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In monkeys infected with an AIDS-like virus, a combination of a broadly neutralizing antibody and an immune stimulator during antiretroviral therapy suppressed viral rebound after antiretroviral drug discontinuation.

Yuan et al. present crossNN, an explainable machine learning tool to classify tumors based on DNA methylation data from several platforms with different epigenome coverage and sequencing depth, benchmark against other models and validate externally.

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 large-scale multi-omics analysis reports oncogenic alterations that drive medulloblastoma progression, rather than initiation, and the findings show how single-cell technologies can be used for early detection and diagnosis of medulloblastoma.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

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.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

A genome-wide association study suggests 41 previously unreported loci on top of the 23 known loci that influence the disease risk for lumbar disc herniations. Many of these loci harbour genes implicated in disc structure and inflammation, as well as genes related to the nervous system and nerve function.

Results from a study of five patients with refractory systemic lupus erythematosus, who were treated with anti-CD19 CAR T cell therapy under a compassionate-use program, demonstrate remission of SLE disease with follow-up of up to 17 months.

Genome-wide analyses identify 43 loci associated with forearm fracture, including some influencing bone quality parameters. Follow-up work shows that Tac4 knockout mice exhibit reduced mechanical bone strength with no effect on bone mineral density.

Quantifying the total-body virus burden in HIV-infected individuals is necessary to understand viral persistence and guide development of cure strategies. Here, Estes et al. find a high burden of residual virus in tissues of SIV-infected monkeys and HIV-infected humans, and evidence of low-level viral replication, even under antiretroviral therapy.

The oxidoreductase (NXR) multiprotein complex is a key enzyme in the nitrogen cycle. A detailed structural and biochemical characterization of NXR from the anammox bacterium Kuenenia stuttgartiensis shows that this complex is a filament-forming protein that catalysers both nitrite oxidation and nitrate reduction, and elucidates the mechanisms governing complex assembly and function.

Perro and colleagues develop a CD3⁺ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.

Vaccines that protect nonhuman primates from lethal Ebola virus infection have been developed, but their protective mechanisms have not been clearly delineated. Nancy Sullivan et al. now report that the protective efficacy of a recombinant Ad5-based Ebola virus vaccine relies primarily on CD8⁺ T cells rather than on antibodies. The findings suggest that clinical development of T cell–based vaccines against Ebola virus is warranted.

Tweaking immune characteristics of donors and recipients could allow for successful cross-species organ transplantation. Here, the authors show that an anti-CD40 antibody therapy of baboons that received heart transplants from genetically modified pigs is key to their long-term survival.

Recommendations are given on optimal read coverage and selection of calling algorithm to maximize the reproducibility of cancer mutation detection in whole-genome or whole-exome sequencing.

RNase H2 removes mutagenic rNMPs from genomic DNA. The authors demonstrate how nicked rNMPs are repaired when they are encountered in S phase. This study unveils genetic interactions that could potentially be exploited in RNase H2-deficient pathologies.

Depletion of CD8⁺ T cells before infection or early antiretroviral therapy initiation elucidates the role of cytotoxic T lymphocytes during formation of the latent simian immunodeficiency virus reservoir.

Thirst is regulated by hierarchical neural circuits in the lamina terminalis, and these integrate the instinctive need for water with consequent drinking behaviour to maintain internal water homeostasis.

The substrate specificity of phosphoprotein phosphatases PP1 and PP2A depends on their catalytic and regulatory subunits. Using proteomics approaches, the authors here provide insights into the sequence specificity of the catalytic subunits and their distinct contributions to PP1 and PP2A selectivity.

Tumor–normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking ‘tumor-only’ or ‘matched tumor–normal’ analyses.

The interleukin-15 superagonist N-803, combined with the depletion of CD8⁺ lymphocytes, induced a robust and persistent reactivation of the virus in vivo in both antiretroviral-therapy-treated SIV-infected macaques and HIV-infected humanized mice.

Somatostatin is secreted by delta cells and inhibits insulin and glucagon secretion. Here Vergari et al. demonstrate a mechanism for somatostatin secretion that is dependent on decreased extracellular potassium and increased intracellular sodium levels, and is altered in islets from patients with diabetes.

In this Review, Malfait and Schnitzer provide an accessible discussion of the peripheral and central mechanisms involved in OA pain, and explain how NSAIDs, antidepressants and anti-NGF antibodies modulate these pain pathways to exert their analgesic effects. They propose that an enhanced understanding of such mechanisms might permit a more targeted and individualized approach to pain management in the future.

MRI is a powerful technology for assessment of renal oxygenation. This Review highlights important considerations for the physiological interpretation of renal oxygenation changes measured by MR oximetry and discusses use of this technology in research as well as potential clinical applications.

Modeling brain modular structure by accounting for higher-order interactions reveals a novel organization of the transmodal cortex and highlights brain areas with high and low topological specialization in healthy individuals and across the lifespan.

Severe osteoarthritis (OA) is the main cause of an increasing need for joint replacements and is, therefore, a large burden on both patients and the health-care sector. This Review discusses the genetic contribution to hip and knee OA and the authors suggest that identifying individuals at a high risk of OA with a combination of genetic markers might aid preventive and disease-management strategies.

Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.

Geoffrey Woods, Jan Senderek and colleagues show that biallelic mutations in PRDM12 cause congenital insensitivity to pain. They further show that PRDM12 is expressed in nociceptors and their progenitors and participates in sensory neuron development in Xenopus.

Hydrazine is an intermediate in the process of anaerobic ammonium oxidation which has a major role in the Earth’s nitrogen cycle; the crystal structure of a hydrazine synthase enzyme provides insights into the mechanism of hydrazine synthesis.

webKnossos is a browser-based tracing and annotation tool for 3D electron microscopy data sets that is optimized for seamless data viewing. The tool’s flight-mode view facilitates fast neurite tracing because of its egocentric viewpoint.