Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist.

TGF-β Receptor-dependent Tissue Factor Release and Proteomic Profiling of Extracellular Vesicles from Mechanically Compressed Human Bronchial Epithelial Cells.

In asthma, tissue factor (TF) levels are elevated in the lung. In our previous studies using mechanically compressed human bronchial epithelial (HBE) cells, which are a well-defined in vitro model of bronchoconstriction during asthma exacerbations, we detected TF within extracellular vesicles (EVs) released from compressed HBE cells. Here, to better characterize the potential role of this mechanism in asthma, we tested the extent to which the transcriptional regulation of epithelial cell-derived TF varied between donors with and without asthma.

Selective Mu-Opioid Receptor Imaging Using F-Labeled Carfentanils.

Carfentanil, a highly potent synthetic opioid, paradoxically serves as a crucial positron emission tomography (PET) imaging tool in neurobiological studies of the mu-opioid receptor (MOR) system when labeled with carbon-11 ([C]CFN). However, its clinical research use is hindered by extreme potency and the limited availability of short-lived carbon-11 ( = 20.4 min).

Analysis of Orthopaedic Surgery Residency Match Results: 2016 to 2022.

: Objective data examining match trends and applicant characteristics are in high demand given the stakes involved with the orthopaedic surgery match. Our study sought to analyse the trends among matched orthopaedic surgery applicants to clarify how medical students can best prepare for and assess their chances of a successful orthopaedic residency match. : We used the publicly available National Residency Matching Program (NRMP) tool to gather characteristics for matched and unmatched orthopaedic surgery applicants from 2016 to 2022 and compare the probability of matching for all applicants versus each subgroup of reported applicant characteristics using risk difference (RD) and two-tailed p-values.

Impact of Hurricanes and Floodings on Mental Health Outcomes Within the United States: A Systematic Review and Meta-Analysis.

Objective: Given the US population concentration near coastal areas and increased flooding due to climate change, public health professionals must recognize the psychological burden resulting from exposure to natural hazards.

Methods: We performed a systematic search of databases to identify articles with a clearly defined comparison group consisting of either pre-exposure measurements in a disaster-exposed population or disaster-unexposed controls, and assessment of mental health, including but not limited to, depression, post-traumatic stress (PTS), and anxiety.

Results: Twenty-five studies, with a combined total of 616 657 people were included in a systematic review, and 11 studies with a total of 2012 people were included in a meta-analysis of 3 mental health outcomes.

Tudor-Containing Methyl-Lysine and Methyl-Arginine Reader Proteins: Disease Implications and Chemical Tool Development.

Tudor domains are histone readers that can recognize various methylation marks on lysine and arginine. This recognition event plays a key role in the recruitment of other epigenetic effectors and the control of gene accessibility. The Tudor-containing protein family contains 42 members, many of which are involved in the development and progression of various diseases, especially cancer.

The Society of Thoracic Surgeons Expert Consensus Statements on a Framework for a Standardized National Robotic Curriculum for Thoracic Surgery Trainees.

Objective: With robotic technology's rapid growth and integration, an urgent need to bridge the educational gap in thoracic surgical training has emerged. This document, a result of consensus among a group of experts in the practice and training of robotic surgery from The Society of Thoracic Surgeons, aims to provide a framework for a standardized national robotic curriculum for thoracic surgery trainees.

Methods: The Society of Thoracic Surgeons Task Force on Robotic Thoracic Surgery and Workforce on E-learning and Educational Innovation assembled an expert group with the input of the Thoracic Surgery Director's Association.

A structure-based mechanism for initiation of AP-3 coated vesicle formation.

Adaptor protein complex-3 (AP-3) mediates cargo sorting from endosomes to lysosomes and lysosome-related organelles. Recently, it was shown that AP-3 adopts a constitutively open conformation compared to the related AP-1 and AP-2 coat complexes, which are inactive until undergoing large conformational changes upon membrane recruitment. How AP-3 is regulated is therefore an open question.

Early antiviral CD4+ and CD8+ T cells are associated with upper airway clearance of SARS-CoV-2.

T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19.

Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells.

Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease.

Interindividual variability in CYP3A-mediated venetoclax metabolism in vitro and in vivo in patients with chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge.

Long G4-rich enhancers target promoters via a G4 DNA-based mechanism.

Several studies have now described instances where G-rich sequences in promoters and enhancers regulate gene expression through forming G-quadruplex (G4) structures. Relatedly, our group recently identified 301 long genomic stretches significantly enriched for minimal G4 motifs (LG4s) in humans and found the majority of these overlap annotated enhancers, and furthermore, that the promoters regulated by these LG4 enhancers are similarly enriched with G4-capable sequences. While the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study tested an alternative hypothesis: that LG4 enhancers interact with cognate promoters via a direct G4:G4 DNA-based mechanism.

A Scoping Review of End-of-Life Discussions and Palliative Care: Implications for Neurological Intensive Care in Latin America and the Caribbean.

Palliative care (PC) is essential to improve quality of life for individuals with life-limiting acute neurological conditions, particularly in resource-limited settings. In Latin America and the Caribbean (LAC), there is limited health care professional training and education on PC. We reviewed the peer-reviewed literature discussing end-of-life care, withdrawal of life-sustaining treatments (WOLST), and PC in the acute inpatient setting.

Complex blunt traumatic abdominal wall hernias: Experience from a high-volume abdominal core health center.

Background: Traumatic abdominal wall hernias are rare and commonly involve the lateral abdominal wall due to shearing off the oblique and transversus abdominis muscles from the iliac crest. The vast majority of the current literature focuses on the index trauma admission, includes few patients, and provides little to no detail about the hernia repair itself. We aim to report our center's high-volume experience with a definitive repair of chronic traumatic lateral abdominal wall hernias.

Baseline characteristics for phase II of the Kinshasa Malaria Cohort Study: cohort profile.

Purpose: The Democratic Republic of Congo has one of the highest burdens of malaria in the world, accounting for 12.3% of malaria cases and 11.6% of malaria deaths.

Association of food insecurity with mental health status, mental health services utilisation and general healthcare utilisation among US adults.

Background: Food insecurity poses a substantial threat to mental health. However, there is limited understanding of how food-insecure adults experience mental health challenges and access necessary health services. We examined the association of food insecurity with mental health status, mental health service utilisation and general healthcare utilisation among US adults.

Impact of white matter hyperintensity volume on cognition among US Mexican American adults.

Objective: Higher white matter hyperintensity (WMH) volume is a marker of cardiovascular disease (CVD) risk. CVD risk factors increase risk for Alzheimer's disease and related dementias (ADRD). Mexican Americans (MA) and individuals of other Hispanic/Latino heritages have higher risk for CVD and ADRD.

Examination of Sex Differences in Energy Availability, Disordered Eating, and Compulsive Exercise Among Male and Female Adolescent Athletes.

Objective: The primary aim of this study was to examine sex differences in energy availability (EA) and its relationships with disordered eating, compulsive exercise, and body mass index (BMI) among adolescent athletes.

Design: Cross-sectional study.

Setting: University hospital pediatric sports medicine center.