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.

CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells.

Clinical application of autologous chimeric antigen receptor (CAR)-T cells is complicated by limited targeting of cancer types, as well as the time-consuming and costly manufacturing process. We develop CD70-targeted, induced pluripotent stem cell-derived CAR-natural killer (NK) (70CAR-iNK) cells as an approach for universal immune cell therapy. Besides the CD70-targeted CAR molecule, 70CAR-iNK cells are modified with CD70 gene knockout, a high-affinity non-cleavable CD16 (hnCD16), and an interleukin (IL)-15 receptor α/IL-15 fusion protein (IL15RF).

Assessment of the safety and gut microbiota modulation ability of an infant formula containing Bifidobacterium animalis ssp. lactis CP-9 or Lactobacillus salivarius AP-32 and the effects of the formula on infant growth outcomes: insights from a four-month clinical study in infants under two months old.

Background: Breast milk is a natural treasure for infants, and its microbiota contains a rich array of bacterial species. When breastfeeding is not possible, infant formula with probiotics can be used as a sole source or as a breast milk supplement. The main aim of this study was to evaluate the growth outcomes and tolerance of infants consuming an infant formula containing Bifidobacterium animalis ssp.

Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery.

Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impedes drug discovery. Here, we devise a robust protocol for the generation of human induced VECs (iVECs) through manipulation of cell-cycle dynamics via the retinoic signaling pathway.

Neuroprotective Effects of Rapid Local Ischemic Postconditioning in Successful Endovascular Thrombectomy Patients.

Background: We aim to assess the efficacy of rapid local ischemic postconditioning (RL-IPostC) following successful reperfusion in patients with acute ischemic stroke with anterior circulation large vessel occlusion who underwent endovascular thrombectomy.

Methods: We conducted an ambidirectional cohort study with 78 prospectively enrolled patients with RL-IPostC and endovascular thrombectomy and 129 retrospectively enrolled patients with endovascular thrombectomy. The RL-IPostC procedure involved 5 cycles of 15-s balloon inflation and deflation in the ipsilateral internal carotid artery.

Production of α-Glycerylphosphorylcholine in Fermented Roots, Tubers, and Fruits.

Vegetables and fruits, high in starch and sugars, are promising substrates for bioethanol production, but can also yield valuable nootropic compounds, such as α-glycerylphosphorylcholine (α-GPC). This compound is a known cognitive enhancer that works by increasing the release of acetylcholine, a neurotransmitter essential for learning and memory. In this study, select root and tuber crops, as well as fruits, were subjected to fermentation to observe the co-production of ethanol and α-GPC.

A human monoclonal antibody targeting the monomeric N6 neuraminidase confers protection against avian H5N6 influenza virus infection.

The influenza neuraminidase (NA) is a potential target for the development of a next-generation influenza vaccine, but its antigenicity is not well understood. Here, we isolate an anti-N6 human monoclonal antibody, named 18_14D, from an H5N6 avian influenza virus (AIV) infected patient. The antibody weakly inhibits enzymatic activity but confers protection in female mice, mainly via ADCC function.

What tool or method do you wish existed?

We asked researchers from a range of disciplines across biology, engineering, and medicine to describe a current technological need. The goal is to provide a sample of the various technological gaps that exist and inspire future research projects.

A Feasibility Study of AI-Assisted Compressed Sensing in Prostate T2-Weighted Imaging.

Rationale And Objectives: To evaluate the image quality and PI-RADS scoring performance of prostate T2-weighted imaging (T2WI) based on AI-assisted compressed sensing (ACS).

Materials And Methods: In this prospective study, adult male urological outpatients or inpatients underwent prostate MRI, including T2WI, diffusion-weighted imaging and apparent diffusion coefficient maps. Three accelerated scanning protocols using parallel imaging (PI) and ACS: T2WI, T2WI and T2WI were evaluated through comparative analysis.

Deep migration learning-based recognition of diseases and insect pests in Yunnan tea under complex environments.

Background: The occurrence, development, and outbreak of tea diseases and pests pose a significant challenge to the quality and yield of tea, necessitating prompt identification and control measures. Given the vast array of tea diseases and pests, coupled with the intricacies of the tea planting environment, accurate and rapid diagnosis remains elusive. In addressing this issue, the present study investigates the utilization of transfer learning convolution neural networks for the identification of tea diseases and pests.

