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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.

Cottam et al. identify distinct pathways for D-ribulose utilisation in pathogenic Escherichia coli and Citrobacter rodentium, providing mechanistic details and suggesting convergent evolution towards utilisation of this nutrient in nature.

Probing endogenous protein localization and function in vivo remains challenging due to laborious gene targeting and monofunctional alleles. Here, using a toolkit consisting of genetically-encoded epitope probes, their cognate tags, and an array of adapter proteins, the authors describe a methodology that enables visualization and manipulation of endogenous proteins in vertebrate systems.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a promising candidate for tuberculosis treatment regimens.

Here, the authors present a multi-omics examination of stool samples obtained from individuals with diverticulitis and controls, uncovering disruptions in the balance of microbial composition and metabolites, as well as co-occurring microbe-metabolite associations relevant to the disease.

This study characterizes the three-dimensional (3D) genome architecture of 15 primary human cancer types from The Cancer Genome Atlas. The analyses identify different archetypes of enhancer usage and enhancer rewiring events due to different classes of mutations and structural variants.

The study reports the cloning of paired NLR genes CNL and NL from wild emmer wheat and demonstrates their coordinated function in conferring Yr84-mediated wheat stripe rust resistance.

Saheki and colleagues show that extended synaptotagmins (E-Syts), ER proteins that function as tethers to the plasma membrane, can transfer lipids between bilayers in a Ca²⁺- and SMP-domain-dependent manner, thus regulating plasma membrane lipid homeostasis.

Whole-genome sequencing analysis of 81 prehistoric individuals reveals how the genetic makeup of people from the North Pontic region was influenced by waves of migration during the Eneolithic period and Early Bronze Age.

Here, Cottam et al. identify an L-arabinose transporter in Enterohaemorrhagic Escherichia coli and show that metabolism of this dietary sugar upregulates the type 3 secretion system, thus enhancing its fitness within the host gut.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

Data collected by the Parker Solar Probe in the solar corona are used to determine the organization of Alfvén waves, revealing an increasing flow velocity peaking at 35–50 km s⁻¹.

Here the authors show that gain-of-function mutant p53s predispose cells to chromosomal instability by targeting MCMs, leading to activation of a cGAS-STING-non-canonical NF-κB signaling that promotes tumor metastasis and immunosuppression.

Mammalian gene silencing is associated with both histone and DNA methylation. The PRMT5 arginine histone methyltransferase is now found to affect DNA methylation at the γ-globin locus in mice. This is mediated by an effect on recruitment of the DNA methyltransferase DNMT3A, but through interaction with the product of PRMT5 activity. This suggests that DNMT3A reads the histone methylation, coupling it to nearby DNA methylation.

Bacteria can affect cellular processes in other bacteria and in eukaryotic cells by injecting effectors using a type VI secretion system (T6SS). Here, Sá-Pessoa et al. describe how a T6SS effector from the bacterial pathogen Klebsiella pneumoniae triggers the fragmentation of the mitochondrial network in eukaryotic cells.

Adipogenesis associated Mth938 Domain Containing gene (AAMDC) is frequently amplified in the IntClus2 subgroup of ER + breast cancer. Here, the authors show that AAMDC drives tumourigenesis through activating PI3K-AKT-mTOR pathway for metabolic reprogramming.

Aegilops sharonensis is a wild diploid relative of wheat. Here, the authors assemble the genome of Ae. sharonensis and use the assembly as an aid to clone the Ae. sharonensis-derived stem rust resistance gene Sr62 in the allohexaploid genome of wheat.

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

The antidiabetic action of metformin raises heptocyte intracellular AMP levels, causing allosteric inhibition of fructose-1,6-bisphosphatase and thus reductions in gluconeogenesis.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

The etiology of TDP-43 proteinopathy in ALS and FTD is complex. Here, the authors show that prior to disease onset in the rNLS8 mouse model, cortex neurons elicit a transient increase in protective chaperones that combat TDP-43 aggregation.

A pangenome analysis of 76 wild and domesticated barley accessions in combination with short-read sequence data of 1,315 barley genotypes indicates that allelic diversity at structurally complex loci may have helped crop plants to adapt to agricultural ecosystems.

BiTE-secreting CAR-T cells overcome antigen escape from EGFRvIII-targeted therapy for glioblastoma.

Bacterially produced bile acids inhibit T_H17 cell function, which may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.

Activity-based probes (ABPs) are widely used for system-wide profiling of enzymatic activity. Electrophilic ABPs applied to genomic RNA libraries led to the isolation of a 42-nt RNA motif that was adapted as an alkylation-based RNA labeling strategy.

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.

Characterization of a biosynthetic pathway for the sulfonation of steroidal metabolites, such as cholesterol, by gut bacteria may have implications for immune cell trafficking and inflammatory bowel disease.

Circadian rhythms are known to impact a range of biological processes including in the immune system. Here the authors show how circadian rhythms modulate the T cell response to vaccination via regulation of dendritic cell metabolism.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

CD8⁺ T resident memory (T_RM) cells are important in protection against virus infection and NFκB signalling may function in this process. Here the authors use an inducible transgenic mouse models where T cell intrinsic NFκB levels can be increased or decreased which affects how CD8⁺ TRM cells seed into the lungs after influenza infection.

Biochemical and functional analysis with deletion mutants shows that altering the properties of biomolecular condensates driven by the ERC1/ELKS scaffold protein interferes with tumor cell motility.

CRISPR-mediated gene knockout and activation are used to identify molecules in cancer cells and macrophages that regulate antibody-dependent cancer cell phagocytosis.

Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.

IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice.