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Multiplexed assays of variant effect can resolve clinical variants but are incompatible with secreted proteins. Here Popp et al. develop MultiSTEP, a generalizable surface-tethering method to assess variant effects in secreted proteins at scale.

In chemical-genetic and lipidomics analyses, the clinical candidate oncology drug tegavivint induced an unconventional form of nonapoptotic cell death that required the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase.

Metabolic enzymes of the tricarboxylic acid cycle, such as 2-oxoglutarate dehydrogenase, are differentially expressed in absorptive and secretory lineages, guiding cell fate establishment and offering insights for targeted regenerative therapies.

Macrophage-augmented organoids integrate macrophages into organoids that are cultured from human liver tissue for analysis of immune responses during three different viral infections.

Developing high-productive and energy-saving systems in formate electrosynthesis is attractive but challenging. Here, the authors report an efficient Rh-dispersed In₂O₃ catalyst for CO₂ reduction, benefiting the ampere-level formate coproduction when pairing with anodic aldehyde oxidative dehydrogenation.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

Miao et al. show that loss of neuronal Vps13d in mice leads to mitochondrial dysfunction, GSDME-mediated mitochondrial DNA release, cGAS–STING inflammatory signaling and activation of microglia, culminating in neuronal loss.

The mechanisms underlying the regulation of the skin thermal barrier are poorly understood. Here the authors show that the thermal properties of the skin are reactive to diet and that skin is a target for dietary fat delivery.

A combination of pyrimidine biosynthesis inhibitors and antiviral nucleoside analogues can boost the antiviral effect of nucleoside analogues against SARS-CoV-2.

Dual leucine-zipper kinase (DLK) drives several forms of neurodegeneration but inhibitors of DLK’s kinase ___domain cause adverse effects. Zhang et al describe an alternative strategy to block DLK signaling by targeting the axonal palmitoylation of DLK.

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.

A key challenge in the self-assembly of block copolymers is obtaining independent control over molecular structure and hierarchical structure in all dimensions using scalable one-pot chemistry. Here the authors show the ring opening polymerization-induced crystallization-driven self-assembly of poly-L-lactide-block-polyethylene glycol block copolymers into 1D, 2D and 3D nanostructures.

Peroxisomes are essential but their role in cell fate regulation remains understudied. Here, the authors reveal that young and old peroxisomes are not equally distributed in asymmetrically dividing stem cells, and peroxisome inheritance influences daughter cell fate.

Self-related cognitions are central to identity and wellbeing. Using 7-Tesla MRI, Kung et al map a dynamic network centred on the habenula demonstrating its role in encoding self-directed thinking and adaptive responses to negative self-cognitions.

While BH3-mimetics can be effective for treatment of haematological malignancies, their efficacy in solid tumours is limited. Here, using a range of patient-derived prostate cancer models, the authors demonstrate that increased replication stress induced by RB1 loss confers sensitivity to BH3 mimetics targeting BCL-XL.

A study finding an oestrogen-sensing signalling pathway that promotes melanoma metastasis only in female mice emphasizes the importance of recognizing sex-specific factors in cancer management.

The WHO’s designation of mpox as a public health emergency of international concern underscores the need for diagnostics to combat this escalating threat. Here, the authors present a portable POC molecular platform based on power-free DNA extraction and colourimetric LAMP.

Computational and spectroscopic studies of molecular lanthanide complexes have implicated 4f orbitals in metal–ligand bonding interactions. Now, a comparative study of isostructural d-block, actinide and lanthanide complexes has shown that 4f-orbital covalency enables ring-opening isomerization in a Ce(IV)–cyclopropenyl complex in the solid state, a reaction not observed for the other complexes studied.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

Covalent inhibitors that selectively target bacterial enzymes are potential antibiotic drug candidates. Here, the authors apply high-throughput screening to identify selective covalent inhibitors that target serine hydrolases in Staphylococcus aureus

SAVANA is a tool to detect somatic structural variants and copy number aberrations using long-read sequencing data, offering high sensitivity, specificity and compatibility with or without germline controls.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

De novo design of self-assembling protein nanostructures and materials is of significant interest, however design of complex, multi-component assemblies is challenging. Here, the authors present a stepwise hierarchical approach to build such assemblies using helical repeat and helical bundle proteins as building blocks, and provide an in-depth structural characterization of the resulting assemblies.

The authors determine the synaptic wiring diagram of a vertebrate circuit and reveal behaviorally associated modules. A model based on this connectome predicts neural coding and dynamics that are verified with calcium imaging data.

MERS-CoV ORF4b antagonizes host innate immune response, partially via blocking nuclear import adapter IMPα activity and preventing nuclear translocation of NF-κB. Here, Munasinghe and Edwards et al. biochemically and structurally define the interaction between ORF4b and IMPα-family members and find a non-canonical interaction between ORF4b NLS and IMPα2 and IMPα3.

Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

A microfluidics- and electron-microscopy-based method enables the characterization of polyclonal antibody responses to infection and vaccination.

Comparison of genome-wide association studies of HTT CAG repeat expansion in blood to expansion-driven clinical traits in Huntington’s disease identifies shared and distinct modifiers implicating DNA mismatch repair with tissue and cell-type specificity.

Strong lasing effects similar to those in the optical regime can occur at 1.5–2.1 Å wavelengths during high-intensity XFEL-driven Kα₁ lasing of copper and manganese.

Gomez et al. show that boosting angiotensin-converting enzyme expression in microglia promotes phagocytic clearance of Aβ and endolysosomal trafficking, driven by spleen tyrosine kinase signaling in the 5xFAD transgenic model of Alzheimer’s disease.

A screening approach finds VH-___domain antibodies that bind the SARS-CoV-2 Spike protein receptor-binding ___domain at its interface with host ACE2. Bi-paratopic and multivalent binders have high affinity and potency.

Boiko et al. enhance expressiveness and interpretability of molecular representation in graph neural networks by including quantum-chemical-rich information into molecular graphs.

Upon encounter of abasic lesions, a highly-prevalent DNA damage, RNA polymerase I experiences a two-step pausing-stalling mechanism that is described here through cryo-EM analysis. The structures uncover the nucleotide entry mechanism and provide insights into intrinsic RNA cleavage.

The role of glioma cellular metabolism in response to oncolytic herpes virus (oHSV) therapy remains to be studied. Here the authors report that oHSV induces metabolic reprogramming in IDH wildtype glioma cells, leading to ferroptosis and anti-tumor immune response. Pharmacological blockade of mutant IDH enhances glioma cell sensitivity to oHSV therapy.

The taurine–taurine transporter axis is a critical dependency of aggressive myeloid leukaemias.

This study reports unexpected structural diversity in computationally designed protein assemblies due to subunit flexibility. Fixing flexibility in one design restores the intended architecture, suggesting a strategy to design dynamic assemblies.

Clear cell renal cell carcinoma (ccRCC) usually metastasizes to the lungs. Here, the authors discover that SWI/SNF ATPase subunit SMARCA4 silencing of HLF regulates ccRCC lung metastasis by modulating the integration of collagen's mechanical cues with the actin cytoskeleton through leupaxin.

Gain-of-function mutations in CTNNB1 (encoding for b-catenin) leading to deregulated Wnt/β-catenin signaling are frequently observed in patients with hepatocellular carcinoma (HCC). Here the authors show that inhibiting b-catenin with lipid nanoparticles encapsulating siRNA targeting CTNNB1 impairs tumor growth and promotes anti-tumor immunity in preclinical HCC models.

The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.

The generation of spatiotemporal optical vortices in the extreme-ultraviolet regime is demonstrated via high harmonic generation. Topologically coupled at the nanometre and attosecond domains, these light beams are attractive for exploring electronic dynamics in magnetic materials, chiral media and nanostructures.

Early expression of intraneuronal amyloid-β (not phospho-tau) and inflammatory and glycosylation pathway transcripts distinguish neocortical RORB⁺ and GAD1⁺ neurons selectively vulnerable to neurodegeneration in Alzheimer’s disease.

In this study, Rödström et al. use cryo-EM to reveal a range of structural features in THIK-1 K⁺ channel and demonstrate how these features define many functional properties of the channel, thus expanding its potential as a drug target.

Grasslands tend to be limited by both nutrient and water availability. Here the authors use standardized field experiments to show that the effects of nutrient addition on grassland biomass may cancel out the negative impact of drought, but the outcome depends on aridity and other local conditions.