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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.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Known to augment host innate immunity, Zhou and Ahearn et al. shows that a SARS-CoV2 NSP15 mutant also increases viral recombination and reduces sub-genomic message. Results articulate a novel role for NSP15 in viral transcription and recombination.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

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.

Sinonasal squamous cell carcinoma (SNSCC) is an uncommon tumor, which has been associated with the human papillomavirus (HPV). Here the authors perform comprehensive genome-wide characterization of HPV-associated and HPV-independent SNSCC patient samples to reveal molecular patterns of tumorigenesis and identify HPV-driven mutational profiles.

The activity and stability of supported metal catalysts is in large part influenced by their interaction with the support. Now, neural network molecular dynamics simulations are combined with interpretable machine learning to reveal the governing factors of metal–support interactions for Pt nanoparticles on various oxide supports, identifying key features and proposing sinter-resistant supports.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

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.

Inactivating PPP2R1A mutations correlate with better survival after immune checkpoint blockade in patients with ovarian clear cell carcinoma, suggesting that targeting the phosphatase 2A (PP2A) pathway may represent an effective startegy for improving responses to immunotherapy.

Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Epichaperomics allow the study of protein-protein interactions and their alterations, but probes have been limited to capturing HSP90 epichaperomes. Here, the authors introduce and validate a toolset of HSP70 epichaperome ligands, and use them in epichaperomics to identify a mechanism with which cancer cells can enhance the fitness of mitotic protein networks.

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.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

An extinction-risk assessment of reptiles shows that at least 21.1% of species are threatened by factors such as agriculture, logging, urban development and invasive species, and that efforts to protect birds, mammals and amphibians probably also benefit many reptiles.

Screening in Escherichia coli and biochemical experiments show that in Arabidopsis thaliana, OSCA2.1 and OSCA2.2 function as plant sensors of hypo-osmolarity, utilize Ca²⁺ oscillations as second messengers and have crucial roles in pollen germination.

Drawing on 51,269 participants across 9 independent, geographically diverse datasets, an AI model identifies the etiologies contributing to dementia in individuals, harnessing a broad array of data, including demographics, medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging.

Control of the electrical properties of materials by means of magnetic fields or vice versa may facilitate next-generation spintronic devices, but is still limited by their intrinsically weak magnetoelectric effect. Here, the authors report the existence of an enhanced magnetoelectric effect in a Y-type hexaferrite, and reveal its underlining mechanism.

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.

To overcome limitations of previous genome-wide association studies of coronary artery disease, this study incorporates a cohort of individuals containing large fractions of Black and Hispanic individuals to provide a wider view of the genetic landscape of this disease.

Defects affect the performance of photovoltaic devices, but their exact role is still under scrutiny. Luria et al. use 3D imaging of current pathways in a working CdTe solar cell with nanoscale resolution and observe electrically active defects, which contribute to conduction.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.

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.

Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.

Lionel Arnaud and colleagues identify null alleles of ABCG2 as the genetic basis of the Junior blood group system.

Yu et al. developed AIPatient, a virtual patient that uses a large language model-based AI in curating a medical knowledge base that holds realistic and personality-aware clinical conversations. The system shows high accuracy in answering questions and medical-term recognition, with readable, reliable, and consistent outputs for medical training.

Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19.

This comprehensive study of the most enigmatic serotonin receptor 5-HT_5AR includes lots of pharmacological investigations, inactive and active state structures with antagonist, partial agonist and full agonists. Also, a highly potent and selective antagonist was developed.

MHC-I mediated antigen presentation is an important element of the anti-tumour immune response. Here authors identify a tumour immune escape mechanism by which the cancer cells express the ubiquitin E3 ligase UHRF1 in the cytoplasm instead of the nuclear expression pattern observed in normal tissues, and this results in degradation of MHC-I and thus diminished antigen presentation and anti-tumour T cell response.

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.

Inflammation promotes insulin resistance in adipocytes, but the mechanism is unclear. Here, the authors show that the inflammatory transcription factor IRF3 drives expression of AIG1, which encodes a hydrolase that breaks down a class of insulin-sensitizing lipid called FAHFAs.

The roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behavior is of great interest. Ferguson et al. selectively and transiently disrupt either one pathway or the other. They find that disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas disrupting striatonigral neurons impaired its persistence.

Cryo-electron microscopy structures of the thyrotropin receptor reveal the basis for the activation of the receptor by autoantibodies in patients with Graves’ disease.

An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity.

An extensive map of human DNase I hypersensitive sites, markers of regulatory DNA, in 125 diverse cell and tissue types is described; integration of this information with other ENCODE-generated data sets identifies new relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns.

Guo et al. show that ligand-induced EGFR activation suppresses invasion by upregulating BIN3 and inhibiting DOCK7-regulated Rho GTPase activity in EGFR-amplified glioblastoma, which is in contrast to the known oncogenic role for EGFR signalling.

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.

The timing of measles vaccination in infants affects the risk of infection in young children and the duration of protection provided. Here, the authors investigate optimal vaccination timing by characterising antibody kinetics following different vaccine schedules in two cohorts of children in southern China.

A pharmacological screen has identified the histone methyltransferase G9a as a target to reactivate imprinted genes in a mouse model of Prader–Willi Syndrome that improves growth and survival.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

A new approach for rational enzyme design uses gain-of-function cancer mutations to guide homologous mutations in homoisocitrate dehydrogenase, yielding a biocatalytic path to (R)-2-hydroxyadipate, a precursor for the major commodity chemical adipic acid.

Manipulation of topology of the electronic structure is highly desirable for practical applications of topological materials. Here the authors demonstrate tuning and annihilation of Weyl nodes in momentum space by means of the Zeeman effect in a strongly correlated topological semimetal Ce₃Bi₄Pd₃.