Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14.

Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most -methyladenosine (mA) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for mA can promote oncogenesis.

Chirality Evolution of Supramolecular Helices by Electron Transfer Assisted Secondary Nucleation.

Chirality evolution is ubiquitous and important in nature, but achieving it in artificial systems is still challenging. Herein, the chirality evolution of supramolecular helices based on l-phenylalanine derivative (LPF) and naphthylamide derivate (NDIAPY) is achieved by the strategy of electron transfer (ET) assisted secondary nucleation. ET from LPF to NDIAPY can be triggered by 5 s UV irradiation on left-handed LPF-NDIAPY co-assemblies, leading to NDIAPY radical anions and partial disassembly of the helices.

Prevalence of Transcription Factor 4 Gene Triplet Repeat Expansion Associated with Fuchs' Endothelial Corneal Dystrophy in the United States and Global Populations.

Objective: An intronic cytosine-thymine-guanine (CTG) triplet repeat expansion in the transcription factor 4 gene () gene (CTG18.1) confers significant risk for the development of Fuchs' endothelial corneal dystrophy (FECD). The objective of this study was to conduct an unbiased survey of the CTG18.

Prospective clinical performance of CoVarScan in identifying SARS-CoV-2 Omicron subvariants.

The purpose of this work was to evaluate the performance of CoVarScan, a multiplex fragment analysis approach, in identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of the Omicron lineage rapidly and accurately. The ability to identify variants with high fidelity and low turnaround time is important both epidemiologically and clinically for pandemic monitoring and therapeutic monoclonal antibody (mAb) selection. Currently, the gold-standard test for this task is whole-genome sequencing (WGS), which is prohibitively expensive and/or inaccessible due to equipment requirements for many laboratories.

Gain of function NOTCH3 variants cause familial partial lipodystrophy due to activation of senescence pathways.

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr in NOTCH3 meeting the filtering criteria.

Surface frustrated Lewis pairs in titanium nitride enable gas phase heterogeneous CO photocatalysis.

Gas-phase heterogeneous catalytic CO hydrogenation to commodity chemicals and fuels via surface frustrated Lewis pairs is a growing focus of scientific and technological interest. Traditional gas-phase heterogeneous surface frustrated Lewis pair catalysts primarily involve metal oxide-hydroxides (MOH•••M). An avenue to improve the process performance metrics lies in replacing the Lewis base MOH with a stronger alternative; an intriguing example being the amine MNH in metal nitrides.

AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice.

The SLC6A1 gene encodes the gamma-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed two AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1 KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1-/- or Slc6a1+/- mice, as well as improvement in several behavioral phenotypes of Slc6a1-/- mice.

Simultaneous Fabrication of P and M Helices in One-Component Chiral System by Methanol-Water Mediated Dual Assembly Pathway.

The synergetic evolution of multiple chiral structures stemmed from same building units is ubiquitous in nature and vital to living systems, but achieving it in artificial systems remains a challenge. Herein, we report a methanol-water mediated dual assembly pathway strategy for simultaneous construction of P and M helices in one-component chiral system. The conformation of l-phenylaniline derivates (LBpyF) is controlled to folded state in CHOH due to the hydrogen bonds as well as C-H⋅⋅⋅π interaction between LBpyF and CHOH.

Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression.

Chiral Hydrogel Nerve Conduit Boosts Peripheral Nerve Regeneration via Regulation of Schwann Cell Reprogramming.

The Schwann cell (SC) is essential in peripheral nerve regeneration by reprogramming into a stem-like "repair Schwann cell" (rSC) phenotype; however, maintaining the rSC stemness remains an unmet challenge. Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood. Herein, inspired by natural chiral components in the SC microenvironment, chiral hydrogel nerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe) in polymeric chitosan-gelatin conduits.

EPOP Restricts PRC2.1 Targeting to Chromatin by Directly Modulating Enzyme Complex Dimerization.

Polycomb repressive complex 2 (PRC2) mediates developmental gene repression as two classes of holocomplexes, PRC2.1 and PRC2.2.

Increased Risk of Glaucoma in Fuchs Endothelial Corneal Dystrophy Is Independent of TCF4 Trinucleotide Repeat Expansion.

Purpose: The purpose of this study was to determine the prevalence of glaucoma and/or ocular hypertension (G/OHTN) in patients with Fuchs endothelial corneal dystrophy (FECD) and correlate with FECD severity and TCF4 cytosine-thymine-guanine18.1 (CTG18.1) trinucleotide repeat expansion genotype.

CT-Guided Microwave Ablation with Vertebral Augmentation for Spinal Metastases with Posterior Wall Defects.

Purpose: To evaluate the efficacy and safety of combined microwave ablation (MWA) and vertebral augmentation (VA) in the treatment of spinal metastases with posterior wall defects.

Patients And Methods: A retrospective review was conducted for 67 patients (42 men, 25 women) with painful spine metastases and posterior wall defects who underwent MWA combined with VA. Among these patients, 52 vertebrae had no epidural invasion and 33 had mild invasion but did not compress the spinal cord.

Identification of FDA-approved drugs that induce heart regeneration in mammals.

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay.

Crystal Water in Minerals Modulates Oxygen Activation for Hydrogen Peroxide Photosynthesis.

Sunlight-responsive minerals contribute significantly to biogeochemical cycles by activating oxygen (O) to generate reactive oxygen species (ROS). However, the role of crystal water, incorporated into minerals through hydration during rock cycles, in O activation remains largely unexplored. Here, we construct tungstite models containing oxygen vacancies to elucidate the modulation of mineral-based ROS dynamics by the synergy between oxygen vacancy and crystal water.

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5).

Lysozyme 1 Inflamed CCR2 Macrophages Promote Obesity-Induced Cardiac Dysfunction.

Background: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.

Interaction energy flow paths analysis of PMSG-based wind power integrated systems during LVRT and its parameter adjustment strategy.

To solve the problem of oscillation instability in permanent magnetic synchronous generator (PMSG)-based wind power connected systems during low-voltage ride through (LVRT) process, a parameter adjustment strategy based on interaction energy path optimization is proposed in this paper. Firstly, a modular state-space model of PMSG under fault transient conditions is constructed, and the system is divided into five subsystems. Then, the dynamic energy function of subsystems reflecting the oscillation stability of the system is derived.

Non-uniform line-of-sight measurements of nitric oxide using mid-infrared Faraday rotation spectroscopy.

Traditional absorption spectroscopy relies on detecting intensity variations along the line-of-sight to gauge average concentration and temperature. While methods like profile fitting and temperature binning offer insights into the non-uniformity of the path, they fall short of accurately capturing the precise spatial distribution with a single line-of-sight measurement. We propose a novel measurement scheme for non-uniformly distributed concentration of nitric oxide (NO) along the line-of-sight utilizing a single laser and path, by incorporating Faraday rotation spectroscopy with magnetic fields changing over time and space.

Construction of an exogenously and endogenously Co-activated DNA logic amplifier for highly reliable intracellular MicroRNA imaging.

DNA-based molecular amplifiers offer significant promise for molecular-level disease diagnosis and treatment, yet tailoring their activation for precise timing and localization remains a challenge. Herein, we've pioneered a dual activation strategy harnessing external light and internal ATP to create a highly controlled DNA logic amplifier (FDLA) for accurate miRNA monitoring in cancer cells. The FDLA was constructed by tethered the two functionalized catalytic hairpin assembly (CHA) hairpin modules (ATP aptamer sealed hairpin aH1 and photocleavable (PC-linker) sites modified hairpin pH2) to DNA tetrahedron (DTN).