Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms.

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

Objective: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

Novel Somatic UBA1 Variant in a Patient With VEXAS Syndrome.

Objective: Somatic mutations in UBA1 have recently been causally linked to a severe adult-onset inflammatory condition referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Ubiquitin-activating enzyme E1 (UBA-1) is of fundamental importance to the modulation of ubiquitin homeostasis and to the majority of downstream ubiquitylation-dependent cellular processes. Direct sequencing analysis of exon 3 containing the prevalent variants p.

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women.

Background: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive.

Objectives: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S.

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors.

Strengthening Causal Inference in Exposomics Research: Application of Genetic Data and Methods.

Advances in technologies to measure a broad set of exposures have led to a range of exposome research efforts. Yet, these efforts have insufficiently integrated methods that incorporate genetic data to strengthen causal inference, despite evidence that many exposome-associated phenotypes are heritable. Objective: We demonstrate how integration of methods and study designs that incorporate genetic data can strengthen causal inference in exposomics research by helping address six challenges: reverse causation and unmeasured confounding, comprehensive examination of phenotypic effects, low efficiency, replication, multilevel data integration, and characterization of tissue-specific effects.

Novel Variant Causing Familial Hyperkalemic Hypertension Impairs Regulation and Function of Ubiquitin Ligase Activity.

Familial hyperkalemic hypertension is caused by pathogenic variants in genes of the CUL3 (cullin-3)-KLHL3 (kelch-like-family-member-3)-WNK (with no-lysine [K] kinase) pathway, manifesting clinically as hyperkalemia, metabolic acidosis, and high systolic blood pressure. The ubiquitin E3 ligase CUL3-KLHL3 targets WNK kinases for degradation to limit activation of the thiazide-sensitive NCC (Na-Cl cotransporter). All known variants in lead to exon 9 skipping (CUL3Δ9) and typically result in severe familial hyperkalemic hypertension and growth disturbances in patients.

Novel somatic mutations in UBA1 as a cause of VEXAS syndrome.

Poulter and colleagues describe a series from the United Kingdom of 10 male patients with VEXAS syndrome, including 2 with novel genetic changes affecting methionine 41 of E1.

Correction: A kinase-dependent checkpoint prevents escape of immature ribosomes into the translating pool.

[This corrects the article DOI: 10.1371/journal.pbio.

Association of Weight Loss Between Early Adulthood and Midlife With All-Cause Mortality Risk in the US.

Importance: Describing potential mortality risk reduction associated with weight loss between early adulthood and midlife is important for informing primary and secondary prevention efforts for obesity.

Objective: To examine the risk of all-cause mortality among adults who lost weight between early adulthood and midlife compared with adults who were persistently obese over the same period.

Design, Setting, And Participants: Combined repeated cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey III (1988-1994) and continuous waves collected in 2-year cycles between 1999 and 2014.

Obesity Progression Between Young Adulthood and Midlife and Incident Arthritis: A Retrospective Cohort Study of US Adults.

Objective: To examine the association between weight change from young adulthood to midlife and the risk of incident arthritis.

Methods: Using data from the National Health and Nutrition Examination Survey, we categorized participants into weight-change categories based on their recalled weight during young adulthood and midlife. We estimated the association of weight change and developing an arthritis condition over 10 years using adjusted Cox models.

A kinase-dependent checkpoint prevents escape of immature ribosomes into the translating pool.

Premature release of nascent ribosomes into the translating pool must be prevented because these do not support viability and may be prone to mistakes. Here, we show that the kinase Rio1, the nuclease Nob1, and its binding partner Pno1 cooperate to establish a checkpoint that prevents the escape of immature ribosomes into polysomes. Nob1 blocks mRNA recruitment, and rRNA cleavage is required for its dissociation from nascent 40S subunits, thereby setting up a checkpoint for maturation.

Exploring the advantages and limitations of sampling methods commonly used in research facilities for zebrafish health inspections.

Examining zebrafish populations for the presence of disease is an integral component of managing fish health in research facilities. Currently, many different strategies are used for zebrafish fish health inspections, which is a scenario that may result in subjective and biased diagnostic evaluations. The goal of this study was to compare the success of pathogen detection between a sample size of randomly selected fish ( = 60) that provides 95% confidence in pathogen detection based on a presumed pathogen prevalence level ≥5%, and other subpopulations and sample numbers commonly submitted for diagnostic testing within a 1000 tank, 30,000 fish, recirculating research system.

The contribution of obesity to prescription opioid use in the United States.

The prevalence of obesity has grown rapidly over the past several decades and has been accompanied by an increase in the prevalence of chronic pain and prescription opioid use. Obesity, through its association with pain, may represent an important contributor to opioid use. This cross-sectional study investigated the relationship between obesity and prescription opioid use among adults aged 35 to 79 years using data from the National Health and Nutrition Examination Survey (NHANES, 2003-2016).

A smart curtailment approach for reducing bat fatalities and curtailment time at wind energy facilities.

The development and expansion of wind energy is considered a key global threat to bat populations. Bat carcasses are being found underneath wind turbines across North and South America, Eurasia, Africa, and the Austro-Pacific. However, relatively little is known about the comparative impacts of techniques designed to modify turbine operations in ways that reduce bat fatalities associated with wind energy facilities.

Ribosome biogenesis factor Ltv1 chaperones the assembly of the small subunit head.

The correct assembly of ribosomes from ribosomal RNAs (rRNAs) and ribosomal proteins (RPs) is critical, as indicated by the diseases caused by RP haploinsufficiency and loss of RP stoichiometry in cancer cells. Nevertheless, how assembly of each RP is ensured remains poorly understood. We use yeast genetics, biochemistry, and structure probing to show that the assembly factor Ltv1 facilitates the incorporation of Rps3, Rps10, and Asc1/RACK1 into the small ribosomal subunit head.