Cardiac repair post-myocardial infarction: Roles of the primary cilium and the long non-coding RNA Malat1

Complete occlusion of a coronary artery causes myocardial infarction (MI), resulting in cardiomyocyte cell death. The surviving myocardium undergoes a deleterious remodeling process which causes further injury, and can ultimately result in heart failure. Despite therapeutic advances that have prolonged life, MI remains a leading cause of death worldwide and imparts a significant economic burden. The advancement of treatments to improve cardiac repair post-MI requires the discovery of new targeted treatment strategies. Epicardial-to-mesenchymal transition (EMT) occurs post-MI as a mechanism to support neovascularization and cardiac healing. However, the endogenous EMT is not enough to support sufficient repair. The transcription factor Wilms’ tumor 1 (Wt1) and the primary cilium regulate EMT. Furthermore, the long non-coding RNA (lncRNA) Malat1 is not only known to regulate EMT, but also mitigates cell death from injury. Little is known about the roles of Wt1, primary cilia, and Malat1 in relation to neonatal cardiac regeneration and adult cardiac repair post-MI. The aim of thesis was to investigate cardiac repair mechanisms related to EMT, primary cilia, and Malat1. To study the effects of deficiency of Wt1 and Malat1, a reproducible model of cardiac regeneration using coronary artery ligation to induce MI was developed in neonatal mice. We demonstrated the robust capacity for neonatal cardiac regeneration as neither Wt1 nor Malat1 deficiency affected the regenerative response. In the adult mouse, MI was induced to investigate the role of the primary cilium in EMT and repair post-MI, and the effects of Malat1 deficiency on acute MI pathology. We found that indeed epicardial cells are ciliated, and primary ciliary disassembly supports EMT post-MI, which enhances the contribution of epicardium-derived cells (EPDCs) to neovascularization. This reduced deleterious cardiac remodeling and preserved cardiac function. Contrastingly, Malat1 deficiency augmented cardiac cell death from MI. Unexpectedly, rather than affecting apoptosis, Malat1 deficiency augmented necroptotic cell death post-MI. Overall, this thesis is the first to show that in the adult heart, the primary cilium regulates epicardial EMT and the lncRNA Malat1 governs the propensity for necroptosis from ischemic injury. Both the primary cilium and Malat1 may serve as targets in the development of therapeutics to treat MI in the future

Homocysteine levels and treatment effect in the prospective study of pravastatin in the elderly at risk

Objectives: To assess the effect of preventive pravastatin treatment on coronary heart disease (CHD) morbidity and mortality in older persons at risk for cardiovascular disease (CVD), stratified according to plasma levels of homocysteine.<p></p> Design: A post hoc subanalysis in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), started in 1997, which is a double-blind, randomized, placebo-controlled trial with a mean follow-up of 3.2 years.<p></p> Setting: Primary care setting in two of the three PROSPER study sites (Netherlands and Scotland).<p></p> Participants: Individuals (n = 3,522, aged 70–82, 1,765 male) with a history of or risk factors for CVD were ranked in three groups depending on baseline homocysteine level, sex, and study site.<p></p> Intervention: Pravastatin (40 mg) versus placebo.<p></p> Measurements: Fatal and nonfatal CHD and mortality.<p></p> Results: In the placebo group, participants with a high homocysteine level (n = 588) had a 1.8 higher risk (95% confidence interval (CI) = 1.2–2.5, P = .001) of fatal and nonfatal CHD than those with a low homocysteine level (n = 597). The absolute risk reduction in fatal and nonfatal CHD with pravastatin treatment was 1.6% (95% CI = −1.6 to 4.7%) in the low homocysteine group and 6.7% (95% CI = 2.7–10.7%) in the high homocysteine group (difference 5.2%, 95% CI = 0.11–10.3, P = .046). Therefore, the number needed to treat (NNT) with pravastatin for 3.2 years for benefit related to fatal and nonfatal CHD events was 14.8 (95% CI = 9.3–36.6) for high homocysteine and 64.5 (95% CI = 21.4–∞) for low homocysteine.<p></p> Conclusion: In older persons at risk of CVD, those with high homocysteine are at highest risk for fatal and nonfatal CHD. With pravastatin treatment, this group has the highest absolute risk reduction and the lowest NNT to prevent fatal and nonfatal CHD.<p></p&gt

Seismic waveform tomography of the central and eastern Mediterranean upper mantle

Abstract. We present a seismic waveform tomography of the upper mantle beneath the central and eastern Mediterranean down to the mantle transition zone. Our methodology incorporates in a consistent manner the information from body and multimode surface waves, source effects, frequency dependence, wavefront healing, anisotropy and attenuation. This allows us to jointly image multiple parameters of the crust and upper mantle. Based on the data from ∼ 17 000 unique source–receiver pairs, gathered from 80 earthquakes, we image radially anisotropic S velocity, P velocity and density. We use a multi-scale approach in which the longest periods (100–150 s) are inverted first, broadening to a period band of 28–150 s. Thanks to a strategy that combines long-period signals and a separation of body and surface wave signals, we are able to image down to the mantle transition zone in most of the model domain. Our model shows considerable detail in especially the northern part of the domain, where data coverage is very dense, and displays a number of clear and coherent high-velocity structures across the domain that can be linked to episodes of current and past subduction. These include the Hellenic subduction zone, the Cyprus subduction zone and high-velocity anomalies beneath the Italian peninsula and the Dinarides. This model is able to explain data from new events that were not included in the inversion.</jats:p

The Role of Change Agent and Event Context in Sport-for-Development Projects

This study aims to contribute to the debate around the role of change agents and event contexts by providing a case study of the Spetses Mini Marathon event conducted in Spetses, an island located 54 nautical miles south of Athens, Greece. The idea of the event was conceived in 2010 by a private public relations and communication entity in Greece with the vision to stage an annual, mass participation sport event in collaboration with the local Municipality. Against the background of an economic crisis and an increasingly unstable political situation in the country that resulted in tensions in and between communities, the purpose of this study was to: (a) identify perceptions of various stakeholders towards the role of external private for-profit entities (i.e., change agents) in S4D event projects, (b) examine organizational matters that result in social impacts/outcomes for the host community through S4D projects, and (c) discuss the (potentially important role of the) event context and origin as the foundation for initiation and sustainability of S4D projects

Monitoring of Cell Layer Integrity with a Current-Driven Organic Electrochemical Transistor

The integrity of CaCo-2 cell barriers is investigated by organic electrochemical transistors (OECTs) in a current-driven configuration. Ion transport through cellular barriers via the paracellular pathway is modulated by tight junctions between adjacent cells. Rupturing its integrity by H2O2 is monitored by the change of the output voltage in the transfer characteristics. It is demonstrated that by operating the OECT in a current-driven configuration, the sensitive and temporal resolution for monitoring the cell barrier integrity is strongly enhanced as compared to the OECT transient response measurement. As a result, current-driven OECTs are useful tools to assess dynamic and critical changes in tight junctions, relevant for clinical applications as drug targeting and screening

The structure and energetics of 3^3He and 4^4He nanodroplets doped with alkaline earth atoms

We present systematic results, based on density functional calculations, for the structure and energetics of $^3$He and $^4$He nanodroplets doped with alkaline earth atoms. We predict that alkaline earth atoms from Mg to Ba go to the center of $^3$He drops, whereas Ca, Sr, and Ba reside in a deep dimple at the surface of $^4$He drops, and Mg is at their center. For Ca and Sr, the structure of the dimples is shown to be very sensitive to the He-alkaline earth pair potentials used in the calculations. The $5s5p\leftarrow5s^2$ transition of strontium atoms attached to helium nanodroplets of either isotope has been probed in absorption experiments. The spectra show that strontium is solvated inside $^3$He nanodroplets, supporting the calculations. In the light of our findings, we emphasize the relevance of the heavier alkaline earth atoms for analyzing mixed $^3$He-$^4$He nanodroplets, and in particular, we suggest their use to experimentally probe the $^3$He-$^4$He interface.Comment: Typeset using Revtex, 20 pages and 8 Postscript file

Поведение водорода при кристаллизации и охлаждении железа

С позиций теории направленной химической связи показано, что растворимость водорода в жидком железе и его аллотропических формах α–, γ– и δ–Fe коррелирует с изменением параметра Δе (положительная величина Δе соответствует донорному характеру связи, отрицательная – акцепторному)

Boer-en-zorg : onderzoek naar de kernkwaliteit van de zorgboerderij

De zorglandbouwsector heeft in de afgelopen periode een explosieve groei doorgemaakt en het aantal cliënten is navenant toegenomen. De toekomst van de zorglandbouw zal onder meer afhangen van de tevredenheid van de cliënten en de manier waarop vormgegeven wordt aan de professionalisering. Hoewel de kwaliteit en effectiviteit van zorgboerderijen duidelijk worden ervaren, zijn deze nog steeds niet wetenschappelijk onderbouwd. Er is daarom behoefte aan gegevens over meerwaarde van de zorgboerderij en informatie over aspecten die het succes van zorgboerderijen bepalen