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Cristofaro, Brunella. "Neurotrophin-3 : a novel mediator of angiogenesis and arteriolar genesis." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520610.
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Kang, Kyoung-Lae. "Novel genres or generic novels considering Korean movies adapted from amateur Internet novels /." Connect to this title online, 2008. http://scholarworks.umass.edu/theses/96/.
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Stringer, Hillary. "Patrol: Excerpts From a Novel." Thesis, University of North Texas, 2014. https://digital.library.unt.edu/ark:/67531/metadc700057/.
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The dissertation consists of a critical preface and excerpts from the novel Patrol. The preface explores how the novel Patrol utilizes characters that engage with tropes of the Romantic Genius in order to establish their subjectivity while navigating the standardizing mechanisms of twenty-first century information technologies. The preface analyzes how the rise of the organic food movement, the usage of biotech genetic engineering, and the tactics of Big Data-era marketing all inform the critical underpinnings of Patrol, situating the novel in conversation with works of fiction and nonfiction that also explore the interplay of these topics with contemporary American culture. Set primarily in Cincinnati, Ohio, the bifurcated narrative of the novel Patrol enlists the perspectives of both a science-tech father from the Boomer generation, Tim Smith, and his millennial public relations-major daughter, Sarah Smith. Both work in industries that seek to utilize the concept of the individual genius in service of quantification. Tim and Sarah’s interactions with Alexandra Smith, a family member who transitions from female to male over the course of the novel, cause both protagonists to recognize that their own identities are malleable, and this discovery goads each into reexamining their career choices and personal relationships. The plot depicts the outcome of these explorations, culminating in a series of choices for Tim and Sarah that showcase the fundamental change in each character. Unable to simply quantify themselves and those around them, Tim and Sarah instead adopt a more nuanced view of the world that seeks to find a balance between the individualistic conceit of the Romantic genius and the quantifying mandates of technology.
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Solinas, Antonio. "Novel approaches in genetic analysis." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274529.
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Ranasinghe, Rohan T. "Novel techniques for genetic analysis." Thesis, University of Southampton, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430494.
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McCubbin, T. Paul. "Novel #Beta#-spectrin isoforms." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279964.
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Martin, Stephen Lewis. "Novel methods for mutagenesis." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302789.
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Entesarian, Miriam. "Molecular Genetic Studies of ALSG, Kostmann Syndrome and a Novel Chromosome 10 Inversion." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100598.
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In summary, this thesis presents the localisation and identification of genetic variants of which some are disease associated and some considered to be neutral. Knowledge of the basic mechanisms behind human disorders is important both from a biological and medical point of view. The thesis is based on four papers of which the first two clarify the genetic basis of autosomal dominant aplasia of lacrimal and salivary glands (ALSG). ALSG is a rare disorder with high penetrance and variable expressivity characterized by dry mouth and eyes. In paper I, we located the ALSG gene to a 22 centiMorgan region on chromosome 5 through a genome-wide linkage scan with microsatellite markers in two families. Mutations were found in the gene encoding fibroblast growth factor 10 (FGF10) situated in the linked chromosome 5 region. Mice having only one copy of the FGF10 gene (Fgf10+/- mice) have a phenotype similar to ALSG, providing an animal model for the disorder. In paper II, we describe two additional patients with ALSG and missense mutations in FGF10, providing further genotype-phenotype correlations. The aim of paper III was to identify a gene involved in autosomal recessive severe congenital neutropenia (SCN), also referred to as Kostmann syndrome. The disease is characterized by a very low absolute neutrophil count and recurrent bacterial infections. Affected individuals from the family with SCN originally described by Dr Kostmann were genotyped with whole-genome SNP arrays. Autozygosity mapping identified a shared haplotype spanning 1.2 Mb on chromosome 1q22. This region contained 37 known genes, of which several were associated with myelopoiesis. Our finding contributed to the identification of the gene mutated in Kostmann syndrome. In paper IV a cytogenetic inversion on chromosome 10 was mapped and characterized. Sequence- and haplotype analysis of carriers from four non-related Swedish families revealed identical inversion breakpoints and established that the rearrangement was identical by descent. A retrospective study of karyotypes together with screening of large sample sets established that the inversion is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. No consistent phenotype was found associated with the inversion. Genetic research increases the understanding of our genomes and makes it possible to discover variants contributing to disease. Identification of such genetic variants further enables studies of gene function and pathogenesis. The finding of the disease associated variants in this thesis will eventually contribute to improved diagnosis, prognosis, risk assessment and a future treatment of patients.
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Bin, Kaderi Mohamed Arifin. "Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110371.
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The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
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Hu, Xiaotong, and 胡曉彤. "Novel IGH translocations in gastric non-Hodgkin's B-cell lymphoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38688098.
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Brown, Gerald Francis. "Novel aspects of grass carp GHR gene regulation." Thesis, Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41897080.
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Catti, Federica. "4,5-dihydropyrazoles : novel chemistry and biological activity." Thesis, St Andrews, 2007. http://hdl.handle.net/10023/351.
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Stolk, Megan. "Characterisation of novel TAC3 a d TACR3 gene variants and polymorphisms in patients with pre-eclampsia /." Thesis, Stellenbosch : University of Stellenbosch, 2007. http://hdl.handle.net/10019.1/1748.
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Thesis (MSc (Genetics))—University of Stellenbosch, 2007.In South Africa, pre-eclampsia is the second highest cause of maternal deaths. The incidence of this disease in the Western Cape alone is 6.8% and places a large burden of health care facilities. The placenta and implantation thereof is thought to play the most significant role in the onset of this disease. Among the many theories for its aetiology, is the acknowledged two - stage theory. This is based on evidence that pre-eclamptic placentas demonstrate altered remodelling and invasion into the uterine endometrium and myometrium. The sub-optimal endometrium invasion leads to less oxygenation of the placental environment causing transient hypoxia. Consequently, the placenta is thought to release unknown factors into the maternal circulation which then culminates in clinical features associated with pre-eclampsia. Neurokinin B is thought to be one of these placental factors and subsequently binds to the NKB receptor in the maternal system. Endothelium-derived nitric oxide synthase has recently been shown to activate this receptor. The aim of this study was to investigate the role of neurokinin B (TAC3) and the neurokinin B receptor (TACR3) genes in the predisposition of pre-eclampsia and their interaction with eNOS in the South African coloured population together with a matched control cohort.
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Williamson, Phillip C. "A Novel Mechanism for Site-Directed Mutagenesis of Large Catabolic Plasmids Using Natural Transformation." Thesis, University of North Texas, 2001. https://digital.library.unt.edu/ark:/67531/metadc2828/.
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Natural transformation is the process by which cells take up DNA from the surrounding medium under physiological conditions, altering the genotype in a heritable fashion. This occurs without chemical or physical treatment of the cells. Certain Acinetobacter strains exhibit a strong tendency to incorporate homologous DNA into their chromosomes by natural transformation. Transformation in Acinetobacter exhibits several unique properties that indicate this system's superiority as a model for transformation studies or studies which benefit from the use of transformation as an experimental method of gene manipulation. Pseudomonas putida is the natural host of TOL plasmids, ranging between 50 kbp and 300 kbp in size and encoding genes for the catabolism of toluene, meta-toluate, and xylene. These very large, single-copy plasmids are difficult to isolate, manipulate, or modify in vitro. In this study, the TOL plasmid pDKR1 was introduced into Acinetobacter calcoaceticus strains and genetically engineered utilizing natural transformation as part of the process. Following engineering by transformation, the recombinant DNA molecule was returned to the native genetic background of the original host P. putida strain. Specific parameters for the successful manipulation of large plasmids by natural transformation in Acinetobacter were identified and are outlined. The effects of growth phase, total transforming DNA concentration, transforming DNA conformation, and gene dosage on transformation efficiency are presented. Addition of Acinetobacter plasmid DNA sequences to the manipulated constructs did not have an effect on transformation rates. Results suggest that a broadly applicable and efficient method to carry out site-directed genetic manipulations of large plasmids has been identified. The ability to easily reintroduce the recombinant DNA molecules back into the original host organism was maintained.
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梁嘉玲 and Ka-ling Leung. "Novel molecular targets of Burkholderia pseudomallei." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31224726.
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Leung, Ka-ling. "Novel molecular targets of Burkholderia pseudomallei /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23440144.
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López, Vernaza Manuel A. "Genetic screen for novel polycomb group (PcG) genes and targets in Arabidopsis thaliana." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4386.
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Polycomb Group (PcG) proteins are responsible for post-transcriptional modifications in histone tails leading to chromatin condensation and changes in gene expression. In Arabidopsis thaliana, curly leaf (CLF) is a member of the Polycomb Reporssive Complex 2 (PRC2), which cnfers a repressive epigenetic mark, namely trimethylation of histone H3 at lysine 27 (H3K27me3). In the clf mutant, the expression of the floral organ identity gene AGAMOUS (AG) is derepressed in vegetative stages and coincides with loss of H3K27me3 at the AG locus. Recent whole genome prfiling studies have suggested that PcG genes regulate mang more developmental regulators than AG (about 15% of Arabidopis genes). However, it remains unclear what the relevance of PcG regulation of these targets is for plant development; in addition, it is not known how changes in J3K27me3 casue gene repression in plants. To unravel the role of CLFcin A. thaliana, a T-DNA mutagenesis in the clf background was performed to identify mutations enhancing or suppressing the Clf- phenotype, as these may identify additional PcG genes and targets. Firstly, I screened an A. thaliana T-DNA mutagenized population and identified four mutations suppressing the Clf- phenotype: suppressor of polycomb 1 to 4 (sop1, sop2, sop3 and sop4). Secondly, I characterized these four mutants. The sop1 mutant had normal flowering time and the suppressed phenotype is due to a loss of function mutation in SEPALLATA3 (SEP3). I establied the SEP3 is an activator and a co-factor of AG. Also, I found that SEP3 is stronlgy mis-expressed in clf mutants and SEP3 chromatin is enriched the H3K27me3, which stronly suggests that SEP3 is a direct target of CLF. In addition, I showed that a mutation in Flowering Locus T (FT), which is a positive regulator of SEP3, suppreesed the Clf- phenotype suggesting the FT is also a target of CLF. Suppressors sop3, sop3 and sop4 are late flowering, unlike sop1, and show increased expression of Flowering Locus C (FLC), a MADS-box transcription factor gene that represses flowering. I found that the sop4 mutation in likely casued by disruption of FPA, a predicted RNA binding protein that promotes flowering time by repressing FLC. Consistent with this, sop4 mutants show hight levels of FLC. Unexpectedly, fpa clf (sop4) mutatns are much later flowering than clf FRI mutants, which have similarly high levels of FLC. This suggests that FPA may regulate other genes controlling flowering thant FLC. The genes involved in sop2 and sop3 mutants remain to be identified. In this thesis I brought genetic and molecular evidence showing that CLF, though the PRC2, control floral induction (FLC), floral integration (FT) and floral organ formation (SEP3 and AG) in A. thaliana.
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Mansfield, Robert Patrick William. "Developments in genetic engineering of novel acetogens." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/51833/.
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The development of processes for sustainable energy and chemical production is of great importance for the health of our planet. Utilising suitable feedstocks such as renewable resources and existing waste streams is central to making such processes a reality. Microorganisms can be employed in the processing of a diverse range of such feedstocks, offering unique routes of production for useful and valuable chemical products. Acetogenic organisms, capable of fermenting single carbon (C1) feedstocks are especially interesting from the perspective of industrial application. Their natural metabolism and biochemistry enables fixation of low energy C1 compounds, under conditions which would typically be unfeasible with traditional chemical catalysts. Genetic research and development of new acetogenic species opens the door to industrially feasible, and economically attractive, sustainable bioprocessing. This study outlines the genetic development of the methanol and syngas fermenting acetogen E. limosum. This includes establishing gene-transfer and genetic engineering tools in this organism for first time. Additionally, we demonstrate the genetic engineering of synthetic metabolic pathways in this strain to enable production of valuable chemicals, acetone and isopropanol. Gene-transfer is a cornerstone of modern genetic research in microorganisms, and so effective methods of establishing it are of significant value. We present the development of an improved methodology for enabling and enhancing gene transfer in recalcitrant microorganisms which contain active restriction modification (RM) systems. The method harnesses lambda-red recombineering to support the rapid creation of tailored methylation donor (MD) strains for the preparation and protection of transforming plasmids. The process is uniquely designed in a manner which enables compatibility with both electroporation and conjugation methods of gene transfer.
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Crompton, Michael. "Edison : a novel model of otitis media." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:1e13bb89-893e-434e-acc1-f39d0563d6cb.
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Otitis media (OM) is characterised by inflammation of the middle ear and is a common cause of conductive hearing impairment that places a substantial social, medical and economic burden on healthcare systems globally. Despite the importance of the disease, the aetiology of chronic middle ear inflammatory disease remains poorly understood. The development and persistence of chronic OM is multi-factorial with a significant genetic component. A new mouse model of chronic OM, edison, was generated by N-ethyl-N-nitrosourea (ENU) mutagenesis and discovered in a recessive screen at MRC Harwell. Homozygous edison mice have craniofacial abnormalities, an emphysema-like lung phenotype and spontaneously develop a conductive hearing loss at 28 days as measured by ABR. Histological analysis shows the hearing loss is associated with the development of chronic OM in the middle ear, characterised by mucosal inflammation and highly cellular ear exudates. Similar to the Jeff and Junbo mutants, edison shows raised levels of Vegfa, Tnfα and Il-1β in middle ear fluids. A putative functional mutation was identified, resulting in a missense Leu972Pro change in a relatively unknown gene, Nischarin (Nisch). The identification of additional ENU-induced Nisch alleles, and subsequent characterisation, validated Nisch as the causative gene in edison. NISCH selectively binds ITGA5, which is thought to have a role in modulating VEGF signalling through SRC and FAK kinases. A significant genetic interaction between Nisch and Itga5 exists and impacts upon development of chronic OM. Mice heterozygous for Itga5-null and homozygous for edison alleles show a significantly increased penetrance and severity of chronic OM. Analysis of downstream pathways suggests that the edison allele is impacting upon both RAC1 and TGF-β/SMAD signalling. I also explored the potential use of the edison mouse as a model for bacterial challenge with the human otopathogen, NTHi. Similar to the Junbo infection model at MRC Harwell, the edison mouse was identified as a robust OM model for bacterial NTHi infection. The edison mouse highlights a new candidate gene for susceptibility to chronic OM and will provide further insight into the genetic pathways and pathogenic processes involved in chronic OM.
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Kelly, Emma Naomi. "PITAIRE : a novel CDK-related protein kinase." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263563.
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Liu, Leah. "Novel Regulators of Liver Development and Metabolism." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17463147.
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Chronic liver diseases such as non-alcoholic fatty liver disease and alcoholic liver disease are significant health concerns worldwide. Despite knowledge of disease features and environmental causes, we lack understanding of the genetic factors and molecular mechanisms that can be targeted for liver disease therapeutics. Many of these factors are also essential during embryonic development and organogenesis. Here, we use liver development in zebrafish as a model and paradigm for the discovery of regulators impacting liver disease pathogenesis. A chemical screen in zebrafish identified the endocannabinoid (EC) signaling pathway as a regulator of liver development. This pathway was previously implicated in animal models of chronic liver disease, but little was known about its role in development. We generated cannabinoid receptor mutant zebrafish using genome editing and show that EC signaling is required for hepatic maturation and outgrowth, but not earlier milestones such as hepatic specification. Mutant zebrafish also exhibited defects in lipid processing, and we found that methionine metabolism, involving sterol regulatory element binding proteins (SREBPs), is an integral mediator in this process. In a separate study, we used zebrafish to functionally annotate a panel of candidate genes identified by a genome-wide association study (GWAS) for elevated liver plasma enzymes, which are used as a clinical liver disease marker. We prioritized GWAS candidates for morpholino knockdown in zebrafish and discovered effects on hepatic progenitor and hepatocyte development as well as differences in susceptibility to metabolic and toxic injury. Our approach can be applied to other GWAS data sets to rapidly assess additional characteristics during zebrafish development. The work presented here gives valuable insight into how regulators of hepatogenesis also have roles in metabolism and disease.Medical Sciences
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Altemose, Nicolas Frank. "Novel genetic and molecular properties of meiotic recombination protein PRDM9." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:1afe17c3-5f75-4166-8697-7da1471a5230.
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Meiotic recombination is a fundamental biological process in sexually reproducing organisms, enabling offspring to inherit novel combinations of mutations, and ensuring even segregation of chromosomes into gametes. Recombination is initiated by programmed Double Strand Breaks (DSBs), the genomic locations of which are determined in most mammals by PRDM9, a rapidly evolving DNA-binding protein. In crosses between different mouse subspecies, certain Prdm9 alleles cause infertility in hybrid males, implying a critical role in fertility and speciation. Upon binding to DNA, PRDM9 deposits a histone modification (H3K4me3) typically found in the promoters of expressed genes, suggesting that binding might alter the expression of nearby genes. Many other questions have remained about how PRDM9 initiates recombination, how it causes speciation, and why it evolves so rapidly. This body of work investigates these questions using complementary experimental and analytical methodologies. By generating a map of human PRDM9 binding sites and applying novel sequence analysis methods, I uncovered new DNA-binding modalities of PRDM9 and identified sequence-independent factors that predict binding and recombination outcomes. I also confirmed that PRDM9 can affect gene expression by binding to promoters, identifying candidate regulatory targets in meiosis. Furthermore, I showed that PRDM9âÃôs DNA-binding domain also mediates strong protein-protein interactions that produce PRDM9 multimers, which may play an important functional role. Finally, by generating high-resolution maps of PRDM9 binding in hybrid mice, I provide evidence for a mechanism to explain PRDM9-mediated speciation as a consequence of the joint evolution of PRDM9 and its binding targets. This work reveals that PRDM9 binding on one chromosome strongly impacts DSB formation and/or repair on the homologue, suggesting a novel role for PRDM9 in promoting efficient homology search and DSB repair, both critical for meiotic progression and fertility. One consequence is that PRDM9 may play a wider role in mammalian speciation.
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Archacki, Stephen R. "MOLECULAR IDENTIFICATION OF NOVEL GENES ASSOCIATED WITH ATHEROSCLEROSIS." Cleveland State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=csu1310652996.
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Jonnala, Ramakanth S. "Protein composition-functionality relationships using novel genetic lines." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/578.
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Iatan, Iulia. "Novel genetic and molecular regulation of HDL metabolism." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121170.
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Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. Low levels of high-density lipoprotein cholesterol (HDL-C) constitute a major independent risk factor for CAD, influenced by a combination of genetic and environmental factors. In this thesis, we aimed to advance our understanding of the genetic regulation of HDL-C, through the identification and characterization of novel candidate genes, and to delineate the molecular mechanisms underlying HDL biogenesis, in the hopes of better elucidating the complexities of HDL metabolism. First, we examined whether variation at the PCSK5 gene locus influences HDL-C levels. Through familial segregation analyses and two-stage genetic association studies in unrelated subjects of French Canadian descent and low HDL-C Finnish families (ntotal=883), we reported a region-wide significance of PCSK5 SNPs with HDL-C, suggesting that genetic variability at the PCSK5 locus regulates HDL-C levels, possibly through the inactivation of endothelial lipase. Second, to search for rare-low frequency variants responsible for low HDL-C, we used whole exome sequencing in a multigenerational French Canadian family (n=75) with HDL-C<5th age-sex specific percentile. Through this approach, we identified a complex combination of two non-synonymous variants, in the ATP-binding cassette transporter (ABCA1) and the lipoprotein lipase genes, predicted to be damaging and causing low HDL-C. These results emphasize the need for exome sequencing of complex lipid traits in unexplained familial cases. Third, we sought to characterize a novel genetic determinant involved in HDL-C regulation. Recent studies from our group identified the WW domain-containing oxidoreductase (WWOX) gene locus to be associated with low serum HDL-C levels in 9,798 subjects. In this study, we examined the role of WWOX in lipoprotein and HDL metabolism using a combination of in vivo functional studies, by means of total Wwox knock-out and Wwox liver-specific mouse models, gene microarray and next generation resequencing analyses in HDL-deficient French Canadian families. We demonstrated that the effects of WWOX on lipoprotein metabolism involve multiple mechanisms, including cholesterol homeostasis, apoA-I and ABCA1-mediated pathways and fatty acid/triglyceride metabolism. Fourth, with novel insight into genetic regulations of HDL metabolism, we focused on elucidating the mechanistic basis of nascent HDL formation. Specifically, we investigated the lipidation of ApoA-I and its interaction with an ABCA1/phosphatidylcholine(PC)-rich microdomain, the high-capacity binding site (HCBS). Using sucrose gradient fractionation, we also demonstrated that the ABCA1/ HCBS partitions to nonraft domains, thus playing a pivotal role in the selective desorption of PC molecules by apoA-I, creating an optimal environment for nascent HDL formation and cholesterol release.In summary, this work has collectively advanced our understanding of the molecular and genetic basis of HDL metabolism. It has brought to light novel genes governing plasma HDL-C levels in humans, highlighting the need to use multiple integrative genetic approaches to identify causal common and rare variants conferring susceptibility to low HDL-C. These findings have also helped elucidate the mechanistic basis of the nascent HDL genesis pathway. Together, this thesis has combined genetic and biochemical strategies to provide a more comprehensive understanding of the complexities of the HDL metabolism and cellular cholesterol transport, which may lead to the characterization of novel therapeutic targets for CAD.La maladie coronarienne athérosclérotique (MCAS) est la principale cause de mortalité et de morbidité à l'échelle mondiale. Un niveau bas des lipoprotéines de cholestérol de haute densité (HDL-C) représente un facteur de risque majeur pour la MCAS et est influencé par une combinaison des facteurs génétiques et environnementaux. Dans cette thèse, nous avons abordé la régulation génétique des HDL-C grâce à l'identification et la caractérisation de nouveaux gènes candidats, et de mécanismes moléculaires liés à la biogenèse des HDL, dans l'espoir de mieux élucider la complexité du métabolisme des HDL.En premier, nous avons examiné si la variation au niveau du locus du gène proprotéine convertase PCSK5 peut affecter les niveaux de HDL-C. Grâce aux analyses de ségrégation familiale et aux études d'association génétique dans une population canadienne-française et chez des familles finlandaises (nTotal=883) avec un niveau de HDL-C bas, nous avons constaté une large corrélation régionale entre les variations polymorphiques (SNPs) de PCSK5 et HDL-C. Ceci suggère que la variabilité génétique au niveau du locus PCSK5 réglemente le HDL-C, éventuellement par le biais de l'inactivation de la lipase endothéliale, une enzyme clé dans la modulation des niveaux plasmatiques de HDL-C. Deuxièmement, pour rechercher des variants de fréquence rare qui sont responsables d'un bas niveau de HDL-C, nous avons utilisé la technique du séquençage de l'exome dans une famille multi-générationnelle canadienne-française (n=75) avec un HDL-C<5e percentile spécifique (âge-sexe). Grâce à cette approche, nous avons identifié une combinaison complexe de deux variants non-synonymes dans le transporteur ABCA1 et dans le gène de la lipoprotéine lipase provoquant un taux faible de HDL-C. Ces résultats soulignent la nécessité du séquençage de l'exome des traits lipidiques complexes dans les cas familiaux inexpliqués. Troisièmement, nous avons caractérisé un nouveau gène impliqué dans la régulation du HDL-C. Nous avons examiné le rôle de WWOX dans le métabolisme du HDL en utilisant des études fonctionnelles in vivo avec des souris Wwox total knock-out (KO) et des souris Wwox KO spécifiques au foie, une technologie des puces à ADN et du reséquençage dans des familles canadiennes-françaises déficientes en HDL. Nous avons démontré que l'effet de WWOX sur le métabolisme des lipoprotéines implique plusieurs mécanismes, y compris l'homéostasie du cholestérol, les voies de régulation à travers l'ApoA-I et l'ABCA1 et le métabolisme d'acides gras/triglycérides. Quatrièmement, nous voulions élucider le mécanisme de formation du HDL naissant. Plus précisément, nous avons étudié la lipidation de l'ApoA-I et son interaction avec des sites constitués de microdomaines ABCA1/phosphatidylcholine (PtdC) que nous avons appelés « site de liaison de grande capacité (HCBS) ». En utilisant un gradient de densité de sucrose, nous avons observé que l'ABCA1 et le HCBS sont localisés dans des domaines membranaires solubles aux détergents et que l'ApoA-I désorbe sélectivement la PtdC de ces domaines ainsi créant un environnement optimal pour la formation des molécules naissantes de HDL et la libération de cholestérol.Collectivement, ce travail a élargi notre compréhension des sciences moléculaires et génétiques du métabolisme du HDL. Il a mis en lumière de nouveaux gènes impliqués dans la régulation des niveaux de HDL-C, soulignant la nécessité d'utiliser plusieurs approches intégratives génétiques pour identifier les causes des variants communs et rares conférant une susceptibilité à un faible taux de HDL-C. Ces résultats ont également contribué à élucider le mécanisme de biogenèse du HDL naissant. Ainsi, cette thèse a combiné des stratégies génétiques et biochimiques pour fournir une meilleure compréhension de la complexité du métabolisme des HDL et du transport du cholestérol cellulaire, qui pourrait ainsi conduire à l'élaboration des nouvelles cibles thérapeutiques pour la MCAS.
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Keylock, Annette Ai Lin. "Novel genetic causes of cerebral and systemic vasculopathies." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10048485/.
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Vasculopathies are a varied group of disorders that affect the vascular tree resulting in arterial stenosis or dilatation causing multi-organ ischaemia and significant cardiac and cerebral circulation complications. Commonly, vasculopathies present in infancy and segregate within families so a genetic cause is often suspected but not always identified by the current routinely available genetic tests in the UK National Health Service (NHS). Due to the overlapping phenotypes of these disorders genetic sequencing is required for accurate diagnosis and appropriate clinical intervention. In this thesis, a cohort of children with cerebral and systemic vasculopathies was subject to next-generation genetic sequencing. Several discoveries were made and various families are discussed herein. Firstly, a novel heterozygous mutation in MYH11, a gene affecting smooth muscle myosin heavy chain, was identified in a child with a moyamoya-like cerebrovascular disease and renal artery stenosis. This expanded the vasculopathic phenotype associated with MYH11, which previously was associated with familial aortopathy. Secondly, multiple members of three families diagnosed with a moyamoya arteriopathy were studied and were all found to have heterozygous mutations in c-CBL, an E3 ubiquitin ligase that down regulates various receptor tyrosine kinases. Detailed in vitro functional expression studies were undertaken in the patients with mutations in c-CBL showing impaired CBL-mediated degradation of cell-surface receptors in a dominant negative fashion. These results were compatible with dysregulated intracellular signaling through RAS. Lastly, three families with systemic vasculopathies associated with heterozygous mutations in RNF213 were also studied. This protein possesses both ubiquitin ligase and ATPase activity and adversely affects endothelial cell function. For the first time I showed that heterozygous mutations in RNF213 cause a vasculopathy that is not confined to the cerebral circulation.
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Chai, Shin Luen Chai. "Novel Genetic Modifiers in a Monogenic Cardiac Arrhythmia." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1516618028568975.
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Hjorth-Hansen, Henrik. "Novel cytokines in growth control and bone disease of multiple myeloma." Doctoral thesis, Norwegian University of Science and Technology, Faculty of Medicine, 2001. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-315.
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Myelomatose (benmargskreft) er en blodsyk dom som rammer ca 200 nordmenn årlig. Sykdommen kan ikke kureres og karakteriseres av symptomer som benmargssvikt og infeksjonstendenns, men kanskje først og fremst av sykelig nedbrytning av skjelettet. Pasientene rammes i høy utstrekning av benbrudd, hvirvelsammenfall og skjelettsmerter. Mekanismene for bennedbrytning og vekstkontroll står sentralt i avhandlingsarbeidet som består av fem artikler om cytokiners rolle i myelomatose. Cytokiner er signalsubstanser som benyttes i celle-celle-kommunikasjon. Det er sannsynligvis ubalanse av cytokiner som forårsaker den sykelige nedbrytningen av bensubstansen.
Det første delarbeidet omhandler funnet av hepatocyttvekstfaktor (HGF) som er uttrykt hos nesten alle pasienter med myelomatose Dette påvises med forskjellige teknikker og det benyttes bl a en separasjonsmetode for myelomceller basert på Ugelstadkuler som ble utviklet ved IKM i 1993. Videre påvises forhøyede nivåer av HGF i serum fra pasienter. Et interessant funn er at HGF reseptor også er uttrykt i pasientprøver, hvilket kan tale for at myelomceller kan ha en selvstimulerende (autokrin) funksjon.
I det andre delarbeidet vises en dyremodell for myelomatose i immundefekte mus. Et hovedpoeng er at det lar seg gjøre å få vekst av myelomceller i musebenmarg med påvisbare tegn til patologisk bennedbrytning på røntgen og ved histologisk undersøkelse. Musene har forhøyede nivåer av HGF i serum. Benlesjonene ble karakterisert ved hjelp av histomorfometri. Denne undersøkelse viste 99% reduksjon av de bendannende cellene (osteoblaster) og 33% reduksjon av bennedbrytende celler (osteklaster).
I tredje delarbeidet viser man at HGF induserer interleukin (IL)-11-produksjon i osteoblaster. IL-11 er en kjent påskynder av benresorpsjon og osteoklastaktivator. Et interessant fenomen er at HGF ser ut til å være bundet til heparansulfat på cellemembranen og at slikt membranbundet HGF virker bedre enn løselig HGF. Effekten av HGF potensieres av cytokinene TGF-beta og IL-1. En styrke ved arbeidet er at såvel ferskisolerte pasientceller som cellelinjer viser identiske mønstre. Arbeidet angir en mulig måte som HGF kan befremme bennedbrytning.
I fjerde delarbeid vises at cytokinet IL-15 forhindrer programmert celledød (apoptose) i myelomcellelinjen OH-2. Det var fra før kjent at myelomceller relativt hyppig lar seg stimulere av cytokinet IL-6, som fortsatt er den mest anerkjente myelomvekstfaktoren. IL-15 var tilnærmet like potent antiapoptotisk som IL-6, og befremmet også kortvarig proliferasjon. IL-15s effekt kunne potensieres av TNF-alfa
I femte delarbeid påvises at cytokinet benmorfogent protein (BMP)-4 hemmer vekst av myelomceller. BMP-4 befremmer bendannelse. Effekten av BMP-4 kom fram i IL-6-stimulerte cellelinjer og pasientprøver. Effekten skyldtes såvel induksjon av apoptose som stopp i cellesyklus G1-fase. Dette er et mulig viktig funn siden man kan tenke seg at pasienter med myelomatose kunne behandles med BMP-4 eller lignende substanser. På slik måte ville såvel skjelettnedbrytningen som myelomcellevekst kunne påvirkes gunstig.
Arbeidet bidrar til forståelse av molekylære mekanismer for bendestruksjon og myelomcellevekst og ble veiledet av profesor dr. med. Anders Waage. Henrik Hjorth-Hansen har vært stipendiat i Den norske kreftforening, og undersøkelsen ble dessuten støttet av Kreftfondet ved RiT og Blix’ legat.
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Maskos, Uwe. "A novel method of nucleic acid sequence analysis." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306792.
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Nichol, Richard Bradley. "A novel diacylglycerol-binding protein in Dictyostelium discoideum." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249562.
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Read, Tara. "Elucidating a novel gene associated with myoclonus dystonia." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28248.
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Myoclonus Dystonia (MD) is an autosomal dominant disease with high but incomplete penetrance and is characterized by both involuntary myoclonic jerks and dystonic posturing. Our group has found that mutations within the epsilon sarcoglycan (SGCE) gene on chromosome 7q21 are associated with MD in 30-40% of affected individuals in 31 families studied, supporting the basis for genetic heterogeneity. Novel mutations have been found in SGCE by screening these families for point mutations and large deletions and duplications through the use of sequencing, high performance liquid chromatography (HPLC) and multi˙ligation probe amplification (MLPA) analysis. A 10cM genome wide linkage analysis of a large Canadian family provided significant LOD scores for microsatellite markers within the 18p11 region, now designated as the DYT 15 locus. Further haplotype analysis has narrowed a non-recombinant region associated with the disease phenotype to a 3.18 Mb region in this locus. Since the current understanding of Myoclonus Dystonia is poor, it is difficult to predict genes that could be responsible for MD. Sarcoglycans are essential constituents of the dystrophin-glycoprotein complex and are involved in linking the extracellular lamanin matrix to the actin filaments within the cytoplasm; therefore focus is given to the examination of potentially related structural genes that are expressed in the brain. By analyzing such candidate genes in a panel of affected individuals, we believe that a novel gene will be elucidated and provide insight into the mechanism of Myoclonus Dystonia.
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Omar, Ameen Abdulqader. "The Iraqi Kurdish novel, 1970-2011 : a genetic structuralist approach." Thesis, University of Exeter, 2016. http://hdl.handle.net/10871/24105.
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This thesis explores the emergence and development of the Iraqi Kurdish novel between 1970 and 2011, aiming to demonstrate that it engages with political discourses, and that the political situation influenced the themes and structural development of the novel. It will seek to elucidate why, when we examine the history of Kurdish literature over the last fifty years, the first point that may attract our attention is its emergence from the political events. Based on this notion the current study has been divided into three historical phases; 1970-1991, 1991-2003 and 2003-2011. A chapter has been dedicated to each stage, examining two novels from each period, one from the Soranî and one from the Behdînî dialect. Chapter Two discusses the historical background of Iraqi Kurdistan and its influence on the emergence of the novel. Chapter One has been allocated to establishing the methodological background of the textual analysis, which has adopted Lucien Goldmann’s genetic structuralist theory. Such a theory, I will argue, proves helpful in order to discover the link between socio-political conditions and the form of literary works within a society, as Goldmann himself tried to do through his theoretical approach. Chapter Six discusses the results of the study. The thesis demonstrates how the political situation has formed the Iraqi Kurdish novel in terms of both formal and thematic structures, examining the notions of both the ’hero’ and the ‘world vision’ in the novels. It explores the reasons behind the dominant tragic world vision in the first stage, the hopeless worldview in the second, and the self-critical vision in the third phase. In addition, it examines the problematic nature of the hero in the novels, from their emergence until 2011.
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Vyas, Aditi. "Identification of Novel Stat92E Target Genes in Drosophila Hematopoiesis." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450868635.
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Travis, Kristina. "Identification of Novel Developmental Genes in Streptomyces Coelicolor." Otterbein University Distinction Theses / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=otbndist16204640123321.
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Robert, Stanley. "Functional characterisation of Polycomblike and a novel, chromosomal protein interactor from Drosophila melanogaster /." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phr642.pdf.
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Lambert, Carol-Ann. "A novel marker technique : using miniature inverted-repeat transposable elements (MITEs) in combination with resistant gene analogues (RGAs)." Thesis, Stellenbosch : Stellenbosch University, 2001. http://hdl.handle.net/10019.1/52117.
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Thesis (PhD)--Stellenbosch University, 2001.ENGLISH ABSTRACT: Given the organisation of the maize genome as well as demands placed on the saturation of molecular linkage maps it would be desirable to identify informative molecular markers that is located or linked to genic rich areas. Sequences of gene products from different gene classes were investigated. Proteins containing a nucleotide binding site (NBS) and leucine-rich repeat (LRR) region comprise the largest class of disease resistance proteins. Resistant gene analogue (RGA) primers belonging to this specific class were derived from previous published literature studies. By means of similarity studies of short stretches of conserved amino acid and DNA sequences, primers were developed that belonged to the peroxidase and reductase gene classes. A novel class of transposable element was identified, that occurred in the gene rich areas of a diverse range of grass genomes. Of all the MITE families described so far, the Heartbreaker (Hbr) and Hb2 family elements were of particular interest. The unique properties of MITEs, especially their high copy number, polymorphism, stability and preference for genic areas together with the RGA primers, were exploited to develop a new marker technique for the isolation of a class of molecular marker with a strong preference for genic areas. Using the publicly available recombinant inbred population, Tx303 x C0159, 196 MITE/RGA markers were added to the existing recombinant inbred linkage map consisting of ±1033 already established markers. It became apparent that just like loci for disease resistance, the 196 MITE/RGA fragments were not randomly distributed across the maize genome but occurred in clusters spread across the ten maize chromosomes. Ninety-two (92) of the MITE/RGA fragments showed significant correlation to previously mapped maize resistance genes. To establish the conservation and specificity of both the Hbr and Hb2 elements, sequences of 19 MITE/RGA fragments were ascertained. When comparing the partial MITE element sequences from these fragments, a high degree of element conservation was observed. One fragment showed good sequence correlation to a NADPH He Toxin reductase protein product and mapped to the same chromosomal location as the hm1 gene locus in maize. This fragment can be considered a candidate gene for resistance against the pathogen, Helminthosporium carbonum. The Hbr primer used proved to be very specific for the Heartbreaker MITE element, this was in contrast to the non-specificity of the Hb2 primer. The applicability of this technique was tested on two maize diseases that cause immense damage in the maize production industries in South Africa. Fourteen MITE/RGA markers were used to fine map the putative chromosomal locations for the HtN1, Ht1, Ht2 and Ht3 genes that confer resistance. against Setosphaeria turcica, the northern corn leaf blight (NelS) pathogen in maize. Three MITE/RGA fragments were identified that aided in the saturation of the linkage map for quantitative trait resistance (QTl) against gray leaf spot (GlS) in maize. This novel MITE/RGA technique presented a unique opportunity to search for additional candidate genes by using polymerase chain reaction (peR) analysis. When compared to the conventional amplified fragment length polymorphism (AFLP) technique, the MITE/RGA technique proved to be just as efficient but was more cost effective and less time consuming.
