Global ETD Search

231	Duplicacions segmentàries a la regió cromosòmica humana 8P23.1: evolució i expansió d'una nova família gènica Bosch Pages, Nina 19 December 2008 (has links) Les duplicacions segmentàries (DSs), o també anomenades duplicons o Low copy Repeats (LCRs), són regions de coma mínim 1 kb amb un alt nivell d'identitat (>90%), que estan presents almenys dues vegades en el genoma. La regió 8p23.1 consta de 6.5 Mb a la part distal del braç curt del cromosoma 8 i està flanquejada per duplicacions segmentàries. Degut a la seva arquitectura genòmica aquesta regió és susceptible a patir reordenaments mediats per recombinació homòloga no al·lèlica entre les DSs, com per exemple la inversió polimòrfica de 8p23.1 [inv(8)(p23)], present en un de cada quatre individus de la població general europea i japonesa, així com d'altres reorganitzacions menys corrents.El treball realitzat en aquesta tesi doctoral pretén aprofundir en la caracterització de la complexa arquitectura genòmica d'aquesta regió. En la nostra primera aproximació a l'estudi de les DSs que flanquegen la regió cromosòmica 8p23.1, es va identificar una nova família gènica específica de primats, la família gènica FAM90A.Així, bona part d'aquesta tesi doctoral està centrada en l'anàlisi de l'origen, formació, evolució i expansió de FAM90A en els homínids. Per altra banda també s'ha analitzant en detall la variabilitat de FAM90A com a variant en número de còpia (CNV) en diferents poblacions humanes.Finalment, s'ha establert la freqüència de la inversió que afecta a 8p23.1 en població espanyola. També s'ha procedit a genotipar diversos individus homozigots per la inversió i s'ha predit l' estatus de la inversió en 150 individus del projecte HapMap i s'ha analitzat l'efecte que té aquesta reorganització sobre els nivells d'expressió dels gens de la regió. / Segmental duplications (SDs), also known as duplicons or Low Copy Repeats (LCRs), are regions of a minimum of 1 kb with a high sequence identity level (>90%), which are present at least two times in the genome. The 8p23.1 region extends 6.5 Mb at the distal part of the short arm of chromosome 8 and it is flanked by segmental duplications. Due to its genomic architecture the region is prone to suffer rearrangements mediated by non-allelic homologous recombination between these SDs, such as the polymorphic inversion of 8p23.1 [inv(8)(p23)], which is present in one out of every four of European and Japanese general population individuals, as well as other less frequent rearrangements.The aim of the work presented in this doctoral thesis is to get insights in the characterization of the genomic architecture of this complex region. Our first approach to study the SDs flanking 8p23.1 region resulted in the identification of a novel gene family which is primate specific, the FAM90A gene family. Thus, this doctoral thesis is mainly focused on the analysis of the origins, formation, evolution and expansion of FAM90A in hominoids. It has also been analyzed in detail the variability of FAM90A as a copy number variant (CNV) in different human populations.Finally, it has been established the frequency of the inversion affecting 8p23.1 region in the Spanish population. Several homozygous inverted individuals have been genotyped and the status for the inversion has been predicted for 150 HapMap individuals, as well as the effect of this rearrangement on the gene expression levels of the genes contained in the region. NAHR Chromosomal rearrangements 8p23.1 Defensins Correlation Gene fusion Gene expansion Mosaicism Inversions Primates Structural variant Copy number variant or CNV Gene family FAM90A Segmental duplicactions Illumina SNPassoc WGS Real time- PCR FISH Ka/Ks Polimorfisme Trastorn genòmic NAHR Reordenaments cromosòmics 8p23.1 Defensines Correlació Fusió gènica Expansió gènica Mosaicisme Inversions Primats Variant estructural Variant en número de còpia o CNV Família gènica FAM90A Duplicacions segmentàries Genomic disorder Polymorphism Ka/Ks FISH Real time PCR WGS SNPassoc Illumina 57
