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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.
151

Insulin signalling to glycogen synthesis in cultured human muscle cells

Armstrong, Jane Louise January 2001 (has links)
No description available.
152

HOST-GUEST COMPLEXES OF CUCURBIT[7]URIL WITH CATIONIC DRUGS AND AMINO ACID DERIVATIVES

Gamal Eldin, MONA 26 September 2013 (has links)
The host-guest chemistry between cucurbit[7]uril (CB[7]) and cationic organic guests of medicinal and biological interest are described in this thesis. In the first part, three cationic steroidal neuromuscular blockers (SNMBs) were studied, along with guests that model their monocationic N-alkyl-N-methylheterocyclic (morpholinium, pyrrolidinium and piperidinium) terminal groups of the SNMBs, and dicationic guests in which the two N-methylheterocyclic rings are linked by a decamethylene chain, modelling a variety of NMBs. Other cationic drugs related to acetylcholine processes in neuromuscular blockage were also studied. In the second part, the amino acids lysine, and its mono-, di- and trimethylated and acetylated Nε derivatives, and arginine, and mono- and (symmetric and asymmetric) dimethylarginine, were investigated as guests, along with analogs of arginine. The nature and strength of the complexation between CB[7] and these guests in aqueous solution were determined by 1H NMR spectroscopy and ESI mass spectrometry. The CB[7] showed high binding affinity (KCB[7] = 106-109 M-1) towards the N-alkyl-N-methylheterocyclic cations with a trend of piperidinium > pyrrolidinium > morpholinium, which reflects the relative hydrophobicities of the guests. The CB[7] forms 1:1 and 2:1 host-guest complexes with dicationic model guests, with the CB[7] initially encapsulating the decamethylene chain. The second CB[7] binds to a terminal site, resulting in electrostatic repulsions with the first CB[7], which are resolved by the translocation of the first CB[7] to the opposite terminal site. This 2:1 binding mode is also observed with CB[7] and the SNMBs, and the trend in KCB[7] with these SNMB terminal sites is comparable to that observed for the monocationic model guests. The other cationic drugs also form stable host-guest complexes with CB[7], and the binding constants displayed dependences on the size, charge, and hydrophobicity of the guests. The CB[7] exhibits significant selectivity towards different lysine and arginine derivatives, which can be related to the relative hydrophobicity afforded by the methyl substituents and the positioning of the guest within the CB[7] cavity. The 3500-fold selectivity for Nε,Nε,Nε-trimethyllysine over lysine by CB[7] is the highest observed for a synthetic macrocyclic receptor, while a modest selectivity of symmetrical over asymmetrical dimethylarginine by CB[7] is observed. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-09-26 14:33:40.063
153

Synthesis and Characterization of Monosaccharide-derived Low Molecular Weight Gelators

Williams, Kristopher Aaron 20 May 2011 (has links)
Low molecular weight gelators (LMWGs) are interesting materials whose applications are as diverse and wide ranging as their molecular structures. These materials self-assemble through the formation of non-covelent intermolecular forces and interactions to form supramolecular assemblies that trap solvent within their matrices. Because of the non-covalent nature of the forces of self-assembly, the gelation process is typically thermally reversible. In addition, low molecular weight gelators can also be modified to respond to various stimuli, such as change in pH, presence of enzymes or metal cations, or exposure to light. The design of low molecular weight gelators is often difficult, and most new classes of low molecular weight gelators are discovered by serendipity. As such, it is often useful to use structural templates in the design of LMWGs. Biomolecules, such as steroids, amino acids and peptides, and carbohydrates make excellent templates due to their inherent propensity to self assemble. A review of the current literature regarding the use of biomolecules as templates for the design and synthesis of LMWGs will be presented in chapter 1. Our research group has been active in the research of carbohydrate-based LMWGs for several years, and these results are also briefly reviewed in the related chapters. The synthesis and characterization of ester derivatives of D-galactose, D-glucose, and amide derivatives of D-glucosamine will be discussed in chapters 2-4, along with their evaluation for gelation in aqueous and organic solvents, such as hexane, ethanol, water, and aqueous DMSO or ethanol mixtures.
154

Estudo por R.P.E. do cobre (II) (&#945 - amino isobutirato) / Study by EPR copper (II) (&#945 - amino isobutyrate)

Saab, Sergio da Costa 26 November 1992 (has links)
Neste trabalho são apresentados estudos de Cu(&#945-AIB)2 utilizando-se a técnica de RPE à temperatura ambiente nas freqüências de 9,7 GHz e 34 GHz. Os espectros de R. P. E. mostram uma única ressonância tanto em banda X (9,7 GHz) quanto em banda Q (34 GHz), devido ao efeito de estreitamento por troca. Os valores das componentes do tensor g e da largura de linha foram determinados a partir dos espectros obtidos variando o ângulo entre H e os eixos do cristal a´, b e c em três planos a´b, a´c, e bc. O tensor g reflete as propriedades moleculares do complexo, com o íon Cu(II) em uma simetria axial e também a orientação destas moléculas dentro da cela unitária do cristal. A variação angular da largura de linha é analisada em termos da simetria do íon Cu(II) na rede cristalina e das contribuições das interações dipolar e Zeeman Residual. O parâmetro da interação de troca |J\'|, é obtido através da contribuição da interação Zeeman residual na largura de linha, |J\'| ~ 0,34K. É também observada uma característica magnética bidimensional no complexo Cu(&#945-AIB)2 concordando com os resultados cristalográficos. / In this work is presented a study of the complex Cu(&#945-AIB) 2 using EPR spectroscopy at room temperature, in two frequency bands (9.7 and 34 GHz). The EPR spectra, in both bands and any direction of the extremal magnetic field consist of a single resonance line. This fact can be understood considering the exchange narrowing between non-equivalent Cu(II) íons. The elements of the g tensor and line width were determined from the angular dependence of the EPR spectrum, in three ortogonal crystal planes a´b, a´c and ab (a´=b x c). The angular dependence of the g tensor reflects the molecular properties of the complex Cu(&#945-AIB)2 the axial symmetry of the molecule and the orientation on the crystal unit cell. The most important contributions to the line width were found to be: 2D dipolar interactions, the residual Zeeman effect and defects compatible to the symmetry of the crystal. The Exchange parameter, |J\'| ~ 0.34K, was obtained from the residual Zeeman contribution to the line width (Q band). The low dimension found for dipolar interations agrees with crystallographic results.
155

Catalysis and Regulation of the Allosteric Enzyme Aspartate Transcarbamoylase

Mendes, Kimberly Rose Marie January 2010 (has links)
Thesis advisor: Evan R. Kantrowitz / The understanding of how cells regulate and control all aspects of their function is vital for our ability to intervene when these control mechanisms break down. Almost all modes of cellular regulation can be related in some manner to protein conformational changes such as the quaternary conformational changes of allosteric enzymes that alter enzyme activity to regulate metabolism. The control of metabolic pathways by allosteric enzymes is analogous to a molecular valve with "on" and "off" positions. In the "off" position, flow through the pathway is severely hindered, while in the "on" position the flow is normal. For a comprehensive understanding of allosteric regulation we must elucidate in molecular detail how the allosteric signal is transmitted to the active site to alter enzyme activity. In this work we use unnatural amino acid mutagenesis to introduce a fluorescent amino acid into the allosteric binding site of aspartate transcarbamoylase (ATCase), the enzyme responsible for regulation of pyrimidine nucleotide biosynthesis. The fluorescence from the amino acid is exquisitely sensitive to the binding of the allosteric effectors ATP, CTP, UTP, and GTP. In particular we show how the asymmetric nature of the allosteric sites of the enzyme are used to achieve regulatory sensitivity over a broad range of mixed heterotropic effector concentrations as is observed in the cell. Furthermore, employing the method of random sampling - high dimensional model representation (RS-HDMR) we derived a model for how ATCase is regulated when all four nucleotides are present at fluctuating concentrations, consistent with physiological conditions. We've discovered the fundamental requirements to induce the allosteric transition to the R state by showing that although ATCase can accept L-asparagine as an unnatural substrate, the transition to the R allosteric state requires the correct positioning of the alpha-carboxylate of its natural substrate L-aspartate. However, linking the functionalities of L-asparagine and carbamoyl phosphate into a single molecule is sufficient to correctly position the bi-substrate analog in the active site to induce the allosteric transition to the R-state. The cooperative nature of ATCase was further investigated through the isolation of a unique quaternary structure of ATCase consisting of two catalytic trimers linked covalently by disulfide bonds. By relieving the quaternary constraints imposed by the bridging regulatory subunits of the native holoenzyme, the flexibility of the c6 subunit significantly enhanced enzyme activity over the native holoenzyme. Unlike the native c3 catalytic subunit, the c6 species displays homotropic cooperativity for L-aspartate demonstrating that, when two catalytic trimers are linked, a binding event at one or more active sites can be transmitted through the molecule to the other active sites in the absence of regulatory subunits. The catalytic reaction of ATCase follows an ordered sequential mechanism that is complicated by the transition from the T state to the R state upon the binding of the second substrate L-aspartate. Acquiring X-ray crystal structures at each step along the pathway has advanced our understanding of the catalytic mechanism, yet R-state structures are difficult to obtain. Using a mutant version of ATCase locked in the R-allosteric state by disulfide bonds we captured crystallographic images of ATCase in the R state bound to the true substrates (CP and Asp), products (CA and Pi), and in the process of releasing the final product (Pi) prior to reversion of the molecule to the T state. These structures depict the steps in the catalytic cycle immediately before the catalytic reaction occurs, immediately after the reaction, and after the first product has been released from the active site. This work also focuses on developing allosteric inhibitors of the enzyme fructose-1,6-bisphosphatase (FBPase), one of the enzymes responsible for regulation of the gluconeogenesis pathway. Inhibitors of FBPase could serve as potential therapeutic agents against type-2 diabetes. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
156

Profiling L-serine Transport Throughout Growth and Meiotic Maturation in Mouse Oocytes

Zhang, Han 27 May 2019 (has links)
With the increasing demand for assisted reproduction, more knowledge and understanding towards health requirements of oocytes and their inner workings are required. With current IVF success rates of approximately 40%, oocyte and embryo culture conditions in vitro can be improved by first understanding the finer details of oocyte function. As such, there is a need to better understand the mechanisms through which oocytes can acquire certain nutrients. This thesis focuses on the amino acid serine, which has been shown to improve outcome in developing embryos and also plays a variety of roles in the body that may carry over to oocyte health as well. Using radiolabeled [3H] serine, we measured uptake of serine as a function of time throughout growth and meiotic maturation in mouse oocytes. Serine transport appeared in oocytes during growth and became absent in mature eggs. With a competition assay using substrates diagnostic for several different amino acid transporter systems and culture with and without sodium in the external medium, I identified Na+-dependent SNAT7 of the System A/N (SLC38) family to be the most likely transporter in oocytes. Quantitative RT-PCR was consistent with this result. Transporter activity is also not activated by progression of meiotic maturation, as indicated by unperturbed transport when dbcAMP was provided to maintain meiotic arrest. However, a biological regulator of arrest, NPPC, resulted in enhanced transport activity in vitro. This may be due to signalling mechanisms of the NPPC pathway affecting regulation of serine uptake, which presents a direction for future research.
157

Development of novel analogues of the anti-proliferative marine natural product bisebromoamide : synthesis and structure activity relationship studies

Johnston, Heather Jennifer January 2014 (has links)
The linear peptide bisebromoamide was isolated by the Suenaga group in 2009 from the marine cyanobacterium Lyngbya sp. It exhibits antiproliferative activity at nanomolar levels against a wide range of cell lines. Current SAR data indicates that there is some flexibility in the structure with respect to stereochemistry, but the range of modifications that have been biologically tested is limited, as reviewed in Chapter 1. Bisebromoamide contains a number of non-commercial amino acids and an oxopropyl pyrrolidine moiety which had not been found in a natural product previously. Several new synthetic routes towards the non-commercial amino acid fragments have been developed, as described in Chapter 2, including two ring-closure-based approaches to the substituted proline derivative 4-methyl proline (4-MePro). While the presence of six amide bonds makes solid phase peptide synthesis (SPPS) an appealing approach to the synthesis of bisebromoamide, the 4-MePro moiety is attached to a thiazoline and it is well documented that the α-position of an amino acid will racemise, under both acidic and basic conditions, when attached to a thiazoline or oxazoline. Previous reports indicated that the methyl group of the thiazoline was not essential for biological activity and so to increase stability it was replaced with a thiazole. The total synthesis of a series of novel bisebromoamide analogues, via an SPPS approach which enables facile modification of the final structure, is described in Chapter 3. The simple and adaptable SPPS route developed lends itself to SAR studies and allows modifications such as an alanine scan, truncations and incorporation of modified proline derivatives to be achieved rapidly. The promising anticancer activity of bisebromoamide makes the biological activity of these analogues of particular interest and the results of current biological testing are reported in Chapter 4.
158

Modelling the skin and systemic dispositions of amino acids to assess the potential for transdermal, non-invasive monitoring : phenylalanine as a case study

Woodford, Andrew January 2017 (has links)
This thesis investigates the potential for monitoring current and historic blood serum concentrations of amino acids via transdermal extraction using phenylalanine as a case study. This work furthers the field of non-invasive monitoring of amino acid disorders which have several advantages over invasive methods such as blood tests. In this thesis we derive models to simulate blood serum concentrations, the formation of the skin reservoir and, finally, transdermal extraction of amino acids under an applied electric field. Chapter 1 concerns itself with the biological background and sets up motivation of the thesis by discussing amino acids, associated amino acid disorders, the overarching clinical problem, skin structure and transdermal extraction methods. Chapter 2 then considers mathematical techniques utilised throughout the thesis. Chapter 3 formulates a model for the distribution of phenylalanine in blood serum. One compartment and two compartment approaches are considered in both a fasting state and a non-fasting state. We consider if these have a noticeable effect on the blood serum concentration of phenylalanine. Having obtained a model for the distribution of phenylalanine in blood serum, chapter 4 models the formation of reservoirs of amino acids in the skin. Prior work has identified the existence of such a reservoir, but its formation has not been addressed. The models developed consider the effect of the removal of outer layers of skin, the stratum disjunctum, and production of amino acids in the skin. Unknown parameters are estimated by comparing the model to in vivo and in vitro data. Chapter 5 and 6 are concerned with transdermal extraction under an applied electric field. Chapter 5 formulates the velocity induced by applying an electric field across a charged interface. Chapter 6 utilises these results for modelling extraction of compounds through the skin under an applied electric field.
159

Padrões espaço-temporais do registro fóssil com base em acumulações de moluscos da plataforma continental do sul do Brasil

Ritter, Matias do Nascimento January 2018 (has links)
A resolução temporal é uma questão-chave em Paleontologia, uma vez que a sua magnitude define a precisão dos estudos não somente paleoecológicos como também evolutivos. A resolução temporal é estimada pela magnitude de time-averaging (mistura de gerações em uma camada, uma amostra). Tais estimativas têm sido amplamente conduzidas em ambientes marinhos recentes. A plataforma continental do sul do Brasil (PSB; 22°S – 34°S) tem sido um laboratório natural para estudos desta natureza desde o início do século XXI. Consequentemente, possui um amplo acervo de dados disponíveis para comparação. Neste contexto, esta tese visou responder (i) qual a magnitude do time-averaging em acumulações de bivalves da PSB? (ii) como este processo varia ao longo de gradientes espaciais? e (iii) como o time-averaging reflete na informação biológica preservada no registro fóssil? Para isto, mais de 140 espécimes de bivalves foram datados integrando racemização de aminoácidos e 14C AMS. Além disto, análises tafonômicas foram realizadas em todas as amostras datadas, incluindo mais sete amostras em sedimentos lamosos. A resolução temporal (time-averaging) e a variabilidade total de idades (mistura temporal) basearam-se em uma nova abordagem numérica, a estatística bayesiana, que integra os erros e as incertezas derivadas da distribuição posterior dos resíduos associados com os modelos resultantes das calibrações das idades. As tendências onshore-offshore — aumento da mediana e da uniformidade das curvas de frequência de distribuição de idades, redução da variabilidade tafonômica, ainda que a escala do time-averaging seja invariante — provavelmente refletem a interação entre as mudanças do nível relativo do mar e da bioprodutividade mais elevada em águas menos profundas. / The temporal resolution of the fossil record plays a key role in paleontology because it determines the scale and the precision of paleoecological and evolutionary studies. The temporal resolution of the fossil record is estimated by the magnitude of time-averaging (non-contemporaneous generations preserved in a single layer, a bulk-sample). Quantitative estimates of time-averaging have been conducted primarily on mollusk shells from modern shallow-water marine settings. Most of them have been addressed in the Southern Brazilian continental shelf (SBS; 22°S up to 34°S), which is considered a natural laboratory for several similar studies since the earlier of current century (XXI). Consequently, the SBS has several available datasets that allow comparisons of the new results displayed here with those previous data. Thus, this thesis aimed answer (i) what is the magnitude of time-averaging on SBS mollusk death assemblages? (ii) how does time-averaging vary across spatial gradients? and (iii) how does time-averaging can reflect on the preservation of the fossil record? Here, >140 specimens were individually dated using amino acid racemization calibrated using radiocarbon ages (14C). In addition, taphonomic analyses were conducted in all samples, including more seven muddy sites. The time-averaging and the total age variability was based on a Bayesian approach that integrates the estimation errors and uncertainties derived from the posterior distribution associated with the 14C–AAR calibration average model. The onshore-offshore trends — increased median age, decreased skewness of age distributions, decreased taphonomic variation, yet the invariant scale of time-averaging — likely reflect the interplay between sea-level changes and elevated bioproductivity in shallower water settings.
160

Examining the Effects of D-Amino Acids on Translation

Fleisher, Rachel Chaya January 2016 (has links)
The ribosome is responsible for mRNA-templated protein translation in all living cells. The translational machinery (TM) has evolved to use 20 amino acids each esterified onto one of several tRNA bodies. While the active site of the ribosome, known as the peptidyl transferase center (PTC), is able to handle a remarkable amount of substrate diversity, many classes of unnatural amino acids are not compatible with the TM. For example, in the field of unnatural amino acid mutagenesis, the site-specific incorporation of biologically useful amino acids into proteins, such as fluorophores, has often proven to be unfeasible. This runs counter to the accepted notion that the ribosome is blind to the structure of the amino acid and is capable of accepting any amino acid as long as the mRNA codon: tRNA anticodon pairing is correct. Two studies by our group set out to test the hypothesis that the ribosome can indeed discriminate the structure of the amino acid. Using a fully purified E. coli translation system, the first study showed that natural amino acids misacylated onto fully modified but non-native tRNAs show small but reproducible effects on the steps of aminoacyl-tRNA (aa-tRNA) selection. The second study, in which I participated, utilized D-aa-tRNAs in the same E. coli translation system to study how amino acids of the inverted stereochemistry to those found in ribosomally-synthesized proteins affect translation elongation. We showed that these unnatural substrates serve as peptidyl acceptors but once translocated into the P-site of the ribosome, fail as peptidyl donors and stall translation elongation by inactivating the PTC. The motivation of my work has been to further characterize the effects of D-aa-tRNAs on translation elongation. To this end, I examined how the PTC is affected structurally and functionally by the presence of ribosomal substrates containing D-amino acids. Chapter one contains an introduction to this work. Chapter two describes chemical probing experiments that demonstrate that the presence of peptidyl-D-aminoacyl-tRNAs in the P-site of the ribosome allosterically modulates the secondary structure of ribosomal exit tunnel nucleotides A2058 and A2059. Chapter three describes how the reactivity of peptidyl-D-aminoacyl-tRNAs to form tripeptides is highly dependent on the identity of the amino acid it is reacting with; protein yields can be close to what is obtained with natural amino acids or almost completely abolished. Chapter four contains the methods used to do this research. From the observations presented here as well as from the work of other laboratories, a picture of the PTC emerges in which the pairing of the A- and P- site substrates is integral in either promoting or suppressing catalysis by the PTC. This work has implications for the field of unnatural amino acid mutagenesis, particularly for strategies to improve the incorporation of interesting unnatural amino acid by the ribosome. In addition, this work adds an important aspect to the growing body of knowledge of ribosome stalling at the PTC.

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