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1
Man, Yang Kee Stella. "Molecular investigations of familial paraganglioma." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408678.
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Bell, Andrew John. "Spectroscopic investigations of molecular dynamics." Thesis, University of Southampton, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280858.
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Maughan, Juanita Amanda. "Molecular investigations of plant cytochrome P450." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388204.
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MacCarthy-Morrogh, Lucy. "Molecular investigations of BtK and WASP." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286330.
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Tassell, M. J. "Computational investigations of molecular actinide chemistry." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1386659/.
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This thesis is a computational study of the first members of the actinide series, thorium, protactinium, uranium, neptunium, plutonium, americium and curium. There are two general themes that occur throughout this thesis; the first is the electronic structures of the aforementioned actinides, and in particular what is the role of the 5f and 6d orbitals in the electronic structure of some early actinide complexes. The second is how covalent are the interactions between the early actinides and lighter members of the periodic table, in particular carbon, halogens and the chalcogens. The principal quantity that has been probed to assess this covalency is the electron density. Chapter 2 makes use of both time dependent density functional theory (TDDFT) and multiconfigurational self-consistent field theory (CASPT2) to assess the experimentally determined Cl K edge spectra of [AnCl6]2-; An = Th, Pa, U, Np and Pu. Particular attention is applied to the [NpCl6]2- and [PuCl6]2- spectra as an anomalous transition splitting pattern is seen. Quantum theory of atoms in molecules (QTAIM) theory has been used to probe the actinide cyclopentadienyl bond in chapter 3 and the actinide halogen bond in chapter 4. Unlike more traditional Mulliken and orbital analysis QTAIM is based on the topology of the electron density and is therefore an observable quantity. The actinide halide bond is then also probed with bond orders derived from QTAIM. The [M{N(EPPh2}2]3 ;(M = La, Ce, Eu, U, Pu, Am, Cm; E = S, Se) molecules studied in chapter 5 have been purposely synthesized so as to assess the degree of covalency between An(III) and La(III) chalcogen bonds. Natural population analysis and QTAIM is used to study these complexes.
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Blundell, M. P. "Molecular investigations into Wiskott-Aldrich Syndrome." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444028/.
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Wiskott-Aldrich Syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by eczema, thrombocytopaenia and immunodeficiency. WAS encodes for a haematopoietic restricted protein, WASp, involved in transduction of signals from the cell membrane to the actin cytoskeleton. Mutations lead to impaired actin dynamics in response to stimuli and are seen as defects of receptor capping, chemotaxis, phagocytosis and proliferation. This leads to susceptibility to pyogenic, viral and opportunistic infections and increased incidence of lymphoproliferative disease and malignancy. Due to the high morbidity and mortality associated with mismatched transplantation, WAS is considered a good target for gene therapy. We were able to reconstitute a murine model of WAS using a gamma retroviral vector, with reconstitution of specialised actin structures, podosomes, as a functional readout. Reservations concerning the safety of such vectors, following adverse events in a clinical trial, led to the development of third generation self-inactivating lentiviral vectors. Under the promotion of CMV, SFFV LTR or short sequences of the proximal endogenous Wiskott-promoter, WASp was able to restore cytoskeletal abnormalities in dendritic cells in-vitro from WASp-deficient mice. In addition we have demonstrated stable expression of WASp in T cell, B cell and myeloid lineages following transduction and engraftment of lineage negative murine bone marrow (up to 9 months) using both an SFFV LTR and endogenous promoter sequences. We have demonstrated the ability to restore cytoskeletal abnormalities and proliferative responses from the reconstituted mice. Recently a novel mutation in WAS has led to the discovery of a constitutively active WASp, with a novel monocytopaenic and neutropaenic phenotype. Here we characterised the patient phenotype of a novel constitutively active WASpn94T mutant. In addition to monocytopaenia and neutropaenia, there was abnormal cytoskeletal actin, manifesting itself as abnormal podosome distribution and an inability to phagocytose or produce an oxidative burst to physiological stimuli. There was also increased apoptosis in the bone marrow and evidence of genomic instability. Utilising lentiviral vectors, WASpI294T was expressed in a cell line to elucidate the possible mechanisms responsible for the patient phenotype. These studies demonstrate the efficacy and feasibility of a lentiviral vector-mediated gene therapy strategy for WAS using endogenous promoters where a more regulated expression level may be achieved.
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Hughes, Fiona Lesley. "Molecular investigations of subgroup I geminiviruses." Doctoral thesis, University of Cape Town, 1991. http://hdl.handle.net/11427/21979.
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Bibliography: pages 139-150.The diversity of Subgroup I geminiviruses causing streak disease in maize, sugarcane, and indigenous wild grasses was investigated. The virus. isolates studied originated from maize (several southern African isolates), two sugarcane cultivars (from Natal province, South Africa, and from Mauritius), wheat, and three grasses (Panicum, Setaria, and Eleusine spp. from South Africa). The following methods were used: analysis of restriction fragment length polymorphisms (RFLPs) between viral genomes in individual infected plants; DNA cross-hybridization between virus isolates; restriction endonuclease mapping of whole virus genomes; and nucleic acid sequencing. The complete genome of the Natal sugarcane streak virus isolate was sequenced. Partial sequences were obtained for other isolates, either by sequencing the ends of cloned viral genomes, or by sequencing a 250 base pair fragment of a highly conserved open reading frame that had been amplified using the polymerase chain reaction technique. The viruses being studied were compared both among themselves and with other Subgroup I geminiviruses of known DNA sequence, on the basis of sequence (nucleotide and amino acid) and restriction map data. Distance matrix methods were used to infer phylogenetic relationships between Subgroup I geminiviruses from restriction map and sequence data. Phylogenies deduced from sequence data were considered to be more accurate than those deduced from map data. Regardless of the method of analysis used, however, the relationships between the Subgroup I geminiviruses studied here remained constant. Thus, three strains of MSV (maize, Setaria, and Eleusine strains) were distinguished. Streak viruses distinct from MSV were also identified: panicum streak virus (PanSV), and two distantly related strains (Natal and Mauritius) of sugarcane streak virus (SSV). Restriction mapping of different geographical isolates of the maize strain of MSV demonstrated that variation existed within a single strain of virus. RFLP analysis indicated that minor variation existed between virus genomes within single diseased plants. Methods used to. type Subgroup I geminiviruses were evaluated, and discrepancies in the serological typing of geminiviruses from Subgroups I and III were pointed out. A unified scheme was proposed for distinguishing between distinct Subgroup I geminiviruses and strains of geminiviruses. The origins of maize and sugarcane streak viruses were speculated upon.
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Kersell, Heath Ryan. "Investigations on the Complex Rotations of Molecular Nanomachines." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1307126123.
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Nair, Nisanth N. "Molecular dynamics investigations of clusters and solids." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974372943.
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Birkenheuer, Adam Joseph. "Canine Babesiosis: Epidemiological, Molecular and Therapeutic Investigations." NCSU, 2004. http://www.lib.ncsu.edu/theses/available/etd-04192004-164025/.
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Canine babesiosis is an emerging infectious disease in the United States (US). An epidemic of Babesia gibsoni infections in the US was identified. An association between dog breed and B. gibsoni infections was detected. Babesia gibsoni-infected dogs were more likely to be American pit bull terriers and B. canis vogeli infected dogs were more likely to be greyhounds. An association between a recent dog bite and B. gibsoni infection was detected, implicating direct dog-to-dog transmission as a route of infection in the US. Several genes from canine Babesia spp. were characterized, including 18S ribosomal RNA (rRNA), internal transcribed spacer regions (ITS), cytochrome B (cytB), and rhoptry-associated protein-1 (RAP-1). These genetic data were used to develop a sensitive and specific diagnostic semi-nested polymerase chain reaction (PCR) test for canine babesiosis. Using this assay, a novel large Babesia organism was identified in a blood sample obtained from a clinical patient. Molecular and phylogenetic characterization of this large Babesia spp. determined that it was most closely related to B. bigemina. Lastly, an atovaquone and azithromycin drug combination was shown to be the first treatment to clear canine B. gibsoni infections.
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Johnson, Daniel. "Molecular level investigations of coiled-coil proteins." Thesis, University of Nottingham, 2006. http://eprints.nottingham.ac.uk/10174/.
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The coiled-coil is a very common protein structural motif, consisting of two or more alpha helices intertwined in a supercoil. In biological systems it is found in proteins which fulfil a number of roles, for example in structural proteins such as keratin, as well as a large number of transcription factors and other DNA binding proteins, where it functions as a dimerisation domain. This versatile motif has also been adapted for a number of applications including the production of responsive hydrogels; the construction of self-assembling fibres for tissue engineering applications; as a cross-linking agent in drug delivery applications, as well as in the creation of biosensor surfaces. In this study two different types of protein containing coiled-coil domains are examined. It is the aim of this work to increase the understanding of how behaviour of this motif at the molecular level relates to those at the macroscopic. The first set of proteins of interest in this thesis form pH-responsive hydrogel systems utilising a variant of the coiled-coil motif, the leucine zipper, as their cross-linking domain. These consist of two or more leucine zippers separated by random coil spacer sections. When the leucine zipper sequences dimerise, they cross-link the proteins forming a gel matrix. As charges within the leucine zippers alter, as the pH of their environment is altered, their relative stability changes causing them to associate or dissociate. This is reflected in a change in the physical characteristics of gels from visco-elastic solids to viscous liquids which is reversible. The bulk properties of these materials is well characterised, but relatively little information is known at the molecular level. Starting at the single molecule level and scaling up to the mesoscale, the behaviour of hydrogel-forming proteins has been probed using a range of techniques, particularly with respect to the interactions of the coiled-coil forming domains. Studies described in this thesis have concentrated on the change of physical characteristics of these proteins and their assemblies as pH was altered. We have thus been able to connect behaviour of these proteins at the molecular scale to bulk properties of solutions and materials formed from them. In the final experimental chapter a coiled-coil structure of more complex architecture is examined. This is formed of a ternary complex of three proteins which assemble into a two-stranded leucine zipper domain, designed as a cross-linking motif for nano-particle assemble. Force was used to probe the kinetic stability and mechanical strength of this assembly. With the increasing use of the coiled-coil motif as a cross-linking domain in the use of biomaterials it is increasingly important to be able to connect the behaviour of such materials to the behaviour of the coiled-coil motif at the molecular scale, to gain further insight into the mechanistics behind their behaviour.
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Clark, Helen M. "Cytogenetic and molecular investigations of malignant lymphomas." Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316515.
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Kortunov, Pavel, Sergey Vasenkov, Jörg Kärger, Elía M. Fé, M. Perez, Michael Stöcker, George K. Papadopoulos, et al. "Investigations of molecular diffusion in FCC catalysts." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-196587.
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Natha, Khilona. "Molecular Forensic Investigations into Animal Sexual Abuse." Master's thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/32938.
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Animal sexual abuse (ASA) involves the sexual molestation of animals by humans. The identification of semen provides a legally-accepted indicator that sexual activity occurred, while forensic DNA analysis provides a lead to a potential suspect. After conducting a systematic literature review, no previous research investigating semen and/or DNA recovery from animals over time was found. Therefore, this pilot study aimed to assess the recovery of human semen and DNA from animal fur over a two-week period to establish baseline data pertaining to evidence retention in the ASA context. This pioneer study also attempted to contribute towards the development of a suitable animal fur model on which to perform experiments. Daily swabbing and testing of semen from three fur models (unpreserved baboon fur, preserved nyala hides and faux fur) showed that semen could still be detected at 14 days using standard presumptive and confirmatory tests. Although DNA degradation showed a statistically significant increase over time, forensically usable DNA profiles (≥ 12 fully typed short tandem repeat loci) were consistently obtained. There was significantly higher DNA degradation in samples from the baboon fur compared to the others, while DNA concentrations were significantly different between each fur model. These differences highlight that future research must consider the choice of fur model to best represent the animal of interest; e.g. dissected fur from a recently deceased animal would best mimic a fatal ASA case. The insight regarding the choice of animal model hopes to be of benefit for future research, which should focus on the influence of more realistic variables (e.g. movement and body heat) on semen and DNA retention on animal fur. Overall, this study successfully generated baseline data, and provides a foundation for additional research, which hopes to eventually assist in the interpretation of forensic evidence in the global burden of ASA.
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Kortunov, Pavel, Sergey Vasenkov, Jörg Kärger, Elía M. Fé, M. Perez, Michael Stöcker, George K. Papadopoulos, et al. "Investigations of molecular diffusion in FCC catalysts." Diffusion fundamentals 2 (2005) 97, S. 1-2, 2005. https://ul.qucosa.de/id/qucosa%3A14435.
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Whitmore, Steven Scott. "Molecular investigations of age-related macular degeneration." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1798.
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An estimated 170.38 million elderly adults suffer from some stage of age-related macular degeneration (AMD) worldwide, a vision defect that damages the macula, the central region of the retina required for sharp vision, such as reading, driving, and recognizing faces. Genetic factors strongly modify one's risk for developing AMD, and most of these genetic changes are found in genes of the alternative complement cascade, a component of the immune system. The lack of effective AMD prevention calls for the identification of druggable molecules and pathways.
In my research, I use microarrays and RNA sequencing to investigate the events occurring in early AMD, the reasons for macular susceptibility to AMD, and the events triggering aberrant blood vessel growth in late AMD. First, I found that genes associated with endothelial cells tend to be expressed at lower levels in human donors eyes affected by early AMD than in control eyes, concordant with previous studies indicating loss of choriocapillaris in early AMD. Second, I found that molecular signals across regions of the retina, retinal pigment epithelium, and choroid generally mirror the distribution of cell types in these regions. Third, I found that damage to cultured primate chorioretinal endothelial cells by the end product of complement activation, membrane attack complex, produces an environment conducive to choroidal neovascularization, a symptom of late-stage AMD. I propose a model that bridges genetic variants in the complement cascade genes with blood vessel loss in early AMD and the pathological growth of blood vessels in late AMD.
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O'Neill, Andrew. "Investigations in molecular structure : from scattering to molecular complexes of brominated compounds." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1709/.
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The main focuses of this research were to examine the capabilities of solution techniques to attempt to monitor the nucleation process in crystallisation, and to investigate structural outcomes of crystallisation processes, with reference to polymorphism and intermolecular interactions. To achieve this, work on the investigation of nucleation and early-stage crystallisation was carried out at the Department of Pharmaceutical Sciences at the University of Strathclyde and also at the central synchrotron facility of Station 2.1 at the SRS Daresbury. Small angle X-ray scattering (SAXS) was carried out on solutions of methyl-4-hydroxybenzoate (pMHB) and 2-bromobenzoic acid. These studies were carried out after developing solution methods to enable us to determine the point at which crystals emerged from solution. This was achieved using Focussed Beam Reflectance Measurements. Structural studies were also carried out on pMHB to examine its polymorphic behaviour and crystal structures were solved at various temperatures from 100K to 300K. The crystal structure of methyl-2,5- dibromobenzoate was also solved at 100K after discovering it sublimes at room temperature. This structure could only be solved from a twinned crystal and indicated the appearance of interesting halogen interactions occurring. Structural studies have also been carried out using the bromanilic acid molecule as a focus to generate a number of co-crystal complexes to examine their halogen bonding capability and to determine any structural significances in their formation. Co-crystal complexes of bromanilic acid and a variety of molecules were made in 1:1 and 1:2 ratios to see if any additional halogen interactions could be observed or induced, in addition to the expected hydrogen-binding interactions. The co-crystals included a range of picolines and lutidines as well as bromo-substituted pyridines to attempt to induce halogen interactions. This generated a number of new compounds whose structures were determined using single crystal X-ray diffraction and the interactions were monitored to observed whether any defined patterns with regards to the tendency of bromanilic acid co-crystallisations to produce predictable patterns of intermolecular interactions could be determined.
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Seibt, Joachim. "Theoretical investigations on the spectroscopy of molecular aggregates." kostenfrei, 2009. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3721/.
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Norton, Lisa K. "Spectroscopic investigations of dendritic polymers as molecular containers." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6102.
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Thesis (M.S.)--University of Missouri-Columbia, 2008.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on September 22, 2008) Includes bibliographical references.
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Waghorn, Philip A. "Investigations into porphyrins as potential molecular imaging agents." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526421.
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Wentworth, Jonathan. "Molecular and cytogenetic investigations of some Alopecurus species." Thesis, University of East London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365947.
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Gilder, Michael Frederick James. "Molecular investigations in animal models of Huntington's disease." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325046.
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Reid, E. S. "Cellular and molecular investigations of undiagnosed neurometabolic disorders." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1516116/.
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Inborn errors of metabolism (IEM) affect 1 in 500 newborns causing significant disease-burden and mortality throughout childhood. However, despite extensive genetic and biochemical investigations the cause of disease remains unknown in up to 50% of patients with neurological symptoms; so-called neurometabolic disorders (NMD). The overarching aim of this thesis was to determine the cellular and molecular aetiologies for the clinical phenotypes seen in patients with undiagnosed NMD. In order to improve the diagnosis of these disorders in clinical practice, a comprehensive targeted gene panel of 614 genes known to cause IEM was designed and a cohort of 44 patients was analysed. A definitive or probable genetic diagnosis was achieved in 53% of patients without a prior genetic diagnosis. Method optimisation and validation, comparison to other diagnostic strategies and the advantages and disadvantages of targeted sequencing are reviewed. Case reports, novel mutations/phenotypes and their contribution to the expansion of the literature are described. Whole exome sequencing and functional characterisation was also undertaken for patients who had been extensively clinically investigated previously. Five patients identified with mutations in the mitochondrial glutamate transporter, SLC25A22, presenting with novel biochemical phenotypes are described and novel transporter functions are postulated. One patient diagnosed with a potassium channelopathy with biochemical abnormalities and anticonvulsant responses suggestive of an inborn error of vitmain B6 metabolism is documented and the mechanisms underlying the generalised anticonvulsant effects of vitamin B6 are postulated. Characterisation of a possible novel inborn error of lysine metabolism in a patient presenting with hyperlysinaemia and motor neuron disease is also discussed. These studies also demonstrate the complexity of unravelling the relationship between genotype and phenotype and highlight the need for novel functional assays to assess the pathogenicity of sequence variants. Mass spectrometry-based assays were developed to enable characterisation of disorders affecting vitamin B6 homeostasis, including pyridox(am)ine 5'-phosphate oxidase (PNPO), antiquitin and PROSC deficiency, the latter being a novel disorder. The differences between pyridoxine- and pyridoxal phosphate-responsive PNPO deficiency and fibroblast vitamer profiles in all patients were all investigated. Finally, multiple methodologies were employed with the aim of understanding the biological function of PROSC.
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Shalaby, Nevine. "Genetic and molecular investigations of Drosophila Notch signaling." Thesis, Boston College, 2009. http://hdl.handle.net/2345/921.
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Thesis advisor: Marc A. T. MuskavitchNotch signaling is an evolutionarily conserved developmental pathway regulated by two classes of transmembrane proteins: the Notch receptors and the Delta/Serrate/LAG-2 (DSL) ligands. Notch and DSL ligands mediate cell-cell communication that results in a downstream signaling cascade that affects many aspects of metazoan development. Additional regulatory mechanisms that affect Notch signaling are being discovered continuously, and recent findings highlight the importance of endocytosis, ubiquitylation and subcellular trafficking as essential requirements for proper signaling. In order to obtain further insights into the regulation of Notch signaling, I took a two-fold approach, combining genetic and molecular techniques in Drosophila. First, I took part in a large-scale transposon-based screen in the developing Drosophila eye to identify additional genes involved in the pathway. We screened 10,447 transposon lines from the Exelixis collection for modifiers of cell fate alterations caused by overexpression of Delta, and we identified 170 distinct modifier lines that may affect up to 274 genes. I further analyzed a previously uncharacterized gene, which we have named Amun, and showed that it localizes to the nucleus and contains a putative DNA glycosylase domain. Further analyses of Amun reveal that altered levels of Amun function interfere with cell fate specification during eye and sensory organ development. Second, to investigate structural requirements for ubiquitylation of Delta, I analyzed four individual lysine residues in the Delta intracellular domain, and assessed their necessity for Delta signaling activity. I find that a conserved residue, DeltaK742, is essential for Notch signaling in the Drosophila imaginal wing disc and is apparently required for ubiquitylation of Delta by the E3 ubiquitin ligase, Mind bomb1 (one of two E3 ubiquitin ligases required for Delta signaling activity). Taken together, the findings from this thesis research contribute to the advancement of our understanding of different aspects of Notch signaling and Notch-mediated development
Thesis (PhD) — Boston College, 2009
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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Lambert, J. R. "Investigations into the molecular pathogenesis of essential thrombocythaemia." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1334502/.
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In order to explore the phenotypic heterogeneity of the myeloproliferative neoplasm essential thrombocythaemia (ET), the role of the JAK2 mutation V617F in the pathogenesis of the disease was investigated, in particular its relationship to myeloid clonality. The clinical, haematological and molecular characteristics of 133 ET patients were studied. JAK2 V617F was detected in 55 (41%) patients; a clonal X-chromosome inactivation pattern (XCIP) was found in 24 (39%) of the 62 evaluable female patients. There was no association between JAK2 mutational status and XCIP status or thrombotic risk, but higher JAK2 V617F mutant levels were noted in patients who had a thrombosis. A trend towards a higher thrombotic rate was observed in patients whose XCIP was clonal. In 10 untreated JAK2 V617F-positive ET patients, JAK2 WT thrombopoiesis was not suppressed despite the presence of a thrombocytosis, suggesting that the regulation of JAK2 WT thrombopoiesis was abnormal. Eleven patients were screened for the presence of more than one JAK2 V617F-positive population using an exonic SNP located near the mutation. In ten (91%) of these the mutation appeared to have been independently acquired on at least two occasions. Furthermore, XCIP analysis of JAK2 V617Fpositive erythroid colonies from six ET patients revealed that in one patient the V617F-positive populations were not derived from a single clonal population. An association between the reported JAK2 haplotype (known as ‘46/1’) and JAK2 V617F-positive ET patients was observed in the cohort studied. Methylation studies indicated that this haplotype introduced additional methylated sites near to the mutation locus, which may potentially affect conformation of the DNA and mutability of the JAK2 locus. Together, the studies reported in this thesis suggest that JAK2 V617F is not the initiating event at least in some cases of ET, and that its presence does not invariably indicate the presence of a monoclonal disorder.
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Waghorn, Philip Alan. "Investigations into porphyrins as potential molecular imaging agents." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669974.
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Van, der Walt Eric. "Experimental investigations of mastrevirus molecular biology and evolution." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/4346.
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Includes abstract.Includes bibliographical references (leaves 138-161).
This dissertation describes three major sets of experiments, all of which involved the construction and use of various reciprocal chimaeric MSV constructs. First, chimaeric viruses were used in genetic complementation-type experiments to investigate the biological significance of interactions between the two virion-sense open reading frames (ORFs) of MSV, their products, and the rest of the genome. Six chimaeric MSV constructs were made by reciprocally exchanging the ORFs encoding movement protein (MP) and coat protein (CP) individually, and in pairs, between MSV-Kom and MSV-Set, which share just 78% overall nucleotide identity. Analysis of symptomatology and infection efficiency of chimaeras and wild-type parental viruses revealed evidence of functionally relevant specific interactions between MSV MP and CP.
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Wright, Mitchell Henry. "Physiological and Molecular Investigations of Manganese Transforming Bacteria." Thesis, Griffith University, 2014. http://hdl.handle.net/10072/368137.
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Bacteria plays a critical role in the geochemical cycling of manganese in aquatic environments. They are readily able to transform manganese through oxidative and reductive processes. In natural environments, it is well known that some bacteria are able to oxidise Mn(II) to Mn(IV) under aerobic conditions, while others reduce Mn(IV) to Mn(II) under anaerobic conditions. In the current project, manganese transforming bacteria were investigated on both a physiological and molecular basis to further understand bacterial transformation.
Paralana hot springs (PHS), an aqueous environment rich in heavy metals, was used as a model environment in the study. The diversity of microorganisms in PHS was initially investigated using both culture dependent and independent techniques. Metagenomic 16S rRNA screening revealed bacteria belonging to 24 different phyla, 11 of which have been previously determined to contain manganese oxidisers. Mesophilic and thermophilic bacteria were detected and isolated, with many able to oxidise and/or reduce manganese as well as other metals (including iron, arsenic, cobalt, manganese, molybdenum, selenium, uranium and vanadium). Subsequent 16S rRNA analysis of obtained isolates revealed a number of novel bacteria, including the manganese transforming bacteria; Bacillus sp. DLH-1207, Bacillus sp. PMO and Paenibacillus sp. AEM-1106.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Campana, Federica. "Molecular dynamics investigations of drug-cell membrane interactions." Doctoral thesis, Universita degli studi di Salerno, 2013. http://hdl.handle.net/10556/1325.
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2011 - 2012The cell membrane functions as a platform for the assembly of many signal transduction pathways and provides an additional level of regulation in cell signaling networks. The complex dynamic structure of the plasma membrane allows lipid–lipid and lipid–protein interactions, as well as the interaction of lipid–protein complexes with the submembrane cytoskeleton. The existence of membrane microdomains adds further complexity to such interactions, as well as the messages propagated in cells through G proteins and other non-permanent (extrinsic) membrane proteins. Each G protein can simultaneously bear a myristoyl, palmitoyl and isoprenyl moiety and therefore, many lipid molecules associated with G proteins may arise in G protein coupled receptor (GPCR)-rich membrane microdomains. These lipids can regulate the biophysical properties of membranes, which in turn modulate the interaction and activity of G proteins. The aim of the first part of my work was to understand the effect of these moieties on membrane structure and G protein-membrane interactions. Although recent studies found that the Gβγ dimer drives the interaction of G-proteins with nonlamellar-prone membranes, little is known about the molecular basis of this interaction. For this reason, I also investigated the interaction of the C-terminus of the Gγ protein with model membranes with or without the isoprenyl moieties. From the very beginning of my work, my studies have focused on the interaction of saturated and unsaturated fatty acids with cell membranes. Many of these molecules, in fact, have proven to be active against certain types of cancers and other diseases. Among all these molecules it is important to remember the Minerval, an analogue of oleic acid developed in the laboratory of Prof. Escribà, which has led to a reduction of up to 80% in the development of lung cancer and glioma cells. A promising molecule with high anti-inflammatory activity and synthesized by the group of Prof. Escribà like the previous one, is a modification of arachidonic acid: the 2-hydroxy arachidonic acid (AAOH). Due to the similarity with arachidonic acid (AA), that is the natural substrate of cyclooxygenase (COX), the second part of my work consisted in the investigation of the interaction of AAOH with COX-1 and COX-2. The results, in terms of free energy of binding and the Fukui function, demonstrated the potential of AAOH as non-toxic non-steroidal anti-inflammatory drug (NSAID). Recent findings pointed unambiguously to membranes as additional cellular sensors in activating a stress protein response, from prokaryotes to mammalian cells, at the beginning of temperature rise or other stresses. Aging or pathophysiological conditions can also be linked to the development of subtle membrane changes or “membrane-defects”, responsible for a dysregulated expression of heat shock proteins (HSPs). Chaperone co-inducers, among which can be mentioned the hydroxylamines such as BGP-15 and NG-094, are substances that cannot induce HSPs by itself, but can enhance HSP induction in combination with other mild stresses. A chaperone co-inducer also has the ability to lower the temperature threshold of the heat shock response and may provide suitable therapeutic candidates for many disease states since they are capable of affecting stressed rather than unstressed cells. The third part of my work consisted in molecular dynamics investigations of BGP-15 and NG-094 on membranes made of sphingomyelin and cholesterol at different composition to understand some aspects of membrane functioning. BGP-15 and NG-094 can induce an alteration in membrane’s fluidity similar to those induced by heat and a strong reorganization of sphingomyelin headgroups with an increased penetration of water. Taken together, all the results suggested that hydroxylamines have a strong effect on microdomains reorganization showing a great potential to become a new class of pharmaceuticals to combat most various protein-misfolding diseases and aging. All these investigations are relevant in the context of the physiology of cells, whose alterations may lead to pathologies whose treatment could be addressed by modifying membrane lipid composition and structure through so-called “Membrane-lipid therapy”. [edited by author]
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Iancu, Violeta. "Single Molecule Switches and Molecular Self-Assembly: Low Temperature STM Investigations and Manipulations." Ohio : Ohio University, 2006. http://www.ohiolink.edu/etd/view.cgi?ohiou1159980375.
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Lama, Manoj. "Immunological and molecular investigations of childhood asthma in the Sub-Himalayan region of West Bengal, India." Thesis, University of North Bengal, 2014. http://hdl.handle.net/123456789/979.
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GC, Jeevan. "Molecular Dynamics Investigations of Structural Conversions in Transformer Proteins." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3225.
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Multifunctional proteins that undergo major structural changes to perform different functions are known as “Transformer Proteins”, which is a recently identified class of proteins. One such protein that shows a remarkable structural plasticity and has two distinct functions is the transcription antiterminator, RfaH. Depending on the interactions between its N-terminal domain and its C-terminal domain, the RfaH CTD exists as either an all-α-helix bundle or all-β-barrel structure. Another example of a transformer protein is the Ebola virus protein VP40 (eVP40), which exists in different conformations and oligomeric states (dimer, hexamer, and octamer), depending on the required function.I performed Molecular Dynamics (MD) computations to investigate the structural conversion of RfaH-CTD from its all-a to all-b form. I used various structural and statistical mechanics tools to identify important residues involved in controlling the conformational changes. In the full-length RfaH, the interdomain interactions were found to present the major barrier in the structural conversion of RfaH-CTD from all-a to all-b form. I mapped the energy landscape for the conformational changes by calculating the potential of mean force using the Adaptive Biasing Force and Jarzynski Equality methods. Similarly, the interdomain salt-bridges in the eVP40 protomer were found to play a critical role in domain association and plasma membrane (PM) assembly. This molecular dynamic simulation study is supported by virus like particle budding assays investigated by using live cell imaging that highlighted the important role of these saltbridges. I also investigated the plasma membrane association of the eVP40 dimer in various PM compositions and found that the eVP40 dimer readily associates with the PM containing POPS and PIP2 lipids. Also, the CTD helices were observed to be important in stabilizing the dimer-membrane complex. Coarse-grained MD simulations of the eVP40 hexamer and PM system revealed that the hexamer enhances the PIP2 lipid clustering at the lower leaflet of the PM. These results provide insight on the critical steps in the Ebola virus life cycle.
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van, Kleef Eduard Hendrik. "Optical preparation of reagent states in molecular dynamics investigations." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357947.
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Shiell, Ralph C. "Experimental investigations of doubly charged atomic and molecular species." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294869.
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Baker, Andrea Catherine. "Investigations into the molecular biology of the freshwater Cyanophages." Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421416.
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Aust, Jonathan Gavin. "Molecular and physiological investigations of fish renin-angiotensin systems." Thesis, University of Exeter, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248168.
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Argyropoulos, George. "Molecular and genetic investigations of testicular development in mice." Thesis, University of Essex, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280829.
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Fairbairn, L. J. "Investigations on erythrocyte membrane proteins using molecular cloning techniques." Thesis, University of Bristol, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379600.
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Sheikh, Sohail Hamid. "Investigations of molecular fluorescence based measurement of DDT residues." Thesis, Cranfield University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267496.
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Fairfax, Benjamin Peter. "Investigations into GABAB receptor surface stability and molecular interactions." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446808/.
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Whereas most G-protein-coupled receptors (GPCRs) are monomeric in structure, gamma-Aminobutyric acid type B (GABAB) receptors are heterodimers of two seven transmembrane protein subunits, GABAB(1) and GABAB(2). GABAB receptor function is dependent upon the co-expression of both these proteins which, when individually expressed, are devoid of receptor activity. Desensitisation of cell surface receptors allows tissues to rapidly adjust their response to agonist. A conserved mechanism ensures that GPCR signalling is closely followed by desensitisation. This entails the phosphorylation of activated receptors enabling interaction with arrestin proteins and subsequent internalisation. It is not known if heterodimeric GABAB receptors employ this method of desensitisation. Data presented here result from experiments to determine whether GABAB receptor cell surface stability is controlled in a similar manner to that of other GPCRs. Also documented is the study of a putative interaction between the protein kinase AMPK and the GABAB(1) subunit. Initial whole cell labelling studies demonstrated that both GABAB(1) and GABAB(2) are basally phosphorylated. Dissimilar to other GPCRs, agonist did not increase levels of phosphorylation and this remained true upon overexpression of G protein receptor kinases. Because GABAB receptors lacked the internalisation promoting increase in phosphorylation upon agonist, it was predicted that they might have enhanced surface stability. This was confirmed in heterologous systems where GABAB receptors did not demonstrably internalise after agonist application even when arrestins were overexpressed. GABAB receptors in cultured cortical neurones showed a similar lack of internalisation in response to agonist. Biotinylation of neuronal surface receptors demonstrated that GABAB receptors reside for an unusually long time at the plasma membrane. Chronic agonist decreased the surface receptor half-life, but this did not correlate with an increase in internalised receptor. Interestingly, chronic agonist did not significantly reduce total receptor protein levels, suggesting GABAB receptors may not downregulate. Protein kinase A (PKA) stimulation, both exogenously and through intracellular pathways, counteracted the agonist-induced degradation and demonstrated that this particular kinase can control GABAB receptor surface numbers. Protection from degradation was correlated with increased phosphorylation at serine 892 within GABAB(2), a residue previously demonstrated to be a PKA substrate. Subsequent experiments were carried out to identify kinases capable of phosphorylating GABAB(1). Affinity purification assays isolated a kinase from brain able to interact with and phosphorylate a twenty amino acid stretch of the carboxy-terminal domain of GABAB(1). Yeast two-hybrid studies identified the catalytic subunit of AMPK as a putative interacting protein with GABAB(1). AMPK was found to phosphorylate GABAB(1) at serines 917 and 923 within the carboxy-terminal domain. Phosphorylation of serine 917 was further confirmed with a phospho-specific antibody raised to this residue. AMPK affinity purifies with GABAB(1) carboxy-terminal domain GST fusion proteins and also co-immunoprecipitates with GABAB receptors from brain. Preliminary investigations indicate that AMPK activation increases surface GABAB receptor levels in cortical neurones and may affect the protein protein interactions of GABAB(1). The results presented in this thesis suggest GABAB receptors are highly stable at the neuronal surface. The activation of PKA and AMPK may be mechanisms by which neurones are able to regulate plasma membrane GABAB receptors.
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Jaureguiberry, G. "Genetic and molecular investigations into Amelogenesis Imperfecta and Nephrocalcinosis." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1436084/.
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Background Calcium has a critical role in cell physiology and needs a tight regulation to maintain an adequate activity and movement. This exquisite regulation involves cellular, paracellular and interstitial systems. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 16 families with a total of 25 patients, who exhibited nephrocalcinosis and amelogenesis imperfecta. To identify the genetic defect we performed linkage analysis, exome capture, next generation and Sanger sequencing. Human dissected kidney was used to perform expression studies. Patient gingival fibroblasts were cultured in vitro and used for cell biological studies. Patients’ spot urines were analysed by Proton-NMR spectroscopy. Results All patients with ectopic calcifications in teeth, gingiva and kidney exhibited biallelic mutations in FAM20A. A total of 20 different mutations were identified and all of them segregated with the disease. Expression of FAM20A was detected in kidney, including the interstitium. Patient fibroblasts showed an increased content of chondroitin sulfate and extracellular free ionised calcium concentrations. Calcification was induced in patient gingival fibroblasts and reverted by overexpressing FAM20A. Urine samples from patients exhibited reduced citrate and increased acetate concentrations. Conclusions The combination of nephrocalcinosis without hypercalcemia or hypercalciuria, amelogenesis imperfecta and other ectopic calcifications are part of an autosomal recessive disorder caused by mutations in FAM20A. The inhibitory effect of FAM20A on glycosaminoglycans is essential to maintain interstitial free ionised calcium in equilibrium, suggesting a new concept in the understanding of nephrocalcinosis and the importance of the interstitial buffer system in calcium homeostasis and biomineralization.
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Mancl, Jordan Michael. "Molecular Investigations of Protein Assemblies Involved in Prokaryotic Virulence." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/102298.
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Protein complexes mediate a diverse range of behavior in prokaryotic cells, yet the exact molecular mechanisms explaining how many of these complexes assemble and function remain unknown. This work focuses on understanding the molecular mechanisms of two different protein assemblies responsible for regulating virulence in the opportunistic pathogen Pseudomonas aeruginosa. P. aeruginosa utilizes type IV pili (T4P) to adhere to, and move along, surfaces. Assembly of T4P is powered by a dedicated cytoplasmic ATPase, PilB. The structural study of PilB from a related system (chapter 2) resulted in the formulation of the first model describing the mechanism of force generation resulting from ATP hydrolysis, which explains how T4P are assembled. Chapter 3 focuses on the RetS/GacS interaction, which is responsible for globally regulating virulence in P. aeruginosa. A comprehensive structural study reveals a dynamics of a novel regulatory interaction and the discovery of a potentially universal transmembrane signaling mechanism.Doctor of Philosophy
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Mullins, Charles Buddie Weinberg Henry Weinberg Henry. "Molecular beam investigations of surface chemical reactions and dynamics /." Diss., Pasadena, Calif. : California Institute of Technology, 1990. http://resolver.caltech.edu/CaltechETD:etd-03122007-135158.
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Mandhare, A. B. "NMR assisted investigations of molecular mobility in polymeric gels." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 1998. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2934.
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Harris, Sarah Anne. "Theoretical investigations of DNA structure and dynamics." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368362.
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Dunne, Emma Maria. "Investigations in trypanosome diversity and evolution using molecular phylogenetic analysis." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289775.
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Borwick, Simon John. "Computational investigations and rationalisations of molecular packing in crystalline materials." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398133.
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Jonasson, L. "Computational investigations of the electronic structure of molecular actinide compounds." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/15798/.
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In this PhD thesis the electronic structure of a range of actinide compounds has been investigated using density functional theory. The reason for using DFT instead of other methods is mainly due to the size of the compounds which makes multireference calculations prohibitively expensive, but also to make comparisons with previously calculated DFT results. The first chapter presents the basic concepts of electronic structure theory and the chemical properties of the actinides and lanthanides. The theoretical foundation of DFT and the consequences of relativity are also introduced. In the second chapter the bonding in mixed MUCl6, MUCl8 2-, NpReCl8 2- and PuOsC NpReCl8 2- (M = Mo, W) systems is investigated and compared with previous work on the M2Cl6, M2C NpReCl8 2- U2Cl6 and U2C NpReCl8 2- systems. The study shows that the total bonding energy in the mixed compounds is the average of the two “pure” compounds. The third chapter deals with systems of plenary or lacunary Keggin phosphomolybdate coordination to actinide (Th), lanthanide (Ce, La, Lu) and transition metal (Hf, Zr) cations: [PMo12O40]3-, [PMo11O39]2 14-, [PMo12O40]2 6- and [PMo11O39][PMo12O40]10-. These large, highly anionic systems proved to be very challenging computationally. The main result of the study confirms that the bonding is ionic and that there are few differences in the behaviour of the transition metals. In the fourth chapter the electronic spectrum of NpO2 2+, NpO2Cl4 2- and NpO2(OH)4 2- is calculated using time dependent DFT. TDDFT has proved adequate for the uranium analogues of these systems and this extends previous work on f0 systems to f1 systems. The results show that TDDFT is in poor agreement with both experimental results and multireference calculations for these compounds. In chapter five, group 15 and 16 uranyl analogues have been investigated. For the UE2 (E = O, S, Se, Te) analogues the geometry bends for all chalcogens heavier than O. The UE2 2+ analogues remain linear all the way down group 16. In U(NCH3)2 2+ the formation of a {pi} “back bone” along the axis of the molecule was noted. The {sigma}-bonding valence MOs stabilize while the {pi} MOs are destabilized down group 15 and 16. Chapter six is a summary of the results in this thesis and an outlook on potential future work.
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Mossman, Sally Patricia. "Investigations into the biology and molecular biology of alphaherpesvirus saimiri." Thesis, University of Liverpool, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291968.
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Cooke, James C. "Molecular investigations of phaeochromocytoma tumourigenesis in von Hippel-Lindau disease." Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417558.
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