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STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

Li et al. identify dynorphin as an endogenous ligand for orphan receptor GPR139 introducing it as a non-canonical member of the opioid receptor family that triggers excitatory signaling to balance the inhibitory effects of opioids.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.

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.

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.

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.

Vascular cells express various G-protein-coupled receptors (GPCRs) with yet unknown function, among them orphan receptor GPR153. GPR153 is upregulated in injured vessels, where it promotes smooth muscle proliferation and endothelial inflammation, and its inactivation protects mice in models of vascular diseases.

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.

Here, Zerio et al. use cryo-electron microscopy to show how the helicase domain of DNA polymerase θ aligns broken DNA strands by matching short sequences, a process linked to cancer. These findings may guide future therapies targeting error-prone DNA repair.

Biomolecular condensates form via phase separation of multivalent macromolecules. Phase separation is governed by solubility whereas multivalence drives percolation, also known as gelation. The authors in this work identify the distinct energy and length scales that influence phase separation versus percolation.

Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.

Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.

The pathogenesis of Streptococcus pyogenes (GAS) causing scarlet fever has been associated with the presence of prophages, such as ΦHKU.vir, and their products. Here, the authors characterize the exotoxins SpeC and Spd1 of ΦHKU.vir and show these to act synergistically to facilitate nasopharyngeal colonization in mice.

The authors uncovered an antiparasitic molecule that exhibits broad-spectrum activity against parasitic flukes through engagement of a recently discovered transient receptor potential ion channel.

Knock-in mice conditionally or constitutively expressing Cas12 variants enable a wide range of ex vivo and in vivo applications requiring multiplexed genome engineering.

Kinetic rates of protein–protein interactions can be measured with high throughput via biolayer interferometry.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

A selective inhibitor of the deubiquitinase USP7 binds an allosteric site to inhibit its MDM2-stabilizing activity, resulting in stabilization of p53 and p21, which confers hypersensitivity to cancer cells for killing by the compound.

The treatment of snakebite envenoming is currently suboptimal. Existing antivenoms often lack efficacy and may cause adverse reactions. Here, the authors derive, develop, and demonstrate the utility of toxin-specific broadly-neutralizing human monoclonal antibodies with established reactivity across related venom toxins from different snake species and show efficacy in rodent models.

Selvakumar, Clayton et al. use a porcine model of myocardial infarction and PSC-CM transplantation and identify atrial and pacemaker-like cardiomyocytes as the cause of engraftment arrhythmias and surface marker signatures to distinguish between arrhythmogenic and non-arrhythmogenic cardiomyocytes.

Zhao et al. identified β₂-microglobulin (β₂M) as an essential factor driving β-amyloid (Aβ) neurotoxicity and cognitive impairment in mouse models of Alzheimer’s disease (AD) and implicated targeting β₂M–Aβ coaggregation as a strategy for AD therapeutics.

The function of a poorly characterized transmembrane protein, TMEM164, was annotated by integrated genetic dependency mapping, AlphaFold2 structural modeling and lipidomics as an acyltransferase that generates ferroptotic C20:4 ether phospholipids.

A method is developed for expressing large dystrophins to enhance muscle function in mouse models of muscular dystrophy, with potential clinical benefits for numerous disorders caused by mutations in large genes that exceed the adeno-associated virus capacity.

A rapid, split luciferase test for SARS-CoV-2 antibodies in blood and saliva compatible with lyophilization and use in low-resource settings.

Identical twins from a single embryo are formed in multiple species, albeit rarely. It is not clear how such twinning is suppressed during early development. Here they show that calcium signalling activity is propagated through the extraembryonic tissue to prevent ectopic primitive streak formation during gastrulation.

Foot-and-mouth disease virus binds αvβ6 integrin, via a conserved RGD motif in the flexible, exposed GH loop of capsid protein VP1, for cell entry. Here Kotechaet al.visualize this interaction with the VP1 GH loop extending away from the viral surface, engaging αvβ6 in an open, active state.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

WalKR is an essential two-component regulator that controls peptidoglycan synthesis in the human pathogen Staphylococcus aureus. Here, the authors provide biochemical, structural, and functional evidence supporting that the binding of a zinc ion inhibits autophosphorylation and thus alters WalKR regulatory activity.

The neuraminidase-targeting monoclonal antibody FNI9 potently inhibits the enzymatic activity of influenza A and B viruses via receptor mimicry.

HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.

Raman spectroscopic imaging (RSI) can provide information on the chemical composition of a sample, but application to living organisms has lacked sufficient spatial resolution and signal strength. Here the authors apply confocal RSI to whole-mount zebrafish embryos to distinguish different infectious bacteria and to living zebrafish embryos to monitor the wound healing process.

One common cause of vision loss after retinal detachment surgery is retinal scarring. Here the authors demonstrate that a bio-functional polymer can prevent retinal scarring by suppression of epithelial-mesenchymal transition and hyper-proliferation of retinal pigment epithelial cells.

Many babies have now been born to mothers who were exposed to SARS-CoV-2 during their pregnancy. Here the authors look at the effect of this exposure on the immunology of human neonates, showing immune changes and increased neonatal cytokine responses despite limited evidence of vertical transmission.

Using a composite bioinformatics approach, the DNA:DNA:RNA triplex-forming lncRNAs HIF1α-AS1 was identified in human endothelial cells which recruits an epigenetic silencing complex to limit expression of triplex target genes.

A preclinical safety study of adeno-associated viruses (AAVs) for RNA interference (RNAi) for spinocerebellar ataxia type 1 therapy showed toxicity in nonhuman primates but not rodents, due to unexpected AAV inverted terminal repeat transcriptional activity that was mitigated on altering the RNAi expression environment.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

The unification of the theory of relativity and quantum mechanics is a long-standing challenge in physics. Here the authors investigate the effects of a wide range of accelerations on an entangled photon pair, providing an upper bound for the effects of non-inertial frames on quantum systems.

Primary and metastatic tumours have different metabolic phenotypes due to changes in nutrient availability. Here the authors perform multi-omic analyses of primary and metastatic renal cancer cells grown in a physiological medium and show that the reprogramming of the branched-chain amino acid catabolism and urea cycle through re-expression of ASS1 allows metabolic flexibility during renal cancer progression.

Established bacterial glycoengineering platforms limit access to protein and glycan substrates. Here the authors design a cytoplasmic protein glycosylation system, Glycoli, to generate a variety of multivalent glycostructures.

A resistance mechanism for a class of drugs targeting histone acetyltransferase inhibitors was identified where metabolic rewiring creates high concentrations of acetyl-CoA that outcompete drug-target engagement.

Viruses rely on the translational machinery of the host cell to synthesis viral proteins. We show that KSHV manipulates the composition of host cell ribosomes creating a specialised ribosome to specifically translate viral mRNAs.

Pneumococcal infection of the cerebrospinal fluid results in bacterial lysis, the release of toxic factors and induction of neuroinflammation. Here, the authors show that the virulence factor pneumolysin enhances the neuroinflammatory response to Streptococcus pneumoniae by the enhancement of endocytosis.

Structural changes in the capping groups of inverted cyanoacrylamide-based kinase inhibitors resulted in alterations in residence time, with some compounds exhibiting sustained pharmacological effects in vivo.

Functional assessments and applications of polysaccharides are hampered by broad product distributions. Neutral drift libraries now identify specific amino acids and binding sites that determine product outcome in a polysialyltransferase, allowing the preparation of glycan chains with defined lengths.