Escalation of genome defense capacity enables control of an expanding meiotic driver.

From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases.

Self-reported hearing loss and health during a pandemic: Findings from a cross-sectional analysis using a 2021 household survey.

Background: The COVID-19 pandemic differentially impacted individuals with hearing loss, likely in part due to increased communication difficulties from masking, a commonly implemented protective measure.

Objective: This study examines the association between self-reported hearing loss and health during the pandemic.

Methods: This study uses data from the COVID-19 Survey collected by the Survey of the Health of Wisconsin from February to March 2021.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice.

Examining aid fragmentation and collaboration opportunities in Cambodia's health sector.

Background: Cambodia's health sector faces significant challenges exacerbated by aid fragmentation, where development aid is dispersed among numerous small, uncoordinated projects. This study examines the distribution of health sector aid among Cambodia's principal donors to identify priorities, overlaps, and potential collaboration opportunities, addressing the urgent need for aid efficiency and alignment with national health priorities.

Methods: Utilizing OECD datasets and the Herfindahl-Hirschman Index (HHI) for the years 2010-2021, this study quantifies aid fragmentation within Cambodia's health sector.

Escalation of genome defense capacity enables control of an expanding meiotic driver.

From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, which controls selfish elements in the metazoan germline, diverse target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases via enzymatic cleavage.

Sense of community and mental health: a cross-sectional analysis from a household survey in Wisconsin.

Background: In the USA, one in five adults live with a mental illness, and researchers have estimated that nearly half of the population will have a mental illness over the course of their lifetime. Research has shown significant associations between social relationships and mental health outcomes at the individual and population levels. This study aims to examine whether sense of community, a type of social capital, is associated with mental health.

Harnessing the Electronic Medical Record to Improve the Utilization of Ultrasound Screening for Abdominal Aortic Aneurysms.

Purpose: The US Preventive Services Task Force recommends one-time ultrasound screening to detect abdominal aortic aneurysms (AAAs) in male smokers. Despite this recommendation, AAA screening is still underutilized. The aim of this study was to determine the effectiveness of an electronic medical record (EMR) automated ordering program in increasing AAA screening at an integrated health care system.

"Please Don't Forget Us": A Descriptive Qualitative Study of Caregivers of Older Adults With Alzheimer's Disease and Related Dementias During the COVID-19 Pandemic.

The current descriptive qualitative study explored the perceived impact of the coronavirus disease 2019 pandemic on sleep disturbances and nighttime agitation; the reported use of antipsychotics and other sedating medications; and the overall well-being of older adults with Alzheimer's disease and related dementias (ADRD) and their caregivers. One investigator conducted in-depth, phone interviews with caregivers of nursing home residents with ADRD (four family caregivers [FCs], three nurse practitioners [NPs]) and seven FCs of older adults with ADRD who lived with them at home. Caregivers described multiple sleep disturbances.

Draft Genome Sequences of Three Antibiotic-Producing Soil Bacteria, Staphylococcus pasteuri WAM01, Peribacillus butanolivorans WAM04, and Micrococcus yunnanensis WAM06, with Growth-Inhibiting Effects against Commensal Strains.

We report the isolation, identification, and assemblies of three antibiotic-producing soil bacteria (Staphylococcus pasteuri, Peribacillus butanolivorans, and Micrococcus yunnanensis) that inhibit the growth of commensals in coculture. With pathogenic strains becoming increasingly resistant to antibiotics, bioprospecting for novel antimicrobials using commensal relatives may facilitate discovery of clinically useful drugs.

Religion, Spirituality, and Coping During the Pandemic: Perspectives of Dementia Caregivers.

Religious and spiritual (R/S) practices support individuals during difficult situations. The COVID-19 social distancing restrictions may have limited access to R/S practices for older adults with Alzheimer's disease related dementia (ADRD) and their caregivers, affecting coping and well-being. This qualitative study explored the impact of social distancing on R/S practices and coping in ADRD-caregiver dyads from the perspective of caregivers.

Seasonal COVID-19 surge related hospital volumes and case fatality rates.

Background: Seasonal and regional surges in COVID-19 have imposed substantial strain on healthcare systems. Whereas sharp inclines in hospital volume were accompanied by overt increases in case fatality rates during the very early phases of the pandemic, the relative impact during later phases of the pandemic are less clear. We sought to characterize how the 2020 winter surge in COVID-19 volumes impacted case fatality in an adequately-resourced health system.

Temporal variations in the severity of COVID-19 illness by race and ethnicity.

Introduction: Early reports highlighted racial/ethnic disparities in the severity of COVID-19 seen across the USA; the extent to which these disparities have persisted over time remains unclear. Our research objective was to understand temporal trends in racial/ethnic variation in severity of COVID-19 illness presenting over time.

Methods: We conducted a retrospective cohort analysis using longitudinal data from Cedars-Sinai Medical Center, a high-volume health system in Southern California.

A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination.

Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin-proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data.

High-Throughput Quantitative Assay Technologies for Accelerating the Discovery and Optimization of Targeted Protein Degradation Therapeutics.

The aberrant regulation of protein expression and function can drastically alter cellular physiology and lead to numerous pathophysiological conditions such as cancer, inflammatory diseases, and neurodegeneration. The steady-state expression levels of endogenous proteins are controlled by a balance of de novo synthesis rates and degradation rates. Moreover, the levels of activated proteins in signaling cascades can be further modulated by a variety of posttranslational modifications and protein-protein interactions.

Identification of Functional Limitations and Discharge Destination in Patients With COVID-19.

Objectives: The objectives of this study were to identify functional limitations in patients with coronavirus 2019 (COVID-19) admitted to acute care hospitals; to evaluate functional limitations by demographic, medical, and encounter characteristics; and to examine functional limitations in relation to discharge destination.

Design: and Setting:This is a cross-sectional, retrospective study of adult patients with COVID-19 who were discharged from 2 different types of hospitals (academic medical center and a community hospital) within 1 health care system from January 1 to April 30, 2020.

Participants: Patients were identified from the Cedars-Sinai COVID-19 data registry who had a new-onset positive test for severe acute respiratory syndrome coronavirus 2.

Pre-existing traits associated with Covid-19 illness severity.

Importance: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear.

Objective: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection.

Design: Retrospective observational study.

Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring.

Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 (COVID-19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID-19-positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs.

Ca/calmodulin-dependent regulation of polycystic kidney disease 2-like-1 by binding at C-terminal domain.

Polycystic kidney disease 2-like-1 (PKD2L1), also known as polycystin-L or TRPP3, is a non-selective cation channel that regulates intracellular calcium concentration. Calmodulin (CaM) is a calcium binding protein, consisting of N-lobe and C-lobe with two calcium binding EF-hands in each lobe. In previous study, we confirmed that CaM is associated with desensitization of PKD2L1 and that CaM N-lobe and PKD2L1 EF-hand specifically are involved.

The role of calmodulin in regulating calcium-permeable PKD2L1 channel activity.

Polycystic kidney disease 2-like-1 (PKD2L1), polycystin-L or transient receptor potential polycystin 3 (TRPP3) is a TRP superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. Although the calmodulin (CaM) inhibitor, calmidazolium, is an activator of the PKD2L1 channel, the activating mechanism remains unclear.

Englerin A-sensing charged residues for transient receptor potential canonical 5 channel activation.

The transient receptor potential canonical (TRPC) 5 channel, known as a nonselective cation channel, has a crucial role in calcium influx. TRPC5 has been reported to be activated by muscarinic receptor activation and extracellular pH change and inhibited by the protein kinase C pathway. Recent studies have also suggested that TRPC5 is extracellularly activated by englerin A (EA), but the mechanism remains unclear.

Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators.

Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired.

Gα-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation.

Hypertension and aneurysm are frequently associated with autosomal dominant polycystic kidney disease (ADPKD) caused by polycystin-1 (PC1) mutations, which is closely related to endothelial dysfunction. PC1 is an atypical G-protein-coupled receptor that activates G-proteins by self-cleavage; currently, however, the molecular and cellular mechanisms of the associated intracellular signaling and ion channel activation remain poorly elucidated. Here, we report an activation mechanism of a calcium-permeable canonical transient receptor potential 4 (TRPC4) channel by PC1 and its endothelial function.