Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.

Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1).

Large language models improve the identification of emergency department visits for symptomatic kidney stones.

Recent advancements of large language models (LLMs) like generative pre-trained transformer 4 (GPT-4) have generated significant interest among the scientific community. Yet, the potential of these models to be utilized in clinical settings remains largely unexplored. In this study, we investigated the abilities of multiple LLMs and traditional machine learning models to analyze emergency department (ED) reports and determine if the corresponding visits were due to symptomatic kidney stones.

TrueSpot: A robust automated tool for quantifying signal puncta in fluorescent imaging.

Characterizing the movement of biomolecules in single cells quantitatively is essential to understanding fundamental biological mechanisms. RNA fluorescent in situ hybridization (RNA-FISH) is a technique for visualizing RNA in fixed cells using fluorescent probes. Automated processing of the resulting images is essential for large datasets.

Structures and mRNP remodeling mechanism of the TREX-2 complex.

mRNAs are packaged with proteins into messenger ribonucleoprotein complexes (mRNPs) in the nucleus. mRNP assembly and export are of fundamental importance for all eukaryotic gene expression. Before export to the cytoplasm, mRNPs undergo dynamic remodeling governed by the DEAD-box helicase DDX39B (yeast Sub2).

Viral Transcript and Tumor Immune Microenvironment-Based Transcriptomic Profiling of HPV-Associated Head and Neck Squamous Cell Carcinoma Identifies Subtypes Associated with Prognosis.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed five distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal).

Magnesium Depletion Score and Mortality in Individuals with Metabolic Dysfunction Associated Steatotic Liver Disease over a Median Follow-Up of 26 Years.

Unlabelled: Metabolic dysfunction associated steatotic liver disease (MASLD) has been associated with increased risks of all-cause and cardiovascular disease (CVD) mortality. Identification of modifiable risk factors that may contribute to higher risks of mortality could facilitate targeted and intensive intervention strategies in this population. This study aims to examine whether the magnesium depletion score (MDS) is associated with all-cause and CVD mortality among individuals with MASLD or metabolic and alcohol associated liver disease (MetALD).

Plasma Endothelin-1 Levels: Non-Predictors of Alzheimer's Disease Reveal Age Correlation in African American Women.

Alzheimer's disease (AD) and related dementias (ADRD) disproportionately impact racial and ethnic minorities. Contributing biological factors that explain this disparity have been elusive. Moreover, non-invasive biomarkers for early detection of AD are needed.

The Role of Individual Residues in the N-Terminus of Arrestin-1 in Rhodopsin Binding.

Sequences and three-dimensional structures of the four vertebrate arrestins are very similar, yet in sharp contrast to other subtypes, arrestin-1 demonstrates exquisite selectivity for the active phosphorylated form of its cognate receptor, rhodopsin. The N-terminus participates in receptor binding and serves as the anchor of the C-terminus, the release of which facilitates arrestin transition into a receptor-binding state. We tested the effects of substitutions of fourteen residues in the N-terminus of arrestin-1 on the binding to phosphorylated and unphosphorylated light-activated rhodopsin of wild-type protein and its enhanced mutant with C-terminal deletion that demonstrates higher binding to both functional forms of rhodopsin.

Differences in Characteristics of Peripartum Patients Who Did and Did Not Require an Upgrade to the Intensive Care Unit: A Propensity Score Matching Study.

This study sought to identify predictors for peripartum patients admitted to non-intensive care wards who later upgraded to the Intensive Care Unit (ICU). This was a retrospective observational study of patients admitted to the Maternal Fetal Ward between 01/2017 and 12/2022, who later upgraded to the ICU. Upgraded patients were 1:1 propensity score matched with those who remained on the Maternal Fetal Ward (control).

The Clinical Utility of a Next-Generation Sequencing-Based Approach to Detecting Circulating HPV DNA in Patients with Advanced Anal Cancer.

Background: To extend the practicality of liquid biopsy beyond the historical HPV circulating tumor DNA (ctDNA) assays, we evaluated the clinical relevance of a novel next-generation sequencing HPV ctDNA assay in patients with locally advanced and metastatic squamous cell cancer of the anal canal (mSCCA).

Methods: ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4 Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types.

Next-Generation Immunotherapy for Hepatocellular Carcinoma: Mechanisms of Resistance and Novel Treatment Approaches.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15-20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC.

Phase II Study of Nanoliposomal Irinotecan (Nal-IRI) with 5-Fluorouracil and Leucovorin in Refractory Advanced High-Grade Neuroendocrine Cancer of Gastroenteropancreatic (GEP) or Unknown Origin.

Background: Neuroendocrine carcinomas (NECs) are treated with a frontline platinum-etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity.

Methods: We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy.

Immune evasion in ovarian cancer: implications for immunotherapy and emerging treatments.

Ovarian cancer (OC) is the most lethal gynecologic malignancy, characterized by multiple histological subtypes, each with distinct pathological and clinical features. Current treatment approaches include cytotoxic chemotherapies, poly(ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, hormonal therapy, immunotherapy, and antibody-drug conjugates (ADCs). In this review we discuss immune evasion mechanisms in OC and the role of genetics, the tumor microenvironment, and tumor heterogeneity in influencing these processes.

Practice Advisory for Postoperative Pain Management of Cardiac Surgical Patients: A Report by Society of Cardiovascular Anesthesiologists.

Moderate to severe pain after cardiac surgery is relatively common, which increases the risk of postoperative cardiopulmonary complications and delays hospital discharge. Opioids have been useful agents for postoperative pain control after cardiac surgery, but are associated with serious adverse effects. As a result, multimodal analgesia has been adopted widely to decrease reliance on opioids for treating postoperative pain, reduce opioid-related adverse effects, and promote early recovery.

Macromolecular interactions and geometrical confinement determine the 3D diffusion of ribosome-sized particles in live cells.

The crowded bacterial cytoplasm is composed of biomolecules that span several orders of magnitude in size and electrical charge. This complexity has been proposed as the source of the rich spatial organization and apparent anomalous diffusion of intracellular components, although this has not been tested directly. Here, we use biplane microscopy to track the 3D motion of self-assembled bacterial genetically encoded multimeric nanoparticles (bGEMs) with tunable size (20 to 50 nm) and charge (-3,240 to +2,700 e) in live cells.

The impact of resective epilepsy surgery on the brain network: evidence from post-surgical imaging.

Resective epilepsy surgery can be an effective treatment for patients with medication-resistant focal epilepsy. Epilepsy resection consists of the surgical removal of an epileptic focus to stop seizure generation and disrupt the epileptic network. However, even focal surgical resections for epilepsy lead to widespread brain network changes.

Magnetic field probe-based co-simulation method for irregular volume-type inductively coupled wireless MRI radiofrequency coils.

Background: Inductively coupled wireless coils are increasingly used in MRI due to their cost-effectiveness and simplicity, eliminating the need for expensive components like preamplifiers, baluns, coil plugs, and coil ID circuits. Existing tools for predicting component values and electromagnetic (EM) fields are primarily designed for cylindrical volume coils, making them inadequate for irregular volume-type wireless coils.

Purpose: The aim of this study is to introduce and validate a novel magnetic (H-) field probe-based co-simulation method to accurately predict capacitance values and EM fields for irregular volume-type wireless coils, thereby addressing the limitations of current prediction tools.

In Silico Prediction of Maize microRNA as a Xanthine Oxidase Inhibitor: A New Approach to Treating Hyperuricemia Patients.

Introduction: Hyperuricemia is characterized by increased uric acid (UA) in the body. The ability to block xanthine oxidase (XO) is a useful way to check how different bioactive molecules affect hyperuricemia. Previous reports showed the significant effect of corn against hyperuricemia disorder with its anti-XO activity.

Prenatal syphilis and adverse pregnancy outcomes in women with HIV receiving ART in Brazil: a population-based study.

Background: We aimed to examine factors associated with prenatal syphilis, including prenatal care, and pregnancy outcomes of pregnant women with HIV in Brazil.

Methods: Retrospective data were gathered from a national cohort of Brazilian women with HIV on antiretroviral therapy who became pregnant between January 2015 and May 2018. Prenatal syphilis was defined by clinical diagnoses with treatment or any positive syphilis laboratory result between 30 days before conception and pregnancy conclusion.

Estimating financial and health burden by initial Medicare plan choice and history of cancer.

Understanding the downstream consequences of initial Medicare plan selection is necessary to ensure access to and affordability of health care services, especially for older adults with serious illness. We used 2008-2020 data from the Health and Retirement Study to estimate financial and health burden by initial Medicare plan selection (traditional Medicare without supplemental coverage, traditional Medicare plus supplemental coverage, or Medicare Advantage) and self-reported history of cancer. Initially choosing benefits with greater financial protections (either traditional Medicare plus supplemental coverage or Medicare Advantage) relative to traditional Medicare without supplemental coverage was associated with lower levels of out-of-pocket spending and a lower likelihood of reporting cost-related medication nonadherence and fair or poor health.

Steroid-refractory immune mediated hepatitis managed with budesonide in patients with metastatic melanoma: proof of concept and literature review.

Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma. However, some patients develop ICI-associated toxicities like hepatitis (ie, immune-mediated hepatitis; IMH). Although these toxicities usually resolve with steroids, steroid-refractory events may occur, which may be a major source of morbidity and mortality without obviously defined treatment algorithms.

Public perceptions of meniscus tears: Evaluating knowledge gaps and the role of education.

Background: Meniscus tears are common, occurring acutely during sports or as degenerative tears with aging. Limited information exists about the public's understanding of these injuries and their management.

Hypothesis/purpose: This study aimed to evaluate the public's baseline understanding of meniscus tear management and assess the effectiveness of an educational intervention to improve their understanding.

The Dynamics of Cognitive Decline towards Alzheimer's Disease Progression: Results from ADSP-PHC's Harmonized Cognitive Composites.

Introduction: Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer's disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies.

Methods: Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used.

Activity dependent Clustering of Neuronal L-Type Calcium Channels by CaMKII.

Neuronal excitation-transcription (E-T) coupling pathways can be initiated by local increases of Ca concentrations within a nanodomain close to the L-type voltage-gated Ca channel (LTCC). However, molecular mechanisms controlling LTCC organization within the plasma membrane that help creation these localized signaling domains remain poorly characterized. Here, we report that neuronal depolarization increases Ca1.

Metabolic tug-of-war: Microbial metabolism shapes colonization resistance against enteric pathogens.

A widely recognized benefit of gut microbiota is that it provides colonization resistance against enteric pathogens. The gut microbiota and their products can protect the host from invading microbes directly via microbe-pathogen interactions and indirectly by host-microbiota interactions, which regulate immune system function. In contrast, enteric pathogens have evolved mechanisms to utilize microbiota-derived metabolites to overcome colonization resistance and increase their pathogenic potential.