232	Analysis of genetic variation in microrna-mediated regulation and the susceptibility to anxiety disorders Muiños Gimeno, Margarita 18 December 2009 (has links) We have investigated genetic variation in microRNA-mediated regulation as a susceptibility factor for anxiety disorders following two different approaches. We first studied two isoforms of the candidate gene NTRK3 by re-sequencing its different 3'UTRs in patients with Panic (PD) and Obsessive Compulsive disorders (OCD) as well as controls. Two rare variants that altered microRNA-mediated regulation were identified in PD. Conversely, association of a common SNP with OCD hoarding subtype was found. Moreover, we have also studied a possible involvement of microRNAs in anxiety disorders. Consequently, we have analysed the genomic organisation and genetic variation of miRNA-containing regions to construct a panel of SNPs for association analysis. Case-control studies revealed several associations. However, it is worth remarking the associations of miR-22 and miR-488 with PD; two microRNAs for which functional assays and transcriptome analysis after microRNA overexpression showed significant repression of a subset of genes involved in physiological pathways linked to PD development. / Hem investigat la variació genètica a la regulació mediada per microRNAs com a factors de susceptibilitat pels trastorns d'ansietat seguint dues aproximacions diferents. Primer vam estudiar dues isoformes del gen candidat NTRK3 mitjançant la reseqüenciació dels seus diferents 3'UTRs a pacients de pànic (TP), a pacients amb trastorn obsessiu compulsiu (TOC) i a controls. Dues variants rares que alteren la regulació mediada per microRNAs foren identificades per TP. D'altra banda, es trobà associació d'un SNP comú amb el subtipus acumulador de TOC. A més, també hem estudiat la possible implicació dels microRNAs als trastorns d'ansietat. Conseqüentment, hem analitzat l'organització genòmica i la variació genètica a regions que contenen microRNAs per construir un panell d'SNPs per fer anàlisis d'associació. Els estudis cas-control van revelar algunes associacions. Tanmateix, val la pena destacar les associacions del miR-22 i el miR-488 amb TP; dos microRNAs pels quals assajos funcionals i anàlisis de transcriptoma després de la seva sobreexpressió han mostrat una repressió significativa d'un grup de gens implicats en vies fisiològiques lligades al desenvolupament del TP. isoforma anàlisi de transcriptoma PCR assaig de luciferasa variant comuna variant rara reseqüenciar estudis d'associació poly-miRTS trastorn obsessiu-compulsiu trastorn de pànic trastorn d'ansietat variació genètica intraespecífica SNP NTRK3 gen candidat element regulador microRNA variació genòmica desordres poligènics trets complexes isoform transcriptome analysis PCR luciferase assay common variant rare variant re-sequencing association studies poly-miRTS obsessive-compulsive disorder panic disorder anxiety disorder genetic variation within species SNP NTRK3 candidate gene regulatory element microRNA genome variation polygenic disorders complex traits 57
233	Enabling traceability of design rationale using the concept of product family description (PFD) Poorkiany, Morteza January 2011 (has links) This thesis work is based on the previous researches in design automation at Sandvik Coromant. The concept of product family description (PFD) has been introduced to the company to improve documentation of knowledge in engineering design process. Current documentation at the company for engineering design covers mostly the design definition part of the knowledge. PFD is constituted by design definition and completed by design rationale. This kind of documentation improves reusing, revising and expanding the knowledge at the company. On the other side, PFD is an input for design programming and a good engineering design description for a product provides more efficiency in design programming. The project is started by a survey for several principles and applications for knowledge modelling. Product variant master (PVM) and Semantic MediaWiki are selected by the results of the survey. To show the concept of PVM, modelling of a test product is done in product model manager (PMM) software. The main part of the project is setting up product family description (PFD) by capturing design rationale for the test product, implementing in Semantic MediaWiki. Since the design rationale