Unravelling the druggability and immunological roles of the SOCS-family proteins.

The Suppressor of Cytokine Signalling (SOCS) protein family play a critical role in cytokine signalling and regulation of the JAK/STAT pathway with functional consequences to the immune response. Members of this family are implicated in multiple different signalling cascades that drive autoimmune diseases and cancer, through their binding to phosphotyrosine modified proteins as well as ubiquitination activity as part of Cullin5 RING E3 ligases. Here we review the SOCS family members CISH and SOCS1-SOCS7, with a focus on their complex role in immunity.

The BSSO Foundry: A community of practice for ontologies in the behavioural and social sciences.

There has been a rapid expansion in the quantity and complexity of data, information and knowledge created in the behavioural and social sciences, yet the field is not advancing understanding, practice or policy to the extent that the insights warrant. One challenge is that research often progresses in disciplinary silos and is reported using inconsistent and ambiguous terminology. This makes it difficult to integrate and aggregate findings to produce cumulative bodies of knowledge that can be translated to applied settings.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

Anhedonia in Major Depressive Disorder: Prevalence and Treatment Expectations and Satisfaction with Treatment Goals Among Patients and Physicians in Asia-Pacific.

Purpose: To explore the prevalence of anhedonia (ANH) in major depressive disorder (MDD) and treatment expectation and satisfaction among patients with MDD and physicians in the Asia-Pacific region.

Methods: This cross-sectional web-based survey was conducted in April-May 2023 among physicians and individuals aged ≥18 years with self-reported physician diagnosis of MDD (9-item Patient Health Questionnaire [PHQ-9] score ≥ 10) further stratified by anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS): MDD-ANH (SHAPS score > 2) and MDD non-ANH (SHAPS score ≤ 2). The study assessed the prevalence of anhedonia in MDD as well as the perspectives on the treatment of anhedonia in MDD in terms of expectations and satisfaction among patients and physicians.

Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

Importance: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD.

Objective: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations.

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells.

A promising drug target, SETDB1, is a dual Kme reader and methyltransferase, which has been implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identified a low micromolar small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization led to the discovery of UNC10013, the first covalent 3TD ligand targeting Cys385 of SETDB1.

Navigating uncertainty in maximum body size in marine metazoans.

Body size is a fundamental biological trait shaping ecological interactions, evolutionary processes, and our understanding of the structure and dynamics of marine communities on a global scale. Accurately defining a species' body size, despite the ease of measurement, poses significant challenges due to varied methodologies, tool usage, and subjectivity among researchers, resulting in multiple, often discrepant size estimates. These discrepancies, stemming from diverse measurement approaches and inherent variability, could substantially impact the reliability and precision of ecological and evolutionary studies reliant on body size data across extensive species datasets.

Deep PIM kinase substrate profiling reveals new rational cotherapeutic strategies for acute myeloid leukemia.

Provirus integration site for Moloney murine leukemia virus (PIM) family serine/threonine kinases perform protumorigenic functions in hematologic malignancies and solid tumors by phosphorylating substrates involved in tumor metabolism, cell survival, metastasis, inflammation, and immune cell invasion. However, a comprehensive understanding of PIM kinase functions is currently lacking. Multiple small-molecule PIM kinase inhibitors are currently being evaluated as cotherapeutics in patients with cancer.

Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Unlabelled: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV non-structural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign.

Subjective Causes for Failure to Return to Sport After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis.

Context: While current literature has explored the outcomes of athletes who return to sport (RTS) after anterior cruciate ligament (ACL) injuries, less is known about the outcomes of those who are unsuccessful in returning to sport.

Objective: To determine the rate of athletes who did not RTS after primary ACL reconstruction (ACLR) and to identify the specific subjective reasons for failure to RTS.

Data Sources: A comprehensive search of the PubMed/MEDLINE, Scopus, and Web of Science databases was conducted through April 2021.

The Prevalence of Financial Conflict of Interest Disclosures by Endovascular Specialists on X (Twitter).

