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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.

Bicycling offers great benefits for urban residents in low- and middle-income countries, yet pathways to scale its adoption remain poorly understood. This study reveals the current state of bicycling infrastructure and policy, as well as key barriers, through fieldwork in four cities.

European Space Agency’s Solar Orbiter will contribute to a ‘golden age’ of solar science.

Reanalysis of radiometric data from Cassini indicates that Titan does not contain a subsurface ocean, as strong tidal dissipation observed in its gravity field is not consistent with the presence of a liquid layer.

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.

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.

Light represses biofilm formation and production of virulence factors in the pathogenic bacterium Pseudomonas aeruginosa. Here, Manias et al. identify a periplasmic microprotein that regulates this process by activating the degradation of a component of the light-sensing pathway.

The study by Russo et al. demonstrates alterations in the presence of senescence hallmarks across cell types, inducers, and model systems. These findings spotlight TFAP4 as a key regulator of senescence phenotypes in aging and Parkinson’s Disease.

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.

Repetitive head impacts from contact sports are associated with brain inflammation, vascular damage and neuron loss that are independent of hyperphosphorylated tau pathology.

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.

MatterGen is a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints.

Electrochemical energy can be produced by using solar energy to oxidize water, providing an abundant source of electrons, which are needed in fuel synthesis. The operation of an efficient and stable semiconductor nanocomposite anode, made of a protective TiO₂ layer that protects a silicon substrate during photoelectrochemical water oxidation in both dark and light conditions, is now reported.

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.

Numerical simulations reveal that the transfer of ions from Earth’s atmosphere to the Moon is efficient only in the sustained presence of a geomagnetic field, suggesting that lunar soils may record the histories of the atmosphere, solar wind, and geodynamo.

Analysis of the longest-lived mammal, the bowhead whale, reveals an improved ability to repair DNA breaks, mediated by high levels of cold-inducible RNA-binding protein.   

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.

The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.

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.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

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.

Cell death contributes to tissue homeostasis and plays critical roles in inflammation and host defense. Our increasing understanding of the physiological importance of cell death underlines the need to more fully elucidate its underlying mechanisms in health and disease. Molecular and structural insight into the cell death apparatus could provide strategies to target the loss of cells in pathophysiological contexts. We asked experts studying a range of cell death types to share with us what they are most excited to tackle and what the field needs for progress.

The Habitable Worlds Observatory will look for inhabited worlds beyond our Solar System in the 2040s and scientists are dreaming of what else it might do.

Druckman et al. document gaps in trust in scientists in the USA. People from groups less represented among scientists (for example, women and those with lower economic status) are less trusting. Increasing the representation of these groups within science increases trust.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

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.

Effective transport layers are essential to suppress non-radiative recombination losses. Here, the authors introduce phenylamino-functionalized ortho-carborane as an interfacial layer, and realise inverted perovskite solar cells with efficiency of over 23% and operational stability of T97 = 400 h.

Xu, Meng, St-Germain et al. report that S1P in HDL induces a calcium signalling cascade involving E-Syt1 that ultimately promotes the formation of contact sites between the endoplasmic reticulum and the plasma membrane, as well as HDL-derived cholesterol transport.

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.

Robots benefit from touch perception, but sensing multi-directional forces is challenging. Here, the authors introduce a theory using taxel value isolines for superresolution sensing, improving sensor design and performance under shear forces.

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).

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.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

The Antarctic Circumpolar Current (ACC) since the Last Interglacial is reconstructed, showing orbital-scale shifts in ACC position driven by eccentricity and precession, possibly counteracting the predicted southward shift due to global warming.

Silane, which is a precursor to the sandy surfaces of rocky planets and dusty clouds on gas giants, is seen directly in another world—a low-metallicity brown dwarf in which oxidation is slow and gas mixing is fast.

Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.

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.

New field measurements and modeling show meltwater refreezing in Greenland’s bare ice may reduce runoff to surrounding oceans, highlighting a process climate models can incorporate for improved predictions of future sea-level rise.

Solar photovoltaics is entering a multi-terawatt era, driven by decades of cost, performance and reliability gains. In this Perspective Alberi et al. discuss the role of historical and future learning, highlighting the increasing importance of sustainability considerations.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

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.