Epithelial outgrowth through mesenchymal rings drives alveologenesis.

Determining how alveoli are formed and maintained is critical to understanding lung organogenesis and regeneration after injury. To study the cellular dynamics of this critical stage of lung development, we have used scanned oblique-plane illumination microscopy of living lung slices to observe alveologenesis in real time at high resolution over several days. Contrary to the prevailing notion that alveologenesis occurs by airspace subdivision via ingrowing septa, we find that alveoli form by ballooning epithelial outgrowth supported by contracting mesenchymal ring structures.

Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells.

Greater recalled pain and movement-evoked pain are associated with longer 400-meter walk and repeat stair climb time: the Study of Muscle, Mobility and Aging.

Background: Musculoskeletal pain frequently accompanies the development of mobility disability and falls in old age. To better understand this, we aimed to quantify the impact of different pain measures-recalled pain and movement-evoked pain-on 400-meter walk and stair climb time in older adults participating in the Study of Muscle, Mobility and Aging (SOMMA).

Methods: In SOMMA (N=879, age=76.

Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease.

The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.

DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases.

Background: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods: We calculated the American Heart Association's Life's Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses.

Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing.

Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action.

Proteome-wide association studies for blood lipids and comparison with transcriptome-wide association studies.

Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWASs) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in blood.

Benefits of Tadalafil and Sildenafil on Mortality, Cardiovascular Disease, and Dementia.

Background: Erectile dysfunction and lower urinary tract symptoms, from benign prostatic hyperplasia and bladder neck obstructions, are prevalent in men and associated with an increased risk of cardiovascular diseases. Phosphodiesterase-5 (PDE-5) inhibitors, such as tadalafil and sildenafil, are used to treat erectile dysfunction and may also offer cardiovascular benefits due to their vasodilatory effects. This study evaluates the impact of these PDE-5 inhibitors on all-cause mortality, cardiovascular disease, and dementia in middle-aged men with erectile dysfunction and lower urinary tract symptoms over a 3 year follow-up period.

Rare variants and survival of patients with idiopathic pulmonary fibrosis.

Background: The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival.

Community design of the Brooklyn Health Equity Index.

Health equity drives quality care. Few reliable metrics that capture patients' perceptions of health equity exist. We report on the development of a patient-centered metric for health systems change in central Brooklyn, which stands out as an outlier in New York City with a disproportionate burden of poverty, disease, and death.

Progressive Early Interstitial Lung Abnormalities in Persons at Risk for Familial Pulmonary Fibrosis: A Prospective Cohort Study.

Relatives of patients with familial pulmonary fibrosis (FPF) are at increased risk to develop FPF. Interstitial lung abnormalities (ILAs) are a radiologic biomarker of subclinical disease, but the implications of very mild abnormalities remain unclear. To quantify the progression risk among FPF relatives with abnormalities below the threshold for ILAs as described by the Fleischner Society and to describe the characteristics of participants with new or progressive ILAs during observation.

Role of Walking Energetics and Perceived Fatigability Differs by Gait Speed: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Slower gait speed may be driven by greater energy deficits and fatigability among older adults. We examined associations of walking energetics and perceived physical fatigability with gait speed among slower and faster walkers. Additionally, we used statistical mediation to examine the role of fatigability in the associations of walking energetics and gait speed using the Study of Muscle, Mobility and Aging (SOMMA).

Comparing immobilisation devices in gynaecological external beam radiotherapy: improving inter-fraction reproducibility of pelvic tilt.

Introduction: The aim was to determine which immobilisation device improved inter-fraction reproducibly of pelvic tilt and required the least pre-treatment setup and planning interventions.

Methods: Sixteen patients were retrospectively reviewed, eight immobilised using the BodyFIX system (BodyFIX®, Elekta, Stockholm, Sweden) and eight using the Butterfly Board (BB) (Bionix Radiation Therapy, Toledo, OH, USA). The daily pre-treatment images were reviewed to assess setup variations between each patient and groups for pelvic tilt, pubic symphysis, sacral promontory and the fifth lumbar spine (L5).

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.

Muscle Mitochondrial Bioenergetic Capacities Are Associated With Multimorbidity Burden in Older Adults: The Study of Muscle, Mobility and Aging.

Background: The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity.

Methods: The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 76.