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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.

Mutations in the serine/threonine kinase ataxia teleangiectasia mutated (ATM) have been linked to pancreatic ductal adenocarcinoma (PDAC) cohorts. Here Russellet al. show that loss of ATM induces a greater number of proliferative precursor lesions in a mouse model, recapitulating many features of human PDAC subtypes.

The structure of a neutralizing human monoclonal antibody isolated from an individual immunized in a Plasmodium vivax Duffy binding protein vaccine clinical trial, in complex with its target, elucidates the mechanism by which parasite invasion of immature red blood cells is inhibited.

In this study, the authors report that a bat influenza A (H9N2) virus shows receptor binding features similar to avian influenza viruses, efficiently infects ex-vivo human respiratory cells and replicates in the lungs of mice and upper respiratory tract of ferrets following airborne transmission.

Elevated hepatic alanine catabolism is shown to promote hyperglycaemia and reduce skeletal muscle protein synthesis, thereby linking sarcopenia with hyperglycaemia in the context of type 2 diabetes.

Sleep pressure and circadian rhythms influence one another. However, the regulatory mechanisms are unclear. Here, the authors show that adenosine A₁/A_2A receptor antagonists, such as caffeine, shift circadian rhythms and enhance the effects of light, providing a molecular link between sleep pressure and circadian rhythm.

Targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

A soluble bacterial transhydrogenase from Escherichia coli (EcSTH) was validated as a genetically encoded tool to induce NADH reductive stress in mammalian cells revealing unique transcriptional and metabolic signatures.

Structural classification of mutations in the epidermal growth factor receptor causing non-small cell lung cancer is a better predictor of patient outcomes following drug treatment than traditional exon-based classification.

Previous work has shown in iPSC derived neurons that synaptic impairments are associated with a 4bp DISC1 deletion. Here the authors demonstrate a role for the PDE4 signalling pathway in these synaptic impairments.

DBlink uses deep learning to capture long-term dependencies between different frames in single-molecule localization microscopy data, yielding super spatiotemporal resolution videos of fast dynamic processes in living cells.

The development of direct-acting antivirals to combat COVID-19 remains an important goal. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. The most promising inhibitor blocks viral replication in mammalian cells.

Older people have suboptimal responses to primary series vaccines, which can place them at risk for adverse coronavirus disease 2019 outcomes. Here the authors show that booster vaccines provide a substantial increase in antibody levels in the short term but that there is significant waning 100 d after booster shots.

The metabolic reaction catalysed by the isocitrate dehydrogenase 1 (IDH1) enzyme is commonly perturbed in some glioma subtypes due to gain-of-function mutations in the IDH1 gene. Here, Chaumeil et al.present a method that detects mutant IDH1 activity by measuring the levels of different hyperpolarized metabolites produced by wild-type and mutant IDH1.

TMT is a chemical that evokes innate defensive behaviors yet the molecular mechanisms are not well understood. Here the authors perform a large-scale forward genetics screen in mice and identify Trpa1, a pungency/irritancy receptor, as a chemosensor for predator odor-evoked innate fear and defensive behaviors.

A monobody was identified that binds to an allosteric lobe at the α4-β6-α5 interface to block H- and K-RAS signaling and transformation by disrupting RAS dimerization and nanoclustering.

The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K.

Kelly et al. offer a method for controlling the tropism of replicating viruses. Viral replication in a specific target tissue is inhibited by incorporation of tissue-specific microRNA targets within the viral genome. Using an oncolytic picornavirus that causes myositis in tumor-bearing mice, they show the virus is unable to replicate in muscle but still retains oncolytic activity, with implications for the clinical use of oncolytic viruses and vaccine development.

Identifying a chemical substance using mass spectrometry without knowing its structure is challenging. To help detect novel designer drugs from their mass spectra, Skinnider et al. describe a generative model that is biased towards creating potentially psychoactive molecules and thus helps identify potential candidates for a specific sample.

Here, Rickettsia parkeri is shown to be sensitive to type I interferons (IFN-I) and IFN-γ and to benefit from inflammasome-mediated antagonism of IFN-I, highlighting similarities between the immune responses against this obligate cytosolic bacterial pathogen and those that target viral pathogens.

Deep characterization of uveitis in a rhesus monkey confirms Ebola virus RNA persistence is associated with severe immunopathology in the eye, with broader implications for the prevention and treatment of sight-threatening uveitis in human survivors of Ebola virus.

Reinke et. al. show that targeting host proteins like cathepsins is a promising strategy for treating SARS-CoV-2 and other viral infections due to their mutational stability in contrast to highly mutable viral targets.

Circularly polarized light is unexpectedly detected in the afterglow of γ-ray burst GRB 121024A measured 0.15 days after the burst, and is shown to be intrinsic to the afterglow and unlikely to be produced by dust scattering or plasma propagation effects.

Amitai et al. identified 4 potential small molecule antidotes toward nerve agents poisoning by high-throughput-screening of over 150,000 compounds. Unique non-quaternary oximes represent new potential antidotes for future development as they detoxified nerve agents and also reactivated nerve agent-inhibited butyrylcholinesterase.