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Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth muscle dysfunction syndrome.

Elevated temperatures inactivate a type I restriction endonuclease in P. aeruginosa for ~60 generations via proteolytic degradation triggered by DNA hypomodification, preventing self-targeting and enabling recovery of restriction activity.

Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH) shows limited efficacy in pancreatic ductal adenocarcinoma (PDAC) models. Here the authors find that targeting the anti-apoptotic protein BCL-XL synergizes with DHODH inhibition in promoting apoptosis in PDAC cells, patient-derived organoids, and PDAC mouse models.

Ribonucleoproteins, nucleic acids and proteins are delivered into target cell types with nanosyringes.

The cell cycle of the archaeon Saccharolobus islandicus displays similarities to that of eukaryotic cells. Here, the authors use transcriptomic analysis of synchronized cultures to show that various metabolic pathways, cell motility, and antiviral defense systems are cell cycle-regulated in this organism.

Single-cell transcriptomics revealed that malaria parasites have unexpected flexibility in surface antigen expression, potentially providing parasites with greater adaptive capacity to maintain chronic asymptomatic infections.

Flores et al. show that brain-penetrant eIF2B agonists suppress ISR activation in cellular and mouse models of ALS and reduce ISR biomarkers in humans, enabling further clinical studies of ISR inhibition in individuals with neurological diseases

Targeting CD8⁺ T cell exhaustion is a strategy to enhance immune checkpoint inhibition and to fight cancer. Here the authors show a NRF2-dependent role for the prostaglandin I₂ receptor PTGIR in controlling T cell exhaustion.

Dysregulated CD4 T cells that recognize gut commensal antigens are able to infiltrate the central nervous systems and are re-stimulated by host proteins, resulting in neuroinflammation.

Kinesin-1 utilizes ATP-driven conformational changes to transport vital intracellular cargoes along microtubules. The authors use cryo-EM to reveal a missing structural transition state of the kinesin-1 motor domain during ADP release that is unaffected by its autoinhibitory tail.

mRNA medicines hold enormous promise for drugging targets outside the reach of classic small molecules. Here, the authors develop a modular platform to design programmable mRNA therapeutics that act by modifying epigenetic state.

Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder, yet it remains unclear which cell types are most impacted by MYT1L loss. Here authors use single-nuclei RNA sequencing to profile the forebrains of MYT1L-deficient mice at three developmental stages and reveal MYT1L deficiency disrupts cortical neuron proportions and gene expression, primarily affecting excitatory neuron maturation programs.

Mouse models show that respiratory infections from viruses such as influenza and SARS-CoV-2 can trigger metastasis of dormant breast cancer cells in the lungs, a finding supported by epidemiological data from two large human cohorts.

Functional CRISPR screens in patient-matched pre-treatment and post-treatment glioblastoma models identify the PTP4A–ROBO1 axis as a driver of tumorigenicity and enriched ROBO1 expression in recurrent glioblastoma that can be targeted with CAR T cell therapy.

In human spinal ligament tissue exposed to high stress, fibrotic regions displaying elevated Rho-associated kinase signalling and an increased density of myofibroblasts expressing smooth muscle actin α contribute to degenerative spinal disease.

Here, the authors use cryo-EM and machine-learning-based tools to analyze structurally heterogeneous ribosome assembly intermediates. They uncover a new proofreading function of the bacterial methyltransferase KsgA, wherein this assembly factor recognizes and drives partial disassembly of translationally incompetent particles, thereby affording these intermediates another opportunity to assemble in an active form.

FoxO3a signalling has limited influence over acute bacterial infection. Here the authors show that FoxO3a promotes survival of mice in response to chronic Salmonellatyphimurium infection by restraining oxidative stress and ERK signalling.

Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

Robbins and colleagues show that cigarette smoke-induced endothelial dysfunction enables atherosclerotic plaque macrophages to drive abdominal aortic aneurysm formation in a mouse model of atherosclerosis.

In an experimental autoimmune encephalomyelitis model in mice, a subset of astrocytes retains an epigenetically regulated memory of past inflammation, causing exacerbated inflammation upon subsequent rechallenge.

Multiple GTP-binding proteins (GTPBPs) aid ribosome maturation. Here, authors pinpoint GTPBP8’s involvement in human mitoribosome maturation, demonstrating its specific binding to mitoribosomal large subunit RNA, which is necessary for ribosome assembly and protein synthesis.

Cryo-electron microscopy structures of a folding intermediate on the BAM complex of Escherichia coli reveal how interactions between the BamA catalyst and substrate permit stable association during folding, followed by rapid turnover.

Impaired gut barrier function is a central driver of alcohol-related liver disease. This study indicates that the postbiotic ReFerm® improves gut barrier function and reduce liver stiffness and liver fibrosis, suggesting the gut barrier function as a potential treatment target.

Sun and colleagues report that the transcription factor TCF19 regulates calcium signaling and cell cycling progression in NK cells and is required for innate and adaptive NK cell responses to viral infection.

Building crystal structures into the electron density is an important step in protein structure solution. Here, the authors recruit online game players, students, and experienced crystallographers to compete in a competition to solve a new structure, and find that crowdsourcing model-building works.

The improper timing of transforming growth factor-β production is a hallmark of severe COVID-19 that may impede natural killer cell function and early control of infection.

Epicardial engineered heart muscle allografts from induced pluripotent stem cell-derived cardiomyocytes can safely and effectively remuscularize chronically failing hearts in rhesus macaques, leading to improved cardiac function and paving the way for human clinical trials.

The targeted integration of large DNA payloads into primary human T cells can be efficiently achieved non-virally by leveraging Cas9-based editing and the DNA-repair pathway homology-mediated end joining.

Repeated vaccination is needed to maintain high levels of SARS-CoV-2 immunity in vulnerable populations, but there is concern that it could lead to immune exhaustion. Here, the authors assess the evidence for immune exhaustion following multiple SARS-CoV-2 vaccination three vulnerable population cohorts in Canada.

A population epigenomic analysis of wild Arabidopsis thaliana accessions is presented, obtained by sequencing their whole genomes, methylomes and transcriptomes; thousands of DNA methylation variants are identified, some of which are associated with methylation quantitative trait loci.

A computational deep learning approach is used to design synthetic proteins that target the neosurfaces formed by protein–ligand interactions, with applications in the development of new therapeutic modalities such as molecular glues or cell-based therapies.

Primary T cells with multiple genetic modifications are rapidly isolated by negative selection.

The ascomycete Cenococcum geophilum is a beneficial mycorrhizal symbiont found frequently on tree roots. Here the authors use comparative genomics and transcriptomics to define genomic signatures that differentiate the beneficial C. geophilumfrom its saprotrophic and pathogenic relatives.

Black and white fonio are two small indigenous grain cereals grown in West Africa. Here, the authors reveal their independent domestication and cultivation histories through population genetics and demographic history analyses.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

By individually replacing 16 yeast genes encoding ABC transporters by GFP, mating and selecting for strains with accumulated mutations the authors create a Green Monster, a strain with deletions in all 16 genes.