Mapping glioma progression: single-cell RNA sequencing illuminates cell-cell interactions and immune response variability.

Background: Glioma, the most common primary cancer of the central nervous system, characterizes significant heterogeneity, presenting major challenges for therapeutic approaches and prognosis. In this study, the interactions between malignant glioma cells and macrophages/monocytes, as well as their influence on tumor progression and treatment responses, were explored using comprehensive single-cell RNA sequencing analysis.

Methods: RNA-seq data from the TCGA and CGGA databases were integrated and an in-depth analysis of glioma samples was performed using single-cell RNA sequencing, functional enrichment analysis, developmental trajectory analysis, cell-cell communication analysis, and gene regulatory network analysis.

A discrete-time split-state framework for multi-state modeling with application to describing the course of heart disease.

In chronic disease epidemiology, the investigation of disease etiology has largely focused on an endpoint, while the course of chronic disease is understudied, representing a knowledge gap. Multi-state models can be used to describe the course of chronic disease, such as Markov models which assume that the future state depends only on the present state, and semi-Markov models which allow transition rates to depend on the duration in the current state. However, these models are unsuitable for chronic diseases that are largely non-memoryless.

Comparison of magnetocardiography and coronary computed tomographic angiography for detection of coronary artery stenosis and the influence of calcium.

Objectives: This study aimed to compare the diagnostic performance of magnetocardiography (MCG) and coronary computed tomography angiography (CCTA) in detecting coronary artery stenosis in relation to coronary calcification.

Methods: A total of 587 patients who underwent invasive coronary angiography (ICA) with both CCTA and MCG between September 1, 2022, and August 31, 2023, were included. The patients were divided into three subgroups based on their coronary artery calcium score (CACS), namely less than 100, 100-400, and 400 and above, as determined by the Agatston score.

Selective inhibition of TGF-β-induced epithelial-mesenchymal transition overcomes chemotherapy resistance in high-risk lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer, and it demonstrates limited treatment options and worse survival. Identifications of a prognostic model and chemoresistance mechanism can be helpful for improving stratification and guiding therapy decisions. The integrative development of machine learning-based models reveals a random survival forest (RSF) prognostic model for LUSC.

Cardiovascular disease, bone fracture, and all-cause mortality risks among postmenopausal women by arthritis and veteran status: A multistate Markov transition analysis.

Arthritis, a chronic inflammatory condition linked to cardiovascular disease (CVD) and bone fracture, is more frequent among military veterans and postmenopausal women. This study examined correlates of arthritis and relationships of arthritis with risks of developing CVD, bone fractures, and mortality among postmenopausal veteran and non-veteran women. We analyzed longitudinal data on 135,790 (3,436 veteran and 132,354 non-veteran) postmenopausal women from the Women's Health Initiative who were followed-up for an average of 16 years between enrollment (1993-1998) and February 17, 2024.

Design and Discovery of Preclinical Candidate LYG-409 as a Highly Potent and Selective GSPT1 Molecular Glue Degraders.

Molecular glue degraders induce "undruggable" protein degradation by a proximity-induced effect. Inspired by the clinical success of immunomodulatory drugs, we aimed to design novel molecular glue degraders targeting GSPT1. Here, we report the design of a series of GSPT1 molecular glue degraders.

Long-Term Natural Hydroxyapatite and Synthetic Collagen Hydroxyapatite Enhance Bone Regeneration and Implant Fixation Similar to Allograft in a Sheep Model of Implant Integration.

There is an increasing demand for a suitable bone substitute to replace current clinical gold standard autografts or allografts. Majority of previous studies have focused on the early effects of substitutes on bone formation, while information on their long-term efficacies remains limited. This study investigated the efficacies of natural hydroxyapatite (nHA) derived from oyster shells and synthetic hydroxyapatite mixed with collagen (COL/HA) or chitosan (CS/HA) on bone regeneration and implant fixation in sheep.

Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule exhibited pronounced Brd4 protein degradation with low nM DC values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines.

Superolateral capsule pathway: a new arthroscopic viewing approach for spotting femoral fixation device in anterior cruciate ligament reconstruction.

Background: This study aimed to describe the arthroscopic superlateral capsule pathway technique for spotting femoral fixation device deployment, and to compare the results with normal procedure.

Methods: A total of 69 patients underwent ACLR (Anterior Cruciate Ligament Reconstruction) with or without the SCP (superolateral capsule pathway) during procedure were retrospectively selected and evaluated. A total of 36 patients underwent SCP and 33 patients underwent ACLR without SCP.

Multimodal Trajectory Prediction for Diverse Vehicle Types in Autonomous Driving with Heterogeneous Data and Physical Constraints.

The accurate prediction of vehicle behavior is crucial for autonomous driving systems, impacting their safety and efficiency in complex urban environments. To address the challenge of multi-agent trajectory prediction, we propose a novel model integrating multiple input modalities, including historical trajectories, map data, vehicle features, and interaction information. Our approach employs a Conditional Variational Autoencoder (CVAE) framework with a decoder that predicts control actions using the Gaussian Mixture Model (GMM) and then converts these actions into dynamically feasible trajectories through a bicycle model.

Pesticide avermectin B1a exerts cytotoxicity by blocking the interaction between mini-chromosome maintenance 6 protein (MCM6) and chromatin licensing and DNA replication factor 1 (CDT1).

Avermectin B1a, a widely used pesticide, has recently raised safety concerns since it possesses potential cytotoxicity toward mammalian cells. Nevertheless, the exact mechanisms that underlie the cytotoxicity induced by avermectin B1a remain elusive. The loading of the mini-chromosome maintenance 6 protein (MCM6) onto chromatin at replication origins by chromatin licensing and DNA replication factor 1 (CDT1) is an essential step for licensing DNA for replication.

YAP acts as an independent prognostic marker and regulates growth and metastasis of gastrointestinal stromal tumors via FBXW7-YAP pathway.

Background: Although imatinib (IM) and subsequent tyrosine kinase inhibitors (TKIs) significantly improve the prognosis of GIST patients by delaying metastasis and recurrence, most patients experience limited efficacy due to toxicity and secondary resistance. We evaluated Yes-associated protein (YAP), a coactivator of the Hippo pathway accounting for IM resistance and aggressive GIST phenotypes, in GISTs. The degradation of YAP is mediated by FBXW7, and FBXW7 predicts recurrence and IM efficacy for GIST patients.

The regulation of ovarian degeneration in Pampus argenteus by heat shock protein genes under low-temperature stress.

Temperature is a crucial environmental factor that significantly impacts the growth, development, metabolism, and physiological functions of fish. To study the effects of low-temperature on the gonadal development of silver pomfret (Pampus argenteus), a cold period by gradually lowering the water temperature from 18°C to 9°C was simulated. The results showed that hsp70, hsp90a, and hsp90b were widely expressed in the tissues of P.

Biomechanical comparison of Gofried positive support reduction of Pauwels type III femoral neck fractures: A finite elements analysis.

Objective: This study aims to investigate the biomechanical characteristics of non-anatomical reduction and different screw positions on the stability of Pauwels type III femoral neck fractures.

Methods: Three-dimensional finite element models of femoral neck fractures were constructed using CT images. Four types of internal fixation methods were simulated, including biplane double-supported screw fixation (BDSF), three inverted triangular parallel cannulated screws (3CS), new parallel cannulated screws with posterior screws moving down (New 3CS), and two parallel cannulated screws (2CS).

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.

Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke.

Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia.

Emergency department discharges directly to hospice: Longitudinal assessment of a streamlined referral program.

Introduction: 80 % of Americans wish to die somewhere other than a hospital, and hospice is an essential resource for providing such care. The emergency department (ED) is an important location for identifying patients with end-of-life care needs and providing access to hospice. The objective of this study was to analyze a quality improvement (QI) program designed to increase the number of patients referred directly to hospice from the ED, without the need for an observation stay and without access to in-hospital hospice.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

Aims: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL.

Methods: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution.

Molecular Dynamics Investigation of Metastable Structure and Hybridization Bond Evolution in High-Entropy CoCrFeNi Heterostructured Amorphous Carbon Films.

Heterogeneous element doping in amorphous carbon films can reduce residual stresses and improve plastic deformation. Nevertheless, the effects of dopant content and size on the metastable transition mechanism between sp-C and sp-C atoms during the deformation process are unclear and difficult to be in situ observed and researched, experimentally. In this work, the mechanical properties and the structural evolution during the nanoindentation of amorphous CoCrFeNi sphere-doped carbon heterostructured films with different radii were simulated.

An Energy Efficient and Temperature Stable Digital FLL-based Wakeup Timer with Time-Domain Temperature Compensation.

This brief presents an on-chip digital intensive frequency-locked loop (DFLL)-based wakeup timer with a time-domain temperature compensation featuring a embedded temperature sensor. The proposed compensation exploits the deterministic temperature characteristics of two complementary resistors to stabilize the timer's operating frequency across the temperature by modulating the activation time window of the two resistors. As a result, it achieves a fine trimming step (± 1 ppm), allowing a small frequency error after trimming (<± 20 ppm).