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Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

The antiviral protein SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of the immune regulator RESIST.

The impact of breakage fusion bridge (BFB) cycles on tumour heterogeneity and clinical outcomes remains poorly understood. Here, the authors develop OM2BFB, an algorithm to detect and reconstruct BFB amplifications using optical genome maps and use it to study BFB events across 2557 primary tumours and cancer cell lines.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

Population mobility is associated with SARS-CoV-2 transmission but its impacts on other respiratory viruses are not well understood. Here, the authors investigate associations between mobile phone-derived mobility metrics and the dynamics of 18 respiratory viruses in Seattle, Washington from 2018 to 2022.

How NRXN1 variants affect multiple neuropsychiatric disorders is explored.

Rao and Cai et al. perform a detailed metabolic comparison between primary tumours from patients and their matching xenografts, which identify conserved as well as divergent metabolic patterns.

Imaging and sequencing approaches are combined to show that extrachromosomal DNA (ecDNA) in cancer is circular and has unique chromatin structure that amplifies oncogene output.

Green spaces are known to help cool cities, but they contribute humidity while reducing heat—and both matter. Using smart sensors mounted on bicycles, this study finds that daytime temperature reductions in urban green spaces are largely offset by humidity increases but that urban vegetation causes a net reduction in humid heat at night.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

The failure of metabolic tissues to respond to insulin is an early marker of type 2 diabetes. Here, the authors show, using global phosphoproteomics, that insulin resistance is caused by a marked rewiring of both canonical and non-canonical insulin signalling, and includes dysregulated GSK3 activity.

The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.

An antibody screen of two distinct multiple sclerosis cohorts reveals an autoantibody signature that is detectable years before symptom onset and linked to a common microbial motif.

Here, the authors present a multi-omic framework using single cell technology to identify non-coding genetic variants in cranial motor neuron disorders, offering insights into their genetic basis and methods for studying other Mendelian diseases.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Methods to produce haplotype-resolved genome assemblies often rely on access to family trios. The authors present FALCON-Phase, a tool that combines ultra-long range Hi-C chromatin interaction data with a long read de novo assembly to extend haplotype phasing to the contig or scaffold level.

As COVID-19 vaccine coverage increases, screening programs that focus on the unvaccinated population test fewer individuals. This modeling study identifies vaccine coverage and effectiveness scenarios where such programs are (and are not) impactful.

The ligandability of the human proteome can be expanded using covalent chemistry. A multi-tiered chemical proteomic strategy now provides in-depth maps of tryptoline acrylamide–protein interactions in cancer cells. This platform afforded the discovery of stereoselective covalent ligands for hundreds of human proteins, including compounds that disrupt protein–protein interactions regulating the cell cycle.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

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.

The oxysterol 25-hydroxycholesterol reduces the levels of plasma membrane accessible cholesterol via acyl-CoA cholesterol acyltransferase to inhibit infection and dissemination of intracellular bacterial pathogens, including Listeria monocytogenes.

Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

The intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide leads to weeks-long retention of the cytokines in the tumours with minimal side effects, as shown in multiple syngeneic mouse models.

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.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

Observations from the Lucy spacecraft of the small main-belt asteroid (152830) Dinkinesh reveals unexpected complexity, with a longitudinal trough and equatorial ridge, as well as the discovery of the first contact binary satellite.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

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.

Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.

Determining which covalent binding events impact protein function is challenging. Now, a strategy has been reported that integrates base editing and chemical proteomics to infer the functionality of ligandable cysteines in cancer dependency proteins by quantifying the impact of their missense mutation on cancer cell proliferation.

The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid

Point-scanning super-resolution imaging uses deep learning to supersample undersampled images and enable time-lapse imaging of subcellular events. An accompanying ‘crappifier’ rapidly generates quality training data for robust performance.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

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.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

A pan-cancer analysis finds that extrachromosomal DNA is pervasive and associated with oncogene amplification and poor patient outcomes.