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Adolescent drug use augments psychiatric risk. Here the authors show that abused drugs dysregulate adolescent Netrin-1/DCC signaling, triggering ectopic long-distance dopamine axon growth in males while Netrin1 compensatory events protect females.

The many different behaviors mediated by the posterior parietal cortex (PPC) could arise from distinct specialized categories of neurons or from a single population of PPC neurons that is leveraged in different ways. The authors test this by studying rat PPC neurons during tasks involving multisensory decisions and conclude that a single network of neurons can support different behavioral demands.

Montage parallel array cryo-tomography adopts principles of montage tomography via regular array beam-image-shift montage acquisition and is robust for imaging large fields of view while retaining high-resolution structural information in cryo-electron tomography.

Sézary syndrome is a T cell malignancy that has been poorly characterized at the genome level. In this study, Kielet al. perform whole-genome analyses and identify mutations in the JAK–STAT pathway and show that primary cells are sensitive to JAK inhibitors.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

The US COVID-19 Scenario Modeling Hub produced medium to long term projections based on different epidemic scenarios. In this study, the authors evaluate 14 rounds of projections by comparing them to the epidemic trajectories that occurred, and discuss lessons learned for future similar projects.

Unique surface imperfections serve as an easily identifiable feature in the fight against fraud.

Modular synthetic G-protein-coupled receptors with nanobody-based ligand-recognition domains can be designed and used to programme transgene expression, real-time fluorescence or endogenous G-protein activation in response to soluble or cell-surface ligands, enabling control of diverse cellular behaviours.

Single-cell analysis of patient brains and cortical organoids links disrupted developmental metabolic reprogramming to postnatal synaptic dysfunction in dup15q syndrome, revealing shared neuronal changes with idiopathic autism.

Family-based exome sequencing in a large autism study has identified 27 high-confidence gene targets and accurately estimates the contribution of both de novo gene-disrupting and missense mutations to the incidence of simplex autism, with target genes in affected females overlapping those in males of lower but not higher IQ; targets also overlap known targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes.

It is hoped that quantum computers may be faster than classical ones at solving optimization problems. Here the authors implement a quantum optimization algorithm over 23 qubits but find more limited performance when an optimization problem structure does not match the underlying hardware.

Sustainable and regenerative agriculture often employs diverse systems of crop rotation to reduce environmental impacts and sequester carbon. A long-term field study, however, reveals a trade-off between soil organic carbon storage and nitrogen supply.

Longitudinal multi-omics reveals shifts to the human microbiome across multiple body sites and the associated immune responses during short-term spaceflight.

A transcriptome-wide characterization of the molecular pathology of post-traumatic stress disorder (PTSD) postmortem brains provides a comprehensive resource for mechanistic insight and therapeutic development.

Incessant telomere synthesis in cancer cells depends on specific mutations in the TERT promoter, enabling its activation by transcription factors ETS1 and p52. Here, the authors elucidate the structural basis for p52/ETS1 binding to mutant TERT, suggesting a general mechanism for TERT reactivation in cancer.

A multi-ancestry transcriptome-wide association study using an optimal linear combination of association statistics provides insights into tobacco use biology and suggests opportunities for drug repurposing.

Naturally occurring tumour-binding IgG antibodies are shown to initiate the rejection of allogeneic tumours, whereby Fc-receptor-mediated uptake of tumour immune complexes into dendritic cells activates tumour-reactive T cells, and intra-tumoral injection of allogeneic IgG together with dendritic cell adjuvants induces systemic T-cell-mediated antitumour responses.

There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

Human mobility plays a central role in the spread of infectious diseases and can help in forecasting incidence. Here the authors show a comparison of multiple mobility benchmarks in forecasting influenza, and demonstrate the value of a machine-learned mobility map with global coverage at multiple spatial scales.

The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs.

Pyrolysis gas chromatography–mass spectrometry reveals the presence of microplastics and nanoplastics in human kidney, liver and brain tissue samples from 2016 and 2024, with higher proportions found in the brain.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

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.

Lithium-ion batteries are prone to unpredictable failure during fast charging, known as lithium plating. Now, innovative testing protocols can quickly quantify lithium plating and inform battery design strategies to mitigate it.

This study develops a method for spatially resolving multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice and uncovers heterogeneous haematopoietic stress responses in different bones.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.

This study provides the first evidence in humans that tirzepatide modulates brain electrophysiology, with changes in low-frequency accumbens power linked to food preoccupation.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.

The systemic immune features that distinguish COVID-19 from common infections remain incompletely elucidated. Here McClain et al. compare RNA sequencing in peripheral blood between subjects with SARS-CoV-2 and other respiratory infections and demonstrate dysregulated immune responses in COVID-19 with both heterogeneous and conserved components.

Two below-threshold surface code memories on superconducting processors markedly reduce logical error rates, achieving high efficiency and real-time decoding, indicating potential for practical large-scale fault-tolerant quantum algorithms.

Mapping the yeast ABC transporter interactome suggests functional significance of transporter-transporter interactions and also shows function of some transporters in zinc homeostasis.

Cyclophanes—consisting of aromatic rings formed into a macrocycle—can display interesting properties but are challenging targets for synthesis. Here, the authors report a route to form cyclophanes by dynamic covalent chemistry, forming disulfides that can be subsequently converted to stable thioethers.

Under extreme conditions, nonlinear lattice dynamics in a material can manifest and reveal unexpected properties. Here, using inelastic neutron scattering and first-principles calculations the authors find the presence of nonlinear travelling waves in a fluorite structured system, which exhibit characteristics different from regular phonons.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Physical realizations of qubits are often vulnerable to leakage errors, where the system ends up outside the basis used to store quantum information. A leakage removal protocol can suppress the impact of leakage on quantum error-correcting codes.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4– and IL-13–producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

Crystal structures of the σ₂ receptor are determined and used to perform a docking screen of nearly 500 million molecules, identifying σ₂-selective ligands and providing insight into the role of σ₂ in neuropathic pain.