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1
Sidiqi, Mahjooba. "The structure and RNA-binding of poly (C) protein 1." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0077.
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[Truncated abstract] Regulation of mRNA stability is an important posttranscriptional mechanism involved in the control of gene expression. The rate of mRNA decay can differ greatly from one mRNA to another and may be regulated by RNA-protein interactions. A key determinant of mRNA decay are sequence instability (cis) elements often located in the 3' untranslated region (UTR) of many mRNAs. For example, the AU rich elements (AREs), are such well characterized elements, and most commonly involved in promoting mRNA degradation, and specific binding of proteins to these elements leading to the stabilization of some mRNAs. Other cis-elements have been described for mRNA in which mRNA stability is a critical component of gene regulation. This includes the androgen receptor (AR) UC-rich cis element in its 3'UTR. The AR is a key target for therapeutics in human prostate cancer and thus understanding the mechanism involved in regulating its expression is an important goal. The [alpha]CP1 protein, a KH-domain containing RNA-binding protein has been found to bind this UC-rich region of the AR and is thought to play an important role in regulating AR mRNA expression. [alpha]CP1 protein is a triple KH (hnRNP K homology) domain protein with specificity for Crich tracts of RNA and ssDNA (single stranded DNA). Relatively little is known about the structural interaction of [alpha]CP1 with target RNA cis elements, thus the present study aimed to better understand the nature of interaction between 30 nt 3'UTR UC-rich AR mRNA and [alpha]CP1 protein using various biophysical techniques, in an attempt to determine which [alpha]CP1 domain or combination of domains is involved in RNA-binding. These studies could ultimately provide novel targets for drugs aimed to regulate AR mRNA expression in prostate cancer cells. At the commencement of this study little was known about the structure of the [alpha]CP1- KH domains and their basis for poly (C) binding specificity. ... Additional studies addressed the significance of the four core recognition nucleotides (TCCC) using a series of cytosine to thymine mutants. The findings verified some of the results predicted from structural studies, especially the need for maximum KH binding to a core tetranucleotide recognition sequence. Our mutational studies of the four core bases confirmed the importance of cytosine in positions two and three as no binding was observed, while some binding was observed when the fourth base was mutated. In summary, the work presented in this thesis provides new detailed insight into the molecular interactions between the [alpha]CP1-KH domain and AR mRNA. Furthermore, these studies shed light on the nature of protein/mRNA interactions in general, as well as the specific complex that forms on AR mRNA. These studies have provided new understanding into the mode of [alpha]CP1 binding at a target oligonucleotide binding site and, provide a foundation for future studies to define structure of multiprotein/oligonucleotide complexes involved in AR mRNA gene regulation. Understanding the detailed interaction between the AR mRNA and [alpha]CP1 could provide possible targets for drug development at reducing AR expression in prostate cancer cells by interfering with the interaction of [alpha]CP1 and AR-mRNA.
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Geli, Rolfhamre Patricia. "From penicillin binding proteins to community interventions : mathematical and statistical models related to antibiotic resistance /." Stockholm : Department of Mathematics, Stockholm University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8477.
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Roussel, Céline. "Etude du rôle des chélateurs calciques sur les oscillations du potentiel membranaire neuronal: approche expérimentale et théorique." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210854.
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Les neurones sont des cellules excitables capables de coder et transmettre l’information sous forme d’oscillations du potentiel membranaire. Cette activité électrique est produite par une modification des flux ioniques transmembranaires. Les neurones constituent un exemple d’oscillateur cellulaire dont la dynamique non linéaire permet l’apparition d’une activité électrique complexe. Dans ce système, les ions calciques sont des messagers intracellulaires importants. Ils servent de médiateur entre un signal électrique et un signal chimique, par une modulation de l’activité enzymatique de certaines protéines. Ils interviennent dans de nombreuses fonctions neuronales, dont l’excitabilité électrique. Un des mécanismes mis en place par les neurones pour contrôler l’homéostasie du calcium intracellulaire provient de protéines cytoplasmiques capables de lier les ions calciques. Ces protéines jouent un rôle de « tampon » du calcium. Cependant, toutes leurs fonctions n’ont pas encore été mises en évidence. C’est l’objectif de notre travail. Nous avons voulu comprendre le rôle joué par une protéine « tampon » particulière, la calrétinine, sur le mode de décharge électrique d’un neurone où elle est exprimée en abondance, le grain cérébelleux. Pour cela, nous avons utilisé une approche théorique et expérimentale. <p>Au niveau théorique, nous avons élaboré un modèle mathématique de l’activité électrique du grain cérébelleux, prenant en compte la chélation du calcium intracellulaire. Il permet de clarifier le rôle de la chélation du calcium intracellulaire sur les oscillations du potentiel membranaire. La modélisation de l’activité électrique du grain cérébelleux repose sur le formalisme développé par Hodgkin et Huxley pour l’axone géant de calmar. Dans ce contexte, l’application de la conservation de la charge au circuit équivalent de la membrane cellulaire fournit un système d’équations différentielles ordinaires, non linéaires. Dès lors, notre modèle nous a permis d’étudier l’impact des variations de la concentration de chélateur calcique sur les oscillations du potentiel membranaire. Nous avons ainsi pu constater qu’une diminution de la concentration en chélateur calcique induisait une augmentation de l’excitabilité électrique du grain cérébelleux, sans altérer le régime d’oscillations. Par contre, en augmentant fortement la concentration en chélateur calcique, nous avons montré que le grain cérébelleux changeait de dynamique oscillatoire, montrant des transitions d’un mode de décharge périodique régulier vers des oscillations en salve du potentiel membranaire.<p>Au niveau expérimental, nous avons vérifié les résultats prévus par le modèle théorique. Nous avons ainsi montré que des grains de souris transgéniques déficientes en calrétinine présentaient une excitabilité électrique accrue par rapport aux grains contrôles.<p>Puis, en restaurant un niveau de chélation calcique normal dans ces grains, par perfusion intracellulaire de chélateur calcique, nous montrons qu’ils retrouvent un niveau d’excitabilité normal. Ensuite, nous avons introduit dans des grains cérébelleux de souris sauvages, une forte concentration en chélateur calcique exogène. Conformément aux résultats théoriques, nous avons pu observer des transitions vers des oscillations en salve du potentiel membranaire. Enfin, nous avons montré que l’absence de calrétinine affecte les paramètres morphologiques du grain cérébelleux des souris transgéniques déficientes en calrétinine.<p>En conclusion, ces résultats suggèrent que le mode de décharge des cellules excitables peut être modulé d’une façon importante par les protéines liant le calcium. De ce fait, des changements dans le niveau d’expression et/ou dans la localisation subcellulaire des protéines liant le calcium pourraient aussi jouer un rôle critique dans la régulation de processus physiologiques contrôlés par l’excitabilité membranaire. De plus, les mécanismes que nous avons mis en évidence pourraient être à l’origine d’un nouveau principe de régulation de la signalisation dans les circuits neuronaux et pourraient jouer un rôle fonctionnel dans le contrôle du codage de l’information et de son stockage dans le système nerveux central.<br>Doctorat en sciences, Spécialisation physique<br>info:eu-repo/semantics/nonPublished
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Hinkle, Adam R. "Tight-binding calculation of electronic properties of oligophenyl and oligoacene nanoribbons." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1398716.
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Within recent years, allotropic structures of carbon have been produced in the forms of tubes and ribbons which offer the promise of extraordinary electronic and thermal properties. Here we present analyses of oligophenyl and oligoacene systems–infinite, one-dimensional chains of benzene rings linked along the armchair and zigzag directions. These one-dimensional structures, which are amenable to calculation by analytical means, exhibit features very similar to carbon nanotubes and nanoribbons. Using a tight-binding Hamiltonian we analytically determine the density of states, local density of states, and energy-band structure for the phenyl and the acene. We also examine the effect of disorder on the energies and the corresponding states.<br>Department of Physics and Astronomy
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Chiang, T. "Mathematical and statistical models for the analysis of protein." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597600.
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Protein interactions, both amongst themselves and with other molecules, are responsible for much of the work within the cellular machine. As the number of protein interaction data sets grow in number and in size, from experiments such as Yeast 2-Hybrid or Affinity Purification followed by Mass Spectrometry, there is a need to analyse the data both quantitatively and qualitatively. One area of research is determining how reliable a report of a protein interaction is – whether it could be reproduced if the experiment were repeated, or if it were tested using an independent assay. One might aim to score each reported interaction using a quantitative measure of reliability. Ultimately, protein interactions need to be addressed at the systems level where both the dynamic and functional nature of protein complexes and other types of interactions is ascertained. In this dissertation, I present two methodological developments that are useful towards elucidating the nature of protein interaction graphs in the model organism <i>Saccharomyces cerevisiae</i>. The first one aims to estimate the <i>sensitivity</i> and <i>specificity</i> of a protein interaction data set, and does that, as much as possible, by looking at the data set’s internal consistency and reproducibility. The second method aims to estimate the node degree distribution, using a multinomial model which is fit by maximum likelihood. In the development of the methods for the analysis of the protein interactions, computational tools were built in the statistical environment R. Such tools are necessary for the implementation of each analytic step, for rendering visualisations of intermediate and conclusive results, and for the construction of optimal work-flows so as to make our research reproducible and extensible. We have also included such a work-flow in this dissertation as well as the software engineering component of the research.
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Gregor, Craig Robert. "Epitopes, aggregation and membrane binding : investigating the protein structure-function relationship." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/5833.
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The three-dimensional structure of a protein, formed as a result of amino-acid sequences folding into compact domains, is regarded as a key factor in its biological function. How and why proteins fold into specific topologies, remain the key focus of scientific research in the field of biophysics. By stripping down complex reactions down to the most basic elements, biophysicists aim to develop simplified models for biological phenomena such as antibody discrimination, viral fusion or self-assembly. Focusing on small model peptide systems, rather than the full proteins from which they were derived, was hoped to result in accurate structural measurements and provide a more transparent comparison between simulation and experiment. The aim of this research was therefore to investigate how accurate these models were when compared against experiment. Furthermore, while breaking down the complex biological phenomena into simple models, there was also a conscious effort to ensure that the models were representative of real biological systems, and a major focus was therefore aimed at determining whether any meaningful biomedical insight may be extrapolated from such models. Peptides found in hormones (human chorionic gonadotropin, luteinizing hormone), viruses (HIV) and amyloid diseases (transthyretin) were selected in order to probe a variety of questions in relation to the aforementioned biological phenomena. Namely, how the primary sequence influenced the three-dimensional structure (and thus its biological function), how its environment could influence such a confirmation, and how these systems aggregated. This doctoral study has made use of a combination of computer simulations and experimental techniques to investigate a selection of biologically relevant peptides; utilising classical atomistic molecular dynamics (MD) simulations to characterise the free-energy landscapes of the chosen peptides, and compare these findings with the secondary structure content predicted by spectroscopic methods such as circular dichroism and infrared spectroscopy. The peptide systems studied within, were found to be characterised by rugged free-energy landscapes unlike their protein counterparts (defined by singular, deep minima). Furthermore, these landscapes were found to be highly plastic and sensitive to changes in the local environment.
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Allison, Jerry Dewell. "An implementation of the competitive Gaussian model for metal-humic binding in a general speciation model." Diss., Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/25965.
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Nordling, Erik. "Biocomputational studies on protein structures /." Stockholm, 2002.
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Smoler, Eliezer. "Mathematical models to predict milk protein concentration from dietary components fed to dairy cows." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308060.
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Chu, Vano. "Molecular recognition in the streptavidin-biotin system /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8106.
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Adhikari, Sombudha. "IDENTIFICATION OF PROTEIN PARTNERS FOR NIBP, A NOVEL NIK-AND IKKB-BINDING PROTEIN THROUGH EXPERIMENTAL, COMPUTATIONAL AND BIOINFORMATICS TECHNIQUES." Master's thesis, Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/216569.
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Bioengineering<br>M.S.<br>NIBP is a prototype member of a novel protein family. It forms a novel subcomplex of NIK-NIBP-IKKB and enhances cytokine-induced IKKB-mediated NFKB activation. It is also named TRAPPC9 as a key member of trafficking particle protein (TRAPP) complex II, which is essential in trans-Golgi networking (TGN). The signaling pathways and molecular mechanisms for NIBP actions remain largely unknown. The aim of this research is to identify potential proteins interacting with NIBP, resulting in the regulation of NFKB signaling pathways and other unknown signaling pathways. At the laboratory of Dr. Wenhui Hu in the Department of Neuroscience, Temple University, sixteen partner proteins were experimentally identified that potentially bind to NIBP. NIBP is a novel protein with no entry in the Protein Data Bank. From a computational and bioinformatics standpoint, we use prediction of secondary structure and protein disorder as well as homology-based structural modeling approaches to create a hypothesis on protein-protein interaction between NIBP and the partner proteins. Structurally, NIBP contains three distinct regions. The first region, consisting of 200 amino acids, forms a hybrid helix and beta sheet-based domain possibly similar to Sybindin domain. The second region comprised of approximately 310 residues, forms a tetratrico peptide repeat (TPR) zone. The third region is a 675 residue long all beta sheet and loops zone with as many as 35 strands and only 2 helices, shared by Gryzun-domain containing proteins. It is likely to form two or three beta sheet sandwiches. The TPR regions of many proteins tend to bind to the peptides from disordered regions of other proteins. Many of the 16 potential binding proteins have high levels of disorder. These data suggest that the TPR region in NIBP most likely binds with many of these 16 proteins through peptides and other domains. It is also possible that the Sybindin-like domain and the Gryzun-like domain containing beta sheet sandwiches bind to some of these proteins.<br>Temple University--Theses
12
Balderson, Stephanie D. "Investigations of Insulin-Like Growth Factor I Cell Surface Binding: Regulation by Insulin-Like Growth Factor Binding Protein-3 and Heparan Sulfate Proteoglycan." Thesis, Virginia Tech, 1997. http://hdl.handle.net/10919/30494.
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The primary aim of this text is to gain insight on how cellular activation by a insulin-like growth factor (IGF-I), in the presence of insulin-like growth factor binding protein-3 (IGFBP-3), is influenced by heparan sulfate proteoglycans (HSPG). Initial research will be presented, assumptions and hypotheses that were included in the development of mathematical models will be discussed, and the future enhancements of the models will be explored. There are many potential scenarios for how each component might influence the others. Mathematical modeling techniques will highlight the contributions made by numerous extracellular parameters on IGF-I cell surface binding. Tentative assumptions can be applied to modeling techniques and predictions may aid in the direction of future experiments.
Experimentally, it was found that IGFBP-3 inhibited IGF-I Bovine Aortic Endothelial (BAE) cell surface binding while p9 HS slightly increased IGF-I BAE cell surface binding. IGFBP-3 has a higher binding affinity for IGF-I (3 x 10-9 M) than p9 HS has for IGF-I (1.5 x 10-8 M) as determined with cell-free binding assays. The presence of p9 HS countered the inhibiting effect of IGFBP-3 on IGF-I BAE cell surface binding.
Although preliminary experiments with labeled p9 HS and IGFBP-3 indicated little to no cell surface binding, later experiments indicated that both IGFBP-3 and p9 HS do bind to the BAE cell surface. Pre-incubation of BAE cells with either IGFBP-3 or p9 HS resulted in an increase of IGF-I BAE cell surface binding . There was a more substantial increase of IGF-I surface binding when cells were pre-incubated with IGFBP- 3 than p9 HS. There was a larger increase of IGF-I BAE cell surface binding when cells were pre-incubated with p9 HS than when p9 HS and IGF-I were added simultaneously. This suggests that IGFBP-3 and p9 HS surface binding plays key role in IGF-I surface binding, however, p9 HS surface binding does not alter IGF-I surface binding as much as IGFBP-3 surface binding seems to.
Experimental work helps further the understanding of IGF-I cellular activation as regulated by IGFBP-3 and p9 HS. Developing mathematical models allows the researcher to focus on individual elements in a complex systems and gain insight on how the real system will respond to individual changes. Discrepancies between the model results and the experimental data presented indicate that soluble receptor inhibition is not sufficient to account for experimental results.
The alliance of engineering analysis and molecular biology helps to clarify significant principles relevant to the conveyance of growth factors into tissue. Awareness of the effects of individual parameters in the delivery system, made possible with mathematical models, will provide guidance and save time in the design of future therapeutics involving growth factors.<br>Master of Science
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Henne, Randal Marlow. "Computational studies of G-protein coupled receptors /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8048.
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Brown, Jennifer Louise. "Investigation of the molecular interactions between an anti-peptide antibody and its ligand." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318221.
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Robertson, Timothy Allen. "Development and validation of statistical potential functions for the prediction of protein/nucleic-acid interactions from structure /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/9268.
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Ge, Wanwan [Verfasser]. "Discovery and prediction of protein binding sites in DNA and RNA sequences using Bayesian Markov models / Wanwan Ge." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2021. http://d-nb.info/1236753968/34.
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Lee, Pui-chi, and 李佩芝. "Phenotypic characterization of adipocyte fatty acid binding protein knockout mice under high fat high cholesterol diet-induced obesity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197517.
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Background and objectives:
A lot of studies proved that adipocyte fatty acid binding protein (A-FABP), an adipokine mainly expressed in adipocytes and macrophages, is the key link between obesity and inflammation which is suggested to be a therapeutic target for obesity-related diseases. Loss-of-function study was employed by using A-FABP knockout (KO) mice generated by our group to investigate role of A-FABP in high fat high cholesterol (HFHC) diet-induced obesity.
Key findings:
1. Our study confirmed that HFHC diet-induced A-FABP KO mice have a significantly increased body weight when compared to the wild-type (WT) control mice.
2. Higher adiposity was the major reason for the A-FABP KO mice to be heavier than the WT controls under HFHC diet induction.
3. The marked increase of the weight of subcutaneous fat and peri-renal fat contributed to the higher adiposity of the HFHC-diet induced A-FABP KO mice when compared to the WT controls.
4. The HFHC-diet induced A-FABP KO mice significantly consumed less oxygen and produced less carbon dioxide suggesting the reduced energy expenditure but had higher weekly energy intake when compared with the WT controls, leading to higher adiposity.
5. The A-FABP KO mice were protected against HFHC diet induced glucose intolerance, insulin resistance, hyperglycemia and hyperinsulinemia when compared with the WT controls. There was also a better insulin secretion in response to glucose stimulation in A-FABP KO mice under prolonged HFHC diet induction when compared with the WT controls.
6. The A-FABP KO mice were protected against the development of hypercholesterolemia and hypertriglycemia when compared the WT controls under HFHC diet induction. However, there was no significant difference in the fasting serum free fatty acids (FFA) level among A-FABP WT and KO mice fed with standard chow (STC) or HFHC diet.
7. A-FABP KO mice were protected against isolated systolic hypertension (ISH) under HFHC diet induction.
8. The A-FABP KO mice were protected against HFHC diet-induced liver injury as indicated by a lower serum ALT level suggesting a better liver function when compared with the WT controls.
9. Under HFHC diet induction, M1 macrophage polarization was dominant in fat tissues of A-FABP WT mice but M2 macrophage polarization was dominant in fat tissues of A-FABP KO mice, suggesting an improved inflammatory status in the adipose tissue of the A-FABP KO mice when compared with the WT controls. This may also be the reason for why HFHC diet-induced A-FABP KO mice have an increased body weight but are metabolically healthier compared to their WT controls.
Conclusions:
A-FABP KO mice had a significant higher body weight and higher adiposity due to the reduced energy expenditure and increased weekly food intake as indicated in the metabolic cage study and the reason for metabolic healthier is due to the alleviated HFHC diet induced M1 macrophage polarization in various adipose tissues suggesting an improved inflammatory status in A-FABP KO mice comparing to the WT controls.<br>published_or_final_version<br>Medicine<br>Master<br>Master of Philosophy
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Tsilo, Lipontseng Cecilia. "Protein secondary structure prediction using neural networks and support vector machines." Thesis, Rhodes University, 2009. http://hdl.handle.net/10962/d1002809.
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Predicting the secondary structure of proteins is important in biochemistry because the 3D structure can be determined from the local folds that are found in secondary structures. Moreover, knowing the tertiary structure of proteins can assist in determining their functions. The objective of this thesis is to compare the performance of Neural Networks (NN) and Support Vector Machines (SVM) in predicting the secondary structure of 62 globular proteins from their primary sequence. For each NN and SVM, we created six binary classifiers to distinguish between the classes’ helices (H) strand (E), and coil (C). For NN we use Resilient Backpropagation training with and without early stopping. We use NN with either no hidden layer or with one hidden layer with 1,2,...,40 hidden neurons. For SVM we use a Gaussian kernel with parameter fixed at = 0.1 and varying cost parameters C in the range [0.1,5]. 10- fold cross-validation is used to obtain overall estimates for the probability of making a correct prediction. Our experiments indicate for NN and SVM that the different binary classifiers have varying accuracies: from 69% correct predictions for coils vs. non-coil up to 80% correct predictions for stand vs. non-strand. It is further demonstrated that NN with no hidden layer or not more than 2 hidden neurons in the hidden layer are sufficient for better predictions. For SVM we show that the estimated accuracies do not depend on the value of the cost parameter. As a major result, we will demonstrate that the accuracy estimates of NN and SVM binary classifiers cannot distinguish. This contradicts a modern belief in bioinformatics that SVM outperforms other predictors.
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Gaudreault, Mathieu. "Collapse transition of SARWs with hydrophobic interaction on a two dimensional lattice." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112623.
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We study the collapse transition of a lattice based protein model including an explicit coarse-grained model of a solvent. This model accounts for explicit hydrophobic interactions, and it is studied by Monte Carlo simulation. The protein is modelled as self-avoiding random walk with nearest neighbor interactions on a two dimensional lattice. Without the solvent, universal quantities of the chain around the collapse transition temperature are well known. Hydrophobicity is then modelled through a lattice of solvent molecules in which each molecule can have Q states depending of an orientation variable. Only one state is energetically favored, when two neighboring solvent molecules are both in the same state of orientation. The monomers are placed in interstitial position of the solvent lattice, and are only allowed to occupy sites surrounded by solvent cells of the same orientation. The potential of mean force between two interstitial solute molecules is calculated, showing a solvent mediated attraction typical of hydrophobic interactions. We then show that this potential increases with the energy of hydrogen bond formation as it appears in the model, while its characteristic range decreases. More importantly, we show that the chain embedded in the solvent undergoes a collapse transition, with the temperature of the transition being shifted relative to that of the chain in isolation. We calculate several critical exponents near the collapse transition, and we observe that their values are not conserved in presence of the explicit solvent.
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Betz, Michael [Verfasser], and Gerhard [Akademischer Betreuer] Klebe. "Development of models to describe the dynamics and interaction with water molecules in protein-ligand binding / Michael Betz. Betreuer: Gerhard Klebe." Marburg : Philipps-Universität Marburg, 2015. http://d-nb.info/1081215569/34.
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Ye, Dewei, and 叶得伟. "Toll-like receptor-4 mediates obesity-induced nonalcoholic steatohepatitis through activation of X-box binding protein-1 in mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47752919.
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Background and objectives:
Nonalcoholic steatohepatitis (NASH), which is characterized by concurrent
existence of hepatic steatosis and predominantly lobular necroinflammation, represents
the more advanced stage in the spectrum of nonalcoholic fatty liver disease (NAFLD).
NASH exhibits dramatically increased risk of progression to end-stage liver diseases
than simple steatosis. Therefore, the progression of hepatic steatosis to steatohepatitis is
the crucial step in the development of obesity-related NASH. Toll like receptor 4
(TLR4), a master regulator of innate immunity, is the principal receptor for endotoxin,
which is a central mediator of liver inflammation associated with both alcoholic and
nonalcoholic liver disease. However, due to a lack of suitable animal models which
fully recapitulate the natural history of obesity-induced NASH, the precise
pathophysiological function of TLR4 signaling in the development of this disease
remains poorly understood.
The objective of this study is to investigate the role of TLR4 in mediating
inflammatory responses in obesity-induced NASH using both in vivo and ex vivo
approaches, and to unveil cellular and molecular mechanisms responsible for TLR4
actions.
Key findings:
1. To address the role of TLR4 in the pathogenesis of NASH, we crossed ApoEdeficient
mice (ApoE-/-) with TLR4 mutant mice (TLR4-/-) to generate ApoE-/-
/TLR4 wild type mice (ApoE-/-/TLR4-WT) and ApoE-/-/TLR4-/- mice. Noticeably,
when fed with high fat high cholesterol (HFHC) diet, ApoE-/-/TLR4-WT mice
developed the typical pathology of NASH (hepatic steatosis, lobular inflammation,
and hepatocyte ballooning) in the context of obesity and metabolic syndrome,
suggesting HFHC-fed ApoE-/- mice as a suitable animal model for NASH.
2. TLR4 inactivation protected ApoE-/- mice against HFHC diet-induced liver injury,
as indicated by a significant improvement in liver histology, a a marked reduction
in serum ALT activity, a dramatic repression of inflammatory infiltrates, as well as
an obvious decrease in hepatic production of pro-inflammatory cytokines.
3. In ApoE-/-/TLR4-WT mice, TLR4 expression was selectively elevated in Kupffer
cells in response to HFHC diet feeding.
4. The activation of XBP1, a transcription factor involved in endoplasmic reticulum
stress, was markedly elevated in liver of ApoE-/-/TLR4-WT mice fed with HFHC
diet, whereas this change was abrogated in HFHC diet-fed ApoE-/-/TLR4-/- mice.
5. In rat primary Kupffer cells, treatment with anti-oxidants blocked endotoxininduced
activation of XBP1 and NF-κB, leading to decreased cytokine production.
In addition, siRNA-mediated knockdown of XBP1 inhibited NF-κB activation and
cytokine production resulted from the treatment with the TLR4 agonist LPS.
6. In ApoE-/-/TLR4-WT mice, adenovirus-mediated expression of dominant negative
XBP1 had no obvious effect on HFHC diet-induced hepatic steatosis and ROS
production, but markedly decreased lobular inflammation, NF-κB activation,
cytokine production in the liver and significantly reduced serum levels of ALT.
Conclusions:
These findings support the role of TLR4 in Kupffer cells as a key player in
mediating the progression of simple steatosis to NASH, by inducing ROS-dependent
activation of XBP1. In light of the obligatory role of XBP1 in TLR4-induced liver
inflammation and injury, therapeutic interventions that inhibit TLR4/XBP1 activation
may represent a promising strategy for treatment of NASH.<br>published_or_final_version<br>Medicine<br>Doctoral<br>Doctor of Philosophy
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Nelson, Michael R. Jr. "Ab initio molecular orbital studies: Rydberg states of H₄ barriers to internal rotation studies binding of CO₂ to carbonyl groups isoprene and ozone complexes." Diss., Georgia Institute of Technology, 1998. http://hdl.handle.net/1853/30278.
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Subramanian, Kartik. "Spatiotemporal Model of the Asymmetric Division Cycle of Caulobacter crescentus." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/65156.
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The life cycle of Caulobacter crescentus is of interest because of the asymmetric nature of cell division that gives rise to progeny that have distinct morphology and function. One daughter called the stalked cell is sessile and capable of DNA replication, while the second daughter called the swarmer cell is motile but quiescent. Advances in microscopy combined with molecular biology techniques have revealed that macromolecules are localized in a non-homogeneous fashion in the cell cytoplasm, and that dynamic localization of proteins is critical for cell cycle progression and asymmetry. However, the molecular-level mechanisms that govern protein localization, and enable the cell to exploit subcellular localization towards orchestrating an asymmetric life cycle remain obscure. There are also instances of researchers using intuitive reasoning to develop very different verbal explanations of the same biological process. To provide a complementary view of the molecular mechanism controlling the asymmetric division cycle of Caulobacter, we have developed a mathematical model of the cell cycle regulatory network.
Our reaction-diffusion models provide additional insight into specific mechanism regulating different aspects of the cell cycle. We describe a molecular mechanism by which the bifunctional histidine kinase PleC exhibits bistable transitions between phosphatase and kinase forms. We demonstrate that the kinase form of PleC is crucial for both swarmer-to-stalked cell morphogenesis, and for replicative asymmetry in the predivisional cell. We propose that localization of the scaffolding protein PopZ can be explained by a Turing-type mechanism. Finally, we discuss a preliminary model of ParA- dependent chromosome segregation. Our model simulations are in agreement with experimentally observed protein distributions in wild-type and mutant cells. In addition to predicting novel mutants that can be tested in the laboratory, we use our models to reconcile competing hypotheses and provide a unified view of the regulatory mechanisms that direct the Caulobacter cell cycle.<br>Ph. D.
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Kambafwile, Henry Kunda. "Synthesis of activity-based protein profiling probes for malaria and hypertension disease models & potential novel ACE inhibitors with an attenuated zinc binding group." Doctoral thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/11736.
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Includes bibliographical references.<br>Angiotensin-converting enzyme (ACE) and P. falciparum A M1 (PfA-M1) are both zinc metalloproteases implicated in hypertension and malaria, respectively. Hypertension affects approximately 26 % of the world’s population while each year over 300 million cases of malaria occur worldwide resulting in between 1.5 and 2.7 million deaths annually. Hypertension treatment with current ACE inhibitors is marred by unpleasant side effects, such as cough and angioedema. In malaria, the parasites continuously develop resistance to anti-malarial drugs where the disease is endemic. There is therefore a need for continuous research into the application of new techniques as well as the design of new small molecule chemical entities as probes or chemotherapeutic agents.
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Xian, Lede. "Electronic structure and interlayer coupling in twisted multilayer graphene." Diss., Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/51811.
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It has been shown recently that high-quality epitaxial graphene (EPG) can be grown on the SiC substrate that exhibits interesting physical properties and has great advantages for varies device applications. In particular, the multilayer graphene films grown on the C-face show rotational disorder. It is expected that the twisted layers exhibit unique new physics that is distinct from that of either single layer graphene or graphite. In this work, by combining density functional and tight-binding model calculations, we investigate the electric field and doping effects on twisted bilayer graphene (TBG), multiple layer effects on twisted triple-layer graphene, and wave packet propagation properties of TBG. Though these studies, we obtain a comprehensive description of the interesting interlayer interaction in this twisted multilayer graphene system.
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Fisch, Thomas Martin. "Effects of insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression on adrenal and renal growth processes and functions: findings in transgenic mouse models." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-34045.
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Scott, Carol Elizabeth DeWeese. "Molecular modeling and experimental characterization of HLA-DQ proteins and protein/peptide complexes : correlation with insulin-dependent diabetes mellitus (IDDM) /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8089.
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Kaminishi, Tatsuya, Andreas Schedlbauer, Attilio Fabbretti, Letizia Brandi, Lizarralde Borja Ochoa, Cheng-Guang He, Pohl Milon, Sean R. Connell, Claudio O. Gualerzi, and Paola Fucini. "Crystallographic characterization of the ribosomal binding site and molecular mechanism of action of Hygromycin A." Oxford University Press, 2015. http://hdl.handle.net/10757/608247.
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Hygromycin A (HygA) binds to the large ribosomal subunit and inhibits its peptidyl transferase (PT) activity. The presented structural and biochemical data indicate that HygA does not interfere with the initial binding of aminoacyl-tRNA to the A site, but prevents its subsequent adjustment such that it fails to act as a substrate in the PT reaction. Structurally we demonstrate that HygA binds within the peptidyl transferase center (PTC) and induces a unique conformation. Specifically in its ribosomal binding site HygA would overlap and clash with aminoacyl-A76 ribose moiety and, therefore, its primary mode of action involves sterically restricting access of the incoming aminoacyl-tRNA to the PTC.<br>Bizkaia:Talent and the European Union's Seventh Framework Program (Marie Curie Actions; COFUND; to S.C., A.S., T.K.); Marie Curie Actions Career Integration Grant (PCIG14-GA-2013-632072 to P.F.); Ministerio de Economía Y Competitividad (CTQ2014-55907-R to P.F., S.C.); FIRB Futuro in Ricerca from the Italian Ministero dell'Istruzione, dell'Universitá e della Ricerca (RBFR130VS5_001 to A.F.); Peruvian Programa Nacional de Innovación para la Competitividad y Productividad (382-PNICP-PIBA-2014 (to P.M. and A.F.)). Funding for open access charge: Institutional funding.<br>Revisión por pares
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Hubig, Christina Stefanie [Verfasser]. "Investigations on the role of the IGF2 mRNA-binding protein p62 and the long non-coding RNA H19 in cell culture and in vivo models of hepatocellular carcinoma / Christina Stefanie Hubig." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2018. http://d-nb.info/1174876999/34.
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Chou, Chiu-wen, and 周秋雯. "A study of the expression of NF-kB in central nervous system of rats with neuropathic pain." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44902542.
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Gebski, Bijanka L. "Investigating TNF inhibition of IGF-1 signalling via JNK in cell culture models of skeletal muscle atrophy." University of Western Australia. School of Anatomy and Human Biology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0097.
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[Truncated abstract] The pro-inflammatory cytokine tumour necrosis factor (TNF) has a critical role in skeletal muscle atrophy. The catabolic effect of TNF is partially due to abrogation of the anabolic insulin-like growth factor 1 (IGF-1) signalling pathway. However, the precise signalling events that lead to the loss of myofibrillar protein following activation of TNF receptor are unknown. The over arching aim of the study is to determine the mechanisms of by which TNF induces atrophy in differentiated muscles cells. To achieve this aim a series of experiments were performed to: 1) investigate the molecular events that lead to TNF mediated myofibre atrophy, 2) determine to what extent c-Jun N-terminal Kinase (JNK) signalling plays a part in TNF induced myotube atrophy, and in TNF-mediated inhibition of IGF-1 induced hypertrophy, and 3) use inhibitors of JNK to block the catabolic effects of TNF. 1) To investigate the molecular events that lead to TNF mediated myofibre atrophy, the experiments were conducted using C2C12 mouse myotube cultures and primary myotube cultures derived from FVB mice, and transgenic mice which over-express Class 2 IGF-1 Ea in skeletal muscles (IGF:C2). The treatment of mature C2C12 and FVB primary myotubes (respectively at 7 and 4 days after fusion medium) with 10 ng/mL of TNF for 3 days resulted in statistically significant myotube atrophy (decreased mean width). The observed TNF-mediated atrophy has not previously been demonstrated in tissue cultured myotubes. In contrast, addition of IGF-1 (20 ng/ml) to 7 day C2C12 myotubes for 3 days resulted in significant hypertrophy. ... The most suitable inhibitor was TAT-TIJIP and was thus used in subsequent studies. Inhibition of JNK activity by TAT-TIJIP was confirmed indirectly by detecting nuclear translocation of c- Jun, which is a downstream target of phosphorylated JNK. Immunohistochemical analyses showed nuclear localisation and phosphorylation of c-Jun in TNF treated myotubes. Nuclear localisation and phosphorylation of c-Jun was not observed in cultures pre-treated with TAT-TIJIP before TNF treatment, nor in the untreated control myotubes. 3) The use of JNK inhibitors to block the catabolic effects of TNF was tested using C2C12 and primary myotube cultures. Pre-treatment of C2C12 and primary FVB myotubes with the JNK inhibitor TAT-TIJIP, 30 min before TNF administration (for 3 days) prevented myotube atrophy. The mean width of myotubes pre-treated with TATTIJIP prior to TNF treatment closely resembled that of the control myotubes. Administration of TNF in combination with TAT-TIJIP for 3 days to C2C12 myotubes prevented myotube atrophy and unexpectedly resulted in hypertrophy when compared to the mean widths of untreated and TAT-TIJIP treated myotubes. This trend was also demonstrated in the FVB primary cultures. These combined results strongly support the role of JNK in TNF-mediated atrophy. Preliminary studies were carried out in vivo using the mdx mouse model of muscular dystrophy, TAT-TIJIP was administered via intraperitoneal injection to the mice for 3 days at a dose of 10 mg/ml, however the results form this study are inconclusive. These novel observations are of considerable interest to the field of muscle wasting because they demonstrate for the first time TNF-mediated myotube atrophy, the role of JNK in situations of TNF induced muscle atrophy, and explore the use of JNK inhibitors to prevent muscle atrophy.
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Rivas, Cruz Manuel A. "Medical relevance and functional consequences of protein truncating variants." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:a042ca18-7b35-4a62-aef0-e3ba2e8795f7.
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Genome-wide association studies have greatly improved our understanding of the contribution of common variants to the genetic architecture of complex traits. However, two major limitations have been highlighted. First, common variant associations typically do not identify the causal variant and/or the gene that it is exerting its effect on to influence a trait. Second, common variant associations usually consist of variants with small effects. As a consequence, it is more challenging to harness their translational impact. Association studies of rare variants and complex traits may be able to help address these limitations. Empirical population genetic data shows that deleterious variants are rare. More specifically, there is a very strong depletion of common protein truncating variants (PTVs, commonly referred to as loss-of-function variants) in the genome, a group of variants that have been shown to have large effect on gene function, are enriched for severe disease-causing mutations, but in other instances may actually be protective against disease. This thesis is divided into three parts dedicated to the study of protein truncating variants, their medical relevance, and their functional consequences. First, I present statistical, bioinformatic, and computational methods developed for the study of protein truncating variants and their association to complex traits, and their functional consequences. Second, I present application of the methods to a number of case-control and quantitative trait studies discovering new variants and genes associated to breast and ovarian cancer, type 1 diabetes, lipids, and metabolic traits measured with NMR spectroscopy. Third, I present work on improving annotation of protein truncating variants by studying their functional consequences. Taken together, these results highlight the utility of interrogating protein truncating variants in medical and functional genomic studies.
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Lagerquist, Hägglund Christine. "Affinity-, Partition- and Permeability Properties of the Human Red Blood Cell Membrane and Biomembrane Models, with Emphasis on the GLUT1 Glucose Transporter." Doctoral thesis, Uppsala University, Department of Biochemistry, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3525.
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<p>The human glucose transporter GLUT1 is abundant in red blood cells, the blood-brain barrier and epithelial cells, where it mediates the transport of the energy metabolite, glucose. In the present work some properties of GLUT1, including affinity binding of both substrates and inhibitors, transport rates as well as permeabilities of aromatic amino acids and drug-membrane interactions were analyzed by chromatographic methods.</p><p>Reconstitution by size-exclusion chromatography on Superdex 75 from a detergent with a low CMC that provides monomeric GLUT1 was examined regarding D-glucose- and CB binding as well as D-glucose transport. Upon steric immobilization in Superdex 200 gel beads, residual detergent could be washed away and dissociation constants in the same range as reported for binding to GLUT1 reconstituted from other detergents were obtained. The transport rate into the GLUT1 proteoliposomes was low, probably due to residual detergent. Binding to GLUT1 at different pH was analyzed and the affinity of glucose and GLUT1 inhibitors was found to decrease with increasing pH (5–8.7). The average number of cytochalasin B-binding sites per GLUT1 monomers was, in most cases, approximately 0.4. GLUT1 may work as a functional monomer, dimer or oligomer. To determine whether GLUT1 was responsible for the transport of the aromatic amino acids tyrosine and tryptophan, uptake values and permeabilities of these amino acids into liposomes and GLUT1 proteoliposomes were compared to the permeabilities of D- and L- glucose in the same systems. Dihydrocytochalasin B was identified to be a new inhibitor of tyrosine and tryptophan transport into red blood cells. Ethanol turned out to inhibit the specific binding between CB and GLUT1 and also to decrease the partitioning of CB and drugs into lipid bilayers. A capacity factor for drug partitioning into membranes that allows comparison between columns with different amount of immobilized lipids was validated, and turned out to be independent of flow rate, amount of lipids and drug concentration in the ranges tested.</p>
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Leon, Ronald P. "Structural and functional analysis of MCM helicases in eukaryotic DNA replication /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Biophysics & Genetics, Program in Molecular Biology) -- University of Colorado Denver, 2007.<br>Typescript. Includes bibliographical references (leaves 90-98). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Yasmin, Lubna. "Exoenzyme S of Pseudomonas aeruginosa : cellular targets and interaction with 14-3-3." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1411.
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Le, Treut Guillaume. "Models of chromosome architecture and connection with the regulation of genetic expression." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS411/document.
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Plusieurs indices suggèrent que le repliement du chromosome et la régulation de l’expression génétique sont étroitement liés. Par exemple, la co-expression d’un grand nombre de gènes est favorisée par leur rapprochement dans l’espace cellulaire. En outre, le repliement du chromosome permet de faire émerger des structures fonctionnelles. Celles-ci peuvent être des amas condensés et fibrillaires, interdisant l’accès à l’ADN, ou au contraire des configurations plus ouvertes de l’ADN avec quelques amas globulaires, comme c’est le cas avec les usines de transcription. Bien que dissemblables au premier abord, de telles structures sont rendues possibles par l’existence de protéines bivalentes, capable d’apparier des régions parfois très éloignées sur la séquence d’ADN. Le système physique ainsi constitué du chromosome et de protéines bivalentes peut être très complexe. C’est pourquoi les mécanismes régissant le repliement du chromosome sont restés majoritairement incompris.Nous avons étudié des modèles d’architecture du chromosome en utilisant le formalisme de la physique statistique. Notre point de départ est la représentation du chromosome sous la forme d’un polymère rigide, pouvant interagir avec une solution de protéines liantes. Les structures résultant de ces interactions ont été caractérisées à l’équilibre thermodynamique. De plus, nous avons utilisé des simulations de dynamique Brownienne en complément des méthodes théoriques, car elles permettent de prendre en considération une plus grande complexité dans les phénomènes biologiques étudiés.Les principaux aboutissements de cette thèse ont été : (i) de fournir un modèle pour l’existence des usines de transcriptions caractérisées in vivo à l’aide de microscopie par fluorescence ; (ii) de proposer une explication physique pour une conjecture portant sur un mécanisme de régulation de la transcription impliquant la formation de boucles d’ADN en tête d’épingle sous l’effet de la protéine H-NS, qui a été émise suite à l’observation de ces boucles au microscope à force atomique ; (iii) de proposer un modèle du chromosome qui reproduise les contacts mesurés à l’aide des techniques Hi-C. Les conséquences de ces mécanismes sur la régulation de la transcription ont été systématiquement discutées<br>Increasing evidences suggest that chromosome folding and genetic expression are intimately connected. For example, the co-expression of a large number of genes can benefit from their spatial co-localization in the cellular space. Furthermore, functional structures can result from the particular folding of the chromosome. These can be rather compact bundle-like aggregates that prevent the access to DNA, or in contrast, open coil configurations with several (presumably) globular clusters like transcription factories. Such phenomena have in common to result from the binding of divalent proteins that can bridge regions sometimes far away on the DNA sequence. The physical system consisting of the chromosome interacting with divalent proteins can be very complex. As such, most of the mechanisms responsible for chromosome folding and for the formation of functional structures have remained elusive.Using methods from statistical physics, we investigated models of chromosome architecture. A common denominator of our approach has been to represent the chromosome as a polymer with bending rigidity and consider its interaction with a solution of DNA-binding proteins. Structures entailed by the binding of such proteins were then characterized at the thermodynamical equilibrium. Furthermore, we complemented theoretical results with Brownian dynamics simulations, allowing to reproduce more of the biological complexity.The main contributions of this thesis have been: (i) to provide a model for the existence of transcrip- tion factories characterized in vivo with fluorescence microscopy; (ii) to propose a physical basis for a conjectured regulatory mechanism of the transcription involving the formation of DNA hairpin loops by the H-NS protein as characterized with atomic-force microscopy experiments; (iii) to propose a physical model of the chromosome that reproduces contacts measured in chromosome conformation capture (CCC) experiments. Consequences on the regulation of transcription are discussed in each of these studies
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Rodrigues, Christelle. "Optimisation des posologies des antiépileptiques chez l’enfant à partir de données pharmacocinétiques pédiatriques et adultes Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy Conditional non-parametric bootstrap for non-linear mixed effect models Pharmacokinetics evaluation of vigabatrin dose for the treatment of refractory focal seizures in children using adult and pediatric data Pharmacokinetic extrapolation from adult to children in case of nonlinear elimination: a case study." Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2398&f=17336.
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Les enfants diffèrent des adultes non seulement en termes de dimension corporelle mais aussi en termes physiologiques. En effet, les phénomènes de développement et maturation interviennent au cours de la croissance. Ces processus ne sont pas linéaires et induisent des différences pharmacocinétiques et pharmacodynamiques. Ainsi, contrairement à la pratique commune, il n’est pas approprié de déterminer les posologies pédiatriques directement à partir des doses adultes. Étudier la pharmacocinétique chez l’enfant est fondamental pour pouvoir déterminer les posologies à administrer. La méthodologie idéale est l’analyse de population à travers des modèles non-linéaires à effets mixtes. Cependant, même si cette méthode permet l’analyse de données éparses et déséquilibrées, le manque de données individuelles doit être compensé par l’inclusion de plus d’individus. Cela pose un problème lorsque l’indication du traitement est une maladie rare, comme le sont les syndromes épileptiques de l’enfance. Dans ce cas, l’extrapolation de modèles adultes à la population pédiatrique peut s’avérer avantageuse. L’objectif de ce travail de thèse était d’évaluer les recommandations posologiques d’antiépileptiques lorsque des données pharmacocinétiques pédiatriques sont suffisamment informatives pour permettre la construction d’un modèle, ou lorsque celles-ci ne sont pas suffisamment importantes ou ne peuvent pas être exploitées correctement. Dans un premier temps, un modèle parent-métabolite de l’oxcarbazépine et de son dérivé mono-hydroxylé (MHD) a été développé chez l’enfant épileptique âgé de 2 à 12 ans. Ce modèle a permis de mettre en évidence que les plus jeunes enfants nécessitent des doses plus élevées, ainsi que les patients co-traités avec des inducteurs enzymatiques. Un modèle a aussi été développé pour les enfants épileptiques de 1 à 18 ans traités avec la formulation de microsphères à libération prolongée d’acide valproïque. Ce modèle a tenu en compte le flip-flop associé à la formulation et la relation non-linéaire entre la clairance et la dose due à la liaison protéique saturable de façon mécanistique. Encore une fois, il a été mis en évidence le besoin de doses plus élevées pour les enfants plus jeunes. Puis, un modèle adulte du vigabatrin a été extrapolé à l’enfant pour déterminer les posologies permettant d’atteindre des expositions similaires à l’adulte pour traiter les épilepsies focales résistantes. A partir des résultats obtenus, qui sont en accord avec les conclusions d’essais cliniques, nous avons pu proposer une dose de maintenance idéale dans cette indication. Enfin, nous avons étudié la pertinence de l’extrapolation par allométrie théorique dans un contexte de non-linéarité avec l’exemple du stiripentol. Nous avons pu en conclure que cette méthode semble apporter de bonnes prédictions à partir de l’âge de 8 ans, contrairement aux molécules à élimination linéaire où cela semble correct à partir de 5 ans. En conclusion, nous avons pu tester et comparer différentes approches pour aider à la détermination de recommandations posologiques chez l’enfant. L’étude de la pharmacocinétique pédiatrique par des essais spécifiques reste indispensable au bon usage du médicament<br>Children greatly differ from adults not only in terms of size but also in physiological terms. Indeed, developmental changes occur during growth due to maturation. These processes occur in a nonlinear fashion and can cause pharmacokinetic and pharmacodynamic differences. Thus, oppositely to common practice, it is not appropriate to scale pediatric doses directly and linearly from adults. The study of pharmacokinetics in children is then essential to determine those pediatric dosages. The more commonly used methodology is population analysis through non-linear mixed effects models. This method allows the analysis of sparse and unbalanced data. In return, the lack of individual data has to be balanced with the inclusion of more individuals. This can be a problem when the indication of treatment is a rare disease, as are epileptic syndromes of childhood. In this case, extrapolation of adult pharmacokinetic models to the pediatric population may be interesting. The objective of this thesis was to evaluate the dosage recommendations of antiepileptic drugs when pediatric pharmacokinetic data are sufficient to be modeled, and when they are not, extrapolating adequately adult information. Firstly, a parent-metabolite model of oxcarbazepine and its monohydroxy derivative (MHD) was developed in epileptic children aged 2 to 12 years. This model showed that younger children require higher doses, as well as patients co-treated with enzyme inducers. A model was also developed for epileptic children aged 1 to 18 years treated with a valproic acid sustained release microsphere formulation. This model took into account the flip-flop associated with the formulation and the non-linear relationship between clearance and dose caused by a saturable protein binding. Again, the need for higher doses for younger children was highlighted. Then, an adult model of vigabatrin was extrapolated to children to determine which doses allow to achieve exposures similar to adults in resistant focal onset seizures. From the results obtained, which are in agreement with the conclusions of clinical trials, we have been able to propose an ideal maintenance dose for this indication. Finally, we studied the relevance of extrapolation by theoretical allometry in a context of non-linearity with the example of stiripentol. We concluded that this method seems to provide good predictions from the age of 8, unlike the linear elimination molecules where it seems correct from 5 years. In conclusion, we were able to test and compare different approaches to help determine dosing recommendations in children. The study of pediatric pharmacokinetics in specific trials remains essential for the proper use of drugs
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Barwich, Ann-Sophie. "Making sense of smell : classifications and model thinking in olfaction theory." Thesis, University of Exeter, 2013. http://hdl.handle.net/10871/13869.
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This thesis addresses key issues of scientific realism in the philosophy of biology and chemistry through investigation of an underexplored research domain: olfaction theory, or the science of smell. It also provides the first systematic overview of the development of olfactory practices and research into the molecular basis of odours across the 19th and 20th century. Historical and contemporary explanations and modelling techniques for understanding the material basis of odours are analysed with a specific focus on the entrenchment of technological process, research tradition and the definitions of materiality for understanding scientific advancement. The thesis seeks to make sense of the explanatory and problem solving strategies, different ways of reasoning and the construction of facts by drawing attention to the role and application of scientific representations in olfactory practices. Scientific representations such as models, classifications, maps, diagrams, lists etc. serve a variety of purposes that range from the stipulation of relevant properties and correlations of the research materials and the systematic formation of research questions, to the design of experiments that explore or test particular hypotheses. By examining a variety of modelling strategies in olfactory research, I elaborate on how I understand the relation between representations and the world and why this relation requires a pluralist perspective on scientific models, methods and practices. Through this work I will show how a plurality of representations does not pose a problem for realism about scientific entities and their theoretical contexts but, on the contrary, that this plurality serves as the most reliable grounding for a realistic interpretation of scientific representations of the world and the entities it contains. The thesis concludes that scientific judgement has to be understood through its disciplinary trajectory, and that scientific pluralism is a direct consequence of the historicity of scientific development.
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"Clues of identification of protein-protein interaction sites." 2005. http://library.cuhk.edu.hk/record=b5892544.
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Leung Ka-Kit.<br>Thesis submitted in: November 2004.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.<br>Includes bibliographical references (leaves 67-71).<br>Abstracts in English and Chinese.<br>Abstract<br>Chapter CHAPTER 1. --- INTRODUCTION --- p.1<br>Chapter 1.1 --- Background of protein structures --- p.1<br>Chapter 1.2 --- Background of protein-protein interaction (PPI) --- p.4<br>Chapter 1.2.1 --- Quaternary structure and protein complex --- p.4<br>Chapter 1.2.2 --- Previous related work --- p.4<br>Chapter 1.2.3 --- The kinetic and thermodynamic formalism --- p.6<br>Chapter CHAPTER 2. --- MATERIALS AND METHODS --- p.10<br>Chapter 2.1 --- Amino acid composition representative power modeling --- p.10<br>Chapter 2.1.1 --- Propensity level modeling --- p.10<br>Chapter 2.1.2 --- Polar atoms visualization --- p.17<br>Chapter 2.2 --- Rigid structure representative power modeling --- p.17<br>Chapter 2.3 --- Electrostatic potential modeling --- p.17<br>Chapter 2.3.1 --- Charge residence --- p.17<br>Chapter 2.3.2 --- Minimum Ribbon (MR) --- p.19<br>Chapter 2.4 --- Examination of interface --- p.23<br>Chapter 2.5 --- Identification procedures of a binding site --- p.24<br>Chapter 2.6 --- System requirements --- p.24<br>Chapter CHAPTER 3. --- RESULTS AND DISCUSSIONS --- p.24<br>Chapter 3.1 --- Polar atoms --- p.25<br>Chapter 3.2 --- Minimum Ribbon (MR) --- p.27<br>Chapter 3.3 --- "Charge complementarity, propensity level and rigid structure orientation" --- p.31<br>Chapter 3.4 --- Identification of interacting site --- p.36<br>Chapter CHAPTER 4. --- CONCLUSIONS --- p.64<br>System requirements --- p.65<br>Basic operation --- p.65<br>Limitation --- p.66
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Hicks, Joshua M. "Analysis of secondary structures in nucleic acid binding proteins and nuclear magnetic resonance investigation of helix propagation and residual motions in proteins." Thesis, 2005. http://hdl.handle.net/1957/29424.
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"Pattern discovery for deciphering gene regulation based on evolutionary computation." Thesis, 2010. http://library.cuhk.edu.hk/record=b6075246.
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On TFBS motif discovery, three novel GA based algorithms are developed, namely GALF-P with focus on optimization, GALF-G for modeling, and GASMEN for spaced motifs. Novel memetic operators are introduced, namely local filtering and probabilistic refinement, to significantly improve effectiveness (e.g. 73% better than MEME) and efficiency (e.g. 4.49 times speedup) in search. The GA based algorithms have been extensively tested on comprehensive synthetic, real and benchmark datasets, and shown outstanding performances compared with state-of-the-art approaches. Our algorithms also "evolve" to handle more and more relaxed cases, namely from fixed motif widths to most flexible widths, from single motifs to multiple motifs with overlapping control, from stringent motif instance assumption to very relaxed ones, and from contiguous motifs to generic spaced motifs with arbitrary spacers.<br>TF-TFBS associated sequence pattern (rule) discovery is further investigated for better deciphering protein-DNA interactions in regulation. We for the first time generalize previous exact TF-TFBS rules to approximate ones using a progressive approach. A customized algorithm is developed, outperforming MEME by over 73%. The approximate TF-TFBS rules, compared with the exact ones, have significantly more verified rules and better verification ratios. Detailed analysis on PDB cases and conservation verification on NCBI protein records illustrate that the approximate rules reveal the flexible and specific protein-DNA interactions with much greater generalized capability.<br>The comprehensive pattern discovery algorithms developed will be further verified, improved and extended to further deciphering transcriptionial regulation, such as inferring whole gene regulatory networks by applying TFBS and TF-TFBS patterns discovered and incorporating expression data.<br>Transcription Factor (TF) and Transcription Factor Binding Site (TFBS) bindings are fundamental protein-DNA interactions in transcriptional regulation. TFs and TFBSs are conserved to form patterns (motifs) due to their important roles for controlling gene expressions and finally affecting functions and appearances. Pattern discovery is thus important for deciphering gene regulation, which has tremendous impacts on the understanding of life, bio-engineering and therapeutic applications. This thesis contributes to pattern discovery involving TFBS motifs and TF-TFBS associated sequence patterns based on Evolutionary Computation (EC), especially Genetic Algorithms (GAs), which are promising for bioinformatics problems with huge and noisy search space.<br>Chan, Tak Ming.<br>Advisers: Kwong-Sak Leung; Kin-Hong Lee.<br>Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: .<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 2010.<br>Includes bibliographical references (leaves 147-153).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Abstract also in Chinese.
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Al-Malah, Kamal Issa Masoud. "Macroscopic model for apparent protein adsorption equillibrium at hydrophobic solid-water interfaces." Thesis, 1993. http://hdl.handle.net/1957/35391.
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Groh, C. M., M. E. Hubbard, P. F. Jones, Paul M. Loadman, Nagarajan Periasamy, B. D. Sleeman, S. W. Smye, Christopher J. Twelves, and Roger M. Phillips. "Mathematical and computational models of drug transport in tumours." 2014. http://hdl.handle.net/10454/10002.
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No<br>The ability to predict how far a drug will penetrate into the tumour microenvironment
within its pharmacokinetic (PK) lifespan would provide
valuable information about therapeutic response. As the PK profile is directly
related to the route and schedule of drug administration, an in silico tool
that can predict the drug administration schedule that results in optimal
drug delivery to tumours would streamline clinical trial design. This paper
investigates the application of mathematical and computational modelling
techniques to help improve our understanding of the fundamental mechanisms
underlying drug delivery, and compares the performance of a simple
model with more complex approaches. Three models of drug transport are
developed, all based on the same drug binding model and parametrized by
bespoke in vitro experiments. Their predictions, compared for a ‘tumour
cord’ geometry, are qualitatively and quantitatively similar. We assess the
effect of varying the PK profile of the supplied drug, and the binding affinity
of the drug to tumour cells, on the concentration of drug reaching cells and the
accumulated exposure of cells to drug at arbitrary distances from a supplying
blood vessel. This is a contribution towards developing a useful drug transport
modelling tool for informing strategies for the treatment of tumour
cells which are ‘pharmacokinetically resistant’ to chemotherapeutic strategies.
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Poiares, João Pedro da Silva Gonçalves. "Development of a QSAR models for the prediction of plasma protein binding." Master's thesis, 2014. http://hdl.handle.net/10437/5858.
Full textAbstract:
Orientação: Paulo Paixão<br>One of the most important factors, affecting the pharmacokinetic profile of a drug is binding to plasma protein. As such, this study aimed at the development of a quantitative structure–activity relationship model, to predict the fraction unbound in plasma (fub) for four species, using artificial neural network ensemble (ANNE).
To this end a database of 363 drugs was used, and molecular descriptors were determined. The dataset was divided in two groups, a train and an external validation, to avoid overfitting. The ANNE optimization reduced the descriptors required to determine the fub to 37, and 150 ANN were randomly selected, trained and the optimal configuration was collected. The different ANNE were built by averaging the output values of the selected ANN and the best ANNE was selected.
The model created was able to predict, with a small amount of error, the fub values (root mean square error of 0.16798 and 0.193705 for train and test dataset respectively), however, it tends to underestimate this value (mean error of -0.00291 and -0.015780 for train and test dataset respectively). The ANNE interpretation showed that the main characteristics of that affect fub were the molecule charge, size, structure and lipophilic and hydrophilic affinity.<br>Um dos factores mais influentes na farmacocinética deum fármaco é a ligação às proteínas
plasmáticas. Sendo assim, com este estudo pretendeu -se desenvolver um modelo QSAR, para
prever facção do fármaco livre no plasma (fub)para quatro espécies, usando um “ensamble
”de redes neuronais (ANNE). Para tal, utilizou –se uma base – de -dados de 363 fármacos, e determinou-se os seus descritores moleculares. Esta base de dados foi dividida em dois grupos, um para treino e outro para validação externa, para evitar “overfitting”. O ANNE foi optimizado, reduzindo o número de descritores para 37, e 150 redes foram aleatoriamente selecionadas, treinadas e a sua configuração optimizada registada. Os diversos ANNE foram obtido através da média aritmética dos valores das redes seleccionadas, e o melhor ANNE foi escolhido. Este modelo foi capaz de prever com um erro reduzido, o valor da fub (erro quadrático médio de 0.16798 e0.193705 para o grupo de treino e teste respectivamente), no entanto tendencialmente subestima o seu valor (erro médio de -0.00291 e -0.015780 para o grupo de treino e teste respectivamente) . A interpretação do modelo permitiu observar que o tamanho da molécula, a sua estrutura, carga, lipofilia e hidrofilia são as características que mais afectam o valor da fub.
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Hsieh, Chun-Chih, and 謝濬智. "Estimating Protein and Amino Acid Requirements of Taiwan Native Chickens by Mathematical Models." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/71195527940275502211.
Full textAbstract:
碩士<br>東海大學<br>畜產與生物科技學系<br>93<br>The objective of this study was to estimate the protein and amino acid (AA) requirement of Taiwan native chickens during 0 to 16 wks by mathematical models. 125 one-day-old four-way crossbred Taiwan native male and female chickens (Taishi Meat No. 13) were divided into five pens with 25 chickens each, respectively. One chicken from each pen closest to the mean body weight were selected weekly, killed and their body and feather protein contents were measured. All the chickens were fed a commercial diet in an open-type house.
Gompertz growth function was used to estimate the growth curve of the chickens; it was further modified and differentiated to calculate the daily body protein deposition rate (dBP/dt) and the daily feather protein deposition rate (dFP/dt) of chickens; linear regression equation was used to calculate the daily body protein requirement for growth (BPG) and the daily feather protein requirement for growth (FPG) of chickens. The daily body protein requirement for maintenance (MPB) and the daily feather protein requirement for maintenance (MPF) was added beyond them, namely AAR=[p dBP/dt＋q dFP/dt]/0.8＋[p MPB＋q MPF] (Gompertz growth model) and AAR=[p BPG＋q FPG]/0.8＋[p MPB＋q MPF] (linear regression) to give the daily digestible protein and AA requirement, where AAR is the daily digestible AA requirement (g/d), p is the individual AA contents of body protein (g/kg), q is the individual AA contents of feather protein (g/kg) and 0.8 is the utilized efficiency of AA.
The results indicated that the daily digestible protein and AA requirements increased curvilinearly with increasing age. They reached a plateau at day 56~63 and 63~70 in male and female, respectively, when the weight gain of them reached the plateau. After that, they decreased curvilinearly when weight gain passed the plateau. The daily digestible protein and AAR of male was significant higher than that of female. The curvilinear relationship between daily digestible protein requirement and body weight were: y = 1.17 + 9.83x — 4.46x2 (male; R2 = 0.98, P < 0.01), y = 1.09 + 8.49x — 5.02x2 (female; R2 = 0.96, P < 0.01) estimated by Gompertz growth model; y = 0.59 + 10.86x — 4.85x2 (male; R2 = 0.98, P < 0.01), y = 0.39 + 9.29x — 4.99x2 (female; R2 = 0.98, P < 0.01) estimated by linear regression. Where y is daily protein requirement (g/d), x = body weight (kg). AA requirement followed similar curvilinear curve as of protein requirement. Our estimated requirements could be used as a reference to determine the protein and AA requirements of Taiwan native chickens in different age, sex and growth rate.
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He, Rong-Heng, and 何榕恒. "FK506-Binding Protein 51 Regulates GABAergic Neurotransmission-related Protein Expression in Peripheral Inflammation- versus Glucocorticoid- induced Anxiety Mouse Models." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/16676195364561600806.
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Barrientos, KS, MF Kendellen, BD Freibaum, BN Armbruster, KT Etheridge, and CM Counter. "Distinct functions of POT1 at telomeres." Thesis, 2008. http://hdl.handle.net/10161/1343.
Full textAbstract:
The mammalian protein POT1 binds to telomeric single-stranded DNA (ssDNA), protecting chromosome ends from being detected as sites of DNA damage. POT1 is composed of an N-terminal ssDNA-binding domain and a C-terminal protein interaction domain. With regard to the latter, POT1 heterodimerizes with the protein TPP1 to foster binding to telomeric ssDNA in vitro and binds the telomeric double-stranded-DNA-binding protein TRF2. We sought to determine which of these functions-ssDNA, TPP1, or TRF2 binding-was required to protect chromosome ends from being detected as DNA damage. Using separation-of-function POT1 mutants deficient in one of these three activities, we found that binding to TRF2 is dispensable for protecting telomeres but fosters robust loading of POT1 onto telomeric chromatin. Furthermore, we found that the telomeric ssDNA-binding activity and binding to TPP1 are required in cis for POT1 to protect telomeres. Mechanistically, binding of POT1 to telomeric ssDNA and association with TPP1 inhibit the localization of RPA, which can function as a DNA damage sensor, to telomeres.<br>Dissertation
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Gumede, Njabulo Joyfull. "Computational and micro-analytical techniques to study the in vitro and in silico models of novel therapeutic drugs." Thesis, 2016. http://hdl.handle.net/10321/1751.
Full textAbstract:
Submitted in fulfillment of the requirements for the Doctor of Philosophy degree in Chemistry, Durban University of Technology, Durban, South Africa, 2016.<br>In drug discovery and development projects, metabolism of new chemical entities (NCEs) is a major contributing factor for the withdrawal of drug candidates, a major concern for other chemical industries where chemical-biological interactions are involved. NCEs interact with a target macro-molecule to stimulate a pharmacological or toxic response, known as pharmacodynamics (PD) effect or through the Adsorption, Distribution, Metabolism, and Excretion (ADME) process, triggered when a bio-macromolecule interacts with a therapeutic drug. Therefore, the drug discovery process is important because 75% of diseases known to human kind are not all cured by therapeutics currently available in the market. This is attributed to the lack of knowledge of the function of targets and their therapeutic use in order to design therapeutics that would trigger their pharmacological responses.
Accordingly, the focus of this work is to develop cost saving strategies for medicinal chemists involved with drug discovery projects. Therefore, studying the synergy between in silico and in vitro approaches maybe useful in the discovery of novel therapeutic compounds and their biological activities. In this work, in silico methods such as structure-based and ligand-based approaches were used in the design of the pharmacophore model, database screening and flexible docking methods. Specifically, this work is presented by the following case studies:
The first involved molecular docking studies to predict the binding modes of catechin enantiomer to human serum albumin (HSA) interaction; the second involved the use of docking methods to predict the binding affinities and enantioselectivity of the interaction of warfarin enantiomers to HSA. the third case study involved a combined computational strategy in order to generate information on a diverse set of steroidal and non-steroidal CYP17A1 inhibitors obtained from literature with known experimental IC50 values. Finally, the fourth case study involved the prediction of the site of metabolisms (SOMs) of probe substrates to Cytochrome P450 metabolic enzymes CYP 3A4, 2D6, and 2C9 making use of P450 module from Schrödinger suite for ADME/Tox prediction.
The results of case study I were promising as they were able to provide clues to the factors that drive the synergy between experimental kinetic parameters and computational thermodynamics parameters to explain the interaction between drug enantiomers and thetarget protein. These parameters were correlated/converted and used to estimate the pseudo enantioselectivity of catechin enantiomer to HSA. This approach of combining docking methodology with docking post-processing methods such as MM-GBSA proved to be vital in estimating the correct pseudo binding affinities of a protein-ligand complexes. The enantioselectivity for enantiomers of catechin to HSA were 1,60 and 1,25 for site I and site II respectively.
The results of case study II validates and verifies the preparation of ligands and accounting for tautomers at physiological pH, as well as conformational changes prior to and during docking with a flexible protein. The log KS = 5.43 and log KR = 5.34 for warfarin enantiomer-HSA interaction and the enantioselectivity (ES = KS/KR) of 1.23 were close to the experimental results and hence referred to as experimental-like affinity constants which validated and verified their applicability to predict protein-ligand binding affinities.
In case study III, a 3D-QSAR pharmacophore model was developed by using 98 known CYP17A1 inhibitors from the literature with known experimental IC50 values. The starting compounds were diverse which included steroidal and non-steroidal inhibitors. The resulting pharmacophore models were trained with 69 molecules and 19 test set ligands. The best pharmacophore models were selected based on the regression coefficient for a best fit model with R2 (ranging from 0.85-0.99) & Q2 (ranging from 0.80-0.99) for both the training and test sets respectively, using Partial Least Squares (PLS) regression. On the other hand, the best pharmacophore model selected was further used for a database screening of novel inhibitors and the prediction of their CYP17A1 inhibition. The hits obtained from the database searches were further subjected to a virtual screening workflow docked to CYP17A1 enzyme in order to predict the binding mode and their binding affinities. The resulting poses from the virtual screening workflow were subjected to Induced Fit Docking workflow to account for protein flexibility during docking. The resulting docking poses were examined and ranked ordered according to the docking scores (a measure of affinity).
Finally, the resulting hits designed from an updated model from case study III were further synthesized in an external organic chemistry laboratory and the synthetic protocols as well as spectroscopic data for structure elucidation forms part of the provisional patent specification. A provisional patent specification has been filed (RSA Pat. Appln. 2015/ 07849). The case studies performed in this thesis have enabled the discovery of non-steroidal CYP17A1 inhibitors.<br>D
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Dang, Truong Khanh Linh. "Probabilistic Models to Detect Important Sites in Proteins." Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-1583-F.
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Lehrer, Helaina. "Investigating the role of the RNA binding protein TDP-43 in Amyotrophic Lateral Sclerosis using animal and cell-based models of disease." Thesis, 2015. https://doi.org/10.7916/D8G44PJQ.
Full textAbstract:
TDP43 is an RNA and DNA binding protein that has been shown to play an integral role in disease mechanisms that underlie ALS. In fact, a common feature of the vast majority of ALS cases is the presence of TDP-43 aggregates in postmortem tissue from the brain and spinal cord. This finding has spurred research to understand the physiological roles of TDP-43 in the absence of disease, and how these roles are affected by disease. Current TDP-43 mouse models fail to faithfully and reproducibly recapitulate key aspects of ALS, possibly due to the transgenic approaches used. To address these concerns, we generated a targeted, conditional mouse model, and embryonic stem cell lines expressing either human WT or M337V mutant TDP-43 at equivalent levels. We show that expression of mutant hTDP-43 in mice with a mixed genetic background leads to selective motor neuron loss, muscle weakness and premature death. However this disease phenotype is not observed with the same TDP43 mutation in a pure Bl6 background. We next sought to identify alterations in the biochemistry of the mutant protein that may underlie its toxicity, such as its interactions with RNA and protein. By creating a library of RNAs bound by TDP-43 in the mouse spinal cord, we found that the M337V mutation does not compromise the ability of TDP43 to bind to target mRNA transcripts, although the mutation does lead to changes in expression of genes known to be involved in inflammation. In addition, we identified 22 proteins that bind to TDP43 in an RNA-dependent manner, and found that the M337V mutation does not alter these interactions. This work establishes novel mouse and cellular models that provide insights into the functions of normal and ALS-causing mutant TDP43 protein.