To see the other types of publications on this topic, follow the link: PPIasa.
Dissertations / Theses on the topic 'PPIasa'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 27 dissertations / theses for your research on the topic 'PPIasa.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Suñé, Rodríguez Guillermo. "Identificación de proteínas que interaccionan con CypA, CypB y FKBP12 y su implicación en la toxicidad renal producida por los inmunosupresores CsA y FK506." Doctoral thesis, Universitat de Barcelona, 2008. http://hdl.handle.net/10803/1017.
Full textAbstract:
La Ciclosporina A (CsA) es un fármaco inmunosupresor que ha supuesto una revolución en el trasplante de órganos. A pesar de sus propiedades anti-inflamatorias, su uso se ha visto limitado por los efectos tóxicos que causa en algunos pacientes. La CsA inhibe la trascripción de genes involucrados en el sistema inmune. Se cree que esta inhibición es la causante de los efectos tóxicos producidos por el fármaco. El modo de acción de CsA está mediado por la unión de sus principales receptores intracelulares, las ciclofilinas (Cyps). Las ciclofilinas son proteínas que están conservadas en todas las especies y su principal función está involucrada en el plegamiento correcto de otras proteínas. Se ha descrito que los efectos tóxicos producidos por CsA podían estar mediados directamente por sus receptores las ciclofilinas. A pesar de que se descrito que las ciclofilinas están involucradas en diferentes funciones, no se les atribuye una función específica.
En nuestro laboratorio hemos estado interesados en las posibles vías que involucran a las Cyps y si éstas tienen relación con lo efectos causados por CsA. En esta tesis se ha intentado identificar proteínas que interaccionan con CypA, CypB y FKBP12 y su implicación en los efectos tóxicos producidos por CsA.
Hemos identificado una serie de interacciones y hemos estudiado más a fondo dos de ellas. Estas interacciones son las ocurridas entre la ciclofilina B y la subunidad beta de la bomba sodio/potasio, la ciclofilina A y la subunidad beta de la bomba sodio/potasio y por último la ciclofilina B y la subunidad b1 de la ATP sintetasa mitocondrial. Una vez identificadas estas interacciones hemos realizado ensayos funcionales con cada una de ellas. Por un lado hemos estudiado si la actividad de la bomba sodio/potasio estaba afectada en células renales humanas tratadas con CsA y células que habían sido silenciadas para la ciclofilina B y ciclofilina A. Por otro lado hemos realizado un estudio de la actividad y expresión de los complejos de la cadena respiratoria mitocondrial en células renales tratadas con CsA y células renales que habían sido silenciadas para los genes CypA y CypB. A parte de las interacciones encontradas, hemos visto que la actividad de la bomba Na/K está disminuida por el fármaco y que en esta disminución estaría involucrada la ciclofilina B, también hemos visto que los complejos de la cadena respiratoria mitocondrial estarían afectados en células tratadas con CsA y en células interferidas tanto para CypB como para CypA.
Como conclusión podríamos sugerir que las ciclofilinas estarían involucradas en los efectos nefrotóxicos que produce la CsA. Estos efectos nefrotóxicos causados por el tratamiento con CsA podrían estar mediados por vias alternativas a la clásicamente descrita, como es la inhibición de la calcineurina. Dichas vías estarían integradas por nuevos efectores tales como Na/K-ATPasa, ATP sintetasa, así como otras putativas dianas que en el futuro serán estudiadas en nuestro laboratorio.
Cyclosporine A is an immunosuppressive drug that has revolutionized organ transplantation. Even though it has anti-inflammatory property, its used has been reduced due to the renal toxic effects caused in some patients. CsA inhibits transcription of genes involved in the immune system. The CsA mode of action involves the binding of its main receptors, the cyclophilins (Cyps).
Cyps are proteins conserved in all species and their main function is the correct folding of immature proteins. It has been describes that the main toxic effects caused by CsA could be mediated directly by its receptors, the cyclophilins. Although Cyps are involved in many processes, there is not a specific function for them.
In our lab, we have identified a number of proteins that interact with Cyclophilin A (CypA), Cyclophilin B (CypB) and FK-Binding Protein 12 (FKBP12) by yeast two hybrid assays. Some of those novel interactions were confirmed by pull-down and co-immunoprecipitation assays. Finally, we have also carried out functional assays in some of those interactions.
As a conclusion, we could suggest that cyclophilins would be involved in the nephrotoxic effects caused by cyclosporine A. Those effects are mediated by alternative pathways. Those pathways would be integrated by novel effectors such as the sodium/potassium ATPase, mitochondrial ATP synthase and also other proteins that will be studied in our lab.
2
Georgiou, Charis. "Rational design of isoform specific ligands." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28713.
Full textAbstract:
Cyclophilins (Cyp) are proteins that catalyze the interconversion of trans/cis isomers of proline belonging to the peptidyl-prolyl isomerases family (PPIase). In addition to their PPIase activity, Cyps have diverse biological roles and have been implicated in a number of different diseases such as HIV-1 and HCV. Although several Cyp inhibitors have been reported in the literature, none are able to inhibit with high specificity various Cyp isoforms. To facilitate the development of isoform-specific Cyp ligands, we have pursued detailed studies of Cyp dynamics and ligand binding thermodynamics using molecular simulations, biophysical assays and protein X-ray crystallography. Research efforts were focussed on the identification of novel Cyp inhibitors using X-ray crystallographic studies and Surface Plasmon Resonance (SPR) experiments on fragments from an in-house bespoke library of small compounds. These biophysical studies revealed a number of fragments that are able to bind to diverse Cyp isoforms with high micromolar – low millimolar activity. To further examine the binding of these fragments to cyclophilins, identify interactions with the proteins and explain specificity trends from SPR and X-ray results, molecular dynamics (MD) simulations and free energy calculations were pursued. Models of apo and holo Cyps in complex with fragments that we had experimentally tested were set up using the Amber, AmberTools and FESetup software. Free energy calculations were performed using the thermodynamic integration (TI) technique with the Sire/OpenMM software. The results were analysed with custom scripts. Correlations between computed and measured binding energies, and calculated and observed binding modes were analysed to help develop guidelines for the development of isoform specific cyclophilin ligands. A detailed comparison of the merits and drawbacks of the experimental and computational techniques used in this work has also been made, and strategies for effective combination of the methodologies in structure-based projects are outlined.
3
Norville, Isobel Harriet. "The identification and characterisation of PPIases from Burkholderia pseudomallei and Burkholderia thailandensis." Thesis, University of Exeter, 2011. http://hdl.handle.net/10036/3152.
Full textAbstract:
The aim of this study was to identify and characterise peptidyl-prolyl cis-trans isomerases (PPIases) from the bacterium Burkholderia pseudomallei, the causative agent of the disease melioidosis. The longer term goal was to assess their potential as vaccine candidates or antimicrobial targets. Using bioinformatic approaches, six putative FK506-binding proteins (FKBPs) proteins and three putative parvulin proteins were identified in B. pseudomallei. Of these, six were expressed and purified as recombinant proteins. The purified proteins were used to immunise BALB/c mice, with some providing protection against a subsequent B. pseudomallei infection. These proteins could therefore be proposed as potential vaccine candidates. Homologues of Mip or SurA, which are associated with virulence in other bacterial species, were identified in B. pseudomallei and closely related B. thailandensis. Recombinant Mip or SurA homologues from B. pseudomallei were shown to have characteristic PPIase enzyme activity. To evaluate the role of the Mip homologue from B. pseudomallei in virulence, an unmarked deletion mutant was constructed. The mutant had reduced intracellular survival; defects in putative virulence mechanisms and attenuated virulence in mice. To assess the role of a SurA homologue, closely related B. thailandensis was used as a model organism, with deletion of the gene resulting in defects in intracellular infection, outer membrane integrity and virulence. This indicates that PPIases from B. pseudomallei and B. thailandensis represent novel virulence determinants and potential antimicrobial targets for therapeutics against melioidosis.
4
Albasri, Hibah Mohammed. "Cell binding factor of Neisseria meningitidis is a PPIase with chaperone activity involved in outer membrane protein biogenesis." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.727113.
Full textAbstract:
Neisseria meningitidis is a major cause of meningitis and septicaemia which remain an important concern worldwide. Despite the advances in understanding the pathogenicity of N. meningitidis; its complexity is still not fully elucidated. Noteworthy, while a large number of complete genome sequences are now available, the annotation of each of the genes is incomplete with information either lacking entirely or based only on homology with genes in other species. In searching for novel genes in N. meningitidis strain MC58 that might be involved in the pathogenicity, a putative operon encoded by the genes NMB0342 to NMB0345 was bioinformatically identified and homology-based searches indicated that two of the genes, NMB0342 and NMB0345, have homologues in other pathogenic bacteria. This project was conducted to characterise the role of NMB0345 in meningococcal pathogenesis.
5
Keogh, Rebecca. "Investigation of Peptidyl-prolyl cis/trans isomerases in the virulence of Staphylococcus aureus." Ohio University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou158764341402963.
Full text
6
Xu, Guoyan. "Pin1 Inhibitors: Towards Understanding the Enzymatic Mechanism." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/37823.
Full textAbstract:
An important role of Pin1 is to catalyze the cis-trans isomerization of pSer/Thr-Pro bonds; as such, it plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including Cdc25, c-Jun, and p53. The expression of Pin1 correlates with cyclin D1 levels, which contributes to cancer cell transformation. Overexpression of Pin1 promotes tumor growth, while its inhibition causes tumor cell apoptosis. Because Pin1 is overexpressed in many human cancer tissues, including breast, prostate, and lung cancer tissues, it plays an important role in oncogenesis, making its study vital for the development of anti-cancer agents.
Many inhibitors have been discovered for Pin1, including 1) several classes of designed inhibitors such as alkene isosteres, non-peptidic, small molecular Pin1 inhibitors, and indanyl ketones, and 2) several natural products such as juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen. These Pin1 inhibitors show promise in the development of novel diagnostic and therapeutic anticancer drugs due to their ability to block cell cycle progression. In order to develop potent Pin1 inhibitors, the concept of transition-state analogues was used for the design of three classes of compounds: ketoamide, ketone, and reduced amide analogues.
Specifically, a convergent synthesis of α-ketoamide inhibitors of Pin1 was developed. An α-hydroxyorthothioester derivative of Ser was reacted directly with an aminyl synthon. The reaction was catalyzed by HgO and HgCl2 to form an α-hydroxyamide. Hydrolysis and coupling were combined in one step in 80% yield. Two diastereomers of a phospho-Ser-Pro α-ketoamide analogue were synthesized. The resulting IC50 values of 100 µM and 200 µM were surprisingly weak for the Pin1 peptidyl-prolyl isomerase.
Diastereomeric ketones were synthesized by coupling cyclohexenyl lithium to the serine Weinreb amide, via the Michael addition of a carboxylate synthon. The IC50 values of the two ketone diastereomers were determined to be 260 μM and 61 μM, respectively.
Five reduced amide inhibitors for Pin1 were synthesized through a selective reduction using borane. The most potent inhibitor was found to be Fmocâ pSerâ Ψ[CH2N]-Proâ tryptamine, which had an IC50 value of 6.3 µM. This represents a 4.5-fold better inhibition for Pin1 than a comparable cis-amide alkene isostere. The co-crystal structure of Acâ pSerâ Ψ[CH2N]-Proâ tryptamine bound to Pin1 was determined to 1.76 à resolution.
Towards understanding the two proposed mechanisms of Pin1 catalysis, nucleophilic-additition mechanism and twisted-amide mechanism, three classes of Pin1 inhibitors (ketoamide, ketone, and reduced amide analogues) involving a total of nine compounds were synthesized and evaluated. The weak inhibitory activities of ketoamide and ketone analogues do not support the nucleophilic-addition mechanism, while the twisted-amide mechanism of Pin1 catalysis is promising based on the reduced amide inhibitors with good potencies.Ph. D.
7
Mercedes-Camacho, Ana Yokayra. "Pin1: WW domain ligands, catalytic inhibitors, and the mechanism." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/77093.
Full textAbstract:
The peptidyl prolyl cis/trans isomerase, PPIase, has been the focus of numerous studies in the field of cell cycle regulation since proline-directed phosphorylation is an essential signaling mechanism that might arrest cancer proliferation. Pin1 is the first phosphorylation-dependent PPIase enzyme to be discovered. The Pin1 regulatory mechanism, acting on other mitotic proteins in vivo and in vitro, remains largely unknown. For the study of Pin1 function, two types of assays were used to identity ligands for Pin1: (1) The Enzyme-Linked Enzyme Binding Assay (ELEBA) for the identification of WW domain ligands, (2) a catalytic assay to identified inhibitors of Pin1 catalytic activity. The ELEBA offers a selective approach for detecting ligands that bind to the Pin1 WW domain from chemical libraries. By using the ELEBA, a pSer-Pro peptidomimetic library of 315 ligands was screened, identifying three promising ligands cis-D2, O2, and M18. Competitive Kd values for cis-D2, O2, and M18 were determined to be 263 ± 6.4, 206 ± 3.4, and 130 ± 3.0μM, respectively. Furthermore, we screened the pSer-Pro peptidomimetic library using a Pin1 discontinuous-catalytic assay to identify inhibitors of Pin1. Ligands D20 and K7 were identified to decrease more than 90% of the Pin1 catalytic activity.
To investigate the nature of the Pin1 interaction with c-Myc, we synthesized and characterized four peptides corresponding to the c-Myc sequence. These peptides were used in NMR isomerization studies of Pin1 by our collaborator Dr. Jeffry Peng (University of Notre Dame). Preliminary work shows that Pin1 binds and isomerizes the Ac–LLPpTPPLSPS–NH₂ peptide at the cMyc pThr58 position.
Finally, we measured a secondary kinetic isotope effect (2º KIE) to study the Pin1 catalytic mechanism of proline isomerization. The ratio of kH/kD for unlabeled and [d₃]Ser-labeled substrate gave a SKIE value of 1.34 ± 0.01. The normal 2º KIE value indicates that carbonyl-serine hybridization is not changing from sp² to sp³. This result supports substrate analogue inhibitor studies, and previous solvent and SKIE results on Pin1, that suggest a twisted amide mechanism assisted by a transient hydrogen bond in the transition state.Ph. D.
8
Brasseur, Anaïs. "Etude de composantes de la voie TOR: caractérisation de TbFKBP12, une protéine de la famille des PPIases (isomérases) impliquée dans l'homéostasie du flagelle chez Trypanosoma brucei." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210240.
Full textAbstract:
Trypanosoma brucei est un parasite africain unicellulaire, responsable chez l’homme de la maladie du sommeil et chez les bovins de la Nagana. Il passe par différents stades lors de son cycle de vie, les deux principaux étant la forme sanguicole qui prolifère dans le sang des mammifères infectés, et la forme procyclique qui colonise le tube digestif du vecteur, la mouche glossine. Les trypanosomes sont extracellulaires, ils possèdent un flagelle qui leur permet de se mouvoir dans les différents milieux qu’ils infestent. La structure de celui-ci contient des éléments conservés au cours de l’évolution. Il constitue donc un excellent modèle de base pour en étudier l’architecture. D’autre part, le flagelle du parasite contient des structures propres à certains kinétoplastides, offrant ainsi une cible thérapeutique aux traitements anti-trypanosomiaux.
Le flagelle est véritablement un organite plurifonctionnel nécessaire à la survie du parasite au sein des divers environnements qu’il rencontre lors de son cycle de développement. Outre son rôle moteur, il permet à la cellule d’échapper au système immunitaire de son hôte mammifère et de s’attacher à l’épithélium des glandes salivaires de l’insecte. Il est également requis pour le bon positionnement des organites, la morphogenèse et la division cellulaire. Enfin, il serait impliqué dans l’activité sensorielle du trypanosome. A ce jour, on ne connait quasiment rien des potentielles voies de « sensing ». Elles doivent pourtant exister, permettant l’appréhension de l’environnement, l’interaction avec les hôtes et la réception de signaux induisant la différenciation.
Cet intérêt pour les voies de signalisation du parasite a abouti à l’étude des composantes de la voie TOR. TOR-Target of Rapamycin est un contrôleur central de la croissance cellulaire qu’il régule en fonction de différents stimuli externes. Il a été démontré depuis que chez T.brucei aussi, TOR régulerait la croissance temporelle et spatiale de la cellule.
La kinase TOR est inhibée par sa liaison avec le complexe rapamycine-FKBP12. Nous avons identifié cette peptidyl-prolyl cis-trans isomérase chez le parasite :TbFKBP12. Elle y serait localisée au niveau du cytosquelette/flagelle. Contrairement à ce qui est observé chez la levure S.cerevisiae, l’isomérase est essentielle chez le trypanosome. Son invalidation par RNAi bloque la cytocinèse des parasites sanguicoles et provoque l’apparition d’axes de clivage internes à la cellule. Chez les formes procycliques par contre, la disparition de la protéine entraîne un défaut sévère de motilité du flagelle qui se traduit par une immobilisation partielle du parasite.
TbFKBP12 est donc impliquée dans l’homéostasie du flagelle chez le trypanosome africain, organite nécessaire à la motilité et à la division cellulaire.
Doctorat en sciences, Spécialisation biologie moléculaire
info:eu-repo/semantics/nonPublished
9
Rivas, Santos Pep. "Design and synthesis of engineered peptides to target undruggable PPIs: from in silico to in vitro studies." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668150.
Full textAbstract:
Major unsolved diseases such as Cancer, cardiopathies or neurodegenerative disorders are frequently related with the malunction of complex protein networks. These networks are integrated by the interaction of multiple proteins that in case of a misregulation can trigger an undesired effect. Therefore, disruption of protein-protein interactions (PPIs), that are involucrated in a protein signalling cascade which is relevant for a particular diseases, is a hot topic in pharmaceutical industry. Unfortunately, traditional small molecules have been found to not be the most suitable inhibitiors of these therapeutic targets as PPI interfaces are characterized by a flat area with a lack of cavities that can fit a small molecule.
In this scenario, peptides has called the attention in the drug discovery field for be a more appropiate candidates to target PPIs. Peptides are found in the chemical space between small molecules and antibodies, usullay contain between 2-50 amino acids and have an approximated weight of 250-10.000 Da. Then, their medium size allows a efficient recognition of the target protein without the need of well formed cavieties on the protein surface. However, peptides are characterized by a poor permeability and low stability in blood stream which had limited their therapeutic application in the past. Opportunately, introduction of non-natural amino acids and D-amino acids, N-alkylations of peptide backbone, cyclization and N-terminal and C-terminal modified cappings improve the biophysical properties along with the affinity for the receptor protein.
Then, the use of engineered peptides, so-called peptidomimetics, is a promissing approach to target PPIs that can improve the binding potency of natural peptides and overcoming their major drawbacks at the same time.
This thesis was carried out at Iproteos, a biotech company positioned in the use of peptidomimetics to target intracellular PPIs. The company has developed an in-house technology coined IPROTech, which is a platform that applys different in silico tools that are focused in the design of peptidomimetics, which are synthesized manually, quantified and finally evaluated in vitro. The experimental results are reintroduced in the platform and the process is repeated iteratively until achieve a final lead candidate.
Hence, in the present work, IPROTech was applied to found de novo peptidomimetic molecules that inhibit the interaction of 4 different PPIs that are considered of therapeutic importance, Talin- Vinculin (Cancer), Rad51-BRCA2 (Cancer), Ras-Effectors (Cancer) and Retromer-L2 (HPVs infection). For each PPI, a collabration project with an academic group expert in field was setted up. Iproteos was in charge of the in silico studies of the target protein in order to design and synthesized a set peptidomimetic sequences that were predicted to disrupt the PPI of interest. On the other hand, the collaborators were responsible of the experimental evualtion of the synthesized compounds.
In this terms, at least 1 hit was found for each PPI when evaluated in vitro, demonstrating an outsanding overall succes-rate of 31 % when all synthesized peptidomimetics were evaluated in vitro. Additinoally, the inclusion of new fancy builduing blocks into the compounds sintheysis, N-alkylation of the peptidomimetics backbone, pearmeability across biological barriers or the use of cyclodextrins as solvating excipient were other points studied as well.Trobar nous fàrmacs capaços de trencar interaccions proteïna-proteïna, que d’alguna manera estan involucrades amb una malaltia, és de gran interès en el camp de la indústria farmacèutica. No obstant això, aquest tipus de diana terapèutica normalment no presenten cap cavitat ben definida a la seva superfície, característica necessària per albergar les tradicionals molècules petites. Per aquest motiu, la utilització de pèptids com a possibles fàrmacs és una aproximació molt prometedora perquè en tenir una mida molecular superior poden establir més interaccions amb la proteïna receptora afavorint així la seva unió. Però, aquesta aproximació està limitada per les propietats bioquímiques dels pèptids, ja que normalment són poc permeables i amb una baixa estabilitat un cop administrats. Afortunadament, els avanços fets en la síntesi de pèptids ha permès afegir modificacions sobre la seqüència dels pèptids per tal de millora les seves propietats, això inclou amino àcids no naturals, N-alquilacions, diferent tipus de N-terminals i C-terminals, entre altres. Els compostos obtinguts quan s’aplica aquesta enginyeria es coneixen com a peptidomimetics. Aquesta tesi es va realitzar a Iproteos. Iproteos és una petita empresa biotecnològica, focalitzada en l’ús de peptidomimetics per tal d’inhibir IPPs relacionades amb alguna malaltia. Per fer possible aquesta tasca, Iproteos ha creat una tecnologia, IPROTech, que agrupa tècniques computacionals per tal de cribrar la proteïna d’interès i genera estructures peptidometiques que més tard són sintetitzades, purificades i quantificades. Per aquesta tesi, es va aplicar la tecnologia IPROTech per trobar peptidomimetics amb la capacitat d’inhibir quatre IPP de rellevància terapèutica, Talina-Vinculina (càncer), Rad51- BRCA2 (càncer), Ras-Effectors (càncer) i Retromer-L2 (HPVs). Per cadascuna d’aquestes dianes, a Iproteos es va realitzar els estudis in silico i la síntesi dels peptidomimetics mentre que l'avaluació experimental la van fer grups acadèmics experts en cada camp. En tots els casos es va trobar almenys un compost capaç de trencar amb la interacció. Addicionalment propietats com la solubilitat, permeabilitat o estabilitat van ser avaluades per aquells compostos actius. Finalment, gràcies a les dades generades, alguns d’aquests compostos es van poder optimitzar obtenint un candidat final més potent encara.
10
Ruiz-Gómez, Gloria, John C. Hawkins, Jenny Philipp, Georg Künze, Robert Wodtke, Reik Löser, Karim Fahmy, and M. Teresa Pisabarro. "Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-215877.
Full textAbstract:
Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.
11
Berg, Christian. "The ever increasing use of acid suppressive therapy : Descriptive analysis of data from the national wholesale and prescription databases on the consumption of proton pump inhibitor in Norway." Thesis, Nordic School of Public Health NHV, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:norden:org:diva-3223.
Full textAbstract:
Pharmacoepidemiological analyses are needed as a background for evaluation of drug use and for making cost-effective priorities. Drug sales and prescription databases provide useful tools for analysis of drug consumption and expenditures. In this essay, an analysis of the sales and prescribing of proton pump inhibitors (PPIs), drugs used for acid related gastric disorders, are presented. Since 1996, the consumption of PPIs in Norway has increased by approximately 10 % per year, with esomeprazole as the most commonly used drug. An increasing number of individuals are using these drugs with considerable costs for the reimbursement schemes, e.g., in 2006 more than 450 million NOK. Verified reflux oesophagitis is the predominant indication for reimbursement prescribing. There are, however, indications of an overprescribing of PPIs. The prescribing in Norway is different from Denmark and Sweden, both regarding choice of drug and level of consumption. The prevalence of PPI use increased with age, reaching a maximum of nearly 12 % in the age groups 70-79 and 80-89 years of age. A considerable proportion is long-term users (> 2 years). These groups have a high risk of polypharmacy treatment. Even though the PPIs have been on the market for many years, negative effects associated with long term use are being discussed and need to be further explored. Attention should be focused on the rational use of PPIs and not only on the reduction of costs for PPI therapy.Farmakoepidemiologiske analyser er nødvendige som bakgrunn for å evaluere legemiddelbruk og gjøre kostnads-effektivitets prioriteringer. Databaser med informasjon om salg og forskrivning av legemidler er nyttige redskaper for slike analyser. I denne oppgaven presenteres en analyse av salgs- og forskrivningsdata for protonpumpehemmere, en legemiddelgruppe som brukes ved syrerelaterte gasterointestinale sykdommer. Forbruket av protonpumpehemmere i Norge har siden 1996 økt med 10 % per år, med esomeprazol som vanligste legemiddel. Et økende antall personer bruker disse legemidlene. Utgiftene for det offentlige trygdesystemet er omfattende, mer enn 450 millioner NOK i 2006. Verifisert spiserørbetennelse er den dominerende årsak til forskrivning angitt på reseptene. Det er indikasjoner på en for høy forskrivning av protonpumpehemmere. Forskrivningen i Norge er forskjellig fra Danmark og Sverige, både med hensyn på valg av legemiddel og forbruksnivå. Prevalens for bruk av protonpumpehemmere øker med alder og når et maksimum på nær 12 % av befolkningen i aldersgruppene 70-79 og 80-89 år. En betydelig andel bruker legemidlene over lengre tid (> 2 år). Dette er grupper som bruker mange legemidler samtidig (polyfarmasi). Selv om protonpumpehemmerne har vært på markedet i mange år, diskuteres fortsatt negative følger av langtidsbruk og det er behov for å studere bruken nærmere. Oppmerksomheten bør rettes mot rasjonell bruk av disse legemidlene, ikke bare hvordan utgiftene til dem skal kunne reduseres.
ISBN 978-91-85721-14-6
12
Ruiz-Gómez, Gloria, John C. Hawkins, Jenny Philipp, Georg Künze, Robert Wodtke, Reik Löser, Karim Fahmy, and M. Teresa Pisabarro. "Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics." Public Library of Science, 2016. https://tud.qucosa.de/id/qucosa%3A30052.
Full textAbstract:
Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.
13
Worseck, Josephine Maria. "Characterization of phosphorylation-dependent interactions involving neurofibromin 2 (NF2, merlin) isoforms and the Parkinson protein 7 (PARK7, DJ1)." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16533.
Full textAbstract:
Veränderungen in phosphorylierungsabhängigen Signalwegen, Akkumulation von Proteinaggregaten im Gehirn und neuronaler Zelltod sind Neurodegenerationskennzeichen und Indikatoren für überlappende molekulare Mechanismen. Um Einblicke in die involvierten Signalwege zu erhalten, wurde mit Hilfe eines modifizierten Hefe-Zwei-Hybrid (Y2H)-Systems für 71 Proteine, die mit neurologischen Erkrankungen assoziiert sind, proteomweit nach Protein-Protein Interaktionen (PPIs) gesucht. Für 21 dieser Proteine wurden PPIs identifiziert. Das Gesamtnetzwerk besteht aus 79 Proteinen und 90 PPIs von denen 5 phosphorylierungsabhängig sind. Ein Teil dieser PPIs wurde in unabhängigen Interaktionsassays mit einer Validierungsrate von 66 % getestet. Der netzwerkbasierte Versuch verbindet erfolgreich neurologische Erkrankungen untereinander aber auch mit zellulären Prozessen. Ser/Thr-Kinase abhängige PPIs verknüpfen zum Beispiel das Parkinson Protein 7 (PARK7, DJ1) mit den E3 Ligase Komponenten ASB3 und RNF31 (HOIP). Die Funktion dieser Proteine bekräftigt den Zusammenhang zwischen dem Ubiquitin-Proteasom-System und der Parkinson Krankheit (PD). Neurofibromin 2 (NF2, merlin) Isoformen und PARK7 interagieren mit der regulatorischen PI3K Untereinheit p55-gamma (PIK3R3). Diese PPIs basieren auf Tyr-Kinase Aktivität im modifizierten Y2H System und funktionellen PIK3R3 pTyr-Erkennungsmodulen (SH2 Domänen) in co-IP und Venus PCA Versuchen. Dies verknüpft den PI3K/AKT Überlebenssignalweg mit zwei unterschiedlichen neurologischen Erkrankungsphenotypen: dem PD assoziierten neuronalen Zelltod und der Neurofibromatose Typ 2-assoziierten Tumorentstehung. Die vergleichende Beobachtung von PIK3R3, AOF2 (KDM1A, LSD1) Interaktionen auf NF2 Isoformlevel offenbart eine Bevorzugung von Isoform 7 bei zytoplasmatischer Lokalisation, wohingegen Isoform 1 PPIs an der Membran lokalisiert sind. Das modifizierungsabhängige und isoformspezifische PPI Netzwerk ermöglichte neue Hypothesen zu molekularen Pathomechanismen.Alterations in phosphorylation-dependent signalling pathways, accumulation of aggregated proteins in the brain and neuronal apoptosis are common to neurodegeneration and implicate overlapping molecular mechanism. To gain insight into involved pathways, a modified yeast-two hybrid (Y2H) system was applied to screen 71 proteins associated with neurological disorders in a proteome-wide manner. For 21 of these proteins interactions were identified including 5 phosphorylation-dependent ones. In total, the network connected 79 proteins through 90 protein-protein interactions (PPIs). A fraction of these Y2H PPIs was tested in secondary interaction assays with a validation rate of 66 %. The described network-based approach successfully identified proteins associated with more than one disorder and cellular functions connected to specific disorders. In particular, the network revealed Ser/Thr kinase-dependent PPIs between the Parkinson protein 7 (PARK7, DJ1) and the E3 ligase components ASB3 and RNF31 (HOIP). The function of these proteins further substantiates the established connection between Parkinson’s disease (PD) and ubiquitination-mediated proteasome (dis)functions. Neurofibromin 2 (NF2, merlin) isoforms and PARK7 were identified as PI3K regulatory subunit p55-gamma (PIK3R3) interactors. These PPIs required Tyr kinase coexpression in the modified Y2H system and functional PIK3R3 pTyr-recognition modules (SH2 domains) in co-IP and Venus PCA experiments. This finding implicates the PI3K/AKT survival pathway in PD-associated neuronal apoptosis and Neurofibromatosis type 2-associated tumour formation. Investigation of PIK3R3, AOF2 (KDM1A, LSD1) and EMILIN1 PPIs on NF2 isoform level revealed preferential isoform 7 binding and cytoplasmic or membrane localisation of these PPIs for isoform 7 or 1, respectively. The generated modification-dependent and isoform-specific PPI network triggered many hypotheses on the molecular mechanisms implicated in neurological disorders.
14
Carvalho, Mafalda Marques Cirne Machado. "Úlcera péptica: etiopatogenia, diagnóstico, aspetos clínicos e tratamento." Master's thesis, [s.n.], 2013. http://hdl.handle.net/10284/4175.
Full textAbstract:
Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasA úlcera péptica é uma doença do trato gastrointestinal caracterizada por lesão da mucosa na presença de ácido e pepsina, como consequência de uma ação corrosiva da hipersecreção de ácido gástrico no tecido, causada por um desequilíbrio entre o sistema protetor da mucosa e fatores agressores. A infeção pela bactéria Helicobacter pylori e os anti-inflamatórios não esteroides são considerados os principais fatores de risco no desenvolvimento desta patologia. A endoscopia digestiva alta é um método que se tem mostrado bastante eficaz no diagnóstico de úlceras pépticas pois permite a observação macroscópica da lesão e diagnóstico histológico e/ou microbiológico. O tratamento mais indicado passa pela administração de inibidores da bomba de protões concomitantemente com terapia antibacteriana para a erradicação da infeção, se presente. Esta monografia tem como objetivo rever as características, nomeadamente a etiopatogenia, diagnóstico, aspeto clínico e tratamento, de uma doença que continua a afetar grande parte da população mundial. Peptic ulcer disease is a gastrointestinal mucosal injury characterized by the presence of acid and pepsin, as a consequence of corrosive action of gastric acid hypersecretion tissue caused by an imbalance between the protective system of the mucosa and the aggressive factors. Infection with Helicobacter pylori and anti-inflammatory drugs are considered the main risk factors in the development of this pathology. Upper gastrointestinal endoscopy has proven quite effective in the diagnosis of peptic ulcers as it provides a macroscopic observation of the lesions and an histological and / or microbiological diagnosis. The most common treatment involves the administration of proton pump inhibitors concomitantly with antibacterial therapy for the eradication of infection, if present. This monograph aims to review the characteristics, including etiology, diagnosis, clinical aspect and treatment of a disease that continues to affect people worldwide.
15
Janse, van Rensburg Hendrika Nicolien. "A longitudinal study of the usage of acid reducing medicine using a medicine claims database / Hendrika Nicolien Janse van Rensburg." Thesis, North-West University, 2007. http://hdl.handle.net/10394/1903.
Full textAbstract:
Acid-related disorders are common, chronic conditions that have considerable impact on a patient's quality of life. In a study conducted by Majumdar et al. (2003:2411) the prevalence of chronic acid-related disorders was 2.3%. Acid-related disorders represent a major financial consideration with respect to the costs of drug prescribing (Whitaker, 1998:6). Health care cost increases each year. This leads to an increased interest in economic evaluation of health care and medical technologies (Anell & Svarvar, 2000:175). Health care providers no longer make treatment decisions independent of the consideration of the resultant cost. The treatment provided must not only provide value but the value must be documented to justify spending money. Economic evaluation research has emerged to offer guidance to policy makers, practitioners, health plans and institutions facing difficult treatment and coverage decisions (Ellis era/., 2002:271).
The main objectives of this study were to investigate the prescribing patterns and cost of acid reducing medicine with special reference to proton pump inhibitors and histamine-2 receptor antagonists in a section of the private health care sector of South Africa from 2001 to 2006. A longitudinal retrospective drug utilisation study was done on acid reducing medicine items claimed through a national medicine claims database. The five study years were 2001, 2002, 2004, 2005 and 2006. All the study years stretched from 1 January to 31 December.
It was determined that acid reducing medicine items prescribed decreased from 2.74% during 2001 to 2.50% during 2006 of all medicine items claimed. The same decreasing trend was observed regarding the cost of acid reducing medicine items. The cost percentage decreased from 4.89% (2001) to 3.72% (2006). However, the average cost per medicine item for the acid reducers increased by 5.35% from 2001 (R230.04 ± 176.29) to 2002 (R243.72 ± 184.18) and then decreased by 15.23% from 2002 to 2004. It again decreased with 15.05% from 2004
(R206.19 ± 179.42) to 2006 (R175.70 ± 172.55). The changes in the average cost of acid reducers were of no practical significance.
Proton pump inhibitors represented about half of the acid reducing medicine items prescribed and more than 70% of the total cost of acid reducing medicine items during the study years. The average cost of PPIs revealed a practical significant decrease (d > 0.8) from 2002 (R372.42 ± 156.62) to 2006 (R241.56 ± 177.21). H2RAs contributed between 15.00% and 18.26% of all acid reducing medicine items while contributing to between 9.68% and 16.85% of the total cost of all acid reducers.
The active ingredient most often prescribed was lansoprazole during 2001 and 2002, esomeprazole during 2004 and omeprazole during 2005 and 2006. Lanzor® 30mg was the acid reducer with the highest cost from 2001 to 2005, while Pariet® 20mg took the lead in 2006. Zantac® 150mg effervescent tablets were the H2RA, with the highest cost, during the five study years.
The percentage innovator items decreased by 4.50% from 2001 to 2002, increased by 1.01% from 2002 to 2004 and decreased again by 31.06% from 2004 to 2006. The slight increase in the percentage innovator medicine items claimed from 2002 to 2004 may be explained by the introduction of Nexiam® (esomeprazole) into the market in 2002. The total number of generic medicine items claimed contributed between 9.62% (n = R1 788 242.25) in 2001 and 30.75% (n = R3 196 163.34) in 2006 of the total cost of acid reducing medicine items.
The average cost per day of innovator medicine items was higher than the average cost per day of generic medicine items. This might be explained by a lower average cost for generic medicine items.
It was also determined that the prevalence of the two-drug regimens was the highest during the five study years. The Helicobacter pylori (H.pylori) eradication treatments, which included different antibiotics, increased from 2.72% in 2001 to 5.05% in 2006.
The PDD for most of the active ingredients of H2RAs and PPIs remained stable during the study years. However, it appears that the PDDs, of the PPIs, active ingredients were more constant than the PDDs, or the H2RAs, active ingredients. The median of the different PPI active ingredients was reasonably more constant than the median of the different H2RA active ingredients. Thus the changes between the PPIs' and H2RAs' active ingredients might be explained by the variation in the median (the number of days the relevant medicine item was claimed for).
It is then also recommended that the aspects of generic substitution as well as the usage of H2RAs as prescribed vs. self medication should be further investigated to increase possible cost savings.Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2008.
16
Ping-ChuanWang and 王彬權. "System Calibration of a Portable Panoramic Image Mapping System (PPIMS)." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/84590485068127570899.
Full textAbstract:
碩士國立成功大學
測量及空間資訊學系碩博士班
100
The development of Mobile Mapping System (MMS) is important for rapid acquisition of 3D spatial information. Nowadays, the Vehicle MMS (VMMS) is one of the system that had well developed and commercialized. This paper proposes a Portable Panoramic Image Mapping System (PPIMS), which is based on MMS. The motivation of this research is concerned about that VMMS will possibility face some problems. Including the stability of electric supply, the difficult preprocess of the system, the precision of image sensors and navigation system, and the limit to get into the mountain and disaster area for the reason of heavy weight and size of VMMS, etc. For easy and portable way to reach to the region which Vehicle can’t do is our research purpose. The PPIMS is composed of six circularly arranged cameras and a GPS antenna fixed on a hexagon platform to capture panoramic images with positions. It is in fact a GPS assisted close-range photogrammetric system. The equipped GPS receiver should have the function of e-GPS (Electronic Global Positioning System), which is based on a Virtual Reference Station (VRS) provided by the National Land Surveying and Mapping Center, Taiwan. Therefore, the platform position can be determined instantaneity for each image set. The advantage of the PPIMS is that the total weight of the platform, cameras and the GPS antenna is less than 2.5 kg, so that it can be carried by a person for data collection. The ability for MMS can be applied for geo-referenced mapping, it must go through a well system calibration .Compared to the VMMS, PPIMS is not loaded the Inertial Navigation System (INS).So the system calibration is to decide the Offset Vector and Orientation between the camera set and the GPS antenna . The field calibration method of VMMS is adopted in this paper, we called it One-step calibration. But it is really difficult to find a qualified outdoor calibration field which can let every image cover enough number of well distributed control points, result in a bad calibration result. Therefore, we set up an indoor panoramic calibration field with a good distribution of control points to determine the relative geometry among cameras first, and followed by using a simple outdoor calibration field to calibrate the relationship between GPS center and cameras. We called that Two-step calibration. In order to solve system calibration, we developed a constrain-aerial triangulation adjustment for second step calculation. Finally, use the calibration value to test the quality of object point determination. The calibration results show that the Orientation in the three direction is in millimeter level of accuracy, the Offset Vector in the three axis is from 1 to 2 centimeter of accuracy, and the accuracy of direct geo-referencing is about 5 centimeter of 3D. It is ample to show achievements of the Two-step system calibration.
17
"Type II secretion and secreted ppiases promote low temperature growth and survival in Legionella pneumophila." NORTHWESTERN UNIVERSITY, 2008. http://pqdtopen.proquest.com/#viewpdf?dispub=3303607.
Full text
18
Po-ChinTsai and 蔡博慶. "Bundle Adjustment and Applications of a Portable Panoramic Image Mapping System (PPIMS)." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/78726245529123166648.
Full textAbstract:
碩士國立成功大學
測量及空間資訊學系碩博士班
100
This study proposes a Portable Panoramic Image Mapping System (PPIMS), which is based on the principle of the Mobile Mapping System (MMS). The motivation of this design is to develop a portable MMS for rapid acquisition of 3D spatial information. The PPIMS is designed for some difficult accessing areas by vehicles, such as a heavily damaged mountain village or a disaster landscape. This system can improve the mobility and convenience of the Land Vehicle MMS, and aim at the three-dimensional model for disaster areas. PPIMS is equipped with 6 circular arranged cameras to capture panoramic images and a GPS receiver for positioning. The system calibration should be performed to get the relative orientations and positions between cameras in the body frame. The orientations and positions of each station are used to rebuild the exterior orientation parameters of each image. Because we do not use the INS, we can’t get the orientations of stations directly. So this study focuses on how to get the orientations of each station and propose an algorithm of bundle adjustment to get these parameters without using control point. Finally, the exterior orientation parameters of each image would be calculated. Based on the result, the precision of the orientations are about 1.2’ to 12’ and the positions are about 2 to 10 cm. The precision will be better when control points are used.
19
Brosi, Helen Beate [Verfasser]. "Characterization of preproinsulin (ppins)-specific CD8 T-cell responses in novel models of autoimmune diabetes / vorgelegt von Helen Beate Brosi." 2010. http://d-nb.info/1004738994/34.
Full text
20
Petty, Duncan R., J. Allan, R. Dawson, and Jonathan Silcock. "How effective are primary care pharmacists at running dyspepsia clinics for patients prescribed PPIs?" 2018. http://hdl.handle.net/10454/16681.
Full textAbstract:
YesIntroduction As a consequence of the low cost and perceived safety, proton pump inhibitors (PPIs) are widely prescribed but they can cause longterm adverse effects and are often overprescribed. For most patients PPIs should not be continued long-term as patients can become dependent on PPIs and they are rarely stepped down/off treatment. We aimed to measure whether a dyspepsia review service could help patients on PPIs to step down/off treatment whilst still keeping them symptom free. Methods Pharmacists were provided with training on dyspepsia management. Four general practices were selected. Patients taking a PPI for more than two months were included. A list of exclusion criteria (e.g. active ulcers, newly initiated) was applied. Between six and eight dyspepsia review clinics were run at each site. Patients were booked into a 15-minute consultation. A concordance style consultation was held with clinicians providing information on dyspepsia management and exploring the patients’ ideas, concerns and expectations about stepping down or stepping off treatment. A follow-up audit was performed at four months to determine if patients had remained stepped down/off. An economic evaluation of clinic costs and drugs savings was performed. Results A total of 508 patients were invited to a review; 136 did not attend and 58 were excluded due to not meeting the inclusion criteria, leaving 314 patients reviewed for step-down/step-off. Successful step down/step off was achieved in 257 people (82% of those reviewed). The total cost savings of PPIs was £7,100. The additional cost of alginates was £1,207 giving a net saving on medicines of £5,893 per annum. Set-up costs were £1,194 and staff costs £3,524 to £5,156 giving total running costs, which vary dependent on the Agenda for Change (AfC) grade of pharmacist involved, of £4,720 - £6,351. Conclusion A dyspepsia review clinic is cost-neutral to run but, given that many patients are on polypharmacy, PPI step down might best be considered as part of a holistic medication review clinic.
Reckitt Benckiser, National Institute for Health Research, Health Education England
21
Chen, Kuan-Chen, and 陳冠臻. "Estimation of Readmission Factors for ACS Patients Who Received Clopidogrel with Clopidogrel PPIs by Data Mining Techniques." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/rup9bt.
Full textAbstract:
碩士國立中正大學
醫療資訊管理研究所
103
Acute coronary syndrome (ACS) refers to any clinical manifestations of myocardial ischemia, which often caused by coronary thrombosis. For secondary prevention, clinic physicians use antiplatelet agents, such as clopidogrel, to decrease platelet aggregation therefore inhibit thrombus formation. While these drugs are effective in reducing the risk of ACS, they can increase the change of GI bleeding. Proton pump inhibitors (PPIs) are widely used to decrease the opportunity of this side effect. However multiple researches have reported use clopidogrel combination with PPIs may affect the effective of clopidogrel. The evident of the effect is inconsistent. To discuss the effects on prognosis of ACS patients who use clopidogrel with PPIs, we retrieved data of ACS inpatients through 2005 to 2010 from National Health Insurance Research Database. We Apply WEKA3.7.3 as our data mining tool and build up various of classifiers to estimate the prognosis factors of ACS patients taking clopidogrel with PPIs. With collect total 2,603 cases, 342 of them received coronary artery bypass graft (CABG), and 2261 received percutaneous coronary intervention (PCI). None of CABG patients experienced readmission after discharged, while 121 PCI patients experienced. Using CART Tree Analysis the readmission risk, we find the risk of male is greater than female. For male who take diltiazem with esomeprazole and nifedipine, the risk is much greater. The risk of readmission of males who are older than 65 is increased. Finally females receiving esomeprazole or pantoprazole have higher chance of readmission.
22
Segoati, Norah Sheillah. "Public Private Institutional Partnerships (PPIPs) in South Africa : the case of service delivery in the health and social development sectors in the Sedibeng District Municipality." Diss., 2015. http://hdl.handle.net/2263/50777.
Full textAbstract:
This study is premised on a new approach in the study of Public Private Partnerships by introducing a new variable, termed the Institution. The study examines and explores the contributions of public private institutional partnerships in health and social development service delivery at the Sedibeng District Municipality (SDM) of South Africa. The involvement of BHP Billiton and Hollard as entities from the Private Sector, and that of the University of North West in South Africa, has proven to be an important catalyst in the unravelling of systemic quagmires towards the improvement of service delivery in the SDM. Thus, the study has shown that the PPIP has generated the much needed expertise in the provision of human resource procurements in the SDM of South Africa. At the same time, this study has adumbrated clearly that the South African government’s continuous attempts to deliver all kinds of services to the community has proven to be a worthwhile strategy. The triangular relationship of the partnership framework comprises of public, private and institutions of higher learning as an alternative service delivery (ASD) mechanism. Although it could be surmised that the private sector exists for profit, universities are responsible for teaching, research and learning as well as community outreach; and government is also expected to create the environments for the procurement and provision of public goods and services. This study has conclusively shown that there is a high probability that the relationship formed through the PPIP framework can enhance an effective, economic and efficient service delivery for the SDM and beyond.
For the purposes of this study, a qualitative methodology was used by applying a triangulation approach. The study further argues that although government cannot provide all the needs and services of its people, it has been able to address to a greater extent these problematic issues by creating strategic partnerships (PPIP) with other stakeholders. In the anticipation of this relationship, leadership and commitment of stakeholders should take a critical role in facilitating the process of partnerships which will result in the formation of networks, human, economic and social capital for development. Finally, this study has shown that through dedicated sets of partnership like the PPiP approach utilized in this study, tensions between stakeholders will be reduced and well managed.Dissertation (PhD)--University of Pretoria, 2015.
tm2015
School of Public Management and Administration
PhD
Unrestricted
23
Velazquez, Hector. "Molecular Dynamics Simulations Towards The Understanding of the Cis-Trans Isomerization of Proline As A Conformational Switch For The Regulation of Biological Processes." 2014. http://scholarworks.gsu.edu/chemistry_diss/89.
Full textAbstract:
Pin1 is an enzyme central to cell signaling pathways because it catalyzes the cis–trans isomerization of the peptide ω-bond in phosphorylated serine/threonine-proline motifs in many proteins. This regulatory function makes Pin1 a drug target in the treatment of various diseases. The effects of phosphorylation on Pin1 substrates and the basis for Pin1 recognition are not well understood. The conformational consequences of phosphorylation on Pin1 substrate analogues and the mechanism of recognition by the catalytic domain of Pin1 were determined using molecular dynamics simulations. Phosphorylation perturbs the backbone conformational space of Pin1 substrate analogues. It is also shown that Pin1 recognizes specific conformations of its substrate by conformational selection. Dynamical correlated motions in the free Pin1 enzyme are present in the enzyme of the enzyme–substrate complex when the substrate is in the transition state configuration. This suggests that these motions play a significant role during catalysis. These results provide a detailed mechanistic understanding of Pin1 substrate recognition that can be exploited for drug design purposes and further our understanding of the subtleties of post-translational phosphorylation and cis–trans isomerization.
Results from accelerated molecular dynamics simulations indicate that catalysis occurs along a restricted path of the backbone configuration of the substrate, selecting specific subpopulations of the conformational space of the substrate in the active site of Pin1. The simulations show that the enzyme–substrate interactions are coupled to the state of the prolyl peptide bond during catalysis. The transition-state configuration of the substrate binds better than the cis and trans states to the catalytic domain of Pin1. This suggests that Pin1 catalyzes its substrate by noncovalently stabilizing the transition state. These results suggest an atomistic detail understanding of the catalytic mechanism of Pin1 that is necessary for the design of novel inhibitors and the treatment of several diseases. Additionally, a set of constant force biased molecular dynamics simulations are presented to explore the kinetic properties of a Pin1 substrate and its unphosphorylated analogue. The simulations indicate that the phosphorylated Pin1 substrate isomerizes slower than the unphosphorylated analogue. This is due to the lower diffusion constant for the phosphorylated Pin1 substrate.
24
Huang, Yung-Chieh, and 黃勇傑. "Effect of Proton Pump Inhibitors (PPIs) with Health Education Intervention on Gastroesophageal Reflux Disease (GERD) and the Disease Impact Scale." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/73628591879568442281.
Full textAbstract:
碩士國防醫學院
公共衛生學研究所
99
Background: Gastroesophageal Reflux Disease (GERD) has become a public issue in Taiwan. The incidence and prevalence rate of GERD growing up with aging, westernized diet, lifestyle changes and obesity. However, current clinical diagnosis and treatment only focus on surgery or drugs to inhibit gastric acid secretion, seldom takes into consideration the effect of health education adjuvant treatment, which includes diet, lifestyle modification and disease knowledge, attitude and practice (KAP). Objectives: The aim of this study was to evaluate the effect of health education adjuvant Proton Pump Inhibitors (PPIs) on diet, lifestyle changes, KAP, GERD clinical symptoms impact scale and severity of the endoscopy. To further explore the predictors of difference on GERD impact scale. Methods: This study design was a Randomized Controlled Trial (RCT) with 6-8 weeks follow-up. A total of 181 subjects with GERD were randomly assigned to experimental (N=92) or control group (N=89). Data were collected from the structured questionnaire survey and upper gastrointestinal endoscopy reports. The questionnaire include demographic, diet habits, lifestyle habits, disease related KAP and modified GERD Impact Scale (mGIS). The experimental group received PPIs therapy adjuvant with health education intervention, while the control group received PPIs therapy and general routine care. All calculations were carried out using SPSS v18.0 statistical software. A p-value <0.05 was considered statistically significant. Results: The experimental group was siginificant better than control group to avoid or decreased drinking tea, coffee, soup after a meal, eating spicy foods, increased physical activity, increased disease knowledge, attitudes and practice and decreased mGIS. The experimental group ∆mGIS score was siginificant better than control group with avoid or decreased poor diet, lifestyle, improved disease knowledge and practice. The multiple linear regression (stepwise) analysis showed that improved knowledge (β=1.221, t=2.716), sleeping with the bed-head raised (β=0.539, t=12.344) and avoid or decreased eating sweets (β=0.101, t=3.644) were ∆mGIS predictor. Conclusions: The findings of this study demonstrated that health education intervention adjuvant PPIs can be offered the best way to improve patients’ poor diet, lifestyle, disease related KAP, and reduced degree of clinical symptoms. However, the effects of health education intervention on endoscopy severity of GERD need the further studies or time to oberserve.
25
Simard, Anne-Marie. "Stabilité de l’acide ribonucléique pour la datation des fluides corporels en biologie judiciaire." Thèse, 2011. http://hdl.handle.net/1866/5887.
Full textAbstract:
Des recherches en sciences judiciaires ont montré récemment une possible corrélation entre le temps d’entreposage d’échantillons de fluides corporels et la dégradation de l’ARN dans ceux-ci. Le moment où une tache a été déposée sur une scène de crime peut être important pour déterminer la pertinence d’un échantillon dans une enquête.
Dans ce mémoire, nous rapportons les profils de dégradation de quatre ARN différents mesurés par RT-qPCR, soit l’ARN ribosomique 18S et les ARNm de la β-actine, de la glyceraldehyde-3-phosphate déhydrogénase et de la cyclophiline A, obtenus de taches de sang, de salive et de sperme, entreposés à la température de la pièce ou au congélateur à -80°C sur une période de 6 mois.
Nos résultats montrent une faible variation interindividuelle pour le sang et le sperme, mais une différence importante entre les donneurs pour la salive. De plus, le profil de dégradation est semblable pour tous les transcrits, mais diffère entre les fluides. La congélation des échantillons stabilise les ARN avant leur analyse. Finalement, la quantité d’ARN détecté est en relation avec le temps d’entreposage et pourrait être utilisée afin d’estimer l’âge des échantillons lorsque l’impact des conditions d’entreposage sur la dégradation de l’ARN sera mieux connu.Recent studies in forensic science have shown a possible correlation between the degradation rate of some RNA transcripts and the age of bloodstains. The time of deposition of a stain can be of major importance to determine the relevance of a sample in a forensic investigation. In this thesis, we describe the degradation profiles of the 18S ribosomal RNA and the β-actin, glyceraldehyde-3-phosphate dehydrogenase and cyclophilin A mRNAs, measured by RT-qPCR and obtained from dried blood, semen and saliva stains stored at room temperature or frozen at -80°C up to 6 months. Our results showed low inter-individual variation for blood and semen stains, but a high variation was observed between donors for saliva. Moreover, degradation profile of each transcripts was similar, but differed between fluids. Freezing samples prevented RNA degradation over time. Finally, RNA quantity was in relation with the time of storage and could be used to estimate the time since deposition of a stain when the effects of various storage conditions on RNA degradation profiles will be better documented.
Projet de recherche réalisé en collaboration avec la section Biologie/ADN du Laboratoire de sciences judiciaires et de médecine légale (LSJML) de Montréal.
26
Pinto, Azevedo-Vethacke Marina Da Conceição [Verfasser]. "The effect of proton pump inhibitors (PPIs) on the orientation of Helicobacter pylori in the gastric mucus of the Mongolian gerbil in vivo / submitted by Marina Da Conceição Pinto Azevedo-Vethacke." 2008. http://d-nb.info/991083601/34.
Full text
27
Van, Rensburg Hendrika Nicolien Janse. "A longitudinal study of the usage of acid reducing medicine using a medicine claims database / H.N. Janse van Rensburg." Thesis, 2007. http://hdl.handle.net/10394/1903.
Full text