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On-demand blood flow increases are essential for brain health, but how flow recovers is unclear. Here, the authors show that brain perfusion triggers vascular Piezo1-mediated mechano-feedback that promotes blood flow recovery to baseline levels.

Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

A retrospective analysis using PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing finds an association between adeno-associated virus type 2 and paediatric hepatitis of unknown cause.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Dietary quality is reported at the global, regional and national level across 185 countries. Though diet quality increased modestly since 1990 at the global level, in South Asia and Sub-Saharan Africa it did not improve. In some regions, children’s dietary quality is lower than that of adults.

Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

Genome-wide association study of cerebrospinal fluid and brain metabolites highlights the unique genetic architecture of metabolite levels and metabolite–trait associations with brain-related phenotypes.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

A large resource of shared tumor neoepitopes aims to accelerate cancer immunotherapy.

Lee, Barone et al. engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation of histone H3, providing a useful tool to illuminate the functional consequences of disconnecting histone modification crosstalk.

Global profiling of hyper-reactive tryptophan sites across whole proteomes using tryptophan chemical ligation by cyclization (Trp-CLiC) reveals a systematic map of tryptophan residues that participate in cation–π interactions, including functional sites that can regulate protein-mediated phase-separation processes.

Immunoselection underpins tumor antigenic variability and is a key impediment to adoptive cell therapies. Darcy, Beavis and colleagues use T cells engineered to express the dendritic cell growth factor Flt3L to co-opt the host endogenous adaptive immune response and control experimental tumor models.

This analysis provides a collection of sequencing datasets generated from long-read and short-read RNA sequencing, serving as a valuable resource for transcriptome profiling.

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.

FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Profiling the resistance landscape to PRC2 inhibitors in EZH2-mutant lymphoma with CRISPR-suppressor scanning reveals drug addiction mutations and a repressive methylation ceiling. Surpassing the ceiling with SETD2 inhibition halts lymphoma growth.

Diet and food intake have been associated with a risk of developing different types of cancer but individual nutritional epidemiology studies are prone to inherent bias. Here, the authors perform an umbrella review of meta-analyses of observational studies and show the level of evidence for associating food and nutrients to cancer risk.

Results of multi-omic profiling of the microbiome and host immunity of individuals treated with VE303 to prevent recurrent Clostridioides difficile infection in the context of a phase 2 trial show robust colonization of VE303 and indicate potential biomarkers of response.

Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.

We model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids, the results implying predictability in the earliest stages of tumorigenesis.

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Cross-talk between innate immune cells helps to enhance the antitumor T cell response during checkpoint blockade therapy.

Systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA for silencing genes in bone-marrow endothelial cells of mice improved the healing of the mice after myocardial infarction.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

The heterogeneity of whole-exome sequencing (WES) data generation methods presents a challenge to joint analysis. Here, the authors present a bioinformatics strategy to generate high-quality data from processing diversely generated WES samples, as applied in the Alzheimer’s Disease Sequencing Project.

Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.

The G-protein-coupled receptor GPR124, acting through the canonical Wnt pathway, is required for the maintenance of blood–brain barrier function in mouse models of stroke and glioblastoma.

The authors perform a meta-analysis of cutaneous squamous cell carcinoma, identifying causal variants within skin-specific regulatory elements.

Human MEF2C haploinsufficiency results in Autism Spectrum Disorder (ASD), but it is unclear if the same is true in mice. Here, the authors show that Mef2c ^+/− mice have behavioral defects and neuronal abnormalities similar to ASD, and symptoms can be ameliorated with the new drug, NitroSynapsin.

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.

The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.

The proliferation of large biobanks necessitates statistical methods designed for genetic analysis on biobank data. Here, the authors have developed a frailty model-based method for GWAS analysis of time-to-event phenotypes in large biobanks that accounts for relatedness in samples and censoring of phenotypes.

Climate change and habitat loss threaten species survival in Madagascar. Ruffed lemurs, a representative species in the eastern rainforest, could lose 38–93% of their habitat from climate change and deforestation by 2070; protecting areas from deforestation is necessary to protect Malagasy biodiversity.

Ballabio and colleagues report that the transcription factor TFEB, which has a known role in autophagy, is induced by starvation and promotes transcription of PGC1α and PPARα. Intriguingly, targeted expression of TFEB in the liver blocks the development of metabolic syndrome in mouse models of obesity.

Regulating telomere length and telomerase activity are critical biological processes implicated in ageing and cancer. Here the authors use mass spectrometry to identify the Cdc48-Npl4-Ufd1 complex, which targets proteins for degradation, as a novel regulator of the yeast telomerase Est1.

A computational model of the spatiotemporal dynamics of the perivascular niche that incorporates relevant cellular and tissue-level phenomena can be used to optimize treatment schedules for glioblastoma.

The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands.

Transcriptomic analysis of BCR-ABL1 lymphoblastic leukemia identifies three subgroups, each associated with a maturation arrest at a specific stage of B-cell progenitor differentiation and distinct genetic and clinical features.

Modeling analysis from the Global Dietary Database estimated that 70% of new global cases of type 2 diabetes are attributable to suboptimal intake of 11 dietary factors, with substantial differences in dietary risks across world regions and nations.

Available evidence supports the existence of functional connections between resident microorganisms and the kidney that are altered in the context of specific kidney diseases. This Roadmap article describes current understanding of the mechanisms by which microorganisms regulate host organ function, highlighting key knowledge gaps that remain to be addressed and opportunities for future research.

Regeneration of myelin is a dynamic, yet enigmatic process. Dombrowski et al. uncover a central role for regulatory T (T_reg) cells in driving oligodendrocyte differentiation, in part via CCN3, a novel factor in T_reg function and oligodendrocyte biology. This identifies T_reg cells as key cellular players in efficient remyelination.

Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

Van den Brink and colleagues show that Nrf2, a regulator of the oxidative stress response, is required for several aspects of haematopoietic stem cell maintenance. Loss of Nrf2 results in the hyper-proliferation of haematopoietic stem and progenitor cells (HSPCs). Nrf2 is also required for HSPC migration and retention to their niche.

Buter et al. elucidated the biological function of the terpene nucleoside 1-TbAd, which is made abundantly by virulent but not avirulent Mycobacterium tuberculosis strains, and demonstrate that 1-TbAd regulates the pH and function of host macrophage endolysosomes.