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Using nasal brush biopsies from the olfactory region, single-cell profiling revealed neuroimmune alterations in Alzheimer’s Disease detectable at a pre-clinical stage, offering an accessible window into early neurodegenerative disease in humans.

Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

MitoCatch is a cell-type-specific mitochondrion-targeting system that links mitochondria and the cell surface by protein binders and delivers mitochondria into the target cell.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

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.

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.

Exposome analyses across 34 countries showed that social exposures were associated with faster functional brain aging and physical exposures with faster structural brain aging.

Microscopic vascular invasion is an indicator of tumour recurrence in lung adenocarcinoma but is challenging to diagnose. Here, the authors use spatial transcriptomics and bulk RNA-seq to identify gene expression changes associated with vascular invasion that are detectable beyond the invasion site.

Here, the authors find that time-varying brain network analysis better captures cognitive processing than static methods and reveals network measurement linked to task performance and psychopathology that offer precise neural markers for mental health risks.

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.

TDP-43 pathology is a key event in ALS/FTD and selectively affects specific neurons in the motor cortex. Here, the authors report which neuron types are affected and demonstrate that transcriptomic changes are cell-type specific.

In this study, the authors analyze data from 143 studies involving 2,743 patients to compare the efficacy of neuromodulatory invasive and non-invasive interventions in the treatment of obsessive–compulsive disorder.

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.

Improved red and green indicators for norepinephrine and their characterization are reported. These indicators allow detection of norepinephrine release in awake behaving mice in dual-color fiber photometry and two-photon imaging applications.

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.

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

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.

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.

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.

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.

How white matter develops along the length of major tracts in humans remains unknown. Here, the authors identify fundamental patterns of human white matter development along distinct axes that reflect brain organization.

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.

The authors show that plasma AT(N) biomarkers can distinguish Alzheimer’s disease and frontotemporal lobar degeneration in diverse Latin American populations. Using machine learning and integrating neuroimaging, significant diagnostic accuracy was achieved, enhancing clinical assessments of these conditions in Latin America.

Bång-Rudenstam et al. report that the acidic tumour microenvironment facilitates the assembly of chondroitin sulfate-enriched glycocalyx to disrupt lipid scavenging and prevent ferroptosis, thereby providing an adaptive mechanism upon tumour acidosis.

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.

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.

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.

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.

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.

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.

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.

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.

Although antiretroviral therapies (ART) have expanded the life expectancy of patients with HIV, they are not curative due to the presence of latently infected cells. Here, the authors present IMC-M113V, a bispecific soluble TCR targeting the HIV peptide Gag_77-85 complexed to HLA-A*02:01 as an approach for targeting HIV reservoirs and test safety, tolerability and pharmacodynamics in a first-in-human clinical trial on 12 HLA-A*02:01-positive male individuals on ART.

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.

An online experiment compared 12 brief online interventions for depression. Most improved mental health immediately, but these gains decreased over time, with only two interventions significantly reducing depression 4 weeks later.

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.

HECT-type ubiquitin ligases control many cellular processes but remain poorly characterised in their full-length form. Here, the authors present a biochemical analysis and cryo-EM structures of the cancer-associated ligase HECTD3 revealing an interesting domain architecture and mechanistic insights.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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