Mitochondrial TERT enhances mitochondria functions in vivo by protecting mitochondrial DNA integrity from oxidative damage : meeting abstract

Mitochondria are essential for respiration and oxidative phosphorylation. Mitochondrial dysfunction due to aging processes is involved in pathologies and pathogenesis of a series of cardiovascular disorders. New results accumulate showing that the enzyme telomerase with its catalytic subunit telomerase reverse transcriptase (TERT) has a beneficial effect on heart functions. The benefit of short-term running of mice for heart function is dependent on TERT expression. TERT can translocate into the mitochondria and mitochondrial TERT (mtTERT) is protective against stress induced stimuli and binds to mitochondrial DNA (mtDNA). Because mtDNA is highly susceptible to damage produced by reactive oxygen species (ROS) which are generated in close proximity to the respiratory chain, the aim of this study was to determine the functions of mtTERT in vivo and in vitro. Therefore, mitochondria from hearts of adult, 2nd generation TERT-deficient mice (TERT -/-) and wt littermates were isolated and state 3 respiration was measured. Strikingly mitochondria from TERT -/- revealed a significantly lower state 3 respiration (TERTwt: 987 +/- 72 pmol/s*mg vs. TERT-/-: 774 +/- 38 pmol/s*mg, p < 0.05, n = 5). These results demonstrated that TERT -/- mice have a so far undiscovered heart phenotype. In contrast mitochondria isolated from liver tissues did not show any differences. To get further insights in the molecular mechanisms, we reduced endogenous TERT levels by shRNA and measured mitochondrial reactive oxygen species (mtROS). mtROS were increased after ablation of TERT (scrambled: 4.98 +/- 1.1% gated vs. shTERT: 2.03 +/- 0.7% gated, p < 0.05, n = 4). We next determined mtDNA deletions, which are caused by mtROS. Semiquantitative realtime PCR of mtDNA deletions revealed that mtTERT protects mtDNA from oxidative damage. To analyze whether mitochondrial integrity is required to protect from apoptosis, vectors with mitochondrially targeted TERT (mitoTERT) and wildtype TERT (wtTERT) were transfected and apoptosis was measured. mitoTERT showed the most prominent protective effect on H2O2 induced apoptosis. In conclusion, mtTERT has a protective role in mitochondria by importantly contributing to mtDNA integrity and thereby enhancing respiration capacity of the heart

Opportunistic, not Optimal Delegation: The Political Origins of Central Bank Independence

Economists have long argued that central banks ran by technocrats have greater independence from the government. But in many countries, politically experienced central bankers are at the helm, including even highly independent central banks. To explain the level of central bank independence awarded, we develop a formal model where nominating politicians screen central bankers for their political ambitions. We show how screening and reelection efforts by the nominating politician changes the level of autonomy associated with different types of candidates. We predict that technocrats are associated with higher levels of independence than nominees with political experience, but as the appointing politician faces tougher reelection, candidates with political experience are associated with higher independence as well. We test our theory using new data from 29 post-communist countries between 1990-2012. We find evidence that the reelection strategy of the nominating politician is an important predictor of the level of central bank independence

MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury

Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency. In vivo experiments in the zebrafish model demonstrated that the tubulus cells of the larvae undergo cell death after the knockdown of mdm2. Doxycycline-induced deletion of MDM2 in tubular cell-specific MDM2-knockout mice Pax8rtTa-cre; MDM2f/f caused acute kidney injury with increased plasma creatinine and blood urea nitrogen and sharp decline of glomerular filtration rate. Histological analysis showed massive swelling of renal tubular cells and later their loss and extensive tubular dilation, markedly in proximal tubules. Ultrastructural changes of tubular epithelial cells included swelling of the cytoplasm and mitochondria with the loss of cristae and their transformation in the vacuoles. The pathological phenotype of the tubular cell-specific MDM2-knockout mouse model was completely rescued by co-deletion of p53. Tubular epithelium compensates only partially for the cell loss caused by MDM2 depletion by proliferation of surviving tubular cells, with incomplete MDM2 deletion, but rather mesenchymal healing occurs. We conclude that MDM2 is a non-redundant survival factor for proximal tubular cells by protecting them from spontaneous p53 overexpression-related cell death

Towards integrated surveillance-response systems for the prevention of future pandemics

Most human pathogens originate from non-human hosts and certain pathogens persist in animal reservoirs. The transmission of such pathogens to humans may lead to self-sustaining chains of transmission. These pathogens represent the highest risk for future pandemics. For their prevention, the transmission over the species barrier - although rare - should, by all means, be avoided. In the current COVID-19 pandemic, surprisingly though, most of the current research concentrates on the control by drugs and vaccines, while comparatively little scientific inquiry focuses on future prevention. Already in 2012, the World Bank recommended to engage in a systemic One Health approach for zoonoses control, considering integrated surveillance-response and control of human and animal diseases for primarily economic reasons. First examples, like integrated West Nile virus surveillance in mosquitos, wild birds, horses and humans in Italy show evidence of financial savings from a closer cooperation of human and animal health sectors. Provided a zoonotic origin can be ascertained for the COVID-19 pandemic, integrated wildlife, domestic animal and humans disease surveillance-response may contribute to prevent future outbreaks. In conclusion, the earlier a zoonotic pathogen can be detected in the environment, in wildlife or in domestic animals; and the better human, animal and environmental surveillance communicate with each other to prevent an outbreak, the lower are the cumulative costs

Importance of cortactin for efficient epithelial NF-ĸB activation by Helicobacter pylori, Salmonella enterica and Pseudomonas aeruginosa, but not Campylobacter spp.

Transcription factors of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF-ĸB) family control important signaling pathways in the regulation of the host innate immune system. Various bacterial pathogens in the human gastrointestinal tract induce NF-ĸB activity and provoke pro-inflammatory signaling events in infected epithelial cells. NF-ĸB activation requires the phosphorylation-dependent proteolysis of inhibitor of ĸB (IĸB) molecules including the NF-ĸB precursors through ubiquitin-mediated proteolysis. The canonical NF-ĸB pathway merges on IĸB kinases (IKKs), which are required for signal transduction. Using CRISPR-Cas9 technology, secreted embryonic alkaline phosphatase (SEAP) reporter assays and cytokine enzyme-linked immunosorbent assay (ELISA), we demonstrate that the actin-binding protein cortactin is involved in NF-ĸB activation and subsequent interleukin-8 (IL-8) production upon infection by Helicobacter pylori, Salmonella enterica and Pseudomonas aeruginosa. Our data indicate that cortactin is needed to efficiently activate the c-Sarcoma (Src) kinase, which can positively stimulate NF-ĸB during infection. In contrast, cortactin is not involved in activation of NF-ĸB and IL-8 expression upon infection with Campylobacter species C. jejuni, C. coli or C. consisus, suggesting that Campylobacter species pluralis (spp.) induce a different signaling pathway upstream of cortactin to trigger the innate immune response

‘I Could Not Bear It’. Perceptions of Chronic Pain among Somali Pastoralists in Ethiopia. A Qualitative Study

Background Pain is a major public health problem in the Global South, particularly among marginalized communities, such as Somali pastoralists. Yet, the topic of chronic pain has not yet been comprehensively studied in Sub-Saharan Africa, specifically in the Somali region of Ethiopia. Therefore, this study aims to explore the perceptions and notions of chronic pain among Somali pastoralists in this context. Methods This study used an explorative qualitative design. We performed semi-structured, face-to-face interviews with 20 purposively selected female and male Somali pastoralists with chronic pain. For data analysis, we applied the Framework Method by Gale et al. and explained patterns drawing on the Enactive Approach to Pain proposed by Stilwell and Harman. Findings Six different themes emerged: (1) “Pain as a symptom of harsh daily life”, (2) “Pain descriptions and dimensions”, (3) “Temporality of pain”, (4) “Pain-related stigma and stoicism” (5) “Mediating role of spirituality”, and (6) “Impact of pain on daily life activities”. Conclusions Somali pastoralists described their chronic pain as a multicausal and relational experience. Pastoralists (especially women) commonly refrained from communicating their pain and represented aspects of social stigma and stoicism. The mediating role of spirituality aided pastoralists to make sense of their pain and to ease its impact on their harsh daily life. The findings of this study can contribute to raise awareness of chronic pain issues among pastoralists. They highlight the need for policymakers to prioritize the improvement of pastoralist-specific pain management. Necessary resources and skills should be available within health care facilities. Pain management should be accessible, affordable and culturally acceptable for this population

Future intensification of precipitation and wind gust associated thunderstorms over Lake Victoria

Severe thunderstorms affect more than 30 million people living along the shores of Lake Victoria (East Africa). Thousands of fishers lose their lives on the lake every year. While deadly waves are assumed to be initiated by severe wind gusts, knowledge about thunderstorms is restricted to precipitation or environmental proxies. Here we use a regional climate model run at convection-permitting resolution to simulate both precipitation and wind gusts over Lake Victoria for a historical 10-year period. In addition, a pseudo global warming simulation provides insight into the region’s future climate. In this simulation, ERA5’s initial and boundary conditions are perturbed with atmospheric changes between 1995–2025 and 2070–2100, projected by CMIP6’s ensemble mean. It was found that future decreases in both mean precipitation and wind gusts over Lake Victoria can be attributed to a weaker mean mesoscale circulation that reduces the trigger for over-lake nighttime convection and decreases the mean wind shear. However, an intensification of extremes is projected for both over-lake precipitation and wind gusts. The observed 7 %K−1 Clausius–Clapeyron extreme precipitation scaling is ascribed to increased water vapor content and a compensation of weaker mesoscale circulations and stronger thunderstorm dynamics. More frequent wind gust extremes result from higher wind shear conditions and more compound thunderstorms with both intense rainfall and severe wind gusts. Overall, our study emphasizes Lake Victoria’s modulating role in determining regional current and future extremes, in addition to changes expected from the Clausius–Clapeyron relation

EU-Raw Materials Intelligence Capacity Platform (EU-RMCP) – Technical system specification

EU-Raw Materials Intelligence Capacity Platform (or EU-RMICP) integrates metadata on data sources related to primary and secondary mineral resources and brings the end users an expertise on the methods and tools used in mineral intelligence. The system is capable of bringing relevant user ‘answers’ of the type 'how to proceed for …' on almost any question related to mineral resources, on the whole supply chain, from prospecting to recycling, taking into account the environmental, political and social dimensions. EU-RMICP is based on an ontology of the domain of mineral resources (coupled with more generic cross-functional ontologies, relative to commodities, time and space), which represents the domain of the questions of the users (experts and non-experts). The user navigates in the ontology by using a Dynamic Graph of Decision (DDG), which allows him/her to discover the solutions which he/she is looking for without having to formulate any question. The system is coupled with a 'RDF Triple Store' (a database storing the ontologies), factSheets, doc-Sheets and flowSheets (i.e., specific formatted forms) related to methods and documentation, scenarios and metadata.JRC.B.6-Digital Econom

Increased red blood cell deformation in children and adolescents after SARS-CoV-2 infection

Severe coronavirus disease 2019 (COVID-19) is associated with hyperinflammation, hypercoagulability and hypoxia. Red blood cells (RBCs) play a key role in microcirculation and hypoxemia and are therefore of special interest in COVID-19 pathophysiology. While this novel disease has claimed the lives of many older patients, it often goes unnoticed or with mild symptoms in children. This study aimed to investigate morphological and mechanical characteristics of RBCs after SARS-CoV-2 infection in children and adolescents by real-time deformability-cytometry (RT-DC), to investigate the relationship between alterations of RBCs and clinical course of COVID-19. Full blood of 121 students from secondary schools in Saxony, Germany, was analyzed. SARS-CoV-2-serostatus was acquired at the same time. Median RBC deformation was significantly increased in SARS-CoV-2-seropositive compared to seronegative children and adolescents, but no difference could be detected when the infection dated back more than 6 months. Median RBC area was the same in seropositive and seronegative adolescents. Our findings of increased median RBC deformation in SARS-CoV-2 seropositive children and adolescents until 6 months post COVID-19 could potentially serve as a progression parameter in the clinical course of the disease with an increased RBC deformation pointing towards a mild course of COVID-19