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Phosphorylation-dephosphorylation and ubiquitination tune TCR signaling to avoid self-reactivity. Kim and colleagues show that acetylation also modulates TCR signaling.

In a phase 2 trial evaluating healthy donor fecal microbial transplantation plus either anti-PD-1 in patients with non-small cell lung cancer or anti-PD-1 and anti-CTLA-4 in patients with melanoma, encouraging efficacy was seen in both cohorts, with responses linked to significantly greater loss of baseline bacterial species.

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.

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.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

The phase 2/3 DEVOTE trial demonstrated that high-dose nusinersen significantly improved motor function and was safe in patients with spinal muscular atrophy, compared with a matched sham control.

Tryptophan metabolism is disrupted in aging and neurological disorders. Here, the authors show that histone deacetylase sirtuin 6 regulates tryptophan usage, and its absence results in neurotoxic products and impaired sleep that can be reversed by inhibiting the tryptophan processing enzyme TDO2.

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.

Bioactivity-guided isolation of specialized metabolites is an iterative process. Here, the authors demonstrate a native metabolomics approach that allows for fast screening of complex metabolite extracts against a protein of interest and simultaneous structure annotation.

Stone tools illustrate behavioural complexities in Middle Pleistocene hominin populations. Here, the authors present small dimensional flakes and hafted tools from Xigou, central China, dated to ~160–72 thousand years ago that demonstrate early, complex technological advancements.

The perceived toxicity of organometallic reagents has limited their use in living systems. Now it has been shown that balancing flexible chelation with biocompatible ligands without precluding chemical reactivity enables organonickel-mediated S-arylation inside cells. This reaction enables deep chemical surveys of reactive proteins and covalent tracking of intracellular viral and bacterial pathogens.

Following its internalisation, active endosomal GLP-1R engages with VAPB and SPHKAP at ER membrane contact sites to assemble a local cAMP/PKA condensate for the control of MICOS complex phosphorylation, mitochondrial remodelling and β-cell function.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.

Rathmell and colleagues show that metabolic reprograming of regulatory T cells is associated with severity of critical illness in patients with and without sepsis.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

Eosinophils exist as a functionally heterogeneous population. Whether the heterogeneity is driven by cell-intrinsic or extrinsic factors is underexplored. Here, by leveraging single-cell transcriptomic data and epigenomic analysis, the authors propose that local environmental cues define the gene expression program of murine esophageal eosinophils and identify AP-1 family members, including ATF3, as key regulators of gene expression.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

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.

Cysteine oxidation transforms non-cleavable heterobifunctional lysine-cysteine cross-linked peptides into MS-cleavable ones, enabling their unambiguous identification at the systems level. Here, using in-cell XL-MS analysis, the authors reveal structural features of cellular networks complementary to existing reagents.

Foamy macrophages are a pathological hallmark of demyelinating brain disorders. Here, the authors identify the molecular mechanisms underlying the faulty regulation of lipid efflux that cause accumulation, suggesting a promising strategy to enhance central nervous system repair.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.

Base editing of the pathogenic trinucleotide repeat expansions underlying Huntington’s disease and Friedreich’s ataxia introduces repeat interruptions that reduce somatic expansion in patient cells and mice.

Optical pooled CRISPR screening is improved by combinatorial oligo hybridization for barcode detection.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

The homeostasis of myelin in the central nervous system is highly regulated, but the underlying mechanisms are unclear. Here, the authors show that the FBXW7 protein has a role in constraining myelin growth in the developing and adult central nervous system, preventing the accumulation of myelin abnormalities. FBXW7 acts in part through targeting the MYRF transcription factor for degradation.

This study uses the rumen gut microbiome to show that core microbes exhibit attributes of ecological generalists with broad functional capacity and traits that enable them to be metabolically independent while also supporting non-core microbes and the host.

This work introduces a high FA⁺ configurational entropy strategy by adding 2NTD, tuning FA⁺ rotation dynamics and stabilizing photoactive phases to yield efficient, stable inverted perovskite devices with scalable potential.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

TCR-engineered T cells have shown limited efficacy in part due to the absence of co-stimulation leading to limited accumulation in solid tumors. The authors here show engineering the CD8β coreceptor with an intracellular CD28 domain enhances cytokine production, persistence, and tumor control in vivo independent of tumor-associated co-stimulatory ligand encounter.

The genomic landscape of diffuse gliomas remains to be characterised. Here, the authors perform whole genome sequencing of 403 tumours and identify recurrent coding and non-coding genetic mutations, their associations with clinical outcomes and potential therapeutic targets.

Carty et al. identify the H3K9 methyltransferases that restrict the size and position of the centromere protein A chromatin domain, maintaining functional centromeres.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

In Caenorhabditis tropicalis, three toxin–antidote elements arose via gene duplication from the essential tRNA-synthetase subunit FARS-3. The ancestral antidote probably acquired affinity for FARS-3, enabling presuppression of toxicity and allowing otherwise deleterious mutant alleles to evolve into selfish genes.

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.

The coordination of nutrient availability in the body is crucial for maintaining metabolic health. Here, the authors discovered that liver glucose and citrate transporters interact to synchronously regulate the uptake of these nutrients, thus driving cellular bioenergetics.

Structural and biochemical studies of the β-barrel-assembly machinery from Flavobacterium johnsoniae reveal a subunit composition and assembly that are distinct from those of the canonical Escherichia coli complex.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Physiological modelling of first-pass metabolism using data from a robotic instrument that fluidically links relevant organ chips predicts human pharmacokinetic parameters for orally administered nicotine and for intravenously injected cisplatin.

Adherent-invasive strains of E. coli are commonly isolated from patients with Crohn’s disease. Here, the authors show that an AIEC harbours a hybrid Type IV secretion system (T4SS) that mediates pilin polymerization and biofilm formation in vivo.

Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is implicated in a range of immunopathology. Here the authors show TIGAR drives inflammation and sepsis via activation of TAK1 and that disruption of TIGAR-TAK1 interaction in a murine model of sepsis reduces immunopathology.

Bacteria of the phylum Bacteroidota move by gliding and export proteins using a type-9 secretion system. Here, Liu et al. show that these two processes use a shared mechanism in which outer membrane proteins are covalently attached by disulfide bonds to a moving track structure inside the cell.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

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.