ETV7 limits the antiviral and antitumor efficacy of CD8 T cells by diverting their fate toward exhaustion.

Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8 T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice.

Multicenter Evaluation of a Weakly Supervised Deep Learning Model for Lymph Node Diagnosis in Rectal Cancer at MRI.

Purpose To develop a Weakly supervISed model DevelOpment fraMework (WISDOM) model to construct a lymph node (LN) diagnosis model for patients with rectal cancer (RC) that uses preoperative MRI data coupled with postoperative patient-level pathologic information. Materials and Methods In this retrospective study, the WISDOM model was built using MRI (T2-weighted and diffusion-weighted imaging) and patient-level pathologic information (the number of postoperatively confirmed metastatic LNs and resected LNs) based on the data of patients with RC between January 2016 and November 2017. The incremental value of the model in assisting radiologists was investigated.

Transcriptome Profiling Identifies Differentially Expressed Genes in Skeletal Muscle Development in Native Chinese Ducks.

China boasts a rich diversity of indigenous duck species, some of which exhibit desirable economic traits. Here, we generated transcriptome sequencing datasets of breast muscle tissue samples from 1D of four groups: Pekin duck pure breeding group (P), Jinling White duck breeding group (J), P ♂ × J ♀ orthogonal group (PJ) and J ♂ × P ♀ reciprocal-cross group (JP) ( = 3), chosen based on the distinctive characteristics of duck muscle development during the embryonic period. We identified 5053 differentially expressed genes (DEGs) among the four groups.

FMRP phosphorylation modulates neuronal translation through YTHDF1.

RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical and clinical studies, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified.

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.

Role of Static and Dynamic Ocular Biometrics Measured in the Dark and Light as Risk Factors for Angle Closure Progression.

Purpose: To assess the role of static and dynamic ocular biometric parameters measured in the dark and light for predicting progression of primary angle closure suspect (PACS) to primary angle closure (PAC).

Design: Retrospective cohort study using prospective randomized controlled trial data from untreated, control eyes.

Methods: Zhongshan Angle Closure Prevention Trial subjects underwent anterior segment optical coherence tomography (AS-OCT) imaging in the dark and light.

DNA-Encoded Macrocyclic Peptide Libraries Enable the Discovery of a Neutral MDM2-p53 Inhibitor.

Synthetic macrocyclic peptides are an emerging molecular class for both targeting intracellular protein-protein interactions (PPIs) and providing an oral modality for drug targets typically addressed by biologics. Display technologies, such as mRNA and phage display, often yield peptides that are too large and too polar to achieve passive permeability or oral bioavailability without substantial off-platform medicinal chemistry. Herein, we use DNA-encoded cyclic peptide libraries to discover a neutral nonapeptide, UNP-6457, that inhibits MDM2-p53 interaction with an IC of 8.

Competing SiCH-H and SiCH-SiH Channels in the Bimolecular Reaction of Ground-State Atomic Carbon (C(P)) with Disilane (SiH, XA) under Single Collision Conditions.

The bimolecular gas-phase reaction of ground-state atomic carbon (C(P)) with disilane (SiH, XA) was explored under single-collision conditions in a crossed molecular beam machine at a collision energy of 36.6 ± 4.5 kJ mol.

Direct Tie2 Agonists Stabilize Vasculature for the Treatment of Diabetic Macular Edema.

Purpose: Diabetic macular edema (DME) is the leading cause of vision loss and blindness among working-age adults. Although current intravitreal anti-vascular endothelial growth factor (VEGF) therapies improve vision for many patients with DME, approximately half do not achieve the visual acuity required to drive. We therefore sought additional approaches to resolve edema and improve vision for these patients.

A Freshwater Fish-Based Diet Alleviates Liver Steatosis by Modulating Gut Microbiota and Metabolites: A Clinical Randomized Controlled Trial in Chinese Participants With Nonalcoholic Fatty Liver Disease.

Introduction: We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured.

High Blood Pressure and Intraocular Pressure: A Mendelian Randomization Study.

Purpose: To test for causality with regard to the association between blood pressure (BP) and intraocular pressure (IOP) and glaucoma.

Methods: Single nucleotide polymorphisms (SNPs) associated with BP were identified in a genome-wide association study (GWAS) meta-analysis of 526,001 participants of European ancestry. These SNPs were used to assess the BP versus IOP relationship in a distinct sample (n = 70,832) whose corneal-compensated IOP (IOPcc) was measured.

Gas-Phase Preparation of Subvalent Germanium Monoxide (GeO, X) via Non-Adiabatic Reaction Dynamics in the Exit Channel.