AFRIKAANSE OPSOMMING: Die organisasie van die mielie genoom as ook die vereistes wat daar geplaas word op die versadiging van koppelingskaarte, vereis dat daar meer klem geplaas word op die ontwikkeling van molekulêre tegnieke wat merkers in geenryke areas identifiseer. Die volgordes van geenprodukte, wat behoort tot verskillende geenklasse, is deeglik bestudeer. Proteïenprodukte wat bestaan uit 'n nukleotiedbindingsarea (NBA) en 'n leusienryke herhalende (LRH) area is een van die grootste klasse waaronder siekteweerstandsproteïene sorteer. Polimerase kettingreaksie (PKR) inleiers wat behoort tot hierdie spesifieke klas, is verkry vanuit vorige publikasies. Deur kort gekonserveerde aminosuur en DNS volgordes te vergelyk is inleiers ontwikkel wat behoort tot die peroksidase en reduktase gene klasse. 'n Nuwe klas transponeerbare elemente wat voorkom in die geenryke areas van diverse gras genome, is geïdentifiseer. Van al die miniatuur inversie herhalende transponeerbare elemente (MITE) wat al geïdentifiseer is, is die twee elemente, Heartbreaker (Hbr) en Hb2, van groot belang. Unieke eienskappe van die MITEs, veral hul hoë kopie aantal, polimorfiese-indeks, stabiliteit asook voorkeur vir geenryke areas, tesame met die weerstandsgeen analoë (WGA) inleiers, is gebruik om 'n nuwe merker tegniek te ontwikkel. Hierdie nuwe tegniek identifiseer 'n klas merker wat 'n sterk voorkeur het vir geenryke areas. Deur gebruik te maak van die openbare beskikbare rekombinante ingeteelde (RI) populasie, Tx303 x C0159, is 196 MITE/WGA-merkers gekarteer op die bestaande RIL koppelingskaart, wat alreeds bestaan uit ±1033 gevestigde merkers. Net soos die lokusse vir siekteweerstand het dit geblyk dat hierdie 196 merkers in groepe voorkom wat verspreid is oor die tien mielie chromosome. Twee-en-negentig (92) van die 196 gekarteerde MITE/WGA-merkers het betekenisvolle korrelasie gewys met reeds gekarteerde mielie weerstandsgene. Die volgordes van 19 MITE/WGAfragmente is bepaal om sodoende die spesifisiteit en mate van konservering van die Hbr and Hb2 elemente te bereken. 'n Hoë mate van element konservering is waargeneem. Een fragment het In baie goeie volgorde korrelasie gewys met In NADPH HG toksien reduktase proteïen produk en karteer op dieselfde chromosomale posisie as die hm1 geen lokus. Hierdie fragment kan gesien word as In kandidaatgeen vir weerstand teen die mielie patogeen, Helminthosporium carbonum. Die toepasbaarheid van hierdie tegniek is getoets op twee siekte toestande, wat lei tot groot verliese in die mielie industrie, in Suid-Afrika. Veertien van die MITE/WGAmerkers is gebruik om die waarskynlike chromosomale posisies van die HtN1, Ht1, Ht2 en Ht3 gene, wat weerstand bied teen Setosphaeria turcica, die noordelike mielie blaarvlek (NMBV) patogeen, fyner te karteer. Drie MITE/WGA fragmente is geïdentifiseer wat gehelp het in die versadiging van die koppelingskaart vir die kwantitatiewe kenmerk weerstandbiedenheid (KKW) teen grys blaarvlek (GBV) in mielies. Deur gebruik te maak van polimerase kettingreaksie (PKR) analise, verskaf hierdie tegniek die moontlikheid om te soek vir addisionele kandidaatgene. Hierdie tegniek is ook vergelyk met die konvensionele geamplifiseerde fragment lengte polimorfisme (AFLP) tegniek. Daar is gevind dat die nuwe tegniek net so informatief is, maar wel meer koste effektief en tyd besparend.
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Worthington, Jenny. "Radiation-controlled gene expression : a novel approach to oxygenation-dependent radiotherapy." Thesis, University of Ulster, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342528.
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McGregor, Nathaniel Wade. "The identification of novel susceptibility genes involved in anxiety disorders." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95859.
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Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis. No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse. The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders. In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction.
AFRIKAANSE OPSOMMING: Die oorsake van angssteurings word steeds nie volledig verstaan nie. Daar is duidelike bewyse vir 'n genetiese komponent, maar daar is ook toenemende fokus op omgewingsfaktore en die interaksie tussen hierdie omgewingsfaktore en genetiese komponente by angssteurings. Geen enkele geen of genetiese komponent is al geïdentifiseer as diè wat betrokke is by die ontwikkeling van angssteurings nie. Dit is waarskynlik weens 'n aantal redes, wat byvoorbeeld, die heterogeneïteit van angssteurings, die bydrae van omgewingsfaktore en metodologiese beperkings (bv. klein steekproef) van die navorsingstudies, insluit. Verder het genetiese assosiasiestudies tot nou toe gewoonlik net op een spesifieke psigiatriese versteuring op 'n slag gefokus. Maar, gegewe die uitdaging om vatbaarheidsgene en / of loci in heterogene steurings soos obsessief – kompulsiewe steuring (OKV) en ander toestande op die angsspektrum te identifiseer, is dit tyd om genetiese en kliniese studies in ‘n aantal steurings - met ‘n oorvleuende kern-element soos angs -, gesamentlik te oorweeg. Bykomend tot die genetiese boustene, is ‘n aantal omgewingsveranderlikes soos traumatiese lewenservarings tydens die kinderjare as risikofaktore vir patologiese angs geidentifiseer. Die hipotese vir hierdie projek is dat daar 'n interaksie tussen genetiese kwesbaarheid (of genetiese risiko) en traumatiese lewensevarings is en dat dit tot die ontwikkeling van 'n / veelvoudige angssteuring(s) kan lei. Inaggenome die fenotipiese oorvleueling tussen die angssteurings, is dit waarskynlik dat diverse netwerke van gene en / of interaktiewe geen-paaie vir die manifestasie van hierdie toestande verantwoordelik is. Sprague Dawley-rotte met gedragswyses aanduidend van angs, in die konteks van omgewingstressore (d.i. skeiding van die ma-rot en bedwang-stres [restraint stress]), is as model gebruik vir die identifisering van nuwe vatbaarheidsgene vir angssteurings in mense. Die striatum is voorheen as ‘n kandidaat in die brein-argitektuur van patologiese angs voorgehou, en is ook ‘n plek met ‘n hoë mate van sinaptiese plastisiteit. Die sinaptiese plastisiteit is ondersoek deur te fokus op die dorsale striatum van die rotbrein en daar is verskeie gene gevind wat anders is in “angstige” rotte in vergelyking met kontroles (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 en Arc). In mense is daar gevind dat die ernstigheidsgraad van vroeë trauma beduidend en positief met die teenwoordigheid van ‘n angssteuring tydens volwassenheid verband hou. Toe die menslike ekwivalente van die vatbaarheidsgene wat met die dieremodel geïdentifiseer is in ‘n mens-kohort met obsessief-kompulsiewe steuring (OKS), panieksteuring (PS) en sosiale angssteuring (SAS) ondersoek is, is gevind dat daar 5 enkele nukleotied polimorfismes (ENPs) is wat met die toestande verband hou. Daar is ook gevind dat vier van hierdie ENPs beduidend verband hou met die ernstigheidsgraad van trauma tydens die kinderjare. Haplotipe analise van variante binne die geïdentifiseerde vatbaarheidsgene het op nuwe haplotipe assosiasies – waarvan 4 op die MMP9-geen geleë is – gedui. Hierdie is dus die eerste studie wat gevind het dat dié spesifieke mutasies van die MMP9-geen met angssteurings verband hou. Hierdie bevinding strook met vorige werk wat daarop dui dat die MMP9-geen by toestande soos kardiovaskulêre siekte en kanker wat ook met verhoogde voorkoms van angssteurings verband hou, betrokke is. Ter afsluiting kan ons sê dat hierdie projek belangrike bevindinge oor die oorsake van angssteurings gemaak het. Die gebruik van ‘n gekombineerde angssteurings-kohort (OKS. PS en SAS) kan moontlik suggereer dat die assosiasies wat ons hier gevind het, waar is vir alle angssteurings en nie net vir ‘n spesifieke afgebakende toestand nie. Traumatiese ervarings tydens die kinderjare is ook bevestig as ‘n risiko vir die ontwikkeling van angssteurings. Hierdie navorsing het ook verskeie nuwe vatbaarheidsgene (MMP9, EGR2, EGR4, NTF4, en ARC), 5 beduidende ENP assosiasies, 4 beduidende ENP-omgewings-interaksies en 5 haplotipe assosiasies (by MMP9 en BDNF) geïdentifiseer as moontlike kandidate wat ‘n rol speel by die ontstaan van patologiese angs. Daar is ook gevind dat die geïdentifiseerde polimorfismes en haplotipes met vatbaarheid vir angssteurings in ‘n geen-omgewing- korrelasie en geen-omgewing- interaksie verband hou. Stellenbosch University http://scholar.sun.ac.za
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Quinn, Bridget A. "Novel Therapeutic Strategies for Pancreatic Cancer." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4671.
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Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly used antibiotic, show potent synergy when used in combination in both pancreatic cancer cells and in multiple immune-deficient and immune-competent mouse models of pancreatic cancer. Sabutoclax alone is capable of inducing cell cycle arrest and apoptosis in cells and its cytotoxicity is enhanced significantly when combined with Minocycline. This combination results in the loss of Stat3 activation both in vitro and in vivo, which is essential for its toxicity. It also inhibits tumor growth and prolongs survival in the KPC transgenic mouse model of pancreatic cancer. Also presented here are studies that demonstrate efficacy in vivo of modified versions of Gemcitabine and Paclitaxel. These drugs are linked to a peptide that shows specificity for the EphA2 receptor, which is overexpressed on the surface of pancreatic cancer cells and only minimally on normal cells. This peptide results in increased cellular uptake of drug, as it is bypassing its normal mechanism of entry. These normal mechanisms are often dysregulated in cancer, leading to decreased uptake and drug resistance. The use of these modified drugs show significantly increased tumor growth inhibition as compared to the parent drug alone. Finally, we provide data on the characterization of a novel transgenic mouse model of pancreatic cancer. This model, the Pan Met View (PMV) mouse, combines the commonly used KPC transgenic mouse model of pancreatic cancer and a mouse that expresses a Luciferase reporter gene under the control of the cancer-specific promoter, CCN1. Our data shows that double transgenic PMV mice can now be used to follow primary tumor and metastasis development in real time by Bioluminescent imaging (BLI) through disease progression and potentially therapy. This strategy will enhance the use of genetically engineered mouse models (GEMMS) to study cancer initiation and progression with potential to non-invasively monitor therapy. These chapters present novel and exciting data that have the potential to open multiple avenues of translational study and result in significant advances in pancreatic cancer therapy.
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Abu-Zayyad, Amineh Naji. "A novel non-spreading variant of transformed hamster fibroblasts." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360924.
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Harrison, Mark. "Studies on novel human DNA damage sensitive cell lines." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299863.
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Hacking, G. N. V. "Novel approaches towards the development of an HIV vaccine." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308246.
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Webb, Tania Elizabeth. "Cloning and characterisation of novel G protein-coupled receptors." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337086.
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Mansoorian, Neda. "Analysis of a novel Myb-like gene from soybean." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26969.
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This thesis reports the identification and characterization of a novel gene, named 7/2, from soybean (Glycine max L. Merrill). Genomic clones of 7/2 from two different cultivars, cvs Maple Arrow and Resnik were isolated and sequenced, and the sequences were compared to each other. These sequences were 100% identical. Alignment with a cDNA sequence from cv. Maple Arrow revealed the structure of the gene as having 6 exons and 5 introns.
The full length cDNA contains an ORF of 798 by encoding a novel protein of 265 amino acids with a calculated molecular weight of 29.98 kDa. The conceptual 7/2 protein is similar in structure to Myb-like transcription factors in that it has an N-terminal DNA binding domain of 52 amino acid and a potential acidic activation domain. Unlike most known plant Myb transcription factors it has one, not two, N-terminal DNA binding repeats. As determined by RT-PCR, the7/2 message is expressed in most soybean tissues but is most highly expressed in nodules. These characteristics suggest that 7/2 may represent a novel soybean regulatory protein.
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Kowalski, Paul Edward. "Novel genetic effects of a human endogenous retrovirus insertion." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ34571.pdf.
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Anwar, Sabina Zareen. "Functional characterisation of synuclein-based novel genetic mouse models." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:b14fc29e-2bc8-4a31-865b-f4ec0e0f6f2c.
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Synucleins are highly conserved presynaptic proteins with unknown function. α-synuclein plays a key role regulating dopamine homeostasis and is intimately involved in Parkinson’s disease (PD) pathogenesis. However, the normal/pathological role of α-synuclein remains unidentified. Studies exploring its function are limited as current transgenic mouse models do not fully recapitulate PD pathology. This thesis reports the functional characterisation of two novel synuclein-based mouse models. I report the molecular and functional characterisation of transgenic mouse lines with wild-type or A30P-mutant human α-synuclein genomic locus carried within a bacterial artificial chromosome. SNCA-A30P+Snca-/- mice exhibited a highly physiologically relevant expression pattern of the transgene, including expression in the substantia nigra pars compacta (SNpc) and a specific, age-related loss of TH+ cells in the SNpc, the key region of preferential cell loss in PD, compared with non-transgenic Snca -/- littermate controls. Analysis of dopamine signalling using fast-scan cyclic voltammetry (FCV) showed young adult SNCA-A30P+Snca-/- mice had an approximately 20% lower evoked extracellular dopamine concentration ([DA]o) compared with non-transgenic Snca -/- littermate controls, a decrease specific to the dorsal striatum. This difference diminished with age and could not be attributed to changes in dopamine reuptake/content. I detail the behavioural and neurochemical phenotype in mice lacking all three synucleins (α/β/γ). Functional compensation between synucleins emphasises the importance of studying their effects by removing all three proteins simultaneously. Triple-null mice exhibited hyperactivity in a novel environment reminiscent of a hyperdopaminergic-like phenotype, but showed no phenotype in anxiety or motor related tests. FCV revealed synuclein triple-null mice had a two-fold increase in [DA]o, specific to the dorsal striatum and not attributable to changes in dopamine reuptake/content, changes in striatal nicotinic receptor activity nor calcium-dependent changes in dopamine exocytosis. Together, the analysis from these two novel mouse models reveal synucleins play an important role in altering synaptic function in the dorsal striatum (the region selectively affected in PD) and contributes to growing evidence suggesting synucleins are negative regulators of synaptic dopamine release.
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Mattioli, Francesca. "Identification of novel genetic causes of monogenic intellectual disability." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ035/document.
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La déficience intellectuelle (DI) est une trouble du neuro développement caractérisée par une extrême hétérogénéité génétique, avec plus de 700 gènes impliqués dans des formes monogéniques de DI. Cependant un nombre important de gènes restent encore à identifier et les mécanismes physiopathologiques de ces maladies neuro développementales restent encore à comprendre. Mon travail de doctorat a consisté à identifier de nouvelles causes génétiques impliquées dans la DI. En utilisant différentes techniques de séquençage de nouvelle génération, j’ai pu augmenter le taux de diagnostic chez les patients avec DI et identifié plusieurs nouvelles mutations (dans AUTS2, THOC6, etc) et nouveaux gènes (BRPF1, NOVA2, etc) impliqués dans la DI. Pour les moins caractérisés, j'ai effectué des investigations fonctionnelles pour valider leur pathogénicité, caractériser les mécanismes moléculaires qu'ils affectent et identifier leur rôle dans cette maladie. Mes travaux de doctorat permettront d’améliorer et d’accélérer la possibilité d’obtenir un diagnostic moléculaire qui donnera accès à un meilleur suivi et à une meilleure prise en charge pour les patients. Cela permettra également de mieux comprendre les mécanismes physiopathologiques impliqués dans ces troubles neuro développementaux. Ces connaissances aideront éventuellement à identifier de nouvelles cibles thérapeutiquesIntellectual disability (ID) is a group of neurodevelopmental disorders characterized by an extreme genetic heterogeneity, with more than 700 genes currently implicated in Mendelian forms of ID but still some are not yet identified. My PhD project investigates the genetic causes of these monogenic ID by using and combining different NGS techniques. By using this strategy, I reached a relative high diagnostic yield and identified several novel mutations (in AUTS2, THOC6) and genes (BRPF1, NOVA2, etc) involved in ID. For the less characterized ones, I performed functional investigations to prove their pathogenicity, delineate the molecular mechanisms altered and identify their role in this disease. Overall, this work improved and provided new strategies to increase the molecular diagnosis in patients with ID, which is important for their healthcare and better management. Furthermore, the identification and the characterization of novel mutations and genes implicated in ID better delineate the implicated pathophysiological mechanisms, opening the way to potential therapeutic targets
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Chan, Ernest Ricky. "Genetic Analysis of Novel Models of Thrombocytopenia and Leucopenia." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1248212698.
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Alphey, Nina. "Modelling optimal strategies for novel genetics-based pest management." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:03656907-ff7d-4afd-a958-9262a200f318.
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Genetic transformation techniques for pest insects have enabled the development of novel methods to mitigate the enormous harm done by insects to human health (through transmission of diseases) and to agriculture (through damage to crops or livestock). I use mathematical modelling to analyse strategies using autocidal genetic constructs (dominant lethal genes that are repressible during mass-rearing); in parallel several research groups are developing the strains and the laboratory and field experimental work. Engineered insects would be released in large numbers and compete for mates, and their progeny would inherit one copy of a dominant lethal gene and die. The lethal mechanism can be made stage- or sex-specific. The aim is to reduce the number of pest insects in a population, suppressing numbers to a less harmful level or local elimination. I examine the evolutionary, ecological, and economic cost and benefit aspects of these novel interventions. I consider application of this genetic technology against agricultural pest insects, combined with genetically modified crop plants engineered to produce insecticidal toxins, to which field-evolved resistance is emerging. Using a theoretical framework, I analyse the gene frequency evolution of resistant alleles and show that strategies using genetic constructs that are selectively lethal only to females could help to manage both pests and resistance. I investigate potential resistance to the lethal mechanism of the genetic construct itself. I use population genetics and population dynamics models to explore the impact of heritable biochemically-based resistance on the effectiveness of genetic strategies for reducing populations of important pests in agriculture or public health. Released insects are homozygous for susceptibility to the lethal construct; this has an inherent element of resistance dilution. Finally, I analyse genetic vector control methods to reduce the transmission of human disease. I combine vector population dynamics and epidemiological models with techniques for assessing cost-effectiveness of a genetic strategy for controlling a vector mosquito, and show that disease elimination is feasible on a practical timescale and economically beneficial.
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Arya, V. B. "Understanding the novel genetic mechanisms of congenital hyperinsulinaemic hypoglycaemia." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1469326/.
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Background: Hyperinsulinaemic hypoglycaemia (HH) is characterized by unregulated secretion of insulin in the presence of hypoglycaemia. Mutations in nine different genes (ABCC8, KCNJ11, GLUD1, HNF4A, HNF1A, GCK, HADH, SLC16A1 and UCP2) have so far been identified as a cause of HH. Mutations in ABCC8 and KCNJ11, which encode the sulfonylurea receptor 1 (SUR1) and potassium inward-rectifying 6.2 (Kir6.2) subunits of ATP-sensitive potassium channel (KATP channel), are the most common cause of HH. At least two (possibly more) well-described histological subtypes are associated with HH: a focal form and a diffuse form. Diffuse HH are most commonly due to recessive and dominant mutations in ABCC8 and KCNJ11. Focal HH results due to somatic loss of the maternal 11p allele (11p15.1 to 11p15.5) involving the ABCC8 and KCNJ11 region in patients with paternally inherited mutation in ABCC8 or KCNJ11. HH can be transient and resolve within few weeks. Transient HH is seen in association with intrauterine growth restriction, maternal diabetes mellitus, perinatal asphyxia, erythroblastosis fetalis, maternal administration of sulfonylureas, and intravenous glucose infusions during labour. In large series of HH patients, the underlying genetic cause was not identified in approximately 50% of the patients. Whole-exome sequencing is a powerful and cost-effective tool for identifying genetic basis of diseases. It involves sequencing the protein coding regions of the human genome. Aim: To identify novel genetic mechanisms of HH. To functionally characterize two novel KATP channel mutations associated with a unique clinical phenotype. Patients: Four patients had protein-sensitive HH with normal serum ammonia. Two families (one consanguineous and one non-consanguineous) had two affected siblings with HH. All these patients had negative molecular genetics for ABCC8, KCNJ11, GLUD1 and HADH. One patient had a unique phenotype of HH and cardiac arrhythmias. In addition, three patients had two novel KATP channel mutations associated with a unique clinical phenotype (transient HH and combined focal/diffuse HH). Methods: Whole-exome sequencing (WES) was performed on nine patients (from seven families), their parents and unaffected siblings to identify novel, deleterious gene variants. Based on the available biological information, two novel gene variants (p.F108del K2P17 and p.A422V Kv6.2) were considered potential disease causing. The mutations were created in plasmid constructs containing the WT cDNA sequence for KCNK17 (K2P17) and KCNG2 (Kv6.2) using site-directed mutagenesis. These constructs were transfected into HEK293 cells, which were studied by whole-cell patch clamping. Two novel KATP channel mutations (p.T1516M SUR1 and p.*391Rext*94 Kir6.2) were also studied. For studying the p.*391Rext*94 Kir6.2 mutation, the WT human cDNA and 3′UTR sequence of KCNJ11 was cloned into pcDNA 3.1 vector. The KATP channel mutations were created in plasmid construct containing the WT cDNA sequence for ABCC8/KCNJ11 using site-directed mutagenesis. These constructs were transfected into HEK293 cells, which were then studied by whole-cell patch clamping. The p.*391Rext*94 Kir6.2 is a non-stop mutation and the transcripts can undergo degradation by non-stop decay phenomenon. The presence of p. *391Rext*94 Kir6.2 mutant transcript in the pancreatic tissue of the affected patient was studied by cDNA sequencing and Western blotting on the patient’s pancreatic tissue extracted RNA and protein fraction respectively. Results: WES identified two potential disease-causing heterozygous gene variants (p.F108del K2P17 and p.A422V Kv6.2) in a family with a phenotype of HH and cardiac arrhythmia, which were confirmed by Sanger sequencing. Whole-cell patch clamping experiments on HEK293 cells proved both variants to be pathogenic under heterozygous expression. Whole-cell patch clamping experiments on the two novel KATP channel mutations (p.T1516M SUR1 and p.*391Rext*94 Kir6.2) was indicative of pathogenic nature of the mutation. Analysis of the pancreatic tissue, obtained at surgery from the patient with non-stop KCNJ11 mutation (p.*391Rext*94 Kir6.2), by cDNA sequencing and Western blotting established the presence of transcript and protein with non-stop mutation. Conclusions: Mutations in KCNK17 (K2P17) and KCNG2 (Kv6.2) are potential novel genetic mechanisms for HH and cardiac arrhythmias. More patients with similar phenotype need to be screened for mutations in these two genes. A novel mechanism for HH (combined focal and diffuse HH phenotype) and molecular basis for a transient type of HH was identified.