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An in vitro toolkit for studying VSG diversification defines key molecular requirements underlying the formation of mosaic VSGs, providing an experimental framework for the exploration of antigen diversification in Trypanosoma brucei and in other pathogenic microorganisms.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

White Americans’ mental representations of those who have never had an abortion, those who had an abortion for medical reasons and those who had an abortion for non-medical reasons differ in the degree to which they resemble the stereotypes of White Americans, wealth, and femininity.

Warm-sensing leptin receptor neurons in the preoptic hypothalamus suppress feeding by reducing meal size and increasing satiety. This study shows they integrate temperature and metabolic signals via melanocortin circuits to regulate body weight.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Using a novel method for isolating cognitive and motor neural dynamics, the authors show that dynamics often attributed to cognitive processes were corrupted by movements and that distinct populations of neurons encode cognitive and motor variables.

This study shows how different myeloid cell types contribute to damage and repair following cerebrovascular injury, a pathology common to many central nervous system disorders, and offers new therapeutic opportunities to improve clinical outcomes.

New optical methods for investigating the activity of small molecules in cells may facilitate development of anticancer therapeutics. Here, the authors use a super-resolution optical platform and single molecule tracking to gain insight into WRN regulation in cancer.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Microglia mediate the early and selective degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic Huntington’s disease via the complement cascade.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Immunization via the respiratory route is predicted to increase the effectiveness of SARS-CoV-2 vaccines. Here, Kaiser et al. describe a murine pneumonia virus vectored vaccine expressing spike protein, and show that intranasal immunization of male rhesus macaques provides good mucosal and systemic immunogenicity and efficacy.

During malaria transmission, the liver acts as a portal into the vertebrate host and is a major vaccine target. Here, Hildebrandt et al combine spatial and single cell transcriptomics to delineate host-parasite interactions within distinct spatial regions of the tissue.

This mega-analysis of brain resting-state functional connectivity in young individuals with major depressive disorder scanned at six sites across four countries identified hub regions of the attentional and default mode networks as predictors of depression severity.

Georgiou et al. found that the sex of the person performing experiments affects mouse behavior, including responses to stress and ketamine. This effect was mediated by corticotropin-releasing factor neurons in the entorhinal cortex that project to CA1.

Repair of muscle damage requires muscle stem cells, which lose regenerative capacity with aging. Here, the authors show that a sensory organelle, the primary cilium, is critical for muscle stem cell proliferation during regeneration and lost with aging.

A combined geochemical and multi-omics analysis across a 4,600-km transect in the central Pacific Ocean reveals that dinoflagellates play a previously unrecognized role in ecosystem and biogeochemical processes.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.

A machine-learning classifier predicts the origin of cancer of unknown primary based on electronic health records and next-generation sequencing data, showing that patients treated accordingly to model predictions had significantly better outcomes.

Long-range cis-regulatory elements play important roles in regulating agronomic traits, but they are largely uncharacterized in crops. This study provides genetic, epigenomic and functional molecular evidence to support their widespread existence in the maize genome.

Spatial metabolomics are used to describe the location and chemistry of small molecules involved in metabolic phenotypes. Here, Conroy et al. present a bioinformatic pipeline to analyze MALDI data and show that it can be used to identify actionable targets such as glycogen in fibrotic lungs of both human and mice.

Ordovas-Montanes and colleagues describe the composition of the nasal cellular ecosystem and signatures of disease severity in vaccinated and unvaccinated adults during infection with the ancestral, Delta and Omicron variants of SARS-CoV-2.

Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.

The clinical benefits of chimaeric antigen receptor (CAR) T therapy are limited by ‘on-target, off-tumour’ effects. In this study, the authors describe a strategy that promotes the recognition of antigen on tumour, but not normal, cells by combining affinity tuning with inducible interleukin-12 expression.

Deep brain stimulation (DBS) has potential for several movement disorders. Here the authors show that DBS improves motor function in a mouse model of ataxia.

The optical detection of two virulence factors of Mycobacterium tuberculosis on extracellular vesicles in blood allowed for the diagnosis of tuberculosis in paediatric cases that were missed by clinical microbiological assays.

Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

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.

Venkei et al. show that Y-linked Su(Ste) piRNAs are produced via 5′-to-3′ phased-biogenesis initiated by maternally deposited 1360/Hoppel-derived piRNAs, leading to silencing of Ste in the male germline.

Salmonella enterica serovar 4,[5],12:i:- (Salmonella 4,[5],12:i:-) is a major pathogen of humans and animals with a reported incidence in Australia three times higher than the UK and USA. Here, the authors report the circulation, antimicrobial resistance signatures, and effects on host cells, of three Salmonella4,[5],12:i:- lineages within Australia.

Cystic fibrosis imposes a decline in quality of life but new treatments are being developed that target specificCFTRvariants. Here the authors identify five genome loci significantly associated with variation in disease severity in a meta-analysis, which may provide targets for individualized treatment of cystic fibrosis.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

An observational study of adolescent females’ Internet use reveals how online behaviours coupled with offline psychosocial and contextual factors are associated with subsequent vulnerability to Internet-initiated victimization.

In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.

Zika virus (ZIKV) infection in pregnant women has been associated with fetal developmental defects. Here, the authors show that a Brazilian ZIKV isolate causes fetal demise in non-human primates and that antibody treatment at time of peak viremia is insufficient to clear ZIKV replication from amniotic fluid.

Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

CRISPR-based microraft followed by guide RNA identification (CRaft-ID) combines microraft arrays, microscopy and CRISPR–Cas9 technology for high-content image-based phenotyping. CRaft-ID was used to identify proteins involved in stress granule formation.

Removal of integrated HIV DNA remains a roadblock for HIV cure. Here, Mancuso et al. show that intravenous administration of an adeno-associated virus-based CRISPR/Cas9 gene editing construct to SIV-infected macaques results in excision of integrated proviral DNA from infected blood cells and tissues known to be viral reservoirs.

Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.

Chemical proteomics identified covalent ligands targeting an isoform-restricted allosteric cysteine in JAK1. The compounds inhibit JAK1-dependent signaling in immune cells with unprecedented selectivity.

Whole genomes of 185 atypical enteropathogenic Escherichia coli (aEPEC) isolates reveal 30 LEE (locus of enterocyte effacement) subtypes in 3 major lineages, varying in insertion site preference and their complement of non-LEE encoded effector genes.

Understanding how a supporting material can change the surface chemistry of the nanoparticle catalysts that it hosts is critical to tuning catalytic properties. Experimental Hammett studies and density functional theory calculations show that differences in reactivity can be attributed to differences in the electron density at metal active sites, which arises from differences in electron donation from the support.

Complex polyketides are usually produced by microbes, whereas the origin of polyketides found in animals remained unknown. This study shows that sacoglossan animals, such as sea slugs, employ fatty acid synthase-like proteins to produce microbe-like polyketides.

Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-Wolbachia drugs.