Die chronische Herzinsuffizienz ist ein schwerwiegendes progredientes Krankheitsbild, das sich neben Dyspnoe und abnehmender Leistungsfähigkeit in einer nachgewiesenen Verschlechterung der HDL-Funktion manifestiert. In zahlreichen Studien, in denen der Einfluss von körperlichem Training auf die Progredienz der chronischen Herzinsuffizienz untersucht wurde, korrelierte dauerhaftes Ausdauertraining mit einer Verbesserung der eNOS-Aktivität und damit der HDLFunktion in Gefäßen. Ein Regulationsmechanismus von Endothelzellen besteht in der Expression von angiogenen microRNAs, die über negative Regulation die Proteinexpression beeinflussen. Ziel dieser Studie ist es nun, einen möglichen Zusammenhang zwischen der HDL-Funktionalität und der microRNA-Expression in Endothelzellen zu prüfen und damit die Funktionsänderung von HDL bei Herzinsuffizienten auf molekularer Ebene nachzuweisen. Zudem soll eine Beeinflussung der HDL-Funktion durch körperliches Training geprüft werden. Dafür wurde das HDL von gesunden und herzinsuffizienten Probanden (NYHAIII-Stadium) vor und nach einem vier- bzw. zwölfwöchigen Trainingsprogramm aus dem Plasma isoliert. Anschließend erfolgte mit dem gewonnenen HDL die 24-stündige Inkubation von HAEC-Kulturen. Nach Isolation der microRNAs aus dem gewonnenen Zelllysat konnte die Menge ausgewählter proangiogener miRs über RT-PCR quantifiziert werden. Die molekularbiologische Analyse der Proben zeigte eine, im Vergleich zu den Kontrollzellen, signifikant verringerte Menge an miR-21, -126 und -222 in den, mit HDLNYHAIII-inkubierten, Endothelzellen. Die miR-Expression der Endothelzellen zeigte nach dem Trainingsprogramm eine Annäherung an das Expressionsniveau der Kontrollen. Aus der dargelegten Studie wird so ersichtlich, dass das HDL von Herzinsuffizienten die Expression von proangiogenen microRNAs in Endothelzellen hemmt, was scheinbar in Korrelation mit der Ausbildung von endothelialen Dysfunktionen bei Herzinsuffizienz steht. Zudem konnte gezeigt werden, dass körperliches Training mit einer verbesserten Endothelfunktion über die Erhöhung der miR-Expression in Endothelzellen einhergeht.

Magister Pharmaceuticae - MPharm / Cardiovascular diseases (CVDs) such as ischaemic heart diseases, heart failure and stroke remain a major cause of death globally. Various deep-rooted factors influence CVD development; these include but are not limited to elevated blood lipids, high blood pressure, obesity and diabetes. A considerable number of proteins are involved directly and indirectly in the transport, maintenance and elimination of plasma lipids, including high and low-density lipoprotein cholesterol (HDL-C and LDL-C). There are several mechanisms involved in the removal of LDL particles from systemic circulation. One such mechanism is associated with the gene that encodes proprotein convertase subtilisin/kexin type 9 (PCSK9), which has become an exciting therapeutic target for the reduction of residual risk of CVDs. Currently, statins are the mainstay treatment to reduce LDL-C, and a need exists to further develop more effective LDL-C-lowering drugs that might supplement statins. This study was aimed at contributing to the generation of knowledge regarding the effect of niacin in reducing LDL levels through PCSK9 interaction. The aims/objectives of this study were achieved by utilizing two approaches, which included animal intervention with niacin followed by genetic screening of five prioritized genes involved in cholesterol synthesis and regulation. For animal intervention, 16 vervet monkeys were divided into two groups of eight animals consisting of a control and an experimental (niacin) group. The control group was given a normal standard diet of pre-cooked maize meal throughout the study, while the experimental group received the same diet supplemented with 100 mg/kg of niacin (SR) for 12 weeks. During the niacin intervention, blood was collected at baseline, every four weeks during the treatment period and the end of the washout period. The collected blood was used for biochemical analysis (total cholesterol, triglycerides, LDL-C, and HDL-C) and downstream genetic applications. The second phase included the screening of PCSK9, LDLR, SREBP-2, CETP and APOB-100 using genotyping and gene expression. Niacin administration produced statistically significant increases in plasma HDL-C at fourtime points (T1, T2, T3 and T4), which resulted in an overall increase in plasma HDL-C. Additionally, niacin administration resulted in a slight reduction in LDL-C and total cholesterol levels. Furthermore, the genotyping analysis revealed 13 sequence variants identified in PCSK9, LDLR, SREBP-2, CETP and APOB-100 genes. Five of these variants were predicted to be disease-causing and correlated with gene expression patterns. Three identified PCSK9 variants (H177N, R148S, G635G) were categorized as LOF mutations, and this was supported by a decline in gene expression in animals harbouring these variants. The LDLR also had LOF variants that were the reason for its decreased mRNA expression. Additionally, SREBP-2 proved to be a key mediator of cholesterol pathways. Therefore, the findings of the study conclusively suggest that niacin does increase HDL-C and decrease LDL-C and total cholesterol. Moreover, an interaction between niacin administration and PCSK9 was observed which resulted in decreased gene expression.

Det här examensarbete har genomförts i samarbete med Sweco Sverige AB på enheten för byggkonstruktion. Syftet med studien var att undersöka tungbetong som ett alternativ till konventionell konstruktionsbetong vid gjutning av vindkraftsfundament. I den här studien har ett vindkraftsfundament i konventionell konstruktionsbetong stått som grund för de dimensioneringsberäkningar som har utförts för att istället kunna använda tungbetong i fundamentet. Ett mål med studien var att med ett fundament i tungbetong minska dimensionerna och således minska klimatpåverkan och kostnaden.  För att undersöka om målet kunde uppnås har beräkningar för fundamentets geometri, krav vid bruksgränstillståndet, ekonomiska data och klimatpåverkan utförts. Från studiens dimensioneringsberäkningar om fundamentets geometri framgår det att fundamentet behöver uppfylla vissa krav på mått och därav är fundamentets radie den parameter som kan minska volymen mest. Det ledde till att volymen på fundamentet i tungbetong blev mindre än den för konventionell konstruktionsbetong.  Tungbetongens resultat blev ur vissa perspektiv bättre än konventionell konstruktionsbetong. Volymen för tungbetongsfundamentet kunde reduceras med 14 %. Detta resulterade i en minskning av koldioxidutsläpp med 7 %, priset ökade däremot med 65 %.  Genom att i detta fall använda sig av tungbetong istället för konventionell betong kunde både volym och koldioxidutsläpp reduceras, däremot till ett väldigt högt pris. / The purpose of the study was to investigate an alternative to conventional construction concrete. In this study, a wind turbine foundation consisting of conventional construction concrete have been analysed and served as a basis for dimension calculations to the foundation of heavy weight concrete.  A goal with the study was to decrease the dimensions of the foundation using heavy weight concrete instead of conventional and therefore also reduce the climate impact as well as the cost of the foundation.  To investigate if the goal is achievable, calculations for the foundation geometry, the requirement of the service limit state, economic data and climate impact have been calculated. In the calculations about the foundation geometry, certain requirements regarding the dimensions needs to be achieved and therefore it is the radius of the foundations that can affect the volume the most. This resulted in a decrease of volume for the heavy weight concrete foundation.  In some perspectives, the heavy weight concrete had better outcome than conventional construction concrete. The volume of the foundation could be reduced by 14 %. This led to a reduction in product emission by 7 %. The price of heavy weight concrete, per cubic meter, is almost five times more expensive than it is for conventional construction concrete and therefore the price was 65 % higher.  This concludes in a possibility to reduce both the volume as well as the CO2-emissions but for a very high price.

Apolipoprotein L1 (APOL1) is a human-specific serum protein bound to high-density lipoprotein (HDL) particles. This protein allows human resistance to infection by African trypanosomes except for two subspecies, Trypanosoma brucei rhodesiense and T. b. gambiense, the causative agents of sleeping sickness or African trypanosomiasis. This disease infects 20 000 people in sub-Saharan Africa and without treatment, infection is almost always fatal. T. b. rhodesiense resists APOL1 through direct protein neutralization by the Serum Resistance-Associated (SRA) protein. T. b. gambiense does not express SRA, and its mechanism of resistance to APOL1 is orchestrated upon a recently characterized multifactorial defense mechanism.<p><p>The mechanism by which the human serum sensitive parasites are killed following APOL1 uptake is described as the result of the lysosomal swelling induced by the generation of ionic pores within the lysosomal membrane.<p>We show here that preventing the osmotic lysosomal swelling in a hyperosmotic culture condition does not prevent the cell death. In addition, APOL1 appears to trigger some programmed cell death events in the cell such as a fast mitochondrial depolarization followed by a DNA laddering and fragmentation. Furthermore, we show an implication of the endonuclease G (TbEndoG), known to be a key actor in the regulation of cell death process and a kinesin (TbKIFC1), which might be the transporter of APOL1 for the endosomes to the mitochondrion.<p> <p>In addition, by producing different recombinant human APOL proteins in E. coli and test their activity on T. brucei, we were able to show that APOL3, an other member of the APOL family, also possesses a trypanolytic activity like APOL1 beneath the fact it is not a secreted protein. APOL3 does not only kill T. b. brucei but is also able to lyse APOL1-resistant subspecies such as rhodesiense and gambiense, in vitro and confirmed in vivo when the recombinant APOL3 were injected in infected mice. A beginning of an action mechanism is described herein showing a pH-independent activity for this protein oppositely to APOL1, conferring its specificity.<p>It is thus conceivable to use this recombinant protein as a first step of a potent curative agent against gambiense or rhodesiense since the few currently available drugs for treatment of African trypanosomiasis, that are outdated, show problems with toxicity and resistance. <p><p>/ <p><p>L’ Apolipoprotéine L1 (APOL1) est une protéine sérique humaine associée aux lipoprotéines de haute densité (HDL). Cette protéine confère la résistance à l'infection des trypanosomes africains à l'exception des deux sous-espèces, Trypanosoma brucei rhodesiense et T. b. gambiense, les agents responsables de la maladie du sommeil ou trypanosomiase africaine. Cette maladie infecte 20 000 personnes en Afrique sub-saharienne et en l'absence de traitement, l'infection est presque toujours mortelle. T. b. rhodesiense résiste à l’APOL1 grâce à une neutralisation directe d’APOL1 par une protéine appelé SRA (Serum Resistant-Associated). T. b. gambiense n'exprime pas SRA, et sa résistance à l’APOL1 est orchestrée par un mécanisme de défense multifactorielle récemment caractérisé 1.<p>Le mécanisme par lequel les parasites sensibles au sérum humain sont tués suivant l’entrée de l’APOL1 est décrit comme le résultat d’un gonflement du lysosome induit par la génération de pores ioniques à l'intérieur de la membrane lysosomiale2. Nous montrons ici que le gonflement osmotique du lysosome peut être empêché en condition de culture hyper osmotique, sans néanmoins empêcher la mort de la cellule. En outre, l’APOL1 semble déclencher des événements de mort cellulaire programmée dans la cellule, tels qu’une dépolarisation mitochondriale rapide suivie d'une fragmentation de l’ADN. De plus, nous montrons une implication de l'endonucléase G (TbEndoG), connu pour être un acteur clé dans la régulation du processus de mort cellulaire et d’une kinésine (TbKIFC1) qui pourrait avoir le rôle de transporter l’APOL1 des endosomes vers la mitochondrie.<p>Nous avons également pu montrer que l’APOL3, un autre membre de la famille des APOLs humaines, possède tout comme l’APOL1, une activité trypanolytique bien que cette protéine ne soit pas sécrétée en condition physiologique. De manière intéressante, l’APOL3 ne tue pas seulement T. b. brucei, mais est également capable de tuer les sous-espèces résistantes à l’APOL1 tels que rhodesiense et gambiense, in vitro et in vivo lorsque de l’APOL3 recombinante est injectée dans des souris infectées. La spécificité d’action de l’APOL3 pourrait être liée à une indépendance au pH, au contraire de l’APOL1. Il pourrait être envisagé d'utiliser cette protéine recombinante comme agent curatif contre gambiense ou rhodesiense du fait que les médicaments actuellement disponibles pour le traitement de la trypanosomiase africaine montrent des problèmes de toxicité et de résistance.<p><p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Background: Several previous studies have reported that dyslipidemia is associated with the risk of hypertension, but these studies are mainly conducted in European and US populations, with a very few studies in the Asian population. Moreover, the effects of atherosclerotic indices, including atherogenic coefficient (AC) and atherogenic risk of plasma (AIP), on hypertension in Asians have not been well described so far. Methods: From 2010 to 2016, altogether 211,833 Chinese adults were ultimately recruited at the health centers in 11 Chinese cities (including Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, and Nantong). Differences in continuous variables between the two groups were analyzed by the Mann–Whitney test, while those in categorical variables were examined by the Chi-squared test. Logistic regression was applied to evaluate the association between lipid profiles and the risk of hypertension. The predictive values of AC and AIP for the incidence of hypertension were analyzed using the area under the receiver operating characteristic (ROC) curve. Meanwhile, Bayesian network (BN) models were performed to further analyze the associations between the different covariates and the incidence of hypertension. Results: A total of 117,056 participants were included in the final analysis. There were significant differences in baseline characteristics between normotension and hypertension groups (p < 0.001). In multivariate logistic regression, the risk of hypertension increased by 0.2% (1.002 [1.001–1.003]), 0.2% (1.002 [1.001–1.003]), and 0.2% (1.002 [1.001–1.003]) per 1 mg/dl increase in total cholesterol (TC), low-density lipoprotein (LDL), and non-high-density lipoprotein cholesterol (non-HDL-c), respectively. However, after adjusting for body mass index (BMI), an increase in HDL level was associated with a higher risk of hypertension (p for a trend < 0.001), and the risk of hypertension increased by 0.6% per 1 mg/dl increase in HDL-c (1.006 [1.003–1.008]). In women, AC had the highest predictive value for the incidence of hypertension with an area under the curve (AUC) of 0.667 [95% confidence interval (CI): 0.659–0.674]. BN models suggested that TC and LDL were more closely related to the incidence of hypertension. Conclusions: Overall, lipid profiles were significantly abnormal in the hypertensive population than in the normotensive population. TC and LDL were strongly associated with the incidence of hypertension. TC, LDL, and non-HDL-c levels show a positive association, HDL-c shows a negative association, while TG is not significantly associated with the risk of hypertension. After adjusting for BMI, HDL-c turns out to be positively associated with the risk of hypertension. In addition, AC has a good predictive value for the incidence of hypertension in women.

No description available.

With the development of information technology, power management for telecom and computer applications become a large market for power supply industries. To meet the performance and reliability requirement, distributed power system (DPS) is widely adopted for telecom and computer systems, because of its modularity, maintainability and high reliability. Due to limited space and increasing power consumption, power supplies for telecom and server systems are required to deliver more power with smaller volume. As the key component of DPS system, front-end AC/DC converter is under the pressure of continuously increasing power density. For conventional industry practices, some limitations prevents front-end converter meeting the power density requirement. In this dissertation, different techniques have been investigated to improve power density of front-end AC/DC converters. For PFC stage, at low switching frequency, PFC inductor size is large and limits the power density. Although increasing switching frequency can dramatically reduce PFC inductor size, EMI filter size might be larger at higher switching frequency because of the change of noise spectrum. Since the relationship between EMI filter size and PFC switching frequency is unclear for industry, PFC circuits always operate with switching frequency lower than 150 kHz. Based on the EMI filter design method, together with a simple EMI noise prediction model, relationship between EMI filter corner frequency and PFC switching frequency was revealed. The analysis shows that switching frequency of PFC circuit should be higher than 400 kHz, so that both PFC inductor and EMI filter size can be reduced. Although theoretical analysis and experimental results verify the benefits of high switching frequency PFC, it is essential to find a suitable topology that allows high switching frequency operation while maintains high efficiency. Three PFC topologies, single switch PFC, three-level PFC with range switch and dual Boost PFC, were evaluated with analysis and experiments. By using advanced semiconductor devices, together with proposed control methods, these topologies could achieve high efficiency at high switching frequency. Thus, the benefits of high frequency PFC can be realized. In front-end converter, large holdup time capacitor size is another barrier for power density improvement. To meet the holdup time requirement, bulky holdup time capacitor is normally used to provide energy during holdup time. Holdup time capacitor requirement can be reduced by using wider input voltage range DC/DC converte. Because LLC resonant converter can realized with input voltage range without sacrificing its normal operation efficiency, it becomes an attractive solution for DC/DC stage of front-end converters. Moreover, its small switching loss allows it operating at MHz switching frequency and achieves smaller passive component size. However, lack of design methodology makes the topology difficult to be implemented. An optimal design methodology for LLC resonant converter has been developed based on the analysis on the circuit during normal operation condition and holdup time. The design method is verified by a 1 MHz switching frequency LLC resonant converter with 76W/in3 power density. When front-end converter operates at high switching frequency, negative effects of circuit parasitics become more pronounced. By integrating active devices together with their gate drivers, Active Integrated power electronics module (IPEM) can largely reduce circuit parasitics. Therefore, switching loss and voltage stress on switching devices can be reduced. Moreover, IPEM concept can be extended into passive integration and EMI filter integration By using this power integration technology, power density and circuit performance of front-end converter can be improved, which is verified by theoretical analysis and experimental results. / Ph. D.

Double-sided module exhibits electrical and thermal characteristics that are superior to wire-bonded counterpart. Such structure, however, induces more than twice the thermo-mechanical stress in a single-layer structure. Compressive posts have been developed and integrated into the double-sided module to reduce the stress to a level acceptable by silicon dice. For a 14 mm x 21 mm module carrying 6.6 mm x 6.6 mm die, finite-element simulation suggested an optimal design having four posts located 1 mm from the die; the z-direction stress at the chip was reduced from 17 MPa to 0.6 MPa. / Ph. D.

No / Ultrasonic technology provides a powerful and noninvasive method of in-process measurement during injection molding and extrusion. Changes in the velocity, attenuation and reflection coefficients of high frequency sound waves can be related to the state and conditions of the materials through which they propagate. The velocity of an ultrasonic wave changes with density and elastic moduli; this allows information on solidification and material properties to be collected during the molding cycle. The time of flight of the wave is a function of velocity and path length. This paper shows that it can be correlated with the residual wall thickness of polymer in the mold during gas assisted injection molding.

Approved for public release; distribution in unlimited. / Future sea bases, such as the Maritime Prepositioning Force (Future), will serve as key distribution nodes and must be able to sustain forces ashore and selectively offload supplies from storerooms quickly and efficiently. Current MPF ships maximize the available cargo storage onboard and have little ability to selectively offload supplies. To make selective offload a reality, MPF(F) requires lower stowage densities and new technologies to efficiently move items, especially for those supplies needed in direct support of forces ashore. The difficult questions are how dense and in what configurations MPF(F) storerooms can be packed, and how items should be retrieved in order to selectively offload supplies and provide acceptable response time. We analyze the trade-off between storage density and mean retrieval time in a dynamic environment for different storage densities and configurations in notional storerooms aboard a future sea base. We examine two demand scenarios and two different retrieval rules to determine how each storage configuration responds to retrieval requests over time. Our results provide insight into the types of storeroom configurations that provide the best mean retrieval times and how a simple retrieval rule can significantly reduce mean retrieval time under certain demand conditions. / Lieutenant Commander, United States Navy