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Immunotherapy with immune checkpoint inhibitors and targeted therapy with BRAF and MEK inhibition have revolutionized the treatment of melanoma. Here the authors report the results of a phase II trial of neoadjuvant cobimetinib (MEK inhibitor) and atezolizumab (anti-PD-L1) with or without the BRAF inhibitor vemurafenib in patients with resectable Stage III melanoma.

We report on the structures of the TAAR1–G-protein complex when bound to methamphetamine and other amines.

The type VI secretion system (T6SS) of Gram-negative bacteria is typically anchored to the cell envelope through a membrane complex (MC), but Bacteroidota appear to lack genes encoding canonical MC components. Here, Bongiovanni et al. identify the Bacteroidota MC and study its biogenesis and connections with the conserved T6SS components.

Sanguina nivaloides thrives in red snowfields worldwide. It cannot be cultivated. Using environmental samples, 3D electron microscopy combined with functional analyzes revealed unique cell architecture features adapted to life in a snowy environment.

Ferrosome organelles produced by Clostridioides difficile are required to support colonization of the inflamed gut, highlighting the potential of targeting ferrosome formation as an antimicrobial strategy against this important pathogen.

Single-cell transcriptomics and protein expression analyses of salivary glands and gingiva, along with the detection of infectious virus and virus-specific antibodies in saliva from SARS-CoV-2-infected individuals, support a potential role for the oral cavity in COVID-19 pathogenesis.

PTPRK is a key protein in the transformation of normal to tumorigenic liver cells in obesity, providing fuel and lipids. Here, the authors show that genetic deletion of PTPRK in mice protects against fatty liver in an obesogenic diet and the development of liver cancer.

WHaloCaMP is a chemigenetic calcium indicator that can be combined with different rhodamine dyes for multiplexed or FLIM imaging in vivo, as demonstrated for calcium imaging in neuronal cultures, brain slices, Drosophila, zebrafish larvae and the mouse brain.

Now a reactivity-based RNA profiling strategy can measure the global off-target transcriptome interactions of small-molecule drugs at single-nucleotide resolution. Using this approach, three FDA-approved drugs were evaluated, uncovering pervasive drug–RNA interactions and interactions that perturb RNA functions in cells.

Here, Chen et. al. characterize the relationship between the gut microbiota and plasma metabolite changes in the context of ST-elevation myocardial infarction (STEMI), unveiling a role of butyrate-producing bacteria and their ketogenesis in post-STEMI cardiac repair, a finding validated in nonhuman primate and mouse models. They show that butyrate supplementation reduces myocardial infarction severity in mice, underscoring the significance of butyrate-producing bacteria and beta-hydroxybutyrate in improving post-MI outcomes.

Systematically culturing combinations of auxotrophic yeast mutants leads to the identification of pairs that form obligatory cross-feeding relationships, some of which are stable over time and can divide metabolic labor for biotechnological applications.

A selective inhibitor of Sec61 blocks protein entry into the secretory pathway and has therapeutic efficacy in rheumatoid arthritis. A cryo-EM structure of the inhibited Sec61 provides a model for client-selective protein translocation inhibition.

Using highly purified protein factors, we provide evidence that BRCA1–BARD1 physically interacts with EXO1, BLM and WRN and upregulates the activity of all three resection pathways.

Bacterial flagellar filaments are composed almost entirely of a single protein—flagellin—which can switch between different supercoiled states in a highly cooperative manner. Here the authors present near-atomic resolution cryo-EM structures of nine flagellar filaments, and begin to shed light on the molecular basis of filament switching.

Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.

The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.

Anti-folate drugs, such as methotrexate, have been largely prohibited for pregnant women because of the teratogenic effect on their descendant. Here, the authors report a intergenerational mechanism by why paternal methotrexate exposure causes craniofacial defects on their offspring.

Uncultured bacteria of the genus Quinella are found in the rumen of ruminant animals, especially in sheep that emit low amounts of methane. Here, Kumar et al. reconstruct genomic sequences from Quinella cells to provide insights into their metabolic capabilities, including lactate and propionate formation as major fermentation pathways and an apparent lack of production of H₂, a major precursor of methane.

IL-2 has been used to expand regulatory T (Treg) cells for treating inflammatory disorders. Here the authors test an engineered IL-2 mutein, delivered subcutaneously as mRNA, to show its increased specificity for activating and expanding Treg cells in both rodents and non-human primates, and to demonstrate its ability to suppress autoimmunity in mouse models.

We carried out genomic and ecological analyses of all eight extant baobab species, providing insights into their evolutionary history and recommendations for conservation efforts.

Angelman syndrome is a neurodevelopmental disorder caused by the deletion of a single gene. Here, researchers discovered a small molecule that could be delivered peripherally to activate a dormant copy of the gene throughout the brain, providing a potential treatment opportunity.

Cryo-electron microscopy structures of human and nematode spliceosomes show that the disassembly of this complex is initiated by the licensing of the disassembly helicase to act on the catalytic U6 small nuclear RNA.

Renner et al. show that HIV-1 concentrates the metabolite IP6 into its virions to catalyze assembly of its iconic conical capsid. Disabling this enrichment mechanism prevents assembly and renders HIV-1 non-infectious.

Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.

Gammage and colleagues find that mitochondrial DNA mutations induce alterations in redox metabolism, a remodeled tumor microenvironment characterized by a loss of neutrophils and consequently enhanced responses to immunotherapy in melanoma.

Basophils have been implicated in systemic lupus erythematosus (SLE), as evidenced by the fact that basophil-deficient mice do not develop the disease. Here, the authors demonstrate that PD-L1 and IL-4 expression in basophils promotes the pathogenic accumulation of follicular helper T cells in patients with SLE and murine models.

A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer’s disease who have the APOE4 genotype.

Anderson localization is a linear phenomenon, with ongoing debate about the impact of nonlinearity. This study shows that nonlinearity strengthens the localization of surface-gravity waves in a canal with a random bottom through experimental measurements and numerical simulations.

Cryo-electron microscopy structures of pig glycine receptors indicate that they are predominantly assembled with 4α:1β stoichiometry via α-homotrimer and homotetramer intermediates.

Monitoring the activity of the processive motor protein kinesin-1 in live cells is currently difficult. Here the authors report the fluorogenic small molecule QPD-OTf, a kinesin-1 substrate that causes activity-dependent dye precipitation.

An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

Mouse fibroblasts can be simultaneously directly reprogrammed into cardiomyocytes, endothelial cells and smooth muscle cells to form cardiac tissue structures that improve cardiac function on implantation into infarcted mouse hearts.

Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.

The overexpression of eight immunomodulatory transgenes in mouse embryonic stem cells allows these immunologically ‘cloaked’ cells as well as tissues derived from them to escape rejection and to survive for months in immunocompetent allogeneic recipients.

Three distinct families of gut bacteria encode an unprecedented number of respiratory-like reductases per genome to perform anaerobic respiration of biomedically relevant substrates.

CCR8 is a promising target in cancer immunotherapy. Here, authors generated mAb1, an antagonist antibody against CCR8 and determined structures of CCR8 in complex with mAb1 or the agonist CCL1, providing insights into CCR8 inhibition and activation.

N-glycosylation is vital for biological processes but difficult to analyse. Here, the authors introduce a scalable method to profile N-glycans across 20 mouse tissues, revealing tissue-specific glycosylation patterns and novel N-glycan structures, offering new insights into glycobiology.

Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.

The range of chemicals detectable by cell-free systems is still limited. Here the authors combine metabolic cascades with transcription factor networks to detect small molecules in complex environments.

Recommendations are given on optimal read coverage and selection of calling algorithm to maximize the reproducibility of cancer mutation detection in whole-genome or whole-exome sequencing.

Analyses of the structure and biochemical properties of the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 reveal details of its role in the repair of DNA double-strand breaks.

Liu et al. show that statin enhances cardiovascular disease protection through epigenetic modulation of YAP–SOX9 signaling, improving endothelial function and offering new therapeutic strategies.

Zou et al. show that SMARCD3 regulates DAB1 activity and Reelin signalling in the developing cerebellum, which can be hijacked to promote medulloblastoma cell migration and metastatic dissemination.

Asian soybean rust caused by Phakopsora pachyrhizi is an important plant pathogen, but an accurate genome assembly for this fungus has been lacking. This study sequenced three independent P. pachyrhizi isolates and generated reference quality assemblies and genome annotations, representing a critical step for further in-depth studies of this pathogen and the development of new methods of control.

This protocol uses the liquid glycan array (LiGA) platform, a library of DNA-barcoded bacteriophages displaying 5–1,500 copies of a glycan, to allow profiling of glycan–glycan-binding protein interactions on the surface of live cells.

Lactate racemase is an enzyme that interconverts the L and D isomers of the common metabolite lactate. Here, the authors show that lactate racemase represents a new type of nickel-dependent enzyme, which is activated by accessory proteins that are widespread among prokaryotic microbes.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer