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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.

The balance between cell proliferation and cell cycle arrest is essential for liver regeneration. Here the authors report the emergence of partially reprogrammed hepatocytes persisting in plastic states during liver tissue injury, which are resistant to proliferation thereby limiting overgrowth and tumorigenesis.

In chemical-genetic and lipidomics analyses, the clinical candidate oncology drug tegavivint induced an unconventional form of nonapoptotic cell death that required the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase.

Current water-soluble prodrug technologies typically result in a lack of overall improvement in oral bioavailability relative to standard formulation strategies. Here, the authors report water soluble promoiety (Sol-moiety) technology that shows improved oral bioavailability over existing water-soluble prodrug technologies and the ability to switch from intravenous to oral administration.

Mosquito salivary glands and malaria parasites exhibit daily rhythms, which impact blood feeding and sporozoite gene expression.

Multimodal data from 347 deeply phenotyped individuals including healthy, prediabetic individuals and individuals with T2D report remotely acquired patterns of glucose control via continuous glucose monitoring, and correlates them with diet and microbiome features and physiological signals, showing that these are able to discriminate individuals with T2D from control also in a large independent cohort.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

The bile ducts of the liver form a network of large ducts and small ductules, though how they are patterned remains unclear. Hrncir et al. show that Sox9 is required for the morphogenesis of small intrahepatic bile ductules in mice, highlighting distinct genetic requirements that drive bile duct heterogeneity.

In a preclinical study, the delivery of an AAV-based gene therapy encoding GDNF in the brain prevented the return to alcohol use behaviors in a non-human primate model.

Secondary malignancies and chimeric antigen receptor (CAR)-T-derived malignant T cell transformation have been reported after CAR-T therapy. Here, the authors describe a patient with diffuse large B-cell lymphoma (DLBCL) who developed new lymphadenopathy 2.5 years after CAR-T in the context of COVID-19 infection with histopathologic features consistent with T-cell lymphoma (TCL).

Gut microbiota play a critical role in drug metabolism. Now, by exploring the human gut microbial metabolism of G-protein-coupled receptor (GPCR)-targeting drugs, uncommon pathways and biotransformations are elucidated, revealing how the activity of the metabolized drugs against target GPCRs is modulated.

Spatial transcriptomics was combined with single-nucleus RNA sequencing to annotate healthy and fibrotic human livers, improving spatial resolution of hepatocytes and receptor-ligand interactions and identifying cell populations that expand with injury.

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.

Meng et al. show that ZBTB43 alters Z-DNA structures to prevent deleterious double-strand breaks and promote DNA methylation at purine–pyrimidine repeats in the mouse germ line.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.

An analysis of the localization and intensity of intracortical microstimulation in three participants with cervical spinal cord injury shows that overlapping projected fields from multiple electrodes produce sensations that are more easily localizable.

A quantitative morphological framework for the human thymus reveals the establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions in fetal and paediatric thymic development.

Here the authors report the structure of the proteasome of Trichomonas vaginalis (Tv), a protozoan causing trichomoniasis. It shows how inhibitors target this enzyme and provides basis for developing specific proteasome inhibitors to treat trichomoniasis.

It is often assumed that neuronal responses to value are linear, in part because this is important for rational economic decision-making. Here, the authors find, in two male macaques, that value is encoded along a curved manifold in the prefrontal cortex and that this curvature imposes bounds on rational decision-making.

This study links the genomic basis of behavioral variation to specific cell populations in the brain. Here, authors find evidence for involvement of neural stem cells in the evolution and expression of bower-building behavior in cichlid fishes.

The Food Compass is a nutrient profiling system to characterize the healthfulness of diverse foods, beverages and meals. In a nationally representative cohort of 47,999 U.S. adults, the authors validate a person’s individual Food Compass Score against health outcomes.

Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.

