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Daniel, Yost, Hsiung, et al. generate a single-cell multiomic atlas of T cell exhaustion in chronic viral infection, which reveals molecular programs of exhausted T cell subsets, identifies divergent clonal exhausted T cell differentiation trajectories and nominates TCR signal strength as a driver of clonal fate.

Whole genome sequencing is emerging as a first-line test for rare genetic diseases. In this study, authors maximise diagnoses by supplementing existing semiautomated analyses with clinically driven reevaluation of genomic data by a specialist multidisciplinary team.

Fragile X syndrome and autism spectrum disorders are associated with circuit hyperexcitability, however, its cellular and synaptic bases are not well understood. Here, the authors report abnormal synaptogenesis with an increased prevalence of polysynaptic spines with normal morphology in a mouse model of fragile X.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells.

Gene rv3722c is essential for in vitro growth of Mycobacterium tuberculosis, but its function is unclear. Here, Jansen et al. show that Rv3722c is the primary aspartate aminotransferase of this pathogen, mediates nitrogen distribution, and is important for virulence during infection of macrophages and mice.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

A well-preserved 319-million-year-old brain of the extinct vertebrate Coccocephalus wildi provides insights into neural anatomy deep within the phylogeny of ray-finned fish.

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 region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations.

There is high prevalence of whole genome duplication (WGD) in high grade serous ovarian cancer. Here, the authors compare tumours with and without WGD and find that those that acquired WGD early during tumour evolution are associated with worse survival and have the lowest expression of MHC-II.

Humans with inherited defects in DOCK8 expression are prone to allergic, type 2 CD4⁺ T cell responses. Mandl and colleagues reveal an important role for cell death in driving such type 2 signals during infection.

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.

Magnetotail reconnection plays a crucial role in explosive energy conversion in geospace. Here, the authors show that magnetotail reconnection starts from electron reconnection in the presence of a strong external driver, which then develops into ion reconnection.

Methicillin-resistant strains of Staphylococcus aureus appeared in European hedgehogs in the pre-antibiotic era as a co-evolutionary adaptation to antibiotic-producing dermatophytes and have spread within the local hedgehog populations and between hedgehogs and secondary hosts.

Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.

How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.

Single-mode, tuneable monolithic semiconductor lasers are important light sources for integrated photonics. Here, Kundu et al. observe the switch-on dynamics and mode competition of a terahertz quantum cascade laser and explain the behaviour with a carrier and photon transport model.

Using TEA-seq, Thomson et al. detail transcriptional and epigenetic alterations in the T cell compartment between healthy children and older adults, leading to the discovery of a novel pediatric CD8αα⁺ population poised for rapid effector responses.

Hyperbolic metamaterials exhibit interesting optical phenomena that could provide useful functionalities, if the losses can be reduced. Here Caldwell et al.show that hexagonal boron nitride supports hyperbolic polaritons, presenting a natural alternative to metamaterial systems.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

In this study, Lin and Zhao et al. show that type I IFN autoantibodies promote West Nile virus infection in enterocytes, which correlates with encephalitis disease risk in humans; while in mice, type I IFN signaling defects associate with gastrointestinal tract and blood-brain barrier permeability and disease severity.

Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.

In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Morgan, Pernes and colleagues perform mass spectrometry-based targeted lipidomics and provide a comprehensive lipid profile of human and mouse immune cells, which they then show confer differential ferroptosis susceptibilities.