MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process

Mitochondria are the major source of reactive oxygen species (ROS), whose aberrant production by dysfunctional mitochondria leads to oxidative stress, thus contributing to aging as well as neurodegenerative disorders and cancer. Cells efficiently eliminate damaged mitochondria through a selective type of autophagy, named mitophagy. Here, we demonstrate the involvement of the atypical MAP kinase family member MAPK15 in cellular senescence, by preserving mitochondrial quality, thanks to its ability to control mitophagy and, therefore, prevent oxidative stress. We indeed demonstrate that reduced MAPK15 expression strongly decreases mitochondrial respiration and ATP production, while increasing mitochondrial ROS levels. We show that MAPK15 controls the mitophagic process by stimulating ULK1-dependent PRKN Ser108 phosphorylation and inducing the recruitment of damaged mitochondria to autophagosomal and lysosomal compartments, thus leading to a reduction of their mass, but also by participating in the reorganization of the mitochondrial network that usually anticipates their disposal. Consequently, MAPK15-dependent mitophagy protects cells from accumulating nuclear DNA damage due to mitochondrial ROS and, consequently, from senescence deriving from this chronic DNA insult. Indeed, we ultimately demonstrate that MAPK15 protects primary human airway epithelial cells from senescence, establishing a new specific role for MAPK15 in controlling mitochondrial fitness by efficient disposal of old and damaged organelles and suggesting this kinase as a new potential therapeutic target in diverse age-associated human diseases

D-Dimer as Biomarker for Early Prediction of Clinical Outcomes in Patients With Severe Invasive Infections Due to Streptococcus Pneumoniae and Neisseria Meningitidis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; no current clinical measure adequately reflects the concept of dysregulated response. Coagulation plays a pivotal role in the normal response to pathogens (immunothrombosis), thus the evolution toward sepsis-induced coagulopathy could be individuate through coagulation/fibrinolysis-related biomarkers. We focused on the role of D-dimer assessed within 24 h after admission in predicting clinical outcomes in a cohort of 270 patients hospitalized in a 79 months period for meningitis and/or bloodstream infections due to Streptococcus pneumoniae (n = 162) or Neisseria meningitidis (n = 108). Comparisons were performed with unpaired t-test, Mann-Whitney-test or chi-squared-test with continuity correction, as appropriate, and multivariable logistic regression analysis was performed with Bayesian model averaging. In-hospital mortality was 14.8% for the overall population, significantly higher in S. pneumoniae than in N. meningitidis patients: 19.1 vs. 8.3%, respectively (p = 0.014). At univariable logistic regression analysis the following variables were significantly associated with in-hospital mortality: pneumococcal etiology, female sex, age, ICU admission, SOFA score, septic shock, MODS, and D-dimer levels. At multivariable analysis D-dimer showed an effect only in N. meningitidis subgroup: as 500 ng/mL of D-dimer increased, the probability of unfavorable outcome increased on average by 4%. Median D-dimer was significantly higher in N. meningitidis than in S. pneumoniae patients (1,314 vs. 1,055 ng/mL, p = 0.009). For N. meningitidis in-hospital mortality was 0% for D-dimer 7,000 ng/mL. Kaplan-Meier analysis of in-hospital mortality showed for N. meningitidis infections a statistically significant difference for D-dimer >7,000 ng/mL compared to values <500 ng/mL (p = 0.021) and 500\u20133,000 ng/mL (p = 0.002). For S. pneumoniae the mortality risk resulted always high, over 10%, irrespective by D-dimer values. In conclusion, D-dimer is rapid to be obtained, at low cost and available everywhere, and can help stratify the risk of in-hospital mortality and complications in patients with invasive infections due to N. meningitidis: D-dimer <500 ng/mL excludes any further complications, and a cut-off of 7,000 ng/mL seems able to predict a significantly increased mortality risk from much <10% to over 25%

Recognition in emergency department of septic patients at higher risk of death: Beware of patients without fever

Background and Objectives: Chances of surviving sepsis increase markedly upon prompt diagnosis and treatment. As most sepsis cases initially show-up in the Emergency Department (ED), early recognition of a septic patient has a pivotal role in sepsis management, despite the lack of precise guidelines. The aim of this study was to identify the most accurate predictors of in-hospital mortality outcome in septic patients admitted to the ED. Materials and Methods: We compared 651 patients admitted to ED for sepsis (cases) with 363 controls (non-septic patients). A Bayesian mean multivariate logistic regression model was performed in order to identify the most accurate predictors of in-hospital mortality outcomes in septic patients. Results: Septic shock and positive qSOFA were identified as risk factors for in-hospital mortality among septic patients admitted to the ED. Hyperthermia was a protective factor for in-hospital mortality. Conclusions: Physicians should bear in mind that fever is not a criterium for defining sepsis; according to our results, absence of fever upon presentation might be indicative of greater severity and diagnosis of sepsis should not be delayed

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

Deep coral oases in the South Tyrrhenian Sea

A Mediterranean ‘‘roche du large’’ ecosystem, represented by four rocky shoals, located a few miles apart on a muddy bottom at 70–130 m depth in the gulf of St. Eufemia (Calabria, South Tyrrhenian Sea), was studied by means of Remotely Operated Vehicle (ROV) photo imaging. The shoals host highly diversified coral communities, mainly composed of arborescent colonies of gorgonians (Callogorgia verticillata, Paramuricea clavata, Paramuricea macrospina, Bebryce mollis, Villogorgia bebrycoides, Corallium rubrum, and Leptogorgia sarmentosa), and antipatharians (Antipathella subpinnata, Antipathes dichotoma and Parantipathes larix). The coral colonies reach high densities (up to ca. 17 colonies m22) and large sizes, such as the over 1.5 m wide antipatharian colonies. We hypothesized that the abundance and composition of the coral assemblages differed significantly among the rocky shoals and with respect to the surrounding soft bottoms. Various environmental variables were tested as possible explanatory factors of the observed differences. Moreover, due to their off- coast localization, we report here that these unique ecosystems are potentially subjected to a strong pressure from the local fishing activities, which were tentatively characterized. The recorded coral b-diversity among the shoals supports the hypothesis that these habitats behave like small oases of hard substrata interspersed in a muddy bottom. Because of their intrinsic beauty and rarity and their biological and ecological value, we stress the need of specific actions aimed at the urgent protection of these oases of biodiversity

Model-based Testing in Cloud Brokerage Scenarios

In future Cloud ecosystems, brokers will mediate between service providers and consumers, playing an increased role in quality assurance, checking services for functional compliance to agreed standards, among other aspects. To date, most Software-as-a-Service (SaaS) testing has been performed manually, requiring duplicated effort at the development, certification and deployment stages of the service lifecycle. This paper presents a strategy for achieving automated testing for certification and re-certification of SaaS applications, based on the adoption of simple state-based and functional specifications. High-level test suites are generated from specifications, by algorithms that provide the necessary and sufficient coverage. The high-level tests must be grounded for each implementation technology, whether SOAP, REST or rich-client. Two examples of grounding are presented, one into SOAP for a traditional web service and the other into Selenium for a SAP HANA rich-client application. The results demonstrate good test coverage. Further work is required to fully automate the grounding

Ischemic strokes in COVID-19: risk factors, obesity paradox, and distinction between trigger and causal association

Background and purpose: Stroke has been described as a COVID-19 complication. However, its occurrence rate, risk factors, and causal relationships are still not well established. Methods: We describe the characteristics of confirmed COVID-19-related strokes among all cases of COVID-19 hospitalized in our health network, from November 1, 2020 to April 30, 2021. Risk factor analysis has been conducted for ischemic stroke (IS), which represents 92% of all confirmed cases of Covid-19-related strokes, and a “causal attribution to infection” classification is provided. Results: In all, 62/4105 hospitalized COVID-19 patients had an acute stroke (1.51%). Severe COVID-19 (OR 2.27—CI 1.06–4.77; p = 0.032), atrial fibrillation (OR 3.65—CI 1.63–7.98; p = 0.001), and ischemic heart disease (OR 4.590—CI 1.714–12.137; p = 0.002) proved to be independent risk factors for IS, while obesity was a protective factor (OR 0.90—CI 0.82–0.97; p = 0.012). COVID-19 had a causal role in 32.1% of IS cases, was a relevant cofactor in 28.6% of cases of IS, and was a possible trigger in 39.3% of events. Conclusion: Our stroke occurrence rate is consistent with other population-based reports (range 0.34–2.7%). Prespecified peculiar clinical and radiological features allow the distinction between “IS caused by COVID-19” and “IS triggered by COVID-19.” Clinical history of vascular diseases and risk factors is crucial in determining the risk of IS in patients with COVID-19. However, the protective effect of a BMI > 30 kg/m2 seems to suggest an obesity paradox

Extração sequencial em solos de Santo Amaro da Purificação (BA) contaminados por chumbo.

O objetivo principal do trabalho é determinar através das técnicas de extração sequencial a associação química do Pb e também a mobilidade deste metal em duas amostras de solos de Santo Amaro da Purificação em duas profundidades, de O a 10cm e de 40 a 60 em, denominadas ta, tb, 2a e 2b, respectivamente