Genome-Wide Methylation Analysis Reveals a -Prominent Causal Cascade on Hypertension.

Background: Despite advances in understanding hypertension's genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease's genetic mechanisms.

Methods: We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing.

Smooth Muscle Ythdf2 Abrogation Ameliorates Pulmonary Vascular Remodeling by Regulating Myadm Transcript Stability.

Background: The N6-methyladenosine (mA) modification of RNA and its regulators have important roles in the pathogenesis of pulmonary hypertension (PH). (YTH N6-methyladenosine RNA binding protein 2) is best known for its role in degrading mA-modified mRNAs such as mRNA, which leads to alternative activation of macrophages in PH. Recent studies have also linked to the proliferation of pulmonary artery smooth muscle cells (PASMCs).

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

Background: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination.

Learning Representations from Heart Sound: A Comparative Study on Shallow and Deep Models.

Leveraging the power of artificial intelligence to facilitate an automatic analysis and monitoring of heart sounds has increasingly attracted tremendous efforts in the past decade. Nevertheless, lacking on standard open-access database made it difficult to maintain a sustainable and comparable research before the first release of the PhysioNet CinC Challenge Dataset. However, inconsistent standards on data collection, annotation, and partition are still restraining a fair and efficient comparison between different works.

Methylation of NRIP3 Is a Synthetic Lethal Marker for Combined PI3K and ATR/ATM Inhibitors in Colorectal Cancer.

Introduction: The aim of this study was to investigate the epigenetic regulation and underlying mechanism of NRIP3 in colorectal cancer (CRC).

Methods: Eight cell lines (SW480, SW620, DKO, LOVO, HT29, HCT116, DLD1, and RKO), 187 resected margin samples from colorectal cancer tissue, 146 cases with colorectal adenomatous polyps, and 308 colorectal cancer samples were used. Methylation-specific PCR, Western blotting, RNA interference assay, and a xenograft mouse model were used.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

Aims: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF.

An immune window of opportunity to prevent spontaneous abortion: prepregnancy peripheral leukocytes and subsets were associated with a decreased risk of spontaneous abortion.

Study Question: Do prepregnancy peripheral leukocytes (PPLs) and their subsets influence the risk of spontaneous abortion (SAB)?

Summary Answer: PPLs and their subsets are associated with the risk of SAB.

What Is Known Already: Compelling studies have revealed the crucial role of maternal peripheral leukocytes in embryo implantation and pregnancy maintenance. Adaptive changes are made by PPLs and their subsets after conception.

Research Progress of ODS FeCrAl Alloys-A Review of Composition Design.

After the Fukushima nuclear accident, the development of new accident-tolerant fuel cladding materials has become a research hotspot around the world. Due to its outstanding corrosion resistance, radiation resistance, and creep properties at elevated temperatures, the oxide dispersion strengthened (ODS) FeCrAl alloy, as one of the most promising candidate materials for accident-tolerant fuel cladding, has been extensively studied during the past decade. Recent research on chemical composition design as well as its effects on the microstructure and mechanical properties has been reviewed in this paper.

Additive Sensory Noise Effects on Operator Performance in a Lunar Landing Simulation.

Adding noise to a system to improve a weak signal's detectability is known as stochastic resonance (SR). SR has been shown to improve sensory perception and cognitive performance in certain individuals, but it is unknown whether this performance improvement can translate to meaningful macrocognitive enhancements in performance for complex, operational tasks. We investigated human operator performance in a lunar landing simulation while applying auditory white noise and/or noisy galvanic vestibular stimulation.

Coating-Free Culture Medium for Establishing and Maintaining Human Induced Pluripotent Stem Cells.

Cell expansion of human pluripotent stem cells (hPSCs) commonly depends on Matrigel as a coating matrix on two-dimensional (2D) culture plates and 3D microcarriers. However, the xenogenic Matrigel requires sophisticated quality-assurance processes to meet clinical requirements. In this study, we develop an innovative coating-free medium for expanding hPSCs.

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model.

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib.