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Using a sample of more than 1 million individuals, Hatoum et al. identify genomic loci associated with general and substance-specific addiction risk.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

A combination of pyrimidine biosynthesis inhibitors and antiviral nucleoside analogues can boost the antiviral effect of nucleoside analogues against SARS-CoV-2.

When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

How white matter develops along the length of major tracts in humans remains unknown. Here, the authors identify fundamental patterns of human white matter development along distinct axes that reflect brain organization.

Endocannabinoid signalling processes are implicated in body weight regulation. Here, authors used viral-genetic tools to identify the enzyme ABHD6 in postsynaptic mesoaccumbal neurons is a key determinant of body weight and reward-relevant behaviour.

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.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Age-related microbiome changes increase medium-chain fatty acid-producing bacteria, driving GPR84-mediated myeloid inflammation, impaired vagal signalling and hippocampal dysfunction; targeting this gut–brain pathway restores memory in aged mice.

This multi-cohort study reports genetic variants in myostatin associated with increased muscle mass, strength, and reduced adiposity. These findings support long-term myostatin blockade for muscle preservation in the context of weight loss.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

The prelimbic region of the prefrontal cortex is involved in goal-directed action. Here the authors investigate the function of the prelimbic pathways projecting along the anterior posterior striatal axis in value based decision making in male mice.

The mitochondrial proteins ISCA1 and ISCA2 form a complex that is involved in the biogenesis of Fe–S clusters. Here the authors report that ISCA1 and ISCA2 interact differently with proteins of the Fe–S machinery and that under certain conditions, ISCA2 seems dispensable for Fe–S biogenesis.

The molecular mechanisms driving proliferation in the pediatric brain cancer epdendymoma are poorly understood. Here the authors show that a YAP1- MAMLD1 fusion drives tumor formation in mice and show that the fusion protein can collaborate with the TEAD and NFI transcription factors.

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.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

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.

Elevated plasma branched-chain amino acid (BCAA) levels have been associated with insulin resistance and type 2 diabetes. Blair et al. show that altering BCAA oxidation in skeletal muscle or liver does not influence insulin sensitivity in male mice, despite the effects on BCAA plasma levels.

Despite their discovery in the 19th century, the islands of Calleja, clusters of densely packed granule cells in the ventral striatum, remain enigmatic. This study reveals that islands of Calleja neurons are critical for grooming control in mice.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

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).

The authors show that tau can be released by neurons and transferred to other neurons via the extracellular space. Moreover, they show that enhancing neuronal activity accelerates transneuronal tau propagation and exacerbates tau pathology.

Ultrasound can be used to non-invasively control neuronal functions. Here the authors report the use of human Transient receptor potential ankyrin 1 (hsTRPA1) to achieve ultrasound sensitivity in mammalian cells, and show that it can be used to manipulate neurons in the mammalian brain.

Xavier Argout and colleagues report the draft genome of Theobroma cacao, the tropical crop that is the source of chocolate. The sequence assembly covers approximately 80% of the genome.

Ovarian and endometrial cancers with CCNE1-amplification are often resistant to standard treatment. Here, the authors identify that CCNE1-amplified gynecological cancer is sensitive to combined PKMYT1 and ATR inhibition via CDK1 activation, resulting in premature mitosis, DNA damage, cell apoptosis and reduced tumour growth and metastasis.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Tuning the catalytic activity of metal nanoparticles by encapsulation is a long known process, but mechanistically poorly understood. Here, Beck and colleagues reveal the encapsulation mechanism by support material and the outstanding role of oxygen in the encapsulation mechanism by extensive in situ characterization.

Parental care in mice evolves through multiple genetic changes; one candidate is vasopressin, the reduced expression of which promotes parental nest-building behaviour in monogamous mice.

The tumor suppressor RAD51C is mutated in ovarian cancers. Through variant analysis the authors identify a mutation cluster in the RAD51C Walker B region important for the repair of DNA double-strand breaks and replicative damage. By identifying Walker B separation-of-function alleles, they show that these activities can be uncoupled.

Modulating mitochondrial NAD⁺ levels by changing the expression of the mitochondrial NAD⁺ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD⁺ levels are a key determinant of the rate of liver regeneration.

The RNA editing enzyme ADAR1 blocks interferon responses triggered by cytosolic RNA sensors, and has been proposed as a potential target in immuno-oncology. Here, the authors report that BRCA1/2 and ADAR1 are synthetic lethal, showing that ADAR1 depletion in BRCA1-mutant cells causes autocrine interferon poisoning

mRNA vaccines have been successfully developed, but a better understanding of in vivo distribution of the encoded antigen may aid further improvements. Here the authors use PET imaging and demonstrate transient expression of the vaccine antigen in the injection site and draining lymph nodes in mice and non-human primates.

Evolutionarily conserved gene modules mediate neurodegenerative dementia in a variety of mouse models and in postmortem brain tissue from patients.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

Multicolour images are difficult to acquire with large-scale microscopy approaches. Here the authors present a microtome-assisted microscope capable of trichromatic two-photon excitation and label-free nonlinear modalities based on wavelength mixing, and use it to analyze astrocyte morphology and neuronal projections in thick brain samples.

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.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Neurons make homeostatic adjustments to the strength of their synapses on the basis of their activity levels. Here the authors show the microRNA miR-92a represses the translation of the AMPA receptor subunit GluA1 and that, during activity blockade, its levels are reduced to increase the incorporation of new AMPA receptors.

The US television series Alphas features an unusual breed of superhero: ordinary people with extreme abilities. In the run-up to the second season, head writer Bruce Miller explains how he sifts through the latest scientific findings to craft an array of superpowers.

Multistage gene burden analysis in exome sequencing data from 32,558 individuals identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease.

A lipid nanoparticle (LNP) component—an adjuvant lipidoid—is developed to enhance the adjuvanticity of LNPs, which significantly increases the innate and adaptive responses of the COVID-19 mRNA vaccines with good tolerability in mice.