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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.

Optical control of integer and fractional Chern insulators is demonstrated by circularly polarized optical pumping in tMoTe₂.

Lucerastat was well-tolerated, but did not reduce neuropathic pain, abdominal pain, or diarrhea compared with placebo. Lucerastat reduced biomarkers of Fabry Disease at 6 months, and these reductions were maintained at the 18-month interim analysis.

Twisted bilayer (tb) MoTe₂ is an ideal platform for investigating the fractional quantum anomalous Hall effect but issues related to air sensitivity make the study of its electronic structure experimentally challenging. As a solution, the authors prepare hBN encapsulated tb-MoTe₂ and using micro-angle resolved photoemission spectroscopy determine the band structure. Furthermore, through in-situ alkali metal deposition, they obtain evidence indicating a direct band gap.

This study shows that the 2025 Mw 7.7 Myanmar earthquake ruptured 500 km of the Sagaing Fault with nearly no shallow slip deficit, revealing that mature, linear strike-slip faults can release strain efficiently, unlike less mature faults.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

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.

Here the authors define an inter-protomeric mechanism of deglycosylation of human IgG antibodies for corynebacterial IgG-specific ENGases and demonstrate that in vivo CU43 treatment preserve the neutralizing capacity of anti-influenza IgG antibodies.

The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.

Controlling light at scales smaller than its wavelength is attractive to manipulate light using small device footprints. Here, the authors propose a scheme to modify light on such small scales using a combination of metamaterial nanocavities coupled to nonlinear semiconductor heterostructures.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.

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.

A foundation model trained on neural activity of visual cortex from multiple mice accurately predicts responses to video stimuli and cell types, dendritic features and connectivity within the MICrONS functional connectomics dataset.

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

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A single-cell multiomics analysis of over 200,000 cells of the primary motor cortex of human, macaque, marmoset and mouse shows that divergence of transcription factor expression corresponds to species-specific epigenome landscapes, and conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome.

Here the authors present a large genetic study in East Asians that identifies 97 genetic regions linked to kidney function. These findings aim at better understanding chronic kidney disease in diverse populations.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

In analogy with quantum Hall systems, it may be possible to find non-abelian anyons in the higher bands of Chern insulators. Now, the phase diagram of the second moiré band of twisted MoTe₂ is explored, laying the groundwork for such investigations.

Antimicrobial peptide mechanism of membrane disruption have not been fully characterized at the cellular level. Here, authors use cryo-electron tomography and AFM to directly visualize the disruption of the outer and inner membranes of Escherichia coli by a de novo-designed peptide.

Kersting’s groundnut is an underutilised crop that is locally important, tolerant to drought and critical to food security. Here, the authors report its genome assembly, population genetics analyses, and candidate genes for seed coat colour.

The topological properties of twisted bilayer MoTe₂ are thought to stem from a spatial texture in the layer polarization of the electronic wavefunctions. This polarization is now measured using scanning tunnelling microscopy.

Recent research sheds light on sex-specific molecular changes in the brains of MDD patients, but their association with specific symptoms is still uncertain. Here, the authors revealed the existence of gene signatures underlying the expression of distinct symptom domains in the brain of men and women with depression.

The bactericidal action of some antibiotics is associated with increased ATP consumption, cellular respiration, and reactive oxygen species formation. Here, Li et al. show that constitutive hydrolysis of ATP and NADH (or ‘bioenergetic stress’) potentiates the evolution of antibiotic resistance and persistence in E. coli.

Rapid extracellular antigen profiling of a cohort of 194 individuals infected with SARS-CoV-2 uncovers diverse autoantibody responses that affect COVID-19 disease severity, progression and clinical and immunological characteristics.

High-order correlated states in atomically thin transition metal dichalcogenides may be facilitated by long-lived optically dark excitons. Here, the authors report experimentally the emergence of neutral and charged biexciton species at low light intensities in encapsulated WSe₂ monolayers.

The authors demonstrate a graphene/CrSBr heterostructure exhibiting anisotropic surface plasmon polariton (SPP) propagation in the mid-infrared and terahertz range. Charge transfer at the interface directs SPPs along the quasi-1D chains that compose each CrSBr layer, with propagation lengths varying by an order of magnitude between the two in-plane crystallographic axes.

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.

Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.

The affected cellular populations during Alzheimer’s disease progression remain understudied. Here the authors use a cohort of 84 donors, quantitative neuropathology and multimodal datasets from the BRAIN Initiative. Their pseudoprogression analysis revealed two disease phases.

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

Developing heat-resistant dielectric polymers for electrification is challenging due to the inverse relationship between thermal stability and electrical insulation. Using a machine learning-driven approach, the researchers identify and validate high-performance polymers that demonstrate promising thermal resilience and energy density for high-temperature applications.

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

A study provides evidence for a shared lymphatic circuit that connects the posterior eye and the brain, allowing the generation of immune responses to protect the CNS against pathogens and tumours following intravitreal immunization.

Machine-learned potentials are accurate but often lack broad applicability. Here, authors develop a general-purpose neuroevolution potential for 16 metals and their alloys, achieving efficient and accurate predictions of various physical properties.

The Reliability eXplorer is a tool for assessing measurement reliability in neuroimaging studies.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Using the unique valley properties of a twisted MoTe₂ bilayer, measurements of the degree of circular polarization of trion photoluminescence reveal optical signatures of a zero-field composite Fermi liquid.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

LINE-1 activity was quantified in a large, pan-cancer dataset, finding locus-specific heterogeneity and new associations using a computational pipeline. A mathematical mediation model of p53 and L1 interactions was inferred. Somatic retrotransposition was seen in Li-Fraumeni Syndrome with heritable TP53 mutations.