": "36697445", "title": "Decision level integration of unimodal and multimodal single cell data with scTriangulate.", "sortKey": "2023-01-decision level integ", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Li G, Song B, Singh H, Surya Prasath VB, Leighton Grimes H, Salomonis N", "citation": "Nature communications, 01 2023", "abstractText": "Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a computational framework to mix-and-match multiple clustering results, modalities, associated algorithms, and resolutions to achieve an optimal solution. Rather than ensemble approaches which select the  consensus , scTriangulate picks the most stable solution through coalitional iteration. When evaluated on diverse multimodal technologies, scTriangulate outperforms alternative approaches to identify high-confidence cell-populations and modality-specific subtypes. Unlike existing integration strategies that rely on modality-specific joint embedding or geometric graphs, scTriangulate makes no assumption about the distributions of raw underlying values. As a result, this approach can solve unprecedented integration challenges, including the ability to automate reference cell-atlas construction, resolve clonal architecture within molecularly defined cell-populations and subdivide clusters to discover splicing-defined disease subtypes. scTriangulate is a flexible strategy for unified integration of single-cell or multimodal clustering solutions, from nearly unlimited sources.", "pubmedLink": "" },   "36637389": { "pmid": "36637389", "title": "Evaluating Linear Ion Trap for MS3-Based Multiplexed Single-Cell Proteomics.", "sortKey": "2023-01-evaluating linear io", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Park J, Yu F, Fulcher JM, Williams SM, Engbrecht K, Moore RJ, Clair GC, Petyuk V, Nesvizhskii AI, Zhu Y", "citation": "Analytical chemistry, 01 2023", "abstractText": "There is a growing demand to develop high-throughput and high-sensitivity mass spectrometry methods for single-cell proteomics. The commonly used isobaric labeling-based multiplexed single-cell proteomics approach suffers from distorted protein quantification due to co-isolated interfering ions during MS/MS fragmentation, also known as ratio compression. We reasoned that the use of MS3-based quantification could mitigate ratio compression and provide better quantification. However, previous studies indicated reduced proteome coverages in the MS3 method, likely due to long duty cycle time and ion losses during multilevel ion selection and fragmentation. Herein, we described an improved MS acquisition method for MS3-based single-cell proteomics by employing a linear ion trap to measure reporter ions. We demonstrated that linear ion trap can increase the proteome coverages for single-cell-level peptides with even higher gain obtained via the MS3 method. The optimized real-time search MS3 method was further applied to study the immune activation of single macrophages. Among a total of 126 single cells studied, over 1200 and 1000 proteins were quantifiable when at least 50 and 75% nonmissing data were required, respectively. Our evaluation also revealed several limitations of the low-resolution ion trap detector for multiplexed single-cell proteomics and suggested experimental solutions to minimize their impacts on single-cell analysis.", "pubmedLink": "" },   "36626225": { "pmid": "36626225", "title": "microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.", "sortKey": "2023-02-microrna-33 deficien", "pubDateYear": "2023", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Ahangari F, Price NL, Malik S, Chioccioli M, Bärnthaler T, Adams TS, Kim J, Pradeep SP, Ding S, Cosmos C, Rose KS, McDonough JE, Aurelien NR, Ibarra G, Omote N, Schupp JC, DeIuliis G, Villalba Nunez JA, Sharma L, Ryu C, Dela Cruz CS, Liu X, Prasse A, Rosas I, Bahal R, Fernández-Hernando C, Kaminski N", "citation": "JCI insight, 02 2023", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.", "pubmedLink": "" },   "36608259": { "pmid": "36608259", "title": "Rare to  Ubiquitinous : Alveolar Capillary Dysplasia, FOXF1, and a Sly Approach to Angiogenesis.", "sortKey": "2023-04-rare to  ubiquitinou", "pubDateYear": "2023", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Cornfield DN, Nogee LM", "citation": "American journal of respiratory and critical care medicine, 04 2023", "pubmedLink": "" },   "36577717": { "pmid": "36577717", "title": "Characterization of a novel Hoxa5eGFP mouse line.", "sortKey": "2023-04-characterization of ", "pubDateYear": "2023", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Li MH, Kuetemeyer JM, Yallowitz AR, Wellik DM", "citation": "Developmental dynamics : an official publication of the American Association of Anatomists, 04 2023", "abstractText": "Hox genes encode transcription factors that are important for establishing the body plan. Hoxa5 is a member of the mammalian Hox5 paralogous group that regulates the patterning and morphology of the cervical-thoracic region of the axial skeleton. Hoxa5 also plays crucial functions in lung morphogenesis.", "pubmedLink": "" },   "36543939": { "pmid": "36543939", "title": "Guiding the choice of informatics software and tools for lipidomics research applications.", "sortKey": "2023-02-guiding the choice o", "pubDateYear": "2023", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Ni Z, Wölk M, Jukes G, Mendivelso Espinosa K, Ahrends R, Aimo L, Alvarez-Jarreta J, Andrews S, Andrews R, Bridge A, Clair GC, Conroy MJ, Fahy E, Gaud C, Goracci L, Hartler J, Hoffmann N, Kopczyinki D, Korf A, Lopez-Clavijo AF, Malik A, Ackerman JM, Molenaar MR, O'Donovan C, Pluskal T, Shevchenko A, Slenter D, Siuzdak G, Kutmon M, Tsugawa H, Willighagen EL, Xia J, O'Donnell VB, Fedorova M", "citation": "Nature methods, 02 2023", "abstractText": "Progress in mass spectrometry lipidomics has led to a rapid proliferation of studies across biology and biomedicine. These generate extremely large raw datasets requiring sophisticated solutions to support automated data processing. To address this, numerous software tools have been developed and tailored for specific tasks. However, for researchers, deciding which approach best suits their application relies on ad hoc testing, which is inefficient and time consuming. Here we first review the data processing pipeline, summarizing the scope of available tools. Next, to support researchers, LIPID MAPS provides an interactive online portal listing open-access tools with a graphical user interface. This guides users towards appropriate solutions within major areas in data processing, including (1) lipid-oriented databases, (2) mass spectrometry data repositories, (3) analysis of targeted lipidomics datasets, (4) lipid identification and (5) quantification from untargeted lipidomics datasets, (6) statistical analysis and visualization, and (7) data integration solutions. Detailed descriptions of functions and requirements are provided to guide customized data analysis workflows.", "pubmedLink": "" },   "36512353": { "pmid": "36512353", "title": "Hospitalizations Associated With Mental Health Conditions Among Adolescents in the US and France During the COVID-19 Pandemic.", "sortKey": "2022-12-hospitalizations ass", "pubDateYear": "2022", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Gutiérrez-Sacristán A, Serret-Larmande A, Hutch MR, Sáez C, Aronow BJ, Bhatnagar S, Bonzel CL, Cai T, Devkota B, Hanauer DA, Loh NHW, Luo Y, Moal B, Ahooyi TM, Njoroge WFM, Omenn GS, Sanchez-Pinto LN, South AM, Sperotto F, Tan ALM, Taylor DM, Verdy G, Visweswaran S, Xia Z, Zahner J, Avillach P, Bourgeois FT,  ", "citation": "JAMA network open, 12 2022", "abstractText": "The COVID-19 pandemic has been associated with an increase in mental health diagnoses among adolescents, though the extent of the increase, particularly for severe cases requiring hospitalization, has not been well characterized. Large-scale federated informatics approaches provide the ability to efficiently and securely query health care data sets to assess and monitor hospitalization patterns for mental health conditions among adolescents.", "pubmedLink": "" },   "36480964": { "pmid": "36480964", "title": "Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia.", "sortKey": "2023-04-novel foxf1-stabiliz", "pubDateYear": "2023", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Pradhan A, Che L, Ustiyan V, Reza AA, Pek NM, Zhang Y, Alber AB, Kalin TR, Wambach JA, Gu M, Kotton DN, Siefert ME, Ziady AG, Kalin TV, Kalinichenko VV", "citation": "American journal of respiratory and critical care medicine, 04 2023", "abstractText": " Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in the  (Forkhead Box F1) gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed.  Identify-small molecule compounds that stimulate FOXF1 signaling.  We used mass spectrometry, immunoprecipitation, and the  ubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV.  We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1-HECTD1 protein-protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells . TanFe increased protein concentrations of FOXF1 and its target genes , , and  in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs of  embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of  mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV with  deletion.  TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.", "pubmedLink": "" },   "36465564": { "pmid": "36465564", "title": "An optimized approach and inflation media for obtaining complimentary mass spectrometry-based omics data from human lung tissue.", "sortKey": "2022-00-an optimized approac", "pubDateYear": "2022", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Lukowski JK, Olson H, Velickovic M, Wang J, Kyle JE, Kim YM, Williams SM, Zhu Y, Huyck HL, McGraw MD, Poole C, Rogers L, Misra R, Alexandrov T, Ansong C, Pryhuber GS, Clair G, Adkins JN, Carson JP, Anderton CR", "citation": "Frontiers in molecular biosciences, 00 2022", "abstractText": "Human disease states are biomolecularly multifaceted and can span across phenotypic states, therefore it is important to understand diseases on all levels, across cell types, and within and across microanatomical tissue compartments. To obtain an accurate and representative view of the molecular landscape within human lungs, this fragile tissue must be inflated and embedded to maintain spatial fidelity of the location of molecules and minimize molecular degradation for molecular imaging experiments. Here, we evaluated agarose inflation and carboxymethyl cellulose embedding media and determined effective tissue preparation protocols for performing bulk and spatial mass spectrometry-based omics measurements. Mass spectrometry imaging methods were optimized to boost the number of annotatable molecules in agarose inflated lung samples. This optimized protocol permitted the observation of unique lipid distributions within several airway regions in the lung tissue block. Laser capture microdissection of these airway regions followed by high-resolution proteomic analysis allowed us to begin linking the lipidome with the proteome in a spatially resolved manner, where we observed proteins with high abundance specifically localized to the airway regions. We also compared our mass spectrometry results to lung tissue samples preserved using two other inflation/embedding media, but we identified several pitfalls with the sample preparation steps using this preservation method. Overall, we demonstrated the versatility of the inflation method, and we can start to reveal how the metabolome, lipidome, and proteome are connected spatially in human lungs and across disease states through a variety of different experiments.", "pubmedLink": "" },   "36454643": { "pmid": "36454643", "title": "Culture impact on the transcriptomic programs of primary and iPSC-derived human alveolar type 2 cells.", "sortKey": "2023-01-culture impact on th", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Alysandratos KD, Garcia-de-Alba C, Yao C, Pessina P, Huang J, Villacorta-Martin C, Hix OT, Minakin K, Burgess CL, Bawa P, Murthy A, Konda B, Beers MF, Stripp BR, Kim CF, Kotton DN", "citation": "JCI insight, 01 2023", "abstractText": "Dysfunction of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, is implicated in pulmonary disease pathogenesis, highlighting the importance of human in vitro models. However, AEC2-like cells in culture have yet to be directly compared to their in vivo counterparts at single-cell resolution. Here, we performed head-to-head comparisons among the transcriptomes of primary (1°) adult human AEC2s, their cultured progeny, and human induced pluripotent stem cell-derived AEC2s (iAEC2s). We found each population occupied a distinct transcriptomic space with cultured AEC2s (1° and iAEC2s) exhibiting similarities to and differences from freshly purified 1° cells. Across each cell type, we found an inverse relationship between proliferative and maturation states, with preculture 1° AEC2s being most quiescent/mature and iAEC2s being most proliferative/least mature. Cultures of either type of human AEC2s did not generate detectable alveolar type 1 cells in these defined conditions; however, a subset of iAEC2s cocultured with fibroblasts acquired a transitional cell state described in mice and humans to arise during fibrosis or following injury. Hence, we provide direct comparisons of the transcriptomic programs of 1° and engineered AEC2s, 2 in vitro models that can be harnessed to study human lung health and disease.", "pubmedLink": "" },   "36413377": { "pmid": "36413377", "title": "LungMAP Portal Ecosystem: Systems-level Exploration of the Lung.", "sortKey": "2024-02-lungmap portal ecosy", "pubDateYear": "2024", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Gaddis N, Fortriede J, Guo M, Bardes EE, Kouril M, Tabar S, Burns K, Ardini-Poleske ME, Loos S, Schnell D, Jin K, Iyer B, Du Y, Huo BX, Bhattacharjee A, Korte J, Munshi R, Smith V, Herbst A, Kitzmiller JA, Clair GC, Carson JP, Adkins J, Morrisey EE, Pryhuber GS, Misra R, Whitsett JA, Sun X, Heathorn T, Paten B, Prasath VBS, Xu Y, Tickle T, Aronow BJ, Salomonis N", "citation": "American journal of respiratory cell and molecular biology, 02 2024", "abstractText": "An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular imaging, and pathological datasets. To centralize and standardize information across broad lung research efforts, we expanded the LungMAP.net website into a new gateway portal. This portal connects a broad spectrum of research networks, bulk and single-cell multiomics data, and a diverse collection of image data that span mammalian lung development and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances, including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, and mouse) to enable consistent queries across technologies, cohorts, age, disease, and drug treatment. These atlases are provided as independent and integrated queryable datasets, with an emphasis on dynamic visualization, figure generation, reanalysis, cell-type curation, and automated reference-based classification of user-provided single-cell genomics datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, supported data types, data portals and datasets from LungMAP, and external research efforts.", "pubmedLink": "" },   "36388965": { "pmid": "36388965", "title": "Cell-intrinsic differences between human airway epithelial cells from children and adults.", "sortKey": "2022-11-cell-intrinsic diffe", "pubDateYear": "2022", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Maughan EF, Hynds RE, Pennycuick A, Nigro E, Gowers KHC, Denais C, Gómez-López S, Lazarus KA, Orr JC, Pearce DR, Clarke SE, Lee DDH, Woodall MNJ, Masonou T, Case KM, Teixeira VH, Hartley BE, Hewitt RJ, Al Yaghchi C, Sandhu GS, Birchall MA, O'Callaghan C, Smith CM, De Coppi P, Butler CR, Janes SM", "citation": "iScience, 11 2022", "abstractText": "The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells, and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium was similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony formation ability, sustained  growth, and outcompeted adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states.", "pubmedLink": "" },   "36351366": { "pmid": "36351366", "title": "Lung Cell Atlases in Health and Disease.", "sortKey": "2023-02-lung cell atlases in", "pubDateYear": "2023", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Adams TS, Marlier A, Kaminski N", "citation": "Annual review of physiology, 02 2023", "abstractText": "The human lung cellular portfolio, traditionally characterized by cellular morphology and individual markers, is highly diverse, with over 40 cell types and a complex branching structure highly adapted for agile airflow and gas exchange. While constant during adulthood, lung cellular content changes in response to exposure, injury, and infection. Some changes are temporary, but others are persistent, leading to structural changes and progressive lung disease. The recent advance of single-cell profiling technologies allows an unprecedented level of detail and scale to cellular measurements, leading to the rise of comprehensive cell atlas styles of reporting. In this review, we chronical the rise of cell atlases and explore their contributions to human lung biology in health and disease.", "pubmedLink": "" },   "36252035": { "pmid": "36252035", "title": "Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.", "sortKey": "2022-10-disruption of proteo", "pubDateYear": "2022", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Katzen J, Rodriguez L, Tomer Y, Babu A, Zhao M, Murthy A, Carson P, Barrett M, Basil MC, Carl J, Leach JP, Morley M, McGraw MD, Mulugeta S, Pelura T, Rosen G, Morrisey EE, Beers MF", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 10 2022", "abstractText": "Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.", "pubmedLink": "" },   "36172120": { "pmid": "36172120", "title": "Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection.", "sortKey": "2022-09-generation and funct", "pubDateYear": "2022", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Zhou T, Gilliam NJ, Li S, Spaudau S, Osborn RM, Anderson CS, Mariani TJ, Thakar J, Dewhurst S, Mathews DH, Huang L, Sun Y", "citation": "bioRxiv : the preprint server for biology, 09 2022", "abstractText": "Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from RNA-seq datasets of  infections and autopsy lung tissues of COVID-19 patients. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection.", "pubmedLink": "" },   "36163190": { "pmid": "36163190", "title": "Airway basal cells show a dedifferentiated KRT17Phenotype and promote fibrosis in idiopathic pulmonary fibrosis.", "sortKey": "2022-09-airway basal cells s", "pubDateYear": "2022", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Jaeger B, Schupp JC, Plappert L, Terwolbeck O, Artysh N, Kayser G, Engelhard P, Adams TS, Zweigerdt R, Kempf H, Lienenklaus S, Garrels W, Nazarenko I, Jonigk D, Wygrecka M, Klatt D, Schambach A, Kaminski N, Prasse A", "citation": "Nature communications, 09 2022", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17 PTEN dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2 or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNAseq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrate that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model.", "pubmedLink": "" },   "36099047": { "pmid": "36099047", "title": "Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling.", "sortKey": "2022-10-single-cell transcri", "pubDateYear": "2022", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Crnkovic S, Valzano F, Fließer E, Gindlhuber J, Thekkekara Puthenparampil H, Basil M, Morley MP, Katzen J, Gschwandtner E, Klepetko W, Cantu E, Wolinski H, Olschewski H, Lindenmann J, Zhao YY, Morrisey EE, Marsh LM, Kwapiszewska G", "citation": "JCI insight, 10 2022", "abstractText": "A central feature of progressive vascular remodeling is altered smooth muscle cell (SMC) homeostasis; however, the understanding of how different cell populations contribute to this process is limited. Here, we utilized single-cell RNA sequencing to provide insight into cellular composition changes within isolated pulmonary arteries (PAs) from pulmonary arterial hypertension and donor lungs. Our results revealed that remodeling skewed the balanced communication network between immune and structural cells, in particular SMCs. Comparative analysis with murine PAs showed that human PAs harbored heterogeneous SMC populations with an abundant intermediary cluster displaying a gradient transition between SMCs and adventitial fibroblasts. Transcriptionally distinct SMC populations were enriched in specific biological processes and could be differentiated into 4 major clusters: oxygen sensing (enriched in pericytes), contractile, synthetic, and fibroblast-like. End-stage remodeling was associated with phenotypic shift of preexisting SMC populations and accumulation of synthetic SMCs in neointima. Distinctly regulated genes in clusters built nonredundant regulatory hubs encompassing stress response and differentiation regulators. The current study provides a blueprint of cellular and molecular changes on a single-cell level that are defining the pathological vascular remodeling process.", "pubmedLink": "" },   "35998893": { "pmid": "35998893", "title": "CellDrift: inferring perturbation responses in temporally sampled single-cell data.", "sortKey": "2022-09-celldrift: inferring", "pubDateYear": "2022", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Jin K, Schnell D, Li G, Salomonis N, Prasath VBS, Szczesniak R, Aronow BJ", "citation": "Briefings in bioinformatics, 09 2022", "abstractText": "Cells and tissues respond to perturbations in multiple ways that can be sensitively reflected in the alterations of gene expression. Current approaches to finding and quantifying the effects of perturbations on cell-level responses over time disregard the temporal consistency of identifiable gene programs. To leverage the occurrence of these patterns for perturbation analyses, we developed CellDrift (https://github.com/KANG-BIOINFO/CellDrift), a generalized linear model-based functional data analysis method that is capable of identifying covarying temporal patterns of various cell types in response to perturbations. As compared to several other approaches, CellDrift demonstrated superior performance in the identification of temporally varied perturbation patterns and the ability to impute missing time points. We applied CellDrift to multiple longitudinal datasets, including COVID-19 disease progression and gastrointestinal tract development, and demonstrated its ability to identify specific gene programs associated with sequential biological processes, trajectories and outcomes.", "pubmedLink": "" },   "35998281": { "pmid": "35998281", "title": "Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.", "sortKey": "2022-12-saracatinib, a selec", "pubDateYear": "2022", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Ahangari F, Becker C, Foster DG, Chioccioli M, Nelson M, Beke K, Wang X, Justet A, Adams T, Readhead B, Meador C, Correll K, Lili LN, Roybal HM, Rose KA, Ding S, Barnthaler T, Briones N, DeIuliis G, Schupp JC, Li Q, Omote N, Aschner Y, Sharma L, Kopf KW, Magnusson B, Hicks R, Backmark A, Dela Cruz CS, Rosas I, Cousens LP, Dudley JT, Kaminski N, Downey GP", "citation": "American journal of respiratory and critical care medicine, 12 2022", "abstractText": " Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common.  Using an  data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis.  We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: )  in normal human lung fibroblasts; )  in bleomycin and recombinant Ad-TGF-β (adenovirus transforming growth factor-β) murine models of pulmonary fibrosis; and )  in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors.  In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis.  These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.", "pubmedLink": "" },   "35980752": { "pmid": "35980752", "title": "Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques.", "sortKey": "2022-09-fetal maturation rev", "pubDateYear": "2022", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Schmidt AF, Schnell DJ, Eaton KP, Chetal K, Kannan PS, Miller LA, Chougnet CA, Swarr DT, Jobe AH, Salomonis N, Kamath-Rayne BD", "citation": "JCI insight, 09 2022", "abstractText": "Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data identify potentially new and prior-associated gestational age differences in distinct lung and neuronal cell populations when compared with existing single-cell and bulk RNA-Seq data. Comparative analyses found hundreds of genes coincidently induced in lung and amniotic fluid, along with dozens in brain and amniotic fluid. These data enable creation of computational models that accurately predict lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Importantly, antenatal steroids induced off-target gene expression changes in the brain, impinging upon synaptic transmission and neuronal and glial maturation, as this could have long-term consequences on brain development. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.", "pubmedLink": "" },   "35961837": { "pmid": "35961837", "title": "Super resolution microscopy analysis reveals increased Orai1 activity in asthma and cystic fibrosis lungs.", "sortKey": "2023-01-super resolution mic", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Goriounova AS, Gilmore RC, Wrennall JA, Tarran R", "citation": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 01 2023", "abstractText": "In diseases such as asthma and cystic fibrosis (CF), the immune response is dysregulated and the lung is chronically inflamed. Orai1 activation is required for the initiation and persistence of inflammation. However, Orai1 expression in the lung is poorly understood. We therefore tested the hypothesis that Orai1 expression was upregulated in asthmatic and CF lungs.", "pubmedLink": "" },   "35840754": { "pmid": "35840754", "title": "Characterizing cis-regulatory elements using single-cell epigenomics.", "sortKey": "2023-01-characterizing cis-r", "pubDateYear": "2023", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Preissl S, Gaulton KJ, Ren B", "citation": "Nature reviews. Genetics, 01 2023", "abstractText": "Cell type-specific gene expression patterns and dynamics during development or in disease are controlled by cis-regulatory elements (CREs), such as promoters and enhancers. Distinct classes of CREs can be characterized by their epigenomic features, including DNA methylation, chromatin accessibility, combinations of histone modifications and conformation of local chromatin. Tremendous progress has been made in cataloguing CREs in the human genome using bulk transcriptomic and epigenomic methods. However, single-cell epigenomic and multi-omic technologies have the potential to provide deeper insight into cell type-specific gene regulatory programmes as well as into how they change during development, in response to environmental cues and through disease pathogenesis. Here, we highlight recent advances in single-cell epigenomic methods and analytical tools and discuss their readiness for human tissue profiling.", "pubmedLink": "" },   "35803279": { "pmid": "35803279", "title": "Klf5 defines alveolar epithelial type 1 cell lineage commitment during lung development and regeneration.", "sortKey": "2022-07-klf5 defines alveola", "pubDateYear": "2022", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Liberti DC, Liberti Iii WA, Kremp MM, Penkala IJ, Cardenas-Diaz FL, Morley MP, Babu A, Zhou S, Fernandez Iii RJ, Morrisey EE", "citation": "Developmental cell, 07 2022", "abstractText": "Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified the transcription factor Klf5 as an essential determinant of alveolar epithelial cell fate across the lifespan. We show that although dispensable for both adult alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 enforces AT1 cell lineage fidelity during development. Using infectious and non-infectious models of acute respiratory distress syndrome, we demonstrate that Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner during lung regeneration. Moreover, ex vivo organoid assays identify that Klf5 reduces AT2 cell sensitivity to inflammatory signaling to drive AT2-AT1 cell differentiation. These data define the roll of a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.", "pubmedLink": "" },   "35768548": { "pmid": "35768548", "title": "International electronic health record-derived post-acute sequelae profiles of COVID-19 patients.", "sortKey": "2022-06-international electr", "pubDateYear": "2022", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Zhang HG, Dagliati A, Shakeri Hossein Abad Z, Xiong X, Bonzel CL, Xia Z, Tan BWQ, Avillach P, Brat GA, Hong C, Morris M, Visweswaran S, Patel LP, Gutiérrez-Sacristán A, Hanauer DA, Holmes JH, Samayamuthu MJ, Bourgeois FT, L'Yi S, Maidlow SE, Moal B, Murphy SN, Strasser ZH, Neuraz A, Ngiam KY, Loh NHW, Omenn GS, Prunotto A, Dalvin LA, Klann JG, Schubert P, Vidorreta FJS, Benoit V, Verdy G, Kavuluru R, Estiri H, Luo Y, Malovini A, Tibollo V, Bellazzi R, Cho K, Ho YL, Tan ALM, Tan BWL, Gehlenborg N, Lozano-Zahonero S, Jouhet V, Chiovato L, Aronow BJ, Toh EMS, Wong WGS, Pizzimenti S, Wagholikar KB, Bucalo M,  , Cai T, South AM, Kohane IS, Weber GM", "citation": "NPJ digital medicine, 06 2022", "abstractText": "The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09-1.55), heart failure (RR 1.22, 95% CI 1.10-1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07-1.31), and fatigue (RR 1.18, 95% CI 1.07-1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58-2.76), venous embolism (RR 1.34, 95% CI 1.17-1.54), atrial fibrillation (RR 1.30, 95% CI 1.13-1.50), type 2 diabetes (RR 1.26, 95% CI 1.16-1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09-1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90-3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21-2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04-1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC.", "pubmedLink": "" },   "35704600": { "pmid": "35704600", "title": "The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.", "sortKey": "2022-06-the balance between ", "pubDateYear": "2022", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Stevens J, Steinmeyer S, Bonfield M, Peterson L, Wang T, Gray J, Lewkowich I, Xu Y, Du Y, Guo M, Wynn JL, Zacharias W, Salomonis N, Miller L, Chougnet C, O'Connor DH, Deshmukh H", "citation": "Science translational medicine, 06 2022", "abstractText": "Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.", "pubmedLink": "" },   "35697747": { "pmid": "35697747", "title": "International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality.", "sortKey": "2022-06-international compar", "pubDateYear": "2022", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Weber GM, Hong C, Xia Z, Palmer NP, Avillach P, L'Yi S, Keller MS, Murphy SN, Gutiérrez-Sacristán A, Bonzel CL, Serret-Larmande A, Neuraz A, Omenn GS, Visweswaran S, Klann JG, South AM, Loh NHW, Cannataro M, Beaulieu-Jones BK, Bellazzi R, Agapito G, Alessiani M, Aronow BJ, Bell DS, Benoit V, Bourgeois FT, Chiovato L, Cho K, Dagliati A, DuVall SL, Barrio NG, Hanauer DA, Ho YL, Holmes JH, Issitt RW, Liu M, Luo Y, Lynch KE, Maidlow SE, Malovini A, Mandl KD, Mao C, Matheny ME, Moore JH, Morris JS, Morris M, Mowery DL, Ngiam KY, Patel LP, Pedrera-Jimenez M, Ramoni RB, Schriver ER, Schubert P, Balazote PS, Spiridou A, Tan ALM, Tan BWL, Tibollo V, Torti C, Trecarichi EM, Wang X,  , Kohane IS, Cai T, Brat GA", "citation": "NPJ digital medicine, 06 2022", "abstractText": "Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach.", "pubmedLink": "" },   "35695966": { "pmid": "35695966", "title": "Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B.", "sortKey": "2023-02-lethal neonatal resp", "pubDateYear": "2023", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Viehl L, Wegner DJ, Hmiel SP, White FV, Jain S, Cole FS, Wambach JA", "citation": "Pediatric nephrology (Berlin, Germany), 02 2023", "abstractText": "Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes.", "pubmedLink": "" },   "35628331": { "pmid": "35628331", "title": "Expression of Oxidative Stress and Inflammation-Related Genes in Nasal Mucosa and Nasal Polyps from Patients with Chronic Rhinosinusitis.", "sortKey": "2022-05-expression of oxidat", "pubDateYear": "2022", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Mihalj H, Butković J, Tokić S, Štefanić M, Kizivat T, Bujak M, Baus Lončar M, Mihalj M", "citation": "International journal of molecular sciences, 05 2022", "abstractText": "Chronic rhinosinusitis (CRS) is a prevalent, multifaceted inflammatory condition affecting the nasal cavity and the paranasal sinuses, frequently accompanied by formation of nasal polyps (CRSwNP). This apparently uniform clinical entity is preceded by heterogeneous changes in cellular and molecular patterns, suggesting the presence of multiple CRS endotypes and a diverse etiology. Alterations of the upper airway innate defense mechanisms, including antimicrobial and antioxidant capacity, have been implicated in CRSwNP etiology. The aim of this study was to investigate mRNA expression patterns of antioxidative enzymes, including superoxide dismutase (SOD) and peroxiredoxin-2 (PRDX2), and innate immune system defense players, namely the bactericidal/permeability-increasing fold-containing family A, member 1 (BPIFA1) and PACAP family members, particularly adenylate-cyclase-activating polypeptide receptor 1 (ADCYAP1) in nasal mucosa and nasal polyps from CRSwNP patients. Additional stratification based on age, sex, allergic comorbidity, and disease severity was applied. The results showed that ADCYAP1, BPIFA1, and PRDX2 transcripts are differentially expressed in nasal mucosa and scale with radiologically assessed disease severity in CRSwNP patients. Sinonasal transcriptome is not associated with age, sex, and smoking in CRSwNP. Surgical and postoperative corticosteroid (CS) therapy improves endoscopic appearance of the mucosa, but variably reverses target gene expression patterns in the nasal cavity of CRSwNP patients. Transcriptional cross-correlations analysis revealed an increased level of connectedness among differentially expressed genes under inflammatory conditions and restoration of basic network following CS treatment. Although results of the present study imply a possible engagement of ADCYAP1 and BPIFA1 as biomarkers for CRSwNP, a more profound study taking into account disease severity and CRSwNP endotypes prior to the treatment would provide additional information on their sensitivity.", "pubmedLink": "" },   "35434692": { "pmid": "35434692", "title": "A single-cell regulatory map of postnatal lung alveologenesis in humans and mice.", "sortKey": "2022-03-a single-cell regula", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Duong TE, Wu Y, Sos BC, Dong W, Limaye S, Rivier LH, Myers G, Hagood JS, Zhang K", "citation": "Cell genomics, 03 2022", "abstractText": "Ex-utero regulation of the lungs  responses to breathing air and continued alveolar development shape adult respiratory health. Applying single-cell transposome hypersensitive site sequencing (scTHS-seq) to over 80,000 cells, we assembled the first regulatory atlas of postnatal human and mouse lung alveolar development. We defined regulatory modules and elucidated new mechanistic insights directing alveolar septation, including alveolar type 1 and myofibroblast cell signaling and differentiation, and a unique human matrix fibroblast population. Incorporating GWAS, we mapped lung function causal variants to myofibroblasts and identified a pathogenic regulatory unit linked to lineage marker , demonstrating the utility of chromatin accessibility data to uncover disease mechanism targets. Our regulatory map and analysis model provide valuable new resources to investigate age-dependent and species-specific control of critical developmental processes. Furthermore, these resources complement existing atlas efforts to advance our understanding of lung health and disease across the human lifespan.", "pubmedLink": "" },   "35395180": { "pmid": "35395180", "title": "Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.", "sortKey": "2022-05-uncompensated mitoch", "pubDateYear": "2022", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Xu X, Jin K, Bais AS, Zhu W, Yagi H, Feinstein TN, Nguyen PK, Criscione JD, Liu X, Beutner G, Karunakaran KB, Rao KS, He H, Adams P, Kuo CK, Kostka D, Pryhuber GS, Shiva S, Ganapathiraju MK, Porter GA, Lin JI, Aronow B, Lo CW", "citation": "Cell stem cell, 05 2022", "abstractText": "Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.", "pubmedLink": "" },   "35355013": { "pmid": "35355013", "title": "Human distal airways contain a multipotent secretory cell that can regenerate alveoli.", "sortKey": "2022-04-human distal airways", "pubDateYear": "2022", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J, Brumwell AN, Katzen J, Slovik KJ, Babu A, Zhou S, Kremp MM, McCauley KB, Li S, Planer JD, Hussain SS, Liu X, Windmueller R, Ying Y, Stewart KM, Oyster M, Christie JD, Diamond JM, Engelhardt JF, Cantu E, Rowe SM, Kotton DN, Chapman HA, Morrisey EE", "citation": "Nature, 04 2022", "abstractText": "The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.", "pubmedLink": "" },   "35354612": { "pmid": "35354612", "title": "The Lung Microenvironment Instructs Gene Transcription in Neonatal and Adult Alveolar Macrophages.", "sortKey": "2022-04-the lung microenviro", "pubDateYear": "2022", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Honda A, Hoeksema MA, Sakai M, Lund SJ, Lakhdari O, Butcher LD, Rambaldo TC, Sekiya NM, Nasamran CA, Fisch KM, Sajti E, Glass CK, Prince LS", "citation": "Journal of immunology (Baltimore, Md. : 1950), 04 2022", "abstractText": "Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. In this study, we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs in mice. Although the core AM signature was similar, murine adult AMs expressed higher levels of genes involved in lipid metabolism, whereas neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by an assay for transposase-accessible chromatin followed by high-throughput sequencing (ATAC-seq) contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-κB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonatal and adult mice, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal mouse AMs retained high expression of some proinflammatory genes, suggesting that the differences in neonatal AMs result from both inherent cell properties and environmental influences.", "pubmedLink": "" },   "35353543": { "pmid": "35353543", "title": "Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.", "sortKey": "2022-03-inflammatory blockad", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Toth A, Steinmeyer S, Kannan P, Gray J, Jackson CM, Mukherjee S, Demmert M, Sheak JR, Benson D, Kitzmiller J, Wayman JA, Presicce P, Cates C, Rubin R, Chetal K, Du Y, Miao Y, Gu M, Guo M, Kalinichenko VV, Kallapur SG, Miraldi ER, Xu Y, Swarr D, Lewkowich I, Salomonis N, Miller L, Sucre JS, Whitsett JA, Chougnet CA, Jobe AH, Deshmukh H, Zacharias WJ", "citation": "Science translational medicine, 03 2022", "abstractText": "Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque () model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.", "pubmedLink": "" },   "35342283": { "pmid": "35342283", "title": "COMPUTATIONAL 2D and 3D MEDICAL IMAGE DATA COMPRESSION MODELS.", "sortKey": "2022-03-computational 2d and", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Boopathiraja S, Punitha V, Kalavathi P, Surya Prasath VB", "citation": "Archives of computational methods in engineering : state of the art reviews, 03 2022", "abstractText": "In this world of big data, the development and exploitation of medical technology is vastly increasing and especially in big biomedical imaging modalities available across medicine. At the same instant, acquisition, processing, storing and transmission of such huge medical data requires efficient and robust data compression models. Over the last two decades, numerous compression mechanisms, techniques and algorithms were proposed by many researchers. This work provides a detailed status of these existing computational compression methods for medical imaging data. Appropriate classification, performance metrics, practical issues and challenges in enhancing the two dimensional (2D) and three dimensional (3D) medical image compression arena are reviewed in detail.", "pubmedLink": "" },   "35315362": { "pmid": "35315362", "title": "Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell-derived alveolar epithelium.", "sortKey": "2022-03-air-liquid interface", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Abo KM, Sainz de Aja J, Lindstrom-Vautrin J, Alysandratos KD, Richards A, Garcia-de-Alba C, Huang J, Hix OT, Werder RB, Bullitt E, Hinds A, Falconer I, Villacorta-Martin C, Jaenisch R, Kim CF, Kotton DN, Wilson AA", "citation": "JCI insight, 03 2022", "abstractText": "Type 2 alveolar epithelial cells (AT2s), facultative progenitor cells of the lung alveolus, play a vital role in the biology of the distal lung. In vitro model systems that incorporate human cells, recapitulate the biology of primary AT2s, and interface with the outside environment could serve as useful tools to elucidate functional characteristics of AT2s in homeostasis and disease. We and others recently adapted human induced pluripotent stem cell-derived AT2s (iAT2s) for air-liquid interface (ALI) culture. Here, we comprehensively characterize the effects of ALI culture on iAT2s and benchmark their transcriptional profile relative to both freshly sorted and cultured primary human fetal and adult AT2s. We find that iAT2s cultured at ALI maintain an AT2 phenotype while upregulating expression of transcripts associated with AT2 maturation. We then leverage this platform to assay the effects of exposure to clinically significant, inhaled toxicants including cigarette smoke and electronic cigarette vapor.", "pubmedLink": "" },   "35308599": { "pmid": "35308599", "title": "POCASUM : Policy Categorizer and Summarizer Based on Text Mining and Machine Learning.", "sortKey": "2021-07-pocasum : policy cat", "pubDateYear": "2021", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Deotale R, Rawat S, Vijayarajan V, Prasath VBS", "citation": "Soft computing, 07 2021", "abstractText": "Having control over your data is a right and a duty that every citizen has in our digital society. It is often that users skip entire policies of applications or websites to save time and energy without realizing the potential sticky points in these policies. Due to obscure language and verbose explanations majority of users of hypermedia do not bother to read them. Further, sometimes digital media companies do not spend enough effort in stating their policies clearly which often time can also be incomplete. A summarized version of these privacy policies that can be categorized into the useful information can help the users. To solve this problem, in this work we propose to use machine learning based models for policy categorizer that classifies the policy paragraphs under the attributes proposed like security, contact etc. By benchmarking different machine learning based classifier models, we show that artificial neural network model performs with higher accuracy on a challenging dataset of textual privacy policies. We thus show that machine learning can help summarize the relevant paragraphs under the various attributes so that the user can get the gist of that topic within a few lines.", "pubmedLink": "" },   "35303432": { "pmid": "35303432", "title": "Excess neuropeptides in lung signal through endothelial cells to impair gas exchange.", "sortKey": "2022-04-excess neuropeptides", "pubDateYear": "2022", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Xu J, Xu L, Sui P, Chen J, Moya EA, Hume P, Janssen WJ, Duran JM, Thistlethwaite P, Carlin A, Gulleman P, Banaschewski B, Goldy MK, Yuan JX, Malhotra A, Pryhuber G, Crotty-Alexander L, Deutsch G, Young LR, Sun X", "citation": "Developmental cell, 04 2022", "abstractText": "Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions.", "pubmedLink": "" },   "35298923": { "pmid": "35298923", "title": "Three-dimensional feature matching improves coverage for single-cell proteomics based on ion mobility filtering.", "sortKey": "2022-05-three-dimensional fe", "pubDateYear": "2022", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Woo J, Clair GC, Williams SM, Feng S, Tsai CF, Moore RJ, Chrisler WB, Smith RD, Kelly RT, Paša-Tolić L, Ansong C, Zhu Y", "citation": "Cell systems, 05 2022", "abstractText": "Single-cell proteomics (scProteomics) promises to advance our understanding of cell functions within complex biological systems. However, a major challenge of current methods is their inability to identify and provide accurate quantitative information for low-abundance proteins. Herein, we describe an ion-mobility-enhanced mass spectrometry acquisition and peptide identification method, transferring identification based on FAIMS filtering (TIFF), to improve the sensitivity and accuracy of label-free scProteomics. TIFF extends the ion accumulation times for peptide ions by filtering out singly charged ions. The peptide identities are assigned by a three-dimensional MS1 feature matching approach (retention time, accurate mass, and FAIMS compensation voltage). The TIFF method enabled unbiased proteome analysis to a depth of >1,700 proteins in single HeLa cells, with >1,100 proteins consistently identified. As a demonstration, we applied the TIFF method to obtain temporal proteome profiles of >150 single murine macrophage cells during lipopolysaccharide stimulation and identified time-dependent proteome changes. A record of this paper s transparent peer review process is included in the supplemental information.", "pubmedLink": "" },   "35290476": { "pmid": "35290476", "title": "Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.", "sortKey": "2022-06-loss of function of ", "pubDateYear": "2022", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "de Souza Cordeiro LM, Bainbridge L, Devisetty N, McDougal DH, Peters DJM, Chhabra KH", "citation": "Diabetologia, 06 2022", "abstractText": "Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity.", "pubmedLink": "" },   "35170262": { "pmid": "35170262", "title": "Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency.", "sortKey": "2022-05-biologic characteriz", "pubDateYear": "2022", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Xu KK, Wegner DJ, Geurts LC, Heins HB, Yang P, Hamvas A, Eghtesady P, Sweet SC, Sessions Cole F, Wambach JA", "citation": "Pediatric pulmonology, 05 2022", "abstractText": "ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allele-specific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsense-mediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exon-intron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.", "pubmedLink": "" },   "35121658": { "pmid": "35121658", "title": "A dominant negative variant of  disrupts maturation of surfactant protein B and surfactant protein C.", "sortKey": "2022-02-a dominant negative ", "pubDateYear": "2022", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Huang H, Pan J, Spielberg DR, Hanchard NA, Scott DA, Burrage LC, Dai H, Murdock D, Rosenfeld JA, Mohammad A, Huang T, Lindsey AG, Kim H, Chen J, Ramu A, Morrison SA, Dawson ZD, Hu AZ, Tycksen E, Silverman GA, Baldridge D, Wambach JA,  , Pak SC, Brody SL, Schedl T", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 02 2022", "abstractText": "Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in  was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in  by knocking the proband variant into the conserved position (Asp135) of the ortholog,  Genetic analysis demonstrated that [Asp135His] is damaging, producing a strong dominant negative gene product. [Asp135His] heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband s lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify  p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.", "pubmedLink": "" },   "35113810": { "pmid": "35113810", "title": "Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation.", "sortKey": "2022-03-maladaptive function", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Riccetti MR, Ushakumary MG, Waltamath M, Green J, Snowball J, Dautel SE, Endale M, Lami B, Woods J, Ahlfeld SK, Perl AT", "citation": "JCI insight, 03 2022", "abstractText": "Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha-positive (PDGFRA+) fibroblasts are critical for alveolarization and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population-targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 postnatal days 0-7, PN0-PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decreased and PDGFRA+ lipofibroblasts increased by transcriptional signature and population size. PDGFRA+ matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.", "pubmedLink": "" },   "35077664": { "pmid": "35077664", "title": "First Steps toward Personalized Therapies for ABCA3 Deficiency.", "sortKey": "2022-04-first steps toward p", "pubDateYear": "2022", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Wambach JA, Nogee LM, Cole FS", "citation": "American journal of respiratory cell and molecular biology, 04 2022", "pubmedLink": "" },   "35045271": { "pmid": "35045271", "title": "Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation.", "sortKey": "2022-04-neonatal hyperoxia a", "pubDateYear": "2022", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Yee M, McDavid AN, Cohen ED, Huyck HL, Poole C, Altman BJ, Maniscalco WM, Deutsch GH, Pryhuber GS, O'Reilly MA", "citation": "American journal of respiratory cell and molecular biology, 04 2022", "abstractText": "Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.", "pubmedLink": "" },   "35020534": { "pmid": "35020534", "title": "Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection.", "sortKey": "2022-03-human airway lineage", "pubDateYear": "2022", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Wang R, Hume AJ, Beermann ML, Simone-Roach C, Lindstrom-Vautrin J, Le Suer J, Huang J, Olejnik J, Villacorta-Martin C, Bullitt E, Hinds A, Ghaedi M, Rollins S, Werder RB, Abo KM, Wilson AA, Mühlberger E, Kotton DN, Hawkins FJ", "citation": "American journal of physiology. Lung cellular and molecular physiology, 03 2022", "abstractText": "There is an urgent need to understand how SARS-CoV-2 infects the airway epithelium and in a subset of individuals leads to severe illness or death. Induced pluripotent stem cells (iPSCs) provide a near limitless supply of human cells that can be differentiated into cell types of interest, including airway epithelium, for disease modeling. We present a human iPSC-derived airway epithelial platform, composed of the major airway epithelial cell types, that is permissive to SARS-CoV-2 infection. Subsets of iPSC-airway cells express the SARS-CoV-2 entry factors angiotensin-converting enzyme 2 (), and transmembrane protease serine 2 (). Multiciliated cells are the primary initial target of SARS-CoV-2 infection. On infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses, and treatment with remdesivir or camostat mesylate causes a decrease in viral propagation and entry, respectively. In conclusion, iPSC-derived airway cells provide a physiologically relevant in vitro model system to interrogate the pathogenesis of, and develop treatment strategies for, COVID-19 pneumonia.", "pubmedLink": "" },   "34998241": { "pmid": "34998241", "title": "CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1.", "sortKey": "2022-01-crispri links covid-", "pubDateYear": "2022", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Fink-Baldauf IM, Stuart WD, Brewington JJ, Guo M, Maeda Y", "citation": "EBioMedicine, 01 2022", "abstractText": "To identify host genetic variants (SNPs) associated with COVID-19 disease severity, a number of genome-wide association studies (GWAS) have been conducted. Since most of the identified variants are located at non-coding regions, such variants are presumed to affect the expression of neighbouring genes, thereby influencing COVID-19 disease severity. However, it remains largely unknown which genes are influenced by such COVID-19 GWAS loci.", "pubmedLink": "" },   "34936882": { "pmid": "34936882", "title": "A census of the lung: CellCards from LungMAP.", "sortKey": "2022-01-a census of the lung", "pubDateYear": "2022", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Sun X, Perl AK, Li R, Bell SM, Sajti E, Kalinichenko VV, Kalin TV, Misra RS, Deshmukh H, Clair G, Kyle J, Crotty Alexander LE, Masso-Silva JA, Kitzmiller JA, Wikenheiser-Brokamp KA, Deutsch G, Guo M, Du Y, Morley MP, Valdez MJ, Yu HV, Jin K, Bardes EE, Zepp JA, Neithamer T, Basil MC, Zacharias WJ, Verheyden J, Young R, Bandyopadhyay G, Lin S, Ansong C, Adkins J, Salomonis N, Aronow BJ, Xu Y, Pryhuber G, Whitsett J, Morrisey EE,  ", "citation": "Developmental cell, 01 2022", "abstractText": "The human lung plays vital roles in respiration, host defense, and basic physiology. Recent technological advancements such as single-cell RNA sequencing and genetic lineage tracing have revealed novel cell types and enriched functional properties of existing cell types in lung. The time has come to take a new census. Initiated by members of the NHLBI-funded LungMAP Consortium and aided by experts in the lung biology community, we synthesized current data into a comprehensive and practical cellular census of the lung. Identities of cell types in the normal lung are captured in individual cell cards with delineation of function, markers, developmental lineages, heterogeneity, regenerative potential, disease links, and key experimental tools. This publication will serve as the starting point of a live, up-to-date guide for lung research at https://www.lungmap.net/cell-cards/. We hope that Lung CellCards will promote the community-wide effort to establish, maintain, and restore respiratory health.", "pubmedLink": "" },   "34848696": { "pmid": "34848696", "title": "Author Correction: High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip.", "sortKey": "2021-11-author correction: h", "pubDateYear": "2021", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Woo J, Williams SM, Markillie LM, Feng S, Tsai CF, Aguilera-Vazquez V, Sontag RL, Moore RJ, Hu D, Mehta HS, Cantlon-Bruce J, Liu T, Adkins JN, Smith RD, Clair GC, Pasa-Tolic L, Zhu Y", "citation": "Nature communications, 11 2021", "pubmedLink": "" },   "34752721": { "pmid": "34752721", "title": "Proteomic Analysis of Human Lung Development.", "sortKey": "2022-01-proteomic analysis o", "pubDateYear": "2022", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Clair G, Bramer LM, Misra R, McGraw MD, Bhattacharya S, Kitzmiller JA, Feng S, Danna VG, Bandyopadhyay G, Bhotika H, Huyck HL, Deutsch GH, Mariani TJ, Carson JP, Whitsett JA, Pryhuber GS, Adkins JN, Ansong C", "citation": "American journal of respiratory and critical care medicine, 01 2022", "abstractText": " The current understanding of human lung development derives mostly from animal studies. Although transcript-level studies have analyzed human donor tissue to identify genes expressed during normal human lung development, protein-level analysis that would enable the generation of new hypotheses on the processes involved in pulmonary development are lacking.  To define the temporal dynamic of protein expression during human lung development.  We performed proteomics analysis of human lungs at 10 distinct times from birth to 8 years to identify the molecular networks mediating postnatal lung maturation.  We identified 8,938 proteins providing a comprehensive view of the developing human lung proteome. The analysis of the data supports the existence of distinct molecular substages of alveolar development and predicted the age of independent human lung samples, and extensive remodeling of the lung proteome occurred during postnatal development. Evidence of post-transcriptional control was identified in early postnatal development. An extensive extracellular matrix remodeling was supported by changes in the proteome during alveologenesis. The concept of maturation of the immune system as an inherent part of normal lung development was substantiated by flow cytometry and transcriptomics.  This study provides the first in-depth characterization of the human lung proteome during development, providing a unique proteomic resource freely accessible at Lungmap.net. The data support the extensive remodeling of the lung proteome during development, the existence of molecular substages of alveologenesis, and evidence of post-transcriptional control in early postnatal development.", "pubmedLink": "" },   "34739767": { "pmid": "34739767", "title": "Reduced Notch1 Cleavage Promotes the Development of Pulmonary Hypertension.", "sortKey": "2022-01-reduced notch1 cleav", "pubDateYear": "2022", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Wang S, Zhu G, Jiang D, Rhen J, Li X, Liu H, Lyu Y, Tsai P, Rose Y, Nguyen T, White RJ, Pryhuber GS, Mariani TJ, Li C, Mohan A, Xu Y, Pang J", "citation": "Hypertension (Dallas, Tex. : 1979), 01 2022", "abstractText": "Clinical trials of Dll4 (Delta-like 4) neutralizing antibodies (Dll4nAbs) in cancer patients are ongoing. Surprisingly, pulmonary hypertension (PH) occurs in 14% to 18% of patients treated with Dll4nAbs, but the mechanisms have not been studied. Here, PH progression was measured in mice treated with Dll4nAbs. We detected Notch signaling in lung tissues and analyzed pulmonary vascular permeability and inflammation. Notch target gene array was performed on adult human pulmonary microvascular endothelial cells (ECs) after inhibiting Notch cleavage. Similar mechanisms were studied in PH mouse models and pulmonary arterial hypertension patients. The rescue effects of constitutively activated Notch1 in vivo were also measured. We observed that Dll4nAbs induced PH in mice as indicated by significantly increased right ventricular systolic pressure, as well as pulmonary vascular and right ventricular remodeling. Mechanistically, Dll4nAbs inhibited Notch1 cleavage and subsequently impaired lung endothelial barrier function and increased immune cell infiltration in vessel walls. In vitro, Notch targeted genes  expression related to cell growth and inflammation was decreased in human pulmonary microvascular ECs after the Notch1 inactivation. In lungs of PH mouse models and pulmonary arterial hypertension patients, Notch1 cleavage was inhibited. Consistently, EC cell-cell junction was leaky, and immune cell infiltration increased in PH mouse models. Overexpression activated Notch1-attenuated progression of PH in mice. In conclusion, Dll4nAbs led to PH development in mice by impaired EC barrier function and increased immune cell infiltration through inhibition of Notch1 cleavage in lung ECs. Reduced Notch1 cleavage in lung ECs could be an underlying mechanism of PH pathogenesis.", "pubmedLink": "" },   "34716329": { "pmid": "34716329", "title": "High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip.", "sortKey": "2021-10-high-throughput and ", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Woo J, Williams SM, Markillie LM, Feng S, Tsai CF, Aguilera-Vazquez V, Sontag RL, Moore RJ, Hu D, Mehta HS, Cantlon-Bruce J, Liu T, Adkins JN, Smith RD, Clair GC, Pasa-Tolic L, Zhu Y", "citation": "Nature communications, 10 2021", "abstractText": "Global quantification of protein abundances in single cells could provide direct information on cellular phenotypes and complement transcriptomics measurements. However, single-cell proteomics is still immature and confronts many technical challenges. Herein we describe a nested nanoPOTS (N2) chip to improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip reduces reaction volume to <30 nL and increases capacity to >240 single cells on a single microchip. The tandem mass tag (TMT) pooling step is simplified by adding a microliter droplet on the nested nanowells to combine labeled single-cell samples. In the analysis of ~100 individual cells from three different cell lines, we demonstrate that the N2 chip-based scProteomics platform can robustly quantify ~1500 proteins and reveal membrane protein markers. Our analyses also reveal low protein abundance variations, suggesting the single-cell proteome profiles are highly stable for the cells cultured under identical conditions.", "pubmedLink": "" },   "34704855": { "pmid": "34704855", "title": "COVID-19 in Early Life: Infants and Children Are Affected Too.", "sortKey": "2021-11-covid-19 in early li", "pubDateYear": "2021", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Leibel SL, Sun X", "citation": "Physiology (Bethesda, Md.), 11 2021", "abstractText": "Compared with adults, children are less likely infected with SARS-CoV-2 and are often asymptomatic when infected. However, infection in children can lead to severe disease. The pandemic affects the lives of all children, especially those with lower socioeconomic status. This review highlights the physiological impacts of COVID-19 in early life.", "pubmedLink": "" },   "34669442": { "pmid": "34669442", "title": "Fatal enhanced respiratory syncytial virus disease in toddlers.", "sortKey": "2021-10-fatal enhanced respi", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Polack FP, Alvarez-Paggi D, Libster R, Caballero MT, Blair RV, Hijano DR, de la Iglesia Niveyro PX, Menendez DR, Gladwell W, Avendano LM, Velozo L, Wanek A, Bergel E, Prince GA, Kleeberger SR, Johnson J, Pociask D, Kolls JK", "citation": "Science translational medicine, 10 2021", "abstractText": "In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type virus were hospitalized. These events hampered RSV vaccine development for decades. Here, we provide a characterization of the clinical, immunopathological, and transcriptional signature of fatal human ERD, outlining evidence for safety evaluation of RSV vaccines and a framework for understanding disease enhancement for pathogens in general.", "pubmedLink": "" },   "34581565": { "pmid": "34581565", "title": "Rapid Automated Annotation and Analysis of N-Glycan Mass Spectrometry Imaging Data Sets Using NGlycDB in METASPACE.", "sortKey": "2021-10-rapid automated anno", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Veličković D, Bečejac T, Mamedov S, Sharma K, Ambalavanan N, Alexandrov T, Anderton CR", "citation": "Analytical chemistry, 10 2021", "abstractText": "Imaging N-glycan spatial distribution in tissues using mass spectrometry imaging (MSI) is emerging as a promising tool in biological and clinical applications. However, there is currently no high-throughput tool for visualization and molecular annotation of N-glycans in MSI data, which significantly slows down data processing and hampers the applicability of this approach. Here, we present how METASPACE, an open-source cloud engine for molecular annotation of MSI data, can be used to automatically annotate, visualize, analyze, and interpret high-resolution mass spectrometry-based spatial N-glycomics data. METASPACE is an emerging tool in spatial metabolomics, but the lack of compatible glycan databases has limited its application for comprehensive N-glycan annotations from MSI data sets. We created NGlycDB, a public database of N-glycans, by adapting available glycan databases. We demonstrate the applicability of NGlycDB in METASPACE by analyzing MALDI-MSI data from formalin-fixed paraffin-embedded (FFPE) human kidney and mouse lung tissue sections. We added NGlycDB to METASPACE for public use, thus, facilitating applications of MSI in glycobiology.", "pubmedLink": "" },   "34522848": { "pmid": "34522848", "title": "An interactive single cell web portal identifies gene and cell networks in COVID-19 host responses.", "sortKey": "2021-10-an interactive singl", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Jin K, Bardes EE, Mitelpunkt A, Wang JY, Bhatnagar S, Sengupta S, Krummel DP, Rothenberg ME, Aronow BJ", "citation": "iScience, 10 2021", "abstractText": "Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a data mine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to interacting with, exploring, and functional evaluating these modules via a new interactive web portal ToppCell (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) alternatively-differentiated monocyte-derived macrophages form a multicelllar signaling cascade that drives T cell recruitment and activation; (2) COVID-19-generated platelet subtypes exhibit dramatically altered potential to adhere, coagulate, and thrombose; and (3) extrafollicular B maturation is driven by a multilineage cell activation network that expresses an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.", "pubmedLink": "" },   "34489955": { "pmid": "34489955", "title": "Protectins PCTR1 and PD1 Reduce Viral Load and Lung Inflammation During Respiratory Syncytial Virus Infection in Mice.", "sortKey": "2021-00-protectins pctr1 and", "pubDateYear": "2021", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Walker KH, Krishnamoorthy N, Brüggemann TR, Shay AE, Serhan CN, Levy BD", "citation": "Frontiers in immunology, 00 2021", "abstractText": "Viral pneumonias are a major cause of morbidity and mortality, owing in part to dysregulated excessive lung inflammation, and therapies to modulate host responses to viral lung injury are urgently needed. Protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are specialized pro-resolving mediators (SPMs) whose roles in viral pneumonia are of interest. In a mouse model of Respiratory Syncytial Virus (RSV) pneumonia, intranasal PCTR1 and PD1 each decreased RSV genomic viral load in lung tissue when given after RSV infection. Concurrent with enhanced viral clearance, PCTR1 administration post-infection, decreased eosinophils, neutrophils, and NK cells, including NKG2D activated NK cells, in the lung. Intranasal PD1 administration post-infection decreased lung eosinophils and  expression. PCTR1 increased lung expression of cathelicidin anti-microbial peptide and decreased interferon-gamma production by lung CD4 T cells. PCTR1 and PD1 each increased interferon-lambda expression in human bronchial epithelial cells  and attenuated RSV-induced suppression of interferon-lambda in mouse lung . Liquid chromatography coupled with tandem mass spectrometry of RSV-infected and untreated mouse lungs demonstrated endogenous PCTR1 and PD1 that decreased early in the time course while cysteinyl-leukotrienes (cys-LTs) increased during early infection. As RSV infection resolved, PCTR1 and PD1 increased and cys-LTs decreased to pre-infection levels. Together, these results indicate that PCTR1 and PD1 are each regulated during RSV pneumonia, with overlapping and distinct mechanisms for PCTR1 and PD1 during the resolution of viral infection and its associated inflammation.", "pubmedLink": "" },   "34469722": { "pmid": "34469722", "title": "Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.", "sortKey": "2021-08-patient-specific ips", "pubDateYear": "2021", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Alysandratos KD, Russo SJ, Petcherski A, Taddeo EP, Acín-Pérez R, Villacorta-Martin C, Jean JC, Mulugeta S, Rodriguez LR, Blum BC, Hekman RM, Hix OT, Minakin K, Vedaie M, Kook S, Tilston-Lunel AM, Varelas X, Wambach JA, Cole FS, Hamvas A, Young LR, Liesa M, Emili A, Guttentag SH, Shirihai OS, Beers MF, Kotton DN", "citation": "Cell reports, 08 2021", "abstractText": "Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPC). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPC-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.", "pubmedLink": "" },   "34466790": { "pmid": "34466790", "title": "YAP regulates alveolar epithelial cell differentiation and  via NFIB/KLF5/NKX2-1.", "sortKey": "2021-09-yap regulates alveol", "pubDateYear": "2021", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Gokey JJ, Snowball J, Sridharan A, Sudha P, Kitzmiller JA, Xu Y, Whitsett JA", "citation": "iScience, 09 2021", "abstractText": "Ventilation is dependent upon pulmonary alveoli lined by two major epithelial cell types, alveolar type-1 (AT1) and 2 (AT2) cells. AT1 cells mediate gas exchange while AT2 cells synthesize and secrete pulmonary surfactants and serve as progenitor cells which repair the alveoli. We developed transgenic mice in which YAP was activated or deleted to determine its roles in alveolar epithelial cell differentiation. Postnatal YAP activation increased epithelial cell proliferation, increased AT1 cell numbers, and caused indeterminate differentiation of subsets of alveolar cells expressing atypical genes normally restricted to airway epithelial cells. YAP deletion increased expression of genes associated with mature AT2 cells. YAP activation enhanced DNA accessibility in promoters of transcription factors and motif enrichment analysis predicted target genes associated with alveolar cell differentiation. YAP participated with KLF5, NFIB, and NKX2-1 to regulate . YAP plays a central role in a transcriptional network that regulates alveolar epithelial differentiation.", "pubmedLink": "" },   "34446466": { "pmid": "34446466", "title": "Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia.", "sortKey": "2022-02-macrophage-derived i", "pubDateYear": "2022", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Hirani D, Alvira CM, Danopoulos S, Milla C, Donato M, Tian L, Mohr J, Dinger K, Vohlen C, Selle J, V Koningsbruggen-Rietschel S, Barbarino V, Pallasch C, Rose-John S, Odenthal M, Pryhuber GS, Mansouri S, Savai R, Seeger W, Khatri P, Al Alam D, Dötsch J, Alejandre Alcazar MA", "citation": "The European respiratory journal, 02 2022", "abstractText": "Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.", "pubmedLink": "" },   "34355203": { "pmid": "34355203", "title": "Differentiation of human pluripotent stem cells into functional airway basal stem cells.", "sortKey": "2021-09-differentiation of h", "pubDateYear": "2021", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Suzuki S, Hawkins FJ, Barillà C, Beermann ML, Kotton DN, Davis BR", "citation": "STAR protocols, 09 2021", "abstractText": "Airway basal cells play an essential role in the maintenance of the airway epithelium. Here, we provide a detailed directed differentiation protocol to generate   induced basal cells (iBCs)   from human pluripotent stem cells. iBCs recapitulate biological and functional properties of airway basal cells including mucociliary differentiation  or  in tracheal xenografts, facilitating the study of inherited and acquired diseases of the airway, as well as potential use in regenerative medicine. For complete details on the use and execution of this protocol, please refer to Hawkins et al. (2021).", "pubmedLink": "" },   "34323115": { "pmid": "34323115", "title": "Low-dose hyperoxia primes airways for fibrosis in mice after influenza A infection.", "sortKey": "2021-10-low-dose hyperoxia p", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Dylag AM, Haak J, Warren R, Yee M, Pryhuber GS, O'Reilly MA", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2021", "abstractText": "It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40×8) that causes a transient change in lung function that resolves, rendering 40×8 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40×8 mice display an early transient activation of TGFβ signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared with infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGFβ signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40×8 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.", "pubmedLink": "" },   "34232960": { "pmid": "34232960", "title": "A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings.", "sortKey": "2021-07-a homozygous stop-ga", "pubDateYear": "2021", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Li Q, Dibus M, Casey A, Yee CSK, Vargas SO, Luo S, Rosen SM, Madden JA, Genetti CA, Brabek J, Brownstein CA, Kazerounian S, Raby BA, Schmitz-Abe K, Kennedy JC, Fishman MP, Mullen MP, Taylor JM, Rosel D, Agrawal PB", "citation": "PLoS genetics, 07 2021", "abstractText": "ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.", "pubmedLink": "" },   "34195595": { "pmid": "34195595", "title": "The critical role of collagen VI in lung development and chronic lung disease.", "sortKey": "2021-06-the critical role of", "pubDateYear": "2021", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Mereness JA, Mariani TJ", "citation": "Matrix biology plus, 06 2021", "abstractText": "Type VI collagen (collagen VI) is an obligate extracellular matrix component found mainly in the basement membrane region of many mammalian tissues and organs, including skeletal muscle and throughout the respiratory system. Collagen VI is probably most recognized in medicine as the genetic cause of a spectrum of muscular dystrophies, including Ullrich Congenital Myopathy and Bethlem Myopathy. Collagen VI is thought to contribute to myopathy, at least in part, by mediating muscle fiber integrity by anchoring myoblasts to the muscle basement membrane. Interestingly, collagen VI myopathies present with restrictive respiratory insufficiency, thought to be due primarily to thoracic muscular weakening. Although it was recently recognized as one of the (if not the) most abundant collagens in the mammalian lung, there is a substantive knowledge gap concerning its role in respiratory system development and function. A few studies have suggested that collagen VI insufficiency is associated with airway epithelial cell survival and altered lung function. Our recent work suggested collagen VI may be a genomic risk factor for chronic lung disease in premature infants. Using this as motivation, we thoroughly assessed the role of collagen VI in lung development and in lung epithelial cell biology. Here, we describe the state-of-the-art for collagen VI cell and developmental biology within the respiratory system, and reveal its essential roles in normal developmental processes and airway epithelial cell phenotype and intracellular signaling.", "pubmedLink": "" },   "34138759": { "pmid": "34138759", "title": "Surfactant protein C mutation links postnatal type 2 cell dysfunction to adult disease.", "sortKey": "2021-07-surfactant protein c", "pubDateYear": "2021", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Sitaraman S, Martin EP, Na CL, Zhao S, Green J, Deshmukh H, Perl AT, Bridges JP, Xu Y, Weaver TE", "citation": "JCI insight, 07 2021", "abstractText": "Mutations in the gene SFTPC, encoding surfactant protein C (SP-C), are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked in a familial, disease-associated SFTPC mutation, L188Q (L184Q [LQ] in mice), into the mouse Sftpc locus. Translation of the mutant proprotein, proSP-CLQ, exceeded that of proSP-CWT in neonatal alveolar type 2 epithelial cells (AT2 cells) and was associated with transient activation of oxidative stress and apoptosis, leading to impaired expansion of AT2 cells during postnatal alveolarization. Differentiation of AT2 to AT1 cells was also inhibited in ex vivo organoid culture of AT2 cells isolated from LQ mice; importantly, treatment with antioxidant promoted alveolar differentiation. Upon completion of alveolarization, SftpcLQ expression was downregulated, leading to resolution of chronic stress responses; however, the failure to restore AT2 cell numbers resulted in a permanent loss of AT2 cells that was linked to decreased regenerative capacity in the adult lung. Collectively, these data support the hypothesis that susceptibility to disease in adult LQ mice is established during postnatal lung development, and they provide a potential explanation for the delayed onset of disease in patients with familial pulmonary fibrosis.", "pubmedLink": "" },   "34127975": { "pmid": "34127975", "title": "Implicating Gene and Cell Networks Responsible for Differential COVID-19 Host Responses via an Interactive Single Cell Web Portal.", "sortKey": "2021-06-implicating gene and", "pubDateYear": "2021", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Jin K, Bardes EE, Mitelpunkt A, Wang JY, Bhatnagar S, Sengupta S, Krummel DP, Rothenberg ME, Aronow BJ", "citation": "bioRxiv : the preprint server for biology, 06 2021", "abstractText": "Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http://toppcell.cchmc.org/COVID-19). As examples, we develop three hypotheses: (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) novel platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.", "pubmedLink": "" },   "34121026": { "pmid": "34121026", "title": "Electrospun core-shell nanofibers with encapsulated enamel matrix derivative for guided periodontal tissue regeneration.", "sortKey": "2021-09-electrospun core-she", "pubDateYear": "2021", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Lam LRW, Schilling K, Romas S, Misra R, Zhou Z, Caton JG, Zhang X", "citation": "Dental materials journal, 09 2021", "abstractText": "The osteogenic effect of a composite electrospun core-shell nanofiber membrane encapsulated with Emdogain (EMD) was evaluated. The membrane was developed through coaxial electrospinning using polycaprolactone as the shell and polyethylene glycol as the core. The effects of the membrane on the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) were examined using Alizarin Red S staining and qRT-PCR. Characterization of the nanofiber membrane demonstrated core-shell morphology with a mean diameter of ~1 µm. Examination of the release of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) from core-shell nanofibers over a 22-day period showed improved release profile of encapsulated proteins as compared to solid nanofibers. When cultured on EMD-containing core-shell nanofibers, PDLSCs showed significantly improved osteogenic differentiation with increased Alizarin Red S staining and enhanced osteogenic gene expression, namely OCN, RUNX2, ALP, and OPN. Core-shell nanofiber membranes may improve outcomes in periodontal regenerative therapy through simultaneous mechanical barrier and controlled drug delivery function.", "pubmedLink": "" },   "34115127": { "pmid": "34115127", "title": "International Analysis of Electronic Health Records of Children and Youth Hospitalized With COVID-19 Infection in 6 Countries.", "sortKey": "2021-06-international analys", "pubDateYear": "2021", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Bourgeois FT, Gutiérrez-Sacristán A, Keller MS, Liu M, Hong C, Bonzel CL, Tan ALM, Aronow BJ, Boeker M, Booth J, Cruz Rojo J, Devkota B, García Barrio N, Gehlenborg N, Geva A, Hanauer DA, Hutch MR, Issitt RW, Klann JG, Luo Y, Mandl KD, Mao C, Moal B, Moshal KL, Murphy SN, Neuraz A, Ngiam KY, Omenn GS, Patel LP, Jiménez MP, Sebire NJ, Balazote PS, Serret-Larmande A, South AM, Spiridou A, Taylor DM, Tippmann P, Visweswaran S, Weber GM, Kohane IS, Cai T, Avillach P,  ", "citation": "JAMA network open, 06 2021", "abstractText": "Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients.", "pubmedLink": "" },   "34101541": { "pmid": "34101541", "title": "Heterogeneity in Human Induced Pluripotent Stem Cell-derived Alveolar Epithelial Type II Cells Revealed with ABCA3/SFTPC Reporters.", "sortKey": "2021-10-heterogeneity in hum", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Sun YL, Hurley K, Villacorta-Martin C, Huang J, Hinds A, Gopalan K, Caballero IS, Russo SJ, Kitzmiller JA, Whitsett JA, Beers MF, Kotton DN", "citation": "American journal of respiratory cell and molecular biology, 10 2021", "abstractText": "Alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, are typically identified through the use of the canonical markers, SFTPC and ABCA3. Self-renewing AEC2-like cells have been generated from human induced pluripotent stem cells (iPSCs) through the use of knock-in SFTPC fluorochrome reporters. However, developmentally, SFTPC expression onset begins in the fetal distal lung bud tip and thus is not specific to mature AEC2s. Furthermore, SFTPC reporters appear to identify only those iPSC-derived AEC2s (iAEC2s) expressing the highest SFTPC levels. Here, we generate an ABCA3 knock-in GFP fusion reporter (ABCA3:GFP) that enables the purification of iAEC2s while allowing visualization of lamellar bodies, organelles associated with AEC2 maturation. Using an SFTPC and ABCA3:GFP bifluorescent line for  distal lung-directed differentiation, we observe later onset of ABCA3:GFP expression and broader identification of the subsequently emerging iAEC2 population based on ABCA3:GFP expression compared with SFTPC expression. Comparing ABCA3:GFP/SFTPC double-positive with ABCA3:GFP single-positive (SP) cells by RNA sequencing and functional studies reveals iAEC2 cellular heterogeneity with both populations functionally processing surfactant proteins but the SP cells exhibiting faster growth kinetics, increased clonogenicity, increased expression of progenitor markers, lower levels of SFTPC expression, and lower levels of AEC2 maturation markers. Over time, we observe that each population (double-positive and SP) gives rise to the other and each can serve as the parents of indefinitely self-renewing iAEC2 progeny. Our results indicate that iAEC2s are a heterogeneous population of cells with differing