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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.

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.

Fast panoramic rotational ultrasound tomography and photoacoustic tomography are integrated for hybrid rotational ultrasound and photoacoustic tomography, for three-dimensional dual-contrast imaging of soft tissue and vasculature across the human body.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

MedHELM, an extensible evaluation framework including a new taxonomy for classifying medical tasks and a benchmark of many datasets across these categories, enables the evaluation of large language models on real-world clinical tasks.

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.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

A previously unknown mechanism contributes to dysfunction of the neurogenic niche during CNS autoimmunity. Natural killer cells are retained specifically in the subventricular zone in chronic disease, killing stem cells and promoting pathology.

Human and rodent supragranular pyramidal neurons differ in HCN channel-related properties. Comparison across primates reveals robust HCN1 expression and HCN channel-dependent physiology, with cell type dependent differences in macaques versus humans.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

Here the authors develop a blood-based proteomic Smoking Index (pSIN) that accurately detects smoking exposure and predicts the risk of mortality and 18 major diseases, offering a molecular measure of smoking-related biological damage and recovery.

Intramolecular coupling of extended biphen[n]arenes is developed to yield cycloparaphenylenes (CPPs). The modular nature of biphen[n]arenes makes it possible to customize CPP structures, which permits tuning of their photophysical properties. The syntheses are short and excellent yields are achieved. Moreover, postsynthetic functionalization is possible.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

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.

Genome assemblies of 100 cultivated and seven semi-wild Gossypium hirsutum accessions provide insights into the evolutionary history of upland cotton and the genetic basis of fiber trait variation.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Electron distributions exhibit velocity-space signatures indicative of the rapid energy released by magnetic reconnection explosions occurring in Earth’s magnetosphere and in plasmas throughout the universe. Here, the authors discover a smile-shaped signature in the electron gradient distribution associated with reconnection occurring at Earth’s dayside magnetopause boundary.

A growing number of compounds are reported to extend lifespan, but it remains unclear whether they reduce mortality across the entire life course or only at specific ages. Here the authors introduce an analytic tool that pinpoints when, for how long, and to what extent presumptive anti-aging treatments alter mortality risk.

In this study, the authors present an fMRI‑based signature of corticospinal connections, which predicts individual pain sensitivity, generalizes to patient cohorts, and tracks changes after brain stimulation, suggesting a biomarker to guide personalized pain care.

Respiration enhances cerebrospinal fluid flow through mechanical and autonomic pathways. Inhale length and diaphragm motion influence its displacement and net flow, identifying a modifiable, noninvasive mechanism relevant to brain homeostasis.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Drug combination discovery remains slow and challenging. Here, the authors introduce Combocat, an open-source framework that combines acoustic liquid handling protocols with machine learning to achieve ultrahigh-throughput drug combination screening; as proof of concept, they use Combocat to screen 9,045 drug combinations in a neuroblastoma cell line.

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.

iGluSnFR4f and iGluSnFR4s are the latest generation of genetically encoded glutamate sensors. They are advantageous for detecting rapid dynamics and large population activity, respectively, as demonstrated in a variety of applications in the mouse brain.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Electrochromic materials are widely explored in energy-saving smart windows, yet combining fast switching, neutral black coloration, and robust long-term durability remains challenging. Here the authors report a solution processed n-doped poly(benzodifurandione) affording an electrochromic black window that overcomes these limitations.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

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.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Antimicrobial resistance poses a significant global health threat, necessitating swift and precise diagnostic solutions. Here, the authors introduce a culture-free diagnostic platform integrating microfluidic cell enrichment, single-cell Raman spectroscopy, and deep learning, that identifies bacterial and fungal infections directly from clinical samples within 20 minutes.

Therapeutic gene editing in vivo is an ongoing challenge. Here, authors demonstrate Cas9 nickase guided DNA ligation as a nonviral method for installing permanent genomic corrections with favorable on target edit profiles in model animal cell types and adult mice.

A comparison of alpha diversity (number of plant species) and dark diversity (species that are currently absent from a site despite being ecologically suitable) demonstrates the negative effects of regional-scale anthropogenic activity on plant diversity.

DNA data storage is an alternative to silicon-based data storage, but it demands advanced encryption and readout techniques. Here, the authors present an enhanced DNA origami cryptography protocol for data storage, using DNA-PAINT super-resolution imaging and unsupervised clustering to retrieve information in DNA cryptography.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.