Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006. / Includes bibliographical references. / Alkyl-substituted anilines have been implicated as important etiological agents in human carcinogenesis. Specifically, 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA), and 3-ethylaniline (3EA) have been associated with an increased risk of human bladder cancer, independent of cigarette smoking, in a published case-control study. Understanding the metabolic activation of and DNA adduct formation by these chemicals is an important first step in elucidating their mechanisms of carcinogenesis and toxicity. Cytochrome P450-mediated metabolism was profiled based on the hypothesis that N-hydroxylated metabolites are critical intermediates in the formation of DNA adducts. This work was extended to assess in vitro DNA adduct formation with the cell-free and cell-based assays. Accelerator Mass Spectrometry (AMS) was used for detection and semi-quantification of DNA adducts formed by 14C-labeled alkylanilines. Data indicated 3,5-DMA formed high levels of DNA adducts, suggesting that it is a potent carcinogen. Additionally, the levels of adducts exhibited inter-species variation. The effects of phase II metabolism on adduct formation were evaluated by comparing the results obtained from the two types of assays and by assessing the effects of phase II enzyme cofactors on the results of cell-free assay. / (cont.) Results implied that sulfotransferase-mediated metabolism promotes cytotoxicity and mutagenicity of all three alkylanilines; however, glucuronidation may provide a protective mechanism. The effects of N-acetyltransferase-mediated metabolism on DNA adduct formation differed for the three alkylanilines; acetyl-CoA enhanced adduct formation by 3-EA and 2,6-DMA, but it reduced 3,5-DMA adduct formation. Human CYP2A6 universally catalyzed the oxidation of all structural isomers of dimethylanilines and ethylanilines, except 3-EA. In the present work, the hypothesis that 3-EA is a mechanism-based inactivator toward human P450 2A6 through covalent binding was examined by using AMS. 3-EA was characterized as a mechanism-based inactivator with a Ki of 34 !iM and a kinact of 0.055 min'. Results suggest that 3-EA might be involved in more than one biological effect in the human body through multiple pathways. Adduct formation and inhibition of CYP 2A6 by 3-EA might shift the biological effects of other compounds activated by CYP 2A6 dynamically and kinetically while appearing in the biological systems simultaneously. / by Hsiao-Lan Patty Sun. / Ph.D.

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2009. / Includes bibliographical references (leaves 96-99). / Humanitarian logistic organizations struggle to make strategic and tactical decisions due to their lack of resources, the unpredictability of humanitarian events and the lack of readily available information; the existing tools that assist optimal decision making require large amounts of precise information. As a consequence of all these challenges, most of the work in humanitarian logistics concentrates on the operational level that can only offer short term benefits. Alternatively, optimal strategic decisions maximize the resources of humanitarian organizations making them more flexible and effective in the long term; this directly impacts the ability to help the millions of people in need. This thesis presents a model that assists the largest humanitarian organization in the world, The World Food Programme, to make optimal strategic decisions. The model uses the Analytic Hierarchy Process, a multiple attribute decision tool that provides structure to decisions where there is limited availability of quantitative information. This methodology uses a framework that determines and prioritizes multiple criteria by using qualitative data and it scores each alternative based on these criteria. The optimal alternative will be the one that has the highest weighted score. This model solves the challenges that The World Food Programme, as any other humanitarian organization face when making complex strategic decisions. The model, not only works with easily acquired information but, it is also flexible in order to consider the ever-changing dynamics in the humanitarian field. / (cont.) The application of this model focuses on the optimization of warehouse locations for the World Food Programme in the Somali region of Ethiopia. However, this model can easily be scaled in order to be used in any other decision making process in the humanitarian field. / by Gina Malaver [and] Colin Regnier. / M.Eng.in Logistics

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2007. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 61). / Although supply chain disruptions are inevitable, frameworks have been developed for addressing supply chain risks. These frameworks present methods on mitigating, reducing or managing the risks through different approaches such as multiple sourcing. The research presented here identified two factors that contribute to successful recovery from supply chain disruptions. One factor is efficient communication between stakeholders in a supply chain. The communication needs to be present before a disruption occurs to enable fast detection. After a disruption occurs efficient communications will help minimize confusion and provide clear understanding of the recovery effort between stakeholders. The other factor is the inventory position downstream of the disruption. In particular, the available days of supply downstream from the disruption relative to the length of the disruption are crucial to the ability of a supply chain to recover from the disruption without disturbing the continuity of supply. In response to the effect of the days of supply compared to the recovery time a simple model is developed for assessing supply chain risk for an enterprise that sells products defined through a bill-of-materials. / (cont.) The model takes into consideration the complexity of a product as more parts and more levels are added to the bill of material. The supply chain risk score metric permits comparison across products, companies and industries. The model is simple to apply by analyzing each part in bill-of-materials by a ranking system comparing the recovery time to the days of supply downstream from the disruption. The supply chain risk score is to be used in parallel with other supply chain metrics in order to determine the best approach in reducing risks to an enterprise. / by Theodore Doucakis. / M.Eng.in Logistics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Engineering Systems Division, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 235-249). / Survivability is the ability of a system to minimize the impact of a finite-duration disturbance on value delivery (i.e., stakeholder benefit at cost), achieved through (1) the reduction of the likelihood or magnitude of a disturbance, (2) the satisfaction of a minimally acceptable level of value delivery during and after a disturbance, and/or (3) a timely recovery. Traditionally specified as a requirement in military systems, survivability is an increasingly important consideration for all engineering systems given the proliferation of natural and artificial threats. Although survivability is an emergent system property that arises from interactions between a system and its environment, conventional approaches to survivability engineering are reductionist in nature. Furthermore, current methods neither accommodate dynamic threat environments nor facilitate stakeholder communication for conducting trade-offs among system lifecycle cost, mission utility, and operational survivability. Multi-Attribute Tradespace Exploration (MATE) for Survivability is introduced as a system analysis methodology to improve the generation and evaluation of survivable alternatives during conceptual design. MATE for Survivability applies decision theory to the parametric modeling of thousands of design alternatives across representative distributions of disturbance environments. To improve the generation of survivable alternatives, seventeen empirically-validated survivability design principles are introduced. The general set of design principles allows the consideration of structural and behavioral strategies for mitigating the impact of disturbances over the lifecycle of a given encounter. / (cont.) To improve the evaluation of survivability, value-based metrics are introduced for the assessment of survivability as a dynamic, continuous, and path-dependent system property. Two of these metrics, time-weighted average utility loss and threshold availability, are used to evaluate survivability based on the relationship between stochastic utility trajectories of system state and stakeholder expectations across nominal and perturbed environments. Finally, the survivability "tear(drop)" tradespace is introduced to enable the identification of inherently survivable architectures that efficiently balance performance metrics of cost, utility, and survivability. The internal validity and prescriptive value of the design principles, metrics, and tradespaces comprising MATE for Survivability are established through applications to the designs of an orbital transfer vehicle and a satellite radar system. / by Matthew G. Richards. / Ph.D.

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. / One solution to the increasing need for liver transplants is to grow implantable liver tissue in the lab. A tissue-engineered liver for transplantation will require complex structures to support cell differentiation and integration with surrounding vasculature. Recent developments in 3D-printing (3DP™) technology allow the construction of such geometrically complex scaffolds out of biodegradable polymers. These artificial tissues should maintain healthy, functional hepatocytes in proper contact with supporting cell types in the context of proper flow cues. This project comprises three major efforts. First, the design and development of a 3D-printed scaffold, constructed of a porous biodegradable polymer matrix, for flow bioreactor culture. Second, the development of protocols for the production, preparation, and flow support of these scaffolds. And third, the employment of standard cell culture methodologies to test the ability of these scaffolds to support liver tissue cultures. Initial cell culture experiments showed similar rates of albumin production in the polymer disk scaffolds compared to cells in silicon-chip scaffolds under appropriately scaled flow conditions, indicating that the polymer scaffolds maintain functioning liver tissue. Further, histology sections of liver tissue grown on these polymer scaffolds show organization of cells into structures reminiscent of in vivo liver. The results of this study show that 3D-printed porous polymer scaffolds have great potential for use as biodegradable tissue culture support devices. It is believed that, combined with printing technologies now under development, the technologies developed in this thesis will help facilitate the construction of an implantable tissue engineered liver. / by James Camp. / S.M.in Bioengineering

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 69). / Partners in Health's (PIH) supply chain in Haiti has become strained over the past five years due to the organization's rapid growth. Under the current system, the majority of PIH's products are obtained through an annually placed order. All goods from this order are stored at the central warehouse in Cange, which acts as a hub, until those goods are needed at individual clinics. As annual orders increase in size to support PIH's expanding operations, the limited size of the central warehouse has become a constraint, making a change in current inventory policies necessary. In order to formulate revised inventory policies for PIH's Haiti operations, we developed a spreadsheet model that uses historical consumption data of drugs and medical supplies to forecast demand over the next three years. This demand data is then be used as input to run and compare the existing annual order policy with ordering policies with more frequent reviews. These inventory policies are then evaluated against the central warehouse size constraints to recommend an inventory policy better suited to meet PIH's needs. We find that more frequent orders drastically reduces warehouse space requirements while maintaining high service levels. It is hoped that PIH can continue to use this model to determine future inventory policy needs. / by Christine L. Heberley and Matthew F. Hoover. / M.Eng.in Logistics

Thesis (M.A.)--Boston University

Thesis (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 59-61). / Enterprises undergo transformation for more efficient and effective performance and growth. The Lean Enterprise Self Assessment Tool (LESAT) is a product of the Lean Advancement Initiative (LAI) and the Massachusetts Institute of Technology (MIT). This tool is used by many enterprises to assess strengths, areas of improvement, and the enterprise's readiness to change. LESAT has been designed for enterprises that offer products only, not services. However, many of the principles and methodologies apply to servicing existing systems, which is a growing industry trend both in the private and public sector. Servicing existing systems accounts for 70% of the United States Department of Defense weapon system's total life-cycle cost. Many enterprises offer services to support, maintain, and upgrade their products. Many enterprises also rely on core internal systems that must be maintained and upgraded such as airline reservation systems or supply chain logistics tools. An extension of LESAT for Servicing Existing Systems is proposed as an assessment tool toward lean effectiveness for products and services. Collaborations with the International Council on Systems Engineering (INCOSE) In- Service Systems Working Group; three aerospace and technology enterprises Boeing, Pratt & Whitney, and Raytheon; as well as review of the literature are used in capturing best practices for success in servicing existing systems. / by Tina Prabha Srivastava. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. / Includes bibliographical references. / Chondroitin sulfate is a critical component of articular cartilage due to its contribution to the tissue's resistance to compressive deformation. Alterations in the biosynthesis of this molecule over time could impact the ability of the tissue to perform its necessary functions. Several factors have been shown to alter the biosynthesis of chondroitin sulfate in cartilage; among them are age, disease, depth of tissue, and mechanical compression. Specifically, mechanical compression has been shown to have a significant effect on the sulfation pattern and chain length and number in cartilage explant studies. The mechanisms that govern these alterations, however, have not been determined. The purpose of this study is to examine the effects of mechanical compression on chondroitin sulfate biosynthesis and analyze the roles of two possible mechanisms; enzyme transcription and organelle deformation. The effects of mechanical compression on the transcription rates of enzymes associated with the biosynthesis of chondroitin sulfate have not been previously studied. To perform this study in a bovine model, portions of the bovine genome had to be sequenced, PCR primers designed, and bulk expression levels determined. Static compression resulted in the significant up-regulation of two genes of interest: chondroitin sulfate and GalNAc 4S,6-sulfotransferase. / (cont.) Dynamic compression resulted in the significant up-regulation of the three sulfotransferases responsible for the bulk of sulfation in cartilage tissue. These results indicate a transient mechanotransduction reaction that differs based on the load regime. The effect of mechanical loading on the biosynthesis of chondroitin sulfate has been studied previously, however, this study seeks to examine more comprehensive loading regimes. Static compression and release resulted in an increase in 6-sulfation and a decrease in 4-sulfation that lasted to 48 hours after release of compression. Dynamic compression and release had the opposite effect on sulfation ratio, with an increase in 4-sulfation compared to 6-sulfation. The transcription changes seen in this study do not indicate the changes that occur in the end products of synthesis. Other factors may play a larger role, such as precursor availability or transport through the Golgi apparatus. Intracellular organelles react to static compression of the surrounding tissue in one of two manners. The majority of organelles deform much as the nucleus, proportionally in volume and shape to the cell. The Golgi apparatus appears to retain a significant portion of its volume relative to the cell and other organelles. In addition, it reforms structurally into a highly ordered stacked appearance. / (cont.) Osmotic forces within the Golgi may allow it to balance the osmotic load in the cytoplasm and resist compression and altered trafficking of the Golgi may in turn produce the altered appearance. Recent microscopy experiments on the Golgi apparatus utilizing two-photon microscopy have allowed us to examine the reaction of live tissue to static compression. These results illustrate the significant, but differing, effects of static and dynamic compression on the biosynthesis of chondroitin sulfate. The effects of these compression types on the transcription of enzymes responsible for this biosynthesis cannot fully explain the changes seen in newly synthesized chondroitin sulfate. Organelle reorganization has been shown to occur in response to static load and it is possible that altered organelle trafficking plays a role in this altered biosynthesis. Further studies are necessary to determine the final effect of the altered transcription and organelle structure on the manufacture of this important cartilage molecule. / by Jon D. Szafranski. / Ph.D.

Thesis (S.M. in Engineering and Management)--Massachusetts Institute of Technology, Engineering Systems Division, June 2013. / Cataloged from PDF version of thesis. "December 2012." / Includes bibliographical references (page 89). / With the ramp up of commercial spaceflight over the last decade with the assistance of the US Government and NASA, commercial spaceflight companies such as Space Exploration Technologies (SpaceX) and Orbital Sciences have taken significant strides in reducing the overall cost of space travel. The overall cost per launch goes far beyond the actual cost of the materials and labor associated with each launch vehicle, and must include all the political, environmental and social costs, which often amount to more than the actual cost of the vehicle itself. The main focus of my thesis is the Flight Termination System (FTS) which is the system used to terminate the flight of the launch vehicle in the event the vehicle veers off course or experiences any anomalies, which would impede its mission and cause a threat to human assets. Because of my work as the lead engineer of the FTS system at SpaceX, this thesis will mainly cover the system used at SpaceX. The FTS system is unique in that the approval of the system is as political and social as it is technical. Systems engineering is applied throughout the process of architecting, designing, testing, and manufacturing, where all stakeholders have a part in the success of each step of the product design. The key to the success of SpaceX lies in innovation, and as this thesis outlines, the FTS system has many innovative products and processes in place, including the establishment of many key relationships with stakeholders. / by Eugene Kwak. / S.M.in Engineering and Management