proliferation versus maturation properties, the majority of which can be tracked and purified using the ABCA3:GFP reporter or surrogate cell surface proteins, such as SLC34A2 and CPM.", "pubmedLink": "" },   "34091802": { "pmid": "34091802", "title": "Interpreting the lipidome: bioinformatic approaches to embrace the complexity.", "sortKey": "2021-06-interpreting the lip", "pubDateYear": "2021", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Kyle JE, Aimo L, Bridge AJ, Clair G, Fedorova M, Helms JB, Molenaar MR, Ni Z, Orešič M, Slenter D, Willighagen E, Webb-Robertson BM", "citation": "Metabolomics : Official journal of the Metabolomic Society, 06 2021", "abstractText": "Improvements in mass spectrometry (MS) technologies coupled with bioinformatics developments have allowed considerable advancement in the measurement and interpretation of lipidomics data in recent years. Since research areas employing lipidomics are rapidly increasing, there is a great need for bioinformatic tools that capture and utilize the complexity of the data. Currently, the diversity and complexity within the lipidome is often concealed by summing over or averaging individual lipids up to (sub)class-based descriptors, losing valuable information about biological function and interactions with other distinct lipids molecules, proteins and/or metabolites.", "pubmedLink": "" },   "34049947": { "pmid": "34049947", "title": "Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis.", "sortKey": "2021-12-fibroblasts positive", "pubDateYear": "2021", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Nakahara Y, Hashimoto N, Sakamoto K, Enomoto A, Adams TS, Yokoi T, Omote N, Poli S, Ando A, Wakahara K, Suzuki A, Inoue M, Hara A, Mizutani Y, Imaizumi K, Kawabe T, Rosas IO, Takahashi M, Kaminski N, Hasegawa Y", "citation": "The European respiratory journal, 12 2021", "abstractText": "The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.scRNA-seq combined with  RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts  the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution.These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.", "pubmedLink": "" },   "34010630": { "pmid": "34010630", "title": "VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.", "sortKey": "2021-06-vegf receptor 2 (kdr", "pubDateYear": "2021", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Jiang M, Fang Y, Li Y, Huang H, Wei Z, Gao X, Sung HK, Hu J, Qiang L, Ruan J, Chen Q, Jiang D, Whitsett JA, Ai X, Que J", "citation": "Developmental cell, 06 2021", "abstractText": "Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.", "pubmedLink": "" },   "33980985": { "pmid": "33980985", "title": "CRISPRi-mediated functional analysis of NKX2-1-binding sites in the lung.", "sortKey": "2021-05-crispri-mediated fun", "pubDateYear": "2021", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Stuart WD, Fink-Baldauf IM, Tomoshige K, Guo M, Maeda Y", "citation": "Communications biology, 05 2021", "abstractText": "The transcription factor NKX2-1/TTF-1 is involved in lung pathophysiology, including breathing, innate defense and tumorigenesis. To understand the mechanism by which NKX2-1 regulates genes involved in such pathophysiology, we have previously performed ChIP-seq and identified genome-wide NKX2-1-binding sites, which revealed that NKX2-1 binds to not only proximal promoter regions but also multiple intra- and inter-genic regions of the genes regulated by NKX2-1. However, the roles of such regions, especially non-proximal ones, bound by NKX2-1 have not yet been determined. Here, using CRISPRi (CRISPR/dCas9-KRAB), we scrutinize the functional roles of 19 regions/sites bound by NKX2-1, which are located in genes involved in breathing and innate defense (SFTPB, LAMP3, SFTPA1, SFTPA2) and lung tumorigenesis (MYBPH, LMO3, CD274/PD-L1). Notably, the CRISPRi approach reveals that a portion of NKX2-1-binding sites are functionally indispensable while the rest are dispensable for the expression of the genes, indicating that functional roles of NKX2-1-binding sites are unequally yoked.", "pubmedLink": "" },   "33979629": { "pmid": "33979629", "title": "Alveolar epithelial cell fate is maintained in a spatially restricted manner to promote lung regeneration after acute injury.", "sortKey": "2021-05-alveolar epithelial ", "pubDateYear": "2021", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Liberti DC, Kremp MM, Liberti WA, Penkala IJ, Li S, Zhou S, Morrisey EE", "citation": "Cell reports, 05 2021", "abstractText": "Alveolar epithelial type 2 (AT2) cells integrate signals from multiple molecular pathways to proliferate and differentiate to drive regeneration of the lung alveolus. Utilizing in vivo genetic and ex vivo organoid models, we investigated the role of Fgfr2 signaling in AT2 cells across the lifespan and during adult regeneration after influenza infection. We show that, although dispensable for adult homeostasis, Fgfr2 restricts AT2 cell fate during postnatal lung development. Using an unbiased computational imaging approach, we demonstrate that Fgfr2 promotes AT2 cell proliferation and restrains differentiation in actively regenerating areas after injury. Organoid assays reveal that Fgfr2-deficient AT2 cells remain competent to respond to multiple parallel proliferative inputs. Moreover, genetic blockade of AT2 cell cytokinesis demonstrates that cell division and differentiation are uncoupled during alveolar regeneration. These data reveal that Fgfr2 maintains AT2 cell fate, balancing proliferation and differentiation during lung alveolar regeneration.", "pubmedLink": "" },   "33974915": { "pmid": "33974915", "title": "Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration.", "sortKey": "2021-10-age-dependent alveol", "pubDateYear": "2021", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Penkala IJ, Liberti DC, Pankin J, Sivakumar A, Kremp MM, Jayachandran S, Katzen J, Leach JP, Windmueller R, Stolz K, Morley MP, Babu A, Zhou S, Frank DB, Morrisey EE", "citation": "Cell stem cell, 10 2021", "abstractText": "Regeneration of the architecturally complex alveolar niche of the lung requires precise temporal and spatial control of epithelial cell behavior. Injury can lead to a permanent reduction in gas exchange surface area and respiratory function. Using mouse models, we show that alveolar type 1 (AT1) cell plasticity is a major and unappreciated mechanism that drives regeneration, beginning in the early postnatal period during alveolar maturation. Upon acute neonatal lung injury, AT1 cells reprogram into alveolar type 2 (AT2) cells, promoting alveolar regeneration. In contrast, the ability of AT2 cells to regenerate AT1 cells is restricted to the mature lung. Unbiased genomic assessment reveals that this previously unappreciated level of plasticity is governed by the preferential activity of Hippo signaling in the AT1 cell lineage. Thus, cellular plasticity is a temporally acquired trait of the alveolar epithelium and presents an alternative mode of tissue regeneration in the postnatal lung.", "pubmedLink": "" },   "33883249": { "pmid": "33883249", "title": "Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.", "sortKey": "2022-01-sphingosine kinase 1", "pubDateYear": "2022", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Ha AW, Bai T, Ebenezer DL, Sethi T, Sudhadevi T, Mangio LA, Garzon S, Pryhuber GS, Natarajan V, Harijith A", "citation": "Thorax, 01 2022", "abstractText": "Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.", "pubmedLink": "" },   "33811184": { "pmid": "33811184", "title": "SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes.", "sortKey": "2021-04-sars-cov-2 induces d", "pubDateYear": "2021", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Li Y, Renner DM, Comar CE, Whelan JN, Reyes HM, Cardenas-Diaz FL, Truitt R, Tan LH, Dong B, Alysandratos KD, Huang J, Palmer JN, Adappa ND, Kohanski MA, Kotton DN, Silverman RH, Yang W, Morrisey EE, Cohen NA, Weiss SR", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 04 2021", "abstractText": "Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in  knockout A549 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in  knockout A549 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.", "pubmedLink": "" },   "33799761": { "pmid": "33799761", "title": "Genetic Testing for Neonatal Respiratory Disease.", "sortKey": "2021-03-genetic testing for ", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Nogee LM, Ryan RM", "citation": "Children (Basel, Switzerland), 03 2021", "abstractText": "Genetic mechanisms are now recognized as rare causes of neonatal lung disease. Genes potentially responsible for neonatal lung disease include those encoding proteins important in surfactant function and metabolism, transcription factors important in lung development, proteins involved in ciliary assembly and function, and various other structural and immune regulation genes. The phenotypes of infants with genetic causes of neonatal lung disease may have some features that are difficult to distinguish clinically from more common, reversible causes of lung disease, and from each other. Multigene panels are now available that can allow for a specific diagnosis, providing important information for treatment and prognosis. This review discusses genes in which abnormalities are known to cause neonatal lung disease and their associated phenotypes, and advantages and limitations of genetic testing.", "pubmedLink": "" },   "33767374": { "pmid": "33767374", "title": "Adiponectin ameliorates hyperoxia-induced lung endothelial dysfunction and promotes angiogenesis in neonatal mice.", "sortKey": "2022-02-adiponectin ameliora", "pubDateYear": "2022", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Shah D, Sandhu K, Das P, Bhandari V", "citation": "Pediatric research, 02 2022", "abstractText": "Bronchopulmonary dysplasia (BPD) is a common respiratory disease of preterm infants. Lower circulatory/intrapulmonary levels of the adipokine, adiponectin (APN), occur in premature and small-for-gestational-age infants and at saccular/alveolar stages of lung development in the newborn rat. However, the role of low intrapulmonary APN during hyperoxia exposure in developing lungs is unknown.", "pubmedLink": "" },   "33744877": { "pmid": "33744877", "title": "Commentary on the Truncated Splice Variant of the GM-CSF Receptor Beta-Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns.", "sortKey": "2021-00-commentary on the tr", "pubDateYear": "2021", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Whitsett JA, Jobe AH", "citation": "Neonatology, 00 2021", "pubmedLink": "" },   "33707239": { "pmid": "33707239", "title": "Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus.", "sortKey": "2021-03-genomic, epigenomic,", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Zepp JA, Morley MP, Loebel C, Kremp MM, Chaudhry FN, Basil MC, Leach JP, Liberti DC, Niethamer TK, Ying Y, Jayachandran S, Babu A, Zhou S, Frank DB, Burdick JA, Morrisey EE", "citation": "Science (New York, N.Y.), 03 2021", "abstractText": "The lung alveolus is the functional unit of the respiratory system required for gas exchange. During the transition to air breathing at birth, biophysical forces are thought to shape the emerging tissue niche. However, the intercellular signaling that drives these processes remains poorly understood. Applying a multimodal approach, we identified alveolar type 1 (AT1) epithelial cells as a distinct signaling hub. Lineage tracing demonstrates that AT1 progenitors align with receptive, force-exerting myofibroblasts in a spatial and temporal manner. Through single-cell chromatin accessibility and pathway expression (SCAPE) analysis, we demonstrate that AT1-restricted ligands are required for myofibroblasts and alveolar formation. These studies show that the alignment of cell fates, mediated by biophysical and AT1-derived paracrine signals, drives the extensive tissue remodeling required for postnatal respiration.", "pubmedLink": "" },   "33705684": { "pmid": "33705684", "title": "Generation of Pulmonary Endothelial Progenitor Cells for Cell-based Therapy Using Interspecies Mouse-Rat Chimeras.", "sortKey": "2021-08-generation of pulmon", "pubDateYear": "2021", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Wang G, Wen B, Ren X, Li E, Zhang Y, Guo M, Xu Y, Whitsett JA, Kalin TV, Kalinichenko VV", "citation": "American journal of respiratory and critical care medicine, 08 2021", "abstractText": " Although pulmonary endothelial progenitor cells (EPCs) hold promise for cell-based therapies for neonatal pulmonary disorders, whether EPCs can be derived from pluripotent embryonic stem cells (ESCs) or induced pluripotent stem cells remains unknown. To investigate the heterogeneity of pulmonary EPCs and derive functional EPCs from pluripotent ESCs. Single-cell RNA sequencing of neonatal human and mouse lung was used to identify the heterogeneity of pulmonary EPCs. CRISPR/Cas9 gene editing was used to genetically label and purify mouse pulmonary EPCs. Functional properties of the EPCs were assessed after cell transplantation into neonatal mice with  mutation, a mouse model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interspecies mouse-rat chimeras were produced through blastocyst complementation to generate EPCs from pluripotent ESCs for cell therapy in ACDMPV mice. We identified a unique population of EPCs, FOXF1cKIT EPCs, as a subset of recently described general capillary cells (gCAPs) expressing SMAD7, ZBTB20, NFIA, and DLL4 but lacking mature arterial, venous, and lymphatic markers. FOXF1cKIT gCAPs are reduced in ACDMPV, and their transcriptomic signature is conserved in mouse and human lungs. After cell transplantation into the neonatal circulation of ACDMPV mice, FOXF1cKIT gCAPs engraft into the pulmonary vasculature, stimulate angiogenesis, improve oxygenation, and prevent alveolar simplification. FOXF1cKIT gCAPs, produced from ESCs in interspecies chimeras, are fully competent to stimulate neonatal lung angiogenesis and alveolarization in ACDMPV mice. Cell-based therapy using donor or ESC/induced pluripotent stem cell-derived FOXF1cKIT endothelial progenitors may be considered for treatment of human ACDMPV.", "pubmedLink": "" },   "33683204": { "pmid": "33683204", "title": "SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung.", "sortKey": "2021-03-sars-cov-2 suppresse", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Mast AE, Wolberg AS, Gailani D, Garvin MR, Alvarez C, Miller JI, Aronow B, Jacobson D", "citation": "eLife, 03 2021", "abstractText": "Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein-kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.", "pubmedLink": "" },   "33654293": { "pmid": "33654293", "title": "Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.", "sortKey": "2021-03-single-cell meta-ana", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Muus C, Luecken MD, Eraslan G, Sikkema L, Waghray A, Heimberg G, Kobayashi Y, Vaishnav ED, Subramanian A, Smillie C, Jagadeesh KA, Duong ET, Fiskin E, Torlai Triglia E, Ansari M, Cai P, Lin B, Buchanan J, Chen S, Shu J, Haber AL, Chung H, Montoro DT, Adams T, Aliee H, Allon SJ, Andrusivova Z, Angelidis I, Ashenberg O, Bassler K, Bécavin C, Benhar I, Bergenstråhle J, Bergenstråhle L, Bolt L, Braun E, Bui LT, Callori S, Chaffin M, Chichelnitskiy E, Chiou J, Conlon TM, Cuoco MS, Cuomo ASE, Deprez M, Duclos G, Fine D, Fischer DS, Ghazanfar S, Gillich A, Giotti B, Gould J, Guo M, Gutierrez AJ, Habermann AC, Harvey T, He P, Hou X, Hu L, Hu Y, Jaiswal A, Ji L, Jiang P, Kapellos TS, Kuo CS, Larsson L, Leney-Greene MA, Lim K, Litviňuková M, Ludwig LS, Lukassen S, Luo W, Maatz H, Madissoon E, Mamanova L, Manakongtreecheep K, Leroy S, Mayr CH, Mbano IM, McAdams AM, Nabhan AN, Nyquist SK, Penland L, Poirion OB, Poli S, Qi C, Queen R, Reichart D, Rosas I, Schupp JC, Shea CV, Shi X, Sinha R, Sit RV, Slowikowski K, Slyper M, Smith NP, Sountoulidis A, Strunz M, Sullivan TB, Sun D, Talavera-López C, Tan P, Tantivit J, Travaglini KJ, Tucker NR, Vernon KA, Wadsworth MH, Waldman J, Wang X, Xu K, Yan W, Zhao W, Ziegler CGK,  ,  ", "citation": "Nature medicine, 03 2021", "abstractText": "Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2TMPRSS2 cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.", "pubmedLink": "" },   "33624948": { "pmid": "33624948", "title": "Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration.", "sortKey": "2021-07-resident interstitia", "pubDateYear": "2021", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Ushakumary MG, Riccetti M, Perl AT", "citation": "Stem cells translational medicine, 07 2021", "abstractText": "Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.", "pubmedLink": "" },   "33622235": { "pmid": "33622235", "title": "Ontology-guided segmentation and object identification for developmental mouse lung immunofluorescent images.", "sortKey": "2021-02-ontology-guided segm", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Masci AM, White S, Neely B, Ardini-Polaske M, Hill CB, Misra RS, Aronow B, Gaddis N, Yang L, Wert SE, Palmer SM, Chan C,  ", "citation": "BMC bioinformatics, 02 2021", "abstractText": "Immunofluorescent confocal microscopy uses labeled antibodies as probes against specific macromolecules to discriminate between multiple cell types. For images of the developmental mouse lung, these cells are themselves organized into densely packed higher-level anatomical structures. These types of images can be challenging to segment automatically for several reasons, including the relevance of biomedical context, dependence on the specific set of probes used, prohibitive cost of generating labeled training data, as well as the complexity and dense packing of anatomical structures in the image. The use of an application ontology helps surmount these challenges by combining image data with its metadata to provide a meaningful biological context, modeled after how a human expert would make use of contextual information to identify histological structures, that constrains and simplifies the process of segmentation and object identification.", "pubmedLink": "" },   "33599610": { "pmid": "33599610", "title": "Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease.", "sortKey": "2021-02-short-term exposure ", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Wu G, Lee YY, Gulla EM, Potter A, Kitzmiller J, Ruben MD, Salomonis N, Whitsett JA, Francey LJ, Hogenesch JB, Smith DF", "citation": "eLife, 02 2021", "abstractText": "Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up- and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.", "pubmedLink": "" },   "33596914": { "pmid": "33596914", "title": "MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha.", "sortKey": "2021-02-microrna 219-5p inhi", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Freeman A, Qiao L, Olave N, Rezonzew G, Gentle S, Halloran B, Pryhuber GS, Gaggar A, Tipple TE, Ambalavanan N, Lal CV", "citation": "Respiratory research, 02 2021", "abstractText": "MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD).", "pubmedLink": "" },   "33591952": { "pmid": "33591952", "title": "IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis.", "sortKey": "2021-03-igf1r controls mecha", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "He H, Snowball J, Sun F, Na CL, Whitsett JA", "citation": "JCI insight, 03 2021", "abstractText": "Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r. Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.", "pubmedLink": "" },   "33568812": { "pmid": "33568812", "title": "In situ mapping identifies distinct vascular niches for myelopoiesis.", "sortKey": "2021-02-in situ mapping iden", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Zhang J, Wu Q, Johnson CB, Pham G, Kinder JM, Olsson A, Slaughter A, May M, Weinhaus B, D'Alessandro A, Engel JD, Jiang JX, Kofron JM, Huang LF, Prasath VBS, Way SS, Salomonis N, Grimes HL, Lucas D", "citation": "Nature, 02 2021", "abstractText": "In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF). Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.", "pubmedLink": "" },   "33564777": { "pmid": "33564777", "title": "International Comparisons of Harmonized Laboratory Value Trajectories to Predict Severe COVID-19: Leveraging the 4CE Collaborative Across 342 Hospitals and 6 Countries: A Retrospective Cohort Study.", "sortKey": "2021-02-international compar", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Weber GM, Hong C, Palmer NP, Avillach P, Murphy SN, Gutiérrez-Sacristán A, Xia Z, Serret-Larmande A, Neuraz A, Omenn GS, Visweswaran S, Klann JG, South AM, Loh NHW, Cannataro M, Beaulieu-Jones BK, Bellazzi R, Agapito G, Alessiani M, Aronow BJ, Bell DS, Bellasi A, Benoit V, Beraghi M, Boeker M, Booth J, Bosari S, Bourgeois FT, Brown NW, Bucalo M, Chiovato L, Chiudinelli L, Dagliati A, Devkota B, DuVall SL, Follett RW, Ganslandt T, García Barrio N, Gradinger T, Griffier R, Hanauer DA, Holmes JH, Horki P, Huling KM, Issitt RW, Jouhet V, Keller MS, Kraska D, Liu M, Luo Y, Lynch KE, Malovini A, Mandl KD, Mao C, Maram A, Matheny ME, Maulhardt T, Mazzitelli M, Milano M, Moore JH, Morris JS, Morris M, Mowery DL, Naughton TP, Ngiam KY, Norman JB, Patel LP, Pedrera Jimenez M, Ramoni RB, Schriver ER, Scudeller L, Sebire NJ, Serrano Balazote P, Spiridou A, Tan AL, Tan BW, Tibollo V, Torti C, Trecarichi EM, Vitacca M, Zambelli A, Zucco C,  , Kohane IS, Cai T, Brat GA", "citation": "medRxiv : the preprint server for health sciences, 02 2021", "abstractText": "To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions.", "pubmedLink": "" },   "33552042": { "pmid": "33552042", "title": "Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia.", "sortKey": "2020-00-lymphocyte-specific ", "pubDateYear": "2020", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Bhattacharya S, Mereness JA, Baran AM, Misra RS, Peterson DR, Ryan RM, Reynolds AM, Pryhuber GS, Mariani TJ", "citation": "Frontiers in immunology, 00 2020", "abstractText": "Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of , and -associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in  signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.", "pubmedLink": "" },   "33507880": { "pmid": "33507880", "title": "Neonatal hyperoxia inhibits proliferation and survival of atrial cardiomyocytes by suppressing fatty acid synthesis.", "sortKey": "2021-03-neonatal hyperoxia i", "pubDateYear": "2021", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Cohen ED, Yee M, Porter GA, Ritzer E, McDavid AN, Brookes PS, Pryhuber GS, O'Reilly MA", "citation": "JCI insight, 03 2021", "abstractText": "Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.", "pubmedLink": "" },   "33479039": { "pmid": "33479039", "title": "Pretreatment of aged mice with retinoic acid supports alveolar regeneration via upregulation of reciprocal PDGFA signalling.", "sortKey": "2021-05-pretreatment of aged", "pubDateYear": "2021", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Gokey JJ, Snowball J, Green J, Waltamath M, Spinney JJ, Black KE, Hariri LP, Xu Y, Perl AK", "citation": "Thorax, 05 2021", "abstractText": "Idiopathic pulmonary fibrosis (IPF) primarily affects the aged population and is characterised by failure of alveolar regeneration, leading to loss of alveolar type 1 (AT1) cells. Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein, we seek to determine the signalling mechanisms that become activated on RA treatment prior to injury, which support alveolar differentiation.", "pubmedLink": "" },   "33398286": { "pmid": "33398286", "title": "DeepImmuno: Deep learning-empowered prediction and generation of immunogenic peptides for T cell immunity.", "sortKey": "2020-12-deepimmuno: deep lea", "pubDateYear": "2020", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Li G, Iyer B, Prasath VBS, Ni Y, Salomonis N", "citation": "bioRxiv : the preprint server for biology, 12 2020", "abstractText": "T-cells play an essential role in the adaptive immune system by seeking out, binding and destroying foreign antigens presented on the cell surface of diseased cells. An improved understanding of T-cell immunity will greatly aid in the development of new cancer immunotherapies and vaccines for life threatening pathogens. Central to the design of such targeted therapies are computational methods to predict non-native epitopes to elicit a T cell response, however, we currently lack accurate immunogenicity inference methods. Another challenge is the ability to accurately simulate immunogenic peptides for specific human leukocyte antigen (HLA) alleles, for both synthetic biological applications and to augment real training datasets. Here, we proposed a beta-binomial distribution approach to derive epitope immunogenic potential from sequence alone. We conducted systematic benchmarking of five traditional machine learning (ElasticNet, KNN, SVM, Random Forest, AdaBoost) and three deep learning models (CNN, ResNet, GNN) using three independent prior validated immunogenic peptide collections (dengue virus, cancer neoantigen and SARS-Cov-2). We chose the CNN model as the best prediction model based on its adaptivity for small and large datasets, and performance relative to existing methods. In addition to outperforming two highly used immunogenicity prediction algorithms, DeepHLApan and IEDB, DeepImmuno-CNN further correctly predicts which residues are most important for T cell antigen recognition. Our independent generative adversarial network (GAN) approach, DeepImmuno-GAN, was further able to accurately simulate immunogenic peptides with physiochemical properties and immunogenicity predictions similar to that of real antigens. We provide DeepImmuno-CNN as source code and an easy-to-use web interface.", "pubmedLink": "" },   "33385216": { "pmid": "33385216", "title": "Lung Gene Expression Analysis Web Portal Version 3: Lung-at-a-Glance.", "sortKey": "2021-01-lung gene expression", "pubDateYear": "2021", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Du Y, Ouyang W, Kitzmiller JA, Guo M, Zhao S, Whitsett JA, Xu Y", "citation": "American journal of respiratory cell and molecular biology, 01 2021", "pubmedLink": "" },   "33290275": { "pmid": "33290275", "title": "MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease.", "sortKey": "2021-01-microrna mir-24-3p r", "pubDateYear": "2021", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Nouws J, Wan F, Finnemore E, Roque W, Kim SJ, Bazan I, Li CX, Skold CM, Dai Q, Yan X, Chioccioli M, Neumeister V, Britto CJ, Sweasy J, Bindra R, Wheelock ÅM, Gomez JL, Kaminski N, Lee PJ, Sauler M", "citation": "JCI insight, 01 2021", "abstractText": "The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.", "pubmedLink": "" },   "33259812": { "pmid": "33259812", "title": "Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.", "sortKey": "2020-12-actionable cytopatho", "pubDateYear": "2020", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, Emili A", "citation": "Molecular cell, 12 2020", "abstractText": "Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.", "pubmedLink": "" },   "33214719": { "pmid": "33214719", "title": "Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19.", "sortKey": "2021-01-leukocyte traffickin", "pubDateYear": "2021", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly EC, Zarbock A, Garbi N, Topham DJ", "citation": "Nature reviews. Immunology, 01 2021", "abstractText": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.", "pubmedLink": "" },   "33188371": { "pmid": "33188371", "title": "Guidelines for reporting single-cell RNA-seq experiments.", "sortKey": "2020-12-guidelines for repor", "pubDateYear": "2020", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Füllgrabe A, George N, Green M, Nejad P, Aronow B, Fexova SK, Fischer C, Freeberg MA, Huerta L, Morrison N, Scheuermann RH, Taylor D, Vasilevsky N, Clarke L, Gehlenborg N, Kent J, Marioni J, Teichmann S, Brazma A, Papatheodorou I", "citation": "Nature biotechnology, 12 2020", "pubmedLink": "" },   "33176330": { "pmid": "33176330", "title": "Alveolar Airspace Size in Healthy and Diseased Infant Lungs Measured via Hyperpolarized 3He Gas Diffusion Magnetic Resonance Imaging.", "sortKey": "2020-00-alveolar airspace si", "pubDateYear": "2020", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Higano NS, Thomen RP, Quirk JD, Huyck HL, Hahn AD, Fain SB, Pryhuber GS, Woods JC", "citation": "Neonatology, 00 2020", "abstractText": "Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants.", "pubmedLink": "" },   "33164753": { "pmid": "33164753", "title": "Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.", "sortKey": "2020-11-single-cell multiomi", "pubDateYear": "2020", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Wang A, Chiou J, Poirion OB, Buchanan J, Valdez MJ, Verheyden JM, Hou X, Kudtarkar P, Narendra S, Newsome JM, Guo M, Faddah DA, Zhang K, Young RE, Barr J, Sajti E, Misra R, Huyck H, Rogers L, Poole C, Whitsett JA, Pryhuber G, Xu Y, Gaulton KJ, Preissl S, Sun X,  ", "citation": "eLife, 11 2020", "abstractText": "Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate -regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene  in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to , a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.", "pubmedLink": "" },   "33159078": { "pmid": "33159078", "title": "mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline.", "sortKey": "2020-11-mtorc1 activation in", "pubDateYear": "2020", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Obraztsova K, Basil MC, Rue R, Sivakumar A, Lin SM, Mukhitov AR, Gritsiuta AI, Evans JF, Kopp M, Katzen J, Robichaud A, Atochina-Vasserman EN, Li S, Carl J, Babu A, Morley MP, Cantu E, Beers MF, Frank DB, Morrisey EE, Krymskaya VP", "citation": "Nature communications, 11 2020", "abstractText": "Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2-deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype.", "pubmedLink": "" },   "33098807": { "pmid": "33098807", "title": "Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells.", "sortKey": "2021-01-derivation of airway", "pubDateYear": "2021", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Hawkins FJ, Suzuki S, Beermann ML, Barillà C, Wang R, Villacorta-Martin C, Berical A, Jean JC, Le Suer J, Matte T, Simone-Roach C, Tang Y, Schlaeger TM, Crane AM, Matthias N, Huang SXL, Randell SH, Wu J, Spence JR, Carraro G, Stripp BR, Rab A, Sorsher EJ, Horani A, Brody SL, Davis BR, Kotton DN", "citation": "Cell stem cell, 01 2021", "abstractText": "The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed differentiation of human iPSCs into airway basal cells ( iBCs ), a population resembling the stem cell of the airway epithelium. Using a dual fluorescent reporter system (NKX2-1;TP63), we track and purify these cells as they first emerge as developmentally immature NKX2-1 lung progenitors and subsequently augment a TP63 program during proximal airway epithelial patterning. In response to primary basal cell medium, NKX2-1/TP63 cells display the molecular and functional phenotype of airway basal cells, including the capacity to self-renew or undergo multi-lineage differentiation in vitro and in tracheal xenografts in vivo. iBCs and their differentiated progeny model perturbations that characterize acquired and genetic airway diseases, including the mucus metaplasia of asthma, chloride channel dysfunction of cystic fibrosis, and ciliary defects of primary ciliary dyskinesia.", "pubmedLink": "" },   "33074772": { "pmid": "33074772", "title": "Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration.", "sortKey": "2021-02-epithelial stem and ", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Alysandratos KD, Herriges MJ, Kotton DN", "citation": "Annual review of physiology, 02 2021", "abstractText": "The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult lung homeostasis, a growing body of literature has demonstrated the capacity of these epithelial lineages to proliferate in response to injury and regenerate lost or damaged cells. In this review, we focus on the regionally distinct lung epithelial cell types that contribute to repair after injury, and we address current controversies regarding whether elite stem cells or frequent facultative progenitors are the predominant participants. We also shed light on the newly emerging approaches for exogenously generating similar lung epithelial lineages from pluripotent stem cells.", "pubmedLink": "" },   "33052459": { "pmid": "33052459", "title": "Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice.", "sortKey": "2021-01-hypothalamic mc4r re", "pubDateYear": "2021", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "de Souza Cordeiro LM, Elsheikh A, Devisetty N, Morgan DA, Ebert SN, Rahmouni K, Chhabra KH", "citation": "Diabetologia, 01 2021", "abstractText": "Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice.", "pubmedLink": "" },   "32995797": { "pmid": "32995797", "title": "SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial derived cells and cardiomyocytes.", "sortKey": "2020-11-sars-cov-2 induces d", "pubDateYear": "2020", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Li Y, Renner DM, Comar CE, Whelan JN, Reyes HM, Cardenas-Diaz FL, Truitt R, Tan LH, Dong B, Alysandratos KD, Huang J, Palmer JN, Adappa ND, Kohanski MA, Kotton DN, Silverman RH, Yang W, Morrisey E, Cohen NA, Weiss SR", "citation": "bioRxiv : the preprint server for biology, 11 2020", "abstractText": "Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection, induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung, and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, while PKR activation is evident in iAT2 and iCM. In SARS-CoV-2 infected Calu-3 and A549  lung-derived cell lines, IFN induction remains relatively weak; however activation of OAS-RNase L and PKR is observed. This is in contrast to MERS-CoV, which effectively inhibits IFN signaling as well as OAS-RNase L and PKR pathways, but similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, both OAS-RNase L and PKR are activated in  knockout A549  cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in  knockout A549  cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.", "pubmedLink": "" },   "32989251": { "pmid": "32989251", "title": "STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury.", "sortKey": "2020-10-stat3-bdnf-trkb sign", "pubDateYear": "2020", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Paris AJ, Hayer KE, Oved JH, Avgousti DC, Toulmin SA, Zepp JA, Zacharias WJ, Katzen JB, Basil MC, Kremp MM, Slamowitz AR, Jayachandran S, Sivakumar A, Dai N, Wang P, Frank DB, Eisenlohr LC, Cantu E, Beers MF, Weitzman MD, Morrisey EE, Worthen GS", "citation": "Nature cell biology, 10 2020", "abstractText": "Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3-BDNF-TrkB axis in orchestrating alveolar epithelial regeneration.", "pubmedLink": "" },   "32979316": { "pmid": "32979316", "title": "SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response.", "sortKey": "2020-12-sars-cov-2 infection", "pubDateYear": "2020", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Huang J, Hume AJ, Abo KM, Werder RB, Villacorta-Martin C, Alysandratos KD, Beermann ML, Simone-Roach C, Lindstrom-Vautrin J, Olejnik J, Suder EL, Bullitt E, Hinds A, Sharma A, Bosmann M, Wang R, Hawkins F, Burks EJ, Saeed M, Wilson AA, Mühlberger E, Kotton DN", "citation": "Cell stem cell, 12 2020", "abstractText": "A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.", "pubmedLink": "" },   "32926149": { "pmid": "32926149", "title": "Airway Gene Expression Correlates of Respiratory Syncytial Virus Disease Severity and Microbiome Composition in Infants.", "sortKey": "2021-05-airway gene expressi", "pubDateYear": "2021", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Chu CY, Qiu X, McCall MN, Wang L, Corbett A, Holden-Wiltse J, Slaunwhite C, Grier A, Gill SR, Pryhuber GS, Falsey AR, Topham DJ, Caserta MT, Walsh EE, Mariani TJ", "citation": "The Journal of infectious diseases, 05 2021", "abstractText": "Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. The causes and correlates of severe illness in the majority of infants are poorly defined.", "pubmedLink": "" },   "32891189": { "pmid": "32891189", "title": "Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.", "sortKey": "2020-10-organoids model tran", "pubDateYear": "2020", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Dost AFM, Moye AL, Vedaie M, Tran LM, Fung E, Heinze D, Villacorta-Martin C, Huang J, Hekman R, Kwan JH, Blum BC, Louie SM, Rowbotham SP, Sainz de Aja J, Piper ME, Bhetariya PJ, Bronson RT, Emili A, Mostoslavsky G, Fishbein GA, Wallace WD, Krysan K, Dubinett SM, Yanagawa J, Kotton DN, Kim CF", "citation": "Cell stem cell, 10 2020", "abstractText": "Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors.", "pubmedLink": "" },   "32878480": { "pmid": "32878480", "title": "Elevated FiO increases SARS-CoV-2 co-receptor expression in respiratory tract epithelium.", "sortKey": "2020-10-elevated fio increas", "pubDateYear": "2020", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Myti D, Gunjak M, Casado F, Khaghani Raziabad S, Nardiello C, Vadász I, Herold S, Pryhuber G, Seeger W, Morty RE", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2020", "abstractText": "The severity of coronavirus disease 2019 (COVID-19) is linked to an increasing number of risk factors, including exogenous (environmental) stimuli such as air pollution, nicotine, and cigarette smoke. These three factors increase the expression of angiotensin I converting enzyme 2 (ACE2), a key receptor involved in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the etiological agent of COVID-19-into respiratory tract epithelial cells. Patients with severe COVID-19 are managed with oxygen support, as are at-risk individuals with chronic lung disease. To date, no study has examined whether an increased fraction of inspired oxygen (FiO) may affect the expression of SARS-CoV-2 entry receptors and co-receptors, including ACE2 and the transmembrane serine proteases TMPRSS1, TMPRSS2, and TMPRSS11D. To address this, steady-state mRNA levels for genes encoding these SARS-CoV-2 receptors were assessed in the lungs of mouse pups chronically exposed to elevated FiO, and in the lungs of preterm-born human infants chronically managed with an elevated FiO. These two scenarios served as models of chronic elevated FiO exposure. Additionally, SARS-CoV-2 receptor expression was assessed in primary human nasal, tracheal, esophageal, bronchial, and alveolar epithelial cells, as well as primary mouse alveolar type II cells exposed to elevated oxygen concentrations. While gene expression of  was unaffected, gene and protein expression of  was consistently upregulated by exposure to an elevated FiO. These data highlight the need for further studies that examine the relative contribution of the various viral co-receptors on the infection cycle, and point to oxygen supplementation as a potential risk factor for COVID-19.", "pubmedLink": "" },   "32877203": { "pmid": "32877203", "title": " Generation of Lung and Thyroid Tissues from Embryonic Stem Cells Using Blastocyst Complementation.", "sortKey": "2021-02- generation of lung ", "pubDateYear": "2021", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Wen B, Li E, Ustiyan V, Wang G, Guo M, Na CL, Kalin GT, Galvan V, Xu Y, Weaver TE, Kalin TV, Whitsett JA, Kalinichenko VV", "citation": "American journal of respiratory and critical care medicine, 02 2021", "abstractText": " The regeneration and replacement of lung cells or tissues from induced pluripotent stem cell- or embryonic stem cell-derived cells represent future therapies for life-threatening pulmonary disorders but are limited by technical challenges to produce highly differentiated cells able to maintain lung function. Functional lung tissue-containing airways, alveoli, vasculature, and stroma have never been produced via directed differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells. We sought to produce all tissue components of the lung from bronchi to alveoli by embryo complementation. To determine whether ESCs are capable of generating lung tissue in  mouse embryos with lung agenesis. Blastocyst complementation was used to produce chimeras from normal mouse ESCs and  embryos, which lack pulmonary tissues.  