Corneal Biomechanics Are Associated With FBN1 Mutations in Patients With Marfan Syndrome and Ectopia Lentis.

Background: We investigated the corneal biomechanical properties and their genotype-phenotype correlation correlations in patients with Marfan syndrome (MFS) and ectopia lentis (EL).

Methods: Patients with MFS with EL underwent panel-based next-generation sequencing in this retrospective cohort study. The FBN1 genotypes were categorized into the dominant-negative (DN) group and the haploinsufficiency (HI) group.

Clinical Translation of Hyperpolarized C Metabolic Probes for Glioma Imaging.

Hyperpolarized carbon-13 (HP-C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HPC techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-C]/[2-C]-pyruvate and [1-C,5-C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents.

NR4A1 Acts as a Novel Regulator of Platelet Activation and Thrombus Formation.

Background: Mounting evidence indicates that nuclear receptors play a critical regulatory role in platelet pathophysiology and thrombotic disorders. Although NR4A (the nuclear receptor subfamily 4 group A) plays an important role in cardiovascular pathophysiology, the expression profile and biological function of NR4A member 1 (NR4A1) in platelets have never been reported.

Methods: We evaluated the functions and the underlying mechanisms of NR4A1 in platelet activation and thrombus formation using platelet-specific NR4A1-deficient mice and NR4A1-specific agonists.

Intestinal Microbiota Contributes to the Development of Cardiovascular Inflammation and Vasculitis in Mice.

Background: Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease, an acute pediatric vasculitis, remains unclear. Here, using a murine model mimicking Kawasaki disease vasculitis, we assessed the contribution of the intestinal microbiota to the development of vascular inflammation.

Methods And Results: We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking Kawasaki disease vasculitis.

AMPK Signaling Pathway Regulates Tendon Regeneration via Fatty Acid Metabolism.

Tendon and ligament injuries are the most common musculoskeletal injuries, and their regeneration is a complex process due to the poor natural healing ability of these tissues. The current therapies for tendon repair are limited in efficacy and their cellular and molecular mechanisms remain unclear. In this study, we identified AMP-activated protein kinase (AMPK) as a markedly upregulated factor in newborn tendons with high regenerative capacity.

Cerebrospinal fluid circulating tumor DNA profiling for risk stratification and matched treatment of central nervous system metastases.

Genomic profiling of central nervous system (CNS) metastases has the potential to guide treatments. In the present study, we included 584 patients with non-small-cell lung cancer and CNS metastases and performed a comprehensive analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinicopathological annotation. CSF ctDNA-positive detection was independently associated with shorter survival than negative detection (hazard ratio (HR) = 1.

A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.

The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson's disease (PD), 27 with Alzheimer's disease (AD), and 15 with both PD and MCI.

Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes : A Target Trial Emulation Study.

Background: Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results.

Objective: To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is).

Design: Target trial emulation study.

Fast reconstruction and optical-sectioning three-dimensional structured illumination microscopy.

Three-dimensional structured illumination microscopy (3DSIM) is a popular method for observing subcellular/cellular structures or animal/plant tissues with gentle phototoxicity and 3D super-resolution. However, its time-consuming reconstruction process poses challenges for high-throughput imaging and real-time observation. Moreover, traditional 3DSIM typically requires more than six layers for successful reconstruction and is susceptible to defocused backgrounds.

Computed tomography radiomics-based combined model for predicting thymoma risk subgroups: a multicenter retrospective study.

Rationale And Objectives: Accurately distinguishing histological subtypes and risk categorization of thymomas is difficult. To differentiate the histologic risk categories of thymomas, we developed a combined radiomics model based on non-enhanced and contrast-enhanced computed tomography (CT) radiomics, clinical, and semantic features.

Materials And Methods: In total, 360 patients with pathologically-confirmed thymomas who underwent CT examinations were retrospectively recruited from three centers.

Development of a novel prognostic nomogram for AIDS-associated diffuse large B-cell lymphoma: a retrospective study from northern China.

Despite advancements in antiretroviral therapy, AIDS-related diffuse large B-cell lymphoma (AR-DLBCL) remains a major cause of morbidity and mortality. Compared to non-HIV-infected individuals, AR-DLBCL presents with considerable disease heterogeneity, which impairs the accuracy of current prognostic tools. This study aims to develop a novel prognostic model to enhance risk assessment for AR-DLBCL.

ACE-Breast-02: a randomized phase III trial of ARX788 versus lapatinib plus capecitabine for HER2-positive advanced breast cancer.

This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m BID, days 1-14, Q3W) and stratified by prior chemotherapy lines (0-1 versus >1) and visceral metastasis (yes versus no).

Photon-counting CT Spectral Localizer Radiographs for Lumbar Areal Bone Mineral Density Quantification: A Clinical Study on Accuracy, Reliability, and Diagnostic Performance for Osteoporosis.

Rationale And Objectives: To explore the accuracy, reliability, and diagnostic performance of photon-counting CT (PCCT) spectral localizer radiographs (SLRs) for quantifying lumbar areal bone mineral density (BMD) and detecting osteoporosis (T-score ≤-2.5).

Materials And Methods: This prospective study recruited consecutive participants from April to July 2024.

Female Sex, Capsular Laxity, and Heightened Beighton Test Score, Femoral Torsion Angle, Neck-Shaft Angle Decrease Whereas Hip Inflammatory Disease and Capsular Repair Increase Hip Capsular Thickness: A Systematic Review.

Purpose: To systematically review factors affecting hip capsule thickness.

Methods: The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The terms "hip," "arthroscopy," "capsule," "capsular," and "thickness" were used to search the PubMed, Ovid [MEDLINE], Cochrane Database, and EMBASE databases from inception to January 15, 2024.

Overview of preclinical and phase II clinical studies on Pegmolesatide's long-term erythropoiesis stimulating effect via EPOR-mediated signal transduction.

Introduction: Anemia is a prevalent complication of chronic kidney disease (CKD), primarily due to insufficient erythropoietin (EPO). Pegmolesatide (by Hansoh Pharma) is currently the only marketed long-acting EPO mimetic peptide (EMP) for the treatment of anemia in both dialysis and non-dialysis CKD patients. This paper aimed to explore the long-acting erythropoiesis stimulating molecular mechanism of Pegmolesatide.

Excision of HIV-1 Provirus in Human Primary Cells with Nanocapsuled TALEN Proteins.

Despite the tremendous success of combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection, the durability and persistence of latent reservoirs of HIV-infected cells in HIV-infected patients remain obstacles to achieving HIV cure. While technically challenging, the most direct means to eradicate latent reservoirs is to destroy the HIV provirus, thus ensuring that HIV virions are not produced while preserving resident cells. Transcription activator-like effector nucleases (TALEN)─a genome editing method with high DNA targeting efficiency─have been investigated as a potential gene therapy by disrupting the HIV-1 coreceptor CCR5 genes in HIV target cells or HIV proviral DNA in infected cells.

Transfer of the Oral Gonadotropin-Releasing Hormone Receptor Antagonist Relugolix Into Breast Milk of Healthy Lactating Women.

Relugolix is an oral gonadotropin-releasing hormone receptor antagonist that suppresses sex steroid hormones and is approved as monotherapy for prostate cancer and as a fixed-dose combination with estradiol/norethindrone for the treatment of endometriosis and uterine fibroids. The aim of this postmarketing study was to determine the pharmacokinetics and quantify the amount of relugolix excreted into breast milk of healthy lactating women. Following a single, oral dose of 40 mg relugolix, breast milk was sampled over 120 h.

Event-Trigger Reinforcement Learning-Based Coordinate Control of Modular Unmanned System via Nonzero-Sum Game.

Decreasing the position error and control torque is important for the coordinate control of a modular unmanned system with less communication burden between the sensor and the actuator. Therefore, this paper proposes event-trigger reinforcement learning (ETRL)-based coordinate control of a modular unmanned system (MUS) via the nonzero-sum game (NZSG) strategy. The dynamic model of the MUS is established via joint torque feedback (JTF) technology.

iDIA-QC: AI-empowered data-independent acquisition mass spectrometry-based quality control.

Quality control (QC) in mass spectrometry (MS)-based proteomics is mainly based on data-dependent acquisition (DDA) analysis of standard samples. Here, we collect 2754 files acquired by data independent acquisition (DIA) and paired 2638 DDA files from mouse liver digests using 21 mass spectrometers across nine laboratories over 31 months. Our data demonstrate that DIA-based LC-MS/MS-related consensus QC metrics exhibit higher sensitivity compared to DDA-based QC metrics in detecting changes in LC-MS status.

UDA-seq: universal droplet microfluidics-based combinatorial indexing for massive-scale multimodal single-cell sequencing.

The use of single-cell combinatorial indexing sequencing via droplet microfluidics presents an attractive approach for balancing cost, scalability, robustness and accessibility. However, existing methods often require tailored protocols for individual modalities, limiting their automation potential and clinical applicability. To address this, we introduce UDA-seq, a universal workflow that integrates a post-indexing step to enhance throughput and systematically adapt existing droplet-based single-cell multimodal methods.

Location-specific net water uptake and malignant cerebral edema in acute anterior circulation occlusion ischemic stroke.

Background And Purpose: Early identification of malignant cerebral edema (MCE) in patients with acute ischemic stroke is crucial for timely interventions. We aimed to identify regions critically associated with MCE using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) to evaluate the association between location-specific-net water uptake (NWU) and MCE.

Materials And Methods: This multicentre, retrospective cohort study included patients with acute ischemic stroke following large anterior circulation occlusion.

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.

Toward expert-level medical question answering with large language models.

Large language models (LLMs) have shown promise in medical question answering, with Med-PaLM being the first to exceed a 'passing' score in United States Medical Licensing Examination style questions. However, challenges remain in long-form medical question answering and handling real-world workflows. Here, we present Med-PaLM 2, which bridges these gaps with a combination of base LLM improvements, medical domain fine-tuning and new strategies for improving reasoning and grounding through ensemble refinement and chain of retrieval.