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Khoo, Benjamin Cheng Choon. "Clinical and phantom-based studies of the validity and value of quantitative radiological hip structural analysis". University of Western Australia. School of Surgery and Pathology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0189.
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[Truncated abstract] Areal bone mineral density (BMD) is measured routinely in the clinic by a quantitative radiological technique, dual-energy X-ray absorptiometry (DXA). BMD is used widely to assess non-invasively but indirectly the mechanical fragility of bone and consequently is able to predict fracture risk. While BMD correlates well with in vitro measurements of bone strength it does not directly measure a mechanical property; half of incident minimally traumatic fractures in women occur with BMD values above the World Health Organisation defined threshold for osteoporosis. This arises partly because the mechanical strength of bone is dependent on its structural geometry and material strength as well as bone mineral mass. Essentially, bones fracture when load stresses exceed the mechanical capacity of the material to withstand them. The structural geometry (i.e., the amount of bone tissue and its complex three-dimensional arrangement within the macroscopic bone envelope) defines the stresses produced by a given load, while the intrinsic load capacity of the material is defined by the composition and microstructure of the bone tissue itself. Hip structural analysis (HSA) is a technique that elucidates the structural geometric component of bone strength; essentially combining information available from conventional DXA images of the proximal femur with a biomechanical beam model based on the stresses arising in a combination of pure bending and axial compression. A version of HSA has recently been released commercially, and has obtained US Food and Drug Administration approval for its clinical application. ... Given the acknowledged limitations of the HSA method when applied to 2-D projection images, a 3-D approach to structural geometry, using imaging modalities such as pQCT and QCT or a recently introduced version of DXA that mimics QCT, is indicated for the future. With that in mind and the possibility of the anthropometric phantom being adopted for future accuracy and precision assessments, improvements in the design of this phantom are recommended. Studies to better understand and verify Contents v the relevance of the 'local buckling' phenomenon as a structural geometric factor in the genesis of macro-fractures are also recommended. In summary, it is essential that superior (compared to BMD) non-invasively determined clinical predictors of bone fragility leading to fracture be investigated. Structural geometric variables are potential candidates. This has led to consideration of; (i) the need to progress beyond BMD for a more sensitive and specific bone strength measurement; (ii) theoretical advantages of structural geometry over BMD; (iii) limitations of the current HSA technique based on DXA, including those introduced by its restrictive assumptions; (iv) the value of HSA in longitudinal studies, exemplified by the 'normal' but rapid skeletal changes seen in human lactation, with possible implications for an analogous study of the menopause; and (v) an investigation, using a custom-designed anthropometric phantom, of the adaptation of HSA to certain emerging imaging modalities and methods able to resolve bone structural geometry in three dimensions.
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Caliskan, Fatma. "Electromagnetic Analysis of Planar Layered Structures". Diss., Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/5116.
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ELECTROMAGNETIC ANALYSIS OF PLANAR LAYERED STRUCTURES
Fatma Caliskan
169 pages
Directed by Dr. Andrew F. Peterson
The electrical design of microelectronic devices and their packaging is complicated because of non-ideal attributes of the actual circuit realization. Electromagnetic modeling offers the possibility of accurately predicting the electrical performance of devices and reducing the cost associated with the design process. The proposed research concerns extensions of electromagnetic modeling techniques and their application to microelectronic package design. The method of moments (MoM) is utilized as a technique in modeling and analyzing these designs. Recently, an alternate approach called the locally corrected Nystrm method (LCN) has been applied to solve integral equations in electromagnetics. Recent research suggests that the LCN is well-suited for higher-order implementations and does not require cell-to-cell current continuity in the underlying representation. Thus it may offer advantages over the MoM, especially for problems involving complex 3-D structures. If cell-to-cell continuity is not required, nonconforming meshes may offer simpler geometrical modeling. In this proposal, we consider applying the above techniques to problems in package designs, which often involve multilayer structures, solid or perforated ground planes, embedded passive devices such as capacitors and spiral inductors, and interconnects in horizontal or vertical directions. Several examples will be used to illustrate the modeling.
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Behrens, Anna-Janina. "Fine structure of the HIV-1 glycan shield". Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:3cec0ef7-c305-411e-a76b-125d5e7e9954.
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The HIV-1 envelope glycoprotein trimer (Env) is covered by an extensive array of glycans that shield it from immune surveillance. The high density of glycans on the trimer surface imposes steric constraints that limit the actions of glycan processing enzymes, such that multiple under-processed structures remain on specific locations. These oligomannose-type glycans are recognized by broadly neutralizing antibodies (bNAbs) that are not thwarted by the glycan shield but, perhaps paradoxically, target it. In multiple studies, bNAbs have been shown to be capable of providing passive protection from viral challenge, making Env a focus of antibody-mediated vaccine design. Here, the development of a workflow for the semi-quantitative, site-specific N-glycosylation analysis of a soluble recombinant, native-like trimer mimic (BG505 SOSIP.664) is reported. The resulting data reveal a mosaic of dense clusters on the outer domain of Env and allow mapping the extremes of simplicity and diversity of glycan processing. Although individual sites usually minimally affect the global integrity of the glycan shield, examples are identified of how deleting certain glycans can subtly influence neutralization by bNAbs that bind at distant sites. Env is a trimer of heterodimers of gp120 and gp41, which is generated by cleavage of an endogenous protease. In this thesis, the detailed effect of protease cleavage on glycan processing is examined by comparing the site-specific N-glycosylation profiles of the native-like trimer mimic to the corresponding uncleaved pseudotrimer and the matched gp120 monomer. Trimer-associated glycan remodeling forms a localized subdomain of the native mannose patch. Furthermore, the glycosylation analysis of further Env immunogens â a glycan-depleted trimer and a flexibly-linked, uncleaved trimer (both based on BG505 SOSIP.664) â provides important insights into the robustness of the HIV-1 glycan shield and the Env maturation pathway. Overall, this thesis reveals how structural constraints shape Env glycosylation and the network of bNAb-targeted glycans that should be preserved on recombinant vaccine candidates.
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Vidimar, Vania. "Characterization of the anticancer properties of Ruthenium-derived compounds : mode of action, optimization and development of experimental tools". Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ105.
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Au cours des dernières années, une nouvelle classe de composés anticancéreux à base de ruthénium, appelés RDCs (Ruthenium-Derived Compounds), a été développé pour dépasser les limitations des agents chimiothérapiques contenants du platine. Contrairement à ces derniers, l’activité anticancéreuse des RDCs est en partie indépendante de l'interaction avec l'ADN. L’objectif principal de ma thèse a été ainsi de comprendre les mécanismes moléculaires quiinter viennent dans l’action anticancéreuse et antimétastatique des RDCs au-delà du dommage à l’ADN.J’ai démontré que le RDC11, contrairement au cisplatine, affecte les voies de signalisation de HIF-1 et mTOR, deux voies qui jouent un rôle clé dans le métabolisme cellulaire et qui sont souvent altérées dans les cellules cancéreuses.En parallèle, j’ai effectué un analyse structure/activité pour sélectionner des nouveaux RDCs ayant meilleures propriétés chimiques et pharmacologiques que le RDC11. Cette étude a permis d’identifier deux nouveaux RDCs qui réduisent la croissance tumorale in vivo avec un dosage beaucoup plus faible que le RDC11 et qui induisent la mort des cellules cancéreuses par une surproduction d'espèces réactives de l'oxygène et par l'activation de la caspase8. En conclusion, mes travaux ont conduit à l’identification de nouveaux mécanismes à la base de l’activité anticancéreuse du RDC11 qui pourraient expliquer certaines différences entre le mode d’action du RDC11 et du cisplatine. De plus, ils ont permis de sélectionner deux nouveaux RDCs plus efficaces que le RDC11. Ces résultat sont un impact important pour le développement de nouvelles thérapies anticancéreuses ou antimétastatiquesIn recent years, a new class of anticancer ruthenium-based drugs, called RDCs (Ruthenium-Derived Compounds), has been developed to overcome the limitations of classic platinum chemotherapeutics. Unlike the latter, the anticancer activity of RDCs is in part independent of DNA interaction. Therefore, the main objective of my thesis work was to elucidate the molecular mechanisms involved in RDCs anticancer and antimetastatic activity beyond DNA damage. I demonstrated that RDC11, unlike cisplatin, affects the HIF-1 and mTOR signaling pathways, two pathways that play a key role in cellular metabolism and that are frequently altered in cancer cells. In parallel, I performed a structure/activity analysis to select new RDCs endowed with better chemical and pharmacological properties than RDC11. This study allowed to identify two novel RDCs that reduce tumor growth in vivo at much lower doses than RDC11 and that induce cancer cell death by an overproduction of reactive oxygen species and activation of caspase 8. In conclusion, my work led to the identification of new mechanisms underlying the anticancer activity of RDC11 that could explain some of the differences between the mode of action of RDC11 and cisplatin. In addition, it allowed to select two novel RDCs which are more effective than RDC11. These results have a significant impact on the development of new anticancer or antimetastatic therapies
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Zeffman, Amanda Tracey. "NMR analysis of the three-dimensional structure of the HIV-1 encapsidation signal". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621828.
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Abrams, Nicola Elaine. "The structure & desorption of molecular species from single crystal metal surfaces". Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387862.
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Dubanchet, Vincent. "Modélisation et contrôle d’un robot spatial flexible pour la capture d’un débris en rotation". Thesis, Toulouse, ISAE, 2016. http://www.theses.fr/2016ESAE0022/document.
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Les débris en orbite sont actuellement une source de préoccupation majeure pour les acteurs du spatial et pour le reste de la population, comme en témoignent les articles de presse et les œuvres cinématographiques sur le sujet. En effet, la présence de ces objets menace directement les astronautes en mission et les satellites en opération. Parmi les nombreuses options déjà envisagées pour les traiter, cette thèse se concentre sur l’approche robotique, en proposant des outils et des méthodes de modélisation et de contrôle pour un satellite chasseur équipé d’un bras manipulateur. Des modèles dynamiques et des schémas de simulation optimisés sont ainsi développés pour tout système multi-corps constitué d’une base mobile supportant un nombre quelconque d’appendices rigides ou flexibles. Par la suite, les trajectoires de capture sont générées en conservant la continuité en accélération avec le mouvement naturel du point cible, dans le but de saisir aussi délicatement que possible le débris en rotation. Le suivi de cette trajectoire par l’effecteur du robot chasseur est alors assuré par une loi de contrôle à deux niveaux, dont le réglage repose sur la synthèse H1 structurée. Une étude de robustesse est également mise en place pour assurer la stabilité et les performances du système en boucle fermée, malgré les changements de configuration du bras. Enfin, la validation des travaux de thèse est réalisée par voie numérique avec un simulateur haute-fidélité, et par voie pratique avec un banc d’essais robotique incluant des composants physiques en temps réelOn-orbit debris are currently causing deep concern for space agencies, related companies, and also among the population. ¿is is evidenced by the numerous scientific articles and recent movies on the matter. Indeed, these objects pose a serious threat for the astronauts on mission and for operational satellites. Among the various technical concepts already designed to address these threats, this thesis focuses on space robotics. Tools and methods are thus introduced for the modeling and control of a chaser satellite equipped with a manipulator. Dynamic models and optimized simulation schemes are developed to handle any multi-body system made up of amoving base embedding various appendages, either rigid or flexible. ¿en, a trajectory planner is designed to ensure acceleration continuity with the natural motion of the debris in order to perform a soft capture. ¿is reference trajectory is tracked by the end-effector of the chaser using a two-level control law, which is tuned by the structured H1 synthesis. A robustness analysis is also presented to assess the stability and the performances of the closed-loop system with respect to the motion of the robotic arm. Finally, the outcome of the thesis is validated by a twofold approach: by numerical means with a highfidelity simulator, and by practical ones with a robotic test bench including physical components in real time
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Cirino, Nick Mario. "Structure-function analysis of the ribonuclease-H domain of human immunodeficiency virus type-1 reverse transcriptase". Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062096231.
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Mathu, Alexander Muchugia Nganga. "Structural analysis of effects of mutations on HIV-1 subtype C protease active site". Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004073.
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HIV/AIDS is a global pandemic that poses a great threat especially in Sub-Saharan Africa where the highest population of those infected with the virus is found. It has far reaching medical, socio-economic and scientific implications. The HIV-1 protease enzyme is a prime therapeutic target that has been exploited in an effort to reduce morbidity and mortality. However problems arise from drug toxicity and drug-resistant mutations of the protease which is a motivation for research for new, safer and effective therapies. Evidence exists to show that there are significant genomic differences in Subtype B and C that have a negative effect on the intrinsic binding of inhibitors. It is imperative to look at all perspectives from epidemiological, molecular to the pharmacological ones so as to achieve rational design of therapeutic agents. This study involved the use of in silico structural analysis of the effects of mutations in the active site. The data was provided by the National Institute of Communicable Diseases consisting of HIV-1 Subtype C protease sequences of 29 infants exhibiting drug-resistance to ritonavir and lopinavir. The major active site mutations causing drug resistance identified in this study were M46I, I54V and V82A using the Stanford HIV database tool. Homology modeling without extra restraints produced models with improved quality in comparison to those with restraints. MetaMQAPII results differed when models were visualized as dimers giving erroneous modeled regions in comparison to monomers. A broader study with a larger dataset of HIV-1 subtype C protease sequences is required to increase statistical confidence and in order to identify the pattern of drug resistant mutations. Homology modeling without extra restraints is preferred for calculating homology models for the HIV-1 subtype C. Further investigations needs to be done to ascertain the accuracy of validation results for dimers from MetaMQAPII as it is designed for evaluation of monomers.
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Tie, Yunfeng. "Crystallographic Analysis and Kinetic Studies of HIV-1 Protease and Drug-Resistant Mutants". Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/2.
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HIV-1 protease is the most effective target for drugs to treat AIDS, however, the long-term therapeutic efficiency is restricted by the rapid development of drug resistant variants. To better understand the molecular basis of drug resistance, crystallographic and kinetic studies were applied to wild-type HIV-1 protease (PR) and drug-resistant mutants, PRV82A, and PRI84V, in complex with substrate analogues, the current drug saquinavir and the new inhibitor UIC-94017 (TMC-114). UIC-94017 was also studied with mutants PRD30N and PRI50V. The drug-resistant mutations V82A, I84V, D30N and I50V participate in substrate binding. Eighteen crystal structures were refined at resolutions of 0.97-1.60A. The high accuracy of the atomic resolution crystal structures helps understand the reaction mechanism of HIV-1 PR. Different binding modes are observed for different types of inhibitors. The substrate analogs have more extended interactions with PR subsites up to S5-S5', while the clinical inhibitors maximize the contacts within S2-S2'. Hydrophobic interactions are the major force for saquinavir binding since it was designed with enhanced hydrophobic groups based on substrate side-chains. In contrast, the new clinical inhibitor UIC-94017 was designed to mimic the hydrogen bonds between substrates and PR. UIC-94017 forms polar interactions with the PR main-chain atoms of Asp29/30, which have been proposed to be critical for its potency against resistant HIV. The mutants showed different structural and kinetic effects, depending on the inhibitor and location of the mutations. The observed structural changes were consistent with the relative inhibition data. Both PRI84V and PRI50V lost favorable hydrophobic interactions with inhibitor compared with PR. Similarly, in PRD30N the UIC-94017 had a water-mediated interaction with the side-chain of Asn30 rather than the direct interaction observed in PR. However, PRV82A compensated for the mutation by shifts of the backbone of Ala82. Furthermore, the complexes of PRV82A showed smaller shifts relative to PR, but more movement of the peptide analog, compared to complexes with clinical inhibitors. The structures suggest that substrate analogs have more flexibility than the drugs to accommodate the structural changes caused by mutation, which may explain how HIV can develop drug resistance while retaining the ability of PR to hydrolyze natural substrates.
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Nnyanzi, David. "The Role of Structural Factors in HIV Transmission in Uganda: a Multi-Level Analysis". Thesis, Boston College, 2011. http://hdl.handle.net/2345/2365.
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Thesis advisor: John B. WilliamsonSince the early 1980s, Uganda has been in the spotlight of global concerns about the HIV/AIDS epidemic that has almost brought the country to its knees. Consequently, a number of social epidemiologists and researchers from different social science fields have, over the past two and half decades, focused their attention on Uganda, attempting to identify the risk factors that expose people to HIV infection in order to inform intervention policy. Although studies coming out of this effort have provided important insights into risks of HIV infection, they have been criticized for almost entirely focusing on individual behavioral factors, such as prostitution and inconsistent condom use, as the primary causal factors of HIV infection, without comprehending the contextual background in which HIV infection takes place. Using the 2000/01 Uganda Demographic and Health Survey and employing multilevel logistic regression methods, I address this concern by investigating the influence of contextual factors on three behaviors related to the risk of HIV infection (HIV testing, multiple sexual partnering, and inconsistent condom use). Analyses reveal that educational attainment, socioeconomic status, and religion significantly predict HIV testing, multiple sexual partnering, and condom use for both men and women - and at both the individual and neighborhood levels. Analyses also reveal that age has an inverted U-shaped association with HIV testing and multiple sexual partnering for both men and women at the individual level. Despite important gains in slowing HIV infection rates over the past two decades, Uganda's increasing burden of the HIV/AIDS epidemic - amid faltering healthcare and other social services investments - is inevitable. It is apparent that there are formidable obstacles to effectively eradicating HIV/AIDS, unless essential social services - such as education, accessible healthcare services - are enhanced, and policies are introduced to improve socioeconomic status of individuals and entire neighborhoods
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Sociology
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Aschman, Nicolas. "Analyses structurelles et fonctionnelles de l'intéraction de la tétherine avec le récepteur ILT7". Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAV064/document.
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Le virus d'immunodéficience humaine 1 (VIH-1) cible spécifiquement les cellules CD4+ et empêche ainsi l'activation de cellules T cytotoxiques et B lors d'une infection secondaire. Le VIH-1 antagonise également la plupart des facteurs de restriction de l'hôte, y compris la tétherine. En l'absence de la protéine virale Vpu, la tétherine inhibe le relarguage de particules virales et provoque leur dégradation. La tétherine est également capable d'induire une signalisation pro-inflammatoire en réponse au bourgeonnement viral ainsi que d'activer le récepteur de cellules dendritiques ILT7. L'objectif principal de cette étude consistait à élucider les bases structurales de l'interaction entre la tétherine et ILT7. Malgré de nombreuses difficultés rencontrées dans la production recombinante de ILT7, on a pu déterminer la structure cristallographique du domaine N-terminale du récepteur. La ligation de la tétherine à l'ectodomaine entier de ILT7, mais pas au domaine N-terminal, a également été montré. Ces résultats constituent une base solide pour la caractérisation plus détaillée de l'interactionHuman immunodeficiency virus 1 (HIV-1) specifically infects CD4+ T cells, thereby preventing an appropriate activation of cytotoxic T cells and B cells in response to opportunistic pathogens. In addition, HIV-1 antagonises host restriction factors, including tetherin. In the absence of the viral protein Vpu, tetherin potently inhibits virus particle release from infected cells. Tetherin also triggers proinflammatory signaling upon sensing virus assembly, and activates the dendritic cell receptor ILT7. The principal objective of this thesis was to elucidate the structural details underlying the interaction of tetherin with ILT7. Despite difficulties in the production of recombinant ILT7, the crystal structure of the N-terminal ILT7 domain could be determined. Furthermore, binding of tetherin to full-length ILT7, but not to the N-terminal domain, could be confirmed by SPR. These results provide a solid basis for the more detailed characterisation of the interaction
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Münter, Sylvia Gabriele. "Analysing the role of a cellular mechanism in HIV infection and evaluation of novel antiviral compounds". Paris 11, 2004. http://www.theses.fr/2004PA112103.
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VIH est responsable du syndrome d'immunodéficience acquise (SIDA). L'étape fondamentale pour découvrir de nouvelles stratégies antivirales reste la compréhension de la pathogénie du SIDA ainsi que les mécanismes moléculaires de l'interaction du virus avec l'hôte. Une caractéristique des lentivirus est le transport actif du complexe de pré-intégration (PIC) dans le noyau de la cellule hôte. Le mécanisme de ce transport n'est pas connu, mais Vpr (viral protein R) pourrait être impliqué dans ce processus. Vpr reste associée au PIC jusqu'à la translocation du génome à travers la membrane nucléaire. Par ailleurs, il a été montré que Vpr est capable d'intéragir avec le complexe du pore nucléaire (NPC). Cela laisse soupçonner que cette interaction est à la base de l'import nucléaire du PIC. Il a également été montré que le cytosquelette joue un rôle prépondérant dans le transport de particules virales. Dans cette perspective, nous avons observé que la membrane nucléaire est entourée d'actine. Nous avons mis au point une nouvelle approche pour visualiser l'actine dans les cellules vivantes, ce qui nous a permis de visualiser un réservoir d'actine qui polymérise autour de l'enveloppe nucléaire ainsi que dans les invaginations de cette membrane. Nous avons montré que des enveloppes nucléaires isolées suffisent à initier la polymérisation de filaments d'actine in vitro. Nos résultats démontrent que la dynamique de l'actine périnucléaire est orchestrée par l'enveloppe nucléaire elle-même. C'est donc via la liaison de Vpr au NPC que le virus pourrait exploiter la présence de l'actine comme stratégie pour pénétrer dans le noyau en dépit de la barrière que constitue l'enveloppeHIV is the causative agent of the acquired immunodeficiency syndrome (AIDS). For the development of novel antiviral compounds, understanding of the lifecycle as well as the molecular mechanisms of host pathogen interactions are a prerequisite. A particular feature of lentiviruses is the active transport of the pre-integration complex (PIC) into the nucleus. The mechanism remains elusive, yet in the case of HIV Vpr is one candidate possibly implicated in the process. The protein stays associated to the PIC until nuclear translocation. It has been shown, that Vpr binds to the nuclear pore complex. This interaction might therefore be the link mediating import of the PIC. Moreover the cytoskeleton has been shown to play a major role in cytoplasmic transport of viral particles. In this context, we observed the nuclear envelope (NE) to be embedded in a perinuclear actin shell and displaying highly dynamic nuclear invaginations. We developed a novel approach to visualize actin inside living cells and thus we could show a high turnover actin pool around the NE and inside NE invaginations of living cells. Although reported in different cell types, the possible role of perinuclear actin filaments in the dynamic structural plasticity of the NE remains unresolved. We could show that NE-membranes alone are sufficient to nucleate polymerizing actin filaments in vitro, involving both actin recruitment to their surface, and filament growth. Accordingly, our results demonstrate that perinuclear actin dynamics are orchestrated by the NE itself. By binding of Vpr to the NPC, the virus could possibly exploit this pool of polymerizing actin as a new strategy to overcome the nuclear membrane
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St, Pierre Valessa. "Quality of Life in Older African American Men Living with HIV/AIDS: A Structural Equation Analysis". Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1308261830.
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James, Colin Hugh. "X-ray structure analysis of HIV-1 and SIV proteinase co-crystallized with isovaleryl pepstatin : conformational variability among inhibitor complexes". Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312710.
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Stephenson, James David. "Structural analysis of the HIV-1 5' untranslated region RNA by single molecule FRET and molecular modelling". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610361.
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Royer, Loic. "Unraveling the Structure and Assessing the Quality of Protein Interaction Networks with Power Graph Analysis". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-62562.
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Molecular biology has entered an era of systematic and automated experimentation. High-throughput techniques have moved biology from small-scale experiments focused on specific genes and proteins to genome and proteome-wide screens. One result of this endeavor is the compilation of complex networks of interacting proteins. Molecular biologists hope to understand life's complex molecular machines by studying these networks. This thesis addresses tree open problems centered upon their analysis and quality assessment.
First, we introduce power graph analysis as a novel approach to the representation and visualization of biological networks. Power graphs are a graph theoretic approach to lossless and compact representation of complex networks. It groups edges into cliques and bicliques, and nodes into a neighborhood hierarchy. We demonstrate power graph analysis on five examples, and show its advantages over traditional network representations. Moreover, we evaluate the algorithm performance on a benchmark, test the robustness of the algorithm to noise, and measure its empirical time complexity at O (e1.71)- sub-quadratic in the number of edges e.
Second, we tackle the difficult and controversial problem of data quality in protein interaction networks. We propose a novel measure for accuracy and completeness of genome-wide protein interaction networks based on network compressibility. We validate this new measure by i) verifying the detrimental effect of false positives and false negatives, ii) showing that gold standard networks are highly compressible, iii) showing that authors' choice of confidence thresholds is consistent with high network compressibility, iv) presenting evidence that compressibility is correlated with co-expression, co-localization and shared function, v) showing that complete and accurate networks of complex systems in other domains exhibit similar levels of compressibility than current high quality interactomes.
Third, we apply power graph analysis to networks derived from text-mining as well to gene expression microarray data. In particular, we present i) the network-based analysis of genome-wide expression profiles of the neuroectodermal conversion of mesenchymal stem cells. ii) the analysis of regulatory modules in a rare mitochondrial cytopathy: emph{Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes} (MELAS), and iii) we investigate the biochemical causes behind the enhanced biocompatibility of tantalum compared with titanium.
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Bennett, A. E. "Structural analysis of an HIV-neutralizing protein and its complex with native viral gp120 : implications for antiviral drug design". Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596573.
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I present a three-dimensional structural analysis of (1) the simian immunodeficiency virus (SIV) gp120-gp41 envelope glycoprotein complex, (2) D1D2-Igαtp, a CD4-antibody construct with extreme HIV-neutralizing capability, and (3) the complex of D1D2-Igαtp with native SIV gp120, using cryo electron tomography and atomic force microscopy, in order to better understand structural determinants of HIV neutralization using this model system. Cryo electron tomographic density maps and atomic force micrographs of D1D2-Igαtp show that the 3-9 antibody-like units of this high-molecular-weight polymer appear to be more flexible than the 5-6 antibody arms of IgM, a naturally-occurring polymeric antibody that was analyzed in parallel. When imaged by cryo electron tomography in complex with the gp120-gp41 spikes of frozen-hydrated SIV virions, D1D2-Igαtp molecules were observed to bridge spikes within and between virions. Notably, these complexes were associated with an increased proportion of ruptured virions compared to control experiments. Further, inter-virus spike crosslinking was associated with close apposition of the membranes of the crosslinked virions, effectively neutralizing all spikes on the closely apposed surfaces by preventing access to the target cell surface. These effects suggest that the ratio of neutralized to CD4-liganded gp120 spikes can be much greater than unity, and imply that the potency of D1D2-Igαtp may be due to its flexibility more than to its polyvalence or steric bulk per se. These observations suggest polyvalence presented on a flexible scaffold as a key design criterion for small molecule and low-molecular-weight HIV entry inhibitor drugs.
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Zhao, Zhong. "Part I. Structure-function studies of adenylate kinase with unnatural amino acids. Part II. Structure-function studies of phosphatidylinositol-specific phospholipase C: Kinetic analysis and the roles of His-32 and Asp-274 /". The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu148794273980584.
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Yang, LIngchun. "NMR analysis of structural features of the HIV-1 nucleocapsid protein in response to mutation and interaction with RNA and drug candidates". Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2008. http://wwwlib.umi.com/cr/syr/main.
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Sheik-Amamuddy, Olivier. "Structural analysis of proteases from South African HIV-1 (subtype C) patients undergoing Lopinavir treatment, using comparative modeling, ligand-docking and molecular dynamics". Thesis, Rhodes University, 2017. http://hdl.handle.net/10962/4931.
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HIV is regarded as one of the most devastating infectious diseases of the last few decades, and has a high prevalence in South Africa, subtype C being the most common. Palliative measures used to fight HIV involve the use various types of inhibitors, including the use of HIV protease inhibitors. Representatives from this class of inhibitors are gradually losing their efficacy due to development of resistance mutations from HIV-1. In this study, compounds from the South African Natural Compound Database (SANCDB) were screened against HIV-1 protease models generated from protease protein sequences belonging to 11 South African HIV patients before and after treatment with Lopinavir. The effect of Lopinavir on the alteration of drug-binding affinity before and after treatment is investigated by molecular docking of the protease against other FDA-approved drugs and detection of mutation types using the HIVdb tool. A network representation of hydrogen bonding between docked ligands and their receptor proteases has been developed and a profiling method of visualizing receptor-ligand docking energies at the local level is presented. Four potential HIV-1 protease inhibitors were identified from the list of 599 natural compounds on the basis of receptor conformation and binding free energy. Ligand stabilities were monitored by 20ns molecular dynamics runs using the GROMACS software.
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Schürig, Margitta Verfasser], i Wulf [Akademischer Betreuer] [Blankenfeldt. "Efficient expression of viral surface proteins by transient gene expression in Hi5 insect cells for functional and structural analysis / Margitta Schürig ; Betreuer: Wulf Blankenfeldt". Braunschweig : Technische Universität Braunschweig, 2019. http://d-nb.info/1176701274/34.
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Zheng, Yue. "Identification d'une plante médicinale africaine par le DNA barcoding et étude de composés à activité anti-HIV de cette plante". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ095/document.
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Mon travail de thèse porte sur l'identification d'un arbre médicinal africain par le DNA barcoding et l'étude de composés à activité anti-VIH de cet arbre. Une première analyse de la séquence du marqueur ITS2 déterminée à partir d'ADN extrait de copeaux de bois a suggéré que la plante pourrait appartenir au genre Cassia ou au genre apparenté Senna. En analysant la séquence de ce marqueur ITS2 et aussi celle du trnHpsbA spacer d'une cinquantaine d'espèces des genres Cassia et Senna j'ai pu identifier la plante comme étant Cassia abbreviata. L'alignement de ces séquences m'a permis d'identifier, pour les deux marqueurs,des structures particulières spécifiques aux espèces du genre Cassia, permettant donc de les différencier des espèces du genre Senna. J'ai utilisé ces alignements pour effectuer une étude phylogenetique qui illustre que,pour les deux marqueurs, les Cassia forment en effet un clade bien séparé du clade des Senna qui peut être divisé en plusieurs sous-clades. Dans un deuxième temps j'ai étudié les effets anti-VIH de l'extrait alcoolique ainsi que de 57 composés purifiés obtenus au laboratoire. L'extrait brut ainsi qu'un des composés purifiés, le piceatannol, ont montré un grand spectre d’activités antivirales pour le VIH et le virus de l’herpès. Ils inhibent,à un stade précoce, l'infection par le VIH de lignées cellulaires de référence et d'isolats cliniques, ceci indépendamment de l'utilisation du co-récepteur (IC50: 10.47-40.77 μg/ml, CC50>1000 μg/ml; IC50: 8.04-47.46 μM, CC50>300 μM, respectivement). Ni l'un ni l'autre n'a d'effet sur CD4 et CCR5/CXCR4. L'extrait brut,mais pas le piceatannol, bloque l'interaction CD4-gp120, suggérant que l'extrait brut cible gp120 alors que le piceatannol agit comme un inhibiteur non-spécifique d'attachement du virus. Aussi, dans un modèle in vitro de tract génital femelle, le piceatannol inhibe l'infection de cellules cibles TZM-Bl par le VIH et n'active pas les cellules PBMCs, suggérant qu'il pourrait être un bon candidat comme microbicide. D'autres composés à activité anti-VIH dans l'extrait comportent l'acide oléanolique, l'acide palmitique, la taxifoline, ainsi que troiscomposés dont la structure est en train d'être élucidéeMy thesis project deals with the identification, by DNA barcoding, of an African medicinal plant and the study of anti-HIV compounds from this plant. A first analysis of the ITS2 marker sequence determined from DNA extracted from the wood suggested that the plant could belong to the Cassia or the related Senna genus. A further analysis of ITS2 as well as of trnH-psbA spacer sequences from about 50 species of the two genera allowed me to identify the plant as Cassia abbreviata. The sequence alignments, which reveal unique features present in the Cassia but not the Senna sequences, were used to construct phylogenetic trees showing the clear separation of the species of the Cassia and the Senna genus. The two markers therefore allow a quick discrimination between the species of the Cassia and the Senna genus and appear to be excellent barcode markers for identification of these species. Following the identification of the plant I have tested the crude ethanol extract as well as 57 purified compounds from the plant for an anti-HIV activity. The extract, as well as one of the compounds, namely piceatannol, showed a broad spectrum of antiviral activities for HIV and HSV. They inhibited HIV-1 infection at the early stage against various reference strains and resistant clinical isolates independent of the co-receptor usage (IC50: 10.47-40.77 μg/ml, CC50>1000 μg/ml; IC50: 8.04-47.46 μM,CC50>300 μM, respectively). Neither the crude extract nor piceatannol had an effect on CD4 and CCR5/CXCR4. The crude extract blocked CD4-gp120 interaction while piceatannol did not, indicating that CE may target gp120 and piceatannol may act as a non-specific viral attachment inhibitor. Moreover, piceatannol inhibited HIV infection of TZM-Bl target cells in an in vitro female genital tract model and did not activate PBMCs, suggesting that it may represent a good candidate as microbicide. Other anti-HIV compounds found in Cassia abbreviata include oleanolic acid, palmitic acid, taxifolin and three other compounds the structure of which is presently being elucidated
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Delmotte, Nausicaa. "Identifications croisées multi-longueurs d'ondes : Application aux populations stellaires des nuages de Magellan et aux étoiles jeunes de notre galaxie". Phd thesis, Université Louis Pasteur - Strasbourg I, 2003. http://tel.archives-ouvertes.fr/tel-00004238.
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Cette thèse bénéficie de la mise à disposition publique récente des grands relevés infrarouges et visibles et s'inscrit dans le cadre de l'Observatoire Virtuel émergent. Nous avons réalisé un "Master Catalogue of stars towards the Magellanic Clouds" (MC2) basé sur l'identification croisée multi-longueur d'onde des catalogues de sources ponctuelles DENIS, 2MASS, GSC-II et UCAC. D'importants résultats sur la précision et la calibration astro-photométriques de ces catalogues ont été établis. Le MC2 est accessible en ligne au travers d'une interface web spécialement conçue pour gérer sa nature composite. Nous avons produit des vues multi-spectrales du GNM, où ses populations stellaires variées se distinguent de façon remarquable dans les diagrammes couleur-couleur et couleur-magnitude construits à partir de magnitudes à la fois visibles et infrarouges. Nous avons calibré les magnitudes absolues des étoiles de type B dans le proche-infrarouge, en fonction de leur type spectral. Nous avons combiné des mesures de distance de grande qualité basées sur les données Hipparcos avec la photométrie homogène des sources ponctuelles proche-infrarouges 2MASS. Les données ont été corrigées de l'extinction et nous avons évalué par le biais de simulations la contribution de divers erreurs de mesure et effets physiques (binarité, rotation) à la dispersion observée sur la calibration. C'est une étape nécessaire à la détermination de la structure du disque jeune Galactique et des distances et propriétés de jeunes amas ouverts découverts par les grands relevés infrarouges tels 2MASS. Nous avons commencé une analyse morphologique et multi-longueur d'onde de régions ionisées et de leurs étoiles dans le GNM, imagées en bande étroite. L'interaction réciproque des étoiles massives avec le milieu interstellaire environnant permet d'approfondir l'histoire de formation stellaire locale et le contenu stellaire de ces régions ainsi que d'obtenir un schéma de leur évolution dynamique.
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Mu-ChunYang i 楊牧君. "Stress Analysis Application of Additive Manufactured Hip Prosthesis with Porous Structures". Thesis, 2018. http://ndltd.ncl.edu.tw/handle/r43mws.
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碩士國立成功大學
材料科學及工程學系
106
For patients recovering from total hip replacement surgery, the stress shielding effect, which is caused by a difference in Young’s modulus between the hip prosthesis and human bone, can lead to prosthesis loosening or dislocation. Additive manufacturing technology, such as electron beam melting (EBM), is mature enough to fabricate porous structures made of Ti6Al4V alloy. This thesis studies the mechanical properties of porous structures and their application to artificial hip prostheses using the finite element method. The study is divided into two parts. The first part establishes the simulation method and the second part discusses the application of the simulation results to hip prostheses. The simulation and experimental results of the Young’s modulus of carbon steel show a very small deviation of about 0.7%. Porous samples with various pore geometries show the trend that higher relative density is accompanied by higher Young’s modulus in both simulation and experiments. Several unit cell structures were chosen for further mechanical simulation. The diagonal unit cell was found to be the most stable. Various compression load, Young’s modulus of cement, hip prosthesis outlook were simulated based on ISO 7206-4. The results show that when the porous structures were applied in a hip prosthesis, the stress concentration value decreased.
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Huang, Yi-Han, i 黃奕涵. "Analysis of WLAN Dual - band Antenna with HIS Structure". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/22862421143171455582.
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碩士國立雲林科技大學
電機工程系碩士班
101
In recently years, smart phones and tablet PCs have become more and more popular because of the fast development of wireless networks. Because of the almost ubiquitous wireless local area networks (WLANs) in urban areas, more and more wireless products support the communication through WLANs. These wireless products will be inevitable to generate electromagnetic waves that may cause adverse effects on human bodies. Hence, how to reduce undesirable electromagnetic radiations has become an important research topic in the area of electromagnetic compatibility (EMC). The thesis proposes a dual-band electromagnetic protection sheet that can be used for the 2.45- and 5.25-GHz WLAN applications. The proposed electromagnetic protection sheet, which is a high-impedance surface (HIS), can be used in conjunction with a dual-band antenna to reduce the radiation in undesired directions while not to downgrade the radiation in the desired direction. The dual-band monopole antenna and dual-band HIS were both designed using the simulator Ansoft HFSS. The reflection coefficient, radiation pattern, total radiated power (TRP), horizon radiated power (HRP), and near-horizon partial radiated power (NHPRP) are all simulated with and without the presence of the HIS. To verify that the designed dual-band monopole antenna in the presence of the dual-band HIS can indeed reduce adverse effects on human bodies, we established a human-head model to simulate the specific absorption rate (SAR). The resulting SAR values are found to be lower than the limits specified by the regulations. In comparison with other types of electromagnetic protection sheets, it is also found that HISs are more valuable in practical applications.
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Shang, Lei active 2013. "Improving secondary structure prediction with covariation analysis and structure-based alignment system of RNA sequences". 2013. http://hdl.handle.net/2152/23111.
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RNA molecules form complex higher-order structures which are essential to perform their biological activities. The accurate prediction of an RNA secondary structure and other higher-order structural constraints will significantly enhance the understanding of RNA molecules and help interpret their functions. Covariation analysis is the predominant computational method to accurately predict the base pairs in the secondary structure of RNAs. I developed a novel and powerful covariation method, Phylogenetic Events Count (PEC) method, to determine the positional covariation. The application of the PEC method onto a bacterial 16S rRNA sequence alignment proves that it is more sensitive and accurate than other mutual information based method in the identification of base-pairs and other structural constraints of the RNA structure. The analysis also discoveries a new type of structural constraint – neighbor effect, between sets of nucleotides that are in proximity in the three dimensional RNA structure with weaker but significant covariation with one another. Utilizing these covariation methods, a proposed secondary structure model of an entire HIV-1 genome RNA is evaluated. The results reveal that vast majority of the predicted base pairs in the proposed HIV-1 secondary structure model do not have covariation, thus lack the support from comparative analysis.
Generating the most accurate multiple sequence alignment is fundamental and essential of performing high-quality comparative analysis. The rapid determination of nucleic acid sequences dramatically increases the number of available sequences. Thus developing the accurate and rapid alignment program for these RNA sequences has become a vital and challenging task to decipher the maximum amount of information from the data. A template-based RNA sequence alignment system, CRWAlign-2, is developed to accurately align new sequences to an existing reference sequence alignment based on primary and secondary structural similarity. A comparison of CRWAlign-2 with eight alternative widely-used alignment programs reveals that CRWAlign-2 outperforms other programs in aligning new sequences with higher accuracy. In addition to aligning sequences accurately, CRWAlign-2 also creates secondary structure models for each sequence to be aligned, which provides very useful information for the comparative analysis of RNA sequences and structures. The CRWAlign-2 program also provides opportunities for multiple areas including the identification of chimeric 16S rRNA sequences generated in microbiome sequencing projects.text
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Patel, Siddharth. "Computational Analyses of Protein Structure and Immunogen Design". Thesis, 2015. http://etd.iisc.ernet.in/2005/3979.
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The sequence of a polypeptide chain determines its structure which in turns determines its function. A protein is stabilized by multiple forces; hydrophobic interaction, electrostatic interactions and hydrogen bond formation between residues. While the above forces are non-covalent in nature the protein structure is also stabilized by disulfide bonds. Structural features such as naturally occurring cavities in proteins also affect its stability. Studying factors which affect a protein’s structural stability helps us understand complex sequence-structure-function relationships, the knowledge of which can be applied in areas such as protein engineering.
The work presented in this thesis deals with various and diverse aspects of protein structure. Chapter 1 gives an overall introduction on the topics studied in this thesis. Chapter 2 focuses on a unique, non-regular, structural feature of proteins, viz. protein cavities. Cavities directly affect the packing density of the protein. It has been shown that large to small cavity creating mutations destabilize the protein with the extent of destabilization being proportional to the size of cavity created. On the other hand, small to large cavity filling mutations have been shown to increase protein stability. Tools which analyze protein cavities are thus important in studies pertaining to protein structure and stability. The chapter presents two methods which detect and calculate cavity volumes in proteins. The first method, DEPTH 2.0, focuses on accurate detection and volume calculation of cavities. The second method, ROBUSTCAVITIES, focuses on detection of biologically relevant cavities in proteins.
We then study another aspect of protein structure – the disulfide bond. Disulfide bonds confer stability to the protein by decreasing the entropy of the unfolded state. Previous studies which attempted to engineer disulfides in proteins have shown mixed results. Previously, disulfide bonds in individual secondary structures were characterized. Analysis of disulfides in α-helices and antiparallel β-strands yielded important common features of such bonds. In Chapter 3 we present a review of these studies. We then use MODIP; a tool that identifies amino acid pairs which when mutated to cysteines will most likely form a disulfide bond, to analyze disulfide bonds in parallel β-strands.
A direct way to analyze sequence-structure relationships is via mutating individual residues, evaluating the effect on stability and activity of the protein and inferring its effect on protein structure. Saturation mutagenesis libraries, where all possible mutations are made at every position in the protein contain a huge amount of information pertaining to the effect of mutations on structure. Making such libraries and screening them has been an extremely resource intensive process. We combine a fast inverse PCR based method to rapidly generate saturation mutagenesis libraries with the power of deep sequencing to derive phenotypes of individual mutants without any large scale screening. In Chapter 4 we present an Illumina data analysis pipeline which analyzes sequencing data from a saturation mutagenesis library, and derives individual mutant phenotypes with high confidence.
In Chapter 5 we apply the insights derived from structure-function studies and apply it to the problem of protein engineering, specifically immunogen design. The Human Immunodeficiency Virus adopts various strategies to evade the host immune system. Being able to display the conserved epitopes which elicit a broadly neutralizing response is the first step towards an effective vaccine. Grafting such an epitope onto a foreign scaffold will mitigate some of the key HIV defenses. We develop a computational protocol which grafts the broadly neutralizing antibody b12 epitope on scaffolds selected from the PDB. This chapter also describes the only experimental work presented in this thesis viz. cloning, expressing and screening the epitope-scaffolds using Yeast Surface Display. Our epitope-scaffolds show modest but specific binding. In a bid to improve binding, we make random mutant libraries of the epitope-scaffolds and screen them for better binders using FACS. This work is on-going and we aim to purify our epitope-scaffolds, characterize them biophysically and eventually test their efficacy as immunogens.
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Brucz, Kimberly Anne. "HIF prolyl 4-hydroxylase (PHD) activity and the structure analysis blueprints for development of specific substrate inhibitors /". 2005. http://wwwlib.umi.com/dissertations/fullcit/1426751.
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Thesis (M.S.)--State University of New York at Buffalo, 2005.Title from PDF title page (viewed on Feb. 3, 2006) Available through UMI ProQuest Digital Dissertations. Thesis adviser: L. Wayne Schultz. Includes bibliographical references.
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Baharuddin, Aida [Verfasser]. "Crystallographic analysis of the molecular evolution of HIV-1 proteinase : structure correlates with viral fitness / vorgelegt von Aida Baharuddin". 2007. http://d-nb.info/986506664/34.
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Song, Kyung Tae Kevin. "Saccharomyces cerevisiae: A Platform for Structure-activity Relationship Analysis and High-throughput Candidate Prioritization". Thesis, 2013. http://hdl.handle.net/1807/35690.
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The budding yeast Saccharomyces cerevisiae has been an invaluable model organism in contributing to the current understanding of cellular biology, owing mainly to its highly tractable genetic system and the completion of its genome sequencing in 1996. Indeed, these bolstered the development of novel methods that have provided great insights into genetic and protein networks in human cells. With the large collection of datasets, S. cerevisiae also became an ideal platform for investigating the mechanism of action of novel compounds. The first part of my thesis uses a validated chemogenomic assay to investigate the mechanism of action of structurally related novel DNA-damaging agents, delineating valuable structure-activity relationship in the process. The second part describes the development of a method that uses drug-induced wild-type growth dynamic to characterize novel compounds, which, in combination with the chemogenomic assay, may complement existing high throughput screening experiments to improve the current drug development process.
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Royer, Loic. "Unraveling the Structure and Assessing the Quality of Protein Interaction Networks with Power Graph Analysis". Doctoral thesis, 2010. https://tud.qucosa.de/id/qucosa%3A24399.
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Molecular biology has entered an era of systematic and automated experimentation. High-throughput techniques have moved biology from small-scale experiments focused on specific genes and proteins to genome and proteome-wide screens. One result of this endeavor is the compilation of complex networks of interacting proteins. Molecular biologists hope to understand life's complex molecular machines by studying these networks. This thesis addresses tree open problems centered upon their analysis and quality assessment.
First, we introduce power graph analysis as a novel approach to the representation and visualization of biological networks. Power graphs are a graph theoretic approach to lossless and compact representation of complex networks. It groups edges into cliques and bicliques, and nodes into a neighborhood hierarchy. We demonstrate power graph analysis on five examples, and show its advantages over traditional network representations. Moreover, we evaluate the algorithm performance on a benchmark, test the robustness of the algorithm to noise, and measure its empirical time complexity at O (e1.71)- sub-quadratic in the number of edges e.
Second, we tackle the difficult and controversial problem of data quality in protein interaction networks. We propose a novel measure for accuracy and completeness of genome-wide protein interaction networks based on network compressibility. We validate this new measure by i) verifying the detrimental effect of false positives and false negatives, ii) showing that gold standard networks are highly compressible, iii) showing that authors' choice of confidence thresholds is consistent with high network compressibility, iv) presenting evidence that compressibility is correlated with co-expression, co-localization and shared function, v) showing that complete and accurate networks of complex systems in other domains exhibit similar levels of compressibility than current high quality interactomes.
Third, we apply power graph analysis to networks derived from text-mining as well to gene expression microarray data. In particular, we present i) the network-based analysis of genome-wide expression profiles of the neuroectodermal conversion of mesenchymal stem cells. ii) the analysis of regulatory modules in a rare mitochondrial cytopathy: emph{Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes} (MELAS), and iii) we investigate the biochemical causes behind the enhanced biocompatibility of tantalum compared with titanium.
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Chen, Langtao. "Essays on Health Information Technology: Insights from Analyses of Big Datasets". 2016. http://scholarworks.gsu.edu/cis_diss/60.
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The current dissertation provides an examination of health information technology (HIT) by analyzing big datasets. It contains two separate essays focused on: (1) the evolving intellectual structure of the healthcare informatics (HI) and healthcare IT (HIT) scholarly communities, and (2) the impact of social support exchange embedded in social interactions on health promotion outcomes associated with online health community use. Overall, this dissertation extends current theories by applying a unique combination of methods (natural language processing, machine learning, social network analysis, and structural equation modeling etc.) to the analyses of primary datasets.
The goal of the first study is to obtain a full understanding of the underlying dynamics of the intellectual structures of HI and its sub-discipline HIT. Using multiple statistical methods including citation and co-citation analysis, social network analysis (SNA), and latent semantic analysis (LSA), this essay shows how HIT research has emerged in IS journals and distinguished itself from the larger HI context. The research themes, intellectual leadership, cohesion of these themes and networks of researchers, and journal presence revealed in our longitudinal intellectual structure analyses foretell how, in particular, these HI and HIT fields have evolved to date and also how they could evolve in the future. Our findings identify which research streams are central (versus peripheral) and which are cohesive (as opposed to disparate). Suggestions for vibrant areas of future research emerge from our analysis.
The second part of the dissertation focuses on comprehensively understanding the effect of social support exchange in online health communities on individual members’ health promotion outcomes. This study examines the effectiveness of online consumer-to-consumer social support exchange on health promotion outcomes via analyses of big health data. Based on previous research, we propose a conceptual framework which integrates social capital theory and social support theory in the context of online health communities and test it through a quantitative field study and multiple analyses of a big online health community dataset. Specifically, natural language processing and machine learning techniques are utilized to automate content analysis of digital trace data. This research not only extends current theories of social support exchange in online health communities, but also sheds light on the design and management of such communities.
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Γαλανάκης, Πέτρος. "Αποτίμηση των καθοριστικών παραγόντων της δομής και της αλληλεπίδρασης πεπτιδικών τμημάτων της HIV-1 gp120 V3 περιοχής και του CCR5 συνυποδοχέα των Τ-λεμφοκυττάρων με χρήση φασματοσκοπίας NMR". Thesis, 2009. http://nemertes.lis.upatras.gr/jspui/handle/10889/4107.
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Η παρεμπόδιση της μόλυνσης ενός κυττάρου από τον HIV επιτυγχάνεται ή με αναστολή της αλληλεπίδρασης της ιικής gp120 με τους CD4 υποδοχείς των κυττάρων, είτε παρεμποδίζοντας τη δράση της gp41 ή τέλος αποτρέποντας τη σύζευξη της gp120 με τους CXCR4 και CCR5 υποδοχείς των χημειοκινών. Ο ρόλος όμως των χημειοκινών και των υποδοχέων τους στη διαδικασία μετάδοσης σημάτων, μέσω των οποίων ενεργοποιούνται αποπτωτικοί μηχανισμοί υγιών, μη μολυσμένων από τον HIV κυττάρων, καθιστά την gp120-CCR5/CXCR4 αλληλεπίδραση ιδιαίτερα θελκτικό επιστημονικά στόχο για το σχεδιασμό αναστολέων του κύκλου αναπαραγωγής του ιού. Σύμφωνα με πλήθος ανοσολογικών, φυσικοχημικών και δομικών μελετών η PND V3 περιοχή της gp120 και το εξωκυττάριο αμινο-τελικό πεπτιδικό τμήμα του CCR5 συνυποδοχέα αποτελούν τις κυρίως εμπλεκόμενες περιοχές στην αλληλεπίδραση των δύο πρωτεϊνών. Η μεταβλητότητα της PND V3 ακολουθίας και ο συσχετισμός της με την υιοθετούμενη διαμόρφωση, η σύνδεση της θέσης και του είδους των αμινοξέων με την ένταση της αλληλεπίδρασης και η συνάρτηση του ιικού τροπισμού με τη βιολογικά ενεργή διαμόρφωση των πεπτιδίων αποτελούν θεμελιώδη στάδια στη διαδικασία κατανόησης του μηχανισμού αλληλεπίδρασης της gp120 με τον CCR5 κυτταρικό συνυποδοχέα και των παραγόντων που την καθορίζουν. Προς αυτή την κατεύθυνση εστιάστηκε και το ενδιαφέρον της διατριβής έχοντας ως πρωτογενείς στόχους την αποτίμηση των καθοριστικών παραγόντων της αλληλεπίδρασης χρησιμοποιώντας πεπτιδικά τμήματα των πρωτεϊνών, τον προσδιορισμό του είδους της και την επίλυση της δομής των συγκεκριμένων τμημάτων μέσω Φασματοσκοπίας Πυρηνικού Μαγνητικού Συντονισμού.
Όπως ήταν αναμενόμενο για ελεύθερα, μικρά σε μέγεθος μόρια που είναι διαλυμένα σε νερό, τα PND V3 πεπτίδα εμφάνισαν την ιδιότητα της διαμορφωτικής ελευθερίας αλλά παρουσίασαν σημαντικό αριθμό NOE συζεύξεων, γεγονός το οποίο επέτρεψε τη σύγκλισή τους προς μία συγκεκριμένη διαμόρφωση. Η διαμόρφωση τύπου U, η οποία είχε παρατηρηθεί στις κρυσταλλικές δομές συμπλόκων της gp120, διατηρείται ανεξαρτήτως της παρουσίας του CCR5. Τα αποτελέσματα των πειραμάτων της φασματοσκοπίας NMR υποδεικνύουν την ύπαρξη ασθενούς ηλεκτροστατικής αλληλεπίδρασης μεταξύ των PND V3 πεπτιδίων και του CCR5Nt. Η συμμετοχή των πεπτιδικών τμημάτων του CCR5Nt στην αλληλεπίδραση αυξάνει προοδευτικά και φαίνεται να είναι ανάλογη του αριθμού των θετικά φορτισμένων αμινοξέων της ακολουθίας των PND V3 πεπτιδίων και προφανέστατα εξαρτώμενη από την κατιονική τους δύναμη.
Τα συμπεράσματα της διατριβής σε συνδυασμό με εκείνα που παράγονται από πλήθος βιολογικών, βιοχημικών και φυσικοχημικών μελετών παράγουν νέα δεδομένα, τα οποία δύναται να χρησιμοποιηθούν στον ορθολογικό σχεδιασμό αναστολέων με αυξημένη συγγένεια δέσμευσης στον συνυποδοχέα CCR5.The obstruction of a cell infection by HIV is succeeded either by inhibiting the interaction between the viral gp120 and the CD4 cell receptors or by preventing the gp41 action and deterring the conjuction of gp120 with the CXCR4 and CCR5 chemokine receptors. The role that chemokines and their receptors play at the process of signal transmission, through which the apoptotic mechanisms of non HIV infected cells are activated, appoints the gp120-CCR5/CXCR4 interaction as a highly attractive scientific target for the design of HIV-1 life cycle inhibitors. According to numerous immunological, physicochemical and structural studies the PND V3 region of gp120 and the extracellular N-terminal peptide fragment of CCR5 coreceptor constiture the primary regions that are involved in the interactions of occurring between the two proteins. The sequence variation of the PND V3 region and its correlation with the adopted conformation, the dependence of the position and type of amino-acid with the intensity of the interaction and the linkage of viral tropism with the peptides biologically active conformation comprise fundamental stages in the process of understanding the mechanism of gp120 – CCR5 interaction and the elements that designate it. The thesis interest was oriented towards this direction while its primary targets were the evaluation of the interaction determinants by using peptide fragments, the designation of the interaction type and the calculation of the specific peptides structures through the use of Nuclear Magnetic Resonance Spectroscopy. As expected for free peptides in solution, the peptides representing the PND V3 region of gp120 exhibit conformational flexibility, but they exhibited a large number of NOEs which allowed convergence to a specific conformation. The PND V3 peptides retain the U-turn conformation observed in the crystal structures of gp120 complexes independently of CCR5 presence. The interaction of different regions of the CCR5Nt peptide is gradually increasing proportionally to the positive charge increase in the V3 peptides. The data demonstrate that the PND V3 and CCR5Nt peptide sequences have propensities for interaction and that their binding and selectivity is determined by simple electrostatic attraction mechanisms. The thesis conclusions combined to those extracted by many biological, biochemical and physicochemical studies bring forth new data that can be used in the rational design of inhibitors that will exhibit increased binding affinity for CCR5 co-receptor.
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Jeffrey, Annah Mandu. "A control theoretic approach to HIV/AIdS drug dosage design and timing the initiation of therapy". Thesis, 2006. http://hdl.handle.net/2263/30379.
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Current research on HIV therapy is diverse and multi-disciplinary. Engineers however, were late in joining the research movement and as such, engineering literature related to HIV chemotherapy is limited. Control engineers in particular, should have risen to the challenge, as it is apparent that HIV chemotherapy and control engineering have a lot in common. From a control theoretic point of view, HIV chemotherapy is control of a time varying nonlinear dynamical system with constrained controls. Once a suitable model has been developed or identified, control system theoretical concepts and design principles can be applied. The adopted control approach or strategy depends primarily on the control objectives, performance specifications and the control constraints. In principle, the designed control system can then be validated with clinical data. Obtaining measurements of the controlled variables however, has the potential to hinder effective control. The first part of this research focused on the application of control system analytical tools to HIV/AIDS models. The intention was to gain some insights into the HIV infection dynamics from a control theoretic perspective. The issues that needed to be addressed are: Persistent virus replication under potent HAART, variability in response to therapy between individuals on the same regimen, transient rebounds of plasma viremia after periods of suppression, the attainment, or lack thereof, of maximal and durable suppression of the viral load. The questions to answer were: When are the above mentioned observed responses to therapy most likely to occur as the HIV infection progresses, and does attaining one necessarily imply the other? Furthermore, the prognostic markers of virologic success, the possibility of individualizing therapy and timing the initiation of antiretroviral therapy such that the benefits of therapy are maximized, are matters that were also investigated. The primary objective of this thesis was to analyze models for the eventual control of the HIV infection. HIV therapy has multiple and often conflicting objectives, and these objectives had to be prioritized. The intention of the proposed control strategy was to produce practical solutions to the current antiretroviral problems. To this end, the second part of the research focused on addressing the HIV/AIDS control issues of sampling for effective control given the invasive nature of drawing blood from a patient and the derivation of drug dosage sequences to strike a balance between maximal suppression and toxicity reduction, when multiple drugs are concomitantly used to treat the infection.Thesis (PhD)--University of Pretoria, 2006.
Electrical, Electronic and Computer Engineering
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