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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.

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.

Here authors show loss of AKAP11, a strong genetic risk factor for bipolar disorder and schizophrenia, disrupts PKA proteostasis and signaling, leading to widespread transcriptomic alterations across the brain, particularly in striatal neurons, as well as altered behavior.

Padawer-Curry et al. show that the hallucinogenic 5-HT2A receptor agonist DOI alters neurovascular coupling in mice, with implications for the interpretation of human fMRI studies of psychedelics.

The dorsal peduncular area of the mouse brain functions as a network hub that integrates diverse cortical and thalamic inputs to regulate neuroendocrine and autonomic responses.

The interactions of CAR-T cells and solid tumors are modeled on a chip.

EchoNext, a deep learning model for electrocardiograms trained and validated in diverse health systems, successfully detects many forms of structural heart disease, supporting the potential of artificial intelligence to expand access to heart disease screening at scale.

An analysis of cell-type diversity in brain samples from a variety of mammalian species, both during development and in adult animals, reveals that the TAC3 initial class of striatal interneurons is conserved across placental mammals and is homologous to Th striatal interneurons in rodents.

Ghatbale et al. adapted a co-evolutionary technique to develop Klebsiella pneumoniae phages to be highly active longitudinally against K. pneumoniae clinical isolates, including drug resistant isolates.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

The authors describe an integrated atlas of the diverse cell types in the mouse primary motor cortex.

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.

Human–artificial intelligence (AI) dialogues can meaningfully impact voters’ attitudes towards presidential candidates and policy, demonstrating the potential of conversational AI to influence political decision-making.

How various factors dynamically influence neuronal variability is a longstanding question. Here, the authors build an encoding model to partition variability, revealing heterogeneous source contributions to individual units and state-dependent changes of variability across the visual hierarchy.

A large, open dataset containing parallel recordings from six visual cortical and two thalamic areas of the mouse brain is presented, from which the relative timing of activity in response to visual stimuli and behaviour is used to construct a hierarchy scheme that corresponds to anatomical connectivity data.

Multi-modal analysis is used to generate a 3D atlas of the upper limb area of the mouse primary motor cortex, providing a framework for future studies of motor control circuitry.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

The authors present a multicenter database to investigate the neural correlates of dreaming, including physiological, behavioral and experiential data. This database could boost the research on the mechanisms of dreaming in humans and the signatures of consciousness.

The mechanisms underlying neuron specification and maturation are unclear. Here the authors provide an integrated epigenomic and transcriptomic analysis of mouse and marmoset neocortical neuronal classes. Pan-neuronal programs active during early development are more evolutionary conserved but not neuron-specific, whereas pan-neuronal programs active during later stages of maturation are more neuron- and species-specific.

The expression of each of the roughly 22,000 genes of the mouse genome has been mapped, at cellular resolution, across all major structures of the mouse brain, revealing that 80% of all genes appear to be expressed in the brain.

ONIX is a data acquisition system for recording freely behaving mice. It can accommodate a variety of recording technologies, while maintaining minimal impact on animal behavior.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

This study estimates the reproductive potential of fish in globally distributed coral reef sites. The results show substantial gains in reproductive potential can be achieved through the 30 × 30 conservation target, particularly for the important fisheries family, Serranidae, demonstrating the possible benefit of protection to population replenishment.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders.

By integrating large-scale genomic and proteomic data in cerebrospinal fluid and plasma, the authors identify 49 proteins linked to MRI markers of cerebral small vessel disease, highlighting extracellular matrix and immune pathways, with biomarker and therapeutic potential.

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.

A comprehensive analysis of gene regulatory elements in 160 distinct cell types from the mouse cerebrum.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Inflammatory monocytes in the brain meninges promote stress-induced fear behaviour, and the pathways involved can be modulated using psychedelic compounds.

Here, the authors use fMRI data to update connectomes with new, asymmetric, and signed weights, leading to an intuitive brain structure that is aligned to functional brain systems, more efficient, subject-specific, state-dependent and varies with age

DeepInterpolation is a self-supervised deep learning-based denoising approach for calcium imaging, electrophysiology and fMRI data. The approach increases the signal-to-noise ratio and allows extraction of more information from the processed data than from the raw data.

Fast spiking interneurons provide perisomatic inhibition in the cortex. Here, Baohan et al. show the failure to develop perisomatic inhibition in heterozygous PTENnull mutant mouse and the underlying mechanism to EphB4 reduction in an experience-dependent manner.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

Amado et al. develop a gene therapy for sporadic ALS using motor neuron-targeting AAVs to deliver RNAi targeting ataxin-2. In a mouse model, survival, strength, and disease-related pathology are improved; and human motor neurons are strongly transduced.

The tooth root is a critical component of the tooth. Here they identify root-forming CXCL12+ apical papilla progenitor cells that provide odontoblasts and cementoblasts in a Wnt-dependent manner, with plasticity to form alveolar bone osteoblasts during regeneration.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

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).

An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

Pyramidal cells are classically thought to comprise the excitatory output of the subiculum. Here, the authors show the existence of “ovoid cells”, excitatory subiculum neurons with specialized gene expression, morphology, projections, and function.

The alveolar bone supports the tooth’s lifelong functionality. Here, the authors identify a tooth-specific mechanism of bone formation in which the Hedgehog–Foxf pathway regulates the alveolar bone osteoblast fates of DF progenitor cells.

Data collected from more than 2,000 taxa provide an unparalleled opportunity to quantify how extreme wildfires affect biodiversity, revealing that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas.

The choroid plexus (ChP) provides molecular cues for brain development. However, the underlying mechanisms are unclear. This study identifies an apocrine secretion mechanism in the ChP that modulates the CSF protein composition and instructs cortical development.

A new algorithm enables scalable and iterative integration of single-cell datasets.