La chimie séparative est un pilier du développement technologique en matière d’extraction, de séparation ou de remédiation sélective de molécules ou de métaux. Elle trouve des applications dans les domaines de l’électronique, des énergies renouvelables, de la médecine ou de la chimie, qui nécessitent plus que jamais l’utilisation de « métaux stratégiques ». L’extraction liquide-liquide est une technique de séparation qui intervient dans les procédés hydrométallurgiques pour la récupération de métaux stratégiques issus de gisements primaires, secondaires et de mines urbaines.Ce travail s’inscrit donc dans une vision globale d’optimisation des procédés d’extraction liquide-liquide appliqués en synergie, par une démarche de compréhension des mécanismes à l’origine de la synergie, et de généralisation de ces mécanismes mis à jour à l’ensemble des systèmes d’extraction synergiques. Cette compréhension des mécanismes devant ainsi permettre de prédire et de concevoir de nouveaux mélanges d’extractants synergiques.Pour mieux comprendre les moteurs à l’origine des phénomènes synergiques, une méthodologie adaptée pour la caractérisation des structures supramoléculaires des systèmes extractants en phase organique a été exploitée pour ces travaux de thèse. L’utilisation des techniques de Diffusion de Rayons-X/Neutrons aux Petits Angles (DXPA/DNPA) et de tensiométrie interfaciale ont été déterminantes pour la compréhension des mécanismes sous-jacents à la synergie. L’approche thermodynamique de l’extraction liquide-liquide qui présente l’intérêt d’estimer quantitativement les moteurs essentiels mis en jeu dans les mécanismes d’extraction liquide-liquide, apparait ainsi comme un outil essentiel pour la compréhension des systèmes synergiques. L’application de ces clés de compréhension a permis de concevoir un nouveau système synergique pour l’extraction des terres rares en milieu phosphorique. / Separative chemistry is a pillar of technologic development in extraction, separation and selective remediation of metals and molecules. It finds its applications in the fields of electronic, renewable energy, medicine and chemistry, which require more than ever the use of “Strategic Metals”. The liquid-liquid extraction is a separation technique that is involved in hydrometallurgical processes for the recovery of strategic metals from primary deposits, secondary and urban mines.This work is part of global vision of optimization of liquid-liquid extraction processes used in synergy, consisting in understanding the mechanisms underlying the synergy, and generalizing these mechanisms to all synergistic extraction systems. The understanding of these mechanisms underlying synergism aims at predicting and developing new synergistic extractants mixtures.To better understand the driving forces at the origin of synergistic phenomena, a suitable methodology for the characterization of supramolecular structures of extractant in the organic phase was exploited during this thesis work. The use of techniques like Small Angle Neutron / X-ray Scattering X-ray (SAXS /SANS) and interfacial tensiometry was crucial for the understanding of the synergistic mechanisms. A thermodynamical was also proposed to estimate quantitatively the key driving forces involved in the liquid-liquid extraction mechanisms. The application of these keys of comprehension helped to design a new synergistic system for the extraction of rare earths elements from phosphoric medium.

Magister Pharmaceuticae - MPharm / The declining efficacy of antimalarial drugs against resistant Plasmodium falciparum strains in several endemic regions has amplified the world’s burden of neglected diseases. This has highlighted the need for alternate strategies for chemotherapy and chemoprophylaxis. Since malaria is prevalent primarily in third world countries, it is critical for novel therapies to be affordable. Previous research has found that some antihistamines possess inherent antimalarial activity and cause a marked reversal of chloroquine resistance in vitro and in vivo. Promising results have been demonstrated when chlorpheniramine was combined with chloroquine to reverse chloroquine resistance in two African studies (Sowunmi et al, 1997; Abok., 1997).Recently, astemizole and its principle human metabolite desmethylastemizole were identified as potent inhibitors of Plasmodium falciparum at sub-micromolar concentrations in both chloroquine sensitive and chloroquine resistant parasites, showing efficacy in vitro and in two mouse models. The promising results observed with these studies warrant a more comprehensive understanding of how antihistamines interact with the malaria parasite. Additionally, analysing the different structural and mechanistic characteristics of antihistamines may lead to the design and development of effective and affordable antimalarial agents or chloroquine resistance modulators.This thesis describes the antimalarial activity of mainly off-patent (generic) antihistamines by comparing the efficacy of a total of 24 antihistamines, representing histamine1, histamine2, and histamine3 receptor antagonists, against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Cyproheptadine, ketotifen, loratadine, desloratadine, 3-(1HImidazol-4-yl) propyldi (p-fluorophenyl) methyl ether hydrochloride and ciproxifan display IC50 values less than 4μg/ml. There was no significant difference in the sensitivity to antihistamines among the chloroquine sensitive and resistant parasites tested. A tricyclic nucleus appears to be an important structural scaffold for antihistamines which exhibit low IC50 values. Synergistic studies indicate that enhancement of the antimalarial effect of chloroquine on P.falciparum was observed with the ethanolamines against the chloroquine sensitive parasites.Cyproheptadine, ketotifen and desloratadine exerted a marked synergistic action with chloroquine against chloroquine sensitive and resistant parasites. Chlorpheniramine exhibited synergism with chloroquine against resistant parasites only.Microscopic studies illustrate the effect of antihistamines on parasite morphology when compared to control. Using immunofluorescence microscopy, it was seen that ketotifen decreases haemoglobin localization while cyproheptadine increases haemoglobin localization in the parasite’s food vacuole. Western blots have confirmed these results, in addition to indicating that chlorpheniramine decreases the haemoglobin content in the parasite. The results confirm that certain antihistamines do indeed cause a reduction in the growth of malaria parasites. Furthermore, the histamine1 and histamine3 receptor antagonists are most active while histamine2 receptor antagonists have no antimalarial activity. Microscopic studies suggest that antihistamines do not exert their antimalarial effect via a single mechanism of action.I wish to express my sincere appreciation to the following people and institutions whose supervision and assistance made the presentation of this thesis possible:My supervisor, Prof. Henry Leng. Thank for always believing in me. Your encouragement, kindness and calm temperament has given me the strength to complete this thesis even when times were tough. Your wisdom and understanding will always be remembered.My co-supervisor, Prof. Pete Smith. I sincerely thank you for allowing me the opportunity to work in your laboratory and for welcoming me into the department. Your kindness and welcoming attitude will forever be appreciated. Thank you for always being patient and understanding.Dr. Uschi Wiehart. Thank you for all the help in the laboratory and always being there for me. I truly value and appreciate your contribution to this thesis. Your friendship has added so much positive energy to my life. Thank you for your wisdom, inspirational advice and unfaltering encouragement Sumaya and Ntokosi, your help, advice and company in tissue culture, are truly appreciated.The UCT, Pharmacology students. Thank for all your assistance.My dearest Pharmaceutical Chemistry colleagues, Jaques Joubert, for your friendship and support and for always listening and Prof. Peter Eagles, your kindness, support and wise advice has given me strength when I needed it most. To my other School of Pharmacy colleagues. Prof. Sarel Malan and team, for your support and motivation.To my family for all your support and wisdom and to my baby brothers; Omar and Uzair for all the joy that you bring to my life.And finally to my dearest husband, Zaheer for all your love and support throughout my studies and for taking me to UCT to culture parasites every weekend

Staphylococcus aureus has developed resistance to several antibiotics including vancomycin, which is often used as a “last resort” treatment. There is an ever-increasing need to develop novel antimicrobial treatments to combat S. aureus and other drug resistant bacteria. Microorganisms are most often found in polymicrobial communities where they either exhibit synergistic or antagonistic relationships. Competition between microorganisms can lead to the discovery of new antimicrobial targets as the specific mechanisms of resistance are elucidated. In addition, synergistic treatments are being evaluated for their combined effect and potential to decrease the concentration of drugs needed, and thus the side effects also. Alcaligenes faecalis is a microorganism that our lab has previously shown to inhibit S. aureus and other various bacterial species. In this study, we found that A. faecalis reduces the planktonic growth of S. aureus by 94.5% and biofilm growth by 76.6%. A. faecalis also has a synergistic effect when paired with bacitracin to reduce the planktonic growth by 99.9% and biofilm growth by 99.7%. Transposon mutagenesis was successfully performed on A. faecalis, and loss of function mutations were attained. Two mutants were no longer able to inhibit the growth of Staphylococcus aureus, Candida albicans, or Bacillus megaterium. Further analysis and genomic sequencing of these mutants is needed to determine the gene(s) that were interrupted and the mechanism of A. faecalis’ antimicrobial activity. The findings of this study may aid in the identification of new therapeutic targets for novel S. aureus treatments.

Doctor Educationis / The fungus Botrytis cinerea is an opportunistic pathogen on a wide variety of crops, causing a disease known as grey mould through infections via wounds or dead plant parts. Synthetic fungicides for controlling this disease are fast becoming ineffective due to the development of resistance. This, coupled with consumers' world wide becoming increasingly conscious of potential environmental and health problems associated with the build-up of toxic chemicals, (particularly in food products), have resulted in pressure to reduce the use of chemical pesticide volumes as well as its residues. An emerging alternative to random chemical synthesis is the study and exploitation of naturally occurring products with fungicidal properties. One group of compounds known as strobilurins produced by Strobilurus species, woodland basidiomycete fungi, is a good example of this phenomenon. Plants produce an enormous array of secondary metabolites, and it is commonly reasoned that a significant part of this chemical diversity serves to protect plants against plant pathogens. A problem with plant-produced compounds as potential fungicides is that in the natural state, they are generally only weakly active compared to synthetic fungicides. There have been reports on the uses of mixtures of synthetic fungicides for the control of plant pathogenic fungi. When utilized in two-way mixtures, such fungicides may maintain or enhance the level of control of a pathogen at reduced rates for both components utilized in combinations, or alone at normal rates. These studies provide an important precedent for the idea of synergism. For this study, we hypothesize that the addition of plant extracts may enhance the antifungal efficacy of the synthetic strobilurin fungicide, kresoxim-rnethyl against B. cinerea. We selected South African medicinal plant species such as Artemesia afra, Elyptropappus rhinocerotis, Galenia africana, Hypoxis hemerocallidea, Siphonochilus aetheopicus, Sutherlundia frutescence, Tulbaghia violacea and Tulbaghia alliaceae for this study. For the in vitro study, indigenous medicinal plant extracts were prepared at twofold dilution concentrations and combined with kresoxim-rnethyl at concentrations of 0.25 and 0.5% (w/v). The B. cinerea mycelial plug assays showed potent antifungal inhibitory effects with the plant extract and kresoxim-rnethyl mixtures. Further analyses of the mixtures indicate synergistic effects between the fungicide and plant extracts. I surmise that these in vitro effects are also achievable in vivo. Combinations of these agents represent an attractive avenue for the development of new management strategies for controlling B. cinerea in the future. A second study was conducted to analyse the final dose rates for synergistic reactions for combinations of kresoxim-methyl and medicinal plant extracts against B. cinerea in vivo. A series of two-fold concentrations of medicinal plant extracts were combined with kresoxim-methyl to conduct decay inhibition studies on Granny Smith apples. Synergistic effects were observed for many of the kresoxim-methyl and plant extract combinations. I, therefore, came to the conclusion that indigenous South African plant species produce modulators that potentiate the activity of fungicides. Whether these synergistic effects are due to the inhibition of fungal multi-drug resistant pumps require further studies at the molecular level. However, these inhibitory effects are likely to be advantageous for developing fungicide formulations and application strategies with low toxicity effects on the environment. This approach not only makes it possible to reduce fungicide concentrations while maintaining adequate decay control, but also ensures a reduction of the chemical residue on the fruit.

No description available.

Within the past several years, a great deal of attention has been focused on the phenomena of drug-drug interactions and their importance in the therapeutic regimen of patients for whom multiple therapeutic agents might be indicated. The rather sudden concern for this aspect of medical and pharmaceutical practice is evidenced by the proliferation of literature devoted to the topic for both professions. While iatrogenic disease has long been recognized as one of the hazards inherent in prescribing practices, only isolated reports of specific interactions were found until recently. Although it cannot be said with certainty when the first interaction of two drugs was noticed, such possibilities began to come to light with the observation that concomitant administration of an antacid with a tetracycline would impair the absorption or the anti- biotic (1). A concerted effort to bring order to our recognising and understanding of such interactions has taken place only within the past ten years

<I>Bean pod mottle virus </I>(BPMV, Genus <I>Comovirus</I>, Family: <I>Comoviridae</I>)is an important virus in soybean (<I>Glycine max</I> (L.) Merrill), causing quality and yield loss due to seed coat mottling and seed weight reduction. Although BPMV has been known in Virginia since 1958 and has always been regarded as causing negligible losses, its impact is changing as BPMV incidence has increased in many soybean growing areas of Virginia and the USA in general. From 1997 to 2001, a total of five BPMV isolates (V-W1, V-W2, V-S98-1, V-S98-15 and V-S01-10) were collected in Virginia and characterized. In this study, the effects of these isolates were studied, alone or with Soybean mosaic virus (SMV, Genus Potyvirus, Family Potyviridae) strain SMV G1, and isolates S98-51 and S98-52, on selected soybean cultivars. Individual isolates of BPMV showed variable symptom severity, and resulted in yield loss of between 40.4 to 58.1%, while SMV caused 23.7% in the most severe interactions. Up to 100% yield loss was realized from double inoculations of selected BPMV and SMV isolates, BPMV V-S98-1 + SMV S98-52 and BPMV S98-15 + SMV S98-52 on Hutcheson and Hutcheson Roundup Ready&#174; (BC5) soybeans, respectively. Time of inoculation, a critical factor in the impact of many virus diseases, affected seed coat mottling in four cultivars and seed weight in two cultivars, in tests with four BPMV isolates and three stages of soybean development. All BPMV isolates inoculated to plants at vegetative stage V1-V3 severely increased seed coat mottling and reduced seed weight than those inoculated at V4-V6 and reproductive stage R1-R3. Seedlings grown from non-mottled seeds germinated more uniformly had fewer thin-stemmed seedlings and grew faster than those grown from mottled seeds. Inoculation of various cultivars and breeding lines showed that there was no correlation between the severity of virus-induced foliar symptoms, relative accumulation of SMV, and extent of seed coat mottling. Thus, by avoiding the presence of BPMV at an early growth stage through proper timing of planting to avoid vectors, proper cultural practices like weed control, use of SMV free seeds, and chemical control, it is possible to greatly improve seed quality and reduce yield losses in soybean. / Ph. D.

No description available.

Steroid hormones confer biological activity to effluents of wastewater treatment plants (WWTPs). The occurrence of estrogen and androgen hormones in addition to their biological effects in the environment have been widely studied and there is a growing consensus that mixtures of steroid hormones; albeit at low ng L-1concentrations, lead to endocrine disruption in some aquatic organisms. These mixtures may also be influenced by the contributions of synthetic estrogens and androgens, which may display either additive or antagonistic activity. In order to measure the ability of a single compound, or complex mixture to influence the function of estrogenic or androgenic signaling pathways bioassays are used. Most commonly, these tests are in vitro and may quantify the ability of a compound to bind and/or (in) activate the steroid receptors. Two commonly used bioassays for estrogenicity detection are the Yeast Estrogen Screen (YES) and the E-Screen assay. The Yeast Androgen Screen (YAS) is commonly used to measure androgenic activity. The yeast (Saccharomyces cerevisiae) are genetically transformed and express either the human Estrogen Receptor (ER) or Androgen Receptor (AR), and contain Estrogen or Androgen Responsive Elements (ERE/ARE) and Lac Z reporting plasmids. Once the receptors become activated, beta-Galactosidase is secreted into the assay medium and the level of beta-Galactosidase secretion relates to the estrogenicity or androgenicity of the sample tested. Due to its simplicity and the moderately fast assay time, the YES and YAS are commonly used assays in the analysis of complex mixtures to identify the major contributors to both estrogenic and (anti)-androgenic activity in environmental water. The effect directed approach combines both chemical methods and bioassays in a chemical fractionation scheme that is directed by the bioassays. In order to confirm the identity of the key contributors, it is important to compare the biological activities that are calculated from the concentrations of the identified hormones (given their individual biological responses) and the total biological activity measured through the use of bioassays, Equation 1. RPsCs+ RP2C2+ ...+RPnCn = IEQ (1) where Cn is the concentration of the nth mixture constituent, RP is the relative (estrogenic or androgenic) potential of the nth mixture constituent as determined in the bioassay, and IEQ is the estimated total induction equivalent concentration of the mixture by chemical methods. Cs and RPs represents the concentration and relative potential of a standard compound respectively. Agreement between the chemically and biologically derived IEQs means that the major contributors to the biological effect have been successfully identified. However, the biological assays measure the contribution of additive, antagonistic and synergistic activity in the mixture; therefore, the biologically derived IEQs represent the net biological activity. Chemical methods are unable to predict these interactions and as such the result of the concentration addition (CA) approach (Equation 1) is often inconclusive and suggestive of interacting components. An interaction model that can estimate the net biological activity of a mixture from the concentrations of individual mixture constituents (chemical methods) is thus necessary. An interaction model that combines both the relative potential (RP) as well as the interaction index (γ) in a parameter called aRP was developed. The aRP is defined by Equation 2 and is used similarly to the CA approach, Equation 3. aRP = interaction index-1RP (2) aRPsCs+ aRP2C2+ ...+aRPnCn = IEQ (3) The aRP can be calculated for any nth mixture constituent by measuring the degree to which the mixture components altered the activity of the standard and assessing those changes as a function of mixture ratios. The interaction method was validated using a mixture of testosterone, with two anti- androgens, di-n-butyl phthalate, and bisphenol A in the YAS. Mixtures of 17ß;-estradiol, estriol, 17α-dihydroequilin and di-n-butyl phthalate were evaluated in the YES assay. Using Equation 3 the net estrogenic and androgenic activity of the mixtures was estimated. There was a significant improvement over the CA based approach in Equation 1. Overall, in 24 out of 32 mixtures tested there was no significant difference between the aRP and observed responses. Large percent errors were observed in the CA model, particularly when the proportion of antagonists was high as the CA model tended to over-predict the responses. On the contrary, only two aRP model predictions exceeded 50% error. Risk assessors should use the CA model with caution as it could over-predict biological responses and an alternative approach such as the aRP model could be used. In this regard, a database of aRP values for identified antagonistic/synergistic compounds could be assembled and estimations of biological activity could be made using these aRP values. The aRP interaction model could also be used to provide fundamental understanding to the behavior of the constituents in a complex mixture. Although the interaction model presented may account for possible deviations from additivity in environmental mixtures, predictions of mixture effects may be complicated by matrix interferences. In this regard, a sensitive bioassay; such as the E-Screen, which is capable of detecting concentrations as low as 0.27 ng L-1 of 17β-estradiol equivalents is beneficial. However, one major drawback to the E-Screen assay is the 6-day analysis time. In order to maintain the sensitivity of the assay and reduce the analysis time, Fourier Transform Infra-red Imaging Spectroscopy (FT-IRIS) was used to probe the bio-molecular level events that occur in single cells prior to a detectable response in cellular proliferation. The investigation revealed that changes occur on the sub-cellular level at 48-hours after incubation which are comparable to the 6 day E-Screen responses (Pearson R = 0.978). The FT-IRIS response appears to be due to the increase in mucins which are known to play a role in cellular signaling and proliferation. The EC50 values for the E-screen and FT-IRIS assay were 2.29 and 2.56 ppt respectively, indicating that the molecular changes, which are observed at the single cell level using FT-IRIS, are reflective of physiological changes that are observed as the cell population responds to 17ß-estradiol. The study indicates that sophisticated imaging and microscopy techniques such as FT-IRIS may play a role in environmental bio-analytical methods. / Civil Engineering

The introduction of herbicide resistant crops offers producers many more options for weed control systems. These crops allow environmentally safe, non-selective herbicides to be used as selective herbicides, broadening the spectrum of weeds controlled, while not harming the crop. As these crops are very new on the market, investigation of their performance under various environmental conditions as well as in various weed control programs is needed. Liberty-link &reg; soybeans are resistant to the herbicide glufosinate, because of the incorporation of a gene encoding phosphinothricin acetyl-transferase (pat), which is able to detoxify glufosinate. Roundup-Ready &reg; soybeans are transformed with an altered, non-sensitive form of 5-enolpyruvylshikimate- 3-phosphate synthase (EPSPS), which confers glyphosate resistance. Field and greenhouse studies were conducted to determine the efficacy of glufosinate and glyphosate on annual and perennial weeds. Also to determine whether the use of ammonium sulfate (AMS) or pelargonic acid (PA), a 9-carbon fatty acid, as additives of glufosinate or glyphosate would increase their efficacy, while maintaining their safety on the transgenic soybeans. Three annual weeds: common lambsquarters, giant foxtail, sicklepod, as well as two perennial weeds: common milkweed and horsenettle were included in studies. Uptake, translocation, and metabolism of 14C-glufosinate + AMS or PA, were studied in the five weeds in order to determine the basis for their differential weed sensitivity to glufosinate, and the effect of the two additives. The effect of temperature on Liberty-Link &reg; and Roundup-Ready &reg; soybeans after application of glufosinate or glyphosate was investigated. Injury was quantified by measuring chlorophyll content of herbicide treated soybean trifoliolates. Uptake, translocation, and metabolism studies of 14C-glufosinate and 14C-glyphosate in transgenic soybeans were conducted to determine the potential cause for the observed temperature-dependent sensitivity. Since glufosinate is a synthetic analog of a naturally occurring bacterial toxin, it was tested for possible bactericidal activity on the soybean pathogen Pseudomonas syringae. Greenhouse and field-studies showed that the 5 weeds responded differently to glufosinate and glyphosate. Common milkweed was the most tolerant to glufosinate and common lambsquarters to glyphosate while giant foxtail was the most sensitive species to both herbicides. Some interactions between AMS or PA and glufosinate or glyphosate were also observed. Uptake and translocation studies showed that AMS increased the uptake of 14C-glufosinate in some weeds, whereas PA had only minimal effects on absorption and translocation of glufosinate. Metabolism of glufosinate was detected only in common lambsquarters. A rate dependent loss of chlorophyll in Liberty-Link &reg; soybeans treated with glufosinate was observed that was greater at 15° C than at 25° or 35° C. Metabolism studies showed a decrease in the rate of glufosinate metabolism 3 hours after treatment in Liberty-Link &reg; soybeans grown at 15° C versus 25° C. Conversely, chlorophyll loss in glyphosate-treated Roundup-Ready soybeans was greater at 35° C than at 15° or 25° C. Translocation studies showed a significantly greater percentage of absorbed 14C-glyphosate translocated to developing meristems at 35° C than at 15° C in Roundup-Ready&reg; soybeans. Glufosinate concentrations of 1 mM and higher significantly inhibited the growth of Pseudomonas syringae (L-529) in liquid media cultures. Typical field use rates of glufosinate also reduced the number of live P. syringae on Liberty-Link&reg; soybean leaves. Overall, the results of this research show that annual and perennial weeds differ in their sensitivity to glufosinate and glyphosate. Additives such as AMS and PA may enhance the efficacy of glufosinate on perennial weed species, and glyphosate in most weeds. Differences in weed sensitivity to herbicides and effects of additives can in most cases be explained by differences in absorption or metabolism. Variable temperatures may affect the engineered resistance of transgenic soybeans to the herbicides glufosinate and glyphosate. The herbicide glufosinate has some bacteriocidal activity on P. syringae. Nomenclature: Glufosinate, 2-amino-4-(hydroxymethylphosphinyl) butanoic acid; Glyphosate, N-(phosphonomethyl)glycine; PA, pelargonic acid (nanoic acid); AMS, ammonium sulfate; giant foxtail, Setaria faberi Herrm.; common lambsquarters, Chenopodium album L.; sicklepod, Cassia obtusifolia L.; horsenettle, Solanum carolinense L.; common milkweed, Ascleipias syriaca L. pat, phosphinothricin acetyl transferase; EPSPS, 5-enolpyruvylshikimate-3-phosphate synthase. / Master of Science