Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. / Includes bibliographical references (leaves 244-249). / 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, supplementary study, simulations also indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time[2]. / (cont.) Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling across a broad spectrum of time scales. T cells orchestrate the adaptive immune response and are central players in maintenance of functioning immune system. Recent studies have reported that T cells can integrate signals between interrupted encounters with Antigen Presenting Cells (APCs) in such a way that the process of signal integration exhibits a form of memory. We carried out a computational study using a simple mathematical model of T cell activation to investigate the ramifications of interrupted T cell-APC contacts on signal integration. We considered several mechanisms of how signal integration at these time scales may be achieved. In another study, we investigated the role of spatially localizing signaling components of the T cell signaling pathway into a structure known as the immunological synapse. We constructed a minimal mathematical model that offers a mechanism for how antigen quality can regulate signaling dynamics in the immunological synapse These studies involving the analysis of signaling dynamics led us to investigate how differences in signal duration might be detected. Signal duration (e.g. the time scales over which an active signaling intermediate persists) is a key regulator of biological decisions in myriad contexts such as cell growth, proliferation, and developmental lineage commitments. Accompanying differences in signal duration are numerous downstream biological processes that require multiple steps of biochemical regulation. We present an analysis that investigates how simple biochemical motifs that involve multiple stages of regulation can be constructed to differentially process signals that persist at different time scales[3]. / (cont.) Topological features of these networks that allow for different frequency dependent signal processing properties are identified. One role of multisite phosphorylation in cell signaling is also investigated. The utilization of multiple phosphorylation sites in regulating a biological response is ubiquitous in cell signaling. If each site contributes an additional, equivalent binding site, then one consequence of an increase in the number of phosphorylations may be to increase the probability that, upon disassociation, a ligand immediately rebinds to its receptor. How such effects may influence cell signaling systems is not well understood. A self-consistent integral equation formalism for ligand rebinding, in conjunction with Monte Carlo simulations, was employed to further investigate the effects of multiple, equivalent binding sites on shaping biological responses. Finally, this thesis also seeks to investigate cell signaling at a global scale. Advances in Mass Spectrometry based phosphoproteomics have allowed for the real-time quantitative monitoring of entire proteomes as signals propagate through complex networks in response to external signals. The trajectories of as many as 222 phosphorylated tyrosine sites can be simultaneously and reproducibly monitored at multiple time points. We develop and apply a method using the principle of maximum entropy to infer a model of network connectivity of these phosphorylation sites. The model predicts a core structure of signaling nodes, affinity dependent topological features of the network, and connectivity of signaling nodes that were hitherto unassociated with the canonical growth factor signaling network. Our combined results illustrate many complexities in the broad array of control properties that emerge from the physical effects that constrain signal propagation on complex biological networks. / (cont.) It is the hope of this work that these studies bring coherence to seemingly paradoxical observations and suggest that cells have evolved design rules that enable biochemical motifs to regulate widely disparate cellular functions. / by Jason W. Locasale. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Engineering Systems Division, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references (p. 213-222). / This research is based on the well-known but seldom stated premise that the design of complex engineered systems is done by people -- each with their own knowledge, thoughts, and views about the system being designed. To understand the implications of this social dimension, the Integrated Concurrent Engineering (ICE) environment, a real-world setting for conceptual space mission design, is examined from technical and social perspectives. An integrated analysis demonstrates a relationship among shared knowledge, process, and product. The design process is analyzed using a parameter-based Design Structure Matrix (DSM). This model, consisting of 682 dependencies among 172 parameters, is partitioned (reordered) to reveal a tightly coupled design process. Further analysis shows that making starting assumptions about design budgets leads to a straightforward process of well-defined and sequentially executed design iterations. To analyze the social aspects, a network-based model of shared knowledge is proposed. By quantifying team members' common views of design drivers, a network of shared mental models is built to reveal the structure of shared knowledge at a snapshot in time. A structural comparison of pre-session and post-session networks is used to compute a metric of change in shared knowledge. Based on survey data from 12 design sessions, a correlation is found between change in shared knowledge and each of several system attributes, including technological maturity, development time, mass, and cost. Integrated analysis of design process and shared knowledge yields three interdisciplinary insights. / (cont.) First, certain features of the system serve a central role both in the design process and in the development of shared knowledge. Second, change in shared knowledge is related to the design product. Finally, change in shared knowledge and team coordination (agreement between expected and reported interactions) are positively correlated. The thesis contributes to the literature on product development, human factors engineering, and organizational and social psychology. It proposes a rigorous means of incorporating the socio cognitive aspects of design into the practice of systems engineering. Finally, the thesis offers a set of recommendations for the formation and management of ICE design facilities and discusses the applicability of the proposed methodology to the full-scale development of complex engineered systems. / by Mark Sean Avnet. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering 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. 195-208). / Citrobacter rodentium is a naturally occurring murine bacterial pathogen which is used to model human diarrheagenic E. coli (EPEC and EHEC) infections in mice. C. rodentium causes colonic hyperplasia and a variable degree of colitis and mortality in the majority of inbred and outbred lines of mice. Differences in C. rodentium-induced disease are determined by the genetic background of the host. Here, C. rodentium infection in resistant outbred Swiss Webster (SW) mice was compared with infection in the cognate inbred FVB strain for the first time. In contrast to subclinical infection in SW mice, adult FVB mice developed overt disease with significant weight loss, severe colitis, and over 75% mortality. Fluid therapy intervention completely prevented mortality in FVB mice, and expression of pro-inflammatory and immunomodulatory genes in the colon was similar in both lines of mice, suggesting that mortality in C. rodentiuminfected FVB mice is due to hypovolemia resulting from severe dehydration. To identify host factors responsible for the development of mortality, gene expression in the distal colon of FVB and SW mice was investigated using a whole mouse genome Affymetrix array. / (cont.) Transcripts represented by 1,547 probe sets (3.4%) were differentially expressed between FVB and SW mice prior to infection and at 4 and 9 days post-inoculation. Data analysis suggested that intestinal ion disturbances rather than immune-related processes are responsible for susceptibility in C. rodentium-infected FVB mice. Marked impairment in intestinal ion homeostasis predicted by microarray analysis was confirmed by quantitative RT-PCR and serum electrolyte measurements that showed hypochloremia and hyponatremia in susceptible FVB mice. C. rodentium infection was next characterized in additional inbred strains of Swiