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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.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Recurrence of meningiomas is unpredictable by current methods based on surgically removed specimens, and identification of patients likely to recur could inform treatment strategy. Here, the authors analysed DNA methylation in liquid biopsy specimens from meningioma patients to help classify recurrence risk noninvasively even before surgery.

Novae, a self-supervised graph attention network, is a foundation model excelling at a diverse spectrum of spatial transcriptomics modeling and analysis tasks.

Toxic chemicals can transform in the environment, often forming more harmful products. This study provides evidence for the aqueous formation of organophosphate esters (OPEs) in aerosols, highlighting their fate and implications for risk assessment.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

OrganEx—an extracorporeal pulsatile-perfusion system with cytoprotective perfusate for porcine whole-body settings—preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs after 1 h of warm ischaemia in pigs.

Though it is the most common joint disease, osteoarthritis has no molecular biomarkers or disease-modifying therapies. Here, the authors show miR-126-3p is a mechanistic biomarker that regulates angiogenesis and mitigates knee osteoarthritis severity.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

SCEP3 is a new synaptonemal complex protein that prevents clustering of crossovers during meiosis in Arabidopsis, so that every pair of homologous chromosomes receives at least one ‘obligate’ crossover.

The association between insulin-dependent diabetes mellitus and HLA is fearsomely complicated. But powerful techniques are being brought to bear on the problem.

Work published over the past month provides insight into the mechanism of genomic imprinting in mice and the possible phenotypic consequences of imprinting in humans.

King Richard III was a controversial English King whose remains are presumably deposited in Grey Friars in Leicester. Here the authors sequence the mitochondrial genome and Y-chromosome DNA of the skeletal remains and living relatives of Richard III and confirm that the remains belong to King Richard III.

Ionic liquid additives increase the power conversion efficiency of perovskite solar cells, but their effect on perovskite crystallization remains unclear. Xu et al. provide mechanistic insights and demonstrate improved operational stability under continous illumination and 90 °C thermal stress.

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.

The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure

The combination of modular tangible interfaces and constrained optimization control enables users to operate shape-changing robots by matching their morphology and ensuring safety, allowing adaptation to different environments and application areas.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Using SCN2A haploinsufficiency as a proof-of-concept, upregulation of the existing functional gene copy through CRISPR activation was able to rescue neurological-associated phenotypes in Scn2a haploinsufficient mice and human neurons.

Machine learning techniques are widely employed in chemical science, but are application specific and their development requires dedicated expertise. Jablonka and colleagues fine-tune the GPT-3 model and show that it can provide surprisingly accurate answers to a wide range of chemical questions.

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

A framework that integrates materials, process design, techno-economics and life-cycle assessment can be used to accelerate the development of carbon-capture technology as we aim for a net-zero world.

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).

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.

Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

UBA1-mutant macrophages exposed to inflammatory stimuli undergo aberrant apoptotic and necroptotic cell death mediated by CASP8 and RIPK3–MLKL, offering insights into the mechanisms underlying VEXAS syndrome.

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.

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.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

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.

At present there are databases with over 500,000 predicted or synthesized MOF structures, yet a method to establish whether a new material adds new information does not exist. Here the authors propose a machine-learning based approach to quantify the structural and chemical diversity in common MOF databases.

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.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCRS regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCRS alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-Δ32 and CCR2-64I polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-64I allele were found in African Americans but not in Caucasians, and the SDF1-3′A/3′A genotype was associated with an accelerated progression to death. In contrast, the CCR5-Δ32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Strong electron–electron interactions in magic-angle twisted bilayer graphene can fundamentally change the topology of the system’s flat bands, producing a hierarchy of strongly correlated topological insulators in modest magnetic fields.

Functional CRISPR screens in patient-matched pre-treatment and post-treatment glioblastoma models identify the PTP4A–ROBO1 axis as a driver of tumorigenicity and enriched ROBO1 expression in recurrent glioblastoma that can be targeted with CAR T cell therapy.