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Ionescu, Ankol et al. show that, in ALS mouse and iPSC models, TDP-43 aggregation at NMJs stems from aberrant axonal translation, normally repressed by muscle EV-derived miR126. Loss of miR126 in ALS increases TDP-43 buildup, impairs local synthesis and triggers degeneration.

Here the authors develop an assay capable of selecting Sec61 inhibitors by exploiting the inactivation of firefly luciferase, once translocated into the endoplasmic reticulum (ER), and the possibility of diverting and “re-lighting” luciferase into the cytosol by a Sec61 inhibitor.

R-loops formed by RNA hybridization to DNA template strand during transcription influence HIV-1 integration into the CD4⁺ T cell genome. The unwinding of R-loops by splicing helicase Aquarius facilitates integration into speckle-associated domains.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

Genome-wide CRISPR/Cas9 screening reveals novel modulators of heparan sulfate proteoglycans that regulate cellular uptake of α-synuclein fibrils, including in human dopaminergic neurons.

Epichaperomes are chaperone assemblies that reorganize protein networks under stress. Here, authors reveal how HSP90 phosphorylation drives epichaperome formation, linking this process to cancer cell behaviors and pluripotent stem cell functions.

The ability to sequence oligonucleotides which consist entirely of artificial bases will facilitate their ongoing development and use. Here authors demonstrate de novo nanopore sequencing of DNA oligomers composed of “P” “Z” “S” and “B” bases with high sequencing accuracy.

Head and neck squamous cell carcinoma (HNSCC) frequency and risk factors vary considerably across regions and ancestries. Here, the authors conduct a multi-ancestry genome-wide association study and fine mapping study of HNSCC subsites in cohorts from multiple continents, finding susceptibility and protective loci, gene-environment interactions, and gene variants related to immune response.

Using single-molecule analysis, the authors establish that direct competition between eIF1 and eIF5 governs accurate yet flexible translation initiation in humans, providing a biophysical framework with broad relevance to health and disease.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

AI decision support system non-homogenously influences clinical decisions in dynamic treatment regimen, as it depends on several factors including prior knowledge, preference, disease type, treatment modality, and AI’s learned behavior and inherent biases.

An E. coli–thylakoid hybrid is produced in which the thylakoid can convert solar energy into energy molecules, such as ATP and NADPH. A dual-channel energy pathway, combining energy molecule supply and electron transfer, enables the E. coli–thylakoid hybrid to produce H₂ at a rate of \(15.1\,{\mathrm{mmol}}\,{\mathrm{h}}^{-1}\,{\mathrm{g}}_{\mathrm{dcw}}^{-1}\).

A method termed ac⁴C-seq is introduced for the transcriptome-wide mapping of the RNA modification N⁴-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

Particle radiation studies have been one of the elementary keystones since the dawn of the nuclear physics. Here, the authors discovered the heaviest proton emitting isotope to date, ¹⁸⁸At, that points to a trend change in binding energy systematics, further implying a novel interaction in heavy nuclei.

The reconstruction of phospholipase Ce in complex with a Fab identifies two of its N-terminal regulatory domains and helps define the basal state of the enzyme.

The emergence of resistant subpopulations often underlies the development of resistance to cancer therapy. Here, using a DNA barcoding approach, the authors demonstrate EGFR TKI treatment in non-small cell lung cancer enriches for resistant subpopulation which can be prevented by treatment with the multikinase inhibitor sorafenib via inhibition of MKNK, STAT3 and MCL1.

The authors show that mitochondria can chronically hyperpolarize under normal or disease conditions and be induced by environmental exposures. This triggers phospholipid remodeling, which in turn affects the epigenome to regulate transcription.

Proteins are often modified by complex carbohydrates (N-glycans). Here, authors identified gene regulators of this process and uncovered links between plasma protein Nglycosylation, metabolic and liver diseases, and anti-inflammatory proteins.

Shabanzadeh et al. identify and validate a pathway whereby RGMa cleavage by SKI-1 modifies gene expression related to blood–brain barrier (BBB) integrity after stroke. SKI-1 inhibition restores BBB integrity and neuronal function in mouse and rabbit stroke models.

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.

Polyproline motifs induce ribosome stalling during translation. Here, Ignatov et al. identify RNA-binding proteins in the pathogenic bacterium Streptococcus pyogenes, and show that one of these proteins, YebC, acts as a translation factor enhancing translation of proteins with polyproline motifs.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Epichaperomics allow the study of protein-protein interactions and their alterations, but probes have been limited to capturing HSP90 epichaperomes. Here, the authors introduce and validate a toolset of HSP70 epichaperome ligands, and use them in epichaperomics to identify a mechanism with which cancer cells can enhance the fitness of mitotic protein networks.

The CPLANE complex is essential for ciliogenesis, and mutations to all but one subunit have been associated with ciliopathies. Here they identify three familial mutations in the final subunit, RSG1, that cause ciliopathy and add to our understanding of ciliary transition zone assembly.

Cellular and molecular heterogeneity contributes to the insufficient immunogenicity of glioblastoma (GBM), ultimately leading to limited immune cell infiltration. Here this group reports a GBM therapeutic strategy by activating endogenous cGAS-STING signaling pathway by modulating mitochondrial electron transport chain thereby augmenting the immune responsiveness of GBM.

Flores et al. show that brain-penetrant eIF2B agonists suppress ISR activation in cellular and mouse models of ALS and reduce ISR biomarkers in humans, enabling further clinical studies of ISR inhibition in individuals with neurological diseases

O-GlcNAc transferase (OGT) mediates antiviral host immune response. Here, the authors identify a catalytic activity-independent function of OGT in restraining influenza A virus replication by translocating to lipid droplets and limiting their accumulation following interaction with viral RNA.

DNA double strand break repair pathways ensure genome stability and prevent disease. Here the authors show that the actin nucleating factor DIAPH1 and γ-actin promote homologous recombination (HR)-dependent repair. Inherited mutations in DIAPH1 or ACTG1 give rise to clinical deficits similar to those associated with defective HR.

Alpha-1-antitrypsin (AAT) deficiency results from misfolding-prone AAT variants. Here the authors show that AAT forms co-translational folding intermediates on the ribosome that persist upon release and determine its folding fate. They show too that the ribosome can also modulate misfolding-prone AAT intermediates during their synthesis.

Aberrant redox homeostasis links lipid metabolism and cell death programs. Here, authors reveal how cell stress reduces growth factor signaling, enriching polyunsaturated fatty acids in phospholipids and sensitizing membranes to oxidative damage.

Biomolecular condensates are made of multiple components but current techniques cannot capture their complex composition quantitatively. Now it has been shown that the dense-phase binodal point defining the composition of multicomponent condensates can be inferred precisely from the intersection of a spectrometrically determined tie-line with an isorefractive line obtained from quantitative phase imaging.

A neutralizing nanobody specific to the prefusion conformation of herpes simplex virus glycoprotein B has cross-species activity and offers insights into virus neutralization, possible immunogens and an attractive avenue for antiviral interventions.

Kaluba, Rogers et al. show that in cancer cells that can metabolize ketones, they may reroute them to produce cytosolic acetyl-CoA and support tumour growth.

FAN1 nuclease removes DNA triplet repeat loops by a process that requires PCNA. Using cryo-EM, the authors elucidate this mechanism, and show that a Huntington’s disease modifying R507H mutation inactivates FAN1 by compromising the FAN1-PCNA complex.

Puigserver and colleagues show that genetic targeting of specific mitochondrial respiratory complex I subunits in melanoma and breast cancer cells boosts tumor immune surveillance via upregulation of antigen-processing and presentation components.

Latorre-Muro et al. show that the cytosolic chaperone PPID drives insertion of the mitochondrial import receptor TOM70 into the mitochondrial outer membrane, thereby regulating body temperature, glucose homeostasis and body weight in obese mice.

The aggregation of the neuronal protein α-Synuclein is associated with the onset of Parkinson’s disease. Here the authors report a two-dimensional Fragment Assisted Structure-based technique to find antagonists of α-Synuclein aggregation and show its promise for identifying lead therapeutics for Parkinson’s disease.

Saeedi Saravi and colleagues demonstrate an age-related increase in the gut microbial metabolite phenylacetic acid (PAA) in humans and mice, linked to Clostridium bacteria. In mice, they find that PAA triggers endothelial senescence, linking the microbiome to vascular aging.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Using brain organoids models, Prigione and colleagues uncovered the impact of Huntington’s disease on human brain developmental and identified early dysregulation of CHCHD2, which disrupted mitochondria and might serve as a therapeutic target.

This study demonstrates that the MKK3b/6 signalling pathway drives the skeletal muscle growth-promoting effects of resistance exercise.

Glycosylation of human IgG antibodies in bacterial hosts has proven challenging. Here, the authors identify a bacterial enzyme enabling E. coli to glycosylate IgGs at native sites, thereby advancing therapeutic antibody development in this host.

This study provides mechanistic insights into how the mycobacterial transcription factor HelD gradually dissociates from RNAP during transcription initiation and protects RNAP from rifampicin until the last possible moment.