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.

Aqueous Proteomic and Metabolomic Profiles in Low-Energy vs High-Energy Femtosecond Laser-Assisted Cataract Surgery.

Purpose: To investigate the aqueous proteomics and metabolomics in low-energy and high-energy femtosecond laser-assisted cataract surgery (FLACS).

Methods: In this prospective observational study, 72 patients were randomized to 3 groups: low-energy FLACS, high-energy FLACS, and conventional phacoemulsification (controls). Aqueous was collected after femtosecond laser treatment or at the beginning of surgery (controls).

A Systematic Method to Detect Next-Generation Sequencing-Based Microsatellite Instability in Plasma Cell-Free DNA: plasmaMSI.

Microsatellite instability (MSI) detection using tumor tissue is a well-established prognostic and predictive biomarker for certain types of cancers. However, tumor tissue samples are less convenient to obtain than blood plasma samples. The main challenge facing next-generation sequencing-based MSI detection in blood plasma samples is the ultralow signal/noise ratio in plasma cell-free DNA (cfDNA).

Factors associated with malignant biopsy results for newly detected lesions within one year after breast cancer surgery.

Rationale And Objectives: This study aimed to identify the factors associated with malignant biopsy results for new lesions within one year after breast cancer surgery.

Materials And Methods: This retrospective study included 192 lesions from 186 patients who underwent biopsy for newly developed breast lesions within one year of breast cancer surgery. All patients underwent breast ultrasound (US) at 6 months and breast US with mammography one year after surgery.

Lipid nanoparticle-mediated mRNA delivery to CD34 cells in rhesus monkeys.

Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse.

Racial Disparities in Preoperative Breast MRI Use and Surgical Margin Outcomes among Patients with Recently Diagnosed Breast Cancer.

Purpose To evaluate racial disparities in preoperative breast MRI use and surgical margin outcomes among patients with recently diagnosed breast cancer. Materials and Methods This retrospective study included patients with breast cancer who presented to a single cancer center between 2008 and 2020, underwent breast surgery, and self-identified as White or Black. Patients were divided into MRI or no-MRI cohorts based on preoperative MRI use.

Imaging Transcriptomics of Brain Functional Alterations in MS and Neuromyelitis Optica Spectrum Disorder.

Background And Purpose: The underlying transcriptomic signatures driving brain functional alterations in MS and neuromyelitis optica spectrum disorder (NMOSD) are still unclear.

Materials And Methods: Regional fractional amplitude of low-frequency fluctuation (fALFF) values were obtained and compared among 209 patients with MS, 90 patients with antiaquaporin-4 antibody (AQP4)+ NMOSD, 49 with AQP4- NMOSD, and 228 healthy controls from a discovery cohort. We used partial least squares (PLS) regression to identify the gene transcriptomic signatures associated with disease-related fALFF alterations.

Assessment of Nonmass Lesions Detected with Screening Breast US Based on Mammographic Findings.

Background Breast nonmass lesions (NMLs) are observed at screening and diagnostic US. However, knowledge is limited on imaging features of NMLs at screening US. Purpose To identify features of NMLs at screening US that are suspicious for malignancy based on mammographic findings.

Comprehensive genome analysis and variant detection at scale using DRAGEN.

Research and medical genomics require comprehensive, scalable methods for the discovery of novel disease targets, evolutionary drivers and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size or location. Here we present DRAGEN, which uses multigenome mapping with pangenome references, hardware acceleration and machine learning-based variant detection to provide insights into individual genomes, with ~30 min of computation time from raw reads to variant detection.

Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging.

Coherent growth of high-Miller-index facets enhances perovskite solar cells.

Obtaining micron-thick perovskite films of high quality is key to realizing efficient and stable positive (p)-intrinsic (i)-negative (n) perovskite solar cells, but it remains a challenge. Here we report an effective method for producing high-quality, micron-thick formamidinium-based perovskite films by forming coherent grain boundaries, in which high-Miller-index-oriented grains grow on the low-Miller-index-oriented grains in a stabilized atmosphere. The resulting micron-thick perovskite films, with enhanced grain boundaries and grains, showed stable material properties and outstanding optoelectronic performances.

Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial.

Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM.

Resorbable Microspheres versus Trisacryl Gelatin Microspheres for Uterine Artery Embolization: A Randomized Controlled Trial.

Background There are insufficient data comparing resorbable microspheres (RMs) with permanent trisacryl gelatin microspheres (TAGMs) for uterine artery embolization (UAE). Purpose To compare therapeutic efficacy and clinical outcomes in participants with symptomatic fibroids after UAE with RMs or TAGMs. Materials and Methods This randomized controlled trial included participants undergoing UAE for symptomatic fibroids at a single institution (from May 2021 to May 2023).

EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.

Background: Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored.

Fibrosis-Encapsulated Tumoroid, A Solid Cancer Assembloid Model for Cancer Research and Drug Screening.

Peritumoral fibrosis is known to promote cancer progression and confer treatment resistance in various solid tumors. Consequently, developing accurate cancer research and drug screening models that replicate the structure and function of a fibrosis-surrounded tumor mass is imperative. Previous studies have shown that self-assembly three-dimensional (3D) co-cultures primarily produce cancer-encapsulated fibrosis or maintain a fibrosis-encapsulated tumor mass for a short period, which is inadequate to replicate the function of fibrosis, particularly as a physical barrier.

Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators.

Increased bronchiectasis risk and related risk factors in inflammatory bowel disease: a 10-year Korean national cohort study.

Background: The association between inflammatory bowel disease (IBD) and an increased risk of bronchiectasis, as well as contributing factors, remains unclear. Additionally, whether bronchiectasis increases disease burden in IBD remains unknown. Therefore, this study aimed to: 1) assess whether IBD increases the risk of incident bronchiectasis; 2) compare the risk of bronchiectasis between individuals with Crohn's disease (CD) and those with ulcerative colitis (UC); 3) identify risk factors for bronchiectasis in individuals with IBD; and 4) examine the disease burden in individuals with IBD and bronchiectasis those without.

Ethanol extract from Astilbe chinensis inflorescence suppresses inflammation in macrophages and growth of oral pathogenic bacteria.

Chronic oral inflammation and biofilm-mediated infections drive diseases such as dental caries and periodontitis. This study investigated the anti-inflammatory and antibacterial potential of an ethanol extract from Astilbe chinensis inflorescence (GA-13-6) as a prominent candidate for natural complex substances (NCS) with therapeutic potential. In LPS-stimulated RAW 264.

Maturation of germinal center B cells after influenza virus vaccination in humans.

Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination.