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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 study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

Regional, place-based biodiversity information is used to comprehensively map and quantify biodiversity intactness of sub-Saharan Africa to inform national and global sustainability policies and planning.

Transition states are central to chemical reactions. Here, the authors derive the analytical Hessians from a neural network potential for organic reactions and yield more efficient and robust saddle point optimization than using quasi-Newton updates.

Hydrogen exchange–mass spectrometry (HX–MS) is used to qualitatively assess how perturbations such as mutations and ligand binding impact protein ensembles. However, in theory, HX–MS data contain the information necessary to derive residue-level energies of local unfolding (ΔG_op). Now, a method called PIGEON-FEATHER has been developed, which can unambiguously determine residue-level ΔG_op from conventional HX–MS datasets.

Parallel operation of two exchange-only qubits consisting of six quantum dots arranged linearly is shown to be achievable and maintains qubit control quality compared with sequential operation, with potential for use in scaled quantum computing.

Integral equations are used in science and engineering to model complex systems with non-local dependencies; however, existing traditional and machine-learning-based methods cannot yield accurate or efficient solutions in several complex cases. Zappala and colleagues introduce a neural-network-based method that can learn an integral operator and its dynamics from data, demonstrating higher accuracy or scalability compared with several state-of-the-art methods.

Being able to perform qubit measurements within a quantum circuit and adapt to their outcome broadens the power of quantum computers. These mid-circuit measurements have now been used to implement a cryptographic proof of non-classical behaviour.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

A study describes a direct computational approach without experimental optimization to design high-affinity proteins that bind small helical peptides.

Immune receptors regulate immune responses and are key cancer immunotherapy targets. Here, the authors designed helical concave scaffolds to bind convex sites in immune receptors, creating high-affinity protein binders for TGFβRII, CTLA-4, and PD-L1. Co-crystal structures confirmed their therapeutic potential.

Head and neck squamous cell carcinoma (HNSCC) frequency and risk factors vary considerably across regions and ancestries. Here, the authors conduct a multi-ancestry genome-wide association study and fine mapping study of HNSCC subsites in cohorts from multiple continents, finding susceptibility and protective loci, gene-environment interactions, and gene variants related to immune response.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

This study used fine-mapping to analyze genetic regions associated with bipolar disorder, identifying specific risk genes and providing new insights into the biology of the condition that may guide future research and treatment approaches.

Using whole-genome data for single-nucleotide polymorphism and results from genome-wide association studies, the authors show that people’s preference for pairing with those with similar phenotypic traits has genetic causes and consequences.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

Genome-wide analyses yield insights into the polygenic effects contributing to clinical heterogeneity in attention deficit hyperactivity disorder, advancing understanding of its genetic etiology and serving as a model for future studies in other complex disorders.

Deconvolution methods infer levels of immune infiltration from bulk expression of tumour samples. Here, authors assess 6 published and 22 community-contributed methods via a DREAM Challenge using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells.

Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.

Folkersen et al. report the first results from the SCALLOP consortium, a collaborative framework for pQTL mapping and biomarker analysis of proteins on the Olink platform. A total of 315 primary and 136 secondary pQTLs for 85 circulating cardiovascular proteins from over 30,000 individuals were identified and replicated to yield new insights for translational studies and drug development.

Laboratory simulation experiments with isomer selective photoionization detection techniques reveal that octasulfur (S₈) and sulfanes can be easily formed in low temperature H₂S interstellar ice analogues exposed to ionizing radiation, suggesting a critical link between sulfur chemistry on ice coated nanoparticles in molecular clouds and the inventory of sulfur compounds in our Solar System.

Spatially resolved JWST spectroscopy of a massive, quiescent galaxy at a redshift of ~4 reveals that it formed its stars and quenched rapidly, despite being surrounded by an abundant gas reservoir and gravitationally bound to a star-bursting companion.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

We investigate the de novo design of allostery and suggest that it can arise from global coupling of the energetics of protein substructures without optimized allosteric communication pathways, providing a roadmap for the design of switchable molecular systems.

Confining plasma and managing disruptions in tokamak devices is a challenge. Here the authors demonstrate a method predicting and possibly preventing disruptions and macroscopic instabilities in tokamak plasma using data from JET.

Endometriosis is a major cause of infertility. Molecular mechanisms underlying the disease involve genetic and environmental risk factors. In a meta-analysis of eleven GWA studies, Sapkota and colleagues identify five novel risk loci, implicating steroid sex hormone pathways in the pathogenesis.

A clinical study of women with abnormal breast mammograms establishes a workflow to evaluate the capability of breast photoacoustic computed tomography in the classification, monitoring and segmentation of lesions.

The collapse of tropical forests during the Permian–Triassic Mass Extinction weakened carbon sequestration, sustaining high CO2 and extreme global warmth for millions of years: an example of a runaway feedback in Earth’s climate-carbon system.

Space interferometry reveals the hidden and filamentary internal structure of the relativistic jet in 3C 279 at microarcsecond angular resolution. These details challenge previous assumptions on the morphology and radio variability of blazars.

A cross-ancestry genome-wide association meta-analysis of lung cancer including 61,047 cases and 947,237 controls identifies five new cross-ancestry susceptibility loci and highlights ancestry-specific effects of common and rare variants on lung cancer risk.

Statistical fine-mapping helps to pinpoint likely causal variants underlying genetic association signals, and can be enhanced by using multi-ancestry datasets. Here, the authors introduce MGflashfm, a fine-mapping method for pinpointing likely causal variants amongst multiple traits and population groups.

As part of our special issue focused on glia, Nature Neuroscience is having conversations with both established leaders in the field and those earlier in their careers to discuss how the field has evolved and where it is heading. Here, we speak with Sonia Mayoral, the Robert J. and Nancy D. Carney Assistant Professor of Neuroscience at Brown University in Providence, RI, USA. We spoke about her work on oligodendrocytes and their interactions with neurons, the importance of exploring glia in brain health and function, and her own academic journey and advice for early-career researchers.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

This mega-analysis of brain resting-state functional connectivity in young individuals with major depressive disorder scanned at six sites across four countries identified hub regions of the attentional and default mode networks as predictors of depression severity.

Schork et al. identify novel variants contributing to shared risk among psychiatric disorders and suggest that these variants act through the disruption of early neurodevelopment.

The quantum critical behaviour of a two-impurity Kondo model variant is observed in a system of hybrid-semiconductor islands that could provide a scalable platform for solid-state quantum simulation