Upregulated proteasome subunits in COVID-19 patients: a link with hypoxemia, lymphopenia and inflammation

Severe COVID-19 disease leads to hypoxemia, inflammation and lymphopenia. Viral infection induces cellular stress and causes the activation of the innate immune response. The ubiquitin-proteasome system (UPS) is highly implicated in viral immune response regulation. The main function of the proteasome is protein degradation in its active form, which recognises and binds to ubiquitylated proteins. Some proteasome subunits have been reported to be upregulated under hypoxic and hyperinflammatory conditions. Here, we conducted a prospective cohort study of COVID-19 patients (n = 44) and age-and sex-matched controls (n = 20). In this study, we suggested that hypoxia could induce the overexpression of certain genes encoding for subunits from the α and β core of the 20S proteasome and from regulatory particles (19S and 11S) in COVID-19 patients. Furthermore, the gene expression of proteasome subunits was associated with lymphocyte count reduction and positively correlated with inflammatory molecular and clinical markers. Given the importance of the proteasome in maintaining cellular homeostasis, including the regulation of the apoptotic and pyroptotic pathways, these results provide a potential link between COVID-19 complications and proteasome gene expressionThis research was funded by Health Research Fund (Fondo de Investigación Sanitario [FIS])-European Regional Development Fund (FEDER), Spain through PI19/01612 (F.G.-R.) and COV20/00207 and PI19-01363 (C.C.-Z.) and ISCIII (CP18/00028), co-funded by ESF, “Investing in your future

NLRP3 Inflammasome Overactivation in Patients with Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is an uncommon and severe subtype of stroke leading to the loss of many years of productive life. We analyzed NLRP3 activity as well as key components of the inflammasome cascade in monocytes and plasma from 28 patients with aSAH and 14 normal controls using flow cytometry, western blot, ELISA, and qPCR technologies. Our data reveal that monocytes from patients with aSAH present an overactivation of the NLRP3 inflammasome, which results in the presence of high plasma levels of interleukin (IL)-1β, IL-18, gasdermin D, and tissue factor. Although further research is needed, we propose that serum tissue factor concentration might be a useful prognosis biomarker for clinical outcome, and for Tako-Tsubo cardiomyopathy and cerebral vasospasm prediction. Remarkably, MCC-950 inhibitor effectively blocks NLRP3 activation in aSAH monocyte culture and supresses tissue factor release to the extracellular space. Finally, our findings suggest that NLRP3 activation could be due to the release of erythrocyte breakdown products to the subarachnoid space during aSAH event. These data define NLRP3 activation in monocytes from aSAH patients, indicating systemic inflammation that results in serum TF upregulation which in turns correlates with aSAH severity and might serve as a prognosis biomarker for aSAH clinical outcome and for cerebral vasospasm and Tako-Tsubo cardiomyopathy prediction.This work was supported by the following fundings: Fondo de Investigación Sanitario (FIS)-Fondos FEDER, Spain: PI19/01612 (F.G-R.) and CP18/00028 and PI19-01363 (C.C-Z.

National Strategy for River Restoration in Spain: A multidisciplinary approach.

A National Strategy for River Restoration is being implemented by the Spanish Ministry of Environmental Affairs, with the scientific assistance of the Universidad Politécnica of Madrid. Theoretical concepts from Fluvial Geomorphology and Ecology, together with Water Framework Directive principles and objectives, have been the basis for this Strategy, whose the main objective is to improve the ecological status of rivers, recovering their natural variability and dynamics

Oxidation of aldehydes used as food additives by peroxynitrite

Benzaldehyde and its derivatives are used as food supplements. These substances can be used mainly as flavorings or as antioxidants. Besides, peroxynitrite, an oxidizing agent, could be formed in canned food. Both species could react between them. The present article has focused on the kinetic study of the oxidation of aldehydes by peroxynitrite. A reaction mechanism that justifies all the experimental results is proposed. This mechanism, in acidic media, passes through three competitive pathways: (a) a radical attack that produces benzoic acid. (b) peracid oxidation, and (c) a nucleophilic attack of peroxynitrous acid over aldehyde to form an intermediate, X, that produces benzoic acid, or, through a Cannizzaro-type reaction, benzoic acid and benzyl alcohol. All rate constants involved in the third pathway (c) have been calculated. These results have never been described in the literature in acid media. A pH effect was analyzed

Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: A prospective cohort study

Introduction: Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I) Methods: This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples drawn within 4 hours after presentation at the emergency department. Results: Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970 GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml, respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt- DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml, respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC) analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP, 3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89 (95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI, 0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml (adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P 6.8 ng/ml (OR, 5.36; 95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality. Conclusions: mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with mt-DNA having better prognostic accuracy.This work was supported partially by grants from Plan Nacional I+D+I (SAF 2008-05347 and SAF2011-23575) and from Fundación Mutua Madrileña de Investigación Biomédica (2008 and 2011) to Francisco Arnalich and Carmen Montie

Responses of riparian guilds to flowalterations in a Mediterranean stream

Questions: Do Mediterranean riparian guilds show distinct responses to stream water declines? If observed,which are the most sensitive and resilient guilds and theirmost affected attributes? Location: Tie¿tar river below the Rosarito dam, central-western Spain. Methods: We identified riparian guilds based on key woody species features and species distribution within this Mediterranean river corridor, and evaluated similarity of their responses to long-term flow alteration (i.e. stream water declines since dam construction in 1959). Hierarchical cluster analysis was used to group surveyed vegetation bands according to species composition. The groups were designated as riparian guilds where each vegetation group comprising a guild: (1) contains species sharing similar features (using PCA); and (2) shares a similar environment (using DCA). Changes in several guild attributes (i.e. dominance and species composition, diversity and establishment patterns) during the regulated period were compared statistically. We used pre- and post-dam established vegetation bands identified based on old (1956) and modern (2006) aerial photographs and field measurements of woody species diameter. Results: Responses to flow alterations varied between guilds according to ecological requirements of their species. The ability to survive water stress (i.e. ?Xeric? guilds) and drag forces caused by floods (?Torrential? guilds) allowed certain pioneer shrub-dominated guilds (e.g. Flueggea tinctoria and Salix salviifolia) to spread on newly emerged surfaces downward to the main channel after flow alterations, although new shrubland had less species diversity than pre-dam shrubland. In contrast, new hydromorphological conditions following damming limited recruitment of native late-successional tree guilds sensitive to floods (to drag forces, inundation and anoxia; i.e. ?Slow-water? and ?Flood-sensitive?, respectively) and those with greater water requirements (i.e. ?Hydric?) (e.g. Alnus glutinosa and Celtis australis), although species diversity increased in this mature forest through co-existence of remaining riparian species and new arrival of upland species. Conclusions: Changes in several riparian attributes after flow alterations differed between guilds. Stream water declines after damming caused shifts in species-poor pioneer shrubland downwards to the watered channel, resulting in severe declines ofmaturenative forest.Understanding vegetation guild responses provides information about general trends in plant populations and assemblage structures expected to occur during river development and flow regulation, increasing our capacity to detect and synthesize complex flowalteration?riparian ecosystem response relationships, and anticipate irreversible impacts

Anti-Inflammatory Activity and Changes in Antioxidant Properties of Leaf and Stem Extracts from Vitex mollis

Vitex mollis is used in traditional Mexican medicine for the treatment of some ailments. However, there are no studies on what happens to the anti-inflammatory activity or antioxidant properties and total phenolic content of leaves and stem extracts of Vitex mollis during the digestion process; hence, this is the aim of this work. Methanolic, acetonic, and hexanic extracts were obtained from both parts of the plant. Extract yields and anti-inflammatory activity (elastase inhibition) were measured. Additionally, changes in antioxidant activity (DPPH and ABTS) and total phenols content of plant extracts before and after in vitro digestion were determined. The highest elastase inhibition to prevent inflammation was presented by hexanic extracts (leaf = 94.63% and stem = 98.30%). On the other hand, the major extract yield (16.14%), antioxidant properties (ABTS = 98.51% and DPPH = 94.47% of inhibition), and total phenols (33.70 mg GAE/g of dried sample) were showed by leaf methanolic extract. Finally, leaf and stem methanolic extracts presented an antioxidant activity increase of 35.25% and 27.22%, respectively, in comparison to their initial values after in vitro digestion process. All samples showed a decrease in total phenols at the end of the digestion. These results could be the basis to search for new therapeutic agents from Vitex mollis

Cryptic population structure reveals low dispersal in Iberian wolves

Abstract Highly mobile mammalian carnivores are expected to have the capability to maintain high levels of gene flow across large geographic scales. Nonetheless, surprising levels of genetic structure have been found in many such populations. We combined genetic and spatial behavioural information from wolves (Canis lupus) in the Iberian Peninsula (Western Europe) during the last two decades to present a particular case of low dispersal levels in a large carnivore population persisting in human-dominated landscapes. We found an exceptionally reticulated pattern of cryptic population structure emerging at two hierarchical levels, in which four or eleven meaningful genetic clusters can be recognized, respectively. These clusters were characterized by moderate-high levels of differentiation (average pairwise FST = 0.09–0.19), low levels of admixture and varying degrees of genetic diversity. The number of dispersers identified among the 11 clusters was very low (<4% out of 218 wolves). Spatial information of tracked wolves further confirmed the geographical genetic patterns (only 2 out of 85 collared wolves overlapped with more than one genetic cluster). The high levels of genetic structure in this population may be determined by the recent demographic history of this population, among other factors. The identification of meaningful genetic clusters has implications for the delineation of conservation units and, consequently, on the conservation and management actions for Iberian wolves

Association of Maternal Microbiota and Diet in Cord Blood Cytokine and Immunoglobulin Profiles

Mothers confer natural passive immunization to their infants through the transplacental pathway during the gestation period. The objective of the present study was to establish at birth the maternal and cord plasma concentration and relationship of immunoglobulins (Igs), cytokines (CKs), and adipokines. In addition, the impact of the maternal microbiota and diet was explored. The plasma profile of these components was different between mothers and babies, with the levels of many CKs, IgM, IgG2a, IgE, IgA, and leptin significantly higher in mothers than in the cord sample. Moreover, the total Igs, all IgG subtypes, IgE, and the Th1/Th2 ratio positively correlated in the mother-infant pair. Maternal dietary components such as monounsaturated fatty acids-polyunsaturated fatty acids and fiber were positively associated with some immune factors such as IgA in cord samples. The microbiota composition clustering also influenced the plasma profile of some factors (i.e., many CKs, some Ig, and adiponectin). In conclusion, we have established the concentration of these immunomodulatory factors in the maternal-neonatal pair at birth, some positive associations, and the influence of maternal diet and the microbiota composition, suggesting that the immune status during pregnancy, in terms of CKs and Igs levels, can influence the immune status of the infant at birth. Keywords: breast milk; cord blood; cytokine; diet; enterotype; immunoglobulin; microbiota