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The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

Live-cell single-molecule imaging reveals that the rate-limiting step in AGO2-mediated mRNA cleavage frequently involves unmasking of target sites by translating ribosomes.

Expanding aptamer binder space through tunable directed coevolution of supramolecular scaffolds helps discover nucleic-acid-based multivalent target binders capable of synergistic engagement that cannot be obtained through monovalent selection.

Genome-scale genetic screens identify the small RNA-binding protein La as a strong mediator of prime editing.

Chagas disease, caused by Trypanosoma cruzi, lacks an effective vaccine. Here, the authors report the cryo-EM structure of TcPOP, a potential vaccine antigen, in open and closed states and validate its immunogenic potential for invasion-blocking antibodies.

Design of cysteine-targeting analogs of a reversible SETDB1 triple Tudor domain (3TD) ligand, UNC6535, led to UNC10013, a potent covalent ligand with high selectivity. UNC10013 demonstrated allosteric inhibition of SETDB1-mediated Akt methylation in cells, a promising approach to SETDB1 therapeutics.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.

Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

During starvation, muscle strength and endurance, are still critical for survival. Seven days of complete fasting did not reduce maximal strength in leg muscles, but maximal endurance capacity was decreased because carbohydrate oxidation was restrained.

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.

Hua et al., identify transcription factors and a short, conserved DNA element that drive gene expression in bundle sheath cells of rice and Arabidopsis, offering a new tool for engineering photosynthesis in crops.

A biocatalytic approach to enantioselective nucleophilic aromatic substitution (S_NAr) was achieved through laboratory evolution of highly efficient and selective S_NArase biocatalysts.

Behavior-guided transcriptomics is an extension to the BEHAV3D protocol, for the integration of T cell live-imaging data with single-cell transcriptomics, enabling analysis of gene programs linked to dynamic T cell behaviors.

Here, the authors apply a standardized system, called TXsystem, to transplant wild mouse gut microbiota into SPF mice, developing “TXwildlings” mice that stably retain natural microbiota and human-like immune traits, enhancing reproducibility and translational relevance.

Mycetoma is a chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogen Madurella mycetomatis. Here, the authors show that iron acquisition pathways in both pathogen and host are upregulated during grain formation in an insect larva infection model.

Protein/protein interaction (PPI) interfaces have emerged as drug targets to develop medications with less side effects. Here, Dvorak et al. show that small molecule targeting of PPIs in the brain is an approach for psychiatric drug discovery.

Dinoflagellates and cyanobacteria produce saxitoxin (STX) congeners that block voltage-gated sodium channels. Here authors show how amphibians may sequester STX congeners using a ‘lock and key’ mode, expanding the understanding of toxic sponge action.

PPARγ nuclear receptor ligand activities can span agonism to inverse agonism. Here, the authors use NMR to show how chemical changes within a ligand series shift the receptor’s dynamic conformational ensemble between active and repressive states.

SARS-CoV-2 has rapidly spread globally and animal models to study transmission are needed. Here, Richard et al. show efficient transmission of SARS-CoV-2 between ferrets via direct contact and via the air, through respiratory droplets and/or aerosols.

The architecture of gene regulatory networks that govern mammalian cells has been poorly understood. Here, Li et al. present a computational systems approach to elucidate the regulatory logic of the gene network for primed state pluripotency.

Embryonal tumour with multilayered rosettes (ETMR) is a rare and aggressive paediatric brain tumour. Here, the authors analyse intratumour heterogeneity and the tumour microenvironment in ETMR using single-cell and spatial transcriptomics, in vitro cultures, and a 3D forebrain organoid model, finding important aspects – such as the communication with pericytes – for ETMR development and response to therapy.

The molecular mechanisms of cell entry for the recently identified highly pathogenic feline coronavirus FCoV-23 are characterized in detail.

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

A technique for the site-directed conjugation of antibodies via the small-protein ubiquitin allows for the efficient multivalent conjugation of antibodies and nanobodies to fusions of ubiquitin with molecular or proteinic moieties.

Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.

Therapeutic interventions for motor axon regeneration following peripheral nerve injury are currently unavailable. Here authors show local administration of a non-muscle myosin II inhibitor at the injury site increases motor and sensory function recovery in vivo.

Extracellular vesicles have been implicated in the transmission of pathogens from the arthropod to the human host. Here the authors show that tick-derived extracellular vesicles play a role in feeding and modulate the outcome of bacterial infection.

Cagrilintide is a long-acting agonist of amylin and calcitonin receptors in late phase trials for obesity. Here, authors present structures of cagilintide with each target receptor, revealing the molecular basis for its non-selective action.

Hu et al. discovered that the truncated form of human epidermal growth factor receptor 2 (HER2), called p95HER2, drives tumor progression and resistance to the antibody–drug conjugate trastuzumab deruxtecan in HER2⁺ breast cancer. Blocking p95HER2 restores antitumor immunity.

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.

The fungal pathogen Candida auris can acquire amphotericin B resistance through clinically rare mutations in sterol biosynthesis genes but at a certain fitness cost, which reduces its infection potential. Compensatory evolution can, however, mitigate this cost.

A microfluidics- and electron-microscopy-based method enables the characterization of polyclonal antibody responses to infection and vaccination.

Clarke et al. identify chromatin factor ZNF280A, which is recruited to damaged chromatin where it promotes long-range DNA-end resection. Loss of ZNF280A is linked to genome instability in patients with 22q11.2 distal deletion syndrome.

G-protein coupled receptors (GPCRs) regulate numerous physiological processes and are a prominent therapeutic target. Here, Patel et al. delineate a β-arrestin independent pathway, driven by myosin VI, to shape GPCR trafficking and signaling.

Vaccination of frontline worker is an important strategy to manage Ebola outbreaks and identifying correlates of protection could lead to development of improved vaccines. Here authors predict the magnitude of the antibody response by analysing blood samples from individuals vaccinated by a heterologous two-dose regimen and using the collected cellular and transcriptomic data for training a machine learning model.

The Michael-type addition reaction is used for carbon-carbon bond formation; however biocatalytic methods for this reaction are rare. Here, the authors generate and exploit mutability landscapes of 4-oxalocrotonate tautomerase to direct the redesign of this promiscuous enzyme into enantio-complementary Michaelases.

Some epidemiological data suggests that SARS-CoV-2 can be transmitted through the air over longer distances. Here, Kutter et al. show in the ferret model that SARS-CoV-2 and SARS-CoV can be transmitted through the air over more than a meter distance, however, data should be interpreted with care, as ferrets are likely more susceptible to coronavirus infections.

No approved vaccines are available against Marburg virus. In this study, the authors developed mRNA vaccines against Marburg virus and the related Ravn virus and show that they induce robust antibody response and provide protection against homologous and heterologous viruses in guinea pigs.

Human proteases TMPRSS2 and TMPRSS11D can be highjacked to mediate cell entry of respiratory viruses. This study examines the biochemical and structural basis of TMPRSS11D auto-activation and substrate specificity, informing peptidomimetic inhibitor development.

Construction and analysis of 2,901 promoter–GFP fusions in Salmonella reveal dynamic, heterogeneous transcriptional activity, including roles for manganese homeostasis and Entner–Doudoroff carbon metabolism in promoting intramacrophage growth and survival of bacteria.

Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.

Owens et al. reported PFI-7, a selective and potent antagonist of GID4 of the CTLH E3 ligase complex, which enables identification of human GID4 targets. This study provides valuable insights into GID4 functions and a powerful tool for advancing new targeted protein degradation strategies.

Hofmann and colleagues describe the mechanism underlying the therapeutic benefit of combinatorial use of SOS1 and KRAS-G12C inhibitors in the context of KRAS-G12C mutant-driven lung and colorectal cancer.

In bacteria Zn2+-dependent deacylases are underexplored. Here, the authors identify bacterial deacylases, providing systemic structure-function analyses to reveal the basis of substrate specificity, acyl-chain preference and inhibition.

Upon the binding of small ligands, nuclear receptors regulate the transcription of genes that are associated with a number of disease mechanisms. Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.