is not documented, it was recorded during several meetings with the designer of the test product. The description is completed by including the argumentations about the rules, figures, dimensions and etc. Also in the project has been tried to improve and revise the description to make it more simple and efficient. Another objective of the project is to show Semantic MediaWiki as a candidate application for modelling knowledge at the company. In this step the applicability and functionality of both PFD and Semantic MediaWiki is seen. In the next stage the project findings and company documentation are evaluated. In this step has been tried to show the pros and cons of the project. The emphasis of the evaluation is on PFD and the alternative application. In the end a conclusion of the whole methods and findings of the project comes with discussion with people who were involved in this work. Product variant master (PVM) product model manager (PMM) product family description (PFD) design definition design rationale Semantic MediaWiki
234	Magnetic field-induced phase transformation and variant reorientation in Ni2MnGa and NiMnCoIn magnetic shape memory alloys Karaca, Haluk Ersin 15 May 2009 (has links) The purpose of this work is to reveal the governing mechanisms responsible for the magnetic field-induced i) martensite reorientation in Ni2MnGa single crystals, ii) stress-assisted phase transformation in Ni2MnGa single crystals and iii) phase transformation in NiMnCoIn alloys. The ultimate goal of utilizing these mechanisms is to increase the actuation stress levels in magnetic shape memory alloys (MSMAs). Extensive experimental work on magneto-thermo-mechanical (MTM) characterization of these materials enabled us to i) better understand the ways to increase the actuation stress and strain and decrease the required magnetic field for actuation in MSMAs, ii) determine the effects of main MTM parameters on reversible magnetic field induced phase transformation, such as magnetocrystalline anisotropy energy (MAE), Zeeman energy (ZE), stress hysteresis, thermal hysteresis, critical stress for the stress induced phase transformation and crystal orientation, iii) find out the feasibility of employing polycrystal MSMAs, and iv) formulate a thermodynamical framework to capture the energetics of magnetic field-induced phase transformations in MSMAs. Magnetic shape memory properties of Ni2MnGa single crystals were characterized by monitoring magnetic field-induced strain (MFIS) as a function of compressive stress and stress-induced strain as a function of magnetic field. It is revealed that the selection of the operating temperature with respect to martensite start and Curie temperatures is critical in optimizing actuator performance. The actuation stress of 5 MPa and work output of 157 kJm−3 are obtained by the field-induced variant reorientation in NiMnGa alloys. Reversible and one-way stress-assisted field-induced phase transformations are observed in Ni2MnGa single crystals under low field magnitudes (<0.7T) and resulted in at least an order of magnitude higher actuation stress levels. It is very promising to provide higher work output levels and operating temperatures than variant reorientation mechanisms in NiMnGa alloys. Reversible field-induced phase transformation and shape memory characteristics of NiMnCoIn single crystals are also studied. Reversible field-induced phase transformation is observed only under high magnetic fields (>4T). Necessary magnetic and mechanical conditions, and materials design and selection guidelines are proposed to search for field-induced phase transformation in other ferromagnetic materials that undergo thermoelastic martensitic phase transformation. magnetic shape memory alloys ferromagnetic shape memory alloys phase transformation martensitic transformation variant reorientation magnetocrystalline anisotropy energy
235	Lietuvių bendrinės kalbos paprastųjų daiktavardžių kirčiavimo realioji vartosena ir kodifikuotos normos / The codified standards and the real usage of common nouns' stress in the Lithuanian language Paliukėnaitė, Gintarė 02 August 2013 (has links) Bendrinėje lietuvių kalboje yra labai daug žodžių, kurių kirčiavimas nėra nusistovėjęs. Ypač tokį kirčiavimą rodo vardažodžiai. Tad šiame darbe bus apžvelgti tokie vardažodžiai, tiksliau pirminiai daiktavardžiai, kurių kirčiavimo normas Valstybinės lietuvių kalbos komisijos Tarties ir kirčiavimo pakomisės buvo koreguotos ir teiktos Rekomendacijoje Dėl kai kurių pirminių (paprastųjų) daiktavardžių kirčiavimo. Taip pat ir tokie pirminiai daiktavardžiai, kurių kirčiavimo normos VLKK nebuvo tikslintos, tačiau gyvojoje kalboje labai dažnai pavartojamos ir jokiuose šaltiniuose nefiksuojami variantai. Įtraukiami ir tokie vardažodžiai, kurie norminamuosiuose leidiniuose nurodomi kaip turintys gretimybes. Šių paprastųjų daiktavardžių kirčiavimo normų paplitimas buvo tiriamas trijose skirtingose Lietuvos vietovėse, t. y. Lazdijų bei Molėtų rajone, Prienų mieste. Pirmajame tyrime, remiantis Valstybinės lietuvių kalbos komisijos teikta Rekomendacija buvo apklausta 500 respondentų. Antrajame iš tų pačių vietovių – 495 kalbos vartotojai. Gauti rezultatai turėjo parodyti, ar tikrai realioji vartosena remia VLKK sprendimą, ar šnekamojoje kalboje nebando įsitvirtinti kirčiavimo variantai, kuriuos normintojai laiko klaidomis. Prieš atliekant abu tyrimus buvo peržiūrėta bei išnagrinėta daug norminamosios literatūros. Lyginamojo metodo taikymas turėjo padėti nustatyti, kaip kito ar vis dar tebekinta tiriamų paprastųjų daiktavardžių kirčiavimo normos. Kiekvienam vardažodžiui, kuris buvo tiriamas... [toliau žr. visą tekstą] / There are many words in standard Lithuanian with unfixed stress. This is especially peculiar to nominal words. Thus this work will deal with such nominal words like simple nouns the stress of which has been corrected by the subcommittee dealing with the norms of stress of the State Committee on pronunciation and stress. These norms were presented in the recommendation called ‘Some simple noun stress’. The work will also deal with such simple nouns the stress of which hasn’t been specified by the State Committee on stress, but which are widely used in the existent language. Their variations of stress are not mentioned in any sources. The nouns having contiguity in standardization editions are also included in this work. The spread of standard stress of simple nouns was researched in three different locations: in Lazdynai and Moletai regions and in the town of Prienai. According to the first research based on the recommendations of the Lithuanian State Committee on language 500 respondents were questioned. During the second research 495 native speakers in the same regions were asked. The results were to show whether the real usage corresponds the standards of the State Committee on language. The results also had to show whether erratic stress variants are established in colloquial speech. Before carrying out both researches a lot of stuff on standardization had been studied and analysed. The method comparison had to help to define if the stress standards of the researched... [to full text] Philology Paprastieji (pirminiai) daiktavardžiai Kirčiavimo norma Kirčiavimo variantas Kirčiavimas Šnekamoji kalba Simple nouns Stress standard Stress variant Stress Colloquial language
236	Mécanisme épigénétique impliqué dans la déposition de CENP-A aux centromeres Shuaib, Muhammad 08 June 2012 (has links) (PDF) La ségrégation fidèle des chromosomes est dirigée par le centromère, un locus chromosomique spécialisé qui est requis pour l'assemblage des kinetochores actifs. Les centromères sont marqués épigénétiquement par la présence d'un nucléosome unique qui contient un variant centromérique de l'histone H3 appelé Centromere protein A (CENP-A). Une question fondamentale est comment CENP-A est spécifiquement déposé aux centromères. L'objectif de ma thèse a été d'identifier les facteurs spécifiques de la déposition de CENP-A. Pour identifier les facteurs spécifiques impliqués dans la déposition de CENP-A aux centromères, j'ai utilisé la méthode de purification TAP-TAG à partir d'une fraction nucléaire soluble de cellules HeLa exprimant stablement une copie ectopique de CENP-A (e-CENP-A). J'ai ainsi pu identifié la protéine Holliday Junction Recognition protein (HJURP). En utilisant un siRNA spécifique de HJURP, j'ai montré que la localisation et la déposition de CENP-A étaient fortement affectées. La protéine recombinante HJURP lie de manière stoechiométrique le tétramère CENP-A/H4 mais il ne lie pas le tétramère H3/H4. La liaison se fait grâce à un petit domaine conservé en position N-terminal de HJURP, dénommé CBD (CENP-A binding domain). De plus, j'ai pu mettre en évidence in vitro que HJURP facilitait la déposition du tétramère CENP-A/H4 sur de l'ADN satellite. L'ensemble de mes résultats démontre très clairement que HJURP est la principale chaperone responsable de la déposition de CENP-A aux centromères. Histone variant CENP-A Centromères Histone chaperone HJURP
237	Validation and Functional Characterization of Novel Neurofibromin Interacting Proteins Arun, Vedant 19 March 2013 (has links) Neurofibromin (NF1) is a 2,818aa protein encoded by the very large NF1 tumour suppressor gene located on chromosome 17q11.2. Loss of function mutations and deletions in NF1 underlie Neurofibromatosis type-1 (NF-1) - the most common inherited syndrome of the nervous system in humans with a birth incidence of 1:3,000. The most visible feature of NF-1 is the neoplastic manifestations known as neurofibromas, however, the syndrome is also characterized by pigmentary defects, peripheral motor dysfunction, learning disabilities and several developmental abnormalities. The molecular etiology of many of these non-neoplastic phenotypes remains unknown. Here we demonstrate that the Tubulin Binding Domain (TBD) of NF1 is a binding partner of the Leucine Rich Pentatrico Peptide Repeat motif-Containing protein (LRPPRC) and cytoplasmic Dynein Heavy Chain (DHC). The NF1-LRPPRC interaction is of high significance as it links NF-1 with Leigh’s Syndrome, French Canadian variant (LSFC) – an autosomal recessive neurodegenerative disorder that arises due to mutations in the LRPPRC gene. This interaction occurs as part of an RNA granule complex, and use of transgenic mouse models establishes an important role of NF1 and LRPPRC in peripheral nerve development. The NF1-DHC interaction is of importance in melanocytes where our studies suggest a possible role in melanosome localization, disruptions in which may underlie the abnormal pigmentary features known as café-au-lait macules that are commonly associated with NF-1. The validation of LRPPRC and DHC as novel NF1 interactors reveal new roles of NF1, which open the door to better understanding the molecular mechanisms that underlie the myriad of NF-1 manifestations. Neurofibromatosis Type 1 Neurofibromin 0379 0307 0317
238	Validation and Functional Characterization of Novel Neurofibromin Interacting Proteins Arun, Vedant 19 March 2013 (has links) Neurofibromin (NF1) is a 2,818aa protein encoded by the very large NF1 tumour suppressor gene located on chromosome 17q11.2. Loss of function mutations and deletions in NF1 underlie Neurofibromatosis type-1 (NF-1) - the most common inherited syndrome of the nervous system in humans with a birth incidence of 1:3,000. The most visible feature of NF-1 is the neoplastic manifestations known as neurofibromas, however, the syndrome is also characterized by pigmentary defects, peripheral motor dysfunction, learning disabilities and several developmental abnormalities. The molecular etiology of many of these non-neoplastic phenotypes remains unknown. Here we demonstrate that the Tubulin Binding Domain (TBD) of NF1 is a binding partner of the Leucine Rich Pentatrico Peptide Repeat motif-Containing protein (LRPPRC) and cytoplasmic Dynein Heavy Chain (DHC). The NF1-LRPPRC interaction is of high significance as it links NF-1 with Leigh’s Syndrome, French Canadian variant (LSFC) – an autosomal recessive neurodegenerative disorder that arises due to mutations in the LRPPRC gene. This interaction occurs as part of an RNA granule complex, and use of transgenic mouse models establishes an important role of NF1 and LRPPRC in peripheral nerve development. The NF1-DHC interaction is of importance in melanocytes where our studies suggest a possible role in melanosome localization, disruptions in which may underlie the abnormal pigmentary features known as café-au-lait macules that are commonly associated with NF-1. The validation of LRPPRC and DHC as novel NF1 interactors reveal new roles of NF1, which open the door to better understanding the molecular mechanisms that underlie the myriad of NF-1 manifestations. Neurofibromatosis Type 1 Neurofibromin 0379 0307 0317
