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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.

Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.

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.

B. thuringiensis spores contain uncharacterized protein filaments that extend from the surface of the exosporium. Here, the authors show that these filaments feature conserved β-barrel neck domains and promote spore clustering through protein contacts and filament bundling, and reveal a mechanism for biofilm-like spore aggregation.

Spatial and temporal variations among individual human cell proteomes are comprehensively mapped across the cell cycle using proteomic imaging and transcriptomics.

In the study, Toledo and colleagues show an experimental and computational workflow to profile human antibodies against disease-causing bacteria (Group A Streptococcus) directly in clinical samples.

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

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.

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

Identification of selective and effective anti-leishmanial compounds with potent in vitro and in vivo activity making them promising candidates for future drug development.

River blindness, a disease affecting millions throughout the tropics, is caused by parasitic worms. Here, Yuet al. report the discovery and structural characterization of potent macrocyclic peptide inhibitors of iPGM, a nematode-specific phosphoglycerate mutase, as potential leads for novel antimicrobial agents.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

Here, the authors perform repurposing screens of the ReFRAME drug library in two cell lines and identify inhibitors of SARS-CoV-2 infection. Antiviral activity of prodrug MK-4482 is confirmed in hamsters.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Group A streptococcus causes a wide range of human diseases and significantly contributes to morbidity and mortality worldwide. Here, Toledo et al show how streptococcus alters the structure and function of endogenous and therapeutic antibodies during infection and how this is affected by the host microenvironment.

Magic state distillation is achieved with logical qubits on a neutral-atom quantum computer using a dynamically reconfigurable architecture for parallel quantum operations.

The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, ultraHTE-amenable reaction conditions are developed through miniaturization of four of the most important drug discovery transformations, and their generality and scalability are tested on a range of natural products and drug candidates.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Here, using clinical samples and autopsy tissues, the authors combine fast-colorimetric test (LAMP) for SARS-CoV-2 infection and large-scale shotgun metatranscriptomics for host, viral, and microbial profiling and provide a map of the viral genetic features of the New York City outbreak and associate specific host responses and gene expression perturbations with SARS-CoV-2 infection.

The ER chaperone BiP is regulated by FICD-mediated AMPylation and deAMPylation. Here, the authors characterise the structure of mammalian AMPylated BiP bound to FICD, by X-ray crystallography and neutron scattering, providing insights into the mechanism of BiP AMPylation and deAMPylation.

Characterizing atrial fibrillation (AF) at the single cell level is challenging. Here, the authors perform snRNA-seq on 18 patients with AF to investigate the cell composition, and gene expression shifts associated with this common arrhythmia.

Alpha-synuclein is associated with neuronal dysfunction in Parkinson’s disease. This study shows that alpha-synuclein interacts with neuronal synaptic vesicles in a calcium-dependent fashion, and this interaction is important for synaptic vesicle clustering.

This study finds that CRISPR-knockout phenotypes from genome-wide screens systematically show increased similarity to knockouts of unrelated genomically proximal genes located on the same chromosome arm. Multiple lines of evidence suggest that this proximity bias is caused by telomeric truncations of chromosome arms and is consistent across cell types, labs and Cas9 delivery methods.

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, but their antibacterial properties can be overlooked. Here the authors show the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers.

VARP is bound to endosomes and functions as a protein:protein interaction platform. Here, the authors present the NMR structure of the complex between the retromer subunit VPS29 and a VARP Zn-fingernail microdomain that is structurally distinct from Zn-fingers and further show that mutations, which abolish VPS29:VARP binding, inhibit trafficking from endosomes to the cell surface.

The efficacy of epidural electrical stimulation (EES) to engage arm muscles and improve movement after spinal cord injury is still unclear. Here, the authors investigated how EES can recruit upper-limb motor neurons by combining computational modelling with experiments in non-human primates.

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.

Zhang et al. use human studies and mechanistic work in mouse models to describe how leucine serves as the key amino acid derived from dietary protein to drive deleterious macrophage mTORC1 signalling and promote cardiovascular disease.

On the basis of new mechanistic studies of a mutant form of the apolipoprotein apoC-III that protects against coronary heart disease, Khetarpal et al. have developed therapeutic apoC-III-targeting monoclonal antibodies that lower circulating apoC-III protein and triglyceride levels in mice.

X-ray and cryo-electron microscopy structures of fungal mitochondrial calcium uniporter proteins reveal a tetrameric architecture and shed light on the function of the channel.

CTL responses are critical in protection against pathogens. Here, using mass spectrometry and flow cytometry, the authors characterize the kinetics of influenza A virus class I MHC epitopes cross-presented in professional antigen presenting cells and identify new epitopes that elicit T cell responses in infected mice.

The identification of processes activated by specific microbes during microbiota colonization of plant roots is hampered by technical issues in metatranscriptomics. Here, Vannier et al. colonized germ-free plants with a defined root microbiota comprising over 100 microbial isolates, and addressed those issues in various ways to identify strain-specific processes as well as common gene sets activated by microbes during root colonization.

NKG7 is a molecule well associated with NK cells but of unknown function. Engwerda and colleagues demonstrate that NKG7 is also associated with T_H1 cells and is essential for type I and cytotoxic responses.

Murray et al. identified and characterized a small-molecule inhibitor of human COQ8A, which belongs to the UbiB protein family and is essential for coenzyme Q biosynthesis.

Smith and colleagues find that a multivariate signature of unresolved inflammation and altered iron homeostasis detected beyond 2 weeks following acute COVID-19 onset was the strongest early differentiator of those who report long COVID symptoms at 3–10 months.

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.

Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.

Fine tuning the immune response in line with the degree of threat is central to recognition of a pathogen versus commensal bacteria. Here the authors implicate a digital all-or-nothing cell response in control of the tissue level immune response.

Mg-protoporphyrin IX monomethyl ester cyclase catalyses the formation of the isocyclic ring in the synthesis of chlorophyll. Kinetic analyses and mass spectrometry identified intermediates in the reaction.

Discovery of a chemical probe targeting the PWWP domain of NSD2 reveals insight into mechanisms that govern NSD2 localization. The compound and its negative control represent valuable tools for further defining NSD2 biology.

Antimicrobial peptide LL37 can bind nucleic acids and potentiate their sensing by endosomal TLRs. Here the authors show that LL37 binds to RNA from neutrophil extracellular traps (NETs), which amplifies inflammation and production of more LL37 and NETs via TLR8/13, suggesting that LL37 contribution to psoriasis may be fueled by NET-associated RNA.

Zhang et al. show that high-protein diets increase atherosclerosis risk through macrophage mTORC1 activation associated with suppressed clearance of damaged mitochondria and increased apoptosis.

A comprehensive characterisation of Omicron-BA.1 and VOC Delta in numerous in vitro and in vivo models uncovers the factors that led to its global dominance.

Mehta et al. show that PARP inhibition induces CSF1R-dependent immune-suppressive macrophages, and that its blockade restores PARP inhibitor efficacy and stimulates CD8⁺ T cell-dependent antitumor immunity in triple-negative breast cancer.

Human leukocyte antigens (HLA) are multi-allelic and polymorphic genes that present antigens to immune cells for inducing protective immunity. Here, using systems biology and structural approaches, the authors show that micropolymorphism of three HLA has effects beyond the modulation of antigen diversity.

Transcriptomic and proteomic profiling of blood samples from individuals with COVID-19 reveals immune cell and hematopoietic progenitor cell alterations that are differentially associated with disease severity.

Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.