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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.

Newly developed mouse models that enable cell-specific analyses of proteostasis dynamics across the lifespan of the mice reveal key aspects of neuronal proteostasis with ageing.

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.

Multi-omics and genetic models show that CGG repeat toxicity in GABAergic neurons drives FXTAS pathology and identify PRKCG as a critical modifier and potential therapeutic target.

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.

SpatialZ generates virtual single-cell spatial transcriptomics slices between experimentally measured sections, enabling accurate and efficient building of 3D cell atlases of different tissues.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

Challenges in mapping modern molecular and anatomical datasets into a common atlas are not fully addressed. Here authors present approaches to aligning multimodal neuroimaging data and quantifying geometric variability. Authors also make sure open-source code, dataset standards, and a web interface are available, enabling large scale integration of datasets essential to modern neuroscience.

Innovator who pioneered scanning electrochemical microscopy, bioassays and solar fuels.

A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

Here Pachicano et al. uncover sublaminar gene expression patterns across the mouse hippocampal CA1 pyramidal layer, revealing distinct molecular architectures within CA1 subregions.

The developmental dynamics of distinct cell types across brain regions remain poorly understood. Here authors generate DevAtlas, a high-resolution developmental 3D atlas, mapping region and cell type-specific growth in GABAergic cells and microglia in early postnatal mouse brains.

Defining the spatial organization of tissues and organs like the brain from large datasets is a major challenge. Here, authors introduce CellTransformer, an AI tool that defines spatial domains in the mouse brain based on spatial transcriptomics, a technology that measures which genes are active in different parts of tissue.

Jaxley is a versatile platform for biophysical modeling in neuroscience. It allows efficiently simulating large-scale biophysical models on CPUs, GPUs and TPUs. Model parameters can be optimized with gradient descent via backpropagation of error.

iGluSnFR4f and iGluSnFR4s are the latest generation of genetically encoded glutamate sensors. They are advantageous for detecting rapid dynamics and large population activity, respectively, as demonstrated in a variety of applications in the mouse brain.

Integrating molecular and anatomical data in the mouse brain requires flexible, reproducible mapping tools. Here the authors demonstrate ANTsX-based workflows for aligning MERFISH, fMOST, MRI, and LSFM data into shared coordinate frameworks.

Improved vaccines and antivirals are needed for many enveloped viruses. Here, the authors identify sulfur-based small molecules that disrupt viral membrane properties, inhibiting fusion and entry, and safely inactivate influenza virus. The resulting inactivated influenza vaccine is protective in mice.

Long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons, which diversify extensively after birth in the cortex and striatum, but show limited postnatal changes in the septum, preoptic area and pallidum.

Neonatal brain injury from intermittent hypoxemia increases fatty acid oxidation and causes long-term changes in hippocampal lipid profile. Here authors demonstrate oral treatment with glycerol-triacetate restores lipid fatty acid profile and promotes functional recovery.

How the pulvinar represents complex visual information, its functional topography, and its relationship to cortical processing of visually presented objects remains unclear. Here authors show that responses to natural scenes in the human pulvinar reveal organized spatial maps for both low-level visual features, such as local contrast, as well as high-level visual features, such as bodies and faces.

The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task in mice.

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 complement cascade is increasingly recognized in the brain. Here, with MERFISH, the authors showed developmentally regulated brain endogenous expression of complement genes and a potential role of the alternative pathway in brain development.

This study identifies key neurocognitive domains that distinguish patients with schizophrenia from healthy individuals using machine learning. Analyzing data from 1,304 participants, it demonstrates that verbal learning and emotion identification effectively classify conditions, promoting efficient neurocognitive profiling strategies.

 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. 

Brain-wide recordings in mice reveal that prior expectations are distributed through recurrent loops across all levels of cortical and subcortical processing.

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.

Silencing of transgenes such as Cas9 limits gene editing and CRISPRa applications. Here, the authors show that adding intronic sequences reduces silencing and boosts transgene expression, enabling improved CRISPRa-mediated gene activation and more stable expression of the transgene over time.

The authors previously pinpointed OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. Here, the authors identify increased IL-18Rα expression on CD8⁺ T cells, which acquire a reduced cytotoxic signature, correlates with severe respiratory viral infection of influenza A virus, RSV and COVID-19.

Navigating the complex structure of the brain poses a challenge to neuroscientists. Here, the authors have trained an AI (DeepSlice) that can automatically register brain images with speed and accuracy, thus simplifying this process.

Tau misfolds in Alzheimer’s disease, but how the link between tau filament structure and pathogenicity is unclear. This study shows that both filament core structure and phosphorylation in the fuzzy coat are required for full seeding capacity.

A pangenome of the Cannabis genus including 193 genomes demonstrates high variability in most of the genome but low diversity in cannabinoid synthesis genes and provides a resource for future genetic studies and crop optimization.

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.

A comprehensive single-cell RNA sequencing study delineates cell-type-specific transcriptomic changes in the brain associated with normal ageing that will inform the investigation into functional changes and the interaction of ageing and disease.

The authors present DNA-Diffusion, a generative AI framework that designs synthetic regulatory elements with tunable cell-type specificity. Experimental validation demonstrates their ability to reactivate AXIN2 expression, a leukemia-protective gene, in its native genomic context.

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 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.

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.

Omics data’s diversity and high-dimensionality challenge integration across technologies and with imaging. Here, authors introduce mapping method xIV-LDDMM that estimates geometric and feature transformations to integrate tissue-scale atlases with molecular and cellular-scale data.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

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.

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 impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.

Cellular state cooccurrence signatures, such as carcinoma ecotypes may serve as potential biomarkers of response to cancer immunotherapy, however, their clinical utility remains unexplored. Here, the authors analyse large real world immunotherapy cohorts and gene expression data and develop a predictive model for response.

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 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.

A complementary metal–oxide–semiconductor (CMOS) imager that has a 512-pixel silicon image sensor post-processed into a 4.1-mm-long, 120-μm-wide shank with a collinear fibre for illumination can be used to record transient fluorescent signals in deep brain regions at 400 frames per second.