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Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Ion-mobility mass spectrometry has been used to identify and characterize the oligomeric assemblies of amyloid-β proteins under physiologically relevant conditions. Hexamers and dodecamers are formed only from Aβ42 proteins and the dodecamer is identified as a candidate for the primary toxic agent in the development of Alzheimer's disease.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Fitness-based analysis of 200,618 UK Biobank exomes and single-cell-derived hematopoietic clones identifies 17 genes under positive selection, including novel drivers of clonal hematopoiesis.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.

Cellular senescence involves extensive structural changes to chromatin, but the role of histone variants and histone cleavage is unknown. Here, Duarte et al.identify histone variant H3.3 and its proteolytically processed form lacking a portion of the N-terminal tail as key regulators of senescence.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

EGF-induced recruitment of UPF1 adjacent to HNRNPC induces splicing surveillance of cell proliferation mRNAs.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

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.

Base editor technology combined with a fluorescent reporter of DNA methyltransferase activity enable in situ mutational scanning of DNMT3A, revealing a requirement of DNA binding by the PWWP histone reader domain for full activity.

A CRISPR–Cas9 screen of chromatin regulators in mouse tumour models treated with immune checkpoint blockade identifies SETDB1 as an epigenetic checkpoint protein that suppresses tumour-intrinsic immunogenicity.

This Review considers the optimal approach to assessing the common medical problem of noncardiac chest pain, for which the appropriate application of investigations is controversial. In addition to musculoskeletal and psychiatric investigations, gastroesophageal investigations include esophagogastroduodenoscopy, radiological assessment, ambulatory esophageal pH monitoring, esophageal manometry, provocative tests, and a proton pump inhibitor test.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.

Quantum supremacy is demonstrated using a programmable superconducting processor known as Sycamore, taking approximately 200 seconds to sample one instance of a quantum circuit a million times, which would take a state-of-the-art supercomputer around ten thousand years to compute.

Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

Not much is known about how intrinsic timescales, which characterize the dynamics of endogenous fluctuations in neural activity, change during cognitive tasks. Here, the authors show that intrinsic timescales of neural activity in the primate visual cortex change during spatial attention. Experimental data were best explained by a network model in which timescales arise from spatially arranged connectivity.

Researchers experimentally demonstrate a fully integrated coherent optical neural network. The system, with six neurons and three layers, operates with a latency of 410 ps.

ERV-specific enhancer-based networks regulate species-specific transcriptomes in mammalian spermatogenesis.

Human pluripotent stem cells were used to develop dorsal and ventral forebrain 3D spheroids, which can be assembled to study interneuron migration and to derive a functionally integrated forebrain system with cortical interneurons and glutamatergic neurons.

Thomas Vaughan and colleagues report a genome-wide association study of esophageal adenocarcinoma together with its precancerous lesion, Barrett's esophagus. They identified three loci associated with susceptibility to this cancer.

Peter Donnelly and colleagues report a genome-wide association study for Barrett's esophagus, a common premalignant condition associated with stomach acid reflux and predisposing to esophageal adenocarcinoma. They identify two loci associated with susceptibility to Barrett's esophagus.

How genetic variation contributes to brain morphology is still poorly understood. Here Chenet al. combine brain imaging with single-nucleotide polymorphism data to discover that a substantial degree of cortical variation is derived from underlying genetic differences.

Christine Skibola and colleagues identify variants at 6p21.32 associated with risk of follicular lymphoma, providing further support that variation in the MHC region influences risk of this disease. They also replicate previously reported risk variants for chronic lymphocytic leukemia.

Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer.

Peptidoglycan stem peptides in the Gram-negative bacterial cell wall regulate the insertion of essential outer membrane proteins, thus representing a potential target for antibiotic design.

Myelin-forming cells derive from oligodendrocyte progenitors. Here the authors identify histone arginine methyl-transferase PRMT5 as critical for developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation, to favor differentiation.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Crystallography and spectroscopy are used to solve high-resolution structures of the intermediates of Kok’s S-state clock in photosystem II.

The crystal structure of BamA, the central component of the β-barrel assembly machinery (BAM) complex, from N. gonorrhoeae and H. ducreyi is determined; the structure consists of an interior cavity capped by extracellular loops, an exterior rim with a narrowed hydrophobic surface and a lateral opening of the barrel domain, providing insight into a possible route for the insertion of β-barrel membrane proteins into the bacterial outer membrane.

Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

Douglas Easton and colleagues report a genome-wide association analyses for breast cancer in ~70,000 cases and ~68,000 controls. They identify three new breast cancer susceptibility loci, two of which show association only with estrogen receptor–positive disease.

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.

A diagnostic tool based on blood RNA-seq is shown to identify causal genes and variants linked to clinical phenotypes in individuals with rare diseases for which whole-exome genetic sequencing was uninformative.

Christopher Haiman and colleagues report a genome-wide association study for estrogen receptor (ER)-negative breast cancer in women of African and European ancestry. They identify a variant at the TERT-CLPTM1L locus on 5p15 as associated with ER-negative and triple-negative breast cancer. This locus also harbors multiple variants associated with a range of other cancers.

Stimulating the intrinsic growth capacity of neurons and providing growth-supportive substrate and chemoattraction can allow axon regrowth across anatomically complete spinal cord injuries in adult rodents.