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‣ Development of simple 3D-printed scaffolds for liver tissue engineering; Development of simple three-dimensional printed scaffolds for liver tissue engineering

Camp, James (James Patrick), 1977-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 58 leaves; 26989988 bytes; 26989732 bytes; application/pdf; application/pdf
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by James Camp.; Thesis (S.M. in Bioengineering)--Massachusetts Institute of Technology, Biological Engineering Division, 2002.; Includes bibliographical references (leaves 51-52).; This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.

‣ Biodegradable microfluidic scaffolds for vascular tissue engineering

Bettinger, Christopher John, 1981-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 96 leaves; 6034088 bytes; 6045112 bytes; application/pdf; application/pdf
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This work describes the integration of novel microfabrication techniques for vascular tissue engineering applications in the context of a novel biodegradable elastomer. The field of tissue engineering and organ regeneration has been born out of the high demand for organ transplants. However, one of the critical limitations in regeneration of vital organs is the lack of an intrinsic blood supply. This work expands on the development of microfluidic scaffolds for vascular tissue engineering applications by employing microfabrication techniques. Unlike previous efforts, this work focuses on fabricating this scaffolds from poly(glycerol-sebacate) (PGS), a novel biodegradable elastomer with superior mechanical properties. The transport properties of oxygen and carbon dioxide in PGS were measured through a series of time-lag diffusion experiments. The results of these measurements were used to calculate a characteristic length scale for oxygen diffusion limits in PGS scaffolds. Microfluidic scaffolds were then produced using fabrication techniques specific for PGS. Initial efforts have resulted in solid PGS-based scaffolds with biomimetic fluid flow and capillary channels on the order of 10 microns in width. These scaffolds have also been seeded with endothelial cells and perfused continuously in culture for up to 14 days resulting in partially confluent channels. More complex fabrication techniques were also demonstrated. A novel electrodeposition technique was used in the fabrication of biomimetic microfluidic masters. Thin-walled devices were also synthesized to accommodate the relatively low gas permeability of PGS.; by Christopher John Bettinger.; Thesis (M. Eng.)--Massachusetts Institute of Technology...

‣ Glycosaminoglycan-protein interactions : the fibroblast growth factor paradigm

Kwan, Chi-Pong, 1973-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 218 leaves; 20110574 bytes; 20110329 bytes; application/pdf; application/pdf
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Specific interactions between heparan sulfate glycosaminoglycans (HSGAGs) and proteins are central to a wide range of biological processes such as anticoagulation, angiogenesis and growth factor activation. The specificity involved in the HSGAG-protein interactions stems from the structural heterogeneity of HSGAGs, which are highly acidic biopolymers associated on the cell surface and in the extracellular matrix. It is believed that structural specificity in the HSGAG-protein interactions determines the biological functions mediated by HSGAG-binding proteins such as basic fibroblast growth factor (FGF2). A number of models have been proposed to account for the mode of FGF-FGFR interactions and the role of HSGAGs in modulating FGF2 signaling. It was hypothesized that one role played by HSGAGs was to stabilize FGF2 oligomers in a "side-by-side" or cis fashion for presentation to fibroblast growth factor receptor (FGFR). In this thesis research, we systematically examined different proposed modes of FGF2 dimerization and showed that extensive oligomerization of a FGF2 mutant protein could be achieved by oxidatively crosslinking. Heparin, a highly sulfated form of HSGAGs, was demonstrated to increase the extent of oligomerization. Therefore...

‣ Biological detection by means of mass reduction in a suspended microchannel resonator

Levy-Tzedek, Shelly
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 37 p.; 2843473 bytes; 2845328 bytes; application/pdf; application/pdf
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Label-free detection is the detection of biomolecules and their interactions, without the use of a molecule external to the interaction, used as a reporter to indicate presence and/or location. The suspended microchannel resonator offers the opportunity to perform such label-free measurements. The goal of this work is to open new avenues of possible applications for the suspended channel. I introduce the concept of detecting mass subtraction as a new approach, rather than the conventional detection of mass addition. In a model implementation scenario of this approach, a mass-intensifying tag bound to a small ligand molecule will be equilibrated with surface-immobilized receptors, and later displaced by an identical, but label-free, ligand molecule. This approach offers opportunities to extend the sensitivity range of the device, as well as introduces new functionality for it. It enables researchers to follow, label-free, real-time enzymatic reactions, relative affinities of different ligands to a receptor, and presence of small molecules in a solution.; by Shelly Levy-Tzedek.; Thesis (S.M.)--Massachusetts Institute of Technology, Biological Engineering Division, 2004.; Includes bibliographical references (p. 33-37).

‣ Nanoscale and microscale approaches for engineering the in vitro cellular microenvironment

Khademhosseini, Ali
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 182 leaves; 12976881 bytes; 12985321 bytes; application/pdf; application/pdf
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Micro- and nanofabrication approaches have dramatically changed our society through their use in microelectronics and telecommunication industries. These engineering tools are also useful for many biological applications ranging from drug delivery to DNA sequencing, since they can be used to fabricate small features at a low cost and in a reproducible manner. The goal of this thesis was to develop techniques based on the merger of novel materials and nano and microfabrication approaches to manipulate cell microenvironment in culture. To control cell migration and to restrict cell or colony size, cells and proteins were patterned by using molding or printing methods. Poly(ethylene glycol)-based molecules and polysaccharides were used to control cell-substrate interactions and to prevent cell adhesion on specific regions of a substrate. To control cell-cell contact, layer-by-layer deposition of ionic biopolymers (i.e. negatively charged hyaluronic acid and positively charged poly-L-lysine) was used to generate patterned co-cultures. In addition, to control cell-soluble factor interactions, microfluidic-based approaches were developed. To pattern cells and proteins within microchannels, a soft lithographic method was developed to pattern microchannel substrates using printing and molding approaches.; (cont.) To easily immobilize cells within channels...

‣ Simulation and optimization tools to study design principles of biological networks

Adiwijaya, Bambang Senoaji
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 146 leaves
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Recent studies have developed preliminary wiring diagrams for a number of important biological networks. However, the design principles governing the construction and operation of these networks remain mostly unknown. To discover design principles in these networks, we investigated and developed a set of computational tools described below. First, we looked into the application of optimization techniques to explore network topology, parameterization, or both, and to evaluate relative fitness of networks operational strategies. In particular, we studied the ability of an enzymatic cycle to produce dynamic properties such as responsiveness and transient noise filtering. We discovered that non-linearity of the enzymatic cycle allows more effective filtering of transient noise. Furthermore, we found that networks with multiple activation steps, despite being less responsive, are better in filtering transient noise. Second, we explored a method to construct compact models of signal transduction networks based on a protein-domain network representation. This method generates models whose number of species, in the worst case, scales quadratically to the number of protein-domain sites and modification states, a tremendous saving over the combinatorial scaling in the more standard mass-action model was estimated to consist of more that 10⁷ species and was too large to simulate; however...

‣ Bayesian network models of biological signaling pathways

Sachs, Karen, Ph. D. Massachusetts Institute of Technology
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 165 p.
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Cells communicate with other cells, and process cues from their environment, via signaling pathways, in which extracellular cues trigger a cascade of information flow, causing signaling molecules to become chemically, physically or locationally modified, gain new functional capabilities, and affect subsequent molecules in the cascade, culminating in a phenotypic cellular response. Mapping the influence connections among biomolecules in a signaling cascade aids in understanding of the underlying biological process and in development of therapeutics for diseases involving aberrant pathways, such as cancer and autoimmune disease. In this thesis, we present an approach for automatically reverse-engineering the structure of a signaling pathway, from high-throughput data. We apply Bayesian network structure inference to signaling protein measurements performed in thousands of single cells, using a machine called a flow cytorneter. Our de novo reconstruction of a T-cell signaling map was highly accurate, closely reproducing the known pathway structure, and accurately predicted novel pathway connections. The flow cytometry measurements include specific perturbations of signaling molecules, aiding in a causal interpretation of the Bayesian network graph structure.; (cont.) However...

‣ Computational structure-based modeling and analysis with application to rational and evolutionary molecular engineering

Armstrong, Kathryn Anne
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 127 leaves
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The design and development of new proteins and small molecules has considerable practical application in medicine, industry, and basic science. Frequently, progress in this area is made by altering an existing small molecule or protein for new function. This thesis presents methods for the analysis and design of rationally and evolutionarily designed molecules and focuses on applying these methods to make protein and small molecule changes more strategically. First, electrostatic analysis of a series of small molecule neuraminidase inhibitors was used to demonstrate that charge optimization improves the electrostatic component of the binding free energy, despite changes in binding mode and discrete chemical constraints. Additionally, chemical changes suggested by charge optimization frequently corresponded to tighter-binding inhibitors, indicating that this technique would be useful for the design of future inhibitors. Second, computational sequence and structure analysis were used to study the PDZ3-CRIPT binding interaction and a method for sequence analysis was developed to locate residues important for binding specificity. Third, computational analysis of the horseradish peroxidase active site suggested five positions as candidates for mutation...

‣ Structure and mechanics of the spasmoneme, a biological spring within the protozoan Vorticella convallaria

France, Danielle Cook
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 135 leaves
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Molecular springs have recently emerged as the basis for the fastest and most powerful movements at the cellular level in biology. The spasmoneme of the protozoan, Vorticella convallaria, is a model molecular spring, relying on energy stored in protein interactions to power contraction over a few hundred micrometers in a few milliseconds. While basic characteristics of Vorticella contraction are known, the underlying biochemical mechanism is unclear. The studies outlined here define and measure key parameters of spasmoneme performance which enable discrimination between proposed movement schemes and identification of new model parameters. Recent work has classified the spasmoneme as a power-limited machine (Upadhyaya, Baraban et al. 2007), where increases in viscous load correspond to decreases in velocity; in this work the maximum load at minimum velocity (the stall force), is measured. Work done by the stalk in contraction is shown to be dependent on its fractional change in length. This energy dependence arises from the basic underlying mechanism, and a major goal of this thesis was to characterize that mechanism by imaging the underlying structure. In the case of the Vorticella spasmoneme, imaging methods like birefringence imaging and electron microscopy...

‣ Towards rational design of peptides for selective interaction with inorganic materials

Krauland, Eric Mark
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 141 p.
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Utilizing molecular recognition and self-assembly, material-specific biomolecules have shown great promise for engineering and ordering materials at the nanoscale. These molecules, inspired from natural biomineralization systems, are now commonly selected against non-natural inorganic materials through biopanning random combinatorial peptide libraries. Unfortunately, the challenge of studying the biological inorganic interface has slowed the understanding of interactions principles, and hence limited the number of downstream applications. This work focuses on the facile study of the peptide-inorganic interface using Yeast Surface Display. The general approach is to use combinatorial selection to suggest interaction principles followed by rational design to refine understanding. In this pursuit, two material groups-II-VI semiconductors and synthetic sapphire (metal oxides)-are chosen as inorganic targets due to their technological relevance and ease of study. First, yeast surface display (YSD) was established as a broadly applicable method for studying peptide-material interactions by screening a human scFv YSD library against cadmium sulfide (CdS), a II-VI semiconductor. The presence of multiple histidine residues was found to be necessary for mediating cell binding to CdS. As a follow-up...

‣ Design principles of mammalian signaling networks : emergent properties at modular and global scales

Locasale, Jason W
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 249 leaves
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This thesis utilizes modeling approaches rooted in statistical physics and physical chemistry to investigate several aspects of cellular signal transduction at both the modular and global levels. Design principles of biological networks and cell signaling processes pertinent to disease progression emerge from these studies. It is my hope that knowledge of these principles may provide new mechanistic insights and conceptual frameworks for thinking about therapeutic intervention into diseases such as cancer and diabetes that arise from aberrant signaling. Areas of interest have emphasized the role of scaffold proteins in protein kinase cascades, modeling relevant biophysical processes related to T cell activation, design principles of signal transduction focusing on multisite phosphorylation, quantifying the notion of signal duration and the time scale dependence of signal detection, and entropy based models of network architecture inferred from proteomics data. These problems are detailed below. The assembly of multiple signaling proteins into a complex by a scaffold protein guides many cellular decisions. Despite recent advances, the overarching principles that govern scaffold function are not well understood. We carried out a computational study using kinetic Monte Carlo simulations to understand how spatial localization of kinases on a scaffold may regulate signaling under different physiological condition. Our studies identify regulatory properties of scaffold proteins that allow them to both amplify and attenuate incoming signals in different biological contexts. In a further...

‣ Tools and reference standards supporting the engineering and evolution of synthetic biological systems

Kelly, Jason R. (Jason Robert)
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 168 p.
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Biological engineers have constructed a number of multi-part synthetic biological systems that conduct logical operations on input signals, produce oscillatory output signals, store memory, or produce desired products. However, very few of these genetically-encoded systems worked as originally designed. The typical process of constructing a functional system involves a period of tuning the system properties to find a functional variant. This tuning process has been optimized and applied with great success to the engineering of individual biological parts by directed evolution. For instance, researchers developing improved enzymes, transcriptional promoters, and fluorescent proteins have generated large libraries of variants and screened these libraries to find individual mutants that met desired performance specifications. In this thesis, I address some of the bottlenecks preventing the application of directed evolution to more complex devices and systems. First, I describe an input / output screening plasmid that was designed to enable screening of higher-order genetic devices based on the equilibrium response of the device. This plasmid includes two fluorescent reporters and an inducible promoter to enable screening of device libraries across a range of inputs. Second...

‣ Engineering the interface between cellular chassis and synthetic biological systems

Canton, Bartholomew (Bartholomew John)
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 176 p.
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The aim of my thesis is to help enable the engineering of biological systems that behave in a predictable manner. Well-established techniques exist to engineer systems that behave as expected. Here, I apply such techniques to two aspects of the engineering of biological systems. First, I address the design and construction of standard biological devices in a manner that facilitates reuse in higher-order systems. I describe the design and construction of an exemplar device, an engineered cell-cell communication receiver using standard biological parts (refined genetic objects designed to support physical and functional composition). I adopt a conventional framework for describing the behavior of engineered devices and use the adopted framework to design and interpret experiments that describe the behavior of the receiver. The output of the device is the activity of a promoter reported in units of Polymerases Per Second (PoPS), a common signal carrier. Second, I begin to address the coupling that exists between engineered biological systems and the host cell, or chassis. I propose that the coupling between engineered biological systems and the cellular chassis might be reduced if fewer resources were shared between the system and the chassis. I describe the construction of cellular chassis expressing both T7 RNA polymerases (RNAP) and orthogonal ribosomes that are unused by the chassis but are available for use by an engineered system. I implement a network in which the orthogonal ribosomal RNA and the gene encoding T7 RNAP are transcribed by T7 RNAP. In turn...

‣ Applying engineering principles to the design and construction of transcriptional devices

Shetty, Reshma P. (Reshma Padmini)
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 203 leaves
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The aim of this thesis is to consider how fundamental engineering principles might best be applied to the design and construction of engineered biological systems. I begin by applying these principles to a key application area of synthetic biology: metabolic engineering. Abstraction is used to compile a desired system function, reprogramming bacterial odor, to devices with human-defined function, then to biological parts, and finally to genetic sequences. Standardization is used to make the process of engineering a multi-component system easier. I then focus on devices that implement digital information processing through transcriptional regulation in Escherichia coli. For simplicity, I limit the discussion to a particular type of device, a transcriptional inverter, although much of the work applies to other devices as well. First, I discuss basic issues in transcriptional inverter design. Identification of key metrics for evaluating the quality of a static device behavior allows informed device design that optimizes digital performance. Second, I address the issue of ensuring that transcriptional devices work in combination by presenting a framework for developing standards for functional composition. The framework relies on additional measures of device performance...

‣ Engineering phosphorylation-dependent post-translational protein devices

Sutton, Samantha C. (Samantha Carol)
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 127 p.
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One goal underlying synthetic biology is to develop standard biological parts that can be reliably assembled into devices encoding higher-order functions. Here, I developed a framework for engineering post-translational devices, which are devices whose inner workings are modulated by non-covalent protein interactions and covalent protein modifications. To test the framework, I designed a scaffold for engineering post-translational devices in yeast, the Phospholocator, that can be used to assemble peptide parts in order to produce devices that couple upstream kinase activity to regulated nuclear translocation. I used the Phospholocator to design, build, and characterize a Phospholocator device, the Cdc28-Phospholocator, whose location is regulated by the activity of cyclin-dependent kinase Cdc28. I next engineered and tested a Fus3-Phospholocator device, whose location is regulated by the activity of the mitogen-activated protein kinase Fus3, in order to demonstrate that the Phospholocator scaffold supports the engineering of many post-translational devices. I used the Cdc28-Phospholocator to follow Cdc28 activity levels throughout the yeast cell cycle, thereby illustrating the utility of the Cdc28-Phospholocator as a tool for biological inquiry. To implement more complex functions...

‣ Selecting high-confidence predictions from ordinary differential equation models of biological networks

Bever, Caitlin Anne
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 153 p.
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Many cellular processes are governed by large and highly-complex networks of chemical interactions and are therefore difficult to intuit. Computational modeling provides a means of encapsulating information about these interactions and can serve as a platform for gaining understanding of the biology and making predictions about cellular response to perturbation. In particular, there has been considerable interest in ordinary differential equation (ODE) models, which have several attractive features: ODEs can describe molecular interactions with mechanistic detail, it is relatively straightforward to implement perturbations, and, in theory, they can predict the concentration and activity of every species as a function of time. However, both the topology and parameters in such models are subject to considerable uncertainty. We explore the ramifications of these sources of uncertainty for making accurate predictions and develop methods of selecting high confidence predictions from uncertain models. In particular, we promote a shift in emphasis from model selection to prediction selection, and use consensus among model ensembles to identify the predictions most likely to be accurate. By constructing decision trees, this consensus can also be used to partition the space of potential perturbations into regions of high and low confidence. We apply our methods to the Fas signaling pathway in apoptosis to satisfy two goals: first...

‣ Genetic engineering of bacteriophage and its applications for biomimetic materials

Lee, Soo-Kwan
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 96 leaves
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Filamentous bacteriophage (M13) are excellent biological build block due to their multiple peptide display system including type 8 (complete peptide display at pVIII) and type 83 (complete peptide display at both pVIII and pIII) display systems. Unlike the phagemid systems, the advantage of these systems is that we can get homogenous peptide display on pVIII resulting in uniform placement of selected molecules as well as defined length and width. In this thesis, type 8 and type 83 phage were constructed and used as biological scaffolds to meet the following four specific aims. First, the self-assembly of engineered M13 bacteriophage as a template for Co-Pt crystals was demonstrated. An phage library with an octapeptide library on the major coat protein (pVIII) was used for selection of binders to cobalt ions. Fibrous structures with directionally ordered phage were obtained by interaction with cobalt ions. Co-Pt alloys were synthesized on the fibrous scaffold, and their magnetic properties were characterized. The mineralization showed organized nanoparticles on fibrous bundles with superparamagnetic properties. Second, an in vitro molecular selection method in non-biological conditions for inorganic synthesis was introduced.; (cont.) A phage display peptide library which is resistant to ethanol was constructed and used for selection against titania in 90% ethanol. The selected peptide...

‣ A directed evolution approach to engineering recombinant protein production in S. cerevisiae

Rakestraw, James A
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 155 leaves
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The continued success of protein therapeutics has put a strain on industry's ability to meet the large demand. Creating a more productive expression host for the manufacture of these proteins is a potential solution. Although heterologous proteins are frequently made in organisms as disparate as E. coli and bovines, the single-celled organism S. cerevisiae has emerged as a well-qualified candidate due to its approachable genetic and fermentation attributes as well as its ability to stably fold disulfide bonded and multi domain proteins. Because S. cerevisiae screens for enhanced protein secretion have traditionally utilized low-throughput and often plate-based methods, a high-throughput, liquid phase assay could offer a real advantage in secretory selection. In this thesis, yeast surface display is investigated as a potential proxy for heterologous protein secretion. Although ultimately unsuitable as a screening proxy, the surface display experiments did show a novel method of improving protein secretion by co-expressing a more stably folded protein with the protein of interest. In these studies the secretion of an scFv-Aga2p fusion was stimulated 1 0-fold by the concomitant surface expression of BPTI.; (cont.) BPTI surface expression also stimulated the secretion of secreted scFv three-fold suggesting a niche for protein coexpression as well as secretion by way of Aga2p fusions. A new screening method was developed that involves the capture of secreted protein on the surface of the cell where it can be labeled and sorted by FACS. This new method was verified to achieve thirty-five fold enrichment per pass for a three-fold enhanced protein secretor making it easily suitable for screening. The new screening methodology...

‣ Analysis of sequence-selective guanine oxidation by biological agents

Margolin, Yelena, 1977-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 155 p.
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Oxidatively damaged DNA has been strongly associated with cancer, chronic degenerative diseases and aging. Guanine is the most frequently oxidized base in the DNA, and generation of a guanine radical cation (G'") as an intermediate in the oxidation reaction leads to migration of a resulting cationic hole through the DNA n-stack until it is trapped at the lowest-energy sites. These sites reside at runs of guanines, such as 5'-GG-3' sequences, and are characterized by the lowest sequence-specific ionization potentials (IPs). The charge transfer mechanism suggests that hotspots of oxidative DNA damage induced by electron transfer reagents can be predicted based on the primary DNA sequence. However, preliminary data indicated that nitrosoperoxycarbonate (ONOOCO2"), a mediator of chronic inflammation and a one-electron oxidant, displayed unusual guanine oxidation properties that were the focus of present work. As a first step in our study, we determined relative levels of guanine oxidation, induced by ONOOCO2 in all possible three-base sequence contexts (XGY) within double-stranded oligonucleotides. These levels were compared to the relative oxidation induced within the same guanines by photoactivated riboflavin, a one-electron reagent. We found that...

‣ Scalable computational architecture for integrating biological pathway models; IFN response to virus infection

Shiva, V. A
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 2 v. (xvii, 303 leaves)
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A grand challenge of systems biology is to model the cell. The cell is an integrated network of cellular functions. Each cellular function, such as immune response, cell division, metabolism or apoptosis, is defined by an interconnected ensemble of biological pathways. Modeling the cell or even one cellular function requires a computational architecture that integrates multiple biological pathway models in a scalable manner while ensuring minimal effort to maintain the resulting integrated model. Scalable is defined as the ease in which more and more biological pathway models can be integrated. Current architectures for integrating biological pathway models are primarily monolithic and involve combining each biological pathway model's software source code to build one large monolithic model that executes on a single computer. Such architectures are not scalable for modeling complex cellular functions or the whole cell. We present Cytosolve, a new computational architecture that integrates a distributed ensemble of biological pathway models and computes solutions in a parallel manner while offering ease of maintenance of the integrated model. The individual biological pathway models can be represented in SBML, CellML or in any number of formats. The EGFR model of Kholodenko with known solutions is used to compare the Cytosolve solution and computational times with a known monolithic approach. A new integrative model of the interferon (IFN) response to virus infection is developed using Cytosolve. Each model within the integrated model...