239	The role of glucose-6-phosphatase catalytic domain in glucose homeostasis Ng, Natasha Hui Jin January 2016 (has links) Over the past decade, there has been unprecedented increase in the number of genetic loci associating with type 2 diabetes (T2D) risk and related glycemic traits, thanks to advances in sequencing technologies and access to large sample sizes. Identification of associated genetic variants across the frequency spectrum can provide valuable insight into disease pathophysiology. However, the translation into biological insights has been slow often due to uncertainties over the underlying effector transcripts. G6PC2/ABCB11 is one locus characterised by common non-coding variants that are strongly associated with fasting plasma glucose (FG) levels in healthy adults. The work presented in this thesis aims to understand how protein-coding variants in glycemic trait loci such as G6PC2 contribute to the variability of glycemic traits and in addition gain further insight into the physiological role of G6PC2. To evaluate the role of coding variants in glycemic trait variation, an exome array genotyping study of non-diabetic European individuals (n=33,407) reported multiple coding variants in G6PC2 that were independently associated with FG. I designed and conducted in vitro assays to functionally assess these variants and showed that they result in loss of function (LOF) due to reduced protein stability. This established G6PC2 as the effector transcript influencing FG and highlighted a critical role for G6PC2 (encoding the islet-specific glucose-6-phosphatase catalytic subunit) in glucose homeostasis. To investigate the role of low frequency (MAF=1-5%) and rare (MAF&LT;1%) coding variants in influencing glycemic traits, recent large-scale exome array meta-analyses and whole exome sequencing were carried out as part of MAGIC (n=144,060) and the T2D-GENES/GoT2D consortia (n=12,940) respectively. G6PC1, a gene homolog of G6PC2 that primarily acts through the liver, was uncovered as a novel glycemic locus. My functional follow-up studies demonstrated that rare coding variants in G6PC1 exhibited LOF to influence both FG and FI levels. As rare variation in G6PC2 not previously identified could also affect G6PC2 function and modulate glycemic traits, I also functionally characterised a suite of rare non-synonymous G6PC2 variants. Most of the variants tested exhibited markedly reduced protein levels and/or loss of glycosylation. Several variants were also found to impact on enzymatic activity through inactivating or activating mechanisms to influence FG levels. Finally, to gain better understanding of the function of G6PC2 I performed gene knockdown studies in the EndoC-βH1 human beta cell model followed by insulin secretion analyses. G6PC2 knockdown resulted in increased insulin secretion at sub-threshold glucose stimulation levels, consistent with studies in knockout mouse models. In addition, expression of LOF G6PC2 variants were found to upregulate ER stress responses. These results warrant further studies of the precise roles that G6PC2, an ER-resident protein, plays in regulating insulin secretory function and ER homeostasis in the beta cell. Overall, my work described multiple rare coding variants in both G6PC1 and G6PC2 that alter protein function to regulate glucose metabolism through diverse mechanisms in different tissues. Improved understanding of these effector transcripts will open up opportunities for the exploration of new therapeutic targets for glucose regulation and T2D.
240	Systémové aspekty implementace projektového řízení v podmínkách rozvoje pivovaru Tambor. / Systemic aspects of project management implementation in conditions of Tambor brewery development. Petrželová, Veronika January 2015 (has links) The goal of the work is considering strategical options of possible development of Tambor brewery with usage of available quantitative methods of system analysis. The work is execution of agreement of given object and University of Life Sciences in Prague.

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