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In this work, authors show how the enterotoxigenic Escherichia coli (ETEC) protease EatA cleaves the human mucus protein MUC2 at a C-terminal site, allowing bacteria to cross the intestinal mucus, reach epithelial cells, and promote infection, as demonstrated using a human MUC2 transgenic mouse model.

The enzymatic properties of RNA-guided nucleases are revealed through massively parallel analysis.

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.

Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Patients with kidney failure undergoing maintenance hemodialysis have poor long-term survival. Here the authors use affinity-based proteomics to identify circulating risk factors for mortality in patients with kidney failure on hemodialysis.

Caspase-2-mediated cleavage of tau is shown to generate a fibrillation-resistant truncation product (Δtau314) that contributes to the missorting of tau into dendritic spines, synaptic dysfunction, neurodegeneration and cognitive impairments in mice.

Lipid nanoparticles (LNPs) delivering mRNA after intratumoral administration could be a promising cancer treatment strategy. Here this group reports the intratumoral delivery of mRNA with LNPs inducing the expression of purine nucleoside phosphorylase and inhibiting the progression of head and neck squamous cell carcinoma in vivo.

The SARS-CoV-2 main protease is an important target for the development of COVID-19 therapeutics. Here, the authors combine X-ray crystallography and mass spectrometry and performed a large scale fragment screening campaign, which yielded 96 liganded structures of this essential viral protein that are of interest for further drug development efforts.

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.

Integrating silencing RNA into the backbone of a microRNA that is highly enriched in small extracellular vesicles reduces the therapeutic dose of the silencing RNA.

Regulatory T cell (T_reg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that T_reg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.

Exome sequencing identifies loss-of-function CELA2A mutations in families with early-onset atherosclerosis and metabolic syndrome. Functional studies show that CELA2A is a circulating enzyme that reduces platelet activation, triggers insulin secretion and degradation, and increases insulin sensitivity.

Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.

Here, Argonaute from the prokaryote Thermus thermophilus is shown to use small DNA guides to interfere directly with invading foreign DNA, rather than being involved in RNA-guided RNA interference, as observed in eukaryotes.

The human gut microbiota can metabolize xanthan gum, a food additive that was introduced to our diets relatively recently in processed foods. A Ruminococcaceae species can degrade this complex polysaccharide and, in some individuals, Bacteroides intestinalis can grow on the released oligosaccharide products.

Lassa virus can cause haemorrhagic fever for which no specific treatment currently exists. Here the authors have cloned 113 monoclonal antibodies from the survivors of Lassa infection and show that the majority of neutralizing antibodies target a complex of GP1 and GP2 viral proteins.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Actin histidine methyltransferase SETD3 is a host factor critical for the replication of enteroviruses. Here, the authors report the 3.5 Å cryoEM structure of SETD3 interacting with enterovirus CV-B3 2A protease, defining the actin-binding SET domain as essential for virus replication.

Ken Ong and colleagues report meta-analysis of 32 genome-wide association studies for age at menarche. They identify 30 loci newly associated with age at menarche, including four that were previously associated with BMI.

Systemic delivery remains a major obstacle in therapeutic applications of siRNAs. Using RNA aptamer–siRNA chimeras with enhanced silencing activity and specificity, Dassie et al. achieve regression of xenograft prostate tumors by intraperitoneal injection.

Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.

The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.

Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

A library of protease-cleavable sensors conjugated to antibodies against the programmed cell death protein 1 allows for the urinary detection of early antitumour responses to immune checkpoint blockade therapy and of resistance to it in mice.

Genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2 identify mucins as key host factors restricting viral infection.

ACE2 and TMPRSS2 have received recent attention as entry factors for SARS-CoV-2. Here the authors analyze nasal airway transcriptome data from 695 children determining ACE2 and TMPRSS2 expression is induced by viral and type2 inflammation, respectively, and both exhibit eQTLs that vary across world populations.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

The TRPM7 channel enables endosomal acidification, which is vital for the entry of many enveloped viruses. Here, the authors show that loss of TRPM7 protects cells from various pandemic-threat viruses, pointing to a new strategy for broad-spectrum antiviral drugs.

Sui et al. elucidate the mechanisms of action for small molecule inhibitors of human triacylglycerol synthesis enzyme DGAT1 and provide insights into how these inhibitors achieve selectivity for DGAT1 rather than other closely related MBOAT enzymes.

CRISPR-Cas9 has been widely used to manipulate genomes, however control over activity is necessary to explore transcriptional or epigenetic regulation. Here the authors use a split Cas9 fused to nuclear receptor ligand-binding domains to achieve tuneable Cas9 activity.

A diterpenoid biosynthetic gene cluster (BGC) has been identified in a few species in the Lamiaceae (mint) family, but its origin and evolution remain unclear. Here, the authors report assembly of genomes of three species within the family and reveal the dynamic evolutionary trajectory of the BGC.

Wang et al. report a structure for human MBOAT7, the enzyme responsible for remodeling acyl chains of phosphatidylinositol. The structure enabled the identification of MBOAT7 inhibitors and provides insights into substrate specificity among MBOATs.

de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.