Purpose: To evaluate conflicts of interest (COIs) among interventional radiologists and related specialties who mention specific devices or companies on the social media (SoMe) platform X, formerly Twitter.

Materials And Methods: In total, 13,809 posts between October 7, 2021, and December 31, 2021, on X were evaluated. Posts by U.

A meta-analysis of the effect of visiting zoos and aquariums on visitors' conservation knowledge, beliefs, and behavior.

Zoos and aquariums are well placed to connect visitors with the issues facing biodiversity globally and many deliver interventions that seek to influence visitors' beliefs and behaviors with respect to conservation. However, despite primary studies evaluating the effect of such interventions, the overall effect of engaging with zoos and the factors that influence this effect remain unclear. We conducted a systematic review to investigate the effect of zoo-led interventions on knowledge, beliefs (attitudes, intentions, self-efficacy, and social norms), and behavior among zoo visitors.

Longitudinal clustering of health behaviours and their association with multimorbidity in older adults in England: A latent class analysis.

Background: Health-risk behaviours such as smoking, unhealthy nutrition, alcohol consumption, and physical inactivity (termed SNAP behaviours) are leading risk factors for multimorbidity and tend to cluster (i.e. occur in specific combinations within distinct subpopulations).

Random variation drives a critical bias in the comparison of healthcare-associated infections.

Objective: To evaluate random effects of volume (patient days or device days) on healthcare-associated infections (HAIs) and the standardized infection ratio (SIR) used to compare hospitals.

Design: A longitudinal comparison between publicly reported quarterly data (2014-2020) and volume-based random sampling using 4 HAI types: central-line-associated bloodstream infections, catheter-associated urinary tract infections, infections, methicillin-resistant infections.

Methods: Using 4,268 hospitals with reported SIRs, we examined relationships of SIRs to volume and compared distributions of SIRs and numbers of reported HAIs to the outcomes of simulated random sampling.

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects.

Methods: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015.

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci.

Halide Chemistry in Tin Perovskite Optoelectronics: Bottlenecks and Opportunities.

Tin halide perovskites (Sn HaPs) are the top lead-free choice for perovskite optoelectronics, but the oxidation of perovskite Sn to Sn remains a key challenge. However, the role of inconspicuous chemical processes remains underexplored. Specifically, the halide component in Sn HaPs (typically iodide) has been shown to play a key role in dictating device performance and stability due to its high reactivity.

Can behavior change techniques be delivered via short text messages?

Despite significant advancements in behavioral science it is unclear whether behavior change techniques (or BCTs) can be delivered to large numbers of people in a cost-effective and reliable way. The current study investigated whether it is possible to reliably deliver BCTs using short text messages. Short text messages were designed to deliver each of the 93 BCTs specified in the BCT taxonomy v1.

Exploring attitudes towards more sustainable dentistry among adults living in the UK.

Introduction Despite evidence that public pressure can promote sustainability in various domains (for example, retail and travel), no research has considered the public's attitudes towards sustainability in dentistry.Methods A questionnaire was developed to measure attitudes towards sustainable dentistry among adults living in the UK and their willingness to make compromises to reduce the impact of their dental treatment on the environment. In total, 344 adults completed the questionnaire that also measured pro-environmental identity and concern, general willingness to make compromises for the environment, and the tendency to engage in ecological behaviours.

The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins α9β1 and α4β1.

Background And Purpose: Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated Ca channels (VGCCs). Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin α9β1, associate with elevated blood pressure; however, neither SVEP1 nor integrin α9β1 has reported roles in vasoregulation.

Variation in the Reporting of Elective Surgeries and Its Influence on Patient Safety Indicators.

Background: US hospital safety is routinely measured via Patient Safety Indicators (PSIs). Receiving a score for most PSIs requires a minimum number of qualifying cases to meet specific criteria; for example, whether an admission was elective. Because admission type is determined by hospitals' internal policies, the study team suspected that hospitals may be exempted from elective-based PSI scores as a result of their internal admission classification policies.

Elucidation of the genetic causes of bicuspid aortic valve disease.

Aims: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect.

Methods And Results: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29.

Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers.