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<p>The prediction and characterisation of chemical and biochemical processes are fundamental tasks in computational chemistry. Small chemical systems can be characterised by the stationary points on potential energy surface and reaction paths linking them. For large biological systems, statistical sampling is required to characterising their average properties.</p> <p>This thesis presents my Ph.D. work on developing new methods to predict and characterise chemical and biological processes. Two path-finding methods for finding the minimum energy reaction path and alternative reaction paths for small gas-phase reactions have been elucidated with examples, and molecular dynamic simulations have been used to characterise the binding affinity of protein-ligand complex and the free energy of protonation processes in a protein.</p> <p>Specifically, the fast marching method (FMM) has been used to find the minimum energy path (MEP) on the potential energy surface (PES) for small gas-phase reactions. In this thesis, FMM is shown to be one of the most general and reliable surface-walking algorithms for finding the MEP. However, it is an expensive method. Some improvements have been illustrated in chapter 2 and chapter 3.</p> <p>I also proposed a new method (called QSM-NT) for finding all stationary points, accordingly all alternative reaction paths on the PES. Unlike other path-finding methods, QSM-NT overcomes the need of an initial guess of the path, and it can find all stationary points on the PES. QSM-NT has been proven to be efficient and reliable through applications on analytical PES and real chemical reaction. The difficulties and pitfalls associated with QSM-NT have been elucidated with examples.</p> <p>Molecular dynamic (MD) simulation and associated postprocessing procedures have been used to study the binding properties of caffeine-A_2A complex. The binding affinities of different binding modes have been calculated using MM/PBSA method. The binding pocket has been characterised with MM/GBSA energy decomposition. Our computational work provides significant insight to the targeted drug design of the adenosine A_2A receptor.</p> <p>The pH-dependent properties of a protein play important roles in the fundamental biological processes. The protonation states, namely, the pK_a values of ionisable residues, especially active-site residues are the prerequisites to understanding of the mechanisms of many biological processes. In this thesis, acetoacetate decarboxylase (AADase) is used as a test case for studying different types of pK_a prediction methods. Our computational results have shown that the site-site interactions from other ionisable residues are crucial to the pK_a prediction of the target residue.</p> <p>This thesis covers the range from small gas phase reaction prediction to large complex biological systems characterisation using quantum mechanical and molecular mechanical methods.</p> / Doctor of Philosophy (PhD)

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Please read the "Conclusions" in the section 05chapter5 of this document / Thesis (PhD (NT Studies))--University of Pretoria, 2007. / New Testament Studies / unrestricted

Biotin är ett vitamin som finns naturligt i livsmedel och det dagliga intaget nås via födan. Höga doser biotintillskott samt höga doser biotin i läkemedel, kan leda till biotininterferens i kliniska immunokemiska analyser. Roche Diagnostics® vill införa nya reagens med högre tröskel för biotininterferens för att minska risken för biotininterferens vid analys av patientplasma. Därför var syftet med studien att metodverifiera fyra nya reagens från Roche Diagnostics® som används vid diagnostisering och behandling av hjärtsvikt, sepsis, och prostatacancer. De fyra reagensen, Elecsys® proBNP II, Elecsys® BRAHMS PCT, Elecsys® total PSA samt Elecsys® free PSA metodverifierades för att användas på Cobas® e801. Studiematerialet bestod av 20 patientprover av litiumheparinplasma per reagens (totalt 80 patientprover). Resultatet av verifieringen av Elecsys® proBNP II visade en korrelation till det befintliga reagenset på r = 0,9998 och Bland-Altman analys visade en spridning av resultaten på &lt; 10 %; inomserieprecisionsstudien gav CV 1,56 %. Elecsys® BRAHMS PCT hade en korrelation på r = 0,9997 och Bland-Altman analysen visade en spridning på &gt; 10 %; inomserieprecisionsstudien gav CV 1,70 %. För Elecsys® total PSA och free PSA fanns korrelationen till det befintliga reagenset på r = 1 respektive 0,9997 och Bland- Altman analysen visade en spridning på &lt; 10 % hos båda reagensen. Inomserieprecisionsstudien gav CV 0,44 % respektive CV 2,67 %. Resultaten för samtliga reagens uppvisar god korrelation till det befintliga reagenset och en hög mätnoggrannhet vilket talar för att de fyra nya reagensen kan tas i bruk. / Biotin is naturally found in foods, and we obtain this vitamin through our daily diet. Biotin supplements as well as high doses of biotin in drugs can lead to biotin interference in clinical immunochemical analyzes. Therefore, the purpose of this study was to methodically verify four new reagents from Roche Diagnostics® with a higher threshold for biotin interference, used in the diagnosis and treatment of heart faliure, sepsis and prostate cancer. The four reagents, Elecsys® proBNP II, Elecsys® BRAHMS PCT, Elecsys® total PSA and Elecsys® free PSA were method-verified for use on Cobas® e801. The study material consisted of 20 patient samples of lithium heparin plasma per reagent. In total 80 samples were analyzed.The result of the verification of Elecsys® proBNP II showed a correlation to the existing reagent of r = 0.9998 and Bland-Altman analysis showed a distribution of the results of &lt;10 %. The withinseries precision study yielded CV 1.56 %. Elecsys® BRAHMS PCT had a correlation of r = 0.9997 and the Bland-Altman analysis showed a distribution of &gt; 10 %. The withinseries precision study gave CV 1.70 %. For Elecsys® total PSA and free PSA, the correlation to the existing reagent was r = 1 and 0.9997, respectively, and the Bland-Altman analysis showed a distribution of &lt;10 % in both reagents. The withinseries precision study yielded CV 0.44 % and CV 2.67 % respectively.The results for all reagents show a good correlation to the existing reagent and a high accuracy of measurement, which indicates that the four new reagents can be used.

Le liquide interstitiel est aujourd’hui considéré comme un candidat prometteur comme alternative, ou complément, à l’analyse sanguine pour la quantification de biomarqueurs. Localisé notamment dans la peau, sa composition demeure peu décrite dans la littérature. Cela peut s’expliquer par le fait que le prélèvement de liquide interstitiel reste problématique. En effet, les méthodes d’extraction actuelles sont chronophages, douloureuses et conduisent au prélèvement de volumes très faibles ne permettant pas toujours une analyse subséquente. L’utilisation de timbres de microaiguilles conçus en hydrogel superabsorbant représente une solution indolore, rapide et efficace pour le prélèvement du liquide interstitiel. Un premier type de timbre a été conçu par photopolymérisation, un processus de fabrication caractérisé par sa rapidité. Ce type de timbre de microaiguilles présente une capacité d’absorption très élevée et peut trouver une application dans l’élaboration des profils protéomique, métabolomique et lipidomique du liquide interstitiel dermique. Le second type de timbres de microaiguilles est obtenu par chauffage d’une formulation contenant des polymères superabsorbants. Ce procédé s’avère plus long mais conduit à un hydrogel superabsorbant riche en groupements chimiques permettant d’envisager une fonctionnalisation pour la capture et la détection in situ de biomarqueurs spécifiques du liquide interstitiel dermique. In fine, les timbres de microaiguilles développés pourraient donc permettre d’approfondir notre connaissance de la composition du liquide interstitiel; mais laissent également entrevoir la possibilité de développer des dispositifs médicaux portables permettant le diagnostic, ou la surveillance, rapide et indolore de certaines pathologies. Ces dispositifs pourraient diminuer les coûts normalement associés à ces pratiques et améliorer la prise en charge des patients. C’est le cas notamment de l’insuffisance cardiaque, dont la gestion pourrait être considérablement facilitée par le suivi à domicile du biomarqueur NT-proBNP. / Nowadays, interstitial fluid is considered a valid alternative for blood analysis and biomarker monitoring. However, its composition is scarcely described in the literature. Notably located in the skin, its collection remains a challenge as current methods are time-consuming, painful and the extracted volume limits subsequent analysis. Here we put forward the use of superabsorbant hydrogel-based microneedle patches to enable a painless, rapid and efficient sampling of dermal interstitial fluid. A first kind of microneedle patch was obtained using UV-curing, a rapid fabrication process. This type of microneedle patch enables the collection of a high volume of liquid and can therefore be utilized for subsequent proteomic, metabolomic and lipidomic analyses of the dermal interstitial fluid that had been extracted in a painless fashion. The second class of microneedle patch developed was fabricated from superabsorbant polymers using heating. Although time consuming, this process produced hydrogel-based microneedle patches that could be functionalized for the in situ detection of specific biomarkers in the dermal interstitial fluid. In fine, the aforementioned microneedle patches have the potential to broaden our understanding of the interstitial fluid composition, as well as be integrated in novel portable biosensing devices for a rapid and painless diagnosis, or for the monitoring of certain medical conditions. For example, quantifying the NT-proBNP biomarker in the dermal interstitial fluid could significantly improve the quality of life of heart failure patients.

International Telemetering Conference Proceedings / October 28-31, 1996 / Town and Country Hotel and Convention Center, San Diego, California / The ever-increasing power of PC hardware combined with the new operating systems available make the PC an excellent platform for a telemetry system. For applications that require multiple users or more processing power than a single PC, a network of PCs can be used to distribute data acquisition and processing tasks. The focus of this paper is on a distributed network approach to solving telemetry test applications. This approach maximizes the flexibility and expandability of the system while keeping the initial capital equipment expenditure low.