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Haematopoietic stem cells are found to be regulated differently in male and female mice — haematopoietic stem cells in females divide more frequently than in males in response to oestrogen and this difference depends on the ovaries but not the testes; using a genetic approach, it is shown that the effect is dependent on expression of oestrogen receptor-α (ERα) in stem cells.

A database of microbial signatures is used for systematic comparison of differential abundance patterns.

Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double strand-break (DSB) repair, directly re-ligates broken DNA ends with minimal errors. In this study, the authors identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) that prioritize ligation and promote NHEJ fidelity.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

Machine learning can be used to identify subtypes of psychiatric disease. Here the authors identified two neurostructural subgroups in schizophrenia, each showing reproducibility and generalizability across different collection locations and illness stages, using the SuStain algorithm.

Dietary inulin fibre alters the composition and metabolism of gut microbiota, resulting in elevated levels of bile acids that subsequently trigger mucosal type 2 inflammation characterized by eosinophilia, with clinical implications for allergy and anti-helminth defence.

The development of a new genetic tool to selectively deplete or modify group 2 innate lymphoid cells (ILC2s) addresses the debate regarding the non-redundant functions of this immune cell type.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Motor cortex is required for flexible motor sequences informed by sensory cues but not for single automatic sequences. However, training automatic sequences alongside flexible ones interferes with their subcortical consolidation.

Gene therapies and cellular programming rely on effective cell transfection. Here it is shown that optimizing the viscosity of cell culture media to match that of biological fluids substantially enhances the transfection efficiency for various gene delivery vehicles across different cell types.

Htet et al. identify and characterize a transcriptional enhancer that regulates cardiomyocyte maturation and function in human pluripotent stem cell and mouse models.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.

Mass cytometry of diagnostic biopsies from children with B cell precursor acute lymphoblastic leukemia identifies a signaling state that predicts relapse.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Advanced ecological modelling reveals how Sahul (Australia and New Guinea) was first peopled, suggesting the most probable routes and surprisingly rapid early settlement of this continent by anatomically modern humans starting 50,000 to 75,000 years ago.

Leukaemic stem cells (LSCs) are responsible for BCR–ABL-driven chronic myeloid leukaemia relapse; here, p53 and MYC signalling networks are shown to regulate LSCs concurrently, and targeting both these pathways has a synergistic effect in managing the disease.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Polygenic risk scores predict the likelihood that an individual will develop a certain cancer, however these are often specific for a given population. Here, the authors show that a risk score developed to assess the risk of breast cancer in European women can also predict risk in Asian populations.

The metabolic dependencies of androgen receptor (AR)-driven growth in prostate adenocarcinoma are largely unknown but could represent a therapeutic target when hormonal manipulations fail. Here the authors demonstrate that the mitochondrial pyruvate carrier (MPC) is transcriptionally regulated by AR and that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions.

Large variability of wood carbon fractions in different trees can lead to an error of up to 8.9% in carbon estimates for forests, according to an analysis of wood carbon data across global forested biomes.

Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.

Single-crystalline perovskite membranes with an ultrahigh dielectric constant show potential as a gate dielectric for two-dimensional field-effect transistors.

A new procedure for cataract removal that preserves lens epithelial progenitor cells in mammals, which require Pax6 and Bmi1 for their self-renewal, achieves lens regeneration in rabbits, macaques and in infants with cataracts.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Longitudinal skin site sampling of residents in a skilled nursing facility sheds light on persistent niches of the emerging fungal pathogen Candida auris.

The COP9 signalosome (CSN) is a protein complex involved in protein degradation and tumorigenesis. Here the authors show that the CSN6 subunit antagonizes the deneddylation function of CSN5 towards ubiquitin ligase Cullin-1, resulting in Fbxw7 ubiquitin ligase degradation and thereby stabilization of the Fbxw7 target Myc.

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.

The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.

Until recently, complex multi-parameters were required for the isolation and identification of haematopoietic stem cells, complicating study of their biology in situ; here the authors have found that expression of a single gene, Hoxb5, defines haematopoietic stem cells with long-term reconstitution capacity, and that these cells are mainly found in direct contact with endothelial cells.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

Prime-editing mouse models enable the study of specific cancer mutations in vivo.

Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

There has been a deluge of reports, in this journal and elsewhere, dealing with the subject of signal transduction and the Ras protein. Why all the fuss? The following is a News and Views article with a difference - an explanation for those not close to events, and a celebration of an achievement in biomedical research.

ctDNA is a known poor prognostic factor for multiple cancer types, but variant-specificity is unknown. Here, the authors show variant-specific association of ctKRAS levels with survival in previously untreated metastatic pancreatic ductal adenocarcinoma patients in multiple cohorts.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Ramabadran et al. identify a DNA methylation-independent role for DNMT3A in stem cell activation, mediated through recruitment of SF3B1 and splicing regulation.

The composition of lipid nanoparticles for the delivery of tumour-antigen-encoding mRNA can be optimized via a screening method to enhance antitumour activity via the modulation of the immune activity of helper T cells.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.