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A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.

This study reports that de novo germline missense variants in SF3B1, distinct from the somatic variants frequently observed in cancer, cause a neurodevelopmental disorder and disrupt global RNA splicing.

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.

Smith et al. present M-PACT, a deep neural network leveraging low-input cell-free DNA methylation profiles to achieve robust classification of pediatric brain tumors and enable cellular deconvolution and sensitive copy-number variation detection.

The Achmatowicz reaction involves the conversion of furans into dihydropyrans, classically with the use of bromine. Here, the authors couple an enzymatic oxygen activation with a chloroperoxidase-mediated oxygen transfer, providing a biocatalytic route to a formal Achmatowicz reaction.

Using genome-wide association studies and meta-analyses on dimensions of personality from large existing datasets, Gupta et al. find novel genomic loci that refine our understanding of the genetic architecture of complex traits.

Asexual-to-sexual switching underpins malaria transmission. Prajapati et al. identify an AP2-G loss-of function mutation and use it as a genetic tool to show that GDV1 is essential for initial ap2-g activation and sexual commitment initiation.

Cardiac fibrosis arises from persistent myofibroblast activity. This study reveals how chromatin factors control scar-forming cells in the heart and shows that inhibiting KAT5 can reduce harmful cardiac fibrosis.

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.

Using activity-based chemical probes, oncogenic IDH1-R132H but not the wild type was found to acquire a unique autopalmitoylation at C269. This mutant-specific modification is critical for the enzyme’s abnormal activity in cancer.

Vaginal birth, exclusive breastfeeding and early contact with siblings promote colonization of the infant gut with bifidobacteria capable of producing aromatic lactates, a microbial and metabolite signal that is inversely related to the risk of allergen-specific sensitization and dermatitis later in life.

Mapping of the neutrophil compartment using single-cell transcriptional data from multiple physiological and patological states reveals its organizational architecture and how cell state dynamics and trajectories vary during health, inflammation and cancer.

Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals, suggesting that a tailored therapeutic strategy is needed to target each subset.

CaBLAM is a bioluminescent genetically encoded calcium indicator that delivers high-contrast signals as shown in cell culture, in the in vivo mouse brain and in zebrafish larvae.

Enzyme promiscuity seeds evolutionary innovation, but how flexible a single enzyme can be (re-)used during evolution remains unclear. Here, the authors show that various evolutionary trajectories applied to succinate semialdehyde dehydrogenase can compensate for the loss of two different functions in E. coli.

MCL1 is an anti-apoptotic protein associated with cancer and therapy resistance. Here, the authors show that MCL1 regulates mTORC1 signalling and metabolism, explaining MCL1-inhibition reported cardiotoxicity, which can be mitigated by dietary leucine supplementation.

The Type 3 Secretion System (T3SS) of Pseudomonas aeruginosa injects effectors into host cells to promote infection. Here, the authors reveal a new regulatory role for the T3SS effector ExoY in modulating ExoT-induced cytotoxicity via cGMP signalling.

An enzymatic reaction installs endogenous β-amino acids in proteins with unique reactivity. Now it has been shows that this reaction can be used for site-specific modification with tetrazine dienophiles to introduce labels onto target proteins. Applications include generation of a radiolabel chelator-modified Her2-binding Affibody and intracellular, fluorescently labelled cell division protein FtsZ.

Genomes of nine brown algal species with different sex determination systems show that U/V sex chromosomes evolved 450–224 Ma and show remarkable conservation of genes within the sex-determining region despite independent expansions of the sex locus in each lineage.

Researchers use a chimeric approach to reveal the first near-atomic resolution structures the yellow fever virion, showing key differences between vaccine and virulent strains that affect how antibodies recognise and neutralise the virus.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

LaccID, an engineered laccase, enables hydrogen-peroxide-free proximity labeling and electron microscopy (EM) in mammalian cells. Notably, LaccID is selectively active at the cell surface, enabling the mapping of the dynamic T cell–tumor surfaceome and its use as a genetically encodable EM tag, expanding the toolkit for cell-based imaging and proteomics.

The multidomain scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) can bind GTP-bound Ras and Rap small GTPases. Here the authors show that, by binding active KRAS, SHANK3 maintains oncogenic KRAS/MAPK/ERK signaling at an optimal level while its depletion in KRAS-mutant cancer cell lines results in ERK signalling overdose and impaired cell proliferation.

Wastewater surveillance can help in pandemic or outbreak response. Here, the authors report an unsupervised learning approach to detect emerging SARS-CoV-2 variants from rural and urban wastewater showing it achieves earlier detection than existing methods and detects new variants without clinical testing data.

Using G•U wobble base pairs at specific loci increases RNA base-editing precision and efficiency.

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.

In this study, the authors identify genetic insertions in the population of hepatitis E virus analyzed in serum samples of a patient with ribavirin treatment failure. They show that these genomic rearrangements promote viral replication without affecting ribavirin sensitivity.

For sexually reproducing organisms, experimental models to study the evolution of primary sex-determining loci are scarce. This study shows male-determining loci on  proto-Y chromosomes of the housefly, containing the same gene, can genomically diverge into regions of various complexity.

The dynamics of microglia states adjacent to or far from amyloid-beta plaques are unclear. Here the authors show that non-plaque-associated microglia modulate the cell population expansion in response to amyloid deposition, and Csf1 signaling regulates their transition to the amyloid-associated state.

The whitefly Bemisia tabaci defends against plant glucosinolate toxins by serial addition of glucose moieties catalyzed by a pair of glycoside hydrolases, preventing toxin activation during feeding on the plant tissue.

On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

RNA base editing represents an exciting modality in precision genetic medicine. Here the authors develop short, metabolically stable RNA oligonucleotides (RESTORE 2.0) that enable precise and efficient RNA base editing, demonstrating successful in-vivo correction of a disease-causing human mutation.

Hanswillemenke, Hofacker and colleagues developed a proximity labeling-based method to identify protein interactome of small molecules and RNA drugs within living cells, facilitating the design and development of RNA drugs with enhanced pharmacological properties.

Few synthetic CO₂-fixation pathways have been tested in vivo. Now, the new-to-nature THETA cycle is designed, realized in vitro and modular implemented in vivo. This cycle involves 17 enzymes, including the two most active carboxylases known so far, to produce the central building block acetyl-CoA using CO₂.

A quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana provides a valuable resource for plant research.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

The consequences of postprandial IL-1β surges in white adipose tissue are unknown. Here the authors show IL-1β regulates WAT remodelling by promoting adipogenesis and energy storage, which is blocked by chronic elevation of this cytokine (as in obesity).

By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, the authors identified a rational approach to select for broad-spectrum antivirals with potential to counteract future pandemic viruses.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.

Targeting of diseased cells is key to the development of next-generation pharmaceuticals, but is often hindered by a lack of specific cell surface markers. Here the authors develop an RNA-based approach, which allows precise control of gene expression, with translation only occurring within preselected cell types of interest.

Heart failure is a leading cause of morbidity and mortality, and ERBB4 signaling has been proposed as a potential therapeutic target. Here they identify small molecule ERBB4 agonists capable of decreasing cardiomyocyte damage and fibrosis in models of cardiovascular disease.

Available enzymatic CO2 reduction strategies are not suitable for aerobic microorganisms and many industrial settings. Here, the authors design a new metabolic pathway that can operate under fully aerobic conditions, ambient CO2 levels, and seamlessly integrate with well-established C1-assimilation pathways.

XPD is part of the TFIIH complex which plays major roles in transcription initiation and nucleotide excision repair (NER). Here the authors present a high-resolution crystal structure of the XPD-MAT1 interface and dissect the role of this interface in transcription and NER.

Gene expression is precisely modulated with CRISPR interference and mismatched guide RNAs.

RNA is implicated in the targeting and function of Polycomb Group (PcG) chromatin regulators. Here the authors show that R-loops, three-stranded nucleic acid structures formed by DNA and RNA, are formed at some PcG binding sites in flies, as they are in mammals. Fly PRC2 can drive formation of RNA-DNA hybrids in vitro.