Genetic Determinants of Dyslipidemia

Dyslipidemia is a chronic deviation from normal blood lipid levels that can lead to atherosclerosis and other cardiovascular diseases; dyslipidemia and its sequelae are caused by the complex interplay of genetic and environmental factors. Although circulating concentrations of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (LDL-C) have a strong genetic underpinning, not much is known about the genetic factors that affect long-term deteriorations in lipid concentrations. Through the work described in this thesis I sought to identify novel genetic loci associated with long-term lipid level changes and identify gene × environment interactions influencing blood lipid and lipoprotein concentrations.In Papers I and II, large European prospective cohort studies with long-term follow-up were analyzed. The Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study (N=3,495) was analyzed in the discovery phase of these studies. The MDC, PIVUS, ULSAM and MRC Ely studies (Nmax=8,263) were utilized as replication cohorts. In Paper III, Scandinavian adults from the GLACIER, MDC, Inter99 and Health 2006 Studies were meta-analyzed (Nmax=18,190). In Paper IV, analyses were conducted in the Diabetes Prevention Program (DPP) (N=2,993) multi-ethnic randomized clinical trial. Participants from the GLACIER Study and DPP, the two discovery studies intensively used in this thesis, were genotyped with the Illumina CardioMetaboChip array.In Paper I, TC- and TG-specific genetic risk scores (GRSs) were robustly associated with TC- and TG level changes, respectively. Three genomic loci, APOE, TRIB1 and APOA1 were associated with either TC- or TG changes and were replicated in subsequent analyses. In Paper II, in addition to the findings of Paper I, seven further loci were associated with TC- or TG changes. Of these, variants at CAPN3, HPR and SIX5 showed suggestive evidence for association with coronary artery disease. In Paper III, a robust sex-heterogeneous interaction between the TG-related GRS and body mass index was observed for circulating blood TG levels. In Paper IV, an interaction between the large HDL particle-associated GRS and the lifestyle intervention for large HDL particle concentrations was observed.In conclusion, this thesis work shows genetic associations for long-term lipid changes and demonstrates examples of gene × environment interactions that influence blood lipid concentrations

Cloning of an engenieered histone cluster in Drosophila melanogaster

Unrepaired DNA damages could lead to cancer formation. To allow repair of these damages, the repair proteins must assess the damage site, so the condensed DNA needs to be looser. Our group is interested in to understand chromatin changes during DNA repair processes by using novel experimental system. In eukaryotic cells the nucleus contains highly condensed DNA. The base of the chromatin structure is the evolutionarily conserved histone protein family. The histone proteins necessary for nucleosome assembly by forming a heterooctamer with two copies of H2A, H2B, H3 and H4. Finally the linker histone H1 requires for the proper chromatin condensation. All of the histone proteins can be post-translationally modified. These PTMs are the main rulers of epigenetic regulation. Processes using DNA as a template (transcription, replication and DNA repair) are greatly affected by the chromatin structure. Unimproved breaks lead genome instability or translocations which easily results tumor formation. Our aim is to understand how does the chromatin structure change around the break during the DNA repair and what is the link between unique histone PTMs and the mechanisms of the repair. We plan to set up an experimental system by which we will be able to study how do unique histone modifications affect the DSB repair. The advantage of this new experimental system is the clone of the histone cluster which contains all of the canonic (H2A, H2B, H3, H4) and linker (H1) histone genes in Drosophila melanogaster

Polimer szerkezeti elemek hegesztésének optimalizálása = Optimalization of welded structures from polymer elements

Pályázatunkban a kézi hőlégfúvós hegesztési eljárást automatizáltuk saját tervezésű és kivitelezésű hegesztőportál segítségével, amellyel célunk az emberi tényezők kizárása, az ellenőrizhetőség kialakítása és a reprodukálhatóság biztosítása volt a hegesztés során. Mérhetővé, valamint szabályozhatóvá tettük a hegesztési paramétereket, ezáltal lehetőség nyílt a hegesztési paraméterek közötti összefüggések feltárására. A független hegesztési paramétereket (hegesztési hőmérséklet, hegesztési térfogatáram) öt szinten, a hegesztő szakembertől függő paramétereket (hegesztési sebesség, hegesztőerő) három szinten vizsgáltuk. Két faktor szerinti keresztosztályozású varianciaanalízis segítségével bebizonyítottuk, hogy a varrat szilárdságára mind a négy hegesztési paraméter hatása szignifikáns és a hegesztett varrat minősége komplexen függ a négy hegesztési paramétertől. Mikro-szakítóvizsgálatokkal elemeztük a varrat deformációját, valamint a hegesztett varrat hőhatásövezetének polarizált fényű mikroszkópos vizsgálata alapján megalkottuk a forrógázos hegesztés során kialakult hőhatásövezet szupermolekuláris szerkezetének modelljét. A külső, mérhető geometria és a varrat szilárdsága közötti kapcsolat elemzéséhez bevezettünk egy dimenzió nélküli mennyiséget, a varratgeometriai tényezőt, amelynek segítségével az ipari gyakorlatban is közvetlenül megállapítható a varrat jósága, roncsolásos vizsgálatok nélkül. | In our project a welding portal was designed and built to make the welding parameters of manual hot-gas welding reproducible and independent of human factors. We made the welding parameters controllable, and hence the observation and definition of the relationship between the welding parameters became possible. The independent parameters (welding temperature, air flow rate) were analysed at five levels, while human-dependent variables (welding speed, welding force) at three levels. On the basis of two way analysis of variance, we concluded that all the four welding parameters have significant impact on welding strength, and they all influence the quality of the welded seam. We analysed the deformation of the seam with micro-tensile tests, and the heat affected zone of the welded seam was analyzed with polarized light microscope. On the basis of the observation the supermolecular model of the heat affected zone was created. A dimensionless quantity was introduced, as the welded seam coefficient, and it turned out to have correlation with the welding strength. With the help of this coefficient the quality of the seam can be determined directly without destructive materials testing in the industrial practice

Autophagy in zebrafish

From a hitherto underappreciated phenomenon, autophagy has become one of the most intensively studied cellular processes in recent years. Its role in cellular homeostasis, development and disease is supported by a fast growing body of evidence. Surprisingly, only a small fraction of new observations regarding the physiological functions of cellular "self-digestion" comes from zebrafish, one of the most popular vertebrate model organisms. Here we review the existing information about autophagy reporter lines, genetic knock-down assays and small molecular reagents that have been tested in this system. As we argue, some of these tools have to be used carefully due to possible pleiotropic effects. However, when applied rigorously, in combination with novel mutant strains and genome editing techniques, they could also transform zebrafish into an important animal model of autophagy research

Examination of temperature probe setup using computational fluid dynamics simulators

Engineering problem solving such as process design, process optimization, safety analysis, etc.; relies widely on mathematical models of the process. One of the most important aspects in a chemical plant is the safety protocols assuring the safety of workers and equipment. In this study Computational Fluid Dynamics (CFD) methods are used to model different temperature probe positions in a pipe elbow. Different models were computed together in order to solve heat transfer model: heat transfer in fluid and solid substances and momentum balance model. Three probe geometries are defined to obtain different results containing velocity field, and heat transfer. Based on the results the geometries and positions are compared to each other in order to find out which position is the most suitable for control studies, based on the time response of the probes. COMSOL Multiphysics was used to implement and to couple of the physics models. Due to the number of the geometries and model parameters (position and the geometry of the probe; inlet velocity) the COMSOL model was connected to MATLAB via COMSOL MATLAB LiveLink for solving the repeatable steps