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Fast-response micrometeorological data obtained from an instrumented 32-m tower at an arid site near Ocotillo, Texas are used to examine the daily time evolution of the lower atmosphere. Correlation coefficients between turbulence properties (fast response wind-speed components and temperature) confirm that over this sparsely vegetated site the effects of convection are observed soon after sunrise, well ahead of the morning transition from stable to unstable stratification. Details of this kind are obscured when results are considered as functions of conventional stability parameters, since such standard analytical methods combine features of the morning and evening transitions into a single presentation. Partial correlation coefficients and semi-partials indicate that the local turbulent kinetic energy is mainly associated with local fluxes of heat and momentum near neutral and in most stable conditions, but decreases substantially during the times of strongest instability (possibly reflecting the scatter introduced by sampling infrequent convective episodes using a single tower). For many of the variables considered here, the standard deviations are about the same as the linear averages, indicating that the distributions are close to log-normal. The present data indicate that if the intent is to address some specific situation then $$\pm $$ 10 % error bounds on turbulence quantities (e.g. fluxes) correspond to averaging over a distance scale of the order of 10 km and a time scale of about 3 h. As the distance and time scales become smaller, the uncertainties due to factors external to the local surface increase. [ABSTRACT FROM AUTHOR]

Background: Understanding the genetic causes for variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from diverse distinct projects and laboratories., Results: We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1,454 unique donor individuals across 653 studies from public databases, we catalog 23,381 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often strongly linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility and diverse complex human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes., Conclusions: Our work provides a proof of principle for caQTL calling from previously ungenotyped samples, and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease., Competing Interests: A.B. is a co-founder and equity holder of CellCipher, Inc, a stockholder in Alphabet, Inc, and has consulted for Third Rock Ventures. N.C. is an employee and shareholder of Exai Bio, Inc. J.K.P. and J.H.L. are employees of Gencove, Inc.

Inference of causal transcriptional regulatory networks (TRNs) from transcriptomic data suffers notoriously from false positives. Approaches to control the false discovery rate (FDR), for example, via permutation, bootstrapping, or multivariate Gaussian distributions, suffer from several complications: difficulty in distinguishing direct from indirect regulation, nonlinear effects, and causal structure inference requiring "causal sufficiency," meaning experiments that are free of any unmeasured, confounding variables. Here, we use a recently developed statistical framework, model-X knockoffs, to control the FDR while accounting for indirect effects, nonlinear dose-response, and user-provided covariates. We adjust the procedure to estimate the FDR correctly even when measured against incomplete gold standards. However, benchmarking against chromatin immunoprecipitation (ChIP) and other gold standards reveals higher observed than reported FDR. This indicates that unmeasured confounding is a major driver of FDR in TRN inference. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests A.B. is a stockholder for Alphabet, Inc.; has consulted for Third Rock Ventures; and is a founder of CellCipher, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

Short telomeres cause age-related disease, and long telomeres contribute to cancer; however, the mechanisms regulating telomere length are unclear. We developed a nanopore-based method, which we call Telomere Profiling, to determine telomere length at nearly single-nucleotide resolution. Mapping telomere reads to chromosome ends showed chromosome end-specific length distributions that could differ by more than six kilobases. Examination of telomere lengths in 147 individuals revealed that certain chromosome ends were consistently longer or shorter. The same rank order was found in newborn cord blood, suggesting that telomere length is determined at birth and that chromosome end-specific telomere length differences are maintained as telomeres shorten with age. Telomere Profiling makes precision investigation of telomere length widely accessible for laboratory, clinical, and drug discovery efforts and will allow deeper insights into telomere biology.

Differential allele-specific expression (ASE) is a powerful tool to study context-specific cis-regulation of gene expression. Such effects can reflect the interaction between genetic or epigenetic factors and a measured context or condition. Single-cell RNA sequencing (scRNA-seq) allows the measurement of ASE at individual-cell resolution, but there is a lack of statistical methods to analyze such data. We present Differential Allelic Expression using Single-Cell data (DAESC), a powerful method for differential ASE analysis using scRNA-seq from multiple individuals, with statistical behavior confirmed through simulation. DAESC accounts for non-independence between cells from the same individual and incorporates implicit haplotype phasing. Application to data from 105 induced pluripotent stem cell (iPSC) lines identifies 657 genes dynamically regulated during endoderm differentiation, with enrichment for changes in chromatin state. Application to a type-2 diabetes dataset identifies several differentially regulated genes between patients and controls in pancreatic endocrine cells. DAESC is a powerful method for single-cell ASE analysis and can uncover novel insights on gene regulation., (© 2023. Springer Nature Limited.)

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10 -9 ) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 ( STN1 ). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B ( SNM1B ) and PARN . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes., Competing Interests: Declaration of Interests: The authors declare the following competing interests: J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI L.W. is on the advisory board for GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK, NIH I.V.Y. is a consultant for ElevenP15 S.A. receives equity and salary from 23andMe, Inc. M.H.C. receives grant support from GlaxoSmithKline S.T.W. receives royalties from UpToDate E.K.S. received grant support from GlaxoSmithKline and Bayer in the past three years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is supported by grants from NIH/NHLBI (HL139054,HL091889,HL132523,HL130045,HL098112,HL056177), the NIH/NIEHS (ES006614), the NIH/NIAID (AI126614), and the NIH/ Office of Director (OD023282). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045. Dr. Martinez is a council member for the Council for the Developing Child. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr. Ellinor has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, LLC and holds stock in Google, Inc. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis

Vesicular stomatitis (VS) is a vector-borne livestock disease caused by vesicular stomatitis New Jersey virus (VSNJV) or vesicular stomatitis Indiana virus (VSIV). The disease circulates endemically in northern South America, Central America, and Mexico and only occasionally causes outbreaks in the United States. Over the past 20 years, VSNJV outbreaks in the southwestern and Rocky Mountain regions occurred with incursion years followed by virus overwintering and subsequent expansion outbreak years. Regulatory response by animal health officials is deployed to prevent spread from lesioned animals. The 2019 VS incursion was the largest in 40 years, lasting from June to December 2019 with 1144 VS-affected premises in 111 counties in eight states (Colorado, Kansas, Nebraska, New Mexico, Oklahoma, Texas, Utah, and Wyoming) and was VSIV serotype, last isolated in 1998. A subsequent expansion occurred from April to October 2020 with 326 VS-affected premises in 70 counties in eight states (Arizona, Arkansas, Kansas, Missouri, Nebraska, New Mexico, Oklahoma, and Texas). The primary serotype in 2020 was VSIV, but a separate incursion of VSNJV occurred in south Texas. Summary characteristics of the outbreaks are presented along with VSV-vector sampling results and phylogenetic analysis of VSIV isolates providing evidence of virus overwintering.

Previous models suggested that regulation of telomere length in Saccharomyces cerevisiae by Tel1(ATM) and Mec1(ATR) would parallel the established pathways regulating the DNA damage response. Here, we provide evidence that telomere length regulation differs from the DNA damage response in both the Tel1 and Mec1 pathways. We found that Rad53 mediates a Mec1 telomere length regulation pathway but is dispensable for Tel1 telomere length regulation, whereas in the DNA damage response, Rad53 is regulated by both Mec1 and Tel1 Using epistasis analysis with a Tel1 hypermorphic allele, Tel1-hy909, we found that the MRX complex is not required downstream of Tel1 for telomere elongation but is required downstream of Tel1 for the DNA damage response. Our data suggest that nucleolytic telomere end processing is not a required step for telomerase to elongate telomeres., (Copyright © 2019 by the Genetics Society of America.)

Background: Elevated expression of the proinflammatory cytokine interleukin 1β (IL-1β) has been observed in expressed prostatic secretions of patients with chronic prostatitis/chronic pelvic pain syndrome, and genetic polymorphisms associated with the IL1B gene are linked to increased risk for aggressive prostate cancer., Methods: To study the role of IL-1β expression in prostate inflammation, we examined IL1B expression in human prostatic proliferative inflammatory atrophy (PIA) lesions and developed a tetracycline-regulated human IL1B transgene in the mouse prostate., Results: Here, we demonstrate that IL1B expression is a common finding in human PIA lesions, which harbored focal IL1B expression in epithelial and stromal compartments. Human IL1B expression in the mouse prostate elicited acute and chronic inflammation. Penetrance and expressivity were variable and tunable by altering transgene dosage and the presence of an exogenous inducible marker antigen (green fluorescent protein). Inflammation was characterized by infiltration of CD4 + T cells, demonstrating an adaptive immune response. Chronic inflammation persisted after doxycycline (Dox) withdrawal. Reactive epithelia increased expression of downstream cytokines, and altered glandular architecture was observed upon sustained induction of IL1B. Immunohistochemical analyses revealed a higher proliferative index and decreased Nkx3.1 expression in inflamed mouse prostates., Conclusions: These data implicate IL-1β in human prostate pathology and this model provides a versatile platform to interrogate molecular mechanisms of inflammation-associated prostate pathologies associated with episodic or sustained IL-1β expression., (© 2019 Wiley Periodicals, Inc.)

This research was motivated by a clinical trial with bladder cancer patients who went through a surgery and were followed up for cancer recurrence. One of the main objectives of the trial was to evaluate the time to cancer recurrence in patients in control and experimental groups. At the time of recurrence, the disease stage was also evaluated. Because the stage of cancer at recurrence significantly impacts future treatment and patient prognosis of survival, analyzing the time to cancer recurrence and the stage at recurrence jointly provides more clinically relevant information than analyzing the time to recurrence alone. In this paper, we propose a stochastic model for the joint distribution of time to recurrence and cancer stage that (1) accounts for the recurrence caused by cancer cells surviving a treatment or a surgery and for the recurrence caused by spontaneous carcinogenesis, and (2) incorporates parameters that have biological meaning. To estimate the parameters, we use the maximum-likelihood method combined with the EM algorithm. To demonstrate the performance of our modeling, we evaluate the data from a clinical trial in patients with bladder cancer. We also use simulations to assess the sensitivity of the method.