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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 cis -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 TMPRSS2 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 SLC6A20 , 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.

The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects aged 0 to 8 years-old with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during post-natal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA in situ hybridization and immunofluorescence imaging. We validated the spatial distribution of AT1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole tissue proteome studies. Finally, the proteome was compared to a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects aged 0 to 8 years-old with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during post-natal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA in situ hybridization and immunofluorescence imaging. We validated the spatial distribution of AT1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole tissue proteome studies. Finally, the proteome was compared to a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.

Abstract The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects 0–8 years of age with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during postnatal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA in situ hybridization and immunofluorescence imaging. We validated the spatial distribution of alveolar type 1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole-tissue proteome studies. Finally, the proteome was compared with a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.

Abstract 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.

Respiratory failure is the leading cause of COVID-19 death and disproportionately impacts adults more than children. Here, we present a large-scale snATAC-seq dataset (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of alveolar epithelial cells expressing ACE2 and TMPRSS2 in adult compared to young lungs. Consistent with expression dynamics, 10 chromatin peaks linked to TMPRSS2 exhibited significantly increased activity with age and harbored IRF and STAT binding sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks with predicted regulatory function, including several associated with respiratory traits and TMPRSS2 expression. Our findings reveal a plausible contributor to why children are more resistant to COVID-19 and provide an epigenomic basis for transferring this resistance to older populations. Competing Interest Statement KJG does consulting for Genentech, DAF is an employee and holds stock in Vertex Pharmaceuticals; no other relationships or activities that could appear to have influenced this work

To estimate the impact of recent changes to the Child and Adult Care Food Program (CACFP) meal pattern on young children's diets in family child care homes (FCCHs) serving racially/ethnically diverse children. In a natural experimental study of thirteen CACFP-participating FCCHs, we used digital photographs taken of children's plates before and after meals matched with menus to measure children's dietary intake both prior to implementation of the new meal patterns (summer/fall of 2017) and again 1 year later (summer/fall of 2018). Generalised estimating equations tested for change in intake of fruits, vegetables, whole grains, 100 % juice, grain-based desserts, meat/meat alternates and milk, adjusting for clustering of observations within providers. FCCHs in Boston, MA, USA. Three- to 5-year-old children attending FCCHs. We observed 107 meals consumed by twenty-eight children at the thirteen FCCHs across an average of 2·5 (sd 1·3) d before the CACFP policy change, and 239 meals consumed by thirty-nine children across 3·8 d (sd 1·4) 1 year later. During lunch, fruit intake increased by about a third of a serving (+0·38 serving, 95 % CI 0·04, 0·73, P = 0·03), and whole grain intake increased by a half serving (+0·50 serving, 95 % CI 0·19, 0·82, P = 0·002). No changes were seen in other meal components. Young children's dietary intake in CACFP-participating FCCHs improved following the CACFP meal pattern change, particularly for fruits and whole grains, which were targets of the new policy. Additional research should examine impacts of the changes in other child care settings, age groups and locales.

[...]1 site had difficulty obtaining accurate email addresses from the EHR. Additionally, our evaluation was limited to sites that had some level of data analytic and informatics expertise. [...]the complexity of implementing OASIS© in sites with limited expertise in using R or accessing the electronic data warehouse may differ. [...]the implementation of OASIS© required contention with system diversity and knowledge gaps in informatics and antibiotic stewardship.

Background: Combating antibiotic resistance, exacerbated by widespread unnecessary outpatient antibiotic prescriptions, necessitates innovative stewardship solutions. Audit and feedback reports are effective but often resource heavy. We introduced a free, open-source system, Outpatient Automated Stewardship Information System (OASIS©), for automating the creation and distribution of recurring audit and feedback reports to clinicians to improve antibiotic prescribing. Methods: We used mixed methods to evaluate implementation of OASIS© across 11 clinics at Denver Health and Hospital Authority (DHHA) and Children’s Hospital Colorado (CHCO) from July 2022 to August 2023. Both sites host their own Epic® electronic healthcare and enterprise data warehouse systems. R statistical software was utilized to retrieve and process the data needed to create individual[HCM1] clinician audit and feedback reports with peer comparison. Reports were provided for 1) antibiotics prescribed for respiratory diagnoses, 2) antibiotics prescribed for respiratory diagnoses where antibiotics are never indicated, 3) first-line antibiotic prescribing for acute otitis media (AOM), and 4) five-day duration of antibiotics for children two years and older with AOM. Feedback reports for each metric were emailed to clinicians for three consecutive months. The primary outcome was adaptations needed to implement OASIS©. Secondary outcomes included fidelity (measured by email readership), time to set up and maintain the program, and barriers and facilitators to implementation (assessed by four qualitative interviews with OASIS© stakeholders). Results: The most significant adaptations made pertained to the automation of OASIS© reports for organizations not using R for data retrieval and reporting, setting up OASIS© specific email addresses, and validating clinician fidelity via read receipts. Fidelity was higher at DHHA (91-100%) compared to CHCO (10-30%). When interviewed, data analysts expressed that time for initial setup ranged from 1-6 hours. After reporting was automated, the estimated monthly time to send reports was 10 minutes. Views on setup complexity were split, but all recognized the readability of the reports and OASIS©’s value for improving prescribing behaviors. The greatest barriers to implementation included obtaining analytic resources for initial setup and the need to download additional R packages. No interviewee had prior experience creating audit and feedback reports. Conclusions: Implementing OASIS© requires addressing system diversity and knowledge gaps in outpatient informatics and antibiotic stewardship. Despite these challenges, the tool proved efficient and beneficial for monitoring and reporting antimicrobial prescribing. This free tool could likely be effectively disseminated to other health systems given the limited time and resources required for adaptations, setup, and monitoring. [HCM1]I

Dating relationships during adolescence is a complex interaction that involves multiple systems however, the systemic factors promoting the development of healthy dating relationships in adolescence are not well understood. The current study aims to address this gap by reviewing studies that assessed factors contributing to healthy adolescent dating relationship skills, competencies, and capacities. Through a social ecological perspective, healthy dating relationship factors were identified across five levels of adolescents’ environments (e.g., individual, peer, family, school, and online) to inform intervention strategies for the promotion of healthy dating relationships. After an iterative screening process, 51 peer-reviewed empirical articles were identified across a search strategy from 2008 to 2018. Amongst the 51 articles, 76 key healthy dating relationship factors were identified across the five social ecological levels: individual ( n  = 34), family ( n  = 16), peer ( n  = 13), school ( n  = 9), and online ( n  = 4). While several healthy dating relationship factors identified in school-based relationship education interventions (school level) overlapped with individual and peer level factors (e.g., communication, listening), the review highlighted two social ecological levels of family and online that can further benefit the efficacy and comprehensiveness of school-based relationship education interventions.

On June 26, 2007, IBM announced the Blue Gene/P(TM) system as the leading offering in its massively parallel Blue Gene® supercomputer line, succeeding the Blue Gene/L(TM) system. The Blue Gene/P system is designed to scale to at least 262,144 quad-processor nodes, with a peak performance of 3.56 petaflops. More significantly, the Blue Gene/P system enables this unprecedented scaling via architectural and design choices that maximize performance per watt, performance per square foot, and mean time between failures. This paper describes our vision of this petascale system, that is, a system capable of delivering more than a quadrillion (10^sup 15^) floating-point operations per second. We also provide an overview of the system architecture, packaging, system software, and initial benchmark results. [PUBLICATION ABSTRACT]