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The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

Heteroplasmic mtDNA mutations cause disease in humans. Here, Chung et al find the PI3K-Akt-mTORC1 pathway constitutively activated in cells with the heteroplasmic m.3243 A > G mutation, and inhibition of the pathway cell autonomously reduces mutant mtDNA load and rescues mitochondrial bioenergetics.

It is generally acknowledged that pathological B-cell receptors drive chronic lymphocytic leukaemia (CLL) via continuous signalling emanating from BCR-BCR homotypic interactions, rather than external antigens. Here the authors show, by analysing the structure and function of three B-cell receptors from patients with stereotyped CLL subset 1 that homotypic interactions and consequential autonomous signalling is not universal and other mechanisms could play roles in leukemic proliferation of CLL cells.

Investigations in wild bats and non-human primates in Brazil and Costa Rica inform about diverse Morbillivirus ecology in neotropical bats and host jumps, and about zoonotic potential of morbilliviruses in Latin America.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Yellow fluorescent proteins (YFPs) photobleach rapidly, restricting microscopy experiments. Here, the authors report mGold2s and mGold2t, YFPs that extend imaging durations up to 25 times longer than standard probes without sacrificing brightness.

Recently, theories have emerged that describe the nonlinear high-energy excitations of one-dimensional electronic fluids. Here, the authors report experimental evidence of their existence and behaviour in tunnelling spectra of short GaAs quantum wires.

VRACs are ubiquitously expressed osmosensitive ion channels assembled from LRRC8A-E subunits. Here, the authors determine the structures of a LRRC8A:D VRAC using cryo-EM and identified that these channels are gated by lipids inside the channel pore.

The therapeutic relevance of telomere maintenance mechanisms in cancer, remains to be explored. Here, the authors integrate multi-omic data and functional readouts, generate a resource of telomere biology metrics and identify potential molecular vulnerabilities.

Previously, OLIG2-expressing stems cells have been identified as having a role in medulloblastoma recurrence. Here, the authors investigate the effects of targeting this OLIG2+ stem cell population in Sonic Hedgehog (SHH) medulloblastoma using CT-179, an OLIG2 inhibitor.

SIVmac239 infection of macaques is a favored model of human HIV infection, but antibody-mediated protection for SIVmac239 is insufficiently understood. Here, Zhao and Berndsen et al isolated nAbs and confirmed protection against SIVmac239 infection in passive transfer studies in macaques. The nAb was used to provide the first high-resolution structure of a rhesus SIV trimer by CryoEM. Analysis of the glycosylation pattern of this SIV trimer suggests a denser glycan shield on Env for rhesus SIV compared to chimpanzee SIV or HIV-1, which partially explains the poor nAb response of rhesus macaques to SIVmac239 infection.

Antibodies against SARS-CoV-2 provide protection against infection, but the virus has evolved to evade them. Here, the authors characterize a human antibody with incomplete neutralization of SARS-CoV-2 variants and engineer it to enhance potency and expand coverage to all tested variants by increasing conformational flexibility.

Bacterial antigens, such as lipopolysaccharides, are complex structures which remain difficult to synthesise or purify for antibody generation. Here, authors present a platform technology using Citrobacter rodentium - an enteric mouse pathogen - to both produce and present complex antigens for antibody generation.

The viscosity of tumour cells is shown to govern their ability to disseminate through the bloodstream and extravasate, establishing a key biomechanical factor of metastasis.

Previously, authors have identified GW461484A (GW) as an inhibitor of the kinase Yck2 in the fungal pathogen Candida albicans. Here, they report the synthesis of GW analogs with improved pharmacological properties and activity in mouse models of systemic candidiasis.

The quantum-confined Stark effect is conventionally observed in inorganic semiconductor multilayer quantum well structures that are expensive to make. Here Walters et al. report large Stark effects in easily made layered hybrid perovskites and exploit the orientational polarizability of dipolar cations.

The authors identify the DedA superfamily protein VMP1 as an ER-resident lipid transporter in human parasites T. gondii and P. falciparum. VMP1 is crucial for the function of secretory organelles, ER maintenance, and homeostasis of lipid droplets.

Cancer cells can squeeze through confined spaces and undergo nuclear deformation, leading to changes in chromatin organisation. Here, the authors show that mechanical constriction in microcapillaries reprograms melanoma cells to a tumorigenic stem cell-like state through the mechanosensor PIEZO1.

The role of non-cancer cells infected by oncolytic viruses (OV) in cancer regression remains elusive. Here the authors engineer OV-sensitive and OV-resistant cancer cell lines and show that OV infection of non-cancer cells can elicit effective antitumour immunity via enhancing DC function and CD8⁺ T cell activation.

Human pathogenic-like Th17 cells express the chemokine receptor CCR6, but how CCR6, together with other chemokine receptors, modulate Th17 functions is still unclear. Here the authors show that CCR2 is coexpressed with CCR6 on these cells, and specifically mediates transendothelial migration, while CCR6 and other chemokine receptors induce T cell arrest on activated endothelial cells.

CD27 is a key T-cell costimulatory receptor, but efforts to target CD27 have been limited by the poor clinical efficacy of first-generation anti-CD27 antibodies. The authors here engineer higher-valency antibodies by more effectively engaging CD27 and selectively binding to FcγRIIB, which enhance anti-tumor activity.

Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.

Here the authors map the dynamics of human NK cell residency and recirculation, showing that CD56^bright NK cells transiently occupy tissues and recirculate via lymphatics, whereas CD56^dim NK cells remain vascular except during inflammation.

Trends in global H₂ sources and sinks are analysed from 1990 to 2020, and a comprehensive budget for the decade 2010–2020 is presented.

In this work, Beyer and colleagues have utilized display screening technologies to comprehensively chart RAS proteins “druggability” and in doing so unravel a targetable ligand-induced pocket in RAS opening unprecedented anti-RAS targeted opportunities.

Payton et al. develop small-molecule inhibitors of kinesin KIF18A able to selectively kill cancer cells with high chromosomal instability and demonstrate that the inhibitors are therapeutically beneficial in cancer patient-derived in vivo models.

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins.

The cytochrome bc₁ oxidase of Mycobacterium tuberculosis is a potential target in the fight against tuberculosis. Here, the authors evaluate the potential of cytochrome bc₁ inhibitors as partner drugs in tuberculosis treatment regimens.

Combination immunotherapy approaches might be effective in inducing sustained control of HIV by slowing rebound and improving CD8⁺ T cell responses.

Here, the authors find that low Nicastrin protein in the disease Hidradenitis Suppurativa enhances immune sensitivity and may be caused by exposure to plastic-associated compounds.

This study shows that the relationship between concentrations of ambient fine particulate matter (PM_2.5) and its health effects may vary in different regions of the world due to significant spatial variations in the toxicities of PM_2.5.

Analyses of single epithelial cells from early-stage lung adenocarcinoma and normal lung identifies a population of intermediate cells that may have an increased likelihood of transforming to tumour cells after injury such as tobacco exposure.

This multi-omic longitudinal analysis of the healthy human peripheral immune system constructs the Human Immune Health Atlas and assembles data on immune cell composition and state changes with age, including responses to cytomegalovirus infection and influenza vaccination.

Superconducting transmon qubits are limited by a tradeoff between anharmonicity and charge-noise sensitivity. Here, the authors show how highly transparent Josephson junctions in hybrid superconducting-semiconducting heterostructures can remove this tradeoff and achieve both benefits.

This study maps Campi Flegrei caldera’s internal structure, linking a gas-enriched reservoir and a deformed caprock to ground uplift and earthquakes. Land instability, seismic events and the risk of a phreatic explosion prompt for updated multi-hazard assessments.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

Conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1⁺ mouse macrophages ameliorates heart failure and substantially reduces fibroblast activation.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.

Anti-FXN nanobodies (NBs) stabilize FRDA FXN variants in vitro. High-resolution structures of NB-FXN complexes were determined. NBs expressed in human cells localize to the mitochondrial matrix and interact with FXN without disrupting cell metabolism.

Here, the authors engineered probiotic bacteria to sense inflammatory biomarkers in the gut and respond by producing protein reporters that can be imaged noninvasively with ultrasound, providing a potentially easier and cheaper approach to diagnose and monitor IBD or other GI conditions.

The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled in the faeces.