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Grubman et al. generated a single-cell transcriptomic atlas of the entorhinal cortex from patients with Alzheimer’s disease and identified transcription factor networks predicted to control disease progression in a cell-subtype-specific way.

Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.

Mycobacterium kansasii can cause serious pulmonary disease. Here, the authors present a population genomics analysis of 358 environmental and clinical isolates from around the world, supporting the idea that municipal water is a main source of infection, and shedding light into the pathogen’s diversity and adaptation to the human host.

Trapped in rock fractures miles below the surface are saline waters that have been isolated for millions of years. In these most remote environments exists an active turnover of dissolved organic molecules, an active carbon cycle.

A set of three papers in Nature reports a new proteomics resource from the UK Biobank and initial analysis of common and rare genetic variant associations with plasma protein levels.

In this Viewpoint, past attendees and organizers of the Little Brain Big Brain share their experience with this unique meeting and their insights into the field of enteric neuroscience and neurogastroenterology.

CYLD cutaneous syndrome (also known as Brooke-Spiegler syndrome) is characterised by germline mutations in the tumor suppressor CYLD. Here, the authors highlight recurrent mutations in DNMT3A and BCOR, indicating a role for epigenetic dysregulation in this rare genetic skin disease.

Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.

A range of techniques are used to investigate the molecular landscape of chronic kidney disease, and the results suggest that distinct populations of pericytes and fibroblasts are the main source of myofibroblasts in kidney fibrosis.

Stress reduces the effects of various cancer therapies, such as chemotherapy and immunotherapy, in mice; this is mediated, at least partially, through Tsc22d3 upregulation in tumor-infiltrating dendritic cells, which leads to immunosuppression.

The Phoenix stream in the Milky Way halo is shown to be a tidally disrupted remnant of an unusually metal-poor globular cluster, which was possibly destroyed during Galactic evolution.

GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor and mediates GDF15's effects through central actions in the hindbrain.

Factor XII initiates the intrinsic blood coagulation cascade and the kinin system. Here the authors show that Factor XII is elevated in the blood of multiple sclerosis patients, activates dendritic cells via CD87 and cAMP, and its blockade inhibits immunopathology in a mouse model of the disease.

The TGF-β signalling pathway promotes cancer progression in late stage breast cancer, but how the pathway is activated is not always clear. In this study, Zhou et al.identify that the expression of nuclear receptor NR4A1 is induced by inflammation and is an activator of TGF-β-induced metastasis.

In a basket trial design, the efficacy of the pan-HER kinase inhibitor neratinib is tested in patients with 21 different tumour types, and responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Follicular helper T (T_FH) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T_FH cells and limits their numbers in vivo. Ablation of these T_FH-like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses.

Large-scale efforts are put into the generation of knockout mutant mice for many individual genes. Here, the authors systematically screen skin from 538 mutant mice and identify 50 mutants with epidermal phenotypes, of which 9 are also associated with human skin defects.

Here, the authors present a multi-omic framework using single cell technology to identify non-coding genetic variants in cranial motor neuron disorders, offering insights into their genetic basis and methods for studying other Mendelian diseases.

Late-time optical and near-infrared observations of the binary neutron star merger GW170817 are at odds with kilonova models but match a Gaussian-structured relativistic jet, which would have launched a high-luminosity short gamma-ray burst to an aligned observer.

Physical activity has demonstrated positive effects in preventing and ameliorating a broad range of diseases, particularly central nervous system disorders. Accordingly, strategies to therapeutically mimic the effects of exercise are gaining interest. Here, Gubert and Hannan focus on the molecular and cellular effects of physical activity in the central nervous system, assessing opportunities for the development of therapeutic exercise mimetics.

In a new study, Yasuhiro Kobayashi and his colleagues show that noncanonical Wnt signaling regulates balanced osteoblast-induced osteoclastogenesis during normal physiology and that this pathway is perturbed in pathophysiological states, such as rheumatoid arthritis. These results explain further how osteoblasts cross-talk with preosteoclasts to ensure matched bone resorption with bone formation during skeletal homeostasis in the adult and also suggest a new target to treat arthritis.

Digenic inheritance of deleterious variants in serine/arginine protein kinase 3 (SRPK3) and titin (TTN) leads to a progressive early onset skeletal muscle myopathy. Zebrafish double mutants exhibit a similar myopathy phenotype accompanied by myofibrillar disorganization.

ANME-1 archaea are important because of their ability to metabolize methane through anaerobic oxidation. Here the authors use metagenomics on hydrothermal samples from the Gulf of California to characterize a family of ANME-1 and its virome.

Increased legume production and consumption is a promising route to future food security for several reasons: legumes are nutritious foods in their own right, and their nitrogen-fixing capabilities can benefit subsequent crop cultivation. However, legumes are currently under-used and yields will need to be improved if legumes are to become a major food crop. This will entail improvement of genetic diversity in legume breeding programmes, more widespread cultivation of legumes currently grown in restricted regions (such as cowpea), and, possibly, increased government price support

Analysis of the transcriptome of more than 1,200 cells from gastrulating mouse embryos using single-cell sequencing, gathering unexpected insights into early mesoderm formation during gastrulation.

The Periodic Table of Food Initiative addresses food biomolecular composition information gaps through a standardized, accessible and enabling platform based on analytical tools, data and capacity building. Data from 1,650 foods serve as starting point for demonstrating the capacity of this initiative to contribute to nutrition, health and food systems transformations.

Premature ovarian insufficiency (POI) is defined as the loss of normal ovarian activity before the age of 40 years, and is a cause of infertility and endocrine dysfunction in women. This Primer outlines the epidemiology and pathophysiology of POI, including associated gene variants, and discusses diagnosis, management and quality of life for women with POI.

This Primer describes the mechanisms underlying the serious effects of Clostridium difficile infection, which is the leading cause of health-care-associated infective diarrhoea. Strategies for diagnosis, prevention and management are also described, illustrating the burden that C. difficile infection places on patients and society.

Caroline Klaver and colleagues report a meta-analysis for refractive error and myopia, including 37,382 individuals from 27 European studies and 8,376 individuals from 5 Asian studies, as part of the Consortium for Refractive Error and Myopia (CREAM).

Friedreich ataxia (FRDA) is a rare multisystem disorder and is the most common early-onset hereditary ataxia in populations of European, Arab and Indian descent. This article reviews the milestones in FRDA translational and clinical research over the past 10 years and outlines the priorities for future FRDA research.

This Review focuses on the cytomegaloviruses and the sophisticated strategies they have evolved to evade immune recognition. The authors suggest a better appreciation of these pathways could have clinical implications beyond antiviral immunity, for instance in understanding immune evasion in cancer.

The vast array of bacterium–animal symbioses at deep-sea hydrothermal vents was thought to be fuelled by just two chemicals. A study of one such symbiosis in its environmental context reveals a third energy source. See Article p. 176

The catalogue of genetic factors that have been implicated in kidney disease continues to grow. In this guide to gene–disease relationships, the authors discuss the crucial process whereby genetic and experimental data are critically evaluated to determine whether a genetic variant has a role in kidney disease, which can affect patient diagnosis, prognosis and management.

This Analysis article discusses characterization of the kinome in human cancers through genomic, proteomic and functional genomic analyses. In particular, it presents an analysis of cancer genomic data to derive a new census of protein kinase cancer drivers.

Changes in S-isotope ratios over time provide clues to understanding the co-evolution of Earth and its biosphere. Here the authors determine the isotope effect of the first reductive enzyme in the sulfate respiration pathway and reinterpret sedimentary S-isotope records based on this biochemical constraint.

Cytotoxic lymphocytes recognize virus-infected and transformed cells and kill them by apoptosis. Recent studies on the structural and cellular biology of the key mediators of this cytotoxicity — perforin and granzymes — have advanced our understanding of their mechanisms of action, their regulation and the pathophysiological consequences of impaired cytotoxicity.

Lipophilic, poorly water-soluble drug candidates are common outcomes of drug discovery programmes. Porter and colleagues discuss mechanisms by which lipids and lipidic excipients can improve oral absorption of lipophilic drugs, and provide a perspective on the future applications of lipid-based delivery systems.

In this Review, Harris et al. summarize the dynamic changes of the immune breast tumour microenvironment (TME) that take place during disease progression and in response to treatment, and outline emerging therapies to target the immune TME in patients with breast cancer.

Here, the authors discuss the biological role of interleukin-2 (IL-2) in the immune system, focusing on recent advances in our understanding of how IL-2 signals have different effects on various T cell populations and how this knowledge can be harnessed in the clinic.