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An atlas study of adipose tissue in people with obesity undergoing weight loss and their lean counterparts reveals that weight loss reduces cell senescence but cannot reverse all the metabolic problems caused by obesity.

Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.

Mitochondrial diseases lead to chronic health impairment, aggravated by infections and other environmental exposures. Here authors show, in a mouse model of polymerase gamma (Polg)-related mitochondrial disease, that Pseudomonas aeruginosa infection prompts innate immune hyperreactivity via interferon-mediated upregulation of caspase11 and guanylate-binding proteins, leading to lung inflammation.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

Leber congenital amaurosis is caused by mutations in RPE65 and leads to retinal degeneration in children. Here, the authors show that in vivo base editing can prolong the survival of cone photoreceptors and rescue their function in a mouse model of the disease.

Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.

Chronic rhinosinusitis with nasal polyps generally has a type 2 inflammatory eosinophilic profile but can have a treatment resistant neutrophilic phenotype. Here the authors characterise nasal polyps using single cell sequencing and spatial transcriptomics and show granzyme K⁺CD8⁺ T cells associated with neutrophilic inflammation which promote release of neutrophilic chemoattractants from fibroblasts.

Gamma delta (γδ) T cells have potential for use in immunotherapy against tumours. Here, the authors demonstrate that treatment of tumours with DNA methyltransferase inhibitors modulates cytoskeleton arrangements, upregulates adhesion molecules and increases tumour killing by γδ T cells.

A neuron-specific activity-dependent DNA repair mechanism is identified, the impairment of which may lead to neurodevelopmental disorders, neurodegeneration and ageing.

Base editors can inactivate splice sites or introduce stop codons into a gene sequence. Here the authors present SpliceR to design, rank, and test sgRNAs for efficient gene disruption in T cells.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Schrank et al. report the design and characterization of an antibody–toxin conjugate targeting CD47, promoting anti-tumor immunity in preclinical cancer models.

McGavern and colleagues identified a CD8⁺ T cell population that expresses GZMK in ʽtau-richʼ brains, where it may play a protective role against neurodegeneration.

The authors use lineage tracing to map the fate of wild-type and Brca1^−/−;Trp53^−/− cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization.

Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG. They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

Isaac et al. present mtFiber-seq, a method that measures individual mitochondrial genome packaging at nucleotide resolution. They show that most nucleoids are in an inaccessible state, modulated by the abundance of the DNA-binding protein TFAM.

A first-in-human phase I clinical trial demonstrates the feasibility and safety of non-viral precision genome-engineering of a personalized adoptive cell transfer anticancer therapeutic.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.

SARS-CoV-2 evolution poses a risk to vaccine and antiviral drug efficacy. Here, Gagne et al. report the development of a variant-agnostic protein, RBD-62, with enhanced ACE2 binding obtained through in vitro evolution and show that RBD-62 inhalation protects nonhuman primates against SARS-CoV-2 Delta challenge.

A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

The efficacy of cancer drugs is profiled by measuring changes in the mass of single tumor cells.

Studying RNA dynamics in vivo often relies on fluorogenic approaches, but these can be hampered by factors such as limited sensitivity and sample autofluorescence. Here, the authors describe an ultrasensitive platform for RNA imaging, which features RNA tags that recruit light-emitting luciferase fragments.

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.

Early lipid accumulation is thought to contribute to liver regeneration through unclear functional mechanisms. Here the authors identify an epigenetic regulator, MIER1, that bridges the acute lipid accumulation and cell cycle gene transcription during liver regeneration after surgical resection in male mice.

In this Consensus Statement, an international group of experts provide updated recommendations on the treatment of acromegaly, including discussion of treatment outcomes.

By demonstrating a computational approach to restore the clinical efficacy of a COVID-19 antibody, the potential to rapidly update clinical antibodies is explored.

Tumor-reactive T cell receptors are rapidly identified from lymphocyte scRNA-seq data.

Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or de novo missense variants in SMCHD1 in arhinia patients. Some of the same mutations in SMCHD1 are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with SMCHD1 to cause arhinia.

There has been active debate over microbial life in Antarctic subglacial lakes owing to a paucity of direct observations from beneath the ice sheet and concerns about contamination in the samples that do exist; here the authors present the first geomicrobiological description of pristine water and surficial sediments from Subglacial Lake Whillans, and show that the lake water contains a diverse microbial community, many members of which are closely related to chemolithoautotrophic bacteria and archaea.

Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.