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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.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

High-pressure minerals in meteorites reflect the conditions prevailing when they were excavated and launched from their parent bodies. Tissint—a recent Martian meteorite—contains an unusual number of large high-pressure minerals, suggesting excavation from an impact of larger magnitude than for previous Martian samples.

A circular economy for plastics offers a promising solution to the pollution crisis. Here the authors take advantage of the unique chemistry of polydiketoenamine resins, showing how plastics can be biorenewable and recyclable by incorporating biosourced triacetic acid lactone.

Integrative analysis of single-cell RNA-sequencing datasets across mouse gastrulation and organogenesis identifies cell states and trajectories at successive developmental stages, along with transcription factors that could potentially mediate lineage choices.

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.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Femtosecond X-ray pulses were used to obtain diffraction data on photosystem II, revealing conformational changes as the complex transitions from the dark S₁ state to the double-pumped S₃ state; the time-resolved serial femtosecond crystallography technique enables structural determination of protein conformations that are highly prone to traditional radiation damage.

Scalable CRISPRa screening of cis-regulatory elements in non-cancer cell lines has proved challenging. Here, the authors describe a scalable, CRISPR activation screening framework to identify regulatory element-gene pairs in diverse cell types including cancer cells and neurons.

The authors describe a mechanism for the clearance of macromolecules from cerebrospinal fluid in which macromolecules traverse from periarterial to perivenous spaces, at sites where intersecting leptomeningeal perivascular (arteriovenous) spaces overlap.

Chiou et al. provide a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques.

The fate of subducted CO₂ remains debated, with estimates mainly from numerical predictions varying from wholesale decarbonation of the shallow subducting slab to massive deep subduction of CO₂. Here, the authors present field-based data and show that ~40% to ~65% of the CO₂ in subducting crust is released via metamorphic decarbonation reactions at forearc depths.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

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.

Orbital angular momentum transfer from optical vortex beams to electronic quantum Hall states is reported in a graphene sheet, showing a robust contribution to the radial photocurrent that depends on the vorticity of light.

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.

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.

Single-cell profiling studies of the human gastrointestinal tract are increasing, offering an excellent opportunity to generate the first Human Gut Cell Atlas. This Roadmap presents a structured direction towards this goal and provides a detailed overview of the major challenges.

FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Central nervous system (CNS)-derived regulatory self-peptides are essential for maintaining a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity.

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.

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.

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.

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.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

Low-carbon chemicals generated from CO₂ provide a possible path to improve the sustainability of microbial bioproduction of food and chemicals. Now, using a metabolic engineering approach, yeast is engineered to produce glucose, myo-inositol, glucosamine, sucrose and starch from C_1–3 molecules.

Primary cilia are highly conserved microtubule-based organelles that play essential roles in several cellular processes including osteogenesis. Here the authors show that intraflagellar protein IFT80 regulates osteoblast differentiation by balancing signalling though the canonical and non-canonical Hedgehog pathways.

The balance between carbonate subduction into the deep Earth and CO₂ release through degassing at volcanoes is critical for the carbon cycle. Geochemical analyses of an exhumed subduction zone complex in Greece show that fluid-mediated reactions could liberate significant amounts of carbon from the subducting slab for later release at arc volcanoes.

The authors investigate the local/regional nature and associated oxidative potential of PM2.5 emission sources in northern India and show that reducing local inefficient combustion emissions can effectively mitigate PM health effects.

Single-cell transcriptome profiling of mouse embryos and newborn pups is combined with previously published data to construct a tree of cell-type relationships tracing development from zygote to birth.

Data from single-cell combinatorial-indexing RNA-sequencing analysis of 2 million cells from mouse embryos between embryonic days 9.5 and 13.5 are compiled in a cell atlas of mouse organogenesis, which provides a global view of developmental processes occurring during this critical period.