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In this work, fragments identified by 19F-NMR are optimized into submicromolar binders of the MITF transcription factor. These results support direct targeting of bHLH-LZ DNA binding domains and provide a foundation for the development of new melanoma therapies.

The neural mechanisms driving seizure development in peritumoral brain regions remain incompletely defined. Here, using patient tissue, glioma mouse model, and computational simulation, the authors identify early pathological activities that are predictive of tumor-associated seizures.

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.

Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.

Expanded FMR1 CGG repeats drive toxic FMRpolyG in premutation disorders. Here, the authors show that IGF2BP3 binds the FMR1 5’UTR to promote non-AUG translation of FMRpolyG and that its loss reduces toxicity.

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.

Sheep producers face growing expectations to produce more food, conserve biodiversity, stay profitable and cut emissions. The authors find that interventions work best when addressing underperforming environmental, economic, or psychological areas.

Anti-tumor functions of low-avidity T cells are often suboptimal. Here the authors show that genetic disruption of TIGIT in TCR-engineered T cells enhances their anti-tumor activity against pancreatic and other gastrointestinal cancers by increasing TCR signal strength.

Using cryo-electron microscopy technologies, Serianni and Škerlová et al. reveal how Np_nNs initiate bacterial transcription as noncanonical RNA caps by showing one nucleobase pairing with the template in canonical mode while the other pairs in reverse Watson–Crick mode.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Fungal parasites infect key nitrogen-fixing cyanobacteria during Baltic Sea blooms, drawing on carbon and nitrogen reserves. Here, authors find up to a fifth of newly fixed nitrogen is diverted to fungi in the cyanobacterium Dolichospermum, altering the fate of new nitrogen and trophic transfer.

Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

mBaoJin is a monomeric derivative of the bright and photostable green fluorescent protein StayGold. mBaoJin offers favorable photophysical properties for use in diverse protein tagging and subcellular labeling applications.

This study assessed the durability of immunity in humans after vaccination with an MVA-based MERS vaccine. The data show that antibodies and T cells persist for at least two years, with the antibodies capable of cross-neutralizing MERS-CoV variants.

The IKKα kinase was previously reported to promote metastasis. Here, the authors reveal that loss of IKKα function promotes colorectal cancer liver metastasis by expanding a CDH17⁺/CLDN2⁺ epithelial subpopulation characterized by tight junction stabilization and collective migration.

HCN4 channels control cardiac pacing. Here, the authors isolated a nanobody (NB5) that binds HCN4 extracellularly in an ortholog- and isoform-specific manner and promotes its activation in sinoatrial node myocytes, leading to an increase in pacemaker rhythm.

GTP-binding protein 1 (GTPBP1) is GTPase closely related to elongation factor eEF1A, but the GTPBP1-mediated elongation is slow. Here, the authors show how the distinct GTPBP1 architecture leads to slow dissociation, delayed tRNA accommodation, an extended proofreading stage and higher accuracy of GTPBP1-mediated decoding.

Base editors are made more precise through deaminase and gRNA engineering.

More frequent fires in the North American boreal are causing shifts from conifer to deciduous forests. This study finds that when deciduous forests burn, their carbon losses are driven by weather, but are lower than in conifer forests, potentially dampening climate–fire feedbacks.

Here the authors report that brown adipocyte-derived vaspin reduces heat-producing activity in brown fat by blocking adrenergic signals, helping to regulate energy expenditure and maintain metabolic balance.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Exai-1, a cell-free RNA foundation model that integrates sequence, structure and expression features, advances liquid biopsy diagnostics by denoising noisy data, augmenting limited datasets and improving the generalizability of cancer detection models.

Ribosomal translation is coupled to cotranslational protein folding, process assisted by dedicated chaperones. Here, authors present structures of the ribosome-bound yeast Hsp70 chaperone Ssb, identifying its ribosomal binding site and revealing its interactions with a model nascent chain.

The study reports the discovery of a persistent bow shock around a diskless magnetic accreting white dwarf, revealing a powerful energy-loss mechanism that challenges current models of accretion and compact binary evolution.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

Small cell lung cancer cells form functional synapses with glutamatergic neurons, receiving synaptic transmissions and deriving a proliferative advantage from these interactions.

In Australia, the geographic and relaxed temporal requirements for the use of renewable energy certificates could ensure that hydrogen is produced with minimal greenhouse gas emissions and at a low cost, according to an analysis that employs an energy system model and scenario approach

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.

Triple artemisinin-based combination therapies, including mefloquine–piperaquine (MQ–PPQ), may delay emergence of multidrug-resistant strains. Here the authors show that resistance to mefloquine alone reduces the efficacy of the MQ-PPQ combination therapy, and that the interaction between the two drugs further inhibits piperaquine’s activity.

Lucerastat was well-tolerated, but did not reduce neuropathic pain, abdominal pain, or diarrhea compared with placebo. Lucerastat reduced biomarkers of Fabry Disease at 6 months, and these reductions were maintained at the 18-month interim analysis.

ChReef is an optogenetic actuator for sustained optogenetic control of excitable cells in a variety of preclinical applications.

Friedreich’s ataxia (FRDA) is a neurodegenerative disorder driven by frataxin (FXN) deficiency. Here, the authors show that FXN loss in human microglia causes mitochondrial and lysosomal defects that trigger neuroinflammation and neurodegeneration, rescued by gene editing.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Researchers find that whether a person is first vaccinated or first infected with COVID-19 influences their antibody and T-cell responses, offering new insights into how hybrid immunity develops and protects over time.

Identifying hippocampal ripples in humans is challenged by epileptic activity and coarse sampling. By comparing high resolution recordings in rodents and limited sampling in humans, the authors identify key ripple features and introduce a pipeline for more accurate ripple detection.

Loss-of-function variants in thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder. Here the authors identify genotype-phenotype relationships, advance insights in MCT8 (dys)function and create a pathogenicity-severity variant classifier.

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.

Mycobacterium tuberculosis uses five ESX systems to secrete multiple effector proteins that are essential for the pathogen’s growth and virulence. Here, Nair et al. identify a protein complex that is required for outer-membrane localization and for secretion of all ESX-dependent proteins into the cytosol of infected macrophages.

Systems of electron spins in nuclear-spin-rich hosts are gaining attention for quantum memory applications. Using spin ensemble studies, the authors propose transition metal ions in halide double perovskites as promising candidates, featuring long electron spin coherence and deterministic nuclear spin control.

Understanding biodiversity loss and achieving global commitments requires effective biodiversity monitoring. This Roadmap outlines the necessary steps to achieve a transnational European Biodiversity Observation Network built around Essential Biodiversity Variables, combining targeted sensing methods, spatial design, data sharing, data integration and modelling workflows, and coordinated governance to deliver policy-ready insights.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

The oomycete Phytophthora infestans is a damaging crop pathogen. Here, the authors show that a group of P. infestans secreted enzymes play roles in penetration and colonization of host plants by oxidising fragments of the polysaccharide pectin in the plant cell wall.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

Saturation mutagenesis screening examines 11,520 point mutations in the kinase domains of FGFR1, FGFR2, FGFR3 and FGFR4, identifying their activating and resistance properties to the FGFR inhibitors pemigatinib and futibatinib.

Sabatino and colleagues examine expanded CD8⁺ T cell clonotypes from a small cohort of multiple sclerosis patients. They identified several cognate peptide epitopes that derive from Epstein–Barr virus, suggesting EBV reactivation may drive pathogenesis in these patients.

Break-induced replication (BIR) repairs broken DNA but can also destabilize genomes. The authors identify 33 new genes controlling BIR completion, showing that spindle assembly and spindle positioning checkpoints coordinate repair, and that nuclear pore proteins regulate BIR at multiple steps.

Cardiac ryanodine receptors (RyR2) are critical for heart contraction. Here, the authors use 3D MINFLUX microscopy to image receptor subunits and RyR2 orientation with nanometre resolution, thereby providing a molecular view of the organisation and clustering of these cardiac muscle receptors.