Browse Articles

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

Abstract An abnormal expansion of a GGGGCC (G 4 C 2 ) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G 4 C 2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.

Characteristics of gut microbiota profiles in Asian elephants (Elephas maximus) with gastrointestinal disorders

CCR5-ligand decorated rilpivirine lipid-based nanoparticles for sustained antiretroviral responses

Boosting skin cancer diagnosis accuracy with ensemble approach

Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy

Exploring lipidome mediated inflammatory pathways in acute pancreatitis using mendelian randomization

Dynamic transitions of initiator binding coordinate the replication of the two chromosomes in Vibrio cholerae

Abstract The replication of the two chromosomes in the pathogenic bacterium Vibrio cholerae is coordinated by the binding of initiator protein RctB to a checkpoint sequence, crtS . Replication of crtS on the primary chromosome (Chr1) triggers replication of the secondary chromosome (Chr2), but the details are poorly understood. Here, we analyze RctB binding patterns in the V. cholerae genome across various cell cycle stages. We find that RctB primarily binds to sites inhibiting replication initiation at the Chr2 origin ( ori2 ). This inhibitory effect is counteracted when crtS is replicated on Chr1, causing a shift in RctB binding to sites that activate replication at ori2 . Structural analyzes indicate the formation of diverse oligomeric states of RctB, coupled to the allosteric effect of DNA, which determine ori2 accessibility. We propose a synchronization model where, upon replication, crtS locally destabilizes the RctB inhibition complex, releasing the Chr2 replication origin.

Partner conflict during their index pregnancy and its correlates among a cohort of six weeks postpartum women in Ethiopia

Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity

Experimental data on aerosols exhaled into the environment from different wind musical instruments

MoS2-confined Rh-Zn atomic pair boosts photo-driven methane carbonylation to acetic acid

The E3 ubiquitin ligase MARCH1 mediates downregulation of plasma membrane GABAB receptors under ischemic conditions by inhibiting fast receptor recycling

AbstractGABAB receptors mediate prolonged inhibition in the brain and are important for keeping neuronal excitation and inhibition in a healthy balance. However, under excitotoxic/ischemic conditions, GABAB receptors are downregulated by dysregulated endocytic trafficking and can no longer counteract the severely enhanced excitation, eventually triggering neuronal death. Recently, we developed interfering peptides targeting protein-protein interactions involved in downregulating the receptors. Treatment with these peptides restored GABAB receptor expression after an ischemic insult and thereby inhibited neuronal overexcitation and progressive neuronal death. In this study, we searched for GABAB receptor interactions that specifically occur under ischemic conditions. We found that the E3 ubiquitin ligase MARCH1 is specifically upregulated under ischemic/excitotoxic conditions. Upregulated MARCH1 interacts with GABAB receptors and triggered downregulation of plasma membrane GABAB receptors by inhibiting fast recycling of the receptors. We developed an interfering peptide that inhibits the MARCH1/GABAB receptor interaction. Treatment of cultured neurons subjected to ischemic stress with this peptide restored receptor expression and as a consequence stopped progressive neuronal death. Thus, inhibiting the interaction of GABAB receptors with MARCH1 to restore cell surface receptor expression might be a promising strategy to prevent progressive neuronal death induced by ischemic conditions.

Organocatalytic enantioselective synthesis of double S-shaped quadruple helicene-like molecules

A hybrid CNN model for classification of motor tasks obtained from hybrid BCI system

Electrostatic in-plane structural superlubric actuator

Risk prediction model for poor prognosis after intravenous thrombolysis among ischemic stroke patients aged ≥ 80 years and analysis of follow-up

Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals

AbstractThe analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.

Oxidative toxicity mediated oophoritis alters ovarian growth in Channa punctatus under prolonged exposure to herbicide, paraquat dichloride

Unveiling the nexus between irradiation and phase reconstruction in tin-lead perovskite solar cells

AbstractTin-lead perovskites provide an ideal bandgap for narrow-bandgap perovskites in all-perovskite tandem solar cells, fundamentally improving power conversion efficiency. However, light-induced degradation in ambient air is a major issue that can hinder the long-term operational stability of these devices. Understanding the specifics of what occurs during this pathway provides the direction for improving device stability. In this study, we investigate the long-term stability problem of tin-lead perovskites under irradiation, counterintuitively discovering an irreversible phase reconstruction process. In-situ photoluminescence spectroscopy is used to monitor the reconstruction process, which involves the reaction of oxygen with photoexcited electrons to form superoxide. It is proposed that Pb-rich regions appear on the surface after Sn2+ oxidation, and these Pb-rich regions are reconstituted from the yellow phase of formamidinium lead iodide to the black phase with prolonged irradiation. This study highlights the phase reconstruction process during the degradation of tin-lead perovskites, providing valuable insights into the superoxide degradation mechanism and guiding further stability improvements for narrow-bandgap tin-lead perovskites and tandem solar cells.

Ribitol and ribose treatments differentially affect metabolism of muscle tissue in FKRP mutant mice

AbstractDystroglycanopathy is characterized by reduced or lack of matriglycan, a cellular receptor for laminin as well as other extracellular matrix proteins. Recent studies have delineated the glycan chain structure of the matriglycan and the pathway with key components identified. FKRP functions as ribitol-5-phosphate transferase with CDP-ribitol as the substrate for the extension of the glycan chain. Supplement of ribitol and ribose have been reported to increase the levels of CDP-ribitol in both cells and in muscles in vivo. Clinical trials with both ribitol and ribose have been reported for treating LGMD2I caused by mutations in the FKRP gene. Here we compared the comprehensive metabolite profiles of the skeletal muscle between ribitol-treated and ribose-treated FKRP mutant mice. The closely related pentose and pentitol show clearly differential impacts on metabolisms despite their similarity in enhancing the levels of CDP-ribitol and matriglycan synthesis. Supplement of ribitol changes lysophospholipid sub-pathway metabolite profiling with a trend towards normalization as reported in the muscle after AAV9-FKRP gene therapy. Ribose treatment significantly increases level of ribonate and elevates levels of advanced glycation end products. Further analysis is required to determine which metabolite is prudent to use for long-term daily treatment of dystroglycanopathies.