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Fine-mapping has previously implicated the non-coding single nucleotide polymorphism rs117701653 as a risk variant for rheumatoid arthritis and type 1 diabetes, however its function remained unclear. Here the authors show that this variant decreases binding of the inhibitory factor SMCHD1 to enhance expression of ICOS, promoting development of potentially pathogenic T peripheral helper cells.

Polymer-coated liposomes specifically target and deliver interleukin-12 to metastatic ovarian cancer, strongly sensitizing the tumours to combination therapy with immune checkpoint inhibitors.

Neuromodulatory neural mechanisms behind contextual processing are not fully understood. Here, the authors show how spatiotemporal dynamics of locus coeruleus-norepinephrine release in dentate gyrus modulate contextual discrimination, opening new avenues for treatment of stress-related disorders.

This study identifies key neurocognitive domains that distinguish patients with schizophrenia from healthy individuals using machine learning. Analyzing data from 1,304 participants, it demonstrates that verbal learning and emotion identification effectively classify conditions, promoting efficient neurocognitive profiling strategies.

How internal states such as confidence and motivation influence motor performance remains unclear. Here, the authors explore brain networks associated with these internal states, finding that the Dorsal Attention Network encodes error states and the Default Network reflects perceived uncertainty.

One of three back-to-back papers to show dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance chimeric antigen receptor T cell therapies for cancer.

Recent protein design methods rely on large neural networks, yet it is unclear which dependencies are critical for determining function. Here, authors show that learning the per residue mutation preferences, without considering interactions, enables design of functional and diverse protein variants.

The role of individual lipid species in Alzheimer’s disease (AD) is not fully understood. Here, the authors performed global lipidomics on post-mortem dorsolateral prefrontal cortex collected from 316 participants in the ROSMAP cohort including asymptomatic and symptomatic AD.

Chronic stress is a risk factor for depression, yet the mechanisms are unclear. Here, the authors show in mice that stress drives interferon-mediated neutrophil recruitment from the skull to the brain’s outer membranes, contributing to depressive behaviors.

By combining satellite observations with ground-based data and expert validation, this analysis demonstrates considerable misestimation of grassland extent and thereby carbon stock estimates in previous global assessments based on remote sensing.

This work uses gene expression and single cell analyses to group extrapulmonary tuberculosis patients into three immune types, revealing immune pathways driving pathogenesis and markers that could improve diagnosis and guide tailored treatments.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Caspase 8 protein expression is largely absent in small cell lung cancer (SCLC) patients. Here, the authors generate a caspase 8 deletion SCLC mouse model and show that it promotes a neuronal progenitor-like cell state and pre-tumoral immunosuppression triggered by necroptosis that promotes metastasis.

The authors show that increased Xist RNA levels can induce de novo silencing of genes that normally escape X inactivation. SPEN depletion prevents the silencing of escape genes upon Xist RNA overexpression in neural progenitors.

A hidden Markov model that uses probabilistic retrospective inference allows for up to one month of unsupervised recalibration in an online cursor-based intracortical brain–machine interface.

Cooperative species of extrachromosomal DNAs are coordinately inherited through mitotic co-segregation.

Large-scale combination drug screens in cancer are extremely challenging because of the immense number of possible combinations. Here, the authors develop BATCHIE, a Bayesian active learning platform to design scalable and maximally informative drug combination screening assays; this is validated in retrospective and prospective cancer studies.

The mystery of mammalian lifespan is examined through DNA methylation dynamics, revealing an inverse relationship between lifespan and average methylation rate changes in bivalent promoter regions. Results vary depending on chromatin context.

DNA replication in the human genome occurs preferentially at initiation zones (IZs). Here, the authors identify TRESLIN-MTBP as a limiting factor for replication initiation whose loading onto DNA-bound MCM defines IZs. This process establishes IZs and replication timing in human cells.

The role of ventral tegmental area GABA neurons in behavior is unclear. Here, authors show that VTA GABA but not dopamine neurons integrate positive and negative valence to encode motivational conflict and guide cost-benefit decision making.

The authors found that the Alzheimer’s disease-associated protein tau, widely considered pathogenic when hyperphosphorylated, has a natural function as part of the innate immune system in the brain and can protect against herpes simplex virus 1.

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.

This research explores the linguistic traces of evidence-based reasoning and intuitive decision-making in congressional speeches from 1879 to 2022. The analysis suggests that evidence-based language has continued to decline since the mid-1970s, together with a decline in legislative productivity.

Bond et al. predict mechanism of action of hit compounds from a pooled screen of Mycobacterium tuberculosis mutants underproducing essential proteins by comparing the strain-specific responses of screening hits to those elicited by known antimicrobials.

Regulating the balance between T_H17 cells that drive autoimmune inflammation and nonpathogenic T_H17 cells is critical for limiting autoimmune pathology. Here, the authors extensively characterize these two cell states at the transcriptomic and epigenetic levels and show how BACH2 is protective in this context.

Individual variation in fMRI-derived brain networks is reproduced in a model using only the smoothness (autocorrelation) of the fMRI time series. Smoothness has implication for aging and can be causally manipulated by psychedelic serotonergic drugs.

Using in silico neuroscience, Gifford et al. developed a neural control algorithm to modulate the representational relationships between visual cortical areas, revealing how these areas jointly represent the world as an interconnected network.

The neurochemical basis of compulsive behaviour is not well understood. Here, the authors show that levels of glutamate and GABA in the supplementary motor area and anterior cingulate cortex relate to compulsive behaviour in healthy controls and individuals with OCD.

The authors present DNA-Diffusion, a generative AI framework that designs synthetic regulatory elements with tunable cell-type specificity. Experimental validation demonstrates their ability to reactivate AXIN2 expression, a leukemia-protective gene, in its native genomic context.

The study shows that the HIV-1 Nef protein stabilizes actin, thereby preventing R12C release and priming of RIG-I–like receptors. HIV-1 containing a mutant Nef unable to bind the actinmodulating kinase PAK2, triggers enhanced interferon responses.

In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Reduced GC-related content in the influenza A virus genome may be a necessary condition for sustained mammalian transmission and should be included in risk assessment tools for pandemic influenza.

Following spinal cord injury, gamified physical therapy that incorporates closed-loop vagus nerve stimulation can aid restoration of arm and hand function.

Brain-wide recordings in mice show that learning leads to sensory evidence integration in many brain areas simultaneously, allowing sensory input to drive global movement preparatory dynamics, which collapse upon movement onset.

The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.

A combination of high-resolution spatial imaging, spatial proteomics and transcriptional data reveals sparse and heterogeneous bacterial signals in gliomas and brain metastases.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Genetic background, plasma metabolome and dietary data from 4,215 women and 1,490 men reveal 57 metabolites whose associations with dementia risk vary by APOE4 genotype and other risk variants.

Liver-restricted viral infection in mice results in secondary lymphoid organ dormancy and the compensatory induction of specialized lymphoid tissue in the liver, the structural features and functional outputs of which are closely mirrored in humans.

Barcoding aids in the optimization of lipid nanoparticles. Here, the authors report on multiplexed mRNA barcoding that enables high-resolution spatiotemporal profiling of lipid nanoparticles, linking accumulation kinetics to functional delivery and revealing zonal liver targeting.

Prions are infectious agents that initiate transmissible spongiform encephalopathies. The study demonstrates that Prion proteins lower cellular oxidative stress via GPX8, remodel membrane lipids, and together with RAC3, sensitize cells to ferroptotic death, highlighting new therapeutic targets in prion diseases.

CSF total tau (t-tau), often used as a marker of neuronal damage, is more strongly linked to synaptic degeneration. Here, the authors show that t-tau better reflects synaptic dysfunction than axonal or neuronal loss in Alzheimer’s disease.

Newly developed mouse models that enable cell-specific analyses of proteostasis dynamics across the lifespan of the mice reveal key aspects of neuronal proteostasis with ageing.

Genetically encoded sensors are generally optimized to function during exponential growth rather than stationary phase, which limits their potential value for metabolic engineering and bioproduction. Here, authors engineer a stationary phase green light sensor and use pulsatile light to optimize production of industrially relevant small molecules.

Large-scale genome-wide analyses identify hundreds of genetic loci associated with hypothyroidism and thyroid hormone levels, demonstrating the potential of using polygenic risk scores to predict disease onset and progression.

Deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of compounds with antibiotic properties.

Here, the authors introduce METRIC, a deep-learning method that corrects measurement errors in self-reported dietary nutrient profiles using assessed data and microbial composition, effectively enhancing dietary accuracy.