A meta-analysis of peer-review data from over 300,000 biological sciences manuscripts reveals worse review outcomes for authors from historically excluded groups, and limited data evaluating the effectiveness of interventions to address bias in peer review.

Microglia clearance activity in adult brain is regulated epigenetically and region-specifically to match neuronal attrition rates. Uncoupling this activity from neural apoptosis leads to aberrant microglia activation & neurodegenerative-like changes.

Resorption of myocardial scar and subsequent regeneration may be influenced by the extent of irreversible pyridinoline and deoxypyridinoline collagen cross-links that develop in the scar. Hydroxylation of lysine in collagen may regulate this process.

Pre-existing high-affinity antibodies alter germinal centre and memory B cell selection by lowering the activation threshold for B cells and through direct masking of their cognate epitopes, thereby permitting a diverse set of abundant lower-affinity clones targeting alternate epitopes to participate in the immune response.

Pyramidal cells are classically thought to comprise the excitatory output of the subiculum. Here, the authors show the existence of “ovoid cells”, excitatory subiculum neurons with specialized gene expression, morphology, projections, and function.

A pan-betacoronavirus vaccine will likely require the elicitation of antibodies against spike regions conserved across diverse coronaviruses. Here, authors computationally engineer and experimentally validate immunogens to elicit antibodies against two such spike regions.

A third dose of an mRNA vaccine against SARS-CoV-2 results in an expanded B cell repertoire that produces antibodies with increased potency and breadth.

Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention.

Human Microrchidia 4 (MORC4) ATPase has been implicated in acute and chronic pancreatitis, inflammatory disorders and cancer. Here the authors describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation.

Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.

Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.

Using genome-wide miRNA mimic and hairpin inhibitor screens, Li et al. identify 31 miRNAs that either inhibit or promote hepatitis C virus (HCV) replication at different steps of the viral life cycle. Furthermore, human liver biopsies show that HCV down-regulates identified miRNAs with antiviral function.

Graft-versus-host disease, a T cell-driven inflammatory condition, is associated with altered microbial bile acid metabolism in both mice and humans and this is linked to outcomes.

Population receptive fields (pRFs) in the visual system are key information-processors, but how they develop is unknown. Here, authors use fMRI and pRF modeling in children and adults to show that in the ventral stream only pRFs in face- and word-selective regions continue to develop, mirroring changes in viewing behavior.

Here, the authors show that deletion of Pglyrp1 promotes antitumor immunity owing to its inhibitory function in CD8⁺ T cells and that targeting it can inhibit development of autoimmune neuroinflammation. These findings indicate that PGLYRP1 might be a target for immunotherapy.

Senescence and quiescence are considered different cell states but are hard to distinguish. Here, single-cell imaging followed by immunostaining reveals that the intensities of senescence biomarkers are graded rather than binary, reflecting the duration of cell-cycle withdrawal rather than irreversible cell-cycle arrest.

Combined multimodal atomic force microscopy, ion microscopy, ion mass spectrometry and infrared spectrometry experiments explore the chemical properties of ferroelastic twin domains in hybrid lead halide perovskites.

The development of metal–organic magnets that combine tunable magnetic properties with other desirable physical properties remains challenging despite numerous potential applications. Now, a mixed-valent chromium–triazolate material has been prepared that exhibits itinerant ferromagnetism with a magnetic ordering temperature of 225 K, a high conductivity and large negative magnetoresistance (23%).

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Neurons with grid firing fields are thought to play important roles in spatial cognition. Here, the authors show that in contrast to assumptions underlying current models and analyses, grid fields are modulated by local head direction; this suggests different mechanisms and new roles for grid firing.

Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.

Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Spatial transcriptomics reveals distinct composition and organization of cells and circuits in the mouse prefrontal cortex (PFC) relative to adjacent cortices, which concur with PFC’s diverse functions, and also help detect neurons involved in chronic pain.

Ghobrial, Getz and colleagues characterize the changes in the tumor immune microenvironment associated with multiple myeloma progression.