chimeras were examined using immunostaining, transmission electronic microscopy, fluorescence-activated cell sorter analysis, and single-cell RNA sequencing. Although peripheral pulmonary and thyroid tissues are entirely lacking in  gene-deleted embryos, pulmonary and thyroid structures in  chimeras were restored after ESC complementation. Respiratory epithelial cell lineages in restored lungs of  chimeras were derived almost entirely from ESCs, whereas endothelial, immune, and stromal cells were mosaic. ESC-derived cells from multiple respiratory cell lineages were highly differentiated and indistinguishable from endogenous cells based on morphology, ultrastructure, gene expression signatures, and cell surface proteins used to identify cell types by fluorescence-activated cell sorter. Lung and thyroid tissues were generated  from ESCs by blastocyst complementation.  chimeras can be used as  bioreactors  for  differentiation and functional studies of ESC-derived progenitor cells.", "pubmedLink": "" },   "32832599": { "pmid": "32832599", "title": "Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis.", "sortKey": "2020-07-single-cell rna-seq ", "pubDateYear": "2020", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, Chu SG, Raby BA, DeIuliis G, Januszyk M, Duan Q, Arnett HA, Siddiqui A, Washko GR, Homer R, Yan X, Rosas IO, Kaminski N", "citation": "Science advances, 07 2020", "abstractText": "We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF.", "pubmedLink": "" },   "32764559": { "pmid": "32764559", "title": "A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency.", "sortKey": "2020-08-a lung tropic aav ve", "pubDateYear": "2020", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Kang MH, van Lieshout LP, Xu L, Domm JM, Vadivel A, Renesme L, Mühlfeld C, Hurskainen M, Mižíková I, Pei Y, van Vloten JP, Thomas SP, Milazzo C, Cyr-Depauw C, Whitsett JA, Nogee LM, Wootton SK, Thébaud B", "citation": "Nature communications, 08 2020", "abstractText": "Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.", "pubmedLink": "" },   "32633718": { "pmid": "32633718", "title": "A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.", "sortKey": "2020-07-a mechanistic model ", "pubDateYear": "2020", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, Mast AE, Justice A, Aronow B, Jacobson D", "citation": "eLife, 07 2020", "abstractText": "Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.", "pubmedLink": "" },   "32603599": { "pmid": "32603599", "title": "Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell.", "sortKey": "2020-11-single-cell transcri", "pubDateYear": "2020", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Guo M, Yu JJ, Perl AK, Wikenheiser-Brokamp KA, Riccetti M, Zhang EY, Sudha P, Adam M, Potter A, Kopras EJ, Giannikou K, Potter SS, Sherman S, Hammes SR, Kwiatkowski DJ, Whitsett JA, McCormack FX, Xu Y", "citation": "American journal of respiratory and critical care medicine, 11 2020", "abstractText": " Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. Identification and characterization of LAM cells in human lung and uterus using a single-cell approach. Single-cell and single-nuclei RNA sequencing on LAM ( = 4) and control ( = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAM cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM. A unique cell type termed LAM was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAM cells expressing signature genes included known LAM markers such as , , , and  and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic  mutations, supporting a potential uterine origin for the LAM cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. A unique population of LAM cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.", "pubmedLink": "" },   "32577635": { "pmid": "32577635", "title": "Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors.", "sortKey": "2020-06-human ipsc-derived a", "pubDateYear": "2020", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Abo KM, Ma L, Matte T, Huang J, Alysandratos KD, Werder RB, Mithal A, Beermann ML, Lindstrom-Vautrin J, Mostoslavsky G, Ikonomou L, Kotton DN, Hawkins F, Wilson A, Villacorta-Martin C", "citation": "bioRxiv : the preprint server for biology, 06 2020", "abstractText": "Development of an anti-SARS-CoV-2 therapeutic is hindered by the lack of physiologically relevant model systems that can recapitulate host-viral interactions in human cell types, specifically the epithelium of the lung. Here, we compare induced pluripotent stem cell (iPSC)-derived alveolar and airway epithelial cells to primary lung epithelial cell controls, focusing on expression levels of genes relevant for COVID-19 disease modeling. iPSC-derived alveolar epithelial type II-like cells (iAT2s) and iPSC-derived airway epithelial lineages express key transcripts associated with lung identity in the majority of cells produced in culture. They express  and , transcripts encoding essential host factors required for SARS-CoV-2 infection, in a minor subset of each cell sub-lineage, similar to frequencies observed in primary cells. In order to prepare human culture systems that are amenable to modeling viral infection of both the proximal and distal lung epithelium, we adapt iPSC-derived alveolar and airway epithelial cells to two-dimensional air-liquid interface cultures. These engineered human lung cell systems represent sharable, physiologically relevant platforms for SARS-CoV-2 infection modeling and may therefore expedite the development of an effective pharmacologic intervention for COVID-19.", "pubmedLink": "" },   "32533910": { "pmid": "32533910", "title": "The past and future of genetics in pulmonary disease: You can teach an old dog new tricks.", "sortKey": "2020-07-the past and future ", "pubDateYear": "2020", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Nogee LM, Hamvas A", "citation": "Pediatric pulmonology, 07 2020", "pubmedLink": "" },   "32533908": { "pmid": "32533908", "title": "Childhood rare lung disease in the 21st century:  -omics  technology advances accelerating discovery.", "sortKey": "2020-07-childhood rare lung ", "pubDateYear": "2020", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Vece TJ, Wambach JA, Hagood JS", "citation": "Pediatric pulmonology, 07 2020", "abstractText": "Childhood rare lung diseases comprise a large number of heterogeneous respiratory disorders that are individually rare but are collectively associated with substantial morbidity, mortality, and healthcare resource utilization. Although the genetic mechanisms for several of these disorders have been elucidated, the pathogenesis mechanisms for others remain poorly understood and treatment options remain limited. Childhood rare lung diseases are enriched for genetic etiologies; identification of the disease mechanisms underlying these rare disorders can inform the biology of normal human lung development and has implications for the treatment of more common respiratory diseases in children and adults. Advances in  -omics  technology, such as genomic sequencing, clinical phenotyping, biomarker discovery, genome editing, in vitro and model organism disease modeling, single-cell analyses, cellular imaging, and high-throughput drug screening have enabled significant progress for diagnosis and treatment of rare childhood lung diseases. The most striking example of this progress has been realized for patients with cystic fibrosis for whom effective, personalized therapies based on CFTR genotype are now available. In this chapter, we focus on recent technology advances in childhood rare lung diseases, acknowledge persistent challenges, and identify promising new technologies that will impact not only biological discovery, but also improve diagnosis, therapies, and survival for children with these rare disorders.", "pubmedLink": "" },   "32500120": { "pmid": "32500120", "title": "CRISPRi-mediated functional analysis of lung disease-associated loci at non-coding regions.", "sortKey": "2020-06-crispri-mediated fun", "pubDateYear": "2020", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Stuart WD, Guo M, Fink-Baldauf IM, Coleman AM, Clancy JP, Mall MA, Lim FY, Brewington JJ, Maeda Y", "citation": "NAR genomics and bioinformatics, 06 2020", "abstractText": "Genome-wide association studies have identified lung disease-associated loci; however, the functions of such loci are not well understood in part because the majority of such loci are located at non-coding regions. Hi-C, ChIP-seq and eQTL data predict potential roles (e.g. enhancer) of such loci; however, they do not elucidate the molecular function. To determine whether these loci function as gene-regulatory regions, CRISPR interference (CRISPRi; CRISPR/dCas9-KRAB) has been recently used. Here, we applied CRISPRi along with Hi-C, ChIP-seq and eQTL to determine the functional roles of loci established as highly associated with asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Notably, Hi-C, ChIP-seq and eQTL predicted that non-coding regions located at chromosome 19q13 or chromosome 17q21 harboring single-nucleotide polymorphisms (SNPs) linked to asthma/CF/COPD and chromosome 11p15 harboring an SNP linked to IPF interact with nearby genes and function as enhancers; however, CRISPRi indicated that the regions with rs1800469, rs2241712, rs12603332 and rs35705950, but not others, regulate the expression of nearby genes (single or multiple genes). These data indicate that CRISPRi is useful to precisely determine the roles of non-coding regions harboring lung disease-associated loci as to whether they function as gene-regulatory regions at a genomic level.", "pubmedLink": "" },   "32460513": { "pmid": "32460513", "title": "Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function.", "sortKey": "2020-08-glucocorticoid regul", "pubDateYear": "2020", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Bridges JP, Sudha P, Lipps D, Wagner A, Guo M, Du Y, Brown K, Filuta A, Kitzmiller J, Stockman C, Chen X, Weirauch MT, Jobe AH, Whitsett JA, Xu Y", "citation": "American journal of physiology. Lung cellular and molecular physiology, 08 2020", "abstractText": "While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene () from fetal pulmonary mesenchymal cells phenocopied defects caused by global  deletion, while lung epithelial- or endothelial-specific  deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFBs), in part by directly activating extracellular matrix-associated target genes, including , , and  and by modulating VEGF, JAK-STAT, and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFBs, which in turn increased proliferation of SOX9+ alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT) and AT cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts, in turn, regulating signals controlling AT/AT progenitor cell proliferation and differentiation and identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.", "pubmedLink": "" },   "32442602": { "pmid": "32442602", "title": "The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration.", "sortKey": "2020-09-the elephant in the ", "pubDateYear": "2020", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Riccetti M, Gokey JJ, Aronow B, Perl AT", "citation": "Matrix biology : journal of the International Society for Matrix Biology, 09 2020", "abstractText": "During lung development, the mesenchyme and epithelium are dependent on each other for instructive morphogenic cues that direct proliferation, cellular differentiation and organogenesis. Specification of epithelial and mesenchymal cell lineages occurs in parallel, forming cellular subtypes that guide the formation of both transitional developmental structures and the permanent architecture of the adult lung. While epithelial cell types and lineages have been relatively well-defined in recent years, the definition of mesenchymal cell types and lineage relationships has been more challenging. Transgenic mouse lines with permanent and inducible lineage tracers have been instrumental in identifying lineage relationships among epithelial progenitor cells and their differentiation into distinct airway and alveolar epithelial cells. Lineage tracing experiments with reporter mice used to identify fibroblast progenitors and their lineage trajectories have been limited by the number of cell specific genes and the developmental timepoint when the lineage trace was activated. In this review, we discuss major developmental mesenchymal lineages, focusing on time of origin, major cell type, and other lineage derivatives, as well as the transgenic tools used to find and define them. We describe lung fibroblasts using function, location, and molecular markers in order to compare and contrast cells with similar functions. The temporal and cell-type specific expression of fourteen  fibroblast lineage  genes were identified in single-cell RNA-sequencing data from LungMAP in the LGEA database. Using these lineage signature genes as guides, we clustered murine lung fibroblast populations from embryonic day 16.5 to postnatal day 28 (E16.5-PN28) and generated heatmaps to illustrate expression of transcription factors, signaling receptors and ligands in a temporal and population specific manner.", "pubmedLink": "" },   "32439709": { "pmid": "32439709", "title": "T integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection.", "sortKey": "2020-06-t integrins cd103 an", "pubDateYear": "2020", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Reilly EC, Lambert Emo K, Buckley PM, Reilly NS, Smith I, Chaves FA, Yang H, Oakes PW, Topham DJ", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 06 2020", "abstractText": "Tissue-resident memory CD8 T (T) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, T are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the T cell surface phenotype develops by 2 wk postinfection, with the majority of the population expressing CD49a and a subset that is also positive for CD103. Despite a previously established role in retaining T in peripheral tissues, CD49a facilitates locomotion of virus-specific CD8 T cells, both in vitro and in vivo. These results demonstrate that CD49a may contribute to local surveillance mechanisms of the T population.", "pubmedLink": "" },   "32405060": { "pmid": "32405060", "title": "A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.", "sortKey": "2020-05-a single-cell and si", "pubDateYear": "2020", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Slyper M, Porter CBM, Ashenberg O, Waldman J, Drokhlyansky E, Wakiro I, Smillie C, Smith-Rosario G, Wu J, Dionne D, Vigneau S, Jané-Valbuena J, Tickle TL, Napolitano S, Su MJ, Patel AG, Karlstrom A, Gritsch S, Nomura M, Waghray A, Gohil SH, Tsankov AM, Jerby-Arnon L, Cohen O, Klughammer J, Rosen Y, Gould J, Nguyen L, Hofree M, Tramontozzi PJ, Li B, Wu CJ, Izar B, Haq R, Hodi FS, Yoon CH, Hata AN, Baker SJ, Suvà ML, Bueno R, Stover EH, Clay MR, Dyer MA, Collins NB, Matulonis UA, Wagle N, Johnson BE, Rotem A, Rozenblatt-Rosen O, Regev A", "citation": "Nature medicine, 05 2020", "abstractText": "Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.", "pubmedLink": "" },   "32380423": { "pmid": "32380423", "title": "Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells.", "sortKey": "2020-05-efficient generation", "pubDateYear": "2020", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Hor P, Punj V, Calvert BA, Castaldi A, Miller AJ, Carraro G, Stripp BR, Brody SL, Spence JR, Ichida JK, Ryan Firth AL, Borok Z", "citation": "iScience, 05 2020", "abstractText": "Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.", "pubmedLink": "" },   "32317643": { "pmid": "32317643", "title": "Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis.", "sortKey": "2020-04-collagen-producing l", "pubDateYear": "2020", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Tsukui T, Sun KH, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, Henderson NC, Adams TS, Schupp JC, Poli SD, Rosas IO, Kaminski N, Matthay MA, Wolters PJ, Sheppard D", "citation": "Nature communications, 04 2020", "abstractText": "Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.", "pubmedLink": "" },   "32243808": { "pmid": "32243808", "title": "The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future.", "sortKey": "2020-04-the cellular and phy", "pubDateYear": "2020", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Basil MC, Katzen J, Engler AE, Guo M, Herriges MJ, Kathiriya JJ, Windmueller R, Ysasi AB, Zacharias WJ, Chapman HA, Kotton DN, Rock JR, Snoeck HW, Vunjak-Novakovic G, Whitsett JA, Morrisey EE", "citation": "Cell stem cell, 04 2020", "abstractText": "The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration. We focus on the cellular compositions within functional niches, cell-cell signaling in homeostatic health, the responses to injury, and new methods to study lung repair and regeneration. We also provide future directions for an improved understanding of the cell biology of the respiratory system, as well as new therapeutic avenues.", "pubmedLink": "" },   "32207533": { "pmid": "32207533", "title": "Resolving single-cell heterogeneity from hundreds of thousands of cells through sequential hybrid clustering and NMF.", "sortKey": "2020-06-resolving single-cel", "pubDateYear": "2020", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Venkatasubramanian M, Chetal K, Schnell DJ, Atluri G, Salomonis N", "citation": "Bioinformatics (Oxford, England), 06 2020", "abstractText": "The rapid proliferation of single-cell RNA-sequencing (scRNA-Seq) technologies has spurred the development of diverse computational approaches to detect transcriptionally coherent populations. While the complexity of the algorithms for detecting heterogeneity has increased, most require significant user-tuning, are heavily reliant on dimension reduction techniques and are not scalable to ultra-large datasets. We previously described a multi-step algorithm, Iterative Clustering and Guide-gene Selection (ICGS), which applies intra-gene correlation and hybrid clustering to uniquely resolve novel transcriptionally coherent cell populations from an intuitive graphical user interface.", "pubmedLink": "" },   "32196812": { "pmid": "32196812", "title": "Functional characterization of four ATP-binding cassette transporter A3 gene (ABCA3) variants.", "sortKey": "2020-07-functional character", "pubDateYear": "2020", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Hu JY, Yang P, Wegner DJ, Heins HB, Luke CJ, Li F, White FV, Silverman GA, Sessions Cole F, Wambach JA", "citation": "Human mutation, 07 2020", "abstractText": "ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase-mediated phospholipid transport into the lamellar bodies (type II mutant). We qualitatively compared wild-type (WT-ABCA3) with four uncharacterized ABCA3 variants (c.418A>C;p.Asn140His, c.3609_3611delCTT;p.Phe1203del, c.3784A>G;p.Ser1262Gly, and c.4195G>A;p.Val1399Met) in A549 cells using protein processing, colocalization with intracellular organelles, lamellar body ultrastructure, and ATPase activity. We quantitatively measured lamellar body-like vesicle diameter and intracellular ABCA3 trafficking using fluorescence-based colocalization. Three ABCA3 variants (p.Asn140His, p.Ser1262Gly, and p.Val1399Met) were processed and trafficked normally and demonstrated well-organized lamellar body-like vesicles, but had reduced ATPase activity consistent with type II mutants. P.Phe1203del was processed normally, had reduced ATPase activity, and well-organized lamellar body-like vesicles, but quantitatively colocalized with both endoplasmic reticulum and lysosomal markers, an intermediate phenotype suggesting disruption of both intracellular trafficking and phospholipid transport. All ABCA3 mutants demonstrated mean vesicle diameters smaller than WT-ABCA3. Qualitative and quantitative functional characterization of ABCA3 variants informs mechanisms of pathogenicity.", "pubmedLink": "" },   "32130910": { "pmid": "32130910", "title": "Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies.", "sortKey": "2020-03-direct comparison of", "pubDateYear": "2020", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Windmueller R, Leach JP, Babu A, Zhou S, Morley MP, Wakabayashi A, Petrenko NB, Viatour P, Morrisey EE", "citation": "Cell reports, 03 2020", "abstractText": "The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury. Several reports have demonstrated that mononucleated cardiomyocytes are more responsive than are binucleated cardiomyocytes to pro-proliferative stimuli. We have developed a strategy to isolate and characterize highly enriched populations of mononucleated and binucleated cardiomyocytes at various times of development. Our results suggest that an E2f/Rb transcriptional network is central to the divergence of these two populations and that remnants of the differences acquired during the neonatal period remain in adult cardiomyocytes. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, directly linking the E2f pathway with nucleation. These data identify key molecular differences between mononucleated and binucleated mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart.", "pubmedLink": "" },   "32091393": { "pmid": "32091393", "title": "Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury.", "sortKey": "2020-02-defining the role of", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Niethamer TK, Stabler CT, Leach JP, Zepp JA, Morley MP, Babu A, Zhou S, Morrisey EE", "citation": "eLife, 02 2020", "abstractText": "Pulmonary endothelial cells (ECs) are an essential component of the gas exchange machinery of the lung alveolus. Despite this, the extent and function of lung EC heterogeneity remains incompletely understood. Using single-cell analytics, we identify multiple EC populations in the mouse lung, including macrovascular endothelium (maEC), microvascular endothelium (miECs), and a new population we have termed -high ECs. -high ECs express a unique gene signature, and ligand-receptor analysis indicates they are primed to receive reparative signals from alveolar type I cells. After acute lung injury, they are preferentially localized in regenerating regions of the alveolus. Influenza infection reveals the emergence of a population of highly proliferative ECs that likely arise from multiple miEC populations and contribute to alveolar revascularization after injury. These studies map EC heterogeneity in the adult lung and characterize the response of novel EC subpopulations required for tissue regeneration after acute lung injury.", "pubmedLink": "" },   "32075728": { "pmid": "32075728", "title": "Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs.", "sortKey": "2020-02-insulin-like growth ", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Oherle K, Acker E, Bonfield M, Wang T, Gray J, Lang I, Bridges J, Lewkowich I, Xu Y, Ahlfeld S, Zacharias W, Alenghat T, Deshmukh H", "citation": "Immunity, 02 2020", "abstractText": "Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.", "pubmedLink": "" },   "32071223": { "pmid": "32071223", "title": "AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria.", "sortKey": "2020-03-ab569, a nontoxic ch", "pubDateYear": "2020", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "McDaniel CT, Panmanee W, Winsor GL, Gill E, Bertelli C, Schurr MJ, Dongare P, Paul AT, Ko SB, Lau GW, Dasgupta N, Bogue AL, Miller WE, Mortensen JE, Haslam DB, Dexheimer P, Muruve DA, Aronow BJ, Forbes MDE, Danilczuk M, Brinkman FSL, Hancock REW, Meyer TJ, Hassett DJ", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 03 2020", "abstractText": "Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO) and Na-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism  in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of  with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.", "pubmedLink": "" },   "32069291": { "pmid": "32069291", "title": "Inferring TF activation order in time series scRNA-Seq studies.", "sortKey": "2020-02-inferring tf activat", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Lin C, Ding J, Bar-Joseph Z", "citation": "PLoS computational biology, 02 2020", "abstractText": "Methods for the analysis of time series single cell expression data (scRNA-Seq) either do not utilize information about transcription factors (TFs) and their targets or only study these as a post-processing step. Using such information can both, improve the accuracy of the reconstructed model and cell assignments, while at the same time provide information on how and when the process is regulated. We developed the Continuous-State Hidden Markov Models TF (CSHMM-TF) method which integrates probabilistic modeling of scRNA-Seq data with the ability to assign TFs to specific activation points in the model. TFs are assumed to influence the emission probabilities for cells assigned to later time points allowing us to identify not just the TFs controlling each path but also their order of activation. We tested CSHMM-TF on several mouse and human datasets. As we show, the method was able to identify known and novel TFs for all processes, assigned time of activation agrees with both expression information and prior knowledge and combinatorial predictions are supported by known interactions. We also show that CSHMM-TF improves upon prior methods that do not utilize TF-gene interaction.", "pubmedLink": "" },   "32061334": { "pmid": "32061334", "title": "Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.", "sortKey": "2020-06-small airways pathol", "pubDateYear": "2020", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Verleden SE, Tanabe N, McDonough JE, Vasilescu DM, Xu F, Wuyts WA, Piloni D, De Sadeleer L, Willems S, Mai C, Hostens J, Cooper JD, Verbeken EK, Verschakelen J, Galban CJ, Van Raemdonck DE, Colby TV, Decramer M, Verleden GM, Kaminski N, Hackett TL, Vanaudenaerde BM, Hogg JC", "citation": "The Lancet. Respiratory medicine, 06 2020", "abstractText": "The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology.", "pubmedLink": "" },   "32024828": { "pmid": "32024828", "title": "Pre-processing visualization of hyperspectral fluorescent data with Spectrally Encoded Enhanced Representations.", "sortKey": "2020-02-pre-processing visua", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Shi W, Koo DES, Kitano M, Chiang HJ, Trinh LA, Turcatel G, Steventon B, Arnesano C, Warburton D, Fraser SE, Cutrale F", "citation": "Nature communications, 02 2020", "abstractText": "Hyperspectral fluorescence imaging is gaining popularity for it enables multiplexing of spatio-temporal dynamics across scales for molecules, cells and tissues with multiple fluorescent labels. This is made possible by adding the dimension of wavelength to the dataset. The resulting datasets are high in information density and often require lengthy analyses to separate the overlapping fluorescent spectra. Understanding and visualizing these large multi-dimensional datasets during acquisition and pre-processing can be challenging. Here we present Spectrally Encoded Enhanced Representations (SEER), an approach for improved and computationally efficient simultaneous color visualization of multiple spectral components of hyperspectral fluorescence images. Exploiting the mathematical properties of the phasor method, we transform the wavelength space into information-rich color maps for RGB display visualization. We present multiple biological fluorescent samples and highlight SEER s enhancement of specific and subtle spectral differences, providing a fast, intuitive and mathematical way to interpret hyperspectral images during collection, pre-processing and analysis.", "pubmedLink": "" },   "32023086": { "pmid": "32023086", "title": "Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.", "sortKey": "2020-05-hyperoxia injury in ", "pubDateYear": "2020", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Sucre JMS, Vickers KC, Benjamin JT, Plosa EJ, Jetter CS, Cutrone A, Ransom M, Anderson Z, Sheng Q, Fensterheim BA, Ambalavanan N, Millis B, Lee E, Zijlstra A, Königshoff M, Blackwell TS, Guttentag SH", "citation": "American journal of respiratory and critical care medicine, 05 2020", "abstractText": " Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis. To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/β-catenin signaling after hyperoxia injury. Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine  hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA  hybridization, quantitative confocal microscopy, and lung morphometry. Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of . Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-κB with BAY11-7082 reduced  expression in the PCLS hyperoxia model and  mouse hyperoxia model, with improved alveolarization in the PCLS model. Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.", "pubmedLink": "" },   "32005814": { "pmid": "32005814", "title": "The in vivo genetic program of murine primordial lung epithelial progenitors.", "sortKey": "2020-01-the in vivo genetic ", "pubDateYear": "2020", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Ikonomou L, Herriges MJ, Lewandowski SL, Marsland R, Villacorta-Martin C, Caballero IS, Frank DB, Sanghrajka RM, Dame K, Kańduła MM, Hicks-Berthet J, Lawton ML, Christodoulou C, Fabian AJ, Kolaczyk E, Varelas X, Morrisey EE, Shannon JM, Mehta P, Kotton DN", "citation": "Nature communications, 01 2020", "abstractText": "Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene networks that regulate these gateway progenitors in vivo. Here we use bulk RNA-sequencing to describe the unique genetic program of in vivo murine lung primordial progenitors and computationally identify signaling pathways, such as Wnt and Tgf-β superfamily pathways, that are involved in their cell-fate determination from pre-specified embryonic foregut. We integrate this information in computational models to generate in vitro engineered lung primordial progenitors from mouse pluripotent stem cells, improving the fidelity of the resulting cells through unbiased, easy-to-interpret similarity scores and modulation of cell culture conditions, including substratum elastic modulus and extracellular matrix composition. The methodology proposed here can have wide applicability to the in vitro derivation of bona fide tissue progenitors of all germ layers.", "pubmedLink": "" },   "32004478": { "pmid": "32004478", "title": "Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.", "sortKey": "2020-04-reconstructed single", "pubDateYear": "2020", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Hurley K, Ding J, Villacorta-Martin C, Herriges MJ, Jacob A, Vedaie M, Alysandratos KD, Sun YL, Lin C, Werder RB, Huang J, Wilson AA, Mithal A, Mostoslavsky G, Oglesby I, Caballero IS, Guttentag SH, Ahangari F, Kaminski N, Rodriguez-Fraticelli A, Camargo F, Bar-Joseph Z, Kotton DN", "citation": "Cell stem cell, 04 2020", "abstractText": "Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life but are difficult to isolate from patients. Here, we engineer AEC2s from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profile the kinetics of their differentiation in comparison to primary fetal and adult AEC2 benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progenitors differentiate in vitro, with some progeny reaching their AEC2 fate target, while others diverge to alternative non-lung endodermal fates. We develop a Continuous State Hidden Markov model to identify the timing and type of signals, such as overexuberant Wnt responses, that induce some early multipotent NKX2-1 progenitors to lose lung fate. Finally, we find that this initial developmental plasticity is regulatable and subsides over time, ultimately resulting in PSC-derived AEC2s that exhibit a stable phenotype and nearly limitless self-renewal capacity.", "pubmedLink": "" },   "31840053": { "pmid": "31840053", "title": "Single-cell connectomic analysis of adult mammalian lungs.", "sortKey": "2019-12-single-cell connecto", "pubDateYear": "2019", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Raredon MSB, Adams TS, Suhail Y, Schupp JC, Poli S, Neumark N, Leiby KL, Greaney AM, Yuan Y, Horien C, Linderman G, Engler AJ, Boffa DJ, Kluger Y, Rosas IO, Levchenko A, Kaminski N, Niklason LE", "citation": "Science advances, 12 2019", "abstractText": "Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.", "pubmedLink": "" },   "31837950": { "pmid": "31837950", "title": "Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung.", "sortKey": "2020-02-collagen vi deficien", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Mereness JA, Bhattacharya S, Ren Y, Wang Q, Anderson CS, Donlon K, Dylag AM, Haak J, Angelin A, Bonaldo P, Mariani TJ", "citation": "The American journal of pathology, 02 2020", "abstractText": "Collagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1 mouse, which does not produce detectable COL6 in the lung. The Col6a1 mouse displayed histopathologic alveolar and airway abnormalities. The airspaces of Col6a1 lungs appeared simplified, with larger (29%; P < 0.01) and fewer (31%; P < 0.001) alveoli. These airspace abnormalities included reduced isolectin B4 alveolar capillaries and surfactant protein C-positive alveolar epithelial type-II cells. Alterations in lung function consistent with these histopathologic changes were evident. Col6a1 mice also displayed multiple airway changes, including increased branching (59%; P < 0.001), increased mucosal thickness (34%; P < 0.001), and increased epithelial cell density (13%; P < 0.001). Comprehensive transcriptome analysis revealed that the loss of COL6 is associated with reductions in integrin-paxillin-phosphatidylinositol 3-kinase signaling in vivo. In vitro, COL6 promoted steady-state phosphorylated paxillin levels and reduced cell density (16% to 28%; P < 0.05) at confluence. Inhibition of phosphatidylinositol 3-kinase, or its downstream effectors, resulted in increased cell density to a level similar to that seen on matrices lacking COL6.", "pubmedLink": "" },   "31761445": { "pmid": "31761445", "title": "Lung regeneration: a tale of mice and men.", "sortKey": "2020-04-lung regeneration: a", "pubDateYear": "2020", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Basil MC, Morrisey EE", "citation": "Seminars in cell & developmental biology, 04 2020", "abstractText": "The respiratory system is the main site of gas exchange with the external environment in complex terrestrial animals. Within the trachea and lungs are multiple different tissue niches each consisting of a myriad of cells types with critical roles in air conduction, gas exchange, providing important niche specific cell-cell interactions, connection to the cardiovascular system, and immune surveillance. How the respiratory system responds to external insults and executes the appropriate regenerative response remains challenging to study given the plethora of cell and tissue interactions for this to occur properly. This review will examine the various cell types and tissue niches found within the respiratory system and provide a comparison between mouse and human lungs and trachea to highlight important similarities and differences. Defining the critical gaps in knowledge in human lung and tracheal regeneration is critical for future development of therapies directed towards respiratory diseases.", "pubmedLink": "" },   "31732721": { "pmid": "31732721", "title": "Derivation of self-renewing lung alveolar epithelial type II cells from human pluripotent stem cells.", "sortKey": "2019-12-derivation of self-r", "pubDateYear": "2019", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Jacob A, Vedaie M, Roberts DA, Thomas DC, Villacorta-Martin C, Alysandratos KD, Hawkins F, Kotton DN", "citation": "Nature protocols, 12 2019", "abstractText": "Alveolar epithelial type II cells (AEC2s) are the facultative progenitors of lung alveoli and serve as the surfactant-producing cells of air-breathing organisms. Although primary human AEC2s are difficult to maintain stably in cell cultures, recent advances have facilitated the derivation of AEC2-like cells from human pluripotent stem cells (hPSCs) in vitro. Here, we provide a detailed protocol for the directed differentiation of hPSCs into self-renewing AEC2-like cells that can be maintained for up to 1 year in culture as epithelial-only spheres without the need for supporting mesenchymal feeder cells. The month-long protocol requires recapitulation of the sequence of milestones associated with in vivo development of the distal lung, beginning with differentiation of cells into anterior foregut endoderm, which is followed by their lineage specification into NKX2-1 lung progenitors and then distal/alveolar differentiation to produce progeny that express transcripts and possess functional properties associated with AEC2s.", "pubmedLink": "" },   "31727986": { "pmid": "31727986", "title": "Bronchopulmonary dysplasia.", "sortKey": "2019-11-bronchopulmonary dys", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH", "citation": "Nature reviews. Disease primers, 11 2019", "abstractText": "In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.", "pubmedLink": "" },   "31726465": { "pmid": "31726465", "title": "CX3CR1 as a respiratory syncytial virus receptor in pediatric human lung.", "sortKey": "2020-04-cx3cr1 as a respirat", "pubDateYear": "2020", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Anderson CS, Chu CY, Wang Q, Mereness JA, Ren Y, Donlon K, Bhattacharya S, Misra RS, Walsh EE, Pryhuber GS, Mariani TJ", "citation": "Pediatric research, 04 2020", "abstractText": "Data on the host factors that contribute to infection of young children by respiratory syncytial virus (RSV) are limited. The human chemokine receptor, CX3CR1, has recently been implicated as an RSV receptor. Here we evaluate a role for CX3CR1 in pediatric lung RSV infections.", "pubmedLink": "" },   "31693907": { "pmid": "31693907", "title": "DoubletDecon: Deconvoluting Doublets from Single-Cell RNA-Sequencing Data.", "sortKey": "2019-11-doubletdecon: deconv", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "DePasquale EAK, Schnell DJ, Van Camp PJ, Valiente-Alandí Í, Blaxall BC, Grimes HL, Singh H, Salomonis N", "citation": "Cell reports, 11 2019", "abstractText": "Methods for single-cell RNA sequencing (scRNA-seq) have greatly advanced in recent years. While droplet- and well-based methods have increased the capture frequency of cells for scRNA-seq, these technologies readily produce technical artifacts, such as doublet cell captures. Doublets occurring between distinct cell types can appear as hybrid scRNA-seq profiles, but do not have distinct transcriptomes from individual cell states. We introduce DoubletDecon, an approach that detects doublets with a combination of deconvolution analyses and the identification of unique cell-state gene expression. We demonstrate the ability of DoubletDecon to identify synthetic, mixed-species, genetic, and cell-hashing cell doublets from scRNA-seq datasets of varying cellular complexity with a high sensitivity relative to alternative approaches. Importantly, this algorithm prevents the prediction of valid mixed-lineage and transitional cell states as doublets by considering their unique gene expression. DoubletDecon has an easy-to-use graphical user interface and is compatible with diverse species and unsupervised population detection algorithms.", "pubmedLink": "" },   "31662342": { "pmid": "31662342", "title": "Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development.", "sortKey": "2020-05-disruption of normal", "pubDateYear": "2020", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Steiner LA, Getman M, Schiralli Lester GM, Iqbal MA, Katzman P, Szafranski P, Stankiewicz P, Bhattacharya S, Mariani T, Pryhuber G, Lin X, Young JL, Dean DA, Scheible K", "citation": "Journal of medical genetics, 05 2020", "abstractText": "Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor , which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype.", "pubmedLink": "" },   "31651362": { "pmid": "31651362", "title": "Comprehensive anatomic ontologies for lung development: A comparison of alveolar formation and maturation within mouse and human lung.", "sortKey": "2019-10-comprehensive anatom", "pubDateYear": "2019", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Pan H, Deutsch GH, Wert SE,  ,  ", "citation": "Journal of biomedical semantics, 10 2019", "abstractText": "Although the mouse is widely used to model human lung development, function, and disease, our understanding of the molecular mechanisms involved in alveolarization of the peripheral lung is incomplete. Recently, the Molecular Atlas of Lung Development Program (LungMAP) was funded by the National Heart, Lung, and Blood Institute to develop an integrated open access database (known as BREATH) to characterize the molecular and cellular anatomy of the developing lung. To support this effort, we designed detailed anatomic and cellular ontologies describing alveolar formation and maturation in both mouse and human lung.", "pubmedLink": "" },   "31600171": { "pmid": "31600171", "title": "Transcriptional regulatory model of fibrosis progression in the human lung.", "sortKey": "2019-11-transcriptional regu", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "McDonough JE, Ahangari F, Li Q, Jain S, Verleden SE, Herazo-Maya J, Vukmirovic M, DeIuliis G, Tzouvelekis A, Tanabe N, Chu F, Yan X, Verschakelen J, Homer RJ, Manatakis DV, Zhang J, Ding J, Maes K, De Sadeleer L, Vos R, Neyrinck A, Benos PV, Bar-Joseph Z, Tantin D, Hogg JC, Vanaudenaerde BM, Wuyts WA, Kaminski N", "citation": "JCI insight, 11 2019", "abstractText": "To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.", "pubmedLink": "" },   "31529053": { "pmid": "31529053", "title": "cellHarmony: cell-level matching and holistic comparison of single-cell transcriptomes.", "sortKey": "2019-12-cellharmony: cell-le", "pubDateYear": "2019", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "DePasquale EAK, Schnell D, Dexheimer P, Ferchen K, Hay S, Chetal K, Valiente-Alandí Í, Blaxall BC, Grimes HL, Salomonis N", "citation": "Nucleic acids research, 12 2019", "abstractText": "To understand the molecular pathogenesis of human disease, precision analyses to define alterations within and between disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform to enable the identification and comparison of normal and diseased transcriptional cell populations. We created cellHarmony, an integrated solution for the unsupervised analysis, classification, and comparison of cell types from diverse single-cell RNA-Seq datasets. cellHarmony efficiently and accurately matches single-cell transcriptomes using a community-clustering and alignment strategy to compute differences in cell-type specific gene expression over potentially dozens of cell populations. Such transcriptional differences are used to automatically identify distinct and shared gene programs among cell-types and identify impacted pathways and transcriptional regulatory networks to understand the impact of perturbations at a systems level. cellHarmony is implemented as a python package and as an integrated workflow within the software AltAnalyze. We demonstrate that cellHarmony has improved or equivalent performance to alternative label projection methods, is able to identify the likely cellular origins of malignant states, stratify patients into clinical disease subtypes from identified gene programs, resolve discrete disease networks impacting specific cell-types, and illuminate therapeutic mechanisms. Thus, this approach holds tremendous promise in revealing the molecular and cellular origins of complex disease.", "pubmedLink": "" },   "31517510": { "pmid": "31517510", "title": "YAP and TAZ in Lung Development: The Timing Is Important.", "sortKey": "2020-02-yap and taz in lung ", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Warburton D", "citation": "American journal of respiratory cell and molecular biology, 02 2020", "pubmedLink": "" },   "31509397": { "pmid": "31509397", "title": "High-Throughput Single Cell Proteomics Enabled by Multiplex Isobaric Labeling in a Nanodroplet Sample Preparation Platform.", "sortKey": "2019-10-high-throughput sing", "pubDateYear": "2019", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Dou M, Clair G, Tsai CF, Xu K, Chrisler WB, Sontag RL, Zhao R, Moore RJ, Liu T, Pasa-Tolic L, Smith RD, Shi T, Adkins JN, Qian WJ, Kelly RT, Ansong C, Zhu Y", "citation": "Analytical chemistry, 10 2019", "abstractText": "Effective extension of mass spectrometry-based proteomics to single cells remains challenging. Herein we combined microfluidic nanodroplet technology with tandem mass tag (TMT) isobaric labeling to significantly improve analysis throughput and proteome coverage for single mammalian cells. Isobaric labeling facilitated multiplex analysis of single cell-sized protein quantities to a depth of ∼1 600 proteins with a median CV of 10.9% and correlation coefficient of 0.98. To demonstrate in-depth high throughput single cell analysis, the platform was applied to measure protein expression in 72 single cells from three murine cell populations (epithelial, immune, and endothelial cells) in <2 days instrument time with over 2 300 proteins identified. Principal component analysis grouped the single cells into three distinct populations based on protein expression with each population characterized by well-known cell-type specific markers. Our platform enables high throughput and unbiased characterization of single cell heterogeneity at the proteome level.", "pubmedLink": "" },   "31508981": { "pmid": "31508981", "title": "A multiomics focusing towards the molecular networks of lung development.", "sortKey": "2019-11-a multiomics focusin", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Clair G", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2019", "pubmedLink": "" },   "31432713": { "pmid": "31432713", "title": "Integrating multiomics longitudinal data to reconstruct networks underlying lung development.", "sortKey": "2019-11-integrating multiomi", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Ding J, Ahangari F, Espinoza CR, Chhabra D, Nicola T, Yan X, Lal CV, Hagood JS, Kaminski N, Bar-Joseph Z, Ambalavanan N", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2019", "abstractText": "A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar lung development is still lacking. To construct such a model, we profiled mRNA, microRNA, DNA methylation, and proteomics of developing murine alveoli isolated by laser capture microdissection at 14 predetermined time points. We developed a detailed comprehensive and interactive model that provides information about the major expression trajectories, the regulators of specific key events, and the impact of epigenetic changes. Intersecting the model with single-cell RNA-Seq data led to the identification of active pathways in multiple or individual cell types. We then constructed a similar model for human lung development by profiling time-series human omics data sets. Several key pathways and regulators are shared between the reconstructed models. We experimentally validated the activity of a number of predicted regulators, leading to new insights about the regulation of innate immunity during lung development.", "pubmedLink": "" },   "31412198": { "pmid": "31412198", "title": "Lipid Coverage in Nanospray Desorption Electrospray Ionization Mass Spectrometry Imaging of Mouse Lung Tissues.", "sortKey": "2019-09-lipid coverage in na", "pubDateYear": "2019", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Nguyen SN, Kyle JE, Dautel SE, Sontag R, Luders T, Corley R, Ansong C, Carson J, Laskin J", "citation": "Analytical chemistry, 09 2019", "abstractText": "Lipids are a naturally occurring group of molecules that not only contribute to the structural integrity of the lung preventing alveolar collapse but also play important roles in the anti-inflammatory responses and antiviral protection. Alteration in the type and spatial localization of lipids in the lung plays a crucial role in various diseases, such as respiratory distress syndrome (RDS) in preterm infants and oxidative stress-influenced diseases, such as pneumonia, emphysema, and lung cancer following exposure to environmental stressors. The ability to accurately measure spatial distributions of lipids and metabolites in lung tissues provides important molecular insights related to lung function, development, and disease states. Nanospray desorption electrospray ionization (nano-DESI) and other ambient ionization mass spectrometry techniques enable label-free imaging of complex samples in their native state with minimal to absolutely no sample preparation. However, lipid coverage obtained in nano-DESI mass spectrometry imaging (MSI) experiments has not been previously characterized. In this work, the depth of lipid coverage in nano-DESI MSI of mouse lung tissues was compared to liquid chromatography tandem mass spectrometry (LC-MS/MS) lipidomics analysis of tissue extracts prepared using two different procedures: standard Folch extraction method of the whole lung samples and extraction into a 90% methanol/10% water mixture used in nano-DESI MSI experiments. A combination of positive and negative ionization mode nano-DESI MSI identified 265 unique lipids across 20 lipids subclasses and 19 metabolites (284 in total) in mouse lung tissues. Except for triacylglycerols (TG) species, nano-DESI MSI provided comparable coverage to LC-MS/MS experiments performed using methanol/water tissue extracts and up to 50% coverage in comparison with the Folch extraction-based whole lung lipidomics analysis. These results demonstrate the utility of nano-DESI MSI for comprehensive spatially resolved analysis of lipids in tissue sections. A combination of nano-DESI MSI and LC-MS/MS lipidomics is particularly useful for exploring changes in lipid distributions during lung development, as well as resulting from disease or exposure to environmental toxicants.", "pubmedLink": "" },   "31273041": { "pmid": "31273041", "title": "Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.", "sortKey": "2019-08-plasma mitochondrial", "pubDateYear": "2019", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Ryu C, Brandsdorfer C, Adams T, Hu B, Kelleher DW, Yaggi M, Manning EP, Walia A, Reeves B, Pan H, Winkler J, Minasyan M, Dela Cruz CS, Kaminski N, Gulati M, Herzog EL", "citation": "The European respiratory journal, 08 2019", "abstractText": "Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human  gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between  concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls,  concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive  concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.", "pubmedLink": "" },   "31272105": { "pmid": "31272105", "title": "Loss of FLCN inhibits canonical WNT signaling via TFE3.", "sortKey": "2019-10-loss of flcn inhibit", "pubDateYear": "2019", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Kennedy JC, Khabibullin D, Hougard T, Nijmeh J, Shi W, Henske EP", "citation": "Human molecular genetics, 10 2019", "abstractText": "Lower lobe predominant pulmonary cysts occur in up to 90% of patients with Birt-Hogg-Dubé (BHD) syndrome, but the key pathologic cell type and signaling events driving this distinct phenotype remain elusive. Through examination of the LungMAP database, we found that folliculin (FLCN) is highly expressed in neonatal lung mesenchymal cells. Using RNA-Seq, we found that inactivation of Flcn in mouse embryonic fibroblasts leads to changes in multiple Wnt ligands, including a 2.8-fold decrease in Wnt2. This was associated with decreased TCF/LEF activity, a readout of canonical WNT activity, after treatment with a GSK3-α/β inhibitor. Similarly, FLCN deficiency in HEK293T cells decreased WNT pathway activity by 76% post-GSK3-α/β inhibition. Inactivation of FLCN in human fetal lung fibroblasts (MRC-5) led to ~ 100-fold decrease in Wnt2 expression and a 33-fold decrease in Wnt7b expression-two ligands known to be necessary for lung development. Furthermore, canonical WNT activity was decreased by 60%. Classic WNT targets such as AXIN2 and BMP4, and WNT enhanceosome members including TCF4, LEF1 and BCL9 were also decreased after GSK3-α/β inhibition. FLCN-deficient MRC-5 cells failed to upregulate LEF1 in response to GSK3-α/β inhibition. Finally, we found that a constitutively active β-catenin could only partially rescue the decreased WNT activity phenotype seen in FLCN-deficient cells, whereas silencing the transcription factor TFE3 completely reversed this phenotype. In summary, our data establish FLCN as a critical regulator of the WNT pathway via TFE3 and suggest that FLCN-dependent defects in WNT pathway developmental cues may contribute to lung cyst pathogenesis in BHD.", "pubmedLink": "" },   "31268347": { "pmid": "31268347", "title": "Integration of transcriptomic and proteomic data identifies biological functions in cell populations from human infant lung.", "sortKey": "2019-09-integration of trans", "pubDateYear": "2019", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Du Y, Clair GC, Al Alam D, Danopoulos S, Schnell D, Kitzmiller JA, Misra RS, Bhattacharya S, Warburton D, Mariani TJ, Pryhuber GS, Whitsett JA, Ansong C, Xu Y", "citation": "American journal of physiology. Lung cellular and molecular physiology, 09 2019", "abstractText": "Systems biology uses computational approaches to integrate diverse data types to understand cell and organ behavior. Data derived from complementary technologies, for example transcriptomic and proteomic analyses, are providing new insights into development and disease. We compared mRNA and protein profiles from purified endothelial, epithelial, immune, and mesenchymal cells from normal human infant lung tissue. Signatures for each cell type were identified and compared at both mRNA and protein levels. Cell-specific biological processes and pathways were predicted by analysis of concordant and discordant RNA-protein pairs. Cell clustering and gene set enrichment comparisons identified shared versus unique processes associated with transcriptomic and/or proteomic data. Clear cell-cell correlations between mRNA and protein data were obtained from each cell type. Approximately 40% of RNA-protein pairs were coherently expressed. While the correlation between RNA and their protein products was relatively low (Spearman rank coefficient  ~0.4), cell-specific signature genes involved in functional processes characteristic of each cell type were more highly correlated with their protein products. Consistency of cell-specific RNA-protein signatures indicated an essential framework for the function of each cell type. Visualization and reutilization of the protein and RNA profiles are supported by a new web application,  LungProteomics,  which is freely accessible to the public.", "pubmedLink": "" },   "31242446": { "pmid": "31242446", "title": "Dnmt1 is required for proximal-distal patterning of the lung endoderm and for restraining alveolar type 2 cell fate.", "sortKey": "2019-10-dnmt1 is required fo", "pubDateYear": "2019", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Liberti DC, Zepp JA, Bartoni CA, Liberti KH, Zhou S, Lu M, Morley MP, Morrisey EE", "citation": "Developmental biology, 10 2019", "abstractText": "Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.", "pubmedLink": "" },   "31233341": { "pmid": "31233341", "title": "Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT Endothelial Progenitor Cells.", "sortKey": "2019-11-postnatal alveologen", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Ren X, Ustiyan V, Guo M, Wang G, Bolte C, Zhang Y, Xu Y, Whitsett JA, Kalin TV, Kalinichenko VV", "citation": "American journal of respiratory and critical care medicine, 11 2019", "abstractText": " Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown. To determine whether c-KIT EC progenitors stimulate alveologenesis in the neonatal lung. We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT EC progenitors. A mouse model of perinatal hyperoxia-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT EC progenitors in the neonatal lung. Pulmonary c-KIT EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT ECs was conserved in mouse and human lungs and enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal hyperoxia decreased the number of c-KIT EC progenitors. Haploinsufficiency or endothelial-specific deletion of  in mice increased apoptosis and decreased proliferation of c-KIT ECs. Inactivation of either  or  caused alveolar simplification. Adoptive transfer of c-KIT ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to hyperoxia. Cell therapy involving c-KIT EC progenitors can be beneficial for the treatment of BPD.", "pubmedLink": "" },   "31227752": { "pmid": "31227752", "title": "Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques.", "sortKey": "2019-06-dosing and formulati", "pubDateYear": "2019", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Schmidt AF, Kannan PS, Bridges JP, Filuta A, Lipps D, Kemp M, Miller LA, Kallapur SG, Xu Y, Whitsett JA, Jobe AH", "citation": "Scientific reports, 06 2019", "abstractText": "Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) - the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.", "pubmedLink": "" },   "31215789": { "pmid": "31215789", "title": "Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis.", "sortKey": "2019-11-complete tracheal ri", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Sinner DI, Carey B, Zgherea D, Kaufman KM, Leesman L, Wood RE, Rutter MJ, de Alarcon A, Elluru RG, Harley JB, Whitsett JA, Trapnell BC", "citation": "American journal of respiratory and critical care medicine, 11 2019", "abstractText": " Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly. To test the hypothesis that CTRD is caused by inherited or  mutations in genes required for normal tracheal development. CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents ( trio analysis ) to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice. The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six , three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD.  variants were identified in  (Sonic Hedgehog), and inherited variants were identified in  (perlecan),  (receptor tyrosine kinase-like orphan receptor 2), and  (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice. The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.", "pubmedLink": "" },   "31162136": { "pmid": "31162136", "title": "Normal lung development needs self-eating.", "sortKey": "2019-06-normal lung developm", "pubDateYear": "2019", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Warburton D, Bellusci S", "citation": "The Journal of clinical investigation, 06 2019", "abstractText": "Autophagy is a Greek-derived concept that means  self-eating  and is increasingly recognized as an important regulator of homeostasis and disease. In this issue of the JCI, Yeganeh et al. report the important finding that intrinsic autophagy is required for normal progression of lung development. Conditional deletion of the beclin 1-encoding gene (Becn1) specifically within lung epithelial cells of embryonic mice resulted in neonatal lethal respiratory distress that was associated with negative impacts on airway branching and differentiation of airway epithelial cell lineages. The authors draw speculative parallels with the alveolar simplification phenotype of bronchopulmonary dysplasia in premature human infants and suggest that stimulation of autophagy by cAMP-dependent kinase activation might conceivably rescue these phenotypes.", "pubmedLink": "" },   "31090574": { "pmid": "31090574", "title": "Genetic causes of surfactant protein abnormalities.", "sortKey": "2019-06-genetic causes of su", "pubDateYear": "2019", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Nogee LM", "citation": "Current opinion in pediatrics, 06 2019", "abstractText": "Mutations in genes encoding proteins critical for the production and function of pulmonary surfactant cause diffuse lung disease. Timely recognition and diagnosis of affected individuals is important for proper counseling concerning prognosis and recurrence risk.", "pubmedLink": "" },   "31085557": { "pmid": "31085557", "title": "Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.", "sortKey": "2019-08-aging human hematopo", "pubDateYear": "2019", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Adelman ER, Huang HT, Roisman A, Olsson A, Colaprico A, Qin T, Lindsley RC, Bejar R, Salomonis N, Grimes HL, Figueroa ME", "citation": "Cancer discovery, 08 2019", "abstractText": "Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. LineageCD34CD38 cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably,  downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. SIGNIFICANCE: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes..", "pubmedLink": "" },   "31028279": { "pmid": "31028279", "title": "Mesenchyme-specific deletion of Tgf-β1 in the embryonic lung disrupts branching morphogenesis and induces lung hypoplasia.", "sortKey": "2019-09-mesenchyme-specific ", "pubDateYear": "2019", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Noe N, Shim A, Millette K, Luo Y, Azhar M, Shi W, Warburton D, Turcatel G", "citation": "Laboratory investigation; a journal of technical methods and pathology, 09 2019", "abstractText": "Proper lung development depends on the precise temporal and spatial expression of several morphogenic factors, including Fgf10, Fgf9, Shh, Bmp4, and Tgf-β. Over- or under-expression of these molecules often leads to aberrant embryonic or postnatal lung development. Herein, we deleted the Tgf-β1 gene specifically within the lung embryonic mesenchymal compartment at specific gestational stages to determine the contribution of this cytokine to lung development. Mutant embryos developed severe lung hypoplasia and died at birth due to the inability to breathe. Despite the markedly reduced lung size, proliferation and differentiation of the lung epithelium was not affected by the lack of mesenchymal expression of the Tgf-β1 gene, while apoptosis was significantly increased in the mutant lung parenchyma. Lack of mesenchymal expression of the Tgf-β1 gene was also associated with reduced lung branching morphogenesis, with accompanying inhibition of the local FGF10 signaling pathway as well as abnormal development of the vascular system. To shed light on the mechanism of lung hypoplasia, we quantified the phosphorylation of 226 proteins in the mutant E12.5 lung compared with control. We identified five proteins, Hrs, Vav2, c-Kit, the regulatory subunit of Pi3k (P85), and Fgfr1, that were over- or under-phosphorylated in the mutant lung, suggesting that they could be indispensable effectors of the TGF-β signaling program during embryonic lung development. In conclusion, we have uncovered novel roles of the mesenchyme-specific Tgf-β1 ligand in embryonic mouse lung development and generated a mouse model that may prove helpful to identify some of the key pathogenic mechanisms underlying lung hypoplasia in humans.", "pubmedLink": "" },   "31018133": { "pmid": "31018133", "title": "Direct Lung Sampling Indicates That Established Pathogens Dominate Early Infections in Children with Cystic Fibrosis.", "sortKey": "2019-04-direct lung sampling", "pubDateYear": "2019", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Jorth P, Ehsan Z, Rezayat A, Caldwell E, Pope C, Brewington JJ, Goss CH, Benscoter D, Clancy JP, Singh PK", "citation": "Cell reports, 04 2019", "abstractText": "Culture and sequencing have produced divergent hypotheses about cystic fibrosis (CF) lung infections. Culturing suggests that CF lungs are uninfected before colonization by a limited group of CF pathogens. Sequencing suggests diverse communities of mostly oral bacteria inhabit lungs early on and diversity decreases as disease progresses. We studied the lung microbiota of CF children using bronchoscopy and sequencing, with measures to reduce contamination. We found no evidence for oral bacterial communities in lung lavages that lacked CF pathogens. Lavage microbial diversity varied widely, but decreases in diversity appeared to be driven by increased CF pathogen abundance, which reduced the signal from contaminants. Streptococcus, Prevotella, and Veillonella DNA was detected in some lavages containing CF pathogens, but DNA from these organisms was vastly exceeded by CF pathogen DNA and was not associated with inflammation. These findings support the hypothesis that established CF pathogens are primarily responsible for CF lung infections.", "pubmedLink": "" },   "30996081": { "pmid": "30996081", "title": "In utero gene editing for monogenic lung disease.", "sortKey": "2019-04-in utero gene editin", "pubDateYear": "2019", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Alapati D, Zacharias WJ, Hartman HA, Rossidis AC, Stratigis JD, Ahn NJ, Coons B, Zhou S, Li H, Singh K, Katzen J, Tomer Y, Chadwick AC, Musunuru K, Beers MF, Morrisey EE, Peranteau WH", "citation": "Science translational medicine, 04 2019", "abstractText": "Monogenic lung diseases that are caused by mutations in surfactant genes of the pulmonary epithelium are marked by perinatal lethal respiratory failure or chronic diffuse parenchymal lung disease with few therapeutic options. Using a CRISPR fluorescent reporter system, we demonstrate that precisely timed in utero intra-amniotic delivery of CRISPR-Cas9 gene editing reagents during fetal development results in targeted and specific gene editing in fetal lungs. Pulmonary epithelial cells are predominantly targeted in this approach, with alveolar type 1, alveolar type 2, and airway secretory cells exhibiting high and persistent gene editing. We then used this in utero technique to evaluate a therapeutic approach to reduce the severity of the lethal interstitial lung disease observed in a mouse model of the human  mutation. Embryonic expression of  alleles is characterized by severe diffuse parenchymal lung damage and rapid demise of mutant mice at birth. After in utero CRISPR-Cas9-mediated inactivation of the mutant  gene, fetuses and postnatal mice showed improved lung morphology and increased survival. These proof-of-concept studies demonstrate that in utero gene editing is a promising approach for treatment and rescue of monogenic lung diseases that are lethal at birth.", "pubmedLink": "" },   "30995076": { "pmid": "30995076", "title": "The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease.", "sortKey": "2019-07-the human lung cell ", "pubDateYear": "2019", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Schiller HB, Montoro DT, Simon LM, Rawlins EL, Meyer KB, Strunz M, Vieira Braga FA, Timens W, Koppelman GH, Budinger GRS, Burgess JK, Waghray A, van den Berge M, Theis FJ, Regev A, Kaminski N, Rajagopal J, Teichmann SA, Misharin AV, Nawijn MC", "citation": "American journal of respiratory cell and molecular biology, 07 2019", "abstractText": "Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas.", "pubmedLink": "" },   "30977807": { "pmid": "30977807", "title": "Lipid Mini-On: mining and ontology tool for enrichment analysis of lipidomic data.", "sortKey": "2019-11-lipid mini-on: minin", "pubDateYear": "2019", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Clair G, Reehl S, Stratton KG, Monroe ME, Tfaily MM, Ansong C, Kyle JE", "citation": "Bioinformatics (Oxford, England), 11 2019", "abstractText": "Here we introduce Lipid Mini-On, an open-source tool that performs lipid enrichment analyses and visualizations of lipidomics data. Lipid Mini-On uses a text-mining process to bin individual lipid names into multiple lipid ontology groups based on the classification (e.g. LipidMaps) and other characteristics, such as chain length. Lipid Mini-On provides users with the capability to conduct enrichment analysis of the lipid ontology terms using a Shiny app with options of five statistical approaches. Lipid classes can be added to customize the user s database and remain updated as new lipid classes are discovered. Visualization of results is available for all classification options (e.g. lipid subclass and individual fatty acid chains). Results are also visualized through an editable network of relationships between the individual lipids and their associated lipid ontology terms. The utility of the tool is demonstrated using biological (e.g. human lung endothelial cells) and environmental (e.g. peat soil) samples.", "pubmedLink": "" },   "30930166": { "pmid": "30930166", "title": "The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.", "sortKey": "2019-04-the pediatric cell a", "pubDateYear": "2019", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Taylor DM, Aronow BJ, Tan K, Bernt K, Salomonis N, Greene CS, Frolova A, Henrickson SE, Wells A, Pei L, Jaiswal JK, Whitsett J, Hamilton KE, MacParland SA, Kelsen J, Heuckeroth RO, Potter SS, Vella LA, Terry NA, Ghanem LR, Kennedy BC, Helbig I, Sullivan KE, Castelo-Soccio L, Kreigstein A, Herse F, Nawijn MC, Koppelman GH, Haendel M, Harris NL, Rokita JL, Zhang Y, Regev A, Rozenblatt-Rosen O, Rood JE, Tickle TL, Vento-Tormo R, Alimohamed S, Lek M, Mar JC, Loomes KM, Barrett DM, Uapinyoying P, Beggs AH, Agrawal PB, Chen YW, Muir AB, Garmire LX, Snapper SB, Nazarian J, Seeholzer SH, Fazelinia H, Singh LN, Faryabi RB, Raman P, Dawany N, Xie HM, Devkota B, Diskin SJ, Anderson SA, Rappaport EF, Peranteau W, Wikenheiser-Brokamp KA, Teichmann S, Wallace D, Peng T, Ding YY, Kim MS, Xing Y, Kong SW, Bönnemann CG, Mandl KD, White PS", "citation": "Developmental cell, 04 2019", "abstractText": "Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.", "pubmedLink": "" },   "30923323": { "pmid": "30923323", "title": "Alteration of cystic airway mesenchyme in congenital pulmonary airway malformation.", "sortKey": "2019-03-alteration of cystic", "pubDateYear": "2019", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Jiang Y, Luo Y, Tang Y, Moats R, Warburton D, Zhou S, Lou J, Pryhuber GS, Shi W, Wang LL", "citation": "Scientific reports, 03 2019", "abstractText": "Congenital pulmonary airway malformation (CPAM) is the most common congenital lesion detected in the neonatal lung, which may lead to respiratory distress, infection, and pneumothorax. CPAM is thought to result from abnormal branching morphogenesis during fetal lung development, arising from different locations within the developing respiratory tract. However, the pathogenic mechanisms are unknown, and previous studies have focused on abnormalities in airway epithelial cells. We have analyzed 13 excised lung specimens from infants (age < 1 year) with a confirmed diagnosis of type 2 CPAM, which is supposed to be derived from abnormal growth of intrapulmonary distal airways. By examining the mesenchymal components including smooth muscle cells, laminin, and elastin in airway and cystic walls using immunofluorescence staining, we found that the thickness and area of the smooth muscle layer underlining the airway cysts in these CPAM tissue sections were significantly decreased compared with those in bronchiolar walls of normal controls. Extracellular elastin fibers were also visually reduced or absent in airway cystic walls. In particular, a layer of elastin fibers seen in normal lung between airway epithelia and underlying smooth muscle cells was missing in type 2 CPAM samples. Thus, our data demonstrate for the first time that airway cystic lesions in type 2 CPAM occur not only in airway epithelial cells, but also in adjacent mesenchymal tissues, including airway smooth muscle cells and their extracellular protein products. This provides a new direction to study the molecular and cellular mechanisms of CPAM pathogenesis in human.", "pubmedLink": "" },   "30923168": { "pmid": "30923168", "title": "The long noncoding RNA Falcor regulates Foxa2 expression to maintain lung epithelial homeostasis and promote regeneration.", "sortKey": "2019-06-the long noncoding r", "pubDateYear": "2019", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Swarr DT, Herriges M, Li S, Morley M, Fernandes S, Sridharan A, Zhou S, Garcia BA, Stewart K, Morrisey EE", "citation": "Genes & development, 06 2019", "abstractText": "Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in  to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.", "pubmedLink": "" },   "30847967": { "pmid": "30847967", "title": "Mapping and correcting hyperpolarized magnetization decay with radial keyhole imaging.", "sortKey": "2019-07-mapping and correcti", "pubDateYear": "2019", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Niedbalski PJ, Willmering MM, Robertson SH, Freeman MS, Loew W, Giaquinto RO, Ireland C, Pratt RG, Dumoulin CL, Woods JC, Cleveland ZI", "citation": "Magnetic resonance in medicine, 07 2019", "abstractText": "Hyperpolarized (HP) media enable biomedical imaging applications that cannot be achieved with conventional MRI contrast agents. Unfortunately, quantifying HP images is challenging, because relaxation and radio-frequency pulsing generate spatially varying signal decay during acquisition. We demonstrate that, by combining center-out k-space sampling with postacquisition keyhole reconstruction, voxel-by-voxel maps of regional HP magnetization decay can be generated with no additional data collection.", "pubmedLink": "" },   "30806029": { "pmid": "30806029", "title": "CFTR dysfunction increases endoglin and TGF-β signaling in airway epithelia.", "sortKey": "2019-02-cftr dysfunction inc", "pubDateYear": "2019", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Nicola T, Kabir FL, Coric T, Wall SB, Zhang W, James M, MacEwen M, Ren C, Halloran B, Ambalavanan N, Harris WT", "citation": "Physiological reports, 02 2019", "abstractText": "Endoglin (ENG) regulates signaling by transforming growth factor-β (TGF-β), a genetic modifier of cystic fibrosis (CF) lung disease severity. We hypothesized that ENG mediates TGF-β pathobiology in CF airway epithelia. Comparing CF and non-CF human lungs, we measured ENG by qPCR, immunoblotting and ELISA. In human bronchial epithelial cell lines (16HBE), we used CFTR siRNA knockdown and functional inhibition (CFTR -172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF-β transcription and signal amplification in 16HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid (BALF) and human CF lung homogenates. ENG transcripts were increased threefold in CF, with a twofold increase in TGF-β signaling. CFTR knockdown in 16HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF-β signaling. Plasmid overexpression of ENG alone nearly doubled TGF-β1 mRNA and increased TGF-β signaling in 16HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF-β signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF-β associated pathobiology in CF.", "pubmedLink": "" },   "30796179": { "pmid": "30796179", "title": "Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity.", "sortKey": "2019-04-circulating truncate", "pubDateYear": "2019", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Reeves EP, Dunlea DM, McQuillan K, O'Dwyer CA, Carroll TP, Saldova R, Akepati PR, Wormald MR, McElvaney OJ, Shutchaidat V, Henry M, Meleady P, Keenan J, Liberti DC, Kotton DN, Rudd PM, Wilson AA, McElvaney NG", "citation": "Journal of immunology (Baltimore, Md. : 1950), 04 2019", "abstractText": "Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune-regulatory and anti-inflammatory functions independent of antiprotease activity. AAT deficiency (AATD) is associated with early-onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed null or Q0), the majority of which arise from premature termination codons in the mRNA coding region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton allele ( ) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0-AAT. A low-abundance, truncated AAT protein was confirmed in plasma of a Q0-AATD patient and was secreted by patient-derived induced pluripotent stem cell-hepatic cells. Functional assays confirmed the ability of purified Q0-AAT protein to bind neutrophil elastase and to inhibit protease activity. Q0-AAT bound IL-8 and leukotriene B, comparable to healthy control M-AAT, and significantly decreased leukotriene B-induced neutrophil adhesion ( = 0.04). Through a mechanism involving increased mRNA stability ( = 0.007), ataluren treatment of HEK-293 significantly increased  mRNA expression ( = 0.03) and Q0-AAT truncated protein secretion ( = 0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.", "pubmedLink": "" },   "30782824": { "pmid": "30782824", "title": "Early lineage specification defines alveolar epithelial ontogeny in the murine lung.", "sortKey": "2019-03-early lineage specif", "pubDateYear": "2019", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Frank DB, Penkala IJ, Zepp JA, Sivakumar A, Linares-Saldana R, Zacharias WJ, Stolz KG, Pankin J, Lu M, Wang Q, Babu A, Li L, Zhou S, Morley MP, Jain R, Morrisey EE", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 03 2019", "abstractText": "During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal-distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.", "pubmedLink": "" },   "30776794": { "pmid": "30776794", "title": "A novel in vitro model of primary human pediatric lung epithelial cells.", "sortKey": "2020-02-a novel in vitro mod", "pubDateYear": "2020", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Wang Q, Bhattacharya S, Mereness JA, Anderson C, Lillis JA, Misra RS, Romas S, Huyck H, Howell A, Bandyopadhyay G, Donlon K, Myers JR, Ashton J, Pryhuber GS, Mariani TJ", "citation": "Pediatric research, 02 2020", "abstractText": "Current in vitro human lung epithelial cell models derived from adult tissues may not accurately represent all attributes that define homeostatic and disease mechanisms relevant to the pediatric lung.", "pubmedLink": "" },   "30604742": { "pmid": "30604742", "title": "Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth.", "sortKey": "2019-01-single cell rna anal", "pubDateYear": "2019", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Guo M, Du Y, Gokey JJ, Ray S, Bell SM, Adam M, Sudha P, Perl AK, Deshmukh H, Potter SS, Whitsett JA, Xu Y", "citation": "Nature communications, 01 2019", "abstractText": "The respiratory system undergoes a diversity of structural, biochemical, and functional changes necessary for adaptation to air breathing at birth. To identify the heterogeneity of pulmonary cell types and dynamic changes in gene expression mediating adaptation to respiration, here we perform single cell RNA analyses of mouse lung on postnatal day 1. Using an iterative cell type identification strategy we unbiasedly identify the heterogeneity of murine pulmonary cell types. We identify distinct populations of epithelial, endothelial, mesenchymal, and immune cells, each containing distinct subpopulations. Furthermore we compare temporal changes in RNA expression patterns before and after birth to identify signaling pathways selectively activated in specific pulmonary cell types, including activation of cell stress and the unfolded protein response during perinatal adaptation of the lung. The present data provide a single cell view of the adaptation to air breathing after birth.", "pubmedLink": "" },   "30596133": { "pmid": "30596133", "title": "Spatial distribution of marker gene activity in the mouse lung during alveolarization.", "sortKey": "2019-02-spatial distribution", "pubDateYear": "2019", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Ljungberg MC, Sadi M, Wang Y, Aronow BJ, Xu Y, Kao RJ, Liu Y, Gaddis N, Ardini-Poleske ME, Umrod T, Ambalavanan N, Nicola T, Kaminski N, Ahangari F, Sontag R, Corley RA, Ansong C, Carson JP", "citation": "Data in brief, 02 2019", "abstractText": "This data is a curated collection of visual images of gene expression patterns from the pre- and post-natal mouse lung, accompanied by associated mRNA probe sequences and RNA-Seq expression profiles. Mammalian lungs undergo significant growth and cellular differentiation before and after the transition to breathing air. Documenting normal lung development is an important step in understanding abnormal lung development, as well as the challenges faced during a preterm birth. Images in this dataset indicate the spatial distribution of mRNA transcripts for over 500 different genes that are active during lung development, as initially determined via RNA-Seq. Images were systematically acquired using high-throughput  hybridization with non-radioactive digoxigenin-labeled mRNA probes across mouse lungs from developmental time points E16.5, E18.5, P7, and P28. The dataset was produced as part of The Molecular Atlas of Lung Development Program (LungMAP) and is hosted at https://lungmap.net. This manuscript describes the nature of the data and the protocols for generating the dataset.", "pubmedLink": "" },   "30507980": { "pmid": "30507980", "title": "New mass spectrometry technologies contributing towards comprehensive and high throughput omics analyses of single cells.", "sortKey": "2019-01-new mass spectrometr", "pubDateYear": "2019", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Couvillion SP, Zhu Y, Nagy G, Adkins JN, Ansong C, Renslow RS, Piehowski PD, Ibrahim YM, Kelly RT, Metz TO", "citation": "The Analyst, 01 2019", "abstractText": "Mass-spectrometry based omics technologies - namely proteomics, metabolomics and lipidomics - have enabled the molecular level systems biology investigation of organisms in unprecedented detail. There has been increasing interest for gaining a thorough, functional understanding of the biological consequences associated with cellular heterogeneity in a wide variety of research areas such as developmental biology, precision medicine, cancer research and microbiome science. Recent advances in mass spectrometry (MS) instrumentation and sample handling strategies are quickly making comprehensive omics analyses of single cells feasible, but key breakthroughs are