Inactivation of thiol-dependent enzymes by hypothiocyanous acid: role of sulfenyl thiocyanate and sulfenic acid intermediates

Myeloperoxidase (MPO) forms reactive oxidants including hypochlorous and hypothiocyanous acids (HOCl and HOSCN) under inflammatory conditions. HOCl causes extensive tissue damage and plays a role in the progression of many inflammatory-based diseases. Although HOSCN is a major MPO oxidant, particularly in smokers, who have elevated plasma thiocyanate, the role of this oxidant in disease is poorly characterized. HOSCN induces cellular damage by targeting thiols. However, the specific targets and mechanisms involved in this process are not well defined. We show that exposure of macrophages to HOSCN results in the inactivation of intracellular enzymes, including creatine kinase (CK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In each case, the active-site thiol residue is particularly sensitive to oxidation, with evidence for reversible inactivation and the formation of sulfenyl thiocyanate and sulfenic acid intermediates, on treatment with HOSCN (less than fivefold molar excess). Experiments with DAz-2, a cell-permeable chemical trap for sulfenic acids, demonstrate that these intermediates are formed on many cellular proteins, including GAPDH and CK, in macrophages exposed to HOSCN. This is the first direct evidence for the formation of protein sulfenic acids in HOSCN-treated cells and highlights the potential of this oxidant to perturb redox signaling processes.     

Advancing marine conservation planning in the Mediterranean Sea

Twenty leading scientists in the field of marine conservation planning attended the first international workshop on conservation planning in the Mediterranean Sea. This globally significant biodiversity hotspot has been subjected to human exploitation and degradation for 1,000s of years. Recently, several initiatives have tried to identify priority areas for conservation across the Mediterranean Sea. However, none of these efforts have led to large-scale actions yet. The aim of the workshop was to establish a network of scientists who are involved in large-scale conservation planning initiatives throughout the Mediterranean basin to promote collaboration and reduce redundancy in conservation initiatives. The three focus groups of the workshop build on existing efforts and intend to deliver: (1) a roadmap for setting conservation priorities, (2) a methodological framework for linking threats, actions and costs to improve the prioritization process, and (3) a systematic conservation planning process tailored to complex environments such as the Mediterranean Sea. Joining forces and involving more scientists (especially from the South-eastern part of the region) in following meetings, the participants endeavour to provide guidelines on how to bridge the science-policy gap and hence aid decision-makers to take efficient conservation actions.     

Taking the example of computer systems engineering for the analysis of biological cell systems

In this paper, we discuss the potential for the use of engineering methods that were originally developed for the design of embedded computer systems, to analyse biological cell systems. For embedded systems as well as for biological cell systems, design is a feature that defines their identity. The assembly of different components in designs of both systems can vary widely. In contrast to the biology domain, the computer engineering domain has the opportunity to quickly evaluate design options and consequences of its systems by methods for computer aided design and in particular design space exploration. We argue that there are enough concrete similarities between the two systems to assume that the engineering methodology from the computer systems domain, and in particular that related to embedded systems, can be applied to the domain of cellular systems. This will help to understand the myriad of different design options cellular systems have. First we compare computer systems with cellular systems. Then, we discuss exactly what features of engineering methods could aid researchers with the analysis of cellular systems, and what benefits could be gained.     

Ocean acidification increases the vulnerability of native oysters to predation by invasive snails

There is growing concern that global environmental change might exacerbate the ecological impacts of invasive species by increasing their per capita effects on native species. However, the mechanisms underlying such shifts in interaction strength are poorly understood. Here, we test whether ocean acidification, driven by elevated seawater pCO₂, increases the susceptibility of native Olympia oysters to predation by invasive snails. Oysters raised under elevated pCO₂ experienced a 20% increase in drilling predation. When presented alongside control oysters in a choice experiment, 48% more high-CO₂ oysters were consumed. The invasive snails were tolerant of elevated CO₂ with no change in feeding behaviour. Oysters raised under acidified conditions did not have thinner shells, but were 29–40% smaller than control oysters, and these smaller individuals were consumed at disproportionately greater rates. Reduction in prey size is a common response to environmental stress that may drive increasing per capita effects of stress-tolerant invasive predators.     

Multidimensional analysis of immune responses identified biomarkers of recent Mycobacterium tuberculosis infection

The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to mycobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the individual adaptive and innate datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical confirmation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC) = 0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC = 0.91), while the innate data EN model performed poorly (average AUROC = 0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test χ² = 6.09, p = 0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models.A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.     

Adaptation and acclimation of photosynthetic microorganisms to permanently cold environments.

Persistently cold environments constitute one of our world's largest ecosystems, and microorganisms dominate the biomass and metabolic activity in these extreme environments. The stress of low temperatures on life is exacerbated in organisms that rely on photoautrophic production of organic carbon and energy sources. Phototrophic organisms must coordinate temperature-independent reactions of light absorption and photochemistry with temperature-dependent processes of electron transport and utilization of energy sources through growth and metabolism. Despite this conundrum, phototrophic microorganisms thrive in all cold ecosystems described and (together with chemoautrophs) provide the base of autotrophic production in low-temperature food webs. Psychrophilic (organisms with a requirement for low growth temperatures) and psychrotolerant (organisms tolerant of low growth temperatures) photoautotrophs rely on low-temperature acclimative and adaptive strategies that have been described for other low-temperature-adapted heterotrophic organisms, such as cold-active proteins and maintenance of membrane fluidity. In addition, photoautrophic organisms possess other strategies to balance the absorption of light and the transduction of light energy to stored chemical energy products (NADPH and ATP) with downstream consumption of photosynthetically derived energy products at low temperatures. Lastly, differential adaptive and acclimative mechanisms exist in phototrophic microorganisms residing in low-temperature environments that are exposed to constant low-light environments versus high-light- and high-UV-exposed phototrophic assemblages.     

Aneurysm severity is suppressed by deletion of CCN4

Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression. We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE^−/−) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4^−/−ApoE^−/− mice and CCN4^+/+ApoE^−/− mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4^−/−ApoE^−/− mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4^−/−ApoE^−/− mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNFα and stimulated macrophage migration by more than threefold. In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00623-5.