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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.

A prospective nationwide genomic screening pilot for ten genes in young adults in Australia detected pathogenic variants in 2% of the population, most of whom were ineligible for government-funded genomic testing.

Nanofibrils constructed from oat protein and carrying iron nanoparticles can increase absorption compared with ferrous sulfate in human studies, offering a promising fortification strategy for treating iron deficiency and improving human nutrition.

In this phase 2 ZUMA-14 clinical trial, Strati et al. reported the safety and efficacy of axicabtagene ciloleucel plus rituximab in adult participants with chemorefractory large B cell lymphomas and compared the results with previous findings from ZUMA-1 cohort 1.

Differentiating DCs express ALDH1A2, which produces retinoic acid and suppresses DC activity. Blocking this pathway with a new inhibitor, KyA33, enhances immune responses and boosts the effectiveness of DC cancer vaccines in mouse models.

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.

Here they show that the E3 ubiquitin ligase CTLH supports mTORC1. Upon CTLH inactivation, ZMYND19 and MKLN19 accumulate, associate, and block mTORC1/RHEB association. CTLH and PI3K inhibition are synthetic lethal for EBV-associated gastric cancer.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate. Through integrated laboratory and clinical studies, the authors identify significant ERBB2 (the gene that encodes the HER2 protein) mutational heterogeneity in patients with urothelial cancer and co-mutation and amplification of ERBB2 as a potential biomarker of exceptional response to T-DXd.

Aircraft measurements over the Amazon show that new particle formation in the upper troposphere emerges when isoprene, emitted by forests, undergoes oxidation in the presence of nitrogen oxides produced by lightning.

The transcription factors TCF1 and LEF1 promote self-renewal and regulatory functions in B-1a cells.

Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.

Early high-resolution images of two 2021 novae reveal eruptions unfolding in multiple stages with colliding outflows that produce shocks and gamma rays, reshaping our understanding of stellar explosions.

Genomic and phenomic screens of 827 wheat landraces from the A. E. Watkins collection provide insight into the wheat population genetic background, unlocking many agronomic traits and revealing haplotypes that could potentially be used to improve modern wheat cultivars.

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.

Understanding the ground state (GS) phase transitions in the quantum tunneling regime of a superconducting system is important for future qubit devices. Here, Shen, Heedt and Borsoi et al. report distinct types of fermion parity GS transitions as a function of magnetic field and gate voltages in a Coulomb-blockaded InSb–Al island.

Scientists disagree about area-based conservation’s role in addressing biodiversity loss. This Perspective examines how conservation scientists, land systems scientists and political ecologists approach these debates differently and argues that environmental data justice frameworks can bridge epistemic divides, helping researchers to develop more effective and equitable conservation interventions.

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.

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.

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.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

The authors study the field-induced ferromagnetic state of MnBi_2-xSb_xTe₄ by quantum oscillations and high-field Hall effect measurements. They confirm a single pair of type-II Weyl nodes, the long-sought “ideal” Weyl semimetal.

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.

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 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.

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.

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.

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.

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.

Combinatorial CRISPR screens are improved by using Cas9 enzymes from two different organisms.

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).

Shen et al. identify a noncanonical role for the inflammasome protein NLR family CARD domain-containing protein 4 (NLRC4) to attenuate tumor development. NLRC4 forms a scaffold to assemble the ataxia telangiectasia and Rad3-related DNA repair complex and the repair kinase checkpoint kinase-1 to promote repair of DNA breaks.

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.

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.

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.

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.

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.

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.

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.