still required to push through remaining bottlenecks. In this review, we discuss the challenges faced by single cell MS-based omics analyses and highlight recent technological advances that collectively can contribute to comprehensive and high throughput omics analyses in single cells. We provide a vision of the potential of integrating pioneering technologies such as Structures for Lossless Ion Manipulations (SLIM) for improved sensitivity and resolution, novel peptide identification tactics and standards free metabolomics approaches for future applications in single cell analysis.", "pubmedLink": "" },   "30487069": { "pmid": "30487069", "title": "Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia.", "sortKey": "2018-11-genomics, microbiomi", "pubDateYear": "2018", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Lal CV, Bhandari V, Ambalavanan N", "citation": "Seminars in perinatology, 11 2018", "abstractText": "Bronchopulmonary Dysplasia (BPD) is a disorder with a multifactorial etiology and highly variable clinical phenotype. Several traditional biomarkers have been identified, but due to the complex disease phenotype, these biomarkers have low predictive accuracy for BPD. In recent years, newer technologies have facilitated the in-depth and unbiased analysis of  big data  in delineating the diagnosis, pathogenesis, and mechanisms of diseases. Novel systems-biology based  omic  approaches, including but not limited to genomics, microbiomics, proteomics, and metabolomics may help define the multiple cellular and humoral interactions that regulate normal as well as abnormal lung development and response to injury that are the hallmarks of BPD.", "pubmedLink": "" },   "30431340": { "pmid": "30431340", "title": "Airway Epithelial Differentiation and Mucociliary Clearance.", "sortKey": "2018-11-airway epithelial di", "pubDateYear": "2018", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Whitsett JA", "citation": "Annals of the American Thoracic Society, 11 2018", "abstractText": "The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system. Mucociliary clearance, mediated by the actions of diverse conducting airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system by secreting fluids, electrolytes, antimicrobial and antiinflammatory proteins, and mucus onto airway surfaces. The mucociliary escalator removes particles and pathogens by the mechanical actions of cilia and cough. Abnormalities in mucociliary clearance, whether related to impaired fluid secretion, ciliary dysfunction, lack of cough, or the disruption of epithelial cells lining the respiratory tract, contribute to the pathogenesis of common chronic pulmonary disorders. Although mucus and other airway epithelial secretions play a critical role in protecting the lung during acute injury, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, which contribute to morbidity in common pulmonary disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, and primary ciliary dyskinesia. In this summary, the molecular and cellular mechanisms mediating airway mucociliary clearance, as well as the role of goblet cell metaplasia and mucus hyperproduction, in the pathogenesis of chronic respiratory diseases are considered.", "pubmedLink": "" },   "30427276": { "pmid": "30427276", "title": "Building and Regenerating the Lung Cell by Cell.", "sortKey": "2019-01-building and regener", "pubDateYear": "2019", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Whitsett JA, Kalin TV, Xu Y, Kalinichenko VV", "citation": "Physiological reviews, 01 2019", "abstractText": "The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding the cellular and molecular mechanisms controlling its morphogenesis provides the framework for understanding the pathogenesis of acute and chronic lung diseases. Recent single-cell RNA sequencing data and high-resolution imaging identify the remarkable heterogeneity of pulmonary cell types and provides cell selective gene expression underlying lung development. We will address fundamental issues related to the diversity of pulmonary cells, to the formation and function of the mammalian lung, and will review recent advances regarding the cellular and molecular pathways involved in lung organogenesis. What cells form the lung in the early embryo? How are cell proliferation, migration, and differentiation regulated during lung morphogenesis? How do cells interact during lung formation and repair? How do signaling and transcriptional programs determine cell-cell interactions necessary for lung morphogenesis and function?", "pubmedLink": "" },   "30413314": { "pmid": "30413314", "title": "Neonatal Lung Disease Associated with TBX4 Mutations.", "sortKey": "2019-03-neonatal lung diseas", "pubDateYear": "2019", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Suhrie K, Pajor NM, Ahlfeld SK, Dawson DB, Dufendach KR, Kitzmiller JA, Leino D, Lombardo RC, Smolarek TA, Rathbun PA, Whitsett JA, Towe C, Wikenheiser-Brokamp KA", "citation": "The Journal of pediatrics, 03 2019", "abstractText": "Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.", "pubmedLink": "" },   "30357827": { "pmid": "30357827", "title": "Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse.", "sortKey": "2019-02-discordant roles for", "pubDateYear": "2019", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Danopoulos S, Thornton ME, Grubbs BH, Frey MR, Warburton D, Bellusci S, Al Alam D", "citation": "The Journal of pathology, 02 2019", "abstractText": "Fibroblast growth factor (FGF) signaling plays an important role in lung organogenesis. Over recent decades, FGF signaling in lung development has been extensively studied in animal models. However, little is known about the expression, localization, and functional roles of FGF ligands during human fetal lung development. Therefore, we aimed to determine the expression and function of several FGF ligands and receptors in human lung development. Using in situ hybridization (ISH) and RNA sequencing, we assessed their expression and distribution in native human fetal lung. Human fetal lung explants were treated with recombinant FGF7, FGF9, or FGF10 in air-liquid interface culture. Explants were analyzed grossly to observe differences in branching pattern as well as at the cellular and molecular level. ISH demonstrated that FGF7 is expressed in both the epithelium and mesenchyme; FGF9 is mainly localized in the distal epithelium, whereas FGF10 demonstrated diffuse expression throughout the parenchyma, with some expression in the smooth muscle cells (SMCs). FGFR2 expression was high in both proximal and distal epithelial cells as well as the SMCs. FGFR3 was expressed mostly in the epithelial cells, with lower expression in the mesenchyme, while FGFR4 was highly expressed throughout the mesenchyme and in the distal epithelium. Using recombinant FGFs, we demonstrated that FGF7 and FGF9 had similar effects on human fetal lung as on mouse fetal lung; however, FGF10 caused the human explants to expand and form cysts as opposed to inducing epithelial branching as seen in the mouse. In conjunction with decreased branching, treatment with recombinant FGF7, FGF9, and FGF10 also resulted in decreased double-positive SOX2/SOX9 progenitor cells, which are exclusively present in the distal epithelial tips in early human fetal lung. Although FGF ligand localization may be somewhat comparable between developing mouse and human lungs, their functional roles may differ substantially. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", "pubmedLink": "" },   "30271681": { "pmid": "30271681", "title": "Epigenetic Regulation of Myofibroblast Phenotypes in Fibrosis.", "sortKey": "2018-03-epigenetic regulatio", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Duong TE, Hagood JS", "citation": "Current pathobiology reports, 03 2018", "abstractText": "Myofibroblasts are the fundamental drivers of fibrosing disorders; there is great value in better defining epigenetic networks involved in myofibroblast behavior. Complex epigenetic paradigms, which are likely organ and/or disease specific, direct pathologic myofibroblast phenotypes. In this review, we highlight epigenetic regulators and the mechanisms through which they shape myofibroblast phenotype in fibrotic diseases of different organs.", "pubmedLink": "" },   "30194354": { "pmid": "30194354", "title": "Cell type-resolved human lung lipidome reveals cellular cooperation in lung function.", "sortKey": "2018-09-cell type-resolved h", "pubDateYear": "2018", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Kyle JE, Clair G, Bandyopadhyay G, Misra RS, Zink EM, Bloodsworth KJ, Shukla AK, Du Y, Lillis J, Myers JR, Ashton J, Bushnell T, Cochran M, Deutsch G, Baker ES, Carson JP, Mariani TJ, Xu Y, Whitsett JA, Pryhuber G, Ansong C", "citation": "Scientific reports, 09 2018", "abstractText": "Cell type-resolved proteome analyses of the brain, heart and liver have been reported, however a similar effort on the lipidome is currently lacking. Here we applied liquid chromatography-tandem mass spectrometry to characterize the lipidome of major lung cell types isolated from human donors, representing the first lipidome map of any organ. We coupled this with cell type-resolved proteomics of the same samples (available at Lungmap.net). Complementary proteomics analyses substantiated the functional identity of the isolated cells. Lipidomics analyses showed significant variations in the lipidome across major human lung cell types, with differences most evident at the subclass and intra-subclass (i.e. total carbon length of the fatty acid chains) level. Further, lipidomic signatures revealed an overarching posture of high cellular cooperation within the human lung to support critical functions. Our complementary cell type-resolved lipid and protein datasets serve as a rich resource for analyses of human lung function.", "pubmedLink": "" },   "30185671": { "pmid": "30185671", "title": "MEG3 is increased in idiopathic pulmonary fibrosis and regulates epithelial cell differentiation.", "sortKey": "2018-09-meg3 is increased in", "pubDateYear": "2018", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Gokey JJ, Snowball J, Sridharan A, Speth JP, Black KE, Hariri LP, Perl AT, Xu Y, Whitsett JA", "citation": "JCI insight, 09 2018", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease causing fibrotic remodeling of the peripheral lung, leading to respiratory failure. Peripheral pulmonary epithelial cells lose normal alveolar epithelial gene expression patterns and variably express genes associated with diverse conducting airway epithelial cells, including basal cells. Single-cell RNA sequencing of pulmonary epithelial cells isolated from IPF lung tissue demonstrated altered expression of LncRNAs, including increased MEG3. MEG3 RNA was highly expressed in subsets of the atypical IPF epithelial cells and correlated with conducting airway epithelial gene expression patterns. Expression of MEG3 in human pulmonary epithelial cell lines increased basal cell-associated RNAs, including TP63, KRT14, STAT3, and YAP1, and enhanced cell migration, consistent with a role for MEG3 in regulating basal cell identity. MEG3 reduced expression of TP73, SOX2, and Notch-associated RNAs HES1 and HEY1, in primary human bronchial epithelial cells, demonstrating a role for MEG3 in the inhibition of genes influencing basal cell differentiation into club, ciliated, or goblet cells. MEG3 induced basal cell genes and suppressed genes associated with terminal differentiation of airway cells, supporting a role for MEG3 in regulation of basal progenitor cell functions, which may contribute to tissue remodeling in IPF.", "pubmedLink": "" },   "30178494": { "pmid": "30178494", "title": "Regularized Latent Class Model for Joint Analysis of High-Dimensional Longitudinal Biomarkers and a Time-to-Event Outcome.", "sortKey": "2019-03-regularized latent c", "pubDateYear": "2019", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Sun J, Herazo-Maya JD, Molyneaux PL, Maher TM, Kaminski N, Zhao H", "citation": "Biometrics, 03 2019", "abstractText": "Although many modeling approaches have been developed to jointly analyze longitudinal biomarkers and a time-to-event outcome, most of these methods can only handle one or a few biomarkers. In this article, we propose a novel joint latent class model to deal with high dimensional longitudinal biomarkers. Our model has three components: a class membership model, a survival submodel, and a longitudinal submodel. In our model, we assume that covariates can potentially affect biomarkers and class membership. We adopt a penalized likelihood approach to infer which covariates have random effects and/or fixed effects on biomarkers, and which covariates are informative for the latent classes. Through extensive simulation studies, we show that our proposed method has improved performance in prediction and assigning subjects to the correct classes over other joint modeling methods and that bootstrap can be used to do inference for our model. We then apply our method to a dataset of patients with idiopathic pulmonary fibrosis, for whom gene expression profiles were measured longitudinally. We are able to identify four interesting latent classes with one class being at much higher risk of death compared to the other classes. We also find that each of the latent classes has unique trajectories in some genes, yielding novel biological insights.", "pubmedLink": "" },   "30153454": { "pmid": "30153454", "title": "FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme.", "sortKey": "2018-11-foxf1 transcription ", "pubDateYear": "2018", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Ustiyan V, Bolte C, Zhang Y, Han L, Xu Y, Yutzey KE, Zorn AM, Kalin TV, Shannon JM, Kalinichenko VV", "citation": "Developmental biology, 11 2018", "abstractText": "Organogenesis is regulated by mesenchymal-epithelial signaling events that induce expression of cell-type specific transcription factors critical for cellular proliferation, differentiation and appropriate tissue patterning. While mesenchymal transcription factors play a key role in mesenchymal-epithelial interactions, transcriptional networks in septum transversum and splanchnic mesenchyme remain poorly characterized. Forkhead Box F1 (FOXF1) transcription factor is expressed in mesenchymal cell lineages; however, its role in organogenesis remains uncharacterized due to early embryonic lethality of Foxf1 mice. In the present study, we generated mesenchyme-specific Foxf1 knockout mice (Dermo1-Cre Foxf1) and demonstrated that FOXF1 is required for development of respiratory, cardiovascular and gastrointestinal organ systems. Deletion of Foxf1 from mesenchyme caused embryonic lethality in the middle of gestation due to multiple developmental defects in the heart, lung, liver and esophagus. Deletion of Foxf1 inhibited mesenchyme proliferation and delayed branching lung morphogenesis. Gene expression profiling of micro-dissected distal lung mesenchyme and ChIP sequencing of fetal lung tissue identified multiple target genes activated by FOXF1, including Wnt2, Wnt11, Wnt5A and Hoxb7. FOXF1 decreased expression of the Wnt inhibitor Wif1 through direct transcriptional repression. Furthermore, using a global Foxf1 knockout mouse line (Foxf1) we demonstrated that FOXF1-deficiency disrupts the formation of the lung bud in foregut tissue explants. Finally, deletion of Foxf1 from smooth muscle cell lineage (smMHC-Cre Foxf1) caused hyper-extension of esophagus and trachea, loss of tracheal and esophageal muscle, mispatterning of esophageal epithelium and decreased proliferation of smooth muscle cells. Altogether, FOXF1 promotes lung morphogenesis by regulating mesenchymal-epithelial signaling and stimulating cellular proliferation in fetal lung mesenchyme.", "pubmedLink": "" },   "30141961": { "pmid": "30141961", "title": "BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis.", "sortKey": "2019-03-bal cell gene expres", "pubDateYear": "2019", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Prasse A, Binder H, Schupp JC, Kayser G, Bargagli E, Jaeger B, Hess M, Rittinghausen S, Vuga L, Lynn H, Violette S, Jung B, Quast K, Vanaudenaerde B, Xu Y, Hohlfeld JM, Krug N, Herazo-Maya JD, Rottoli P, Wuyts WA, Kaminski N", "citation": "American journal of respiratory and critical care medicine, 03 2019", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course.", "pubmedLink": "" },   "30095977": { "pmid": "30095977", "title": "Mechanisms of Ventilator-induced Lung Injury: Is the Elafin in the Room?", "sortKey": "2018-11-mechanisms of ventil", "pubDateYear": "2018", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Lal CV, Ambalavanan N", "citation": "American journal of respiratory cell and molecular biology, 11 2018", "pubmedLink": "" },   "30040246": { "pmid": "30040246", "title": "Derivation of Epithelial-Only Airway Organoids from Human Pluripotent Stem Cells.", "sortKey": "2018-05-derivation of epithe", "pubDateYear": "2018", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "McCauley KB, Hawkins F, Kotton DN", "citation": "Current protocols in stem cell biology, 05 2018", "abstractText": "New protocols to efficiently generate functional airway epithelial organoids from human pluripotent stem cells (PSCs) would represent a major advance towards effective disease modeling, drug screening and cell based therapies for lung disorders. This unit describes an approach using stage-specific signaling pathway manipulation to differentiate cells to proximal airway epithelium via key developmental intermediates. Cells are directed via definitive endoderm (DE) to anterior foregut, and then specified to NKX2-1+ lung epithelial progenitors. These lung progenitors are purified using cell surface marker sorting and replated in defined culture conditions to form three-dimensional, epithelial-only airway organoids. This directed differentiation approach using serum-free, defined media also includes protocols for evaluation of DE induction, intracellular FACS analysis of NKX2-1 specification efficiency and enrichment, and approaches for characterization and expansion of airway organoids. Taken together, this represents an efficient and reproducible approach to generate expandable airway organoids from human PSCs for use in numerous downstream applications. © 2018 by John Wiley & Sons, Inc.", "pubmedLink": "" },   "29975103": { "pmid": "29975103", "title": "Dissociation, cellular isolation, and initial molecular characterization of neonatal and pediatric human lung tissues.", "sortKey": "2018-10-dissociation, cellul", "pubDateYear": "2018", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Bandyopadhyay G, Huyck HL, Misra RS, Bhattacharya S, Wang Q, Mereness J, Lillis J, Myers JR, Ashton J, Bushnell T, Cochran M, Holden-Wiltse J, Katzman P, Deutsch G, Whitsett JA, Xu Y, Mariani TJ, Pryhuber GS", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2018", "abstractText": "Human lung morphogenesis begins by embryonic life and continues after birth into early childhood to form a complex organ with numerous morphologically and functionally distinct cell types. Pulmonary organogenesis involves dynamic changes in cell proliferation, differentiation, and migration of specialized cells derived from diverse embryonic lineages. Studying the molecular and cellular processes underlying formation of the fully functional lung requires isolating distinct pulmonary cell populations during development. We now report novel methods to isolate four major pulmonary cell populations from pediatric human lung simultaneously. Cells were dissociated by protease digestion of neonatal and pediatric lung and isolated on the basis of unique cell membrane protein expression patterns. Epithelial, endothelial, nonendothelial mesenchymal, and immune cells were enriched by fluorescence-activated cell sorting. Dead cells and erythrocytes were excluded by 7-aminoactinomycin D uptake and glycophorin-A (CD235a) expression, respectively. Leukocytes were identified by membrane CD45 (protein tyrosine phosphatase, receptor type C), endothelial cells by platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial cadherin (CD144), and both were isolated. Thereafter, epithelial cell adhesion molecule (CD326)-expressing cells were isolated from the endothelial- and immune cell-depleted population to enrich epithelial cells. Cells lacking these membrane markers were collected as  nonendothelial mesenchymal  cells. Quantitative RT-PCR and RNA sequencing analyses of population specific transcriptomes demonstrate the purity of the subpopulations of isolated cells. The method efficiently isolates major human lung cell populations that we announce are now available through the National Heart, Lung, and Blood Institute Lung Molecular Atlas Program (LungMAP) for their further study.", "pubmedLink": "" },   "29972024": { "pmid": "29972024", "title": "Multifunctional Activity-Based Protein Profiling of the Developing Lung.", "sortKey": "2018-08-multifunctional acti", "pubDateYear": "2018", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Stoddard EG, Volk RF, Carson JP, Ljungberg CM, Murphree TA, Smith JN, Sadler NC, Shukla AK, Ansong C, Wright AT", "citation": "Journal of proteome research, 08 2018", "abstractText": "Lung diseases and disorders are a leading cause of death among infants. Many of these diseases and disorders are caused by premature birth and underdeveloped lungs. In addition to developmentally related disorders, the lungs are exposed to a variety of environmental contaminants and xenobiotics upon birth that can cause breathing issues and are progenitors of cancer. In order to gain a deeper understanding of the developing lung, we applied an activity-based chemoproteomics approach for the functional characterization of the xenometabolizing cytochrome P450 enzymes, active ATP and nucleotide binding enzymes, and serine hydrolases using a suite of activity-based probes (ABPs). We detected P450 activity primarily in the postnatal lung; using our ATP-ABP, we characterized a wide range of ATPases and other active nucleotide- and nucleic acid-binding enzymes involved in multiple facets of cellular metabolism throughout development. ATP-ABP targets include kinases, phosphatases, NAD- and FAD-dependent enzymes, RNA/DNA helicases, and others. The serine hydrolase-targeting probe detected changes in the activities of several proteases during the course of lung development, yielding insights into protein turnover at different stages of development. Select activity-based probe targets were then correlated with RNA in situ hybridization analyses of lung tissue sections.", "pubmedLink": "" },   "29952221": { "pmid": "29952221", "title": "Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice.", "sortKey": "2018-10-iloprost attenuates ", "pubDateYear": "2018", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Olave N, Lal CV, Halloran B, Bhandari V, Ambalavanan N", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2018", "abstractText": "Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O) or hyperoxia (85% O) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg·day, nimesulide (selective COX-2 antagonist) 100 mg·kg·day, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.", "pubmedLink": "" },   "29871822": { "pmid": "29871822", "title": "The Lung and Esophagus: Developmental and Regenerative Overlap.", "sortKey": "2018-09-the lung and esophag", "pubDateYear": "2018", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Morrisey EE, Rustgi AK", "citation": "Trends in cell biology, 09 2018", "abstractText": "Lung and esophageal development and organogenesis involve a complex interplay of signaling pathways and transcriptional factors. Once the lung and esophagus do separate, their epithelial proliferation and differentiation programs share certain common properties that may fuel adaptive responses to injury and subsequent regeneration. Lung and esophageal tissue organogenesis and regeneration provide perspectives on squamous cell cancers and adenocarcinomas in each tissue.", "pubmedLink": "" },   "29844468": { "pmid": "29844468", "title": "Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development.", "sortKey": "2018-05-spatial and temporal", "pubDateYear": "2018", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Luo Y, Li N, Chen H, Fernandez GE, Warburton D, Moats R, Mecham RP, Krenitsky D, Pryhuber GS, Shi W", "citation": "Scientific reports, 05 2018", "abstractText": "Lung alveolarization requires precise coordination of cell growth with extracellular matrix (ECM) synthesis and deposition. The role of extracellular matrices in alveogenesis is not fully understood, because prior knowledge is largely extrapolated from two-dimensional structural analysis. Herein, we studied temporospatial changes of two important ECM proteins, laminin and elastin that are tightly associated with alveolar capillary growth and lung elastic recoil respectively, during both mouse and human lung alveolarization. By combining protein immunofluorescence staining with two- and three-dimensional imaging, we found that the laminin network was simplified along with the thinning of septal walls during alveogenesis, and more tightly associated with alveolar endothelial cells in matured lung. In contrast, elastin fibers were initially localized to the saccular openings of nascent alveoli, forming a ring-like structure. Then, throughout alveolar growth, the number of such alveolar mouth ring-like structures increased, while the relative ring size decreased. These rings were interconnected via additional elastin fibers. The apparent patches and dots of elastin at the tips of alveolar septae found in two-dimensional images were cross sections of elastin ring fibers in the three-dimension. Thus, the previous concept that deposition of elastin at alveolar tips drives septal inward growth may potentially be conceptually challenged by our data.", "pubmedLink": "" },   "29797682": { "pmid": "29797682", "title": "Proteomic Analysis of Single Mammalian Cells Enabled by Microfluidic Nanodroplet Sample Preparation and Ultrasensitive NanoLC-MS.", "sortKey": "2018-09-proteomic analysis o", "pubDateYear": "2018", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Zhu Y, Clair G, Chrisler WB, Shen Y, Zhao R, Shukla AK, Moore RJ, Misra RS, Pryhuber GS, Smith RD, Ansong C, Kelly RT", "citation": "Angewandte Chemie (International ed. in English), 09 2018", "abstractText": "We report on the quantitative proteomic analysis of single mammalian cells. Fluorescence-activated cell sorting was employed to deposit cells into a newly developed nanodroplet sample processing chip, after which samples were analyzed by ultrasensitive nanoLC-MS. An average of circa 670 protein groups were confidently identified from single HeLa cells, which is a far greater level of proteome coverage for single cells than has been previously reported. We demonstrate that the single-cell proteomics platform can be used to differentiate cell types from enzyme-dissociated human lung primary cells and identify specific protein markers for epithelial and mesenchymal cells.", "pubmedLink": "" },   "29789704": { "pmid": "29789704", "title": "Single-cell RNA sequencing for the study of development, physiology and disease.", "sortKey": "2018-08-single-cell rna sequ", "pubDateYear": "2018", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Potter SS", "citation": "Nature reviews. Nephrology, 08 2018", "abstractText": "An ongoing technological revolution is continually improving our ability to carry out very high-resolution studies of gene expression patterns. Current technology enables the global gene expression profiles of single cells to be defined, facilitating dissection of heterogeneity in cell populations that was previously hidden. In contrast to gene expression studies that use bulk RNA samples and provide only a virtual average of the diverse constituent cells, single-cell studies enable the molecular distinction of all cell types within a complex population mix, such as a tumour or developing organ. For instance, single-cell gene expression profiling has contributed to improved understanding of how histologically identical, adjacent cells make different differentiation decisions during development. Beyond development, single-cell gene expression studies have enabled the characteristics of previously known cell types to be more fully defined and facilitated the identification of novel categories of cells, contributing to improvements in our understanding of both normal and disease-related physiological processes and leading to the identification of new treatment approaches. Although limitations remain to be overcome, technology for the analysis of single-cell gene expression patterns is improving rapidly and beginning to provide a detailed atlas of the gene expression patterns of all cell types in the human body.", "pubmedLink": "" },   "29657097": { "pmid": "29657097", "title": "Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium.", "sortKey": "2018-05-single-cell transcri", "pubDateYear": "2018", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "McCauley KB, Alysandratos KD, Jacob A, Hawkins F, Caballero IS, Vedaie M, Yang W, Slovik KJ, Morley M, Carraro G, Kook S, Guttentag SH, Stripp BR, Morrisey EE, Kotton DN", "citation": "Stem cell reports, 05 2018", "abstractText": "Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the characterization of these cells. Here, we engineer mouse and human PSC lines carrying airway secretory lineage reporters that facilitate the tracking, purification, and profiling of this lung subtype. Through bulk and single-cell-based global transcriptomic profiling, we find PSC-derived airway secretory cells are susceptible to phenotypic plasticity exemplified by the tendency to co-express both a proximal airway secretory program as well as an alveolar type 2 cell program, which can be minimized by inhibiting endogenous Wnt signaling. Our results provide global profiles of engineered lung cell fates, a guide for improving their directed differentiation, and a human model of the developing airway.", "pubmedLink": "" },   "29642003": { "pmid": "29642003", "title": "FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.", "sortKey": "2018-04-foxf1 inhibits pulmo", "pubDateYear": "2018", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Black M, Milewski D, Le T, Ren X, Xu Y, Kalinichenko VV, Kalin TV", "citation": "Cell reports, 04 2018", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies, and transgenic mice with fibroblast-specific inactivation of FOXF1, we show that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion and collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step in the acquisition of the pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts.", "pubmedLink": "" },   "29567123": { "pmid": "29567123", "title": "Fibrosis: Lessons from OMICS analyses of the human lung.", "sortKey": "2018-08-fibrosis: lessons fr", "pubDateYear": "2018", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Yu G, Ibarra GH, Kaminski N", "citation": "Matrix biology : journal of the International Society for Matrix Biology, 08 2018", "abstractText": "In recent decades there has been a significant shift in our understanding of idiopathic pulmonary fibrosis (IPF), a progressive and lethal disorder. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models of disease, in recent decades new insights derived from humans with IPF have taken precedence. This is mainly because of the establishment of large collections of IPF lung tissues and patient cohorts, and the emergence of high throughput profiling technologies collectively termed  omics  technologies based on their shared suffix. In this review we describe impacts of  omics  analyses of human IPF samples on our understanding of the disease. In particular, we discuss the results of genomics and transcriptomics studies, as well as proteomics, epigenomics and metabolomics. We then describe how these findings can be integrated in a modified paradigm of human idiopathic pulmonary fibrosis, that introduces the  hallmarks of aging  as a central theme in the IPF lung. This allows resolution of all the disparate cellular and molecular features in IPF, from the central role of epithelial cells, through the dramatic phenotypic alterations observed in fibroblasts and the numerous aberrations that inflammatory cells exhibit. We end with reiterating a call for renewed efforts to collect and analyze carefully characterized human tissues, in ways that would facilitate implementation of novel technologies for high resolution single cell omics profiling.", "pubmedLink": "" },   "29563341": { "pmid": "29563341", "title": "Active epithelial Hippo signaling in idiopathic pulmonary fibrosis.", "sortKey": "2018-03-active epithelial hi", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Gokey JJ, Sridharan A, Xu Y, Green J, Carraro G, Stripp BR, Perl AT, Whitsett JA", "citation": "JCI insight, 03 2018", "abstractText": "Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.", "pubmedLink": "" },   "29552412": { "pmid": "29552412", "title": "Fiber pattern removal and image reconstruction method for snapshot mosaic hyperspectral endoscopic images.", "sortKey": "2018-02-fiber pattern remova", "pubDateYear": "2018", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Wang P, Turcatel G, Arnesano C, Warburton D, Fraser SE, Cutrale F", "citation": "Biomedical optics express, 02 2018", "abstractText": "Hyperspectral endoscopic imaging has the potential to enhance clinical diagnostics and outcome. Most commercial endoscopes utilize imaging fiber bundles to transmit the collected signal from the patient to the medical operator. These bundles consist of several fiber cores surrounded by a cladding layer creating comb structure-like artifacts, which complicate further analysis, both spatially and spectrally. Here we present an optical fiber pattern removal algorithm which we applied to hyperspectral bronchoscopic images robustly and quantitatively without the need for specific optical or electrical hardware. We validate the performance of the pattern removal by using a novel hyperspectral phasor approach. This algorithm can be generalized to all forms of fiber bundle hyperspectral endoscopy.", "pubmedLink": "" },   "29538379": { "pmid": "29538379", "title": "iDREM: Interactive visualization of dynamic regulatory networks.", "sortKey": "2018-03-idrem: interactive v", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Ding J, Hagood JS, Ambalavanan N, Kaminski N, Bar-Joseph Z", "citation": "PLoS computational biology, 03 2018", "abstractText": "The Dynamic Regulatory Events Miner (DREM) software reconstructs dynamic regulatory networks by integrating static protein-DNA interaction data with time series gene expression data. In recent years, several additional types of high-throughput time series data have been profiled when studying biological processes including time series miRNA expression, proteomics, epigenomics and single cell RNA-Seq. Combining all available time series and static datasets in a unified model remains an important challenge and goal. To address this challenge we have developed a new version of DREM termed interactive DREM (iDREM). iDREM provides support for all data types mentioned above and combines them with existing interaction data to reconstruct networks that can lead to novel hypotheses on the function and timing of regulators. Users can interactively visualize and query the resulting model. We showcase the functionality of the new tool by applying it to microglia developmental data from multiple labs.", "pubmedLink": "" },   "29516783": { "pmid": "29516783", "title": "Time-resolved proteome profiling of normal lung development.", "sortKey": "2018-07-time-resolved proteo", "pubDateYear": "2018", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Moghieb A, Clair G, Mitchell HD, Kitzmiller J, Zink EM, Kim YM, Petyuk V, Shukla A, Moore RJ, Metz TO, Carson J, McDermott JE, Corley RA, Whitsett JA, Ansong C", "citation": "American journal of physiology. Lung cellular and molecular physiology, 07 2018", "abstractText": "Biochemical networks mediating normal lung morphogenesis and function have important implications for ameliorating morbidity and mortality in premature infants. Although several transcript-level studies have examined normal lung development, corresponding protein-level analyses are lacking. Here we performed proteomics analysis of murine lungs from embryonic to early adult ages to identify the molecular networks mediating normal lung development. We identified 8,932 proteins, providing a deep and comprehensive view of the lung proteome. Analysis of the proteomics data revealed discrete modules and the underlying regulatory and signaling network modulating their expression during development. Our data support the cell proliferation that characterizes early lung development and highlight responses of the lung to exposure to a nonsterile oxygen-rich ambient environment and the important role of lipid (surfactant) metabolism in lung development. Comparison of dynamic regulation of proteomic and recent transcriptomic analyses identified biological processes under posttranscriptional control. Our study provides a unique proteomic resource for understanding normal lung formation and function and can be freely accessed at Lungmap.net.", "pubmedLink": "" },   "29508300": { "pmid": "29508300", "title": "Single-Cell Transcriptome Analysis Using SINCERA Pipeline.", "sortKey": "2018-00-single-cell transcri", "pubDateYear": "2018", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Guo M, Xu Y", "citation": "Methods in molecular biology (Clifton, N.J.), 00 2018", "abstractText": "Genome-scale single-cell biology has recently emerged as a powerful technology with important implications for both basic and medical research. There are urgent needs for the development of computational methods or analytic pipelines to facilitate large amounts of single-cell RNA-Seq data analysis. Here, we present a detailed protocol for SINCERA (SINgle CEll RNA-Seq profiling Analysis), a generally applicable analytic pipeline for processing single-cell data from a whole organ or sorted cells. The pipeline supports the analysis for the identification of major cell types, cell type-specific gene signatures, and driving forces of given cell types. In this chapter, we provide step-by-step instructions for the functions and features of SINCERA together with application examples to provide a practical guide for the research community. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html .", "pubmedLink": "" },   "29489752": { "pmid": "29489752", "title": "Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor.", "sortKey": "2018-03-regeneration of the ", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Zacharias WJ, Frank DB, Zepp JA, Morley MP, Alkhaleel FA, Kong J, Zhou S, Cantu E, Morrisey EE", "citation": "Nature, 03 2018", "abstractText": "Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.", "pubmedLink": "" },   "29400691": { "pmid": "29400691", "title": "Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation.", "sortKey": "2018-03-claudin-18: unexpect", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Kotton DN", "citation": "The Journal of clinical investigation, 03 2018", "abstractText": "Claudin 18 (CLDN18) is a tight junction protein that is highly expressed in the lung. While mice lacking CLDN18 exhibit the expected loss of epithelial integrity in the lung, these animals also have unexpectedly large lungs. In this issue of the JCI, Zhou, Flodby, and colleagues reveal that the increased lung size of Cldn18-/- mice is the result of increased type 2 alveolar epithelial (AT2) cell proliferation. This increase in proliferation was shown to be driven by translocation of the transcriptional regulator Yes-associated protein (YAP) to the nucleus and subsequent induction of proliferative pathways. CLDN18-deficent mice also had increased frequency of lung adenocarcinomas. Together, the results of this study advance our understanding of the mechanisms that likely regulate homeostasis of the normal lung as well as promote the proliferative state of malignant cells found in lung adenocarcinomas thought to originate from AT2 cells.", "pubmedLink": "" },   "29361566": { "pmid": "29361566", "title": "Runx1 is sufficient for blood cell formation from non-hemogenic endothelial cells  only during early embryogenesis.", "sortKey": "2018-01-runx1 is sufficient ", "pubDateYear": "2018", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Yzaguirre AD, Howell ED, Li Y, Liu Z, Speck NA", "citation": "Development (Cambridge, England), 01 2018", "abstractText": "Hematopoietic cells differentiate during embryogenesis from a population of endothelial cells called hemogenic endothelium (HE) in a process called the endothelial-to-hematopoietic transition (EHT). The transcription factor Runx1 is required for EHT, but for how long and which endothelial cells are competent to respond to Runx1 are not known. Here, we show that the ability of Runx1 to induce EHT in non-hemogenic endothelial cells depends on the anatomical location of the cell and the developmental age of the conceptus. Ectopic expression of Runx1 in non-hemogenic endothelial cells between embryonic day (E) 7.5 and E8.5 promoted the formation of erythro-myeloid progenitors (EMPs) specifically in the yolk sac, the dorsal aorta and the heart. The increase in EMPs was accompanied by a higher frequency of HE cells able to differentiate into EMPs  Expression of Runx1 just 1 day later (E8.5-E9.5) failed to induce the ectopic formation of EMPs. Therefore, endothelial cells, located in specific sites in the conceptus, have a short developmental window of competency during which they can respond to Runx1 and differentiate into blood cells.", "pubmedLink": "" },   "29354322": { "pmid": "29354322", "title": "Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury.", "sortKey": "2017-00-local and sustained ", "pubDateYear": "2017", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Wang LL, Liu Y, Chung JJ, Wang T, Gaffey AC, Lu M, Cavanaugh CA, Zhou S, Kanade R, Atluri P, Morrisey EE, Burdick JA", "citation": "Nature biomedical engineering, 00 2017", "abstractText": "MicroRNA-based therapies that target cardiomyocyte proliferation have great potential for the treatment of myocardial infarction (MI). In previous work, we showed that the miR-302/367 cluster regulates cardiomyocyte proliferation in the prenatal and postnatal heart. Here, we describe the development and application of an injectable hyaluronic acid (HA) hydrogel for the local and sustained delivery of miR-302 mimics to the heart. We show that the miR-302 mimics released in vitro promoted cardiomyocyte proliferation over one week, and that a single injection of the hydrogel in the mouse heart led to local and sustained cardiomyocyte proliferation for two weeks. After MI, gel/miR-302 injection caused local clonal proliferation and increased cardiomyocyte numbers in the border zone of a Confetti mouse model. Gel/miR-302 further decreased cardiac end-diastolic (39%) and end-systolic (50%) volumes, and improved ejection fraction (32%) and fractional shortening (64%) four weeks after MI and injection, compared to controls. Our findings suggest that biomaterial-based miRNA delivery systems can lead to improved outcomes in cardiac regeneration.", "pubmedLink": "" },   "29317474": { "pmid": "29317474", "title": "Reconstructing differentiation networks and their regulation from time series single-cell expression data.", "sortKey": "2018-03-reconstructing diffe", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Ding J, Aronow BJ, Kaminski N, Kitzmiller J, Whitsett JA, Bar-Joseph Z", "citation": "Genome research, 03 2018", "abstractText": "Generating detailed and accurate organogenesis models using single-cell RNA-seq data remains a major challenge. Current methods have relied primarily on the assumption that descendant cells are similar to their parents in terms of gene expression levels. These assumptions do not always hold for in vivo studies, which often include infrequently sampled, unsynchronized, and diverse cell populations. Thus, additional information may be needed to determine the correct ordering and branching of progenitor cells and the set of transcription factors (TFs) that are active during advancing stages of organogenesis. To enable such modeling, we have developed a method that learns a probabilistic model that integrates expression similarity with regulatory information to reconstruct the dynamic developmental cell trajectories. When applied to mouse lung developmental data, the method accurately distinguished different cell types and lineages. Existing and new experimental data validated the ability of the method to identify key regulators of cell fate.", "pubmedLink": "" },   "29282253": { "pmid": "29282253", "title": "Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1.", "sortKey": "2018-02-maturation of hemato", "pubDateYear": "2018", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Tober J, Maijenburg MMW, Li Y, Gao L, Hadland BK, Gao P, Minoura K, Bernstein ID, Tan K, Speck NA", "citation": "The Journal of experimental medicine, 02 2018", "abstractText": "Hematopoietic stem cells (HSCs) mature from pre-HSCs that originate in the major arteries of the embryo. To identify HSCs from in vitro sources, it will be necessary to refine markers of HSCs matured ex vivo. We purified and compared the transcriptomes of pre-HSCs, HSCs matured ex vivo, and fetal liver HSCs. We found that HSC maturation in vivo or ex vivo is accompanied by the down-regulation of genes involved in embryonic development and vasculogenesis, and up-regulation of genes involved in hematopoietic organ development, lymphoid development, and immune responses. Ex vivo matured HSCs more closely resemble fetal liver HSCs than pre-HSCs, but are not their molecular equivalents. We show that ex vivo-matured and fetal liver HSCs express programmed death ligand 1 (PD-L1). PD-L1 does not mark all pre-HSCs, but cell surface PD-L1 was present on HSCs matured ex vivo. PD-L1 signaling is not required for engraftment of embryonic HSCs. Hence, up-regulation of PD-L1 is a correlate of, but not a requirement for, HSC maturation.", "pubmedLink": "" },   "29273797": { "pmid": "29273797", "title": "Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.", "sortKey": "2017-12-thy-1 dependent upta", "pubDateYear": "2017", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Shentu TP, Huang TS, Cernelc-Kohan M, Chan J, Wong SS, Espinoza CR, Tan C, Gramaglia I, van der Heyde H, Chien S, Hagood JS", "citation": "Scientific reports, 12 2017", "abstractText": "Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established. We demonstrate that mEVs, but not fibroblast EVs (fEVs), suppress TGFβ1-induced myofibroblastic differentiation of normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. MEVs display increased time- and dose-dependent cellular uptake compared to fEVs. Removal or blocking of Thy-1, or blocking Thy-1-beta integrin interactions, decreased mEV uptake and prevented suppression of myofibroblastic differentiation. MicroRNAs (miRs) 199a/b-3p, 21-5p, 630, 22-3p, 196a-5p, 199b-5p, 34a-5p and 148a-3p are selectively packaged in mEVs. In silico analyses indicated that IPF lung fibroblasts have increased expression of genes that are targets of mEV-enriched miRs. MiR-630 mimics blocked TGFβ1 induction of CDH2 in normal and IPF fibroblasts, and antagomiR-630 abrogated the effect of mEV on CDH2 expression. These data suggest that the interaction of Thy-1 with beta integrins mediates mEV uptake by lung fibroblasts, which blocks myofibroblastic differentiation, and that mEVs are enriched for miRs that target profibrotic genes up-regulated in IPF fibroblasts.", "pubmedLink": "" },   "29270905": { "pmid": "29270905", "title": "The Oxygen Paradox, the French Paradox, and age-related diseases.", "sortKey": "2017-12-the oxygen paradox, ", "pubDateYear": "2017", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Davies JMS, Cillard J, Friguet B, Cadenas E, Cadet J, Cayce R, Fishmann A, Liao D, Bulteau AL, Derbré F, Rébillard A, Burstein S, Hirsch E, Kloner RA, Jakowec M, Petzinger G, Sauce D, Sennlaub F, Limon I, Ursini F, Maiorino M, Economides C, Pike CJ, Cohen P, Salvayre AN, Halliday MR, Lundquist AJ, Jakowec NA, Mechta-Grigoriou F, Mericskay M, Mariani J, Li Z, Huang D, Grant E, Forman HJ, Finch CE, Sun PY, Pomatto LCD, Agbulut O, Warburton D, Neri C, Rouis M, Cillard P, Capeau J, Rosenbaum J, Davies KJA", "citation": "GeroScience, 12 2017", "abstractText": "A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen  a toxic environmental poison  could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance,  healthspan,   lifespan,  and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as  Adaptive Homeostasis  (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.", "pubmedLink": "" },   "29263307": { "pmid": "29263307", "title": "Alveolar injury and regeneration following deletion of ABCA3.", "sortKey": "2017-12-alveolar injury and ", "pubDateYear": "2017", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Rindler TN, Stockman CA, Filuta AL, Brown KM, Snowball JM, Zhou W, Veldhuizen R, Zink EM, Dautel SE, Clair G, Ansong C, Xu Y, Bridges JP, Whitsett JA", "citation": "JCI insight, 12 2017", "abstractText": "Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants. We conditionally deleted the Abca3 gene in AT2 cells in the mature mouse lung. Loss of ABCA3 caused alveolar cell injury and respiratory failure. ABCA3-related lung dysfunction was associated with surfactant deficiency, inflammation, and alveolar-capillary leak. Extensive but incomplete deletion of ABCA3 caused alveolar injury and inflammation, and it initiated proliferation of progenitor cells, restoring ABCA3 expression, lung structure, and function. M2-like macrophages were recruited to sites of AT2 cell proliferation during the regenerative process and were present in lung tissue from patients with severe lung disease caused by mutations in ABCA3. The remarkable and selective regeneration of ABCA3-sufficient AT2 progenitor cells provides plausible approaches for future correction of ABCA3 and other genetic disorders associated with surfactant deficiency and acute interstitial lung disease.", "pubmedLink": "" },   "29232160": { "pmid": "29232160", "title": "MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia.", "sortKey": "2018-03-microrna-145 antagon", "pubDateYear": "2018", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Lutful Kabir F, Ambalavanan N, Liu G, Li P, Solomon GM, Lal CV, Mazur M, Halloran B, Szul T, Gerthoffer WT, Rowe SM, Harris WT", "citation": "American journal of respiratory and critical care medicine, 03 2018", "abstractText": "MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3 -untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-β.", "pubmedLink": "" },   "29083321": { "pmid": "29083321", "title": "EMC3 coordinates surfactant protein and lipid homeostasis required for respiration.", "sortKey": "2017-12-emc3 coordinates sur", "pubDateYear": "2017", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Tang X, Snowball JM, Xu Y, Na CL, Weaver TE, Clair G, Kyle JE, Zink EM, Ansong C, Wei W, Huang M, Lin X, Whitsett JA", "citation": "The Journal of clinical investigation, 12 2017", "abstractText": "Adaptation to respiration at birth depends upon the synthesis of pulmonary surfactant, a lipid-protein complex that reduces surface tension at the air-liquid interface in the alveoli and prevents lung collapse during the ventilatory cycle. Herein, we demonstrated that the gene encoding a subunit of the endoplasmic reticulum membrane complex, EMC3, also known as TMEM111 (Emc3/Tmem111), was required for murine pulmonary surfactant synthesis and lung function at birth. Conditional deletion of Emc3 in murine embryonic lung epithelial cells disrupted the synthesis and packaging of surfactant lipids and proteins, impaired the formation of lamellar bodies, and induced the unfolded protein response in alveolar type 2 (AT2) cells. EMC3 was essential for the processing and routing of surfactant proteins, SP-B and SP-C, and the biogenesis of the phospholipid transport protein ABCA3. Transcriptomic, lipidomic, and proteomic analyses demonstrated that EMC3 coordinates the assembly of lipids and proteins in AT2 cells that is necessary for surfactant synthesis and function at birth.", "pubmedLink": "" },   "28980276": { "pmid": "28980276", "title": "Quantitative Proteomic Analysis of Mass Limited Tissue Samples for Spatially Resolved Tissue Profiling.", "sortKey": "2018-00-quantitative proteom", "pubDateYear": "2018", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Piehowski PD, Zhao R, Moore RJ, Clair G, Ansong C", "citation": "Methods in molecular biology (Clifton, N.J.), 00 2018", "abstractText": "Traditionally, proteomic studies have been carried out on whole tissues or organs enabling the profiling of thousands of proteins within a single LC-MS analysis. A disadvantage of this approach is that proteomes generated from whole tissues are an  average  that represents a blend of cell types and distinct anatomical regions which can obscure important biological phenomena. Laser capture microdissection (LCM) is an elegant method that allows tissue features of interest, as small as a single cell, to be identified and isolated for downstream analysis. Herein we describe an approach that utilizes an immobilized enzyme reactor (IMER) coupled directly to nanoLC-MS/MS for highly sensitive, automated, quantitative proteomic analysis of the microscopic tissue specimens generated by LCM.", "pubmedLink": "" },   "28965766": { "pmid": "28965766", "title": "Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.", "sortKey": "2017-10-differentiation of h", "pubDateYear": "2017", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Jacob A, Morley M, Hawkins F, McCauley KB, Jean JC, Heins H, Na CL, Weaver TE, Vedaie M, Hurley K, Hinds A, Russo SJ, Kook S, Zacharias W, Ochs M, Traber K, Quinton LJ, Crane A, Davis BR, White FV, Wambach J, Whitsett JA, Cole FS, Morrisey EE, Guttentag SH, Beers MF, Kotton DN", "citation": "Cell stem cell, 10 2017", "abstractText": "Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial  alveolospheres  in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung.", "pubmedLink": "" },   "28947536": { "pmid": "28947536", "title": "Pluripotent stem cell differentiation reveals distinct developmental pathways regulating lung- versus thyroid-lineage specification.", "sortKey": "2017-11-pluripotent stem cel", "pubDateYear": "2017", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Serra M, Alysandratos KD, Hawkins F, McCauley KB, Jacob A, Choi J, Caballero IS, Vedaie M, Kurmann AA, Ikonomou L, Hollenberg AN, Shannon JM, Kotton DN", "citation": "Development (Cambridge, England), 11 2017", "abstractText": "The -directed differentiation of pluripotent stem cells (PSCs) through stimulation of developmental signaling pathways can generate mature somatic cell types for basic laboratory studies or regenerative therapies. However, there has been significant uncertainty regarding a method to separately derive lung versus thyroid epithelial lineages, as these two cell types each originate from Nkx2-1 foregut progenitors and the minimal pathways claimed to regulate their distinct lineage specification  or  have varied in previous reports. Here, we employ PSCs to identify the key minimal signaling pathways (Wnt+BMP versus BMP+FGF) that regulate distinct lung- versus thyroid-lineage specification, respectively, from foregut endoderm. In contrast to most previous reports, these minimal pathways appear to be evolutionarily conserved between mice and humans, and FGF signaling, although required for thyroid specification, unexpectedly appears to be dispensable for lung specification. Once specified, distinct Nkx2-1 lung or thyroid progenitor pools can now be independently derived for functional 3D culture maturation, basic developmental studies or future regenerative therapies.", "pubmedLink": "" },   "28886382": { "pmid": "28886382", "title": "Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung.", "sortKey": "2017-09-distinct mesenchymal", "pubDateYear": "2017", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, Morrisey EE", "citation": "Cell, 09 2017", "abstractText": "The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.", "pubmedLink": "" },   "28862507": { "pmid": "28862507", "title": "A  GLI-tch  in Alveolar Myofibroblast Differentiation.", "sortKey": "2017-09-a  gli-tch  in alveo", "pubDateYear": "2017", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Ahlfeld SK, Perl AK", "citation": "American journal of respiratory cell and molecular biology, 09 2017", "pubmedLink": "" },   "28813672": { "pmid": "28813672", "title": "Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis.", "sortKey": "2017-08-chromatin and transc", "pubDateYear": "2017", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Palpant NJ, Wang Y, Hadland B, Zaunbrecher RJ, Redd M, Jones D, Pabon L, Jain R, Epstein J, Ruzzo WL, Zheng Y, Bernstein I, Margolin A, Murry CE", "citation": "Cell reports, 08 2017", "abstractText": "We analyzed chromatin dynamics and transcriptional activity of human embryonic stem cell (hESC)-derived cardiac progenitor cells (CPCs) and KDR/CD34 endothelial cells generated from different mesodermal origins. Using an unbiased algorithm to hierarchically rank genes modulated at the level of chromatin and transcription, we identified candidate regulators of mesodermal lineage determination. HOPX, a non-DNA-binding homeodomain protein, was identified as a candidate regulator of blood-forming endothelial cells. Using HOPX reporter and knockout hESCs, we show that HOPX regulates blood formation. Loss of HOPX does not impact endothelial fate specification but markedly reduces primitive hematopoiesis, acting at least in part through failure to suppress Wnt/β-catenin signaling. Thus, chromatin state analysis permits identification of regulators of mesodermal specification, including a conserved role for HOPX in governing primitive hematopoiesis.", "pubmedLink": "" },   "28798251": { "pmid": "28798251", "title": "LungMAP: The Molecular Atlas of Lung Development Program.", "sortKey": "2017-11-lungmap: the molecul", "pubDateYear": "2017", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Ardini-Poleske ME, Clark RF, Ansong C, Carson JP, Corley RA, Deutsch GH, Hagood JS, Kaminski N, Mariani TJ, Potter SS, Pryhuber GS, Warburton D, Whitsett JA, Palmer SM, Ambalavanan N,  ", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2017", "abstractText": "The National Heart, Lung, and Blood Institute is funding an effort to create a molecular atlas of the developing lung (LungMAP) to serve as a research resource and public education tool. The lung is a complex organ with lengthy development time driven by interactive gene networks and dynamic cross talk among multiple cell types to control and coordinate lineage specification, cell proliferation, differentiation, migration, morphogenesis, and injury repair. A better understanding of the processes that regulate lung development, particularly alveologenesis, will have a significant impact on survival rates for premature infants born with incomplete lung development and will facilitate lung injury repair and regeneration in adults. A consortium of four research centers, a data coordinating center, and a human tissue repository provides high-quality molecular data of developing human and mouse lungs. LungMAP includes mouse and human data for cross correlation of developmental processes across species. LungMAP is generating foundational data and analysis, creating a web portal for presentation of results and public sharing of data sets, establishing a repository of young human lung tissues obtained through organ donor organizations, and developing a comprehensive lung ontology that incorporates the latest findings of the consortium. The LungMAP website (www.lungmap.net) currently contains more than 6,000 high-resolution lung images and transcriptomic, proteomic, and lipidomic human and mouse data and provides scientific information to stimulate interest in research careers for young audiences. This paper presents a brief description of research conducted by the consortium, database, and portal development and upcoming features that will enhance the LungMAP experience for a community of users.", "pubmedLink": "" },   "28783377": { "pmid": "28783377", "title": "Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.", "sortKey": "2017-12-extracellular mitoch", "pubDateYear": "2017", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Ryu C, Sun H, Gulati M, Herazo-Maya JD, Chen Y, Osafo-Addo A, Brandsdorfer C, Winkler J, Blaul C, Faunce J, Pan H, Woolard T, Tzouvelekis A, Antin-Ozerkis DE, Puchalski JT, Slade M, Gonzalez AL, Bogenhagen DF, Kirillov V, Feghali-Bostwick C, Gibson K, Lindell K, Herzog RI, Dela Cruz CS, Mehal W, Kaminski N, Herzog EL, Trujillo G", "citation": "American journal of respiratory and critical care medicine, 12 2017", "abstractText": "Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.", "pubmedLink": "" },   "28755258": { "pmid": "28755258", "title": "Towards High-Resolution Tissue Imaging Using Nanospray Desorption Electrospray Ionization Mass Spectrometry Coupled to Shear Force Microscopy.", "sortKey": "2018-02-towards high-resolut", "pubDateYear": "2018", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Nguyen SN, Sontag RL, Carson JP, Corley RA, Ansong C, Laskin J", "citation": "Journal of the American Society for Mass Spectrometry, 02 2018", "abstractText": "Constant mode ambient mass spectrometry imaging (MSI) of tissue sections with high lateral resolution of better than 10 μm was performed by combining shear force microscopy with nanospray desorption electrospray ionization (nano-DESI). Shear force microscopy enabled precise control of the distance between the sample and nano-DESI probe during MSI experiments and provided information on sample topography. Proof-of-concept experiments were performed using lung and brain tissue sections representing spongy and dense tissues, respectively. Topography images obtained using shear force microscopy were comparable to the results obtained using contact profilometry over the same region of the tissue section. Variations in tissue height were found to be dependent on the tissue type and were in the range of 0-5 μm for lung tissue and 0-3 μm for brain tissue sections. Ion images of phospholipids obtained in this study are in good agreement with literature data. Normalization of nano-DESI MSI images to the signal of the internal standard added to the extraction solvent allowed us to construct high-resolution ion images free of matrix effects. Graphical Abstract ᅟ.", "pubmedLink": "" },   "28743279": { "pmid": "28743279", "title": "Childhood interstitial lung diseases in immunocompetent children in Australia and New Zealand: a decade s experience.", "sortKey": "2017-07-childhood interstiti", "pubDateYear": "2017", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Saddi V, Beggs S, Bennetts B, Harrison J, Hime N, Kapur N, Lipsett J, Nogee LM, Phu A, Suresh S, Schultz A, Selvadurai H, Sherrard S, Strachan R, Vyas J, Zurynski Y, Jaffé A", "citation": "Orphanet journal of rare diseases, 07 2017", "abstractText": "Childhood interstitial lung disease (chILD) represents a rare heterogeneous group of respiratory disorders. In the absence of randomized controlled clinical trials, global collaborations have utilized case series with an aim to standardising approaches to diagnosis and management. Australasian data are lacking. The aim of this study was to calculate prevalence and report the experience of chILD in Australasia over a decade.", "pubmedLink": "" },   "28702480": { "pmid": "28702480", "title": "Dataset on transcriptional profiles and the developmental characteristics of PDGFRα expressing lung fibroblasts.", "sortKey": "2017-08-dataset on transcrip", "pubDateYear": "2017", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Endale M, Ahlfeld S, Bao E, Chen X, Green J, Bess Z, Weirauch M, Xu Y, Perl AK", "citation": "Data in brief, 08 2017", "abstractText": "The following data are derived from key stages of acinar lung development and define the developmental role of lung interstitial fibroblasts expressing platelet-derived growth factor alpha (PDGFRα). This dataset is related to the research article entitled  Temporal, spatial, and phenotypical changes of PDGFRα expressing fibroblasts during late lung development  (Endale et al., 2017) [1]. At E16.5 (canalicular), E18.5 (saccular), P7 (early alveolar) and P28 (late alveolar), PDGFRα mice, in conjunction with immunohistochemical markers, were utilized to define the spatiotemporal relationship of PDGFRα fibroblasts to endothelial, stromal and epithelial cells in both the proximal and distal acinar lung. Complimentary analysis with flow cytometry was employed to determine changes in cellular proliferation, define lipofibroblast and myofibroblast populations via the presence of intracellular lipid or alpha smooth muscle actin (αSMA), and evaluate the expression of CD34, CD29, and Sca-1. Finally, PDGFRα cells isolated at each stage of acinar lung development were subjected to RNA-Seq analysis, data was subjected to Bayesian timeline analysis and transcriptional factor promoter enrichment analysis.", "pubmedLink": "" },   "28538234": { "pmid": "28538234", "title": "Overview of Lung Development in the Newborn Human.", "sortKey": "2017-00-overview of lung dev", "pubDateYear": "2017", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Warburton D", "citation": "Neonatology, 00 2017", "abstractText": "In human neonates rapid adaptation from an aqueous intrauterine environment to permanent air breathing is the rate-limiting step for extrauterine life, failure of which justifies the existence of neonatal intensive care units. The lung develops at about 4-6 weeks  gestation in humans as a ventral outpouching of the primitive foregut into the surrounding ventral mesenchyme, termed the laryngotracheal groove. At its posterior end lie progenitor cells that form a pair of bronchial tubes, from which arise all the distal epithelial structures of the lung. In humans, formation of the distal gas exchange surfaces begins in utero at about 20 weeks  gestation and is substantially established by term. Stereotypic branching of the proximal airway ends relatively early at 16-18 weeks at the bronchoalveolar duct junctions. Distally, about 5 finger-like alveolar ducts arise from each bronchoalveolar duct junction and ramify outwards towards the pleura. The majority of alveolar air sacs arise from the sides of the alveolar ducts and each of these alveoli can have up to 5 daughter alveoli arising from the outer surface as subsequent buds. At the end of each alveolar duct lie the mouths of 5 interconnected alveoli. Each family of alveoli arising from each bronchoalveolar duct junction has a different shape depending upon the limitations imposed by the pleural surface as well as the interstitial fascial planes.", "pubmedLink": "" },   "28514664": { "pmid": "28514664", "title": "Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress.", "sortKey": "2017-05-lack of mttp activit", "pubDateYear": "2017", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Liu Y, Conlon DM, Bi X, Slovik KJ, Shi J, Edelstein HI, Millar JS, Javaheri A, Cuchel M, Pashos EE, Iqbal J, Hussain MM, Hegele RA, Yang W, Duncan SA, Rader DJ, Morrisey EE", "citation": "Cell reports, 05 2017", "abstractText": "Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.", "pubmedLink": "" },   "28408205": { "pmid": "28408205", "title": "Temporal, spatial, and phenotypical changes of PDGFRα expressing fibroblasts during late lung development.", "sortKey": "2017-05-temporal, spatial, a", "pubDateYear": "2017", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Endale M, Ahlfeld S, Bao E, Chen X, Green J, Bess Z, Weirauch MT, Xu Y, Perl AK", "citation": "Developmental biology, 05 2017", "abstractText": "Many studies have investigated the source and role of epithelial progenitors during lung development; such information is limited for fibroblast populations and their complex role in the developing lung. In this study, we characterized the spatial location, mRNA expression and Immunophenotyping of PDGFRα fibroblasts during sacculation and alveolarization. Confocal microscopy identified spatial association of PDGFRα expressing fibroblasts with proximal epithelial cells of the branching bronchioles and the dilating acinar tubules at E16.5; with distal terminal saccules at E18.5; and with alveolar epithelial cells at PN7 and PN28. Immunohistochemistry for alpha smooth muscle actin revealed that PDGFRα fibroblasts contribute to proximal peribronchiolar smooth muscle at E16.5 and to transient distal alveolar myofibroblasts at PN7. Time series RNA-Seq analyses of PDGFRα fibroblasts identified differentially expressed genes that, based on gene expression similarity were clustered into 7 major gene expression profile patterns. The presence of myofibroblast and smooth muscle precursors at E16.5 and PN7 was reflected by a two-peak gene expression profile on these days and gene ontology enrichment in muscle contraction. Additional molecular and functional differences between peribronchiolar smooth muscle cells at E16.5 and transient intraseptal myofibroblasts at PN7 were suggested by a single peak in gene expression at PN7 with functional enrichment in cell projection and muscle cell differentiation. Immunophenotyping of subsets of PDGFRα fibroblasts by flow cytometry confirmed the predicted increase in proliferation at E16.5 and PN7, and identified subsets of CD29 myofibroblasts and CD34 lipofibroblasts. These data can be further mined to develop novel hypotheses and valuable understanding of the molecular and cellular basis of alveolarization.", "pubmedLink": "" },   "28366587": { "pmid": "28366587", "title": "Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling.", "sortKey": "2017-06-efficient derivation", "pubDateYear": "2017", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "McCauley KB, Hawkins F, Serra M, Thomas DC, Jacob A, Kotton DN", "citation": "Cell stem cell, 06 2017", "abstractText": "Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1 progenitor intermediate into functional proximal airway organoids. We find that human NKX2-1 progenitors have high levels of Wnt activation but respond intrinsically to decreases in Wnt signaling by rapidly patterning into proximal airway lineages at the expense of distal fates. Using this directed approach, we were able to generate cystic fibrosis patient-specific iPSC-derived airway organoids with a defect in forskolin-induced swelling that is rescued by gene editing to correct the disease mutation. Our approach has many potential applications in modeling and drug screening for airway diseases.", "pubmedLink": "" },   "28363760": { "pmid": "28363760", "title": "Interstitial lung disease in newborns.", "sortKey": "2017-08-interstitial lung di", "pubDateYear": "2017", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Nogee LM", "citation": "Seminars in fetal & neonatal medicine, 08 2017", "abstractText": "The term  interstitial lung disease  (ILD) refers to a group of disorders involving both the airspaces and tissue compartments of the lung, and these disorders are more accurately termed diffuse lung diseases. Although rare, they are associated with significant morbidity and mortality, with the prognosis depending upon the specific diagnosis. The major categories of ILD in children that present in the neonatal period include developmental disorders, growth disorders, surfactant dysfunction disorders, and specific conditions of unknown etiology unique to infancy. Whereas lung histopathology has been the gold standard for the diagnosis of ILD, as many of the disorders have a genetic basis, non-invasive diagnosis is feasible, and characteristic clinical and imaging features may allow for specific diagnosis in some circumstances. The underlying mechanisms, clinical, imaging, and lung pathology features and outcomes of ILD presenting in newborns are reviewed with an emphasis on genetic mechanisms and diagnosis.", "pubmedLink": "" },   "28347618": { "pmid": "28347618", "title": "Implementation of Hysterectomy Pathway: Impact on Complications.", "sortKey": "2017-00-implementation of hy", "pubDateYear": "2017", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Linkov F, Sanei-Moghaddam A, Edwards RP, Lounder PJ, Ismail N, Goughnour SL, Kang C, Mansuria SM, Comerci JT", "citation": "Women s health issues : official publication of the Jacobs Institute of Women s Health, 00 2017", "abstractText": "Hysterectomy is one of the most common surgical procedures in the United States. For women who need hysterectomy, it is important to ensure that minimally invasive hysterectomy procedures are used appropriately to reduce surgical complications and improve value of care. Although we previously demonstrated a reduction in total abdominal hysterectomy rates after the implementation of hysterectomy pathway treatment algorithm in 2012, this study focuses on exploring the effect of pathways implementation on surgical outcomes.", "pubmedLink": "" },   "28179507": { "pmid": "28179507", "title": "Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection.", "sortKey": "2017-02-intestinal commensal", "pubDateYear": "2017", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Gray J, Oehrle K, Worthen G, Alenghat T, Whitsett J, Deshmukh H", "citation": "Science translational medicine, 02 2017", "abstractText": "Immature mucosal defenses contribute to increased susceptibility of newborn infants to pathogens. Sparse knowledge of age-dependent changes in mucosal immunity has hampered improvements in neonatal morbidity because of infections. We report that exposure of neonatal mice to commensal bacteria immediately after birth is required for a robust host defense against bacterial pneumonia, the leading cause of death in newborn infants. This crucial window was characterized by an abrupt influx of interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (IL-22ILC3) into the lungs of newborn mice. This influx was dependent on sensing of commensal bacteria by intestinal mucosal dendritic cells. Disruption of postnatal commensal colonization or selective depletion of dendritic cells interrupted the migratory program of lung IL-22ILC3 and made the newborn mice more susceptible to pneumonia, which was reversed by transfer of commensal bacteria after birth. Thus, the resistance of newborn mice to pneumonia relied on commensal bacteria-directed ILC3 influx into the lungs, which mediated IL-22-dependent host resistance to pneumonia during this developmental window. These data establish that postnatal colonization by intestinal commensal bacteria is pivotal in the development of the lung defenses of newborns.", "pubmedLink": "" },   "28145528": { "pmid": "28145528", "title": "Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung.", "sortKey": "2017-02-lipidomics reveals d", "pubDateYear": "2017", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Dautel SE, Kyle JE, Clair G, Sontag RL, Weitz KK, Shukla AK, Nguyen SN, Kim YM, Zink EM, Luders T, Frevert CW, Gharib SA, Laskin J, Carson JP, Metz TO, Corley RA, Ansong C", "citation": "Scientific reports, 02 2017", "abstractText": "Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development.", "pubmedLink": "" },   "28124972": { "pmid": "28124972", "title": "Selecting the most appropriate time points to profile in high-throughput studies.", "sortKey": "2017-01-selecting the most a", "pubDateYear": "2017", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Kleyman M, Sefer E, Nicola T, Espinoza C, Chhabra D, Hagood JS, Kaminski N, Ambalavanan N, Bar-Joseph Z", "citation": "eLife, 01 2017", "abstractText": "Biological systems are increasingly being studied by high throughput profiling of molecular data over time. Determining the set of time points to sample in studies that profile several different types of molecular data is still challenging. Here we present the Time Point Selection () method that solves this combinatorial problem in a principled and practical way.  utilizes expression data from a small set of genes sampled at a high rate. As we show by applying  to study mouse lung development, the points selected by  can be used to reconstruct an accurate representation for the expression values of the non selected points. Further, even though the selection is only based on gene expression, these points are also appropriate for representing a much larger set of protein, miRNA and DNA methylation changes over time. TPS can thus serve as a key design strategy for high throughput time series experiments. Supporting Website: www.sb.cs.cmu.edu/TPS.", "pubmedLink": "" },   "28070014": { "pmid": "28070014", "title": "Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development.", "sortKey": "2017-05-lung gene expression", "pubDateYear": "2017", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Du Y, Kitzmiller JA, Sridharan A, Perl AK, Bridges JP, Misra RS, Pryhuber GS, Mariani TJ, Bhattacharya S, Guo M, Potter SS, Dexheimer P, Aronow B, Jobe AH, Whitsett JA, Xu Y", "citation": "Thorax, 05 2017", "abstractText": " LungGENS , our previously developed web tool for mapping single-cell gene expression in the developing lung, has been well received by the pulmonary research community. With continued support from the  LungMAP  consortium, we extended the scope of the LungGENS database to accommodate transcriptomics data from pulmonary tissues and cells from human and mouse at different stages of lung development. Lung Gene Expression Analysis (LGEA) web portal is an extended version of LungGENS useful for the analysis, display and interpretation of gene expression patterns obtained from single cells, sorted cell populations and whole lung tissues. The LGEA web portal is freely available at http://research.cchmc.org/pbge/lunggens/mainportal.html.", "pubmedLink": "" },   "28004771": { "pmid": "28004771", "title": "Spatially-Resolved Proteomics: Rapid Quantitative Analysis of Laser Capture Microdissected Alveolar Tissue Samples.", "sortKey": "2016-12-spatially-resolved p", "pubDateYear": "2016", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Clair G, Piehowski PD, Nicola T, Kitzmiller JA, Huang EL, Zink EM, Sontag RL, Orton DJ, Moore RJ, Carson JP, Smith RD, Whitsett JA, Corley RA, Ambalavanan N, Ansong C", "citation": "Scientific reports, 12 2016", "abstractText": "Laser capture microdissection (LCM)-enabled region-specific tissue analyses are critical to better understand complex multicellular processes. However, current proteomics workflows entail several manual sample preparation steps and are challenged by the microscopic mass-limited samples generated by LCM, impacting measurement robustness, quantification and throughput. Here, we coupled LCM with a proteomics workflow that provides fully automated analysis of proteomes from microdissected tissues. Benchmarking against the current state-of-the-art in ultrasensitive global proteomics (FASP workflow), our approach demonstrated significant improvements in quantification (~2-fold lower variance) and throughput (>5 times faster). Using our approach we for the first time characterized, to a depth of >3,400 proteins, the ontogeny of protein changes during normal lung development in microdissected alveolar tissue containing only 4,000 cells. Our analysis revealed seven defined modules of coordinated transcription factor-signaling molecule expression patterns, suggesting a complex network of temporal regulatory control directs normal lung development with epigenetic regulation fine-tuning pre-natal developmental processes.", "pubmedLink": "" },   "27998929": { "pmid": "27998929", "title": "SLICE: determining cell differentiation and lineage based on single cell entropy.", "sortKey": "2017-04-slice: determining c", "pubDateYear": "2017", "pubDateMonth": "04", "pubDateQuarter": "q2", "authors": "Guo M, Bao EL, Wagner M, Whitsett JA, Xu Y", "citation": "Nucleic acids research, 04 2017", "abstractText": "A complex organ contains a variety of cell types, each with its own distinct lineage and function. Understanding the lineage and differentiation state of each cell is fundamentally important for the ultimate delineation of organ formation and function. We developed SLICE, a novel algorithm that utilizes single-cell RNA-seq (scRNA-seq) to quantitatively measure cellular differentiation states based on single cell entropy and predict cell differentiation lineages via the construction of entropy directed cell trajectories. We validated our approach using three independent data sets with known lineage and developmental time information from both Homo sapiens and Mus musculus. SLICE successfully measured the differentiation states of single cells and reconstructed cell differentiation trajectories that have been previously experimentally validated. We then applied SLICE to scRNA-seq of embryonic mouse lung at E16.5 to identify lung mesenchymal cell lineage relationships that currently remain poorly defined. A two-branched differentiation pathway of five fibroblastic subtypes was predicted using SLICE. The present study demonstrated the general applicability and high predictive accuracy of SLICE in determining cellular differentiation states and reconstructing cell differentiation lineages in scRNA-seq analysis.", "pubmedLink": "" },   "27957616": { "pmid": "27957616", "title": "Developmental pathways in lung regeneration.", "sortKey": "2017-03-developmental pathwa", "pubDateYear": "2017", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Stabler CT, Morrisey EE", "citation": "Cell and tissue research, 03 2017", "abstractText": "The key processes of lung development have been elucidated in the past several decades, helping to identify and characterize the resident progenitor cells that ultimately generate the mature organ. The adult lung is a complex organ consisting in scores of different cell lineages that are remarkably quiescent in the absence of injury. Despite low cellular turnover, the lung can respond quickly and dramatically to acute damage, with spatially restricted stem and progenitor cells re-entering the cell cycle and differentiating to promote repair. The findings from lung developmental biology are now being used to examine the mechanisms that underlie lung regeneration. The use of in vitro models such as pluripotent stem cells and new methods of gene editing have provided models for understanding lung disease and exploring the mechanisms of lung regeneration and have raised the prospect of correcting lung dysfunction. We outline the way that basic studies into lung developmental biology are now being applied to lung regeneration, opening up new avenues of research that may ultimately be harnessed for treatments of lung disease.", "pubmedLink": "" },   "27942595": { "pmid": "27942595", "title": "Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis.", "sortKey": "2016-12-single-cell rna sequ", "pubDateYear": "2016", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J, Wikenheiser-Brokamp KA, Perl AT, Funari VA, Gokey JJ, Stripp BR, Whitsett JA", "citation": "JCI insight, 12 2016", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating  indeterminate  states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-β, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease.", "pubmedLink": "" },   "27893721": { "pmid": "27893721", "title": "Biomarkers associated with bronchopulmonary dysplasia/mortality in premature infants.", "sortKey": "2017-03-biomarkers associate", "pubDateYear": "2017", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Balena-Borneman J, Ambalavanan N, Tiwari HK, Griffin RL, Halloran B, Askenazi D", "citation": "Pediatric research, 03 2017", "abstractText": "Bronchopulmonary dysplasia (BPD) portends lifelong organ impairment and death. Our ability to predict BPD in first days of life is limited, but could be enhanced using novel biomarkers.", "pubmedLink": "" },   "27880906": { "pmid": "27880906", "title": "Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation.", "sortKey": "2016-11-emergence of a wave ", "pubDateYear": "2016", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Frank DB, Peng T, Zepp JA, Snitow M, Vincent TL, Penkala IJ, Cui Z, Herriges MJ, Morley MP, Zhou S, Lu MM, Morrisey EE", "citation": "Cell reports, 11 2016", "abstractText": "Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2. The number of AT2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in vivo clonal analysis, and ex vivo lung organoid assays reveal that AT2s promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation.", "pubmedLink": "" },   "27870560": { "pmid": "27870560", "title": "Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice.", "sortKey": "2017-03-effect of prenatal v", "pubDateYear": "2017", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Saadoon A, Ambalavanan N, Zinn K, Ashraf AP, MacEwen M, Nicola T, Fanucchi MV, Harris WT", "citation": "American journal of respiratory cell and molecular biology, 03 2017", "abstractText": "Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D-deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D-deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency-associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies.", "pubmedLink": "" },   "27811239": { "pmid": "27811239", "title": "A transcription factor hierarchy defines an environmental stress response network.", "sortKey": "2016-11-a transcription fact", "pubDateYear": "2016", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Song L, Huang SC, Wise A, Castanon R, Nery JR, Chen H, Watanabe M, Thomas J, Bar-Joseph Z, Ecker JR", "citation": "Science (New York, N.Y.), 11 2016", "abstractText": "Environmental stresses are universally encountered by microbes, plants, and animals. Yet systematic studies of stress-responsive transcription factor (TF) networks in multicellular organisms have been limited. The phytohormone abscisic acid (ABA) influences the expression of thousands of genes, allowing us to characterize complex stress-responsive regulatory networks. Using chromatin immunoprecipitation sequencing, we identified genome-wide targets of 21 ABA-related TFs to construct a comprehensive regulatory network in Arabidopsis thaliana Determinants of dynamic TF binding and a hierarchy among TFs were defined, illuminating the relationship between differential gene expression patterns and ABA pathway feedback regulation. By extrapolating regulatory characteristics of observed canonical ABA pathway components, we identified a new family of transcriptional regulators modulating ABA and salt responsiveness and demonstrated their utility to modulate plant resilience to osmotic stress.", "pubmedLink": "" },   "27663992": { "pmid": "27663992", "title": "Searching for better animal models of BPD: a perspective.", "sortKey": "2016-11-searching for better", "pubDateYear": "2016", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Ambalavanan N, Morty RE", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2016", "abstractText": "There have been many efforts to develop good animal models of bronchopulmonary dysplasia (BPD) to better understand the pathophysiology and mechanisms underlying development of BPD as well as to test potential strategies for its prevention and treatment. This Perspectives summarizes the features of common animal models of BPD and the strengths and limitations of such models. Potential optimal approaches to development of animal models are indicated, with the underlying concepts that require emphasis.", "pubmedLink": "" },   "27374190": { "pmid": "27374190", "title": "Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice.", "sortKey": "2016-11-inhibition of regula", "pubDateYear": "2016", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Sureshbabu A, Syed M, Das P, Janér C, Pryhuber G, Rahman A, Andersson S, Homer RJ, Bhandari V", "citation": "American journal of respiratory cell and molecular biology, 11 2016", "abstractText": "Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor, limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.", "pubmedLink": "" },   "27768862": { "pmid": "27768862", "title": "Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.", "sortKey": "2016-12-inactivation of tsc2", "pubDateYear": "2016", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Ren S, Luo Y, Chen H, Warburton D, Lam HC, Wang LL, Chen P, Henske EP, Shi W", "citation": "The American journal of pathology, 12 2016", "abstractText": "The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mammalian/mechanistic target of rapamycin complex 1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver. The Dermo1-Cre-driven Tsc2 conditional knockout mice had body growth retardation and died approximately 3 weeks after birth. Significant phenotypes were observed in the postnatal kidney and lung. Inactivation of Tsc2 in kidney mesenchyme caused polycystic lesions starting from the second week of age, with increased cell proliferation, tubular epithelial hyperplasia, and epithelial-mesenchymal transition. In contrast, Tsc2 deletion in lung mesenchyme led to decreased cell proliferation, reduced postnatal alveolarization, and decreased differentiation with reduced numbers of alveolar myofibroblast and type II alveolar epithelial cells. Two major findings thus result from this model: inactivation of Tsc2 in mesoderm-derived cells causes increased cell proliferation in the kidneys but reduced proliferation in the lungs, and inactivation of Tsc2 in mesoderm-derived cells causes epithelial-lined renal cysts. Therefore, Tsc2-mTOR signaling in mesenchyme is essential for the maintenance of renal structure and for lung alveolarization.", "pubmedLink": "" },   "27736153": { "pmid": "27736153", "title": "SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis.", "sortKey": "2017-02-sh2 domain-containin", "pubDateYear": "2017", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Tzouvelekis A, Yu G, Lino Cardenas CL, Herazo-Maya JD, Wang R, Woolard T, Zhang Y, Sakamoto K, Lee H, Yi JS, DeIuliis G, Xylourgidis N, Ahangari F, Lee PJ, Aidinis V, Herzog EL, Homer R, Bennett AM, Kaminski N", "citation": "American journal of respiratory and critical care medicine, 02 2017", "abstractText": "Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF.", "pubmedLink": "" },   "27488092": { "pmid": "27488092", "title": "The Airway Microbiome at Birth.", "sortKey": "2016-08-the airway microbiom", "pubDateYear": "2016", "pubDateMonth": "08", "pubDateQuarter": "q3", "authors": "Lal CV, Travers C, Aghai ZH, Eipers P, Jilling T, Halloran B, Carlo WA, Keeley J, Rezonzew G, Kumar R, Morrow C, Bhandari V, Ambalavanan N", "citation": "Scientific reports, 08 2016", "abstractText": "Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease.", "pubmedLink": "" },   "27471253": { "pmid": "27471253", "title": "Acute Kidney Injury Urine Biomarkers in Very Low-Birth-Weight Infants.", "sortKey": "2016-09-acute kidney injury ", "pubDateYear": "2016", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Askenazi DJ, Koralkar R, Patil N, Halloran B, Ambalavanan N, Griffin R", "citation": "Clinical journal of the American Society of Nephrology : CJASN, 09 2016", "abstractText": "Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants.", "pubmedLink": "" },   "27453445": { "pmid": "27453445", "title": "Tradeoffs between Dense and Replicate Sampling Strategies for High-Throughput Time Series Experiments.", "sortKey": "2016-07-tradeoffs between de", "pubDateYear": "2016", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Sefer E, Kleyman M, Bar-Joseph Z", "citation": "Cell systems, 07 2016", "abstractText": "An important experimental design question for high-throughput time series studies is the number of replicates required for accurate reconstruction of the profiles. Due to budget and sample availability constraints, more replicates imply fewer time points and vice versa. We analyze the performance of dense and replicate sampling by developing a theoretical framework that focuses on a restricted yet expressive set of possible curves over a wide range of noise levels and by analyzing real expression data. For both the theoretical analysis and experimental data, we observe that, under reasonable noise levels, autocorrelations in the time series data allow dense sampling to better determine the correct levels of non-sampled points when compared to replicate sampling. A Java implementation of our framework can be used to determine the best replicate strategy given the expected noise. These results provide theoretical support to the large number of high-throughput time series experiments that do not use replicates.", "pubmedLink": "" },   "27438473": { "pmid": "27438473", "title": "Flow-based sorting of neonatal lymphocyte populations for transcriptomics analysis.", "sortKey": "2016-10-flow-based sorting o", "pubDateYear": "2016", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Misra RS, Bhattacharya S, Huyck HL, Wang JC, Slaunwhite CG, Slaunwhite SL, Wightman TR, Secor-Socha S, Misra SK, Bushnell TP, Reynolds AM, Ryan RM, Quataert SA, Pryhuber GS, Mariani TJ", "citation": "Journal of immunological methods, 10 2016", "abstractText": "Emerging data suggest an important role for T lymphocytes in the pathogenesis of chronic lung disease in preterm infants. Comprehensive assessment of the lymphocyte transcriptome may identify biomarkers and mechanisms of disease.", "pubmedLink": "" },   "27225964": { "pmid": "27225964", "title": "Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.", "sortKey": "2016-06-challenges, prioriti", "pubDateYear": "2016", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Aschner JL, Gien J, Ambalavanan N, Kinsella JP, Konduri GG, Lakshminrusimha S, Saugstad OD, Steinhorn RH", "citation": "Journal of perinatology : official journal of the California Perinatal Association, 06 2016", "abstractText": "Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases,  precision medicine  and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of  precision medicine  (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.", "pubmedLink": "" },   "27225961": { "pmid": "27225961", "title": "Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants.", "sortKey": "2016-06-management of hypoxe", "pubDateYear": "2016", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Ambalavanan N, Aschner JL", "citation": "Journal of perinatology : official journal of the California Perinatal Association, 06 2016", "abstractText": "While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as  early  or  late  based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual s phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.", "pubmedLink": "" },   "27186799": { "pmid": "27186799", "title": "Greazy: Open-Source Software for Automated Phospholipid Tandem Mass Spectrometry Identification.", "sortKey": "2016-06-greazy: open-source ", "pubDateYear": "2016", "pubDateMonth": "06", "pubDateQuarter": "q2", "authors": "Kochen MA, Chambers MC, Holman JD, Nesvizhskii AI, Weintraub ST, Belisle JT, Islam MN, Griss J, Tabb DL", "citation": "Analytical chemistry, 06 2016", "abstractText": "Lipid identification from data produced with high-throughput technologies is essential to the elucidation of the roles played by lipids in cellular function and disease. Software tools for identifying lipids from tandem mass (MS/MS) spectra have been developed, but they are often costly or lack the sophistication of their proteomics counterparts. We have developed Greazy, an open source tool for the automated identification of phospholipids from MS/MS spectra, that utilizes methods similar to those developed for proteomics. From user-supplied parameters, Greazy builds a phospholipid search space and associated theoretical MS/MS spectra. Experimental spectra are scored against search space lipids with similar precursor masses using a peak score based on the hypergeometric distribution and an intensity score utilizing the percentage of total ion intensity residing in matching peaks. The LipidLama component filters the results via mixture modeling and density estimation. We assess Greazy s performance against the NIST 2014 metabolomics library, observing high accuracy in a search of multiple lipid classes. We compare Greazy/LipidLama against the commercial lipid identification software LipidSearch and show that the two platforms differ considerably in the sets of identified spectra while showing good agreement on those spectra identified by both. Lastly, we demonstrate the utility of Greazy/LipidLama with different instruments. We searched data from replicates of alveolar type 2 epithelial cells obtained with an Orbitrap and from human serum replicates generated on a quadrupole-time-of-flight (Q-TOF). These findings substantiate the application of proteomics derived methods to the identification of lipids. The software is available from the ProteoWizard repository: http://tiny.cc/bumbershoot-vc12-bin64 .", "pubmedLink": "" },   "26938952": { "pmid": "26938952", "title": "Hyperoxia Induces Intracellular Acidification in Neonatal Mouse Lung Fibroblasts: Real-Time Investigation Using Plasmonically Enhanced Raman Spectroscopy.", "sortKey": "2016-03-hyperoxia induces in", "pubDateYear": "2016", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Panikkanvalappil SR, James M, Hira SM, Mobley J, Jilling T, Ambalavanan N, El-Sayed MA", "citation": "Journal of the American Chemical Society, 03 2016", "abstractText": "It is important to understand the molecular mechanisms underlying oxygen toxicity, which contributes to multiple human disorders. The archetype model of oxygen toxicity is neonatal lung injury induced by hyperoxia exposure. Here, we utilized plasmonically enhanced Raman spectroscopy (PERS) in combination with fluorescence and proteomic analysis to provide comprehensive information on hyperoxia-induced biomolecular modifications in neonatal mouse lung fibroblasts (nMLFs). During this study, we made the novel observation that hyperoxia induces intracellular acidification in nMLF, which we probed in real-time using label-free PERS. We found that intracellular acidification induces conformational modifications in proteins followed by significant changes in Raman vibrations corresponding to aromatic amino acids such as phenylalanine and tryptophan as well as cysteine moieties. Hyperoxia-induced intracellular pH changes and subsequent modifications in protein expression and associated post-translational modifications within the cells were further validated by fluorescence and proteomic analysis. These new insights may help identifying unique oxidant stress-induced mechanisms in disease processes and may guide the development of more efficient therapeutic strategies.", "pubmedLink": "" },   "26719145": { "pmid": "26719145", "title": "Regulation of alveolar septation by microRNA-489.", "sortKey": "2016-03-regulation of alveol", "pubDateYear": "2016", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Olave N, Lal CV, Halloran B, Pandit K, Cuna AC, Faye-Petersen OM, Kelly DR, Nicola T, Benos PV, Kaminski N, Ambalavanan N", "citation": "American journal of physiology. Lung cellular and molecular physiology, 03 2016", "abstractText": "MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3  untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.", "pubmedLink": "" },   "26600239": { "pmid": "26600239", "title": "SINCERA: A Pipeline for Single-Cell RNA-Seq Profiling Analysis.", "sortKey": "2015-11-sincera: a pipeline ", "pubDateYear": "2015", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Guo M, Wang H, Potter SS, Whitsett JA, Xu Y", "citation": "PLoS computational biology, 11 2015", "abstractText": "A major challenge in developmental biology is to understand the genetic and cellular processes/programs driving organ formation and differentiation of the diverse cell types that comprise the embryo. While recent studies using single cell transcriptome analysis illustrate the power to measure and understand cellular heterogeneity in complex biological systems, processing large amounts of RNA-seq data from heterogeneous cell populations creates the need for readily accessible tools for the analysis of single-cell RNA-seq (scRNA-seq) profiles. The present study presents a generally applicable analytic pipeline (SINCERA: a computational pipeline for SINgle CEll RNA-seq profiling Analysis) for processing scRNA-seq data from a whole organ or sorted cells. The pipeline supports the analysis for: 1) the distinction and identification of major cell types; 2) the identification of cell type specific gene signatures; and 3) the determination of driving forces of given cell types. We applied this pipeline to the RNA-seq analysis of single cells isolated from embryonic mouse lung at E16.5. Through the pipeline analysis, we distinguished major cell types of fetal mouse lung, including epithelial, endothelial, smooth muscle, pericyte, and fibroblast-like cell types, and identified cell type specific gene signatures, bioprocesses, and key regulators. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html.", "pubmedLink": "" },   "26593076": { "pmid": "26593076", "title": "Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia.", "sortKey": "2015-12-biomarkers, early di", "pubDateYear": "2015", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Lal CV, Ambalavanan N", "citation": "Clinics in perinatology, 12 2015", "abstractText": "The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and the clinical phenotype of BPD is extremely variable. Several clinical and laboratory biomarkers have been proposed for the early identification of infants at higher risk of BPD and for determination of prognosis of infants with a diagnosis of BPD. The authors review available literature on prediction tools and biomarkers of BPD, using clinical variables and biomarkers based on imaging, lung function measures, and measurements of various analytes in different body fluids that have been determined to be associated with BPD either in a targeted manner or by unbiased omic profiling.", "pubmedLink": "" },   "26593074": { "pmid": "26593074", "title": "Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity.", "sortKey": "2015-12-postnatal infections", "pubDateYear": "2015", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Pryhuber GS", "citation": "Clinics in perinatology, 12 2015", "abstractText": "Premature infants suffer significant respiratory morbidity during infancy with long-term negative consequences on health, quality of life, and health care costs. Enhanced susceptibility to a variety of infections and inflammation play a large role in early and prolonged lung disease following premature birth, although the mechanisms of susceptibility and immune dysregulation are active areas of research. This article reviews aspects of host-pathogen interactions and immune responses that are altered by preterm birth and that impact chronic respiratory morbidity in these children.", "pubmedLink": "" },   "26593073": { "pmid": "26593073", "title": "Update on Molecular Biology of Lung Development--Transcriptomics.", "sortKey": "2015-12-update on molecular ", "pubDateYear": "2015", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Mariani TJ", "citation": "Clinics in perinatology, 12 2015", "abstractText": "This article highlights some of the significant advances in our understanding of lung developmental biology made over the last few years, which challenge existing paradigms and are relevant to a fundamental understanding of this process. Additional comments address how these new insights may be informative for chronic lung diseases that occur, or initiate, in the neonatal period. This is not meant to be an exhaustive review of the molecular biology of lung development. For a more comprehensive, contemporary review of the cellular and molecular aspects of lung development, readers can refer to recent reviews by others.", "pubmedLink": "" },   "26572893": { "pmid": "26572893", "title": "Acute changes in fluid status affect the incidence, associative clinical outcomes, and urine biomarker performance in premature infants with acute kidney injury.", "sortKey": "2016-05-acute changes in flu", "pubDateYear": "2016", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Askenazi D, Saeidi B, Koralkar R, Ambalavanan N, Griffin RL", "citation": "Pediatric nephrology (Berlin, Germany), 05 2016", "abstractText": "During the first postnatal weeks, infants have abrupt changes in fluid weight that alter serum creatinine (SCr) concentration, and possibly, the evaluation for acute kidney injury (AKI).", "pubmedLink": "" },   "26493725": { "pmid": "26493725", "title": "Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity.", "sortKey": "2015-10-systems biology eval", "pubDateYear": "2015", "pubDateMonth": "10", "pubDateQuarter": "q4", "authors": "Kamath-Rayne BD, Du Y, Hughes M, Wagner EA, Muglia LJ, DeFranco EA, Whitsett JA, Salomonis N, Xu Y", "citation": "BMC medical genomics, 10 2015", "abstractText": "Amniotic fluid (AF) is a proximal fluid to the fetus containing higher amounts of cell-free fetal RNA/DNA than maternal serum, thereby making it a promising source for identifying novel biomarkers that predict fetal development and organ maturation. Our aim was to compare AF transcriptomic profiles at different time points in pregnancy to demonstrate unique genetic signatures that would serve as potential biomarkers indicative of fetal maturation.", "pubmedLink": "" },   "26471063": { "pmid": "26471063", "title": "Genetic predisposition to bronchopulmonary dysplasia.", "sortKey": "2015-12-genetic predispositi", "pubDateYear": "2015", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Lal CV, Ambalavanan N", "citation": "Seminars in perinatology, 12 2015", "abstractText": "The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene-set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g., CD44 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next-generation sequencing methods in individual infants (personalized genomics).", "pubmedLink": "" },   "26400819": { "pmid": "26400819", "title": "De novo ChIP-seq analysis.", "sortKey": "2015-09-de novo chip-seq ana", "pubDateYear": "2015", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "He X, Cicek AE, Wang Y, Schulz MH, Le HS, Bar-Joseph Z", "citation": "Genome biology, 09 2015", "abstractText": "Methods for the analysis of chromatin immunoprecipitation sequencing (ChIP-seq) data start by aligning the short reads to a reference genome. While often successful, they are not appropriate for cases where a reference genome is not available. Here we develop methods for de novo analysis of ChIP-seq data. Our methods combine de novo assembly with statistical tests enabling motif discovery without the use of a reference genome. We validate the performance of our method using human and mouse data. Analysis of fly data indicates that our method outperforms alignment based methods that utilize closely related species.", "pubmedLink": "" },   "26160872": { "pmid": "26160872", "title": "Increased alveolar soluble annexin V promotes lung inflammation and fibrosis.", "sortKey": "2015-11-increased alveolar s", "pubDateYear": "2015", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Buckley S, Shi W, Xu W, Frey MR, Moats R, Pardo A, Selman M, Warburton D", "citation": "The European respiratory journal, 11 2015", "abstractText": "The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated alveolar epithelial type 2 cells (AEC2), but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly (r>0.95) with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-β, mitogen-activated protein kinase and nuclear factor-κB signalling pathways, as seen in IPF. Chronically increased alveolar annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.", "pubmedLink": "" },   "26130332": { "pmid": "26130332", "title": " LungGENS : a web-based tool for mapping single-cell gene expression in the developing lung.", "sortKey": "2015-11- lunggens : a web-ba", "pubDateYear": "2015", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Du Y, Guo M, Whitsett JA, Xu Y", "citation": "Thorax, 11 2015", "abstractText": "We developed LungGENS (Lung Gene Expression iN Single-cell), a web-based bioinformatics resource for querying single-cell gene expression databases by entering a gene symbol or a list of genes or selecting a cell type of their interest. Gene query provides quantitative RNA expression of the gene of interest in each lung cell type. Cell type query returns associated selective gene signatures and genes encoding cell surface markers and transcription factors in interactive heatmap and tables. LungGENS will be broadly applicable in respiratory research, providing a cell-specific RNA expression resource at single-cell resolution. LungGENS is freely available for non-commercial use at https://research.cchmc.org/pbge/lunggens/default.html.", "pubmedLink": "" },   "26093309": { "pmid": "26093309", "title": "Endodermal Wnt signaling is required for tracheal cartilage formation.", "sortKey": "2015-09-endodermal wnt signa", "pubDateYear": "2015", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Snowball J, Ambalavanan M, Whitsett J, Sinner D", "citation": "Developmental biology, 09 2015", "abstractText": "Tracheobronchomalacia is a common congenital defect in which the walls of the trachea and bronchi lack of adequate cartilage required for support of the airways. Deletion of Wls, a cargo receptor mediating Wnt ligand secretion, in the embryonic endoderm using ShhCre mice inhibited formation of tracheal-bronchial cartilaginous rings. The normal dorsal-ventral patterning of tracheal mesenchyme was lost. Smooth muscle cells, identified by Acta2 staining, were aberrantly located in ventral mesenchyme of the trachea, normally the region of Sox9 expression in cartilage progenitors. Wnt/β-catenin activity, indicated by Axin2 LacZ reporter, was decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Proliferation of chondroblasts was decreased and reciprocally, proliferation of smooth muscle cells was increased in Wls(f/f);Shh(Cre/+) tracheal tissue. Expression of Tbx4, Tbx5, Msx1 and Msx2, known to mediate cartilage and muscle patterning, were decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Ex vivo studies demonstrated that Wnt7b and Wnt5a, expressed by the epithelium of developing trachea, and active Wnt/β-catenin signaling are required for tracheal chondrogenesis before formation of mesenchymal condensations. In conclusion, Wnt ligands produced by the tracheal epithelium pattern the tracheal mesenchyme via modulation of gene expression and cell proliferation required for proper tracheal cartilage and smooth muscle differentiation.", "pubmedLink": "" },   "26001700": { "pmid": "26001700", "title": "Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates.", "sortKey": "2015-11-impact of gestationa", "pubDateYear": "2015", "pubDateMonth": "11", "pubDateQuarter": "q4", "authors": "Saeidi B, Koralkar R, Griffin RL, Halloran B, Ambalavanan N, Askenazi DJ", "citation": "Pediatric nephrology (Berlin, Germany), 11 2015", "abstractText": "Urine proteins may help in understanding physiology and diagnosing disease in premature infants. Determining how urine proteins vary by degree of prematurity, sex, and postnatal day is warranted.", "pubmedLink": "" },   "25932959": { "pmid": "25932959", "title": "Alveolar development and disease.", "sortKey": "2015-07-alveolar development", "pubDateYear": "2015", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Whitsett JA, Weaver TE", "citation": "American journal of respiratory cell and molecular biology, 07 2015", "abstractText": "Gas exchange after birth is entirely dependent on the remarkable architecture of the alveolus, its formation and function being mediated by the interactions of numerous cell types whose precise positions and activities are controlled by a diversity of signaling and transcriptional networks. In the later stages of gestation, alveolar epithelial cells lining the peripheral lung saccules produce increasing amounts of surfactant lipids and proteins that are secreted into the airspaces at birth. The lack of lung maturation and the associated lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome, a common cause of morbidity and mortality associated with premature birth. At the time of birth, surfactant homeostasis begins to be established by balanced processes involved in surfactant production, storage, secretion, recycling, and catabolism. Insights from physiology and engineering made in the 20th century enabled survival of newborn infants requiring mechanical ventilation for the first time. Thereafter, advances in biochemistry, biophysics, and molecular biology led to an understanding of the pulmonary surfactant system that made possible exogenous surfactant replacement for the treatment of preterm infants. Identification of surfactant proteins, cloning of the genes encoding them, and elucidation of their roles in the regulation of surfactant synthesis, structure, and function have provided increasing understanding of alveolar homeostasis in health and disease. This Perspective seeks to consider developmental aspects of the pulmonary surfactant system and its importance in the pathogenesis of acute and chronic lung diseases related to alveolar homeostasis.", "pubmedLink": "" },   "25866971": { "pmid": "25866971", "title": "Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation.", "sortKey": "2015-05-airway epithelial sp", "pubDateYear": "2015", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Rajavelu P, Chen G, Xu Y, Kitzmiller JA, Korfhagen TR, Whitsett JA", "citation": "The Journal of clinical investigation, 05 2015", "abstractText": "Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen.", "pubmedLink": "" },   "25839409": { "pmid": "25839409", "title": "A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor.", "sortKey": "2015-07-a novel pi3k inhibit", "pubDateYear": "2015", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Ishida N, Fukazawa T, Maeda Y, Yamatsuji T, Kato K, Matsumoto K, Shimo T, Takigawa N, Whitsett JA, Naomoto Y", "citation": "Experimental cell research, 07 2015", "abstractText": "The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.", "pubmedLink": "" },   "25727890": { "pmid": "25727890", "title": "Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall.", "sortKey": "2015-05-mesenchymal wnt sign", "pubDateYear": "2015", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Snowball J, Ambalavanan M, Cornett B, Lang R, Whitsett J, Sinner D", "citation": "Developmental biology, 05 2015", "abstractText": "Midline defects account for approximately 5% of congenital abnormalities observed at birth. However, the molecular mechanisms underlying the formation of the ventral body wall are not well understood. Recent studies linked mutations in Porcupine-an O-acetyl transferase mediating Wnt ligand acylation-with defects in the thoracic body wall. We hypothesized that anomalous Wnt signaling is involved in the pathogenesis of defective closure of the thoracic body wall. We generated a mouse model wherein Wntless (Wls), which encodes a cargo receptor mediating secretion of Wnt ligands, was conditionally deleted from the developing mesenchyme using Dermo1Cre mice. Wls(f/f);Dermo1(Cre/+) embryos died during mid-gestation. At E13.5, skeletal defects were observed in the forelimbs, jaw, and rib cage. At E14.5, midline defects in the thoracic body wall began to emerge: the sternum failed to fuse and the heart protruded through the body wall at the midline (ectopia cordis). To determine the molecular mechanism underlying the phenotype observed in Wls(f/f);Dermo1(Cre/+) embryos, we tested whether Wnt/β-catenin signaling was operative in developing the embryonic ventral body wall using Axin2(LacZ) and BatGal reporter mice. While Wnt/β-catenin signaling activity was observed at the midline of the ventral body wall before sternal fusion, this pattern of activity was altered and scattered throughout the body wall after mesenchymal deletion of Wls. Mesenchymal cell migration was disrupted in Wls(f/f);Dermo1(Cre/+) thoracic body wall partially due to anomalous β-catenin independent Wnt signaling as determined by in vitro assays. Deletion of Lrp5 and Lrp6 receptors, which mediate Wnt/β-catenin signaling in the mesenchyme, partially recapitulated the phenotype observed in the chest midline of Wls(f/f);Dermo1(Cre/+) embryos supporting a role for Wnt/β-catenin signaling activity in the normal formation of the ventral body wall mesenchyme. We conclude that Wls-mediated secretion of Wnt ligands from the developing ventral body wall mesenchyme plays a critical role in fusion of the sternum and closure of the secondary body wall. Thus, impaired Wls activity in the ventral body wall mesenchyme is a mechanism underlying ectopia cordis and unfused sternum.", "pubmedLink": "" },   "25621661": { "pmid": "25621661", "title": "Diseases of pulmonary surfactant homeostasis.", "sortKey": "2015-00-diseases of pulmonar", "pubDateYear": "2015", "pubDateMonth": "00", "pubDateQuarter": "q0", "authors": "Whitsett JA, Wert SE, Weaver TE", "citation": "Annual review of pathology, 00 2015", "abstractText": "Advances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis.", "pubmedLink": "" },   "25522349": { "pmid": "25522349", "title": "Multitask learning of signaling and regulatory networks with application to studying human response to flu.", "sortKey": "2014-12-multitask learning o", "pubDateYear": "2014", "pubDateMonth": "12", "pubDateQuarter": "q4", "authors": "Jain S, Gitter A, Bar-Joseph Z", "citation": "PLoS computational biology, 12 2014", "abstractText": "Reconstructing regulatory and signaling response networks is one of the major goals of systems biology. While several successful methods have been suggested for this task, some integrating large and diverse datasets, these methods have so far been applied to reconstruct a single response network at a time, even when studying and modeling related conditions. To improve network reconstruction we developed MT-SDREM, a multi-task learning method which jointly models networks for several related conditions. In MT-SDREM, parameters are jointly constrained across the networks while still allowing for condition-specific pathways and regulation. We formulate the multi-task learning problem and discuss methods for optimizing the joint target function. We applied MT-SDREM to reconstruct dynamic human response networks for three flu strains: H1N1, H5N1 and H3N2. Our multi-task learning method was able to identify known and novel factors and genes, improving upon prior methods that model each condition independently. The MT-SDREM networks were also better at identifying proteins whose removal affects viral load indicating that joint learning can still lead to accurate, condition-specific, networks. Supporting website with MT-SDREM implementation: http://sb.cs.cmu.edu/mtsdrem.", "pubmedLink": "" },   "25521682": { "pmid": "25521682", "title": "Respiratory epithelial cells orchestrate pulmonary innate immunity.", "sortKey": "2015-01-respiratory epitheli", "pubDateYear": "2015", "pubDateMonth": "01", "pubDateQuarter": "q1", "authors": "Whitsett JA, Alenghat T", "citation": "Nature immunology, 01 2015", "abstractText": "The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and  instruct  the professional immune system to protect the lungs from infection and injury.", "pubmedLink": "" },   "25480985": { "pmid": "25480985", "title": "Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung.", "sortKey": "2015-02-hippo/yap signaling ", "pubDateYear": "2015", "pubDateMonth": "02", "pubDateQuarter": "q1", "authors": "Lange AW, Sridharan A, Xu Y, Stripp BR, Perl AK, Whitsett JA", "citation": "Journal of molecular cell biology, 02 2015", "abstractText": "The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.", "pubmedLink": "" },   "25449221": { "pmid": "25449221", "title": "Integrated genomic analyses in bronchopulmonary dysplasia.", "sortKey": "2015-03-integrated genomic a", "pubDateYear": "2015", "pubDateMonth": "03", "pubDateQuarter": "q1", "authors": "Ambalavanan N, Cotten CM, Page GP, Carlo WA, Murray JC, Bhattacharya S, Mariani TJ, Cuna AC, Faye-Petersen OM, Kelly D, Higgins RD,  ", "citation": "The Journal of pediatrics, 03 2015", "abstractText": "To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks  postmenstrual age risk is strongly influenced by heritable factors.", "pubmedLink": "" },   "25387348": { "pmid": "25387348", "title": "Alterations in gene expression and DNA methylation during murine and human lung alveolar septation.", "sortKey": "2015-07-alterations in gene ", "pubDateYear": "2015", "pubDateMonth": "07", "pubDateQuarter": "q3", "authors": "Cuna A, Halloran B, Faye-Petersen O, Kelly D, Crossman DK, Cui X, Pandit K, Kaminski N, Bhattacharya S, Ahmad A, Mariani TJ, Ambalavanan N", "citation": "American journal of respiratory cell and molecular biology, 07 2015", "abstractText": "DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-β signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.", "pubmedLink": "" },   "25275225": { "pmid": "25275225", "title": "Foxm1 regulates resolution of hyperoxic lung injury in newborns.", "sortKey": "2015-05-foxm1 regulates reso", "pubDateYear": "2015", "pubDateMonth": "05", "pubDateQuarter": "q2", "authors": "Xia H, Ren X, Bolte CS, Ustiyan V, Zhang Y, Shah TA, Kalin TV, Whitsett JA, Kalinichenko VV", "citation": "American journal of respiratory cell and molecular biology, 05 2015", "abstractText": "Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68(-)) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs.", "pubmedLink": "" }}
        

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