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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.

This multicenter study demonstrates use of dried and capillary blood as a minimally invasive, scalable approach for Alzheimer’s biomarker testing in research, with potential as a widely scalable population-based research approach, especially in resource-limited settings.

Lianas are an important component of tropical forests. Here the authors compare liana and tree functional trait distributions from across the tropics and use a liana-tree competition model to show that a key hydraulic trait influences liana viability and its response to future climate conditions.

Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.

Krisai et al. compare brain structure and cognitive function in elderly patients with and without atrial fibrillation using brain MRI and cognitive testing. They find that atrial fibrillation is associated with more brain lesions and lower cognitive function, but the cognitive impairment occurs primarily through direct effects of the arrhythmia rather than through brain damage.

Extensive oxidative potential measurements from across Europe analysed with the two most common assays, dithiothreitol and ascorbic acid, using a standardized protocol show the strong influence of site type and suggest pathways for mitigation strategies.

By mapping oxidatively damaged bases and abasic sites at single-nucleotide resolution in human cells, Takhaveev et al. observed transcription-related strand biases, patterns mirroring cancer mutational signatures, and captured the action of the anticancer drug irofulven.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

A benchmarking competition improves tools that predict how regulatory regions control gene expression.

Experimental systems in which non-trivial topology is driven by spontaneous symmetry breaking are rare. Now, topological gaps resulting from two excitonic condensates have been demonstrated in a three-dimensional material.

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.

Here the authors provide a deep tissue analysis of patients with autoimmune kidney diseases, identifying a conserved spatiotemporal immune program for the development of glomerular crescents and sclerosis.

The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.

Liver X receptor drives epithelial Areg-mediated intestinal regeneration, while preventing tumour growth through adaptive immune responses.

Circadian disruption can promote tumour formation. Now it is shown that the loss of circadian synchronization can drive this effect by disrupting the coupling between the circadian rhythm and the cell cycle within individual cells.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

Here the authors show that relaxation dynamics in hybrid perovskites is a phonon-assisted process and does not scale with unit-cell volume nor hydrogen bond length. They reveal two different contributions to relaxation dynamics: thermal and volumetric.

Head and neck squamous cell carcinoma can occur with and without the presence of HPV infection. Here, the authors utilise Mendelian randomization to assess the causal effects of smoking and alcohol on HPV-positive and HPV-negative head and neck cancer development.

Glomerulonephritis is a frequent complication of autoimmune diseases, and involves aberrant activation of immune cells, but the underlying insights remain unclear. Here the authors use both patient data and a mouse glomerulonephritis model to show that increased type I interferon may expand a subset of pro-inflammatory T cells for subsequent kidney pathology.

The development of high-capacity and high-voltage electrode materials can boost the performance of sodium-based batteries. Here, the authors report the synthesis of a polyanion positive electrode active material that enables high-capacity and high-voltage sodium battery performance.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Activated T cells undergo metabolic reprogramming to optimize effector functions, but the underlying mechanisms remain elusive. Here the authors show, using knockout and tumor mouse models, that deficiency of the mitochondrial protein Ant2 in T cells bypasses typical metabolic reprogramming, induces an activated-like metabolic state, and enhances T cell antitumor immunity.

The effects of climate on vector-borne disease systems are highly context-dependent. Here, the authors incorporate laboratory-measured physiological traits of the mosquito Aedes aegypti into climate-driven mechanistic models to predict number, timing, and duration of outbreaks in Ecuador and Kenya.

Recent phone survey data from Ethiopia, Malawi, Nigeria and Uganda reveals the breadth of the socioeconomic impacts of the COVID-19 pandemic on individuals and households.

This study finds that decision markets can be a useful tool for selecting studies for replication. For a sample of 26 online experiments published in PNAS selected by a decision market, the authors find replication rates ranging between 54% and 62%.

Camerer et al. carried out replications of 21 Science and Nature social science experiments, successfully replicating 13 out of 21 (62%). Effect sizes of replications were about half of the size of the originals.

In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.