The subvalent germanium monoxide (GeO, XΣ) molecule has been prepared via the elementary reaction of atomic germanium (Ge, P) and molecular oxygen (O, XΣ) with each reactant in its electronic ground state by means of single-collision conditions. The merging of electronic structure calculations with crossed beam experiments suggests that the formation of germanium monoxide (GeO, XΣ) commences on the singlet surface through unimolecular decomposition of a linear singlet collision complex (GeOO, , C, Σ) via intersystem crossing (ISC) yielding nearly exclusively germanium monoxide (GeO, XΣ) along with atomic oxygen in its electronic ground state [, O(P)]. These results provide a sophisticated reaction mechanism of the germanium-oxygen system and demonstrate the efficient "heavy atom effect" of germanium in ISC yielding (nearly) exclusive singlet germanium monoxide and triplet atomic oxygen compared to similar systems (carbon dioxide and dinitrogen monoxide), in which non-adiabatic reaction dynamics represent only minor channels.

Expanding the phenotypic spectrum of ARCN1-related syndrome.

Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.

Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.

Use of Connected Pen as a Diagnostic Tool to Evaluate Missed Bolus Dosing Behavior in People with Type 1 and Type 2 Diabetes.

This study used connected pen to determine missed bolus dose (MBD) frequency during masked and unmasked continuous glucose monitoring (CGM) periods and examined its link with time-in-range (TIR), time-above-range (TAR), time-below-range (TBR), and key participant characteristics in people with diabetes. This was a 12-week, single-arm, exploratory, two-period study for people with type 1 diabetes (T1D) or type 2 diabetes (T2D). The primary objective was to estimate the average number of MBD during masked and real-time CGM use.

Evaluation of the Diagnostic Performance of Swept-Source Anterior Segment Optical Coherence Tomography in Primary Angle Closure Disease.

Purpose: To evaluate the diagnostic performance of swept-source anterior segment optical coherence tomography (SS-OCT) in differentiating eyes with primary angle closure disease (PACD) from eyes of control subjects, as well as eyes with PAC and PAC glaucoma (PACG) from eyes with PAC suspect (PACS) disease.

Design: Multicenter cross-sectional study.

Methods: Chinese patients were classified into control, PACS, and PAC/PACG groups.

A Crossed Molecular Beams and Computational Study of the Formation of the Astronomically Elusive Thiosilaformyl Radical (HSiS, XA').

The formation pathways to silicon- and sulfur-containing molecules are crucial to the understanding of silicon-sulfur chemistry in interstellar and circumstellar environments. While multiple silicon- and sulfur-containing species have been observed in deep space, their fundamental formation mechanisms are largely unknown. The crossed molecular beams technique combined with electronic structure and Rice-Ramsperger-Kassel-Marcus (RRKM) calculations was utilized to study the bimolecular reaction of atomic silicon (Si(P)) with thiomethanol (CHSH, XA') leading to the thiosilaformyl radical (HSiS, XA') via an exclusive methyl radical (CH, XA″) loss via indirect scattering dynamics which involves barrierless addition and hydrogen migration in an overall exoergic reaction, indicating the possibility that HSiS can form in cold molecular clouds.

An enhanced method for nucleic acid detection with CRISPR-Cas12a using phosphorothioate modified primers and optimized gold-nanopaticle strip.

CRISPR-Cas12a system has been shown promising for nucleic acid diagnostics due to its rapid, portable and accurate features. However, cleavage of the amplicons and primers by the - and -activity of Cas12a hinders the attempts to integrate the amplification and detection into a single reaction. Through phosphorothioate modification of primers, we realized onepot detection with high sensitivity using plasmids of SARS-CoV-2, HPV16 and HPV18.

Three- and 4-Level Lumbar Arthrodesis Using Adjunctive Pulsed Electromagnetic Field Stimulation: A Multicenter Retrospective Evaluation of Fusion Rates and a Review of the Literature.

Background: The incidence of 3- and 4-level lumbar arthrodesis is rising due to an aging population, and fusion rates affect clinical success in this population. Pulsed electromagnetic field (PEMF) stimulation is used as an adjunct to increase fusion rates following multilevel arthrodesis. The purpose of the study was to evaluate the fusion rates for subjects who underwent 3- and 4-level lumbar interbody arthrodesis following PEMF treatment.

Loss of CASK Accelerates Heart Failure Development.

[Figure: see text].

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

Objective: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e.

Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles.

Rationale: HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear.

Objective: To test the hypothesis that HDL's cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus.

A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging.

Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology in vivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo.

Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.

Krüppel-like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)-induced adventitial pathologic changes.

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates.

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses.