Esta dissertação apresenta um estudo sobre a contração de anel de ésteres ß,y-insaturados promovida por trinitrato de tálio (TTN) e de 1,2-di-hidronaftalenos promovida por hidroxi(tosiloxi)iodobenzeno (HTIB), também conhecido como reagente de Koser. Ambos estudos visaram à síntese de indanos funcionalizados. A reação de uma série de ésteres ß,y-insaturados (por exemplo 2-(3,4-di-hidronaftalen-1-il)-proprionato de etila) com TTN em ácido acético forneceu os correspondentes produtos de contração, formando indanos em bons rendimentos. A presença de grupos doadores de elétrons na posição 6 no anel aromático resultou no aumento do rendimento do produto de contração, enquanto que grupos atraentes de elétrons na posição 7 do anel aromático acarretou o decréscimo do rendimento do indano quando comparado a substratos que não são substituídos nesta posição. O aumento da cadeia alquílica na posição alfa-carbonila não interferiu no rendimento do produto desejado. O éster substituído por uma metila na posição 4 do anel ciclo-hexênico levou preferencialmente ao indano trans-1,3-dissubstituído. A reação do 1,2-di-hidronaftaleno com HTIB em metanol levou ao produto de contração de anel 1-dimetoximetil-indano com rendimento moderado, além dos produtos de adição cis e trans-1,2-dimetoxi-1,2,3,4-tetra-hidronaftaleno. No entanto, a reação desse substrato com HTIB em acetonitrila, diclorometano ou trimetil-ortoformiato forneceu o produto de aromatização (naftaleno). Contudo, os produtos de contração, 1-indano-1-il-etanona e 1-(3-metil-indan-1-il)-etanona foram formados em bons rendimentos quando o 4-metil-1,2-di-hidronaftaleno e o 1,4-dimetil-1,2-di-hidronaftaleno, respectivamente, foram tratados com HTIB em acetonitrila. No caso do 1,4-dimetil-1,2-di-hidronaftaleno há uma predominância na formação do isômero trans. Finalmente, para a reação de 4-metil-1,2-di-hidronaftaleno com HTIB em metanol foram formados os produtos de adição (cis e trans-1,2-dimetoxi-1,2,3,4-tetrahidro-1-metil-naftaleno) em ótimos rendimentos. / This dissertation presents a study about the ring contraction of ß,y-unsaturated esters promoted by thallium trinitrate (TTN) and 1,2-dihydronaphthalenes promoted by hydroxy(tosyloxy)iodobenzene (HTIB). Both studies aimed the synthesis of functionalizated indans. The reaction of a series of ß,y-unsaturad esters with TTN in acetic acid led to the corresponding ring contraction products, giving indans in good yields. The presence of electron donating groups in the 6-position of the aromatic ring increases the yield of the ring contraction product. On the other hand, electron withdrawing groups in the 7-position of the aromatic ring leds to a decrease of the yield of the desired product, when compared to substrates which are not substituted in this position. The increasement of the alkane chain at the alpha-carbonyl position did not interfere in the yield of the ring contraction product. The esters substituted by an alkyl group at 4-position of the ciclohexene ring leads to the ring contraction product, where the trans-1,3-disubstituted indan is the major product. The reaction of 1,2-dihydronaphthalene with HTIB in methanol gave the ring contraction product 1-dimetoxymethyl-indan with moderate yield, together with the addition products cis- and trans-1,2-dimetoxy-1,2,3,4-tetrahydronaphthalene. On the other hand, the reaction of 1,2-dihydronaphthalene with HTIB in acetonitrile, dichloro-methane or trimethyl orthoformate gave the aromatization product (naphthalene). The reaction of 4-methyl-1,2-dihydronaphthalene and 1,4-dimethyl-1,2-dihydronaphthalene with HTIB in acetonitrile leads to ring contraction products 1-indan-1-yl-ethanone and 1-(trans-3-methyl-indan-1-yl)-ethanone, respectively, in good yieds. The reaction of 4-methyl-1,2-dihydronaphthalene with HTIB in methanol gave the addition products cis- and trans-1,2-dimetoxy-1,2,3,4-tetrahydro-1-methyl-naphthalene) with very good yield.

Durante a fase de crescimento e terminação, 1890 frangos de corte machos da linhagem Cobb®500 foram submetidos a altas temperaturas e alimentados com dietas experimentais contendo três fontes de metionina (DL-Met, DL-HMTBA e DL-Met/ DL-HMTBA), três níveis de vitamina E (15 UI, 45 UI e 100 UI) e duas relações Arg:Lis (0,9 e 1,5), cujo delineamento fatorial 3 x 3 x 2 totalizou 18 tratamentos, com sete repetições de 15 aves cada. Ao final do período experimental, os parâmetros de desempenho zootécnico como consumo de ração, peso corporal, conversão alimentar e rendimento de carcaça, peito e pernas foram avaliados e, após análise estatística, comprovou-se que não houve interação entre os fatores. Dessa maneira, os efeitos individuais dos elementos testados foram analisados e observou-se que a utilização de diferentes fontes de metionina e a inclusão de vitamina E nas quantidades testadas não apresentaram diferenças significativas. Porém, a maior inclusão de arginina na dieta proporcionou melhora nos resultados de ganho de peso, peso corporal e conversão alimentar, mas não resultou em diferenças significativas nos parâmetros de carcaça avaliados. / During the growing and the finishing, 1890 male broiler chickens of Cobb 500 ® were subjected to high temperatures and fed with experimental diets containing three sources of methionine (DL -Met ,DL - HMTBA and DL-Met/DL - HMTBA), three levels of vitamin E (15 IU, 45 IU and 100 IU) and two relations Arg:Lys (0.9 and 1.5), whose factorial design 3 x 3 x 2 totaled 18 treatments with seven replicates of 15 birds each. At the end of the experimental period, the growth performance parameters such as feed intake, body weight, feed conversion and carcass, breast and legs yieldwere evaluated and, after statistical analysis, it was shown that there was no interaction between factors. Thus, the effects of the tested individual elements were analyzed and it was found that the use of different sources of methionine and the inclusion of vitamin E in the amounts tested showed no significant differences. However, the increased inclusion of arginine in the diet improved results in weight gain, body weight and feed conversion, but resulted in no significant differences in carcass parameters.

The oxysterol, 25-hydroxycholesterol (25-HC), is important for sterol metabolism and emerging evidence suggests that 25-HC plays a more critical role in immunity and infection. However, the precise antiviral mechanism and the target of 25- HC remains unclear. Here efforts were made to investigate the link between viral infection and the triggering of the 25-HC associated interferon (IFN) response, and how this dynamically alters the endogenous level of 3-hydroxy- 3-methylglutaryl-CoA reductase (HMGCR), a key enzyme that catalyses the production of the precursor of cholesterol and oxysterols. In this thesis I have sought to specifically explore the temporal changes and role of HMGCR in DNA virus (cytomegalovirus) and RNA (Influenza) virus infections. I hypothesise that HMGCR is a target for 25-HC associated IFN-mediated host defence against viral infection. To characterise HMGCR and test this hypothesis, the following objectives were defined: (1). To establish an experimental system to quantitatively study the endogenous HMGCR protein level; (2). To investigate the mechanism of the down-regulation of HMGCR involved in the IFN-mediated innate immune response; (3). To study the behaviour of HMGCR in the influenza virus induced 25-HC associated IFN-mediated innate immune response; (4). To study the behaviour of HMGCR in the cytomegalovirus induced 25-HC associated IFN-mediated innate immune response. Chapter 3, describes establishing an experimental system for the quantification of endogenous HMGCR levels. Different protein detection methods, including a modified western blot protocol and immunostaining, were tested. The results of RNA interference of HMGCR demonstrate that under lipid-deficient condition with the supplementation of mevastatin (an HMGCR inhibitor) the modified western blot protocol specifically detects endogenous HMGCR. This chapter lays the foundational work for the temporal analysis and testing the role of HMGCR in infection. In Chapter 4, the mechanism of the degradation of HMGCR following 25-HC and IFN treatments, in wild-type and Ch25h−/− mouse bone marrow derived macrophages (BMDMs), was investigated. Similar to 25-HC, IFN-γ treatment results in the drop of both the transcript and protein abundance of HMGCR in wild-type BMDMs. Differential temporal analysis of RNA and protein alterations and the use of proteasome inhibitors reveals that both 25-HC and IFN-γ lead to a marked reduction of HMGCR protein via a proteasomal degradation mechanism within early times of treatments. Further, the immediate reduction of HMGCR levels induced by IFN-γ was completely abrogated in Ch25h−/− BMDMs. Hence, the reduction of HMGCR following IFN-γ treatment is due to the de novo synthesis in macrophages of 25-HC. However, the decrease of Hmgcr gene expression was observed in not only wild-type but also Ch25h−/− BMDMs, suggesting additional mechanisms for regulating Hmgcr RNA levels. These results demonstrate the mechanism of the down-regulation of HMGCR resulted from the induction of IFN response during viral infection, is only partially due the de novo synthesis of 25-HC. In chapter 5, influenza A virus was used to investigate the role of HMGCR in the IFN-mediated innate immune response. The inhibition of HMGCR by RNA interference inhibited viral growth, suggesting the requirement of HMGCR for optimal intracellular viral growth. Viral infection in wild-type murine BMDMs reduced the endogenous HMGCR levels. However, the reduction of HMGCR at early times was prevented in Ch25h−/− BMDMs. Intriguingly, the decrease of HMGCR at late time points was still observed in Ch25h−/− BMDMs. These results indicate that the down-regulation of HMGCR with influenza virus infection in BMDMs at early times is completely due to the de novo synthesis of 25-HC; whereas at late times alternative pathways or mechanisms exist. Additionally, human epithelial A549 cells and A549/PIV5-V cells that are deficient in STAT1 were used to study the role of IFN pathway in the down-regulation of HMGCR at late times during viral infection. Results from these studies show that at late times the reduction of HMGCR is due to IFN-independent mechanisms. Chapter 6, extends these investigations to the herpes virus murine cytomegalovirus and infection of BMDMs. HMGCR is known to be essential for cytomegaloviral infections and 25-HC, statin and RNAi inhibition of HMGCR restrict viral growth. 25-HC is shown to reduce HMGCR at immediate early times of infection. However, most notably, the down-regulation of HMGCR was also observed in Ch25h−/− BMDMs at late times with murine cytomegalovirus infected BMDMs. These results confirm that alternative pathways or mechanisms exist, playing roles in the crosstalk between cholesterol metabolism and innate immune response. Collectively, this study characterises the role of HMGCR in the 25-HC associated IFN-mediated host defence against viral infection. Results indicate that, in addition to the IFN-mediated host response, alternative pathways or other mechanisms also result in the down-regulation of HMGCR during viral infection. HMGCR is at the crossroad of different pathways or mechanisms, and is therefore not only targeted by 25-HC. Hence, further questions can be addressed from these results: (1). What are the alternative pathways or mechanisms for the down-regulation of HMGCR? (2). How do these pathways or mechanisms work in hosts’ immune system? Answering these questions can contribute to refining the pathway map of innate immunity and understanding the precise role of HMGCR, or even the sterol biosynthesis pathway, in hosts’ immune response against pathogens.

Long lived radioactive species such as ¹²⁹I⁻ and ⁹⁹TcO₄⁻ are formed as by-products of nuclear fission. These species have extremely long half-lives (1.5 million and 211,000 years respectively), are biologically assimilating and due to their anionic nature, can move freely within a geosphere. Historical disposal methods for active species are no longer considered acceptable to the general public and other ways in which to treat the waste are being explored. One remove and concentrate method to remove radioactive species from the biosphere is using alkaline-resistant materials which trap active species that can be encapsulated in a high pH concrete matrix. Layered hydroxides and layered double salts which consist of positively charged layers between which exchangeable anions and water molecules lie are good candidates for these materials due to the basic conditions in which they form. The synthesis, anion exchange properties and stability of copper, lanthanum, nickel and zinc hydroxysalts have been investigated. The structures consist of layers of edge-sharing metal hydroxide octahedra together with an interlayer space containing the anion and in some cases water molecules. Products were characterised by powder X-ray diffraction and vibrational spectroscopy to confirm the identity of structure of the material formed and the anion incorporated. Only Cu2(OH)3(NO3), Cu2(OH)3(OAc).H2O, Ni2(OH)3(NO3) and Zn5(OH)3(NO3).2H2O consistently exhibited exchange capabilities with iodide as the target anion. In terms of exchange rate and efficiency, copper hydroxyacetate is a more suitable precursor as equilibrium is achieved in 10 mins; whereas other LHS containing nitrate as the occupying require longer than 1 day to reach equilibrium. Cu2(OH)3(Ac).H2O has been shown to easily exchange acetate for monovalent anions X- (X = Ha-, NO3-, ClO4-, IO4-, SbO3-, OH-). Exchange reactions with ReO4- (used as a surrogate to TcO4-) and trigonal pyramidal monovalent anions (such as IO3-) were unsuccessful. Exposure to divalent anions (CO32-, Cr2O42-, SeO3-) resulted in no interaction whereas exposure to trivalent PO43- forms Cu3(PO4)2. Quantitative analysis has shown that, contrary to XRPD and FTIR data, full exchange of acetate for an equimolar amount of iodide within a Cu2(OH)3+ framework does not occur with 100% efficiency. Activity counting, gravimetric analysis and ion specific probe analysis suggested that only ~92-93% exchange occurs. The stability of TcO4- and I- analogues with respect to pH has been investigated. Activity counting has shown that even in pH 9.5 solution, 57-73% of 125I- and 99TcO4- immobilised with a Cu2(OH)3+ framework is leached into solution after 16 days. Exposure of Cu2(OH)3I to high carbonate, nitrate and chloride environments shows a progressive loss of iodide into solution as the anionic radius of the incoming anion decreases and the concentration of the incoming anion increases. In the case of chloride and nitrate incoming anions, only a 2:1 chloride to iodide ratio is need for full exchange whereas a ratio of 10:1 nitrate to iodide is required. In situ ion exchange experiments at Diamond allowed the exchange of the hydroxyacetate material to be investigated in flow experiments showing similar facile exchange as demonstrated under batch conditions. Rietveld refinements on deuterated samples of halide analogues of the materials have allowed accurate structure determinations for the first time (Cu2(OD)3Cl - a = 5.726Å, b = 6.125 Å, c = 5.634 Å, β = 93.100°, Cu2(OD)3Br - a = 6.085 Å, b = 6.144 Å, c = 5.650 Å, β = 93.593°, Cu2(OD)3I - a = 6.587 Å, b = 6.179 Å, c = 5.680 Å, β = 95.044°). As the size of the halide increases, the hydroxide coordination alters reflecting to changing sigma/pi donor capability of the halide.

This thesis presents synthesis of tertiary &amp / #945 / -hydroxy phosphonate derivatives. &amp / #945 / -Ketophosphonates is known that they are both acyl anion precursors and electrophiles. In this work, &amp / #945 / -ketophosphonates were used as both acyl anion precursors and electrophiles in the presence of catalytic amount of KCN. &amp / #945 / -Ketophosphonates underwent benzoin-type condensation reaction.

The objective of this presented study was to synthesize optically active compounds considered to be key intermediates in the synthesis of Oseltamivir (Tamiflu) by performing chemical and biotechnological methods. Thereof, the carboethoxy cyclohexenone skeleton first was synthesized utilizing easily available substances. The synthesis of alpha-hydroxy ketones in enantiomerically pure form offers a great importance in the synthesis of biologically active compounds. Toward this fact, the enantioselective synthesis of alpha-hydroxy carboethoxy cyclohexenone scaffold has been accomplished by following the routes which were manganese(III) acetate-mediated chemical oxidation followed by enzyme-mediated hydrolysis and additionally microbial direct biooxidation by whole cells of fungi expressly A. oryzae and A. flavus. A very satisfying results have been obtained by both of the methods.

ABSTRACT EFFECT OF PREPARATION AND OPERATION PARAMETERS ON PERFORMANCE OF POLYETHERSULFONE BASED MIXED MATRIX GAS SEPARATION MEMBRANES Karatay, Elif M.Sc., Department of Chemical Engineering Supervisor : Prof. Dr. Levent Yilmaz Co-supervisor : Assoc. Prof. Dr. Halil Kalip&ccedil / ilar August 2009, 126 pages Membrane processes have been considered as promising alternatives to other competing technologies in gas separation industry. Developing new membrane morphologies are required to improve the gas permeation properties of the membranes. Mixed matrix membranes composing of polymer matrices and distributed inorganic/organic particles are among the promising, developing membrane materials. In this study, the effect of low molecular weight additive (LMWA) type and concentration on the gas separation performance of neat polyethersulfone (PES) membranes and zeolite SAPO-34 containing PES based mixed matrix membranes was investigated. Membranes were prepared by solvent evaporation method and annealed above the glass transition temperature (Tg) of PES in order to remove the residual solvent and erase the thermal history. They were characterized by single gas permeability measurements of H2, CO2, and CH4 as well as scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). Various LMWAs were added to the neat PES membrane at a concentration of 4 wt %. Regardless of the type, all of the LMWAs had an anti-plasticization effect on PES gas permeation properties. 2-Hydroxy 5-Methyl Aniline, HMA, was selected among the other LMWAs for parametric study on the concentration effect of this additive. The incorporation of SAPO-34 to PES membranes increased the permeabilities of all gases with a slight loss in selectivities. However, the addition of HMA to PES/SAPO-34 membranes increased the ideal selectivities well above the ideal selectivities of PES/HMA membranes, while keeping the permeabilities of all the gases above the permeabilities of both pure PES and PES/HMA membranes.

A new phosphineoxy aziridiniyl phosphonates POAP were synthesized as potential organocatalysts and used for silicon based asymmetric Abramov-type phosphonylation of aldehydes with triethyl phosphite. Besides POAP organocatalyst, known chiral phosphineoxy ferrocenyl substituted aziridinyl methanol (POFAM) and aziridinyl phosphonates (AP) were also used for the same reaction. The product &alpha / -hydroxy phosphonates were obtained in good yields up to 99% but with poor enantioselectivities. Highest enantioselectivity (%34) was obtained with POAP organocatalyst. Optimization studies were done with different solvents, ligands, aldehydes, and concentrations.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(農学) / 甲第19046号 / 農博第2124号 / 新制||農||1032 / 31997 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 小川 順, 教授 加納 健司, 教授 植田 充美 / 学位規則第4条第1項該当

La saprolégniose est une maladie fongique causée par le champignon aquatique Saprolegnia sp. qui affecte les poissons sauvages et ceux provenant des piscicultures. L’apparition de touffes cotonneuses semblables à de la ouate de couleur blanche à grise est souvent la première indication de l’infection. Ce saprophyte ubiquitaire se nourrit habituellement des œufs de poissons morts, mais peut se propager rapidement aux œufs sains causant la mort de ces derniers. La saprolégniose est souvent une infection secondaire, mais des souches virulentes peuvent facilement se développer sur les salmonidés ayant subi un stress ou une mauvaise manipulation. De grandes pertes économiques associées à la saprolégniose sont rapportées chaque année à travers le monde surtout dans l’industrie de la pisciculture. Jusqu’en 2002, le contrôle de la saprolégniose pouvait se faire par l’utilisation du vert de malachite, un colorant organique ayant une grande activité antifongique. Malheureusement, cette molécule a été bannie à cause de ses propriétés cancérigènes. Aucun composé aussi efficace n’est actuellement disponible pour traiter les infections de la saprolégniose. Des molécules ou extraits naturels ayant un potentiel antifongique ont donc été testés à l’aide de deux techniques (par graines de chanvre et par cylindre d’agar). Les molécules d’un extrait de propolis (cire de ruches d’abeilles) démontrant de l’activité anti-Saprolegnia ont été identifiées. De plus, une bactérie, Pseudomonas aeruginosa, pouvant être retrouvée dans le même environnement que Saprolegnia sp. a démontré un effet antagoniste au champignon. Une molécule de signalisation intercellulaire produite par P. aeruginosa, 4-hydroxy-2-heptylquinoline (HHQ), a été identifiée comme responsable de l’effet antagoniste contre Saprolegnia sp. / Saprolegniosis, a fungal disease which affects wild and farm fish, is caused by the water mold Saprolegnia sp. Visible cotton-like white or grey patches on fish skin are often the first sign of infection. This ubiquitous saprophyte infects dead fish eggs and then spreads to healthy eggs resulting in major losses due to mortalities. Saprolegniosis is often a secondary infection; however some virulent strains are known to cause primary infection on injured or stressed salmonids. Important economic losses in aquaculture are reported every year worldwide due to saprolegniosis. Infection by Saprolegnia sp. was well controlled with the use of an organic dye with great antifungal efficacy; malachite green. Unfortunately, the use of malachite green was banned in 2002 worldwide due to its carcinogenic and toxicological effects. Up until now, no new treatment as effective as malachite green has been discovered. Natural extracts or molecules with potential antifungal properties have also been tested using two techniques (with hemp seeds and with agar cylinders). Molecules from propolis extracts (beeswax), active against Saprolegnia sp. have been identified. Furthermore, culture supernatant of the bacteria Pseudomonas aeruginosa was found to be able to inhibit the growth of Saprolegnia. The intercellular signal molecule produced by P. aeruginosa 4-hydroxy-2-heptylquinoline (HHQ) was identified as the active compound against Saprolegnia.