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Issa et al. show that the ciliary small guanosine triphosphatase Arl3 displaces the inhibitory regulator Shulin/DNAAF9 from the outer dynein arm, leading to motor activation.

This work reveals how a regulatory domain in O-GlcNAc hydrolase (OGA) shapes enzyme flexibility and activity, uncovering mechanisms that help maintain O-GlcNAc balance in cells.

The expansion of clones with distinct SERPINA1 somatic mutants in the livers of alpha-1 antitrypsin deficiency (A1AT) patients is consistent with convergent evolution. These variants interfere with the auto-polymerization and intra-ER accumulation of the Z-A1AT protein, thus highlighting potentially targetable domains.

Dubiez and colleagues present a cryo-EM structure of the complex responsible for nuclear export of pre-small nuclear RNAs, comprising CBC–PHAX–CRM1–RanGTP. The structure provides insights into the complex architecture, assembly and target RNA recognition.

The mechanisms that regulate the initiation of DNA replication in archaea are poorly understood. Here, Dhanaraju et al. identify a sequence element and its interacting protein required for DNA replication initiation in the model archaeon Sulfolobus islandicus.

An approach combining bioorthogonal chemistry with genetically encoded fluorogen-activating proteins enables subcellular imaging of phospholipids and glycans, as well as the visualization of lipid transport between organelles and lipid asymmetry across membrane leaflets.

Targeting histone deacetylases (HDACs) alone has shown limited success in solid tumours. Here, authors report that the HDAC1/2 inhibitor romidepsin confers responsiveness to receptor tyrosine kinase inhibitors, with enhanced therapeutic effects in models of hepatocellular carcinoma, leading to tumour regression and an immune-stimulatory profile.

Webb, Toporova and colleagues identify a β-hairpin motif in the kinesin-2 family, which controls motility by sequestering the motor domains from their microtubule track.

The Tad pilus is involved in the formation of antibiotic-resistant biofilms in many bacteria, including the human pathogen Pseudomonas aeruginosa. The authors report the structure of the Tad pilus protein RcpC, demonstrating that it forms its alignment complex, bridging the inner and outer-membrane elements.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

Borna disease virus 1 replicates and transcribes its negative sense RNA genome in the nucleus of infected cells. Here, the authors present the cryoEM structures of the large polymerase protein in complex with the tetrameric phosphoprotein, revealing the structural features that govern its activity.

The development of broadly neutralizing monoclonal antibodies is crucial in the fight against viral infections. Here, using combinatorial library technology, the authors identify 3D1, a monoclonal antibody with potential pan-inhibitory activity against a range of viral families, and provide structural analysis to reveal the basis of the broad cross-reactivity.

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.

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.

Human lens clarity and function depends on well-organized cell junctions. Here, the authors used MicroED to reveal the 3.5 Å structure of MP20, showing that MP20 tetramers form adhesive junctions essential for maintaining lens transparency

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Whether anionic phospholipids required for respiratory supercomplex (SC) formation is unclear. Here authors resolve SCs from a wild type and cardiolipin-deficient yeast strain at 3.2- 3.3 Å resolution to show that cardiolipin can be replaced by phosphatidylglycerol.

Cellular quiescence is a reversible dormant state that helps cells survive stress, support tissue regeneration, and promote longevity. Here, the authors show that blocking ribosomal RNA production by rapid depletion of RNase MRP induces a long-lasting quiescence-like state in human cells.

The MmpL5/MmpS5 efflux system is crucial for drug extrusion and siderophore export in M. tuberculosis. Here, the authors report its high-resolution cryo-EM structures, revealing a unique trimeric assembly and a flexible extracellular stalk.

Reversible palmitoylation regulates the activity and localisation of numerous proteins. Here, Kuo et al develop nanobody-based reagents to specifically target palmitoylation of individual proteins, using this approach to tune the biophysical properties of a single ion channel to prevent arrhythmias in cardiac myocytes.

A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a promising candidate for tuberculosis treatment regimens.

The current model for B-family DNA polymerases in archaea is one of single-subunit enzymes in contrast to the multi-subunit complexes in eukaryotes. Here the authors show that PolB1 fromSulfolobus solfataricusexists as a heterotrimeric complex in cell extracts.

An analysis of coral reefs in the tropical western Atlantic suggests that nearly all will be eroding by 2100 if global warming exceeds 2 °C, which will worsen the effects of sea-level rise.

Here the authors discover a small-molecule that inhibits DNA polymerase theta by trapping the enzyme on DNA in the closed conformation. The inhibitor selectively kills BRCA-mutant cells and exhibits strong synergistic activity with PARP inhibitors.

In plants, Rubisco is composed of 16 subunits and requires multiple chaperones to assemble. Features of individual tobacco Rubisco subunits that affect kinetic properties are investigated by coexpression with chaperones in Escherichia coli.

Khan et al. show that Sec18 uses both D1 and D2 AAA+ rings cooperatively, opening them laterally for SNARE substrate loading and for subsequent release of SNAREs.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

A major question in redox signaling is how H₂O₂ oxidizes target protein thiols in the presence of glutathione peroxidases and peroxiredoxins. We reveal signaling by H₂O₂ via its enzymatic conversion to an alkyl hydroperoxide that stereo-specifically escapes peroxidases and oxidizes target proteins.

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

SOCS3 is an important negative feedback inhibitor of JAK–STAT-mediated cytokine signalling. Here the authors implicate cavin-1 — an essential component of caveolae — in the recruitment of SOCS3 to the plasma membrane to prevent sustained cytokine receptor signalling.

Whole-genome sequencing of matched serial tumours from patients identifies two key mutagenic factors (APOBEC3 and chemotherapy) and extrachromosomal DNA-forming structural variants that drive treatment resistance in urothelial cancer.

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.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

Here, the authors reveal that protozoal communities shape rumen microbiome structure, offering fresh insights into how these complex communities coordinate essential metabolic tasks across multiple microbial domains.

Caloric restriction improves Alzheimer’s Disease outcomes in mice, but this diet not only reduces calories, but imposes a prolonged fast between meals. Here, the authors show this fast is essential to improve Alzheimer’s pathology and cognition.

DNA damage threatens genomic stability and must be efficiently repaired. Here, the authors identify a role for the RNA methyltransferase NSUN2 in facilitating DICER-dependent processing of damage-responsive transcripts, promoting efficient double-strand break repair.

Here the authors show that rehabilitating nuclear speckles, membraneless organelles involved in mRNA processing and gene regulation, can boost protein quality control and reduce toxic protein buildup, as well as ameliorate models of diseases like tauopathy and retinal degeneration.

The ability to vaccinate against multiple related pathogens is a significant advantage. Here, the authors report on quartets of linked receptor-binding domains attached to designed nanocages using SpyTag/SpyCatcher links, demonstrating effective vaccination against similar viruses as well as the variant of concern.