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The distinct architecture of the Escherichia coli membrane transporter LetA mediates lipid trafficking across the bacterial envelope in partnership with the tunnel-like complex LetB.

DNA hybridisation thermodynamics parameters underlie rational design of oligonucleotides for diagnostics and nanotechnology. Here, the authors present an accurate method to measure the free energy of a given DNA structure at specific temperature and buffer conditions.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.

NatD is an acetyltransferase responsible for N-α-terminal acetylation of the histone H4 and H2A and has been linked to cell growth. Here the authors show that NatD-mediated acetylation of histone H4 serine 1 competes with the phosphorylation by CK2α at the same residue thus leading to the upregulation of Slug and tumor progression.

A histone ubiquitin-dependent regulatory hub governs stimulus-dependent heterochromatin propagation, with important implications for understanding mechanisms governing rapid changes in the epigenetic landscape in physiology and disease.

A rationally designed assay detects granzyme A activity by integrating peptide-based GzmA-targeted inhibitors and probes with chemiluminescent reporters to monitor inflammatory bowel disease.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

S protein interacts with and activates PBP1a during cell division, as part of a larger GpsB-associated multiprotein complex that coordinates peptidoglycan remodelling in Streptococcus pneumoniae.

In mice, a SPOCD1–TPR-dependent ‘nowhere-to-hide’ mechanism is required for complete non-stochastic piRNA-directed LINE1 DNA methylation by preventing transposons from escaping surveillance within heterochromatin.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Multidrug efflux pumps help bacteria survive stress and promote antibiotic resistance. Here, authors define the molecular detail of an anaerobic-connected pump MdtF uncovering acid-responsive activity which may enable toxin control in certain niches.

Sivanandan, Leitmann, and colleagues present the CellPaint-POSH platform, which combines pooled CRISPR screening with Cell Painting. Using self-supervised deep learning on cell images, the method enables discovery of gene function and biological networks.

Aging is a risk factor for neurodegenerative diseases associated with protein aggregation. Here the authors identify age-related hyperactivation of EPS8/RAC signaling in C. elegans as a driver of pathological protein aggregation, highlighting EPS8 and its regulators as potential therapeutic targets.

The GroEL/ES chaperonin can act during protein synthesis to promote folding. Here, Roeselová et al. show how GroEL captures, remodels and sequesters nascent proteins in its central chamber, while they remain tethered to the ribosome.

ADGRL4 is a cancer-implicated adhesion GPCR whose ability to couple to G proteins had been unclear. Here, authors show that ADGRL4 weakly engages Gq and determine its 3.1 Å active-state structure, revealing its mechanism of activation.

Recent MPXV outbreaks underscore the need for better vaccines and treatments. Here, the authors isolate and structurally characterize potent antibodies interacting with A28 that they identify as a key viral surface protein essential for viral entry and that induces strong, protective antibody response in mice.

The structural anisotropy necessary for the powered directional rotation of chemically fuelled molecular motors had previously been provided by chiral fuels or enzymes. Now it has been shown that asymmetry in the organocatalyst itself is sufficient for directional fuelled rotation. This informs how chemical energy is transduced through catalysis, the fundamental process that powers biology.

Importin β, the prototypical eukaryotic nuclear import receptor, transports a wide variety of cargos into the nucleus. Ko et al. used cryogenic electron microscopy to reveal an unexpected allosteric regulation of Importin β’s affinity for FG-nucleoporins, triggered by Ran-GTP.

Variants in NOS1AP can cause monogenic nephrotic syndrome. Here, the authors show that disrupting the intergenic NOS1AP splice isoform that is more prevalent in podocytes leads to monogenic kidney disease responsive to RAAS inhibition.

Liu, Liu, Wu and Yao et al. developed a peptide inhibitor that selectively blocks the Ada-two-A-containing histone complex by targeting the YEATS2 YEATS domain and suppresses tumor growth in non-small cell lung cancer.

Chronic stress disrupts the brain vasculature and contributes to mood disorders, but mechanisms of resilience remain unclear. Here, the authors show that enriched environments increase astrocytic Fgf2 to prevent stress-induced vascular alterations and depressive behavior with relevance to human depression.

A strategy for isolating Escherichia coli ribosome–nascent chain complexes and analyzing their conformational dynamics and interactors at peptide level using hydrogen–deuterium exchange mass spectrometry is presented.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

Proximity labeling allows proteomic mapping of subcellular structures. Here, Sroka et al. develop in situ APEX activation (iAPEX) to overcome limitations of labeling specificity and H2O2 toxicity, applying their approach to reveal cilia proteomes and expand proteomic access across organelles, cell types and organisms.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

Jee et al. study a cancer hotspot allele of DICER1 that disrupts RNaseIIIb activity. Beyond ablating 5p hairpin cleavage, 3p passenger strands are globally upregulated and active. Thus, this setting induces both loss and gain of miRNA function.

DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

MEKK2, a member of the MAP3K family, plays a pivotal role in signaling cascades that regulate cellular responses such as proliferation, differentiation, and stress adaptation. Here the authors determine the crystal structure of the kinase domain of MEKK. Using a structure-directed approach they deconvolute the molecular basis of its autophosphorylation and its recruitment and phosphorylation of MAP2Ks, MEK5 and MKK6.

Here the authors report a that sprint interval exercise triggers mitochondrial stress and quality control in skeletal muscle in young healthy men, promoting enhanced mitochondrial function and a remodelling after 8 weeks of training.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease and scaffolding activities. However, a significant nonenzymatic IRE1 dependency has been shown in cancer. Here, the authors design a proteolysis-targeting chimera (PROTAC) to fully disrupt cellular IRE1 protein, selectively blocking growth of IRE1-dependent cancer cells.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of frataxin-stimulated NFS1 activity.

After spinal cord injury, lesion-remote astrocytes acquire heterogeneous, spatially restricted reactivity states that shape neuroinflammation, neural repair and neurological recovery.

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.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

The evolutionary diversification of an exocyst subunit was enabled by electrostatic shifts leading to its dissociation from the ancestral complex.

This paper introduces breakage–replication/fusion, a genomic rearrangement process underpinning three patterns of copy-number gains found in cancer and other diseases.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Cytosine modifications within genomic DNA can serve as important epigenetic markers, but sequencing them at single-base resolution requires chemical modification-selective C-to-T code conversion with potential complex analysis. Now an unnatural base pair enables the sequencing of an epigenetic modification—5-formylcytosine—at single-base resolution within a Sanger sequencing format.