Evaluation of synaptotagmin-1 action models by all-atom molecular dynamics simulations.

Neurotransmitter release is triggered in microseconds by the two C domains of the Ca sensor synaptotagmin-1 and by SNARE complexes, which form four-helix bundles that bridge the vesicle and plasma membranes. The synaptotagmin-1 CB domain binds to the SNARE complex via a 'primary interface', but the mechanism that couples Ca-sensing to membrane fusion is unknown. Widespread models postulate that the synaptotagmin-1 Ca-binding loops accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but these models do not seem compatible with SNARE binding through the primary interface, which orients the Ca-binding loops away from the fusion site.

Machine Learning Quantum Mechanical/Molecular Mechanical Potentials: Evaluating Transferability in Dihydrofolate Reductase-Catalyzed Reactions.

Integrating machine learning potentials (MLPs) with quantum mechanical/molecular mechanical (QM/MM) free energy simulations has emerged as a powerful approach for studying enzymatic catalysis. However, its practical application has been hindered by the time-consuming process of generating the necessary training, validation, and test data for MLP models through QM/MM simulations. Furthermore, the entire process needs to be repeated for each specific enzyme system and reaction.

Bullying in adolescents across three years in the context of the COVID-19 pandemic: a repeated cross-sectional and prospective analysis.

Background: Bullying has been identified as a risk factor for many issues among adolescents. Although it was already considered a public health issue in Brazil before the COVID-19 pandemic, little is known about how the pandemic and associated public health measures have affected bullying behavior.

Objective: To explore changes in bullying victimization and perpetration among Brazilian high school students from 2019 to 2022.

Interobserver and intraobserver variability among different vendors for mitral valve assessment: implications for transcatheter mitral valve repair.

Purpose: Pre-procedural imaging is critical for transcatheter mitral valve repair planning in patients with mitral valve disease. As differences among various measurement techniques for valve evaluation are still poorly understood, we sought to assess the intra- and interobserver agreement of complex measurements derived from a prototype mitral evaluation tool (Siemens) and a commercially available tool (CVI42) using both saddle- and D-shaped mitral annulus techniques.

Materials And Methods: Multiphasic cardiac computed tomography angiography data were loaded into each software.

Resolving tissue complexity by multimodal spatial omics modeling with MISO.

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multimodal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with subcellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets.

Longitudinal Treatment Patterns of Chorea in North American Patients with Huntington's Disease: Data from Enroll-HD.

Introduction: Chorea is the primary manifestation of Huntington's disease. Different clinicians pursue varied approaches to chorea management, and real-world evidence describing them is needed. The objective of this study was to assess the presence and severity of chorea, chorea pharmacotherapy, and treatment practice, and patterns in a large natural-history cohort with Huntington's disease.

The Landmark Series: The Future of Pancreatic Cancer Clinical Trials.

Pancreatic cancer has a poor prognosis despite ongoing advances in systemic and multimodal therapies. This review analyzes recent progress and future directions in pancreatic cancer clinical trials, emphasizing the evolution from traditional approaches to a more personalized and biologically-driven treatment paradigm. While improvements in overall survival have been achieved through perioperative therapies, gaps remain in our understanding of optimal treatment strategies.

Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study.

In the MAIA study (median follow-up, 56.2 months), daratumumab plus lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and overall survival versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). In this post hoc analysis of clinically important subgroups in MAIA (median follow-up, 64.

The microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice.

AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex.

Orthogonalized human protease control of secreted signals.

Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. Although protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. In this study, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins.

The highly conserved PIWI-interacting RNA CRAPIR antagonizes PA2G4-mediated NF110-NF45 disassembly to promote heart regeneration in mice.

Targeting the cardiomyocyte cell cycle is a promising strategy for heart repair following injury. Here, we identify a cardiac-regeneration-associated PIWI-interacting RNA (CRAPIR) as a regulator of cardiomyocyte proliferation. Genetic ablation or antagomir-mediated knockdown of CRAPIR in mice impairs cardiomyocyte proliferation and reduces heart regenerative potential.

Loss of correlated proteasomal subunit expression selectively promotes the 20S state which underlies luminal breast tumorigenicity.

Why cancer cells disproportionately accumulate polyubiquitinated proteotoxic proteins despite high proteasomal activity is an outstanding question. While mis-regulated ubiquitination is a contributing factor, here we show that a structurally-perturbed and sub-optimally functioning proteasome is at the core of altered proteostasis in tumors. By integrating the gene coexpression signatures of proteasomal subunits in breast cancer (BrCa) patient tissues with the atomistic details of 26S holocomplex, we find that the transcriptional deregulation induced-stoichiometric imbalances perpetuate with disease severity.

IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer.

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues, induces TLSs.

Precision fetal cardiology detects cyanotic congenital heart disease using maternal saliva metabolome and artificial intelligence.

Prenatal sonographic diagnosis of congenital heart disease (CHD) can lead to improved morbidity and mortality. However, the diagnostic accuracy of ultrasound, the sole prenatal screening tool, remains limited. Failed prenatal or early newborn detection of cyanotic CHD (CCHD) can have disastrous consequences.

Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism.

Effect of electronic cigarette atomising power and flavour on aerosol size-segregated metal concentration and inhalation risk.

Introduction: Although numerous studies have estimated the inhalation dose of metals emitted from electronic cigarettes (e-cigs), the impact of factors including aerosol size and the atomising power of e-cig aerosols on estimating the inhalation dose of metals remains underexplored. A comprehensive understanding of these determinants is essential to assess the health risks associated with inhaling e-cig aerosols, which may contain potentially harmful metals.

Objectives: The aim of this study is to elucidate the mass and inhalation doses of potentially harmful metals in e-cig aerosols by different particle size and their association with the various atomising powers of e-cig devices and flavours.

Prolactin-induced sensitization of trigeminal nociceptors promotes migraine co-morbidity in endometriosis.

Background: Women with endometriosis are more likely to have migraine. The mechanisms underlying this co-morbidity are unknown. Prolactin, a neurohormone secreted and released into circulation from the anterior pituitary, can sensitize sensory neurons from female, but not male, rodents, monkeys and human donors.

Improvement in Distress Tolerance as a Mechanism of Symptom Reduction During Intensive Exposure and Response Prevention-Based Treatment for OCD.

Exposure and Response Prevention (ERP) is an effective treatment for obsessive-compulsive disorder (OCD), yet the specific underlying mechanisms by which ERP improves symptoms remain unclear. Initial theories suggested that habituation to triggering events and stimuli was the key therapeutic factor in ERP, while other theories highlight the role of developing the ability to tolerate distress, rather than reduction of distress. The current study examined improvements in distress tolerance as a mechanism of OCD, anxiety, and depressive symptom reductions during an ERP-based intensive program.

Did Finerenone Improve Health Status in the FINEARTS Trial?: A Critical Reevaluation of the Analysis of Patient-Reported Outcomes in Heart Failure.

Patient-reported health status is an important assessment of patients with heart failure, but current approaches have substantial methodological and analytical limitations. Changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) are commonly presented as a measure of the effect of drugs and devices, most often as the between-group difference in population means or as the odds of showing threshold changes of 5, 10, 15, and 20 points. However, the presentation of mean differences is based on statistical assumptions that are routinely violated in most trials.

Fitness for Purpose of Text-to-Image Generative Artificial Intelligence Image Creation in Medical Imaging.

The recent emergence of text-to-image generative artificial intelligence (AI) diffusion models such as DALL-E, Firefly, Stable Diffusion, and Midjourney has been touted with popular hype about the transformative potential in health care. This hype-driven, rapid assimilation comes with few professional guidelines and without regulatory oversight. Despite documented limitations, text-to-image generative AI creations have permeated nuclear medicine and medical imaging.

Psychometric Evaluation of the Scleroderma Skin Questionnaire: A Novel Patient Reported Outcome for Skin Disease in Patients with Systemic Sclerosis.

Objective: To evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc) related skin symptoms.

Methods: The SSQ was administered to 799 adults (mean age 52.7; 82% female) enrolled in the SSc Collaborative National Quality and Efficacy Registry (CONQUER).

Association between abatacept exposure levels and infection occurrence in patients with rheumatoid arthritis: post hoc analysis of the AVERT-2 study.

Objective: To determine if higher serum exposure during subcutaneous (SC) abatacept treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA).

Methods: Data from AVERT-2 (Assessing Very Early Rheumatoid arthritis Treatment-2, NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody- positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed.

An Update on the Clinical Management of Cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL) is an infection caused by the Leishmania protozoa, which are primarily transmitted through bites of infected female sandflies. This article provides a comprehensive overview of the clinical management of CL, including an in-depth analysis of its epidemiology, prevention and control measures, diagnostic modalities - particularly molecular and serological, differential diagnosis with other lesions, and treatment options. Also discussed are recent concerns regarding the endemicity of CL, with a focus on the significant rise in travel-related cases as well as locally acquired cases, providing insight into the changing epidemiological landscape.