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Effective substrates are key to probing and harnessing protease activity. This work presents CleaveNet, an AI tool that generates efficient, selective substrates, revealing known and distinct cleavage motifs and tuning designs to target activity profiles.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

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.

Grosjean et al. present a network-aware, self-supervised learning approach for screening neuronal activity dynamics. They demonstrate its applicability across a range of neural interventions.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Observations from the JWST MIRI showed the detection of ¹⁴NH₃ and ¹⁵NH₃ isotopologues in the atmosphere of a cool brown dwarf, along with a ¹⁴N/¹⁵N value consistent with star-like formation by gravitational collapse.

This study shows that brain connectivity changes in Huntington’s disease begin decades before symptoms, shifting from hyper- to hypoconnectivity, with links to specific neurotransmitter systems specially in granular and infragranular cortical layers.

Silane, which is a precursor to the sandy surfaces of rocky planets and dusty clouds on gas giants, is seen directly in another world—a low-metallicity brown dwarf in which oxidation is slow and gas mixing is fast.

Using data from 142,238 Mass General Brigham Biobank participants, researchers explored population history and social and genetic risk factors for disease in Greater Boston. The study links genetics and context to guide equitable precision health.

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.

Simulated heatwaves shifted carbon fluxes in estuarine flats, with stronger effects after longer heatwave durations. Findings reveal that degradation state will influence heatwave effects on carbon dynamics including changes in source/sink status.

The GroEL/ES chaperonin can act during protein synthesis to promote folding. Here, Roeselová et al. show how GroEL captures, remodels and sequesters nascent proteins in its central chamber, while they remain tethered to the ribosome.

Neural mechanisms mediating information flow and processing in dendrites are not fully understood. Here the authors developed techniques to map bioelectrical excitations in the dendrites of neurons in acute slices of mouse brain tissue. They developed a holistic picture of the roles of dendritic excitations in spike back-propagation.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

How DNA Polymerase Epsilon accomplishes continuous leading strand synthesis during DNA replication is not understood. Here, the authors describe a two tiers mechanism required to sustain Pol Epsilon processivity: CHTF18-dependent loading of PCNA at leading strand and dsDNA binding by its POLE3-POLE4 subunits.

Here the authors show that gut metagenomes of Indigenous Australian infants living remotely, display greater diversity and abundance of bacteria, viruses and fungi, compared to non-Indigenous infants living in urban Australia, suggesting that while having access to Western foods, the infants start life with a gut microbiome that retains key features of pre-industrialized societies.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

An inherently explainable AI trained on 1,015 expert-annotated prostate tissue images achieved strong Gleason pattern segmentation while providing interpretable outputs and addressing interobserver variability in pathology.

Observations from the JWST MIRI/LRS show the detection of SO₂ spectral features in the 5–12-μm transmission spectrum of the hot, Saturn-mass exoplanet WASP-39b, suggesting that photochemistry is a key process in high-temperature exoplanet atmospheres.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

The authors leveraged a large multimodal sample and combined normative modeling and linked independent component analysis to study a cross-modal signature of face processing within the fusiform gyrus in autism.

Temporal variability of structural-functional coupling (SFC) remains poorly understood. Here, authors show such variability is underpinned by specific transcriptomic and chemoarchitectural signatures, thereby supporting neurocognitive specialization.

Repetitive head impacts from contact sports are associated with brain inflammation, vascular damage and neuron loss that are independent of hyperphosphorylated tau pathology.

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.

Xu et al. show that satellite-measured urbanicity (living in a densely populated area) is correlated with brain volume, cortical surface area and brain network connectivity in a sample of 3,867 people from China and Europe.

This pilot trial showed that perioperative treatment with the isocitrate dehydrogenase (IDH) inhibitor safusidenib of patients with low-grade IDH-mutant glioma, with craniotomy and lumbar puncture before and after treatment, is feasible and safe and enabled in-depth translational investigation of safusidenib treatment-induced changes in the tumor, including electrophysiological effects.

Comprehensive large-scale studies of multi-national populations identified microbiome species consistently associated with favourable and unfavourable health markers, informing future studies of the human gut microbiome and its association with diet and cardiometabolic conditions.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

The transmission spectrum of the exoplanet WASP-39b is obtained using observations from the Single-Object Slitless Spectroscopy mode of the Near Infrared Imager and Slitless Spectrograph instrument aboard the JWST.

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.

PU.1^low CD28-expressing microglia may act as suppressive cells in Alzheimer’s disease, mitigating its progression by reducing neuroinflammation and amyloid plaque load, indicating potential immunotherapeutic approaches for treatment.

GIANT, a genetically informed brain atlas, integrates genetic heritability with neuroanatomy. It shows strong neuroanatomical validity and surpasses traditional atlases in discovery power for brain imaging genomics.

An analysis of rare genetic variants identifies three genes—MAP1A, ANO8 and ANK2—that have a role in attention deficit hyperactivity disorder (ADHD) and investigates the potential underlying biological mechanisms.

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

Using functional MRI, the authors tracked memory recovery over a decade after epilepsy surgery, revealing key brain changes in spared medial temporal structures and contralateral regions, highlighting neural mechanisms behind sustained improvement.

ALI is an approach for analyzing voltage imaging data that is inspired by algorithms used in super-resolution microscopy. It allows resolving the activity of single neurons in densely labeled populations in scattering conditions.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Yuan and colleagues developed an artificial intelligence-based method to derive growth patterns and morphological features from hematoxylin and eosin-stained slides of lung adenocarcinoma samples, for improved tumor grading and patient prognostication.

Comparing white matter disconnectivity across 12 psychiatric and neurological disorders, this study finds that the connections most important for global communication and network integration are particularly vulnerable to alterations across multiple brain disorders.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.