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The discovery that DNA methylation of different CpG sites can serve as digital barcodes of clonal identity led to the development of EPI-Clone, an algorithm that enables single-cell lineage tracing through cellular differentiation at scale.

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.

The SWI/SNF chromatin remodeling complex is frequently mutated in cancer and neurodevelopmental disorders. Here, the authors performed a CRISPR screen and identified MLF2 and RBM15 as modulators of SWI/SNF assembly, revealing new therapeutic targets for diseases caused by impaired chromatin remodeling.

How the numerous neuron subpopulations in the lateral (CeL) and medial (CeM) subdivisions of the central amygdala regulate appetitive behavior is poorly understood. Here, the authors report that appetitive neurons are confined to the CeM with separate subpopulations driving water only, versus water or food consumption.

A human neural organoid cell atlas integrating 36 single-cell transcriptomic datasets shows cell types and states and estimates transcriptomic similarity between primary and organoid counterparts, showing potential to assess organoid fidelity and facilitate protocol development.

Heart failure with preserved ejection fraction (HFpEF), which can be driven by obesity and hypertension, has a high prevalence but limited treatment options. Here, the authors show that nitro-oleic acid restores mitochondrial function and improves heart failure symptoms in a mouse model of HFpEF.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Many pelagic fishes and squids live at ocean depths below the euphotic zone but whether surface predators dive to these depths to feed on them is unclear. Here, the authors tag Chilean devil rays and demonstrate that they regularly make dives to at least 1,500 m, suggesting that the rays forage for food at these depths.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

The high elevation in Earth’s topography of hard rocks, such as granites and basalts, was thought to be caused by their inherent resistance to erosion. Numerical modelling now demonstrates, counterintuitively, that erosion-induced isostatic rebound of rocks, which is density dependent, causes granites and basalts to occupy high elevations because they are more dense than surrounding rocks.

Resistance to anti-EGFR therapy is a clinical issue for patients with advanced head and neck cancers. Here, the authors show that therapy-resistant cancer cells enhance fatty acid metabolism, which can be therapeutically targeted by inhibiting peroxisome proliferator-activated receptor alpha (PPARα).

In this study, the authors report that pluripotent stem cell-derived ventricular progenitors target loss of myocardium and fibrotic scarring to promote heart regeneration, thus offering new potential therapeutic strategies for heart injury.

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.

White matter (WM) astrocytes differ significantly from gray matter astrocytes, with WM astrocytes in the forebrain exhibiting unique proliferation capacity, which is absent in cerebellar WM, suggesting region-specific astrocyte generation.

This work highlights the technical issues in previous approaches and introduces a preprocessing approach along with a software package, MethSCAn, for single-cell bisulfite sequencing data analysis.

Ischemic stroke, caused by sudden oxygen and substrate deprivation of the CNS, is a leading cause of disability and death. Here, the authors characterize in a rodent model the molecular signature of glial cells in response to ischemic stroke at single cell resolution.

The transport measurements of an interacting fermionic quantum gas in an optical lattice provide a direct experimental realization of the Hubbard model—one of the central models for interacting electrons in solids—and give insights into the transport properties of many-body phases in condensed-matter physics.

Optogenetic actuation regimes are often static, which allows perturbation, but not true control of neuronal activity. Here, the authors describe an all-optical method for bidirectional steering of membrane potential, in closed loop, in C. elegans muscles and neurons, and rat hippocampal slice culture. The ‘optogenetic voltage clamp’ uses two microbial rhodopsin actuators and the rhodopsin voltage indicator QuasAr.

Although it has been shown that engineering of conducting polymers such as poly(3,4-ethyldioxythiophene) can improve the Seebeck coefficient and the figure of merit ZT of these materials, the mechanisms underlying this improved thermoelectric behaviour are still not fully understood. It is now reported that the band structure of semicrystalline films of these bipolaronic polymers, resembling that of inorganic semi-metals used for thermoelectric applications, can explain these findings.

A phase I trial of a neoantigen-targeting personalized cancer vaccine led to durable and polyfunctional T cell responses and antitumour recognition, and was associated with no recurrence in patients with high-risk clear cell renal cell carcinoma.

Cultured adult cardiac tissue undergoes rapid dedifferentiation, which hinders chronic in vitro studies. Here the authors investigate biomimetic electromechanical stimulation of adult myocardial slices applying different preload conditions, identifying the optimum sarcomere length for prolonged culturing, and investigating transcriptional profiles associated with functional preservation.

Jakab et al. show that metastasizing tumor cells have a predetermined methylation status that allows them to respond differentially to endothelial cell niche-derived Wnt signals, resulting in either latency or intravascular proliferation.

Lalioti, Romero-Mulero et al. combine metabolomics, lipidomics and transcriptomics of haematopoietic stem and progenitor cells during differentiation, ageing and leukaemia, finding a role for choline and showing that supplementation enhances stemness.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

A global dataset of the satellite-tracked movements of pelagic sharks and fishing fleets show that sharks—and, in particular, commercially important species—have limited spatial refuge from fishing effort.

The combination of mathematical modelling of tumour tissue, optical imaging of cleared tumours from animal models, and in vivo imaging of vascular perfusion in tumours predicts the tumour uptake and distribution of specific therapeutic agents.

The authors use long-term satellite tracking to project climate-induced shifts in whale shark distributions and understand their potential future risk of ship-strike. Under high-emission scenarios, the movement of sharks to current range-edge habitat is linked to 15,000-fold increased co-occurrence with ships.

The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Many methanogenic archaea use H₂ and CO₂ to produce methane. Here, Taubner et al. show that Methanothermococcus okinawensis produces methane under conditions extrapolated for Saturn’s icy moon, Enceladus, and estimate that serpentinization may produce sufficient H₂ for biological methane production.

Histological slides often contain artifacts that affect the performance of downstream image analysis. Here, the authors present GrandQC, a tool that enables high-precision tissue and artifact segmentation in histological slides. This tool can be used to monitor sample preparation and scanning quality across pathology departments.

Optimizing lithium–electrolyte interfaces for Li metal batteries requires the use of powerful surface analysis techniques. Here, the authors demonstrate the value of ToF-SIMS sputter depth profiling in lithium metal battery research and offer guidance for future studies.

Using intergenic regions and coalescent methods to analyse the genomes of 363 bird species, the authors present a well-supported tree confirming that Neoaves experienced rapid radiation at or near the Cretaceous–Palaeogene boundary.

The ecological and evolutionary impacts of disease vary in spatially structured populations. Here, the authors study ~4000 populations of Plantago lanceolata and find that resistance evolution depends on both disease history and population structure, with isolated populations more susceptible to fungal disease.

Interogation of mass-spectrometry-based proteomics of liver and plasma from a cohort of patients with alcohol-related liver disease identifies noninvasive biomarkers associated with early stages of disease progression, including significant fibrosis, inflammation and steatosis.

Normothermic machine perfusion of the liver improved early graft function, demonstrated by reduced peak serum aspartate transaminase levels and early allograft dysfunction rates, and improved organ utilization and preservation times, although no differences were seen in graft or patient survival.

This article describes a mechanism through which CD4⁺ T cells can eradicate MHC-deficient tumours that escape direct CD8⁺ T cell targeting and thereby complement the activity of CD8⁺ T cells and natural killer cells to advance cancer immunotherapies.

A framework based on numerous empirical data, including protein-protein interaction reference sets, provides parameters for assessing the quality and coverage of protein-protein interaction datasets and estimation of the size of the human interactome. Braun et al., also in this issue, use the reference sets to help derive confidence scores for individual protein-protein interactions.

Repeat expansion mutation in C9ORF72 is the most common cause of familial ALS. Here, the authors generate motor neurons from cells of patients with C9ORF72 mutations, and characterize changes in gene expression in these motor neurons compared to genetically corrected lines, which suggest that glutamate receptor subunit GluA1 is dysregulated in this form of ALS.

Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

Alternative splicing is a critical step in eukaryotic gene expression but its molecular rules are not fully understood. Here, the authors develop a high-throughput mutagenesis approach to comprehensively characterise determinants of alternative splicing for the RON proto-oncogene.

Damian Smedley and colleagues report the phenotypic characterization of the first 3,328 genes by the International Mouse Phenotyping Consortium. They develop new mouse models based on genes known to be associated with human mendelian diseases and identify potential disease-associated genes with little or no previous functional annotation.

The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.