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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.

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.

This study uses single-nucleus RNA sequencing to analyze lung tissue from 141 individuals with chronic obstructive pulmonary disease. Distinct patterns of spatially resolved changes in cell composition and cell states that correlate with clinical features are highlighted.

Ramaglia and colleagues show that aberrant formation of B cell-rich lymphoid structures in the brain meninges is associated with high CXCL13:BAFF ratios. Inhibiting the kinase BTK reduces the lymphotoxin signaling needed to sustain such structures, lowers CXCL13:BAFF ratios and reduces cortical tissue injury.

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.

MYC-driven medulloblastoma is an aggressive pediatric tumor with limited treatment options. Here, the authors show that CDK8 regulates ribosome biogenesis and that combined inhibition of CDK8 and mTOR demonstrates therapeutic efficacy in mouse models of this cancer.

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.

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.

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.

MYC-driven medulloblastoma is highly aggressive and associated with poor survival. Here, the authors perform single nuclei multi-omic analysis of matched primary and recurrent tumours and identify potential resistance mechanisms and targetable pathways.

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

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.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

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.

The study reports a metal-organic framework (MOF) - covalent organic framework (COF) nanocomposite with dual amine sites that captures CO₂ efficiently and remains stable under humid, harsh conditions, offering a promising path for next-generation carbon capture.

Living plant collections hold an immense wealth of plant diversity and have critical educational, scientific and conservation roles. This Perspective examines current data management practices of living collections and advocates for higher data standards and a robust and inclusive global data ecosystem.

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.

Nguyen et al. show that the splenic environment provides sequential signals via lymphotoxin and retinoic acid that guide cDC2A development and retention.

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.

The genetic basis of sex differences in Alzheimer’s disease (AD) is not well characterized. Here, authors report 2,320 sex-specific gene associations with 3 AD endophenotypes using bulk RNAseq data from 3 brain regions in ROS/MAP.

The thyroid plays an important role in pregnancy and body temperature maintenance, and both ambient temperature and thyrotropin levels have been reported to associate with risk of preterm birth. Here the authors report that in a nationwide cohort from China biothermal stress during each trimester was associated with increased risks of preterm birth, with synergistic interactions with preconceptional thyrotropin abnormalities.

A combination of mouse model data and data from a randomized phase 2 trial in patients with breast cancer in remission demonstrates feasibility, safety and a reduction in residual tumor cells following treatment with hydroxychloroquine and/or everolimus.

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

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

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.

Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.