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Native state proteomics of PV interneurons revealed unique molecular features of high translational and metabolic activity, and enrichment of Alzheimer’s risk genes. Early amyloid pathology exerted unique effects on mitochondria, mTOR signaling and neurotransmission in PV neurons.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Global patterns in animal size and shape have been long observed, but their underlying drivers are not well understood. Here the authors suggest latitudinal patterns in shorebird size and shape are best explained by thermal adaptation to warm climates.

In the nucleus accumbens, acetylcholine boosts dopamine release to promote effortful behaviour.

Bergmann’s and Allen’s rules are speculated to describe alternative strategies of thermal adaptation. Here, Frӧhlich et al. explore global variation across avian species to show that the way in which relative length of beaks and tarsi co-vary with ambient temperature depends on body mass and vice versa.

A distinctive population with high hunter-gatherer ancestry persisted 3,000 years later than in most European regions, contributing to later Lower Rhine–Meuse Bell Beaker users.

In vitro propagation of the pathogenic bacterium Coxiella burnetii, the causative agent of Q fever, leads to attenuated virulence and lipopolysaccharide (LPS) truncation. Here, Long et al. show that a strain considered to be avirulent (NMII) can be recovered from infected animals, and these isolates display increased virulence and an elongated LPS due to reversion of a 3-bp mutation in a gene.

DBiTplus represents an integrated experimental and computational workflow that unifies sequencing-based and imaging-based spatial omics, demonstrated by combining transcriptomic profiling and multiplexed protein imaging on the same tissue section.

Neural circuits in adult mouse visual cortex are stabilized by astrocytes, which secrete CCN1, resulting in reduced plasticity and increased maturation of multiple cell types.

A comprehensive atlas platform integrating transcriptional and epigenetic data enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.

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.

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.

The anterior cingulate cortex encodes affective pain behaviours modulated by opioids; targeting opioid-sensitive neurons through a new chemogenetic gene therapy replicates the analgesic effects of morphine, providing precise chronic pain relief without affecting sensory detection.

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).

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.

 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. 

Complex infectious conditions, such as sepsis, requires rapid assessment of both pathogens and host responses. Here, the authors develop MIDAS, an assay platform that profiles bacterial RNA and inflammatory proteins simultaneously in under 4 hours.

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.

An exploratory analysis of the phase 3 ECOSPOR III trial shows that a higher dosage of the oral microbiome therapeutic VOWST led to enhanced pharmacokinetics, increased species engraftment and altered microbiome and metabolite profiles, providing mechanistic insights into how it may prevent Clostridioides difficile infection recurrence.

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.

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.

A previously unsampled deep lineage in central Argentina was discovered that had distinctive genetic drift by 8,500 bp and persisted as the main Native American ancestry component in the region up to the present day.

In a trial involving 45 clinics and 15,596 visits, the use of an AI-based screening tool applied to ECG for opportunistic detection of advanced chronic liver disease led to a significant increase in new diagnoses compared to the standard workflow.

Clarke et al. presents a framework for spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Applying this approach, they revealed region-specific metabolic diversity and dysregulation in both normal and diseased mouse brains.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

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.

Human and rodent supragranular pyramidal neurons differ in HCN channel-related properties. Comparison across primates reveals robust HCN1 expression and HCN channel-dependent physiology, with cell type dependent differences in macaques versus humans.

Neurons in cochlear nucleus are highly specialized for neural coding of sounds. Here, authors show all cochlear nucleus cell types are defined by distinct transcriptomic profiles, thus uncovering the molecular logic driving cellular specialization.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

A conserved gene regulatory network involving SOX4, SOX11 and TFAP2D shapes the development of excitatory neurons in ventrolateral pallium and their connectivity with the prefrontal cortex.

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

The Neolithic Revolution marked an important shift from foraging to farming in human society. Here, the authors show that in Europe the spread of farming involved mostly within-group mating and limited cultural transmission.

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.

Regulation of gene expression is a facet of human brain specialization. Here, the authors show that human-like expression of the CLOCK gene in the mouse neocortex enhances cognitive flexibility and neural connectivity, suggesting an evolutionary gain of function that may have contributed to human cognitive specialization.

This study presents MetaVision3D, a pipeline to integrate mass spectrometry imaging sections into 3D reconstructions of metabolomic maps. The authors also provide a comprehensive 3D metabolome atlas of the brains of healthy mice and two disease models.

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.

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.

Gelabert et al. examine genomic and archaeological data from Europe’s earliest farming communities in Central Europe (5500–5000 bce). They find differentiated genetic networks but no evidence of unequal access to resources linked to sex or kin.

Neural mechanisms underlying cross-modal generalization of learned sensorimotor associations are not fully understood. Here authors show that mice use a specialized cortical circuit to generalize learned behaviors between vision and touch. A single region in the dorsal cortex is essential for forming abstract spatial representations that enable cross-modal flexibility.

Herpesvirales utilize a unique nuclear egress route for capsid export. Here the authors show that herpesviruses exploit a cellular membrane protein, once thought to transport chloride, to facilitate membrane fusion and egress from the nucleus.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Patients with myeloma multiple treated with BCMA CAR T cells often relapse with BCMA-negative disease or antigen escape. Here the authors describe the design of TACI-directed single and dual CAR T cells with in vitro and in vivo activity against multiple myeloma, overcoming BCMA antigen loss.

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.

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

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.