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1
Goddard, Maria Nadia. "Manipulating biochemical pathways in rice." Thesis, University of Nottingham, 2004. http://eprints.nottingham.ac.uk/28567/.
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The brown planthopper, Nilaparvata lugens, is a pest of rice in tropical regions. Its direct feeding results in loss in yield and plant death ("hopper bum"). Several compounds that stimulate insect attraction have been detected in rice plants colonised by N. lugens, including 1,2-dimethoxybenzene or veratrole. Electro-physiological studies and highresolution gas chromatography have identified veratrole as an attractant of N. lugens. Veratrole is a product of salicylic acid, a derivative of the phenyl propanoid pathway. Salicylic acid is decarboxylated to catechol, a step which is encoded by salicylate hydroxylase. Catechol is subsequently methylated to veratrole, which is released as a volatile compound from rice leaves. Mature scutellum-derived rice calli from (Oryza sativa) cv.Taipei 309 were transformed, using microprojectile bombardment, with pROB5 containing the hpt gene conferring resistance to the antibiotic hygromycin and pSLJ7307 carrying the nahG gene derived from Pseudomonas putida and coding for the enzyme salicylate hydroxylase. Following selection on hygromycin-containing medium, 17 independent transgenic rice plants were regenerated from >3600 bombarded calli, with a transformation frequency of 0.47%. Transgenic plants were confirmed by RT-PCR. Plant lines were classified as high expressors (10 lines) and low expressors (7 lines) depending on salicylate hydroxylase production. All transgenic lines exhibited higher enzyme activity than wild-type plants. Transgenic plants produced had altered metabolism for antioxidant enzymes such as catalase, ascorbate peroxidase and superoxide dismutase and reactive oxygen species such as hydrogen peroxide. Plants unable to accumulate salicylic acid exhibited delayed transcription of pathogenesis related genes and may therefore be compromised in their ability to respond to pathogen attack and mechanical wounding. Enhanced veratrole production was corroborated using gas chromatography of volatiles released from transgenic undamaged and mechanically damaged plants. Bioassays indicated that N. lugens were more attracted to high expressing plants than to wild-type plants, making more visits to areas containing transgenic rice leaves than areas containing non-transformed leaves and spending longer in these areas. Manipulating the production of veratrole by enhancing salicylate hydroxylase activity has therefore modified attraction of the N. lugens for high expressing nahG positive rice plants.
2
Daae, Elisabeth Bull. "Mathematical modelling of biochemical pathways." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327023.
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Soda, Takahiro. "Converging biochemical pathways in psychiatric disorders." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/73775.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references.
According to the World Health Organization, neuropsychiatric diseases account for approximately one third of years lost to disability. Yet, despite this huge disease burden, there is a lack of new treatments under development: approved treatments all essentially target the same target(s), if the target itself is known. There is now considerable evidence for a common set of heritable risk for psychiatric disorders including schizophrenia, bipolar disorder, as well as autism. Many of these risk alleles affect genes implicated in neuronal development with known roles at an early stage; these genes would have an effect on the individual before the onset of overt symptoms or diagnosis. Furthermore, many of the genes identified are known to participate in established pathways that are relevant for neuronal development and function. It is important then to address the causality between these signaling pathways that are important for neurodevelopment, and the risk of developing neuropsychiatric disorder. The work presented in this thesis represents two projects that aim to work toward this goal. The first project pertains to the mechanisms of transcriptional repression by DISC1 on ATF4-mediated gene transcription. The second project presents some initial steps towards uncovering the role of BCL9 in neuronal development.
by Takahiro Soda.
Ph.D.
4
Mavrovouniotis, Michael L. (Michael Loizos). "Computer-aided design of biochemical pathways." Thesis, Massachusetts Institute of Technology, 1988. http://hdl.handle.net/1721.1/14449.
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Webhofer, Christian. "Antidepressant activated biochemical pathways and biomarker candidates." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-159303.
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Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of increased monoaminergic neurotransmission are poorly understood and yet presumably important for the drugs’ mode of action. In my PhD thesis I employed proteomics and metabolomics technologies combined with in silico analyses and identified cellular pathways affected by antidepressant drug treatment. DBA/2 mice were treated with paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo 15N metabolic labeling combined with mass spectrometry. I also studied chronic changes in the hippocampus using unbiased metabolite profiling and the time course of metabolic changes with the help of a targeted polar metabolomics profiling platform. I identified profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. Paralleling the shift towards aerobic glycolysis upon paroxetine treatment I identified decreased levels of Krebs cycle and oxidative phosphorylation enzyme levels upon the antidepressant-like 15N isotope effect in high-anxiety behavior mice. In the course of my analyses I also identified GABA, galactose-6-phosphate and leucine as biomarker candidates for the assessment of chronic paroxetine treatment effects in the periphery and myo-inositol as biomarker candidate for an early assessment of chronic treatment effects. The identified antidepressant drug treatment affected molecular pathways and novel SSRI modes of action warrant consideration in antidepressant drug development efforts.
6
Tomlinson, Esther Jane. "Studies on the evolution of biochemical pathways." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240380.
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Pooler, Amy Melissa. "Regulation of biochemical pathways involved in neurodegeneration." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/31177.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2005.Includes bibliographical references.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Although much is known about how AD affects the brain, the cause of this disease remains elusive. Current AD treatments target symptoms of the disease but do not prevent or slow the underlying neurodegeneration. Therefore, research into the biochemical mechanisms of AD is necessary in order to develop a better understanding of how to treat it. Misprocessing of the amyloid precursor protein (APP) in the brains of AD patients leads to accumulation of the amyloidogenic peptide AD. A soluble APP fragment (APPS) is formed when APP is cleaved within the AP region, thereby preventing AP formation. Activation of 5-HT2A or 5-HT2c receptors has been shown to increase APPS secretion in vitro; therefore, we determined whether activation of these receptors might have a similar effect in vivo. We found that a 5-HT2A/2c agonist affected brain APP metabolism in guinea pigs by increasing CSF levels of APPS and, following chronic treatment, by decreasing levels of AP. Our data indicate that activation of brain 5-HT2c receptors may be useful for treating AD by reducing AP production. Traumatic brain injury is a risk factor for AD, although the reason is unknown. To explore this relationship, we examined the effect of the inflammatory mediator PGE2 on production of APP in cultured microglia. We found that PGE2 treatment stimulated APP overexpression and that this effect was likely mediated by the prostaglandin EP2 receptor and the cAMP signaling cascade. Therefore, EP2 receptor antagonists may constitute an additional target for prevention of AD following brain injury.
(cont.) The neuropathology associated with AD includes neuritic dystrophy and degeneration. Therefore, restoration of neuritic growth and repair of phospolipid membranes may be important for treating AD. We found that treatment of NGF- differentiated PC 12 cells with the phospholipid precursor uridine enhanced neurite outgrowth by both enhancing phosphatide biosynthesis and by stimulating a G-protein receptor-coupled signaling pathway. Subsequently, we found that the HMG-CoA reductase inhibitor pravastatin enhanced neurite outgrowth in rat hippocampal neurons, not by affecting cholesterol synthesis, but by inhibition of isoprenoid formation. Stimulation of neurite growth by either uridine or statins may reduce AD risk by averting neuritic dystrophy and degeneration. However, further studies must be conducted to determine whether they are able to affect neuritic processes in vivo.
by Amy Melissa Pooler.
Ph.D.
8
Caldecott, Keith. "Role of the xrs double strand break repair pathway in response to DNA damage induced by topoisomerase II-inhibiting antitumour drugs." Thesis, University College London (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279158.
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Schubert, Kathryn M. "Biochemical characterization of signaling pathways regulating cell survival." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ61171.pdf.
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Wegner, Katja. "Visualisation of biochemical pathways and their simulation results." Berlin Logos-Verl, 2006. http://deposit.d-nb.de/cgi-bin/dokserv?id=2865577&prov=M&dok_var=1&dok_ext=htm.
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Nesbeth, Darren Nicholas. "Biochemical studies of intracellular trafficking pathways in eukaryotes." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313830.
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Ruegg, Evonne Teresa Nicole. "Investigating the porphyrias through analysis of biochemical pathways." Thesis, University of Canterbury. Biochemistry, 2014. http://hdl.handle.net/10092/10257.
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ABSTRACT
The porphyrias are a diverse group of metabolic disorders arising from diminished
activity of enzymes in the heme biosynthetic pathway. They can present with acute
neurovisceral symptoms, cutaneous symptoms, or both. The complexity of these
disorders is demonstrated by the fact that some acute porphyria patients with the
underlying genetic defect(s) are latent and asymptomatic while others present with
severe symptoms. This indicates that there is at least one other risk factor required in
addition to the genetic defect for symptom manifestation. A systematic review of the
heme biosynthetic pathway highlighted the involvement of a number of micronutrient
cofactors. An exhaustive review of the medical literature uncovered numerous reports
of micronutrient deficiencies in the porphyrias as well as successful case reports of
treatments with micronutrients. Many micronutrient deficiencies present with
symptoms similar to those in porphyria, in particular vitamin B6. It is hypothesized
that a vitamin B6 deficiency and related micronutrient deficiencies may play a major
role in the pathogenesis of the acute porphyrias. In order to further investigate the
porphyrias, a computational model of the heme biosynthetic pathway was developed
based on kinetic parameters derived from a careful analysis of the literature. This
model demonstrated aspects of normal heme biosynthesis and illustrated some of the
disordered biochemistry of acute intermittent porphyria (AIP). The testing of this
model highlighted the modifications necessary to develop a more comprehensive
model with the potential to investigated hypotheses of the disordered biochemistry of
the porphyrias as well as the discovery of new methods of treatment and symptom
control. It is concluded that vitamin B6 deficiency might be the risk factor necessary
in conjunction with the genetic defect to trigger porphyria symptoms.
13
Papadopoulos, George. "Feature Selection and Parameter Estimation in Biochemical Signaling Pathways." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503053.
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Harding, Richard James. "Biochemical pathways underlying cellular damage in the perfused rat heart." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241343.
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Fiore, Gabriella. "Sepia officinalis ink defence system : biochemical pathways and NO signalling." Thesis, Open University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409864.
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He, Fei. "On robust approaches in systems identification for biochemical signaling pathways." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695231.
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Bent, Andrew F. "Structural and biochemical studies on the biosynthetic pathways of cyanobactins." Thesis, University of St Andrews, 2016. http://hdl.handle.net/10023/10404.
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Cyclic peptides have potential as scaffolds for novel pharmaceuticals, however their chemical synthesis can be challenging and as such natural sources are often explored. Several species of cyanobacteria produce a family of cyclic peptides, the cyanobactins, through the ribosomal synthesis of precursor peptides and post-translational tailoring. The patellamides, a member of the cyanobactin family, are cyclic octapeptides containing D-stereo centres and heterocyclised amino acids. A single gene cluster, patA - patG, contains the genes for the expression of the precursor peptide and the enzymes responsible for post-translational modifications including a heterocyclase, protease, macrocyclase and oxidase. Biochemical and structural analysis on the patellamide and related cyanobactin pathways has been carried out. The crystal structure of PatF, a proposed prenyl transferase, has been determined, highlighting that it is likely evolutionary inactive due to changes to key residues when compared to active homologues. This is in agreement with the knowledge that no naturally prenylated patellamides have been discovered to date. The crystal structure of the macrocyclase domain of PatG has been determined in complex with a substrate analogue peptide. The structure, together with biochemical analysis has allowed a mechanism of macrocyclisation to be proposed, confirming the requirement of a specific substrate conformation to enable macrocyclisation. Using isolated enzymes from the patellamide and related pathways, a small scale library of macrocycles made up of diverse sequences has been created in vitro and characterised by mass spectrometry and in certain cases NMR. In order to further enhance diversity, macrocycles containing unnatural amino acids have been created using three approaches; SeCys derived precursor peptides, intein-mediated peptide ligation and pEVOL amber codon technology. Finally, two oxidase enzymes from cyanobactin pathways have been purified, characterised and confirmed active for thiazoline oxidation. Native X-ray datasets on crystals of the oxidase CyaGox have been collected and phasing trials are on-going.
18
Woods, John Henry. "OOMPF : an Object-Oriented Metabolic Programming Framework." Thesis, Oxford Brookes University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264472.
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Morrison, Erin S., and Alexander V. Badyaev. "Structuring evolution: biochemical networks and metabolic diversification in birds." BioMed Central, 2016. http://hdl.handle.net/10150/620926.
Full textAbstract:
Background
Recurrence and predictability of evolution are thought to reflect the correspondence between genomic and phenotypic dimensions of organisms, and the connectivity in deterministic networks within these dimensions. Direct examination of the correspondence between opportunities for diversification imbedded in such networks and realized diversity is illuminating, but is empirically challenging because both the deterministic networks and phenotypic diversity are modified in the course of evolution. Here we overcome this problem by directly comparing the structure of a “global” carotenoid network – comprising of all known enzymatic reactions among naturally occurring carotenoids – with the patterns of evolutionary diversification in carotenoid-producing metabolic networks utilized by birds.
Results
We found that phenotypic diversification in carotenoid networks across 250 species was closely associated with enzymatic connectivity of the underlying biochemical network – compounds with greater connectivity occurred the most frequently across species and were the hotspots of metabolic pathway diversification. In contrast, we found no evidence for diversification along the metabolic pathways, corroborating findings that the utilization of the global carotenoid network was not strongly influenced by history in avian evolution.
Conclusions
The finding that the diversification in species-specific carotenoid networks is qualitatively predictable from the connectivity of the underlying enzymatic network points to significant structural determinism in phenotypic evolution.
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Chang, Michelle M. (Michelle Miran). "Biochemical and biophysical investigations of N-linked glycosylation pathways in archaea." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/97981.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, February 2015.Cataloged from PDF version of thesis. "December 2014."
Includes bibliographical references.
Asparagine-linked glycosylation is an abundant and complex protein modification conserved among all three domains of life. Much is known about N-glycan assembly in eukaryotes and selected bacteria, in which the oligosaccharyltransferase (OTase) carries out the en bloc transfer of glycans from polyprenyl-PP-linked donors onto asparagine side chains of acceptor proteins. The first aim of this thesis is to elucidate the biochemical details of archaeal N-linked glycosylation, specifically through in vitro analysis of the polyprenyl-P-dependent pathway of the methanogenic archaeon Methanococcus voltae. The archaeal OTase, known as AglB, utilizes a-linked dolichyl-P-trisaccharide substrate as the glycosyl donor for transfer to the acceptor protein. This dolichyl-P-glycan is generated by an initial retaining glycosyltransferase (AglK) and elaborated by additional glycosyltransferases (AglC and AgIA) to afford Dol-P-GlcNAc- Glc-2,3-diNAcA-ManNAc(6Thr)A. Despite the homology to other bacterial or eukaryotic OTases that exploit polyprenyl-PP-linked substrates, the M. voltae AglB efficiently transfers disaccharide to model peptides from the Dol-P-GlcNAc-Glc-2,3-diNAcA monophosphate. While this archaeal pathway affords the same asparagine-linked P-glycosyl amide products generated in bacteria and eukaryotes, these studies provide the first biochemical evidence revealing that despite the apparent similarities of the overall pathways, there are actually two general strategies to achieve N-linked glycoproteins across the domains of life. A second focus of this thesis involves biophysical studies to probe structural features and conformational dynamics of AglB. An intramolecular LRET experimental system was developed to report on substrate binding and the resulting structural transformations in AgIB. There is a strong need for detailed studies on the mechanistic and functional significance of archaeal adaptations of N-linked glycosylation, especially exploring differences between AglB and other OTases that allow AglB to utilize these unique polyprenyl-P-linked substrates. Lastly, a cell-free expression system was established for the efficient synthesis of Alg5, a yeast dolichyl-phosphate glucosyltransferase that shares high sequence similarity to AglK, the first glycosyltransferase in the M. voltae pathway. Dol-P-Glc was generated and examined to unambiguously characterize the stereochemistry of the product of Alg5.
by Michelle M. Chang.
Ph. D.
21
Flach, Edward H. "Reactions in open systems : pattern formation with convection, and open biochemical pathways." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496888.
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Webhofer, Christian [Verfasser], and Walter [Akademischer Betreuer] Zieglgänsberger. "Antidepressant activated biochemical pathways and biomarker candidates / Christian Webhofer. Betreuer: Walter Zieglgänsberger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1038152003/34.
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Stelios, Pavlidis. "Pathway based microarray analysis based on multi-membership gene regulation." Thesis, Brunel University, 2012. http://bura.brunel.ac.uk/handle/2438/6968.
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Recent developments in automation and novel experimental techniques have led to the accumulation of vast amounts of biological data and the emergence of numerous databases to store the wealth of information. Consequentially, bioinformatics have drawn considerable attention, accompanied by the development of a plethora of tools for the analysis of biological data. DNA microarrays constitute a prominent example of a high-throughput experimental technique that has required substantial contribution of bioinformatics tools. Following its popularity there is an on-going effort to integrate gene expression with other types of data in a common analytical approach. Pathway based microarray analysis seeks to facilitate microarray data in conjunction with biochemical pathway data and look for a coordinated change in the expression of genes constituting a pathway. However, it has been observed that genes in a pathway may show variable expression, with some appearing activated while others repressed. This thesis aims to add some contribution to pathway based microarray analysis and assist the interpretation of such observations, based on the fact that in all organisms a substantial number of genes take part in more than one biochemical pathway. It explores the hypothesis that the expression of such genes represents a net effect of their contribution to all their constituent pathways, applying statistical and data mining approaches. A heuristic search methodology is proposed to manipulate the pathway contribution of genes to follow underlying trends and interpret microarray results centred on pathway behaviour. The methodology is further refined to account for distinct genes encoding enzymes that catalyse the same reaction, and applied to modules, shorter chains of reactions forming sub-networks within pathways. Results based on various datasets are discussed, showing that the methodology is promising and may assist a biologist to decipher the biochemical state of an organism, in experiments where pathways exhibit variable expression.
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Sanders, Philip Gordon Thomas. "A biochemical analysis of regulatory interactions between the Notch and Wingless signalling pathways." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614348.
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May, Patrick, Jan-Ole Christian, Stefan Kempa, and Dirk Walther. "ChlamyCyc : an integrative systems biology database and web-portal for Chlamydomonas reinhardtii." Universität Potsdam, 2009. http://opus.kobv.de/ubp/volltexte/2010/4494/.
Full textAbstract:
Background:
The unicellular green alga Chlamydomonas reinhardtii is an important eukaryotic
model organism for the study of photosynthesis and plant growth. In the era of modern highthroughput technologies there is an imperative need to integrate large-scale data sets from highthroughput experimental techniques using computational methods and database resources to provide comprehensive information about the molecular and cellular organization of a single organism.
Results:
In the framework of the German Systems Biology initiative GoFORSYS, a pathway
database and web-portal for Chlamydomonas (ChlamyCyc) was established, which currently features about 250 metabolic pathways with associated genes, enzymes, and compound information. ChlamyCyc was assembled using an integrative approach combining the recently published genome sequence, bioinformatics methods, and experimental data from metabolomics and proteomics experiments. We analyzed and integrated a combination of primary and secondary database resources, such as existing genome annotations from JGI, EST collections, orthology information, and MapMan classification.
Conclusion:
ChlamyCyc provides a curated and integrated systems biology repository that will
enable and assist in systematic studies of fundamental cellular processes in Chlamydomonas. The ChlamyCyc database and web-portal is freely available under http://chlamycyc.mpimp-golm.mpg.de.
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Kluge, Wolfgang. "Translation of potential biomarker molecules and biological pathways for schizophrenia and major depressive disorder to pre-clinical models." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648589.
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Azizi, Bahareh. "Chemical Complementation: A Genetic Selection System in Yeast for Drug Discovery, Protein Engineering, and for Deciphering and Assembling Biosynthetic Pathways." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-07182005-102856/.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.Allen M. Orville, Committee Member ; Sheldon W. May, Committee Member ; Jung H. Choi, Committee Member ; Mostafa A. El-Sayed, Committee Member ; Donald F. Doyle, Committee Chair.
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Atluri, Keerthi. "Drug and gene delivery strategies for targeting mechanobiological and biochemical pathways for joint and bone tissue engineering." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6697.
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A major challenge in drug development is ensuring that each new candidate drug is delivered to the appropriate location, in a timely manner and at an optimal concentration. Low drug solubility, drug instability, drug degradation, drug toxicity, or rapid clearance from the body can reduce the effectiveness of an otherwise promising drug candidate. Formulations such as nano/microparticles and melt extruded pellets made with synthetic and natural polymers are effective solutions for the advancement of drug delivery technology. These polymeric formulations can provide controlled release of therapeutic agents by delivering constant doses over long periods, cyclic dosages, and tunable release of both hydrophilic and hydrophobic drugs in order to improve the bioavailability and bioactivity of a drug. PLGA-based nanoparticles formed by emulsion or nanoprecipitation techniques can be designed to have a range of degradation times. Particle degradation and drug release kinetics can be controlled by the physiochemical properties of the polymer, such as molecular weight, hydrophobicity, and polydispersity. This study is focused on developing polymeric-based delivery systems for small and large molecules as treatment strategies for arthrofibrosis and bone tissue engineering.
In developing arthrofibrotic treatments, several mechanosignaling and biochemical pathways were targeted using small molecule therapeutics such as blebbistatin (a myosin II ATPase inhibitor), paclitaxel (a microtubule stabilizer), sulfasalazine (a kappa B suppressor), beta-aminopropionitrile (a lysyl oxidase inhibitor) and cis-hydroxyproline (inhibits the formation of stable triple helix structure of collagen). The aforementioned drugs were delivered either via PLGA micro/nanoparticles or via pellets formed by melt extrusion. From the studies performed, it was found that blebbistatin delivered by PLGA nanoparticles could reversibly inhibit fibroblast contractile activity and could significantly inhibit collagen synthesis. These findings lay the foundations for further optimization of drug dosing and potentially enabling a new drug delivery technology for treating arthrofibrosis. Sulfasalazine delivered by melt extruded PLGA pellets significantly inhibited myofibroblast numbers as deduced from α-SMA expression and col1A1 gene expression results and thus can be considered a potential treatment for arthrofibrosis.
For bone tissue engineering, plasmids encoding differentiation promoting factors or growth factors such as BMP-2 (pBMP-2), FGF-2 (pFGF-2), PDGF (pPDGF) and VEGF (pVEGF) were delivered via polyethylenimine (PEI), a cationic carrier that interacts electrostatically with negatively charged DNA. The formed nanoplexes were either tested directly or by coating them onto biocompatible titanium metal implants and cultured with human bone marrow derived mesenchymal stem cells (hBMSCs). We found that the combinatorial delivery of pBMP-2 and pFGF-2 significantly enhanced bone regeneration as deduced from Runx-2, alkaline phosphatase and osteocalcin gene expression results as well as from data yielded from alizarin red staining assays and atomic absorption spectroscopy where calcium ion levels were measured. It was also found that pBMP-2 nanoplex-coated titanium discs could significantly enhance bone regenerative gene expression for osteocalcin, Runx-2, and alkaline phosphatase as well as enhance calcium ion expression in human adipose derived mesenchymal stem cells (hADMSCs). Thus, it can be concluded that pFGF-2 and pBMP-2 nanoplexes have osteogenic potential and our studies demonstrate a new methodology with the potential to modify titanium disc implant surfaces for the purposes of enhancing osseointegration.
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Conzelmann, Holger. "Mathematical modeling of biochemical signal transduction pathways in mammalian cells a domain-oriented approach to reduce combinatorial complexity /." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-38819.
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Wanaguru, Madushi Kaushla. "Biochemical investigations of Plasmodium falciparum erythrocyte invasion pathways using recombinant merozoite surface proteins produced in a mammalian expression system." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607835.
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Phillips, Jonathan Adam. "Convergent Biochemical and Biomechanical Pathways in Tissue Remodeling: The Role of α₂β₁ Integrin and MMP Activity: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/274.
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The extracellular matrix is a multi-functional environment that cells inhabit to form living tissue. To maintain the tissue, cells require constant telemetry with the matrix and respond to a variety of cues by remodeling matrix architecture. In this study the physical and biochemical manipulation of the matrix by resident cells is explored to better understand how these are used to remodel tissue.
Cell-populated collagen hydrogels are used as a controllable in vitro tissue model. To directly measure mechanical forces involved with gel contraction, a culture force monitor was designed and built. Measuring dimensional changes together with contractile forces presents a method of separating mechanisms that influence tissue remodeling.
Together, these techniques revealed a correlation between contractile force and gel deformation, suggesting a novel method for examining the material properties of the matrix. Limiting matrix metalloproteinase (MMP) activity altered the correlation as predicted, indicating a stiffer matrix.
Contractile force was found to be regulated independent of MMP activity. In contrast, contractile force was found to be dependent on α2β1 integrin function. Collagen gel contraction correlated with both α2β1 function and MMP activity, and was significantly enhanced when combined.
The results of this study indicate cells have the capacity to use multiple mechanisms for remodeling the extracellular matrix and may alternately use them together or independently to vary the rate of matrix contraction.
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De, Silva Matharage Shenali. "Involvement of AMPK and AP-1 Biochemical Pathways in IL-6 Regulation of Steroidogenic Enzymes in the Adrenal Cortex." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4301.
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The adrenal cortex is a crucial endocrine gland in the mammalian stress response. In chronic inflammatory stress, cortisol is elevated whereas adrenal androgens are decreased. Furthermore, ACTH levels have poor correlation with the plasma cortisol in these conditions, thus suggesting that other factors are driving the stress response during chronic inflammatory stress. Interleukin-6 (IL-6), a cytokine which is released during chronic inflammatory stress, is assumed to be one such factor. Thus the biochemical pathways by which IL-6 increases cortisol release from the zona fasciculata (ZF), and decreases adrenal androgen release from the zona reticularis (ZR) were investigated. Since IL-6 activates AMP-activated kinase (AMPK) in skeletal muscle, AMPK was investigated for IL-6- induced effects in ZF and ZR tissue. The effects of AMPK activation and IL-6 exposure on the expression of the steroidogenic proteins, steroidogenic acute regulatory protein (StAR) and cholesterol side chain cleavage enzyme (P450scc), and on the steroidogenic nuclear factors steroidogenic factor-1 (SF-1) and adrenal hypoplasia congenita, critical region on the X chromosome, gene-1 (DAX-1) were investigated. AMPK activation and IL-6 exposure increased the expression of StAR, P450scc, and SF-1, and decreased DAX-1 in the ZF. Meanwhile, AMPK activation and IL-6 exposure decreased the expression of StAR, P450scc, and SF-1, and increased DAX-1 in the ZR. AMPK inhibition blocked the effects of AMPK activation and IL-6 on the ZF and ZR. Activator Protein-1 (AP-1) was the second biochemical intermediate studied since in other tissues AMPK activation increases the expression and phosphorylation of AP-1 subunits. IL-6 stimulation and AMPK activation increased the expression of the AP-1 subunits cFOS, cJUN, JUN B, and JUN D, while increasing the phosphorylation of cJUN in both the ZF and the ZR. These effects were blocked by AMPK inhibition. Inhibition of AP-1 leads to decreased StAR, P450scc, and SF-1, and increased DAX-1 in the ZF. Meanwhile, AP-1 inhibition leads to increased StAR, P450scc, SF-1, and decreased DAX-1 in the ZR. Therefore the AP-1 complex functions as a biochemical intermediate in the IL-6 and AMPK regulation of steroidogenic enzymes in the ZF and ZR. Overall, the results suggest that IL-6 activates AMPK, which increases the expression and phosphorylation of AP-1 subunits in the ZF and the ZR. However, increased AP-1 activation leads to increased StAR and P450scc in the ZF, but decreased StAR and P450scc in the ZR.
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Tel, Banu Cahide. "Biochemical changes in basal ganglia output pathways following chronic administration of L-dopa and dopamine agonists to MPTP-treated marmosets." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429211.
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Ly, Philip Tuan Thanh. "In vitro analysis of the biochemical pathways activated by cholesteryl glucoside in a motor neuron hybrid model of amyotrophic lateral sclerosis-parkinsonism dementia complex." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31979.
Full textAbstract:
Steryl glycosides are a family of compounds commonly found in the environment with
unclear biological roles. Cycad seeds, a dietary link to the etiology of the Guamanian
amyotrophic lateral sclerosis-Parkinsonism dementia complex (ALS-PDC) have an abundant
amount of steryl glycosides. Previously, our laboratory demonstrated that several members
of the cycad-derived steryl glycosides have toxic properties. Cholesteryl glucosides (CG), a
variant form of the cycad-derived steryl glycosides have been found to induce cell death in
primary rat cortical neurons. However, other groups have demonstrated that CG can protect
fibroblast cells from heat shock. In the present study, we showed that the motor neuronderived
cell line, NSC34 cells, exposed to CG resulted in a concentration- and timedependent
reduction in cell viability. However, a brief exposure of CG for one hour to
NSC34 cells induced cytoprotection against serum deprivation stress. The Kinetworks™
KPSS-1.3 phosphosite screen was used to examine phosphorylation changes during CG
preconditioning and indicated elevated AktSer⁻⁴⁷³ phosphorylation. Suppression of CG-
stimulated Akt phosphorylation with pharmacological inhibitors abolished CG
preconditioning. Furthermore, the results indicated AktSer⁻⁴⁷³ phosphorylation via a PI3K-dependent
and independent way. Erk1, but not Erk2 phosphorylation at its activation site
was inhibited with CG treatment. The role of Erk1 inhibition in CG toxicity remains unclear.
JNK and p38 MAPK were activation were temporally delayed, but were found to not involved
in mediating cell death. A sub-population of NSC34 cells treated with CG for at least 4 days
displayed a differentiated phenotype with enlarged soma and extended neurites. Moreover,
focal neurite swellings with accumulated cytoskeletal proteins and disease-associated
phospho-Tau were observed. CG-treatment did not induce abnormal cytoplasmic
accumulation of TDP43, as seen in sporadic ALS and Guamanian ALS and PDC cases.
Trypan blue staining indicated that the treated-cells with abnormal morphology were viable.
Taken together, these results demonstrated that CG is toxic to NSC34 cells. As a cellular
response to stress, these cells upregulated survival signals and/or undergo differentiation to
resist CG toxicity. A better understanding of the biochemical pathways triggered by CG in
NSC34 cells may provide insights to a common aberrant mechanism underlying the cause
of neuronal death in ALS-PDC.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Newcombe, Anthony Richard. "The biochemical role of the small G protein Rac1 in cell signalling pathways : interaction with RhoGDI and the phagocyte NADPH oxidase component, p67'p'h'o'x." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342224.
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Narasimhan, Sri Devi. "Converging Pathways in the Regulation of Longevity and Metabolism in Caenorhabditis Elegans: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/509.
Full textAbstract:
The lifespan of an organism is determined by a complex array of genetic, environmental and nutritional factors. Yet single gene manipulations have been shown to significantly extend lifespan in several model organisms. Of all the genes that have been studied thus far, components of the insulin/IGF-1 signaling (IIS) pathway have emerged as the most robust regulators of longevity. In addition, IIS also regulates development, energy metabolism and the response to stress in a conserved manner. In Caenorhabditis elegans, signaling through this pathway is initiated by activation of the insulin/IGF-1 receptor tyrosine kinase DAF-2, which then activates a PI3-kinase signaling pathway involving additional downstream serine/threonine kinases such as PDK-1, AKT-1, AKT-2 and SGK-1. The concerted action of these kinases results in the negative regulation of the single FOXO transcription factor homolog DAF-16. Under reduced signaling conditions, active DAF-16 is able to translocate into the nucleus and regulate the expression of hundreds of genes regulating longevity, stress resistance, metabolism and development.
The PTEN phosphatase homolog DAF-18, which antagonizes IIS at the level of PI3-kinase, is a major negative regulator of the pathway. However, not much was known about additional phosphatases that negatively regulated the kinases in the pathway. Dephosphorylation is a critical regulatory mechanism by which cellular signaling homeostasis is maintained. Aberrant hyper-activation of growth factor signaling pathways, including IIS, has been implicated in several cancers. In addition, deregulation of IIS is also closely linked to Type II diabetes. Therefore, the identification phosphatases that balance kinase activity will provide a better understanding of the regulation of the IIS pathway under normal as well as disease conditions. A directed RNAi screen using dauer diapause was conducted in our lab to identify serine/threonine phosphatases that modulated IIS. My work in the Tissenbaum Lab has primarily focused on characterization of the top three candidates from this screen, the genes pptr-1, pdp-1 and fem-2. From these studies, we have also uncovered novel crosstalk between the IIS and TGF-β signaling pathways.
In Chapter 2, we demonstrate that PPTR-1, a PP2A phosphatase regulatory subunit negatively regulates the IIS pathway by modulating AKT-1 dephosphorylation. PPTR-1 modulates several outputs of IIS similar to DAF-18. In addition, PPTR-1 co-localizes and physically interacts with its substrate, AKT-1. PPTR-1 modulates dephosphorylation of AKT-1 at a conserved threonine site and we show the molecular conservation of this interaction in mammalian adipocytes. Ultimately, this negative regulation by PPTR-1 results in increased DAF-16 nuclear localization and transcriptional activity.
Next, in Chapter 3, we show how PDP-1 is a novel link between the IIS and TGF-β signaling pathways. Similar to DAF-18 and PPTR-1, PDP-1 regulates multiple outputs of the IIS pathway and promotes DAF-16 activity. Interestingly, PDP-1 acts at the level of DAF-8 and DAF-14, two R-SMAD proteins that function in a TGF-β pathway. Our data suggests that PDP-1 may negatively regulate TGF-β signaling to downregulate the expression of several insulin(s). Without the insulin ligands, there is less activation of the IIS pathway, and DAF-16 is more active, thereby promoting transcription of genes that act to enhance longevity and stress resistance.
In Chapter 4, we investigate possible crosstalk between IIS and the TGF-β signaling pathways, as the latter was previously considered as a parallel independent pathway. From our studies on PDP-1, we knew that this phosphatase, despite acting in the TGF-β pathway, was a robust modulator of multiple outputs of IIS. Using double mutant combinations as well as RNAi we unravel complex and extensive crosstalk between the two pathways. Importantly, our results suggest that DAF-16 is likely to be the most downstream component of the two pathways.
In Chapter 5, we describe genetic characterization of fem-2, and its regulation of the IIS pathway. RNAi of fem-2 results in robust suppression of dauer formation, similar to pptr-1 and pdp-1 RNAi but this phenotype is only observed in the e1370 allele of daf-2. While knockdown of pptr-1 and pdp-1 suppress dauer formation of additional alleles of daf-2, fem-2 RNAi has no effect. These results reveal a complex genetic interaction between fem-2 and the daf-2 receptor.
Taken together, our results identify several novel regulators of IIS that modulate this pathway by distinct mechanisms.
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Finati, E. "MELATONIN: A PLEIOTROPIC MOLECULE OF NATURAL ORIGIN. EVALUATION OF THE DIFFERENT THERAPEUTIC ACTIVITIES IN ANIMAL MODELS AND / OR HUMAN PATIENTS AND A STUDY OF THE METABOLIC-BIOCHEMICAL PATHWAYS RELATED TO THEM." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217462.
Full textAbstract:
1.0. ABSTRACT
Background
Melatonin (MLT), a pineal gland hormone, seves as a bioclock and bio-calendar to mediate many receptor- or non-receptor functions. In addition to its immunomodulatory and neurological effects, MLT has a relevant oncostatic activity especially with respect to breast and prostate cancers, but the mechanism of action is still unclear. The growth of androgen-independent LNCaP prostate cancer cells has been demonstrated to be inhibited by MLT both in vitro and in vivo in a nude mice xenograft model. Clearly, the oncostatic effects of MLT may not be related to a single function, but rather to a complex interaction of several factors that involve the redox state, the immune system, the modulation of the endocrine system and membrane receptors.
MLT also increases sleepiness, decreases core temperature and increases peripheral temperature in humans. The role of MLT in the treatment of sleep disturbances, to prevent jet lag or as a part of the sepsis treatment is widely discussed; yet the role in critically ill patients still deserves further investigation. Critically ill patients suffer from severe sleep disturbances during their stay in an Intensive Care Unit (ICU). Moreover, these patients require high levels of antioxidants due to their critical illness.
Aims of the thesis
The main object of my PhD thesis was to confirm the pleiotropy of MLT molecule by testing its activity in two of the most promising clinical applications: the cure of prostate cancer and the regulation of the sleep/wake rhythm as adjuvant in the sedative therapy in critically ill patients.
Spcific Aims:
• To evaluate the oncostatic effect of MLT administered intraperitoneally (i.p.) by saline solution on human prostate tumor. To this purpose I have selected an in-vivo experimental model of nude mice (athymic), xenografted subcutaneously with tumor cells of a human prostatic line (LNCaP).
• Using the same animal model and the same administration route (i.p.) and treatment schedule of MLT administered in saline, to investigate the efficacy of a novel and promising pharmaceutical formulation: MLT included in a solid lipid nanoparticles system (SLN-MLT).
• Using the same mouse model of human prostate cancer, to test whether MLT can be administered efficiently using alternative ways that are more sustainable for prolonged treatments than i.p. MLT, e.g., transdermal delivery through the skin barrier directly onto the tumor via a novel and patented technique named cryoRx.
• To focus on the underlying action mechanism of MLT at the tumor cellular micro-environment and the possible influence on such a mechanism of the lipid nanocarrier employed.
• To evaluate in a cohort of ICU patients, if the circadian rhythm of MLT secretion is disrupted and to which extent MLT administration by different routes and different drug formulations (MLT as a tablet administered os, MLT encapsulated in SLN administered os as a suspension and MLT encapsulated in SLN applied transdermally as a suspension with the aid of a patch) is feasible in terms of absorption efficiency and adequacy in achieving and maintaining nocturnal peak plasma hormone.
• To evaluate if the restoration of the melatoninemia by the different ways of drug delivery in critically ill patients may be useful to restore the pleiotropic function of this hormone: facilitate the resolution of sleep-wake cycle disorders, improve the quality of sleep, reduce the number of episodes of anxiety, confusion and agitation, and reduce the amount of sedatives used, especially at night.
Materials and Methods
We used an in vivo model of human prostate tumor LNCaP cells xenografted into nude athymic mice. MLT has been administered i.p. as saline (n=13) and by SLN (n=13) or transdermally by cryoRx (n=14). For each treatment controls were also included. Each group received the same administration schedule: 3 treatments per week, for 6 week. At the end the animals were sacrificed and along the treatment period the mice weight were recorded as well as the tumor volume was measured. MLT concentration was assessed in plasma and tissues by ELISA test and tumors were evaluated for morphology, MLT content and HIF-1α expression.
The clinical effects of MLT administration as well as the pharmacokinetics profiles as a function of different administration ways (oral as MLT, oral as SLN and transdermal as SLN) have been studied in ICU patients. During the 2nd day of the ICU stay, serial withdrawal were taken to determine the endogenous MLT secretion, and then after MLT administration, additional plasma samples were obtained during the 3rd day to evaluate the exogenous plasma MLT content, for a total of 20 withdrawal for each patient. Each blood sample was centrifuged and the plasma stored at -20°C. To determine the MLT concentration we used an ELISA kit that includes a pre-purification of the sample by SPE (solid phase extraction) cartridges.
Results
Tumors developed slowly in all the MLT-treated (topical and i.p.) groups and at the end of the treatment, the mean volume was significantly lower vs control. Both tumoral and plasma MLT levels were significantly higher in treated (topical and i.p.) vs not-treated animals. Harvested tumor showed a strong inflammatory reaction which seemed to surround and infiltrate the tumor cells. In SLN-MLT treated animals, in addition to a strong lymphocyte infiltration, the tumor appeared limited also by the presence of fibroblast type cells. Preliminary results showed HIF-1α expression increased in both treatment groups (topical and i.p.) vs Ctrl.
In the clinical study, we have seen that MLT administration, is safe, reduces need for analgesic and sedative drugs restoring the normal circadian rhythm. In patients who received MLT or SLN-MLT by os, the absorption was rapid: the peak plasma concentration had a median of 30 min and after only 5 min, the MLT levels were significantly higher than physiological ones. The AUC of SLN-MLT was significantly higher than when MLT was administered by saline solution. SLN-MLT by transdermal route, presented a delayed peak plasma concentration (4 h) and a lower bioavailability but MLT plasma levels reached however the pharmacological concentration able to restore the pleiotropic function of this hormone and facilitate the resolution of sleep-wake cycle disorders.
Conclusions
We have confirmed the positive effects of MLT on tumor growth and we have focused on its effect on hypoxia. The possible role as anti-tumor drug candidate deserves to be further investigated. We demonstrated that different alternative and novel ways to deliver MLT are effective as well. This would accelerate the transferability of obtained data towards a therapy. on MLT oncostatic activity.
In the clinical study, we have proved that MLT is able to normalize the sleep-wake cycle, to ameliorate the sleep quality and to reduce the number of sedative drugs used in ICU pts. We proved also that transdermal administration by SLN is effective in rising plasma MLT levels as well as enteral administration and is more practicable in clinical setting.
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Jha, Sumit Kumar. "Model Validation and Discovery for Complex Stochastic Systems." Research Showcase @ CMU, 2010. http://repository.cmu.edu/dissertations/10.
Full textAbstract:
In this thesis, we study two fundamental problems that arise in the modeling of stochastic systems: (i) Validation of stochastic models against behavioral specifications such as temporal logics, and (ii) Discovery of kinetic parameters of stochastic biochemical models from behavioral specifications.
We present a new Bayesian algorithm for Statistical Model Checking of stochastic systems based on a sequential version of Jeffreys’ Bayes Factor test. We argue that the Bayesian approach is more suited for application do- mains like systems biology modeling, where distributions on nuisance parameters and priors may be known. We prove that our Bayesian Statistical Model Checking algorithm terminates for a large subclass of prior probabilities. We also characterize the Type I/II errors associated with our algorithm. We experimentally demonstrate that this algorithm is suitable for the analysis of complex biochemical models like those written in the BioNetGen language. We then argue that i.i.d. sampling based Statistical Model Checking algorithms are not an effective way to study rare behaviors of stochastic models and present another Bayesian Statistical Model Checking algorithm that can incorporate non-i.i.d. sampling strategies.
We also present algorithms for synthesis of chemical kinetic parameters of stochastic biochemical models from high level behavioral specifications. We consider the setting where a modeler knows facts that must hold on the stochastic model but is not confident about some of the kinetic parameters in her model. We suggest algorithms for discovering these kinetic parameters from facts stated in appropriate formal probabilistic specification languages. Our algorithms are based on our theoretical results characterizing the probability of a specification being true on a stochastic biochemical model. We have applied this algorithm to discover kinetic parameters for biochemical models with as many as six unknown parameters.
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Goel, Gautam. "Biochemical Systems Toolbox." Thesis, Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/14509.
Full textAbstract:
The field of biochemical systems modeling and analysis is faced with an unprecedented flood of data from experimental methodologies of molecular biology. While these techniques continue to leapfrog ahead in the speed, volume and finesse with which they generate data, the methods of data analysis and interpretation, however, are still playing the catch-up game. The notions of systems analysis have found a new foothold, under the banner of Systems Biology, with the promise of uncovering the rationale for the designs of biological systems from their parts lists, as they are generated by experimentation and sorted and managed by bioinformatics tools. With an aim to complement hypothesis-driven and reductionistic biological research, and not replace it, a systems biologist relies on the tools of mathematical and computational modeling to be able to contribute meaningfully to any ongoing bio-molecular systems research. These systems analysis tools, however, should not only have their roots steeped well in the theoretical foundations of biochemistry, mathematics and numerical computation, but they should be married to a framework that facilitates the required systems way of thought for all its users computational scientists, experimentalists and molecular biologists alike. Hopefully, such framework-based tools would go beyond just providing fancy GUIs, numerical packages for integrating ODEs and/or optimization libraries. The intent of this thesis is to present a framework and toolbox for biochemical systems modeling, with an application in metabolic pathway analysis and/or metabolic engineering.
The research presented here builds upon the tenets of a very well established and generic approach to biological systems modeling and analysis, called Biochemical Systems Theory (BST), which is almost forty years old. The nuances of modeling and practical hurdles to analysis are presented in the context of a real-time case study of analyzing the glucolytic pathway in the bacterium Lactococcus lactis. Alongside, the thesis presents the features of a MATLAB-based software application that has been built upon the framework of BST and is aptly named as Biochemical Systems Toolbox (BSTBox). The thesis presents novel contributions, made by the author during the course of his research, to state-of-the-art techniques in parameter estimation, and robustness and sensitivity analysis topics that, as this thesis will show, remain to be the most restrictive bottlenecks in the world of biological systems modeling and analysis.
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Hewitson, Kirsty S. "Biochemical characterisation of Escherichia coli biotin synthase." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249509.
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Bennallack, Philip Ross. "Genetic and Biochemical Analysis of the Micrococcin Biosynthetic Pathway." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6182.
Full textAbstract:
Declining antibiotic discovery and flourishing antibiotic resistance have led to a modern antibiotic crisis which threatens to compromise our ability to treat infectious disease. Consequently, there is significant interest in developing new antibiotics with novel modes of action and chemical properties. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural compounds with the appealing attributes of being derived directly from a genetic template while possessing numerous exotic chemical features that contribute to stability and antimicrobial activity. Abundant in nature, their diverse range of biological activities makes them excellent prospects for antibiotic development. Thiopeptides, a RiPP family rich in chemical complexity, represent a particularly promising example. Characterized by post-translationally formed sulfur- and nitrogen-containing heterocycles, more than 100 different thiopeptides have been identified from various cultivable bacterial producers, and the mining of genomic and metagenomic data promises to uncover many more chemical species that have eluded discovery by conventional means. These peptides are potent inhibitors of bacterial protein synthesis and have been shown effective against many drug-resistant pathogens. Despite these attractive properties, therapeutic applications have been limited by the lack of an efficient synthetic route and poor aqueous solubility. Both of these challenges would be greatly alleviated by a more complete understanding of thiopeptide biosynthesis and improved systems for analysis and engineering. Here we describe the characterization of a new thiopeptide gene cluster, which encodes the archetypal thiopeptide micrococcin P1. We describe the identification of the bioactive product and detail the mechanism of immunity in the producing strain. We also describe efforts to engineer this pathway for heterologous expression in Bacillus subtilis. Using this platform, we have been able to dissect this intricate biosynthetic pathway and parse the order and timing of the processing events involved in peptide maturation. The knowledge gained from these studies will inform future efforts to adapt thiopeptides for therapeutic use, and guide efforts to engineer unnatural compounds using the exotic enzymology employed by thiopeptide producing bacteria.
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Hutchinson, Lisa. "Biochemical analysis of components of the wingless/WNT signalling pathway." Thesis, Institute of Cancer Research (University Of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395976.
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Trindade, Maria Margarida Silva. "Mecanismo de defesa e resistência das plantas a agentes patogénicos." Master's thesis, Universidade de Évora, 2021. http://hdl.handle.net/10174/29296.
Full textAbstract:
As plantas são constantemente ameaçadas por diversos microrganismos
patogénicos que prejudicam o seu crescimento e reprodução. Com isto, desenvolveram
eficientes mecanismos de defesa físicos e químicos que podem ser inatos ou induzidos.
Dependendo do tipo de interação com o patogénio, as plantas empregam estratégias
de defesa distintas e específicas para a patogénese, através de um sistema imunológico
multicamada, caracterizado por duas linhas de defesa: uma primeira, extracelular, que
pode desencadear respostas de largo espetro (PTI) e uma segunda, intracelular, em que
ocorre o reconhecimento muito específico do agente patogénico (ETI). Adicionalmente,
embora não tenham um sistema imunológico, podem criar resistência induzida, que se
caracteriza pela sinalização sistémica da resposta de defesa do local de infeção para as
partes distantes do mesmo, estabelecendo uma capacidade defensiva melhorada.
Compreender os mecanismos de defesa das plantas é fundamental para que se
possam obter plantas mais tolerantes ou mimetizar e induzir estes mecanismos; ABSTRACT: Plants defence and resistance mechanisms against pathogens
Plants are constantly threatened by several pathogenic microorganisms that harm
their growth and reproduction. With this, they developed efficient mechanisms of
physical and chemical defence that can be innate or induced. Depending on the type of
interaction with the pathogen, plants employ distinct and specific defence strategies for
the pathogenesis, through a multi-layered immune system, which is characterized by
two lines of defence: a first, extracellular, which can trigger wide-spectrum responses
(PTI) and a second one, with intracellular origin, in which the very specific recognition of
the pathogenic agent occurs (ETI). Additionally, although lacking an immune system,
they can create induced resistance, which is characterized by the systemic signalling of
the defence response from the infection site to the distant parts of it, establishing an
improved defensive capacity.
Understanding the defence mechanisms of plants is essential to obtain more
tolerant plants or to mimic and induce those mechanisms.
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Harding, Angus Silas. "A biochemical analysis of the MAP kinase pathway in mammalian cells /." A biochemical analysis of the MAP kinase pathway in mammalian cellsRead the abstract of the thesis, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17885.pdf.
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Barr, Alastair J. "Biochemical studies on the NKâ†1 tachykinin receptor signal transduction pathway." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357379.
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Xing, Yi. "Structural and biochemical studies on the Wnt/[beta]-catenin signaling pathway and the PI3K/CISK signaling pathway /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/5680.
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Pu, Yang. "The Art of Modeling and Simulation of Multiscale Biochemical Systems." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/52347.
Full textAbstract:
In this thesis we study modeling and simulation approaches for multiscale biochemical systems. The thesis addresses both modeling methods and simulation strategies. In the first part, we propose modeling methods to study the behavior of the insulin secretion pathway. We first expand the single cell model proposed by Bertram et. al. to model multiple cells. Synchronization among multiple cells is observed. Then an unhealthy cell model is proposed to study the insulin secretion failure caused by weakening of mitochondria function. By studying the interaction between the healthy and unhealthy cells, we find that the insulin secretion can be reinstated by increasing the glucokinase level. This new discovery sheds light on antidiabetic medication. In order to study the stochastic dynamics of the insulin secretion pathway, we first apply the hybrid method to model the discrete events in the insulin secretion pathway. Based on the hybrid model, a probability based measurement is proposed and applied to test the new antidiabetic remedy. In the second part, we focus on different simulation schemes for multiscale biochemical systems. We first propose a partitioning strategy for the hybrid method which leads to an efficient way of building stochastic cell cycle models. Then different implementation methods for the hybrid method are studied. A root finding method based on inverse interpolation is introduced to implement the hybrid method with three different ODE solvers. A detailed discussion of the performance of these three ODE solvers is presented. Last, we propose a new strategy to automatically detect stiffness and identify species that cause stiffness for the Tau-Leaping method, as well as two stiffness reduction methods. The efficiency is demonstrated by applying this new strategy on a stiff decaying dimerization model and a heat shock protein regulation model.Ph. D.
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Cunha, Luís Filipe Lopes da. "Genetic, biocheminal, and biophysical studies of the heme biosynthetic pathway." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7274.
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Cunha, Luís Filipe Lopes da. "Genetic, biocheminal, and biophysical studies of the heme biosynthetic pathway." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7274.
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Khartabil, Rana. "User-centered design and evaluation of a dynamic biochemical pathway visualization tool." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26944.
Full textAbstract:
Information visualization is a field of computer science that deals with the computerized visualization of complex information in a form that is easier for human beings to comprehend. Information visualization has applications in many domains, including business, science, and medicine. Visualization of biochemical pathways, as graphs of nodes representing biochemical entities and arcs representing the relationships between entities, is one such application.
This thesis begins by reviewing work that has been done on the usability of information visualization techniques, and in particular these that apply to biochemical pathways. Then, the thesis presents three different usability evaluation techniques that are used to gather information about existing biochemical pathway visualization tools. These are (1) conducting videotaped evaluation sessions of existing biochemical visualization tools, (2) collecting questionnaires, and (3) conducting a brainstorming session. The results from these studies are used to define the requirements, design, and build a biochemical pathway visualization tool, taking into account conclusions drawn from both literature and user studies. The tool is then tested and compared to existing tools.
Results show that the developed tool has more relevant features to biochemical pathway visualization than existing tools, accomplishes certain tasks faster than other tools, and is intuitive and easy to use. In addition, positive feedback from users is documented.
At the end of the thesis, we make some generalizations to the area of information visualization and we then present areas for further research.