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We recently reported the discovery of a lysine–cysteine redox switch in proteins with a covalent nitrogen–oxygen–sulfur (NOS) bridge. Here, a systematic survey of the whole protein structure database discloses that NOS bridges are ubiquitous redox switches in proteins of all domains of life and are found in diverse structural motifs and chemical variants. In several instances, lysines are observed in simultaneous linkage with two cysteines, forming a sulfur–oxygen–nitrogen–oxygen–sulfur (SONOS) bridge with a trivalent nitrogen, which constitutes an unusual native branching cross-link. In many proteins, the NOS switch contains a functionally essential lysine with direct roles in enzyme catalysis or binding of substrates, DNA or effectors, linking lysine chemistry and redox biology as a regulatory principle. NOS/SONOS switches are frequently found in proteins from human and plant pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and also in many human proteins with established roles in gene expression, redox signaling and homeostasis in physiological and pathophysiological conditions.A survey of protein structures identifies widespread lysine–cysteine cross-links in functionally diverse proteins across all domains of life and in various structural motifs, where these redox switches control enzyme catalysis and/or ligand binding.

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M pro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites. Here the authors demonstrate that the SARS-CoV-2 main protease (Mpro) is subject to redox regulation in vitro, reversibly switching between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues.

This study presents a methodology for the automated analysis of commercial medium-range sonar signals for detecting presence/absence of bluefin tuna (Tunnus thynnus) in the Bay of Biscay. The approach uses image processing techniques to analyze sonar screenshots. For each sonar image we extracted measurable regions and analyzed their characteristics. Scientific data was used to classify each region into a class (\"tuna\" or \"no-tuna\") and build a dataset to train and evaluate classification models by using supervised learning. The methodology performed well when validated with commercial sonar screenshots, and has the potential to automatically analyze high volumes of data at a low cost. This represents a first milestone towards the development of acoustic, fishery-independent indices of abundance for bluefin tuna in the Bay of Biscay. Future research lines and additional alternatives to inform stock assessments are also discussed.

Satellite-linked buoys used by tropical tuna purse-seine vessels on drifting fish aggregating devices (DFADs) provide a continuous stream of information on both the ocean characteristics and the presence and size of fish aggregations associated with DFADs, enabling the study of pelagic communities. This unprecedented amount of data is characterized by ocean-scale coverage with high spatial and temporal resolutions, but also by different data formats and specifications depending on buoy model and brand, as well as on the type of data exchange agreements into play. Their use for scientific and management purposes is therefore critically dependent on the abilities of algorithms to process heterogeneous data formats and resolutions. This paper proposes a unified set of algorithms for processing the buoys location data used by the two major purse seine fleets operating in the Atlantic and Indian oceans. Three main issues that need to be addressed prior to the exploitation of the data are identified (structural errors, data records on land and on-board vessels) and five specific filtering criteria are proposed to improve the data cleaning process and, hence, quality. Different filtering procedures are also compared, and their advantages and limitations are discussed.

The underlying molecular mechanisms of cooperativity and allosteric regulation are well understood for many proteins, with haemoglobin and aspartate transcarbamoylase serving as prototypical examples 1 , 2 . The binding of effectors typically causes a structural transition of the protein that is propagated through signalling pathways to remote sites and involves marked changes on the tertiary and sometimes even the quaternary level 1 – 5 . However, the origin of these signals and the molecular mechanism of long-range signalling at an atomic level remain unclear 5 – 8 . The different spatial scales and timescales in signalling pathways render experimental observation challenging; in particular, the positions and movement of mobile protons cannot be visualized by current methods of structural analysis. Here we report the experimental observation of fluctuating low-barrier hydrogen bonds as switching elements in cooperativity pathways of multimeric enzymes. We have observed these low-barrier hydrogen bonds in ultra-high-resolution X-ray crystallographic structures of two multimeric enzymes, and have validated their assignment using computational calculations. Catalytic events at the active sites switch between low-barrier hydrogen bonds and ordinary hydrogen bonds in a circuit that consists of acidic side chains and water molecules, transmitting a signal through the collective repositioning of protons by behaving as an atomistic Newton’s cradle. The resulting communication synchronizes catalysis in the oligomer. Our studies provide several lines of evidence and a working model for not only the existence of low-barrier hydrogen bonds in proteins, but also a connection to enzyme cooperativity. This finding suggests new principles of drug and enzyme design, in which sequences of residues can be purposefully included to enable long-range communication and thus the regulation of engineered biomolecules. Structural and biophysical studies reveal that low-barrier hydrogen bonds enable long-range communication between the active sites of multimeric enzymes and synchronise catalysis.

Disulfide bonds between cysteine residues are important post-translational modifications in proteins that have critical roles for protein structure and stability, as redox-active catalytic groups in enzymes or allosteric redox switches that govern protein function 1 – 4 . In addition to forming disulfide bridges, cysteine residues are susceptible to oxidation by reactive oxygen species, and are thus central not only to the scavenging of these but also to cellular signalling and communication in biological as well as pathological contexts 5 , 6 . Oxidized cysteine species are highly reactive and may form covalent conjugates with, for example, tyrosines in the active sites of some redox enzymes 7 , 8 . However, to our knowledge, regulatory switches with covalent crosslinks other than disulfides have not previously been demonstrated. Here we report the discovery of a covalent crosslink between a cysteine and a lysine residue with a NOS bridge that serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae , the pathogen that causes gonorrhoea. X-ray structure analysis of the protein in the oxidized and reduced state reveals a loaded-spring mechanism that involves a structural relaxation upon redox activation, which is propagated from the allosteric redox switch at the protein surface to the active site in the protein interior. This relaxation leads to a reconfiguration of key catalytic residues and elicits an increase in enzymatic activity of several orders of magnitude. The redox switch is highly conserved in related transaldolases from other members of the Neisseriaceae; for example, it is present in the transaldolase of Neisseria meningitides (a pathogen that is the primary cause of meningitis and septicaemia in children). We surveyed the Protein Data Bank and found that the NOS bridge exists in diverse protein families across all domains of life (including Homo sapiens ) and that it is often located at catalytic or regulatory hotspots. Our findings will inform strategies for the design of proteins and peptides, as well as the development of new classes of drugs and antibodies that target the lysine–cysteine redox switch 9 , 10 . A NOS bridge between cysteine and lysine residues serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae , demonstrating the existence of protein regulatory switches that contain covalent crosslinks other than disulfides.

The origins of enzyme catalysis have been attributed to both transition-state stabilization as well as ground-state destabilization of the substrate. For the latter paradigm, the enzyme orotidine-5′-monophosphate decarboxylase (OMPDC) serves as a reference system as it contains a negatively charged residue at the active site that is thought to facilitate catalysis by exerting an electrostatic stress on the substrate carboxylate leaving group. Snapshots of how the substrate binds to the active site and interacts with the negative charge have remained elusive. Here we present crystallographic snapshots of human OMPDC in complex with the substrate, substrate analogues, transition-state analogues and product that defy the proposed ground-state destabilization by revealing that the substrate carboxylate is protonated and forms a favourable low-barrier hydrogen bond with a negatively charged residue. The catalytic prowess of OMPDC almost entirely results from the transition-state stabilization by electrostatic interactions of the enzyme with charges spread over the substrate. Our findings bear relevance for the design of (de)carboxylase catalysts. Ground state destabilization is often evoked as a possible explanation of orotidine-5′-phosphate decarboxylase catalysis. Now, high-resolution structures of this enzyme provide time-resolved snapshots along its reaction coordinate revealing that transition-state stabilization by electrostatic interactions drives its reactivity.

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that Mpro is subject to redox regulation and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include sulfenylation, disulfide formation between the catalytic cysteine and a proximal cysteine, and generation of an allosteric lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and possess antiviral activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS and SARS-CoV, indicating their potential as common druggable sites. Competing Interest Statement The authors have declared no competing interest.

The factors that predispose an individual to a higher risk of death from COVID-19 are poorly understood. The goal of the study was to identify factors associated with risk of death among patients with COVID-19. This is a retrospective cohort study of people with laboratory-confirmed SARS-CoV-2 infection from February to May 22, 2020. Data retrieved for this study included patient sociodemographic data, baseline comorbidities, baseline treatments, other background data on care provided in hospital or primary care settings, and vital status. Main outcome was deaths until June 29, 2020. In the multivariable model based on nursing home residents, predictors of mortality were being male, older than 80 years, admitted to a hospital for COVID-19, and having cardiovascular disease, kidney disease or dementia while taking anticoagulants or lipid-lowering drugs at baseline was protective. The AUC was 0.754 for the risk score based on this model and 0.717 in the validation subsample. Predictors of death among people from the general population were being male and/or older than 60 years, having been hospitalized in the month before admission for COVID-19, being admitted to a hospital for COVID-19, having cardiovascular disease, dementia, respiratory disease, liver disease, diabetes with organ damage, or cancer while being on anticoagulants was protective. The AUC was 0.941 for this model’s risk score and 0.938 in the validation subsample. Our risk scores could help physicians identify high-risk groups and establish preventive measures and better follow-up for patients at high risk of dying.ClinicalTrials.gov Identifier: NCT04463706

High-resolution electron backscattered diffraction (HR-EBSD) is a powerful tool to describe microstructures at the sub-micrometric scale that achieves a higher degree of angular accuracy compared with conventional EBSD. However, such an EBSD technique is time-consuming and requires data-intensive computing to save and postprocess the results obtained after each scan. In the current work, a simple strategy to transform conventional results into high-resolution results is put forward in an averaging statistical layout. This makes it possible to measure the misorientations more precisely and, subsequently, the geometrically necessary dislocations by lowering the typical noise generated from Hough transformation-based conventional EBSD. Different steel microstructures are analyzed in light of this strategy. The calculated dislocation densities for those microstructures are used as input values for evaluating the initial dislocation density contribution to the yield strength in a newly developed mechanical model.