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In a silent trial involving 197 patients with lung cancer over a span of 4 months, a fine-tuned pathology foundation model was able to identify the presence of EGFR mutations with high accuracy, potentially preventing further genetic testing in 43% of cases.

Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Genome-wide association meta-analyses of attention-deficit/hyperactivity disorder symptom measures and clinical diagnoses identify new risk loci, highlight putative effector genes and yield improved polygenic risk scores.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

The authors identify defective viral particles, in people with non-suppressible HIV-1, that can replicate through superinfection and interfere with the wild-type virus. However, they show no evidence of these preventing disease progression in the individuals studied.

Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

The Zika viral protease NS2B-NS3 is a crucial target for antiviral drug development due to its role in processing viral polyproteins. Here, the authors utilize crystallographic fragment screening and deep mutational scanning to identify binding sites for resistance-resilient inhibitors.

This study discovers human SERF2 as a key partner in stress granule formation by binding specific RNA G-quadruplexes. SERF2 and these RNAs provide a detailed structural model of protein-RNA interactions driving liquid-liquid phase separation in condensates.

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins.

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.

Chemotherapy is commonly used for the treatment of cancer but resistance often occurs. Here, the authors identify mitochondrial DLAT as driver of chemotherapy resistance via interaction with (MTHFD2) and develop a decoy peptide which blocks this interaction, restoring sensitivity to chemotherapy.

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.

Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth muscle dysfunction syndrome.

The EAGLE algorithm and software identifies replicable gene-by-environment interactions based on associations between environment and allele-specific expression.

STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

Wearable sensors typically require innovative methods of energy harvesting for low-power electronics. Here, the authors present an adaptive power management system with a trimodal energy harvesting approach.

Glioblastoma therapy is challenging, and new approaches are needed. Here, the authors report on a mitochondrial targeting nanomotor with self-feedback mechanisms to trigger the mineralisation of mitochondria which together with curcumin, inhibits glioblastoma progression.

Metronomic photodynamic therapy is a long-term, low-dose treatment strategy limited by the need of continuous photosensitizer administration. Here this group reports combining the self-bioluminescent bacteria with a neutral red photosensitizer in alginate microcapsules as a self-driven metronomic photodynamic therapeutic system with preclinical anti-cancer effects.

Glioblastoma (GBM) is an aggressive tumor characterized by an immunosuppressive microenvironment. Here, the authors present a therapeutic approach based on the implantation of a biodegradable scaffold for the sustained, local release of a TLR7/8 agonist at the time of tumor resection, to achieve anti-tumor immunity and protection from future tumor challenge.

An open-access resource, nano-org, enables researchers to explore and compare the nanoscale 2 organisation of proteins imaged using single-molecule localisation microscopy, advancing insights 3 into cell biology, disease, and drug response.

Rodrigues and Queiroz et al. report the discovery of Naiavirus, the largest enveloped virus, isolated from a Brazil biome. With an oval capsid and flexible tail, its giant genome holds many novel genes, underscoring the value of viral isolation studies.

Bennu comprises components of intra- and extra-Solar System origins. The parent bodies of Bennu, Ryugu and CI chondrites likely formed from a shared but heterogeneous reservoir in the outer parts of the solar protoplanetary disk.

A genome-wide association study for attention deficit/hyperactivity disorder (ADHD) identifies 12 loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.

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.

The role of outer mitochondrial membrane proteins in Myocardial Ischemia-reperfusion Injury (MIRI) largely remains unknown. Here, the authors demonstrate that the outer mitochondrial membrane protein Myocardial Mitochondrial Antiviral Signaling (MAVS) protein promotes MIRI suggesting MAVS protein as potential therapeutic target.

Profiling subcellular multi-omics with spatiotemporal resolution remains a key challenge in cell biology. Now an orthogonal photocatalytic labelling strategy has been developed that enables simultaneous, non-genetic profiling of mitochondrial RNA and proteins within the same sample, providing a chemical approach for transcriptomic and proteomic analyses with spatial and temporal precision.

A UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids in peroxisomes is described and a previously unrecognized role for peroxisomes in adipose tissue thermogenesis is identified.

Multicellular tissues behave akin to nematic liquid crystals, which are fluid as well as ordered. Here, the authors develop an image analysis method to capture the nematic ordering of tissues with the complex geometries typical of morphogenesis.

IP6 is a critical host cofactor for HIV-1 assembly and infectivity. In this study, the authors uncover the structural basis by which HIV-1 adapts to a deficiency in IP6 packaging through a G225R mutation at the C-terminus of the capsid protein.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

Mauthe et al. find that protein aggregate clearance requires fragmentation of the aggregate by a chaperone module and a proteasomal regulatory particle for recruitment and clustering of selective autophagy receptors to initiate phagophore formation.

A combination of mouse model data and data from a randomized phase 2 trial in patients with breast cancer in remission demonstrates feasibility, safety and a reduction in residual tumor cells following treatment with hydroxychloroquine and/or everolimus.

Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.

In osteoporosis, bone marrow adipocytes (BMAds) accumulate, but their functions are not well understood. Here, Lin et al. show that BMAds promote senescence in neighbouring cells by releasing excess fatty acids, then develop a BMAd targeting nanoparticle to interfere with BMAd lipid metabolism as a strategy to treat osteoporosis.

The function and regulatory mechanism of mRNA acetylation modification in cancer progression remains largely unknown. Here the authors identify that targeting tumor N4-acetylcytidine (ac4C) RNA acetyltransferase NAT10 improves anti-tumor response via MYC/CDK2/DNMT1/dsRNA/type I IFN pathway, and show the synergic anti-tumor effect of NAT10 inhibition with aPD-1.

There are three different evolutionary pathways leading to post-starburst galaxies in the EAGLE simulations, all consistent with observationally motivated scenarios. These multiple pathways explain the observational diversity of post-starburst galaxies.

A highly potent and selective small-molecule catalytic inhibitor of the protein lysine methyltransferase NSD2 shows therapeutic efficacy in preclinical models of KRAS-driven pancreatic cancer and lung cancer.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.