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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
651

Identification Of Chloroquine Resistant Haplotypes Of Plasmodium Falciparum In India And Development Of New Antimalarial Combinations

Vathsala, P G 11 1900 (has links)
Malaria afflicts 300-500 million people in the world and the mortality ranges from 1-2 million, children in Africa being the most susceptible. With a vaccine not being available against malaria and the front line drugs such as chloroquine and antifolates registering widespread parasite resistance, the challenge of malaria treatment is a formidable task. While, research to discover new drugs has become essential, it has also become necessary to identify therapeutic strategies in the short-term. One approach is to examine whether known drugs used for other applications can be used to treat malaria. A second strategy is to look for natural compounds for antimalarial activity either singly or in combination. Combination therapy has assumed considerable importance in the context of artemisinin derivatives being the sole, tested, efficacious antimalarials left in the basket. A combination therapy with artemisinin derivative may prevent recrudescence due to monotherapy, extend the life of the drug and perhaps bring down the cost of therapy as well. A primary requirement to embark on such studies is to assess the status of drug resistance to the front line drugs in use. In India, chloroquine is still used as the front line drug for malaria therapy. Although, there have been indications and sporadic reports on the development of chloroquine resistance in the country, there has not been a detailed molecular or clinical evaluation for resistance. Keeping all these considerations in mind, the objectives of the present study are as follows: 1. Evaluation of chloroquine resistance inP.falciparum isolates from patients using Pfcrt-mutation as marker. 2. Evaluation of the anti-tubercular drugs, rifampicin and isonicotinic acid hydrazide (INH) for antimalarial activity. 3. Evaluation of curcumin from turmeric singly and in combination with α,β- arteether for antimalarial acitivity. Chapter I deals with the review of literature pertaining to scenario of available antimalarials, efforts to discover new antimalarials based on new drug targets, mechanisms of drug resistance and strategies for combination therapies. Chapter II deals with an evaluation of Pfcrt mutation in clinical samples of P.falciparum malaria in India. After several false starts to find molecular markers to identify chloroquine resistance, mutations in the Pfcrt gene of P.falciparum, K76T mutation in particular, has been shown to correlate very well with chloroquine resistance in culture. A study of 109 P.falciparum – infected blood samples from different parts of India has revealed that close to 95% of the isolates carry the K76T mutation. This was shown on the basis of susceptibility to ApoI restriction digestion of the PCR product covering this region (264 nt) and DNA sequencing of the PCR product. Interestingly, the resistant haplotype in this region of 72-76 amino acids was found to be mostly SVMNT, except for 4 samples with CVIET haplotype. SVMNT has all along been considered to be of South American origin, where as CVIET is of South East Asian/African origin. Subsequent studies by another group in the country has also shown that the Pfcrt - K76T mutation is seen at least in 85% of the cases and in addition to the dominant SVMNT haplotype, newer haplotypes are also seen. The present study has also included an analysis of N86Y mutation in the Pfmdr1 gene based on susceptibility to Afl III restriction enzyme digestion and DNA sequencing of the PCR product (603 nt). Pfmdr1 mutations have been extensively studied in literature for possible correlation to CQR. The net conclusion is that it does not contribute directly to CQR but may have an indirect correlation. It has been shown in Mali that there is very good correlation between Pfcrt - K76T mutation and Pfmdr1 - N86Y mutation in the P.falciparum isolates. However, in the present study with Indian isolates only around 30% of the samples were found to carry the Pfmdr1 - N86Y mutation. While, further studies on the clinical relevance of the extensive Pfcrt mutation seen in the Indian isolates are needed, it is clear that the genetic change towards chloroquine resistance has already taken place in the Indian context. Chapter III is devoted to a study of the antimalarial effects of the anti-tubercular drugs, rifampicin and INH. This is on the basis that rifampicin is an inhibitor of prokaryotic and mitochondrial/chloroplast RNA polymerase. P.falciparum harbors the apicoplast, a remnant of chloroplast with a 35kb DNA. It is known that the β, β’- subunits of the apicoplast RNA polymerase are coded by the apicoplast DNA. There is a report that rifampicin is a slow acting antimalarial in cases of P.vivax -nfection. INH is known to act by inhibiting the enoyl-ACP reductase and β - hydroxy ACP synthase in M.tuberculosis. While, M.tuberculosis is known to manifest Fab I and Fab II pathways of fatty acid biosynthesis, it has recently been shown that P.falciparum manifests the FabII (discrete enzymes) pathway. Thus, it was considered possible that INH may also inhibit the fatty acid biosynthetic pathway of P.falciparum leading to inhibition of phospohlipid and membrane biosynthesis. Studies were, therefore, carried out with rifampicin, INH and the combination on the survival of P.falciparum in culture and P.berghei in mice. With P.falciparum, growth was followed by measuring3[H]-Hypoxanthine incorporation and slide detection of parasites using Giemsa stain. The results indicate that while, rifampicin inhibits P.falciparum growth with an IC50 around 25nM, and INH fails to show any effect even at 200µM concentration. The combination of rifampicin (25nM) and INH (100µM) shows enhanced killing effect. In view of these results, studies were undertaken in mice infected with P.berghei. After 72 hr infection, the mice were orally fed with rifampicin (500 µg/40 g body weight) or INH (1 mg/40 g body weight) or a combination of the two orally for 5 days, starting on day 3. Apart from parasite clearance in blood, protection against mortality is a good index, since all the infected mice die in about 7-8 days. The results indicate that rifampicin leads to around 50% protection and INH treatment gives around 10% protection. However, the combination gives around 83% protection with complete clearance of the parasite in blood. Short- term treatment of infected mice with drugs and an assay of rpoB/C transcription in the parasite using appropriate PCR primers reveal a striking inhibition in combination treatment. Again, when such parasites were put into short-term culture and32P- incorporation into phospholipids was measured, there was striking inhibition with combination treatment. Thus, the results indicate that a combination of rifampicin and INH has potent antimalarial activity in P.berghei-infected mice. The results are dramatic in this case when compared to the results obtained with P.falciparum culture. It is not clear whether the differences are due to differences in action in vitro vs in vivo or due to differences in susceptibility between P.falciparum and P. berghei to the treatment provided. Chapter IV deals with the antimalarial activity of curcumin (diferuloyl methane) from turmeric singly or in combination with artemesinin or its derivative. Curcumin is reported to have a wide variety of biochemical effects and its anti-cancer activity is under serious investigation. There is an earlier report that curcumin shows antimalarial activity against chloroquine-sensitive P.falciparum. In the present study, curcumin was tested against a chloroquine-resistant culture of P.facliparum and it inhibits growth with an IC50 of 5-8 µM. When P.berghei-infected mice were orally fed with curcumin for 5 days, there was delay in the development of parasitemia, with about 30% of the animals protected against mortality by day 28. For reasons mentioned earlier curcumin was tested in combination with artemisinin/derivative in P.falciparum culture and P.berghei in mice. The results indicate that artemisinin and curcumin have an additive inhibitory effect on P.falciparum growth, based on a detailed analysis of the isobolograms. In terms of the mechanism of action, curcumin treatment leads to accumulation of45Ca in the parasite cytoplasm. It also has a striking inhibitory effect on32P-incorporation into parasite proteins and phospholipids, suggesting an interference with phosphorylation mechanisms. None of these effects are seen under artemisinin treatment, which has been reported to specifically inhibit PfATP6 (Ca ATPase) in P.falciparum. In view of the possible different modes of action of artemisinin and curcumin, the combination was tested in P.berghei-infected mice. The infected mice received a single injection of α,β-arteether and 3 oral doses of curcumin (5mg/30g body weight). Curcumin treatment was found to dramatically delay the onset of parasitemia seen in animals treated with α,β-arteether alone due to recrudescence. In particular, a combination with a single injection of α,β-arteether (750µg or 1.5mg/30g body weight) followed by 3 oral doses of curcumin leads to complete prevention of recrudescence and 100% protection against mortality. Several combinations with artemisinin derivative are under investigation and they all suffer from toxic side effects, pharmacokinetic mismatch, known resistance to the combining partner and high cost. It is felt that this artemisinin derivative curcumin combination could prove superior in view of the fact that no resistance is known to curcumin and is safe even at very high doses used in the human. Both the drugs are eliminated fast and curcumin is a cheap chemical and available in plenty from natural source (turmeric). In view of these positive attributes, a clinical trial with this combination is recommended. 121
652

Establishment of an Expression and Purification System for Plasmodium falciparum Multi Drug Resistance (pfmdr) Transporter

Beniamin, Armanos January 2007 (has links)
<p>Malaria is a life threatening parasite disease caused and transmitted by infected female anopheles mosquito. However, the parasite, Plasmodium falciparum, has become resistant to most anti malarial drugs, such as chloroquine, which contributes to fever and anaemia because of its ability to digest the haemoglobin in the red blood cells. The aims of this project were to establish whether “Bac to Bac” Baculoviral Expression System is suitable for expression of pfmdr 1 gene and for purification of the pgh 1 protein. The pfmdr 1 gene encodes an ABC transporter protein, pgh 1, fixed in the cell membrane of the Plasmodium falciparuum gut, which assist in elimination of drug compounds. Furthermore, “Bac to Bac” Baculoviral Expression System uses vectors with histidine tags to clone the pfmdr 1 gene and subsequently transform these into DH10Bac cells to produce the recombinant bacmid DNA. Since pfmdr 1 gene is an AT-rich sequence, PCR was optimized, by lowering the annealing and extension temperature to 47Co and 66Co respectively. The results show that “Bac to Bac” Baculoviral Expression System can be used to express the pfmdr 1 gene, though further experiments has to be performed.</p>
653

Kundcentrerade miljöåtgärder - En studie av Pan Nordic Logistics kunders krav på miljövänliga transporter : Customer centered environmental measures - A study of Pan Nordic Logistics customers demand for environment-friendly transport

Ericson, Frida January 2008 (has links)
<p>Traditional product features such as price, quality and supply service have been extended and nowadays includes environmental aspects as well. It raises new and increasing demands on haulier companies. The transport sector is responsible for a large part of the pollutants causing today’s environmental problems. The business is being closely monitored and to operate environmental friendly is seen as one of the most important elements for the industry’s future development. Haulier companies must not only meet the restrictions of the government, but also respond to the customers’ demands on</p><p>environmental performance.</p><p>The aim of the study is to review the environmental demands of PNLs present customers and what they think their demands will look like in three years time. The scope of the survey is two-fold. The study will partly review if the changing environmental aspects can impact on supply service and price; and partly investigate the importance of an environmental certification. To reach the aim of the study qualitative interviews have been carried out with nine of PNLs present customers. The choice of customers has been made to represent</p><p>an overall picture of PNLs customer portfolio.</p><p>The study concluded that supply service and price is more important than environmental aspects today. The customers are prone to compromise on delivery time and price to the advantage of the environment. But it can not cost too much or take too long, and there must be a possible choice of transport.</p><p>There are today no expressed environmental demands on transport, but the conclusion is that it is only a matter of time before they will prevail. The results prove that environmental issues are estimated to be fundamental for hauliers in the future. It is seen as a competitive advantage to be at the leading edge of offering green transportation alternatives.</p><p>It is considered important today that hauliers pursue environmental issues aggressively. A certification according to ISO or other environmental management systems is considered less important. The results show that environmental management systems and an operative environmental framework will increase in importance in the future when choosing between hauliers.</p>
654

Daily Travel Mode Choice from an Intersectional Perspective : -A Literature Review and a Case Study in Uppsala

Paulusson, Malin January 2015 (has links)
The transport sector is an extensive contributor to the total CO2 emissions, and private transports hold a vast share. This has implications on environmental and human health, which eventually have economic consequences for society. Equal access to opportunities is essential in a sustainable society and public transport is a crucial element. Apart from public transport, physical active transport modes are key components in a sustainable transport system. The aim of this thesis was through an intersectional perspective to gain deeper understanding about travel mode choices and to identify barriers to use of public transport. This thesis comprises an extensive literature review of 62 articles, reviews and publications on travel behavior and travel mode choice undertaken in different parts of Sweden, Germany, UK, Portugal and the USA. A limited case study shares through nine qualitative interviews the travel experiences of four men and five women in different ages in Nåntuna/Vilan and Sävja in Uppsala, Sweden. The influencing factors were categorized and later intersectionally analyzed with the respect to gender, age and socioeconomic class. The analysis revealed that travel mode choices are complex and can be made for various reasons. Access to a car, habits, travel pattern and time indicated to be the most influencing factors. Economic resources seemed to influence the availability of transport mode, and indications could be seen that economic resources might impair gender differences. Looking at preferences and actual mode choice, the study sample illustrates that men, older, and richer, are having more opportunities to take their preferable mode choice. Planning factors appeared to both promote and constrain the use of public transport. Public transport seemed to have hard to meet everyone’s need, and indicated to have low competitiveness to the car. It is suggested that future research focuses on how to meet more people’s need in order to increase the use of public transport by its own attractiveness. Further research is also suggested about the health perspective of physical active modes and public transport. The study revealed difficulties in studying experiences outside the white, majority Swedish norm. More time would have been needed to include ethnicity, as it is an important aspect and should be included in future research. / Transportsektorn bidrar till en omfattande del av det totala koldioxidutsläppet, och privata transporter utgör en ansenlig del av detta. De miljö- och hälsomässiga negativa effekterna är betydande, vilket följaktligen kommer att få sociala och ekonomiska konsekvenser. Det övergripande politiska målet är att öka användandet av hållbara transportmedel, så som fysiskt aktiva färdmedel och kollektivtrafik. Lika möjligheter att nå arbeten och service är en förutsättning för ett hållbart samhälle, och kollektivtrafiken är en viktig nyckel till detta. Förutom kollektivtrafiken är också fysiskt aktiva färdmedel, så som cykling och gång, en nyckelfaktor i ett hållbart transportsystem. Syfte: Syftet med den här masteruppsatsen är att få djupare kunskap om de faktorer som påverkar resebeteende och färdmedelsval, samt att identifiera barriärer för kollektivt resande. Uppsatsen har ett intersektionellt perspektiv och undersöker hur maktfaktorer som kön, ålder och socioekonomisk klass påverkar valet av färdmedel. Metod: En omfattande litteraturstudie om resvanor och resebeteende i Sverige, Tyskland, Storbritannien, Portugal och USA föregick en fallstudie. Med fokus på de två områdena Nåntuna/Vilan och Sävja, i Uppsala, Sverige, genomfördes en mindre fallstudie. Nio kvalitativa intervjuer belyser fyra män och fem kvinnors erfarenheter från sina dagliga färdmedelsval. Resultat: Av dessa framgår att färdmedelsval är komplexa; de kan göras av olika anledningar, samt olika anledningar kan leda till samma val. En mängd olika faktorer indikerade på att påverka valet av färdmedel, bland annat tillgången till bil, vanor, attityder, resmönster och restiden. Dessutom indikerar resultat att maktfaktorer som kön, ålder och socioekonomisk klass formar möjligheterna till att välja färdmedel. Indikationer tyder på att ekonomiska resurser styr tillgången på färdmedelsval samt kan minska könsskillnader. Det emellertid ringa urvalet exemplifierar att män, äldre och rikare har större möjligheter att välja sitt önskvärda färdmedelsval. Respondenternas erfarenheter visar att planeringsfaktorer kan både främja och försvåra användandet av kollektivtrafiken. Kollektivtrafiken verkade ha svårt att möta människors olika behov och därmed vara konkurrenskraftig i förhållande till bilen. Mer forskning om detta är nödvändig för att öka och behålla resenärer utifrån kollektivtrafikens egen attraktionskraft. Vidare så föreslås ytterligare studier om länken mellan hälsa, fysiskt aktiva färdmedelsval och kollektivtrafikanvändande. Studien innefattar inte erfarenheter från personer med annan bakgrund än vit, majoritetssvensk eftersom det hade krävt mer tid än vad denna studie medgav. Det är dock ett viktigt perspektiv för framtida forskning.
655

Kundcentrerade miljöåtgärder - En studie av Pan Nordic Logistics kunders krav på miljövänliga transporter : Customer centered environmental measures - A study of Pan Nordic Logistics customers demand for environment-friendly transport

Ericson, Frida January 2008 (has links)
Traditional product features such as price, quality and supply service have been extended and nowadays includes environmental aspects as well. It raises new and increasing demands on haulier companies. The transport sector is responsible for a large part of the pollutants causing today’s environmental problems. The business is being closely monitored and to operate environmental friendly is seen as one of the most important elements for the industry’s future development. Haulier companies must not only meet the restrictions of the government, but also respond to the customers’ demands on environmental performance. The aim of the study is to review the environmental demands of PNLs present customers and what they think their demands will look like in three years time. The scope of the survey is two-fold. The study will partly review if the changing environmental aspects can impact on supply service and price; and partly investigate the importance of an environmental certification. To reach the aim of the study qualitative interviews have been carried out with nine of PNLs present customers. The choice of customers has been made to represent an overall picture of PNLs customer portfolio. The study concluded that supply service and price is more important than environmental aspects today. The customers are prone to compromise on delivery time and price to the advantage of the environment. But it can not cost too much or take too long, and there must be a possible choice of transport. There are today no expressed environmental demands on transport, but the conclusion is that it is only a matter of time before they will prevail. The results prove that environmental issues are estimated to be fundamental for hauliers in the future. It is seen as a competitive advantage to be at the leading edge of offering green transportation alternatives. It is considered important today that hauliers pursue environmental issues aggressively. A certification according to ISO or other environmental management systems is considered less important. The results show that environmental management systems and an operative environmental framework will increase in importance in the future when choosing between hauliers.
656

Transport processes in the arbuscular mycorrhizal symbiosis

Duensing, Nina January 2013 (has links)
The nutrient exchange between plant and fungus is the key element of the arbuscular mycorrhizal (AM) symbiosis. The fungus improves the plant’s uptake of mineral nutrients, mainly phosphate, and water, while the plant provides the fungus with photosynthetically assimilated carbohydrates. Still, the knowledge about the mechanisms of the nutrient exchange between the symbiotic partners is very limited. Therefore, transport processes of both, the plant and the fungal partner, are investigated in this study. In order to enhance the understanding of the molecular basis underlying this tight interaction between the roots of Medicago truncatula and the AM fungus Rhizophagus irregularis, genes involved in transport processes of both symbiotic partners are analysed here. The AM-specific regulation and cell-specific expression of potential transporter genes of M. truncatula that were found to be specifically regulated in arbuscule-containing cells and in non-arbusculated cells of mycorrhizal roots was confirmed. A model for the carbon allocation in mycorrhizal roots is suggested, in which carbohydrates are mobilized in non-arbusculated cells and symplastically provided to the arbuscule-containing cells. New insights into the mechanisms of the carbohydrate allocation were gained by the analysis of hexose/H+ symporter MtHxt1 which is regulated in distinct cells of mycorrhizal roots. Metabolite profiling of leaves and roots of a knock-out mutant, hxt1, showed that it indeed does have an impact on the carbohydrate balance in the course of the symbiosis throughout the whole plant, and on the interaction with the fungal partner. The primary metabolite profile of M. truncatula was shown to be altered significantly in response to mycorrhizal colonization. Additionally, molecular mechanisms determining the progress of the interaction in the fungal partner of the AM symbiosis were investigated. The R. irregularis transcriptome in planta and in extraradical tissues gave new insight into genes that are differentially expressed in these two fungal tissues. Over 3200 fungal transcripts with a significantly altered expression level in laser capture microdissection-collected arbuscules compared to extraradical tissues were identified. Among them, six previously unknown specifically regulated potential transporter genes were found. These are likely to play a role in the nutrient exchange between plant and fungus. While the substrates of three potential MFS transporters are as yet unknown, two potential sugar transporters are might play a role in the carbohydrate flow towards the fungal partner. In summary, this study provides new insights into transport processes between plant and fungus in the course of the AM symbiosis, analysing M. truncatula on the transcript and metabolite level, and provides a dataset of the R. irregularis transcriptome in planta, providing a high amount of new information for future works. / In der arbuskulären Mykorrhiza (AM) Symbiose werden die Wurzeln fast aller Landpflanzen von Pilzen der Abteilung Glomeromycota besiedelt. Der Pilz erleichtert der Pflanze die Aufnahme von Mineralien, hauptsächlich Phosphat, und Wasser. Im Gegenzug versorgt die Pflanze ihn mit Photoassimilaten. Trotz der zentralen Bedeutung der Austauschmechanismen zwischen Pilz und Pflanze ist nur wenig darüber bekannt. Um die molekularen Grundlagen der Interaktion zwischen den Wurzeln der Leguminose Medicago truncatula und dem arbuskulären Mykorrhizapilz Rhizophagus irregularis besser zu verstehen, werden hier die Transportprozesse, die zwischen den Symbiosepartnern ablaufen, näher untersucht. Die zellspezifische Regulation der Transkription potentieller M. truncatula Transporter Gene in arbuskelhaltigen und nicht-arbuskelhaltigen Zellen mykorrhizierter Wurzeln wird bestätigt. Ein Modell zur möglichen Verteilung von Kohlenhydraten in mykorrhizierten Wurzeln, nach dem Zucker in nicht-arbuskelhaltigen Zellen mobilisiert und symplastisch an arbuskelhaltige Zellen abgegeben werden, wird vorgestellt. Die Analyse eines Mykorrhiza-induzierten Hexose/H+ Symporter Gens, MtHxt1, liefert neue Einsichten in die Mechanismen der Kohlenhydratverteilung in mykorrhizierten Pflanzen. Metabolitanalysen von Wurzeln und Blättern einer knock-out Mutante dieses Gens zeigen dessen Einfluss auf den Kohlenhydrathaushalt der ganzen Pflanze und auf die Interaktion mit dem Pilz. Die Metabolitzusammensetzung von M. truncatula wird durch die Mykorrhiza Symbiose signifikant beeinflusst. Darüber hinaus werden durch Transkriptomanalysen die molekularen Grundlagen der AM Symbiose auf der Seite des Pilzes analysiert. Arbuskeln wurden mittels Laser Capture Mikrodissektion direkt aus mykorrhizierten Wurzeln isoliert. Über 3200 pilzliche Transkripte weisen in diesen Arbuskeln im Vergleich zu extraradikalen Geweben ein deutlich verändertes Expressionslevel auf. Unter diesen Transkripten sind auch sechs zuvor unbekannte Gene, die für potentielle Transporter codieren und mit großer Wahrscheinlichkeit eine Rolle im Nährstoffaustausch zwischen Pilz und Pflanze spielen. Während die Substrate von drei potentiellen MFS Transportern noch unbekannt sind, spielen zwei potentiellen Zuckertransporter möglicherweise eine Rolle im Transport von Kohlenhydraten in Richtung des Pilzes. Zusammengefasst bietet diese Arbeit neue Einsichten in Transportprozesse zwischen Pilz und Pflanze im Laufe der AM Symbiose. M. truncatula Transkript- und Metabolitlevel werden analysiert und die Transkriptomanalyse von R. irregularis liefert einen umfassenden Datensatz mit einer großen Menge an Informationen zu der noch unzureichend erforschten pilzlichen Seite der Symbiose für folgende Arbeiten.
657

Genetic diversity of the Organic Cation Transporter 1 gene within the Cape Coloured Population

Brendon Pearce January 2012 (has links)
<p>The aim of this study was to investigate the genetic diversity of the SLC22A1 gene and to deduce its possible pharmacogenetic implications within the Cape Coloured population of South&nbsp / Africa / a uniquely admixed population of immigrant Europeans, Asians and the indigenous populations. Recent studies have reported an abundance of polymorphic variants within this solute&nbsp / carrier transporter gene encoding for the organic cation transporter 1, as well as evidence linking these variants to an effect on metformin uptake. This study included establishing baseline&nbsp / frequency distribution of previously reported alleles for 20 SNP variants within the SLC22A1 gene, as well as the development of SNaPshot&reg / and Multiplex AS-PCR genotyping assays, and&nbsp / also exploring the possibility of using High-resolution melt (HRM) analysis as a costeffective alternative for SNP genotyping. Ethics clearance was obtained from the Ethics Committee of the&nbsp / University of the Western Cape. Biological samples in the form of buccal (oral) swabs were collected from 132 unrelated voluntary donors from the Cape Coloured population residing in the&nbsp / Cape Metropolitan area. Two SNaPshot&reg / Multiplex Systems were specifically designed for the study,successfully optimized and used for genotyping. Hundred genetic profiles were then generated for a total of 20 SNP variants on SLC22A1 gene, using this primer extension-based genotyping method that enables multiplexing up 10 SNPs. Population genetics data obtained for&nbsp / the investigated SNPs were analysed using various statistical analysis software. Important population genetic parameters were calculated, and possible pharmacogenetics implications were then discussed. Among others, allelic and genotypic frequencies, as well as linkage disequilibrium were determined and compared with world populations. Minor deviation from Hardy- Weinberg equilibrium was observed in the Cape Coloured population. No significantLinkage Disequilibrium between the investigated SNPs was observed in this population. A Multiplex allele specific &ndash / PCR (MAS-PCR) genotyping&nbsp / system was successfully designed and optimized for the genotyping of 10 SNPs from the SLC22A1. This system, also developed specifically for this study, was made of 2 multiplexes each covering 5 SNPs. It is an inexpensive genotyping assay that allows for efficient discrimination of SNP polymorphisms in one reaction tube with standard PCR conditions. A pilot study was&nbsp / conducted to explore the possibility of using High-resolution melt (HRM) analysis as a cost-effective alternative for SNP genotyping. In addition to genotyping, HRM analysis can be used to scan&nbsp / large numbers of samples for novel genetic variations.&nbsp / </p>
658

Étude et modélisation de la cinétique orale de l'amoxicilline chez le porcelet

Bernier, Dave 12 1900 (has links)
Il est rapporté que la biodisponibilité orale de l’amoxicilline chez le porc est environ trois fois moindre que chez l’homme. Pour élucider les raisons de cette différence, la pharmacocinétique artérielle, veineuse porte et urinaire de cet antibiotique a été caractérisée à des doses intragastriques de 4 à 30 mg/kg et différents modèles compartimentaux physiologiques ont été conçus pour l’analyse des données. La biodisponibilité orale de l’amoxicilline est maximale à 4 mg/kg, avec une valeur moyenne de 52%. Les différences porto-systémiques de concentrations plasmatiques d’amoxicilline et la clairance urinaire ont permis de démontrer une augmentation de la clairance hépatique jusqu’à la dose de 30 mg/kg. Un modèle compartimental comprenant deux voies parallèles d’absorption (de type Michaelis- Menten d’accessibilité limitée dans le temps et d’ordre 1), deux compartiments de distribution (central et périphérique) deux voies d’élimination (excrétions urinaire et biliaire) est celui qui prédit le mieux les données observées. Ces résultats mettent en évidence le rôle prépondérant du transporteur saturable PepT1 dans l’absorption orale de l’amoxicilline administrée à faible dose, ainsi que l’importance croissante de l’absorption passive lors d’administration à forte dose. / It was reported that the oral bioavailability of amoxicillin in swine is about three times lower than in human beings. To elucidate the reasons for this difference, arterial, portal venous and urinary pharmacokinetics was documented at intragastric dose amounts ranging between 4 and 30 mg/kg, and several physiologic compartmental models were developed for data analysis. The maximum oral bioavailability of amoxicillin was recorded at 4mg/kg with a mean value of 52%. The portal-systemic plasma concentration differences of amoxicillin and its urinary clearance revealed an increase in hepatic clearance up to the 30 mg/kg dose. A compartmental model with two parallel absorption route (time-constrained Michaelis- Menten and first-order processes), two distribution compartments (central and peripheral) two elimination pathways (urinary and biliary excretions) best fitted the experimental data. These results highlight the paramount role of the PepT1 carriermediated, saturable absorption at low oral amoxicillin doses, as well as the increasing role of passive absorption at high doses.
659

Cellular Transport of Prostaglandins in the Ovine Uterus

Lee, Je Hoon 03 October 2013 (has links)
In ruminants, prostaglandin F2 alpha (PGF2α) is released from the endometrium in a pulsatile pattern at the time of luteolysis. The luteolytic PGF2α pulses are transported from the uterus to the corpus luteum (CL) through the utero-ovarian plexus (UOP) to cause luteolysis. At the time of establishment of pregnancy, interferon tau (IFNT) secreted by the conceptus suppresses the pulsatile release of PGF2α and thereby rescues the CL and maintains its secretion of progesterone. However, basal concentrations of PGF2α are higher in pregnant ewes than in cyclic ewes. The pulsatile release of PGF2α likely requires selective carrier-mediated transport and cannot be supported by a simple diffusion mechanism. The molecular and functional aspects of carrier mediated transport of PGF2α from the uterus to the ovary through the utero- ovarian plexus (UOP) at the time of luteolysis and recognition/establishment of pregnancy are largely unknown ruminants. Results indicate that intrauterine inhibition of (PGT) prevents the pulsatile release of PGF2α independently of spatial expressions of estrogen receptor (ESR-1) and oxytocin receptor (OXTR) proteins by the endometrium at the time of luteolysis in sheep. PGT protein is expressed in the UOP during the estrous cycle and pharmacological inhibition of PGT prevents transport of luteolytic PGF2α pulse through the UOP in sheep. IFNT activates novel JAK-SRC-EGFR-RAS-RAF-ERK1/2-EGR-1 signaling modules in endometrial luminal epithelial (LE) cells and regulates PGT- mediated release of PGF2α through these novel cell-signaling pathways. IFNT stimulates ERK1/2 pathways in endometrial LE cells and inhibition of ERK1/2 inhibits IFNT action and restores spatial expression of OXTR and ESR-1 proteins in endometrial LE cells and restores endometrial luteolytic pulses of PGF2α in sheep. Collectively, the results of the present study provide the first evidence to indicate that transport of endometrial luteolytic PGF2α pulses from the uterus to the ovary through the UOP is controlled by a PGT-mediated mechanism in sheep, new mechanistic insight into molecular mechanisms regulating cellular and compartmental transport of PGF2α at the time of luteolysis, and new mechanistic understanding of IFNT action and release of PGF2α from the endometrial LE cells and thus opens a new arena of research in IFNT signaling and PGT function.
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Human Papillomavirus 16 E7 Inhibits the ability of IFN-γ in Enhancement of MHC Class I Antigen Presentation and CTL Lysis by Affecting IRF-1 Expression in Keratinocytes

Fang Zhou Unknown Date (has links)
The results of experiments aimed at determining whether cytotoxic T lymphocytes (CTLs) can kill keratinocytes (KCs) expressing endogenously loaded antigen indicated that antigen specific cytotoxic T lymphocytes could recognize and kill keratinocytes expressing ovalbumin (OVA) or SIINFEKL peptide. Exposure of the KCs to interferon-gamma (IFN-γ) enhanced this CTL-mediated KC lysis and increased CTL epitope presentation on the surface of target cells. Expression of HPV 16 E7 protein in KCs affected CTL-mediated lysis. Expression of HPV 16 E7 inhibited IFN-γ-mediated up-regulation of SIINFEKL/H-2Kb complexes on keratinocytes, and also inhibited IFN-γ-mediated up-regulation of IRF-1 expression, and consequent up-regulation of TAP1 transcription. Further, overexpression of IRF-1 partially corrected the HPV 16 E7-mediated inhibition of enhanced susceptibility of KC lysis induced by IFN-γ. Thus, the effects of HPV 16 E7 on CTL-mediated lysis of IFN-γ exposed KCs are likely mediated by inhibition of MHC class I antigen presentation by IFN-γ. These findings may help explain why HPV-infected epithelial cells can escape from immune surveillance mediated by CTLs in vivo and in vitro.

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