{   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "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": "" },   "25808019": { "pmid": "25808019", "title": "Acute kidney injury is associated with bronchopulmonary dysplasia/mortality in premature infants.", "sortKey": "2015-09-acute kidney injury ", "pubDateYear": "2015", "pubDateMonth": "09", "pubDateQuarter": "q3", "authors": "Askenazi D, Patil NR, Ambalavanan N, Balena-Borneman J, Lozano DJ, Ramani M, Collins M, Griffin RL", "citation": "Pediatric nephrology (Berlin, Germany), 09 2015", "abstractText": "Acute kidney injury (AKI) impairs electrolyte balance, alters fluid homeostasis and decreases toxin excretion. More recent data suggest it also affects the physiology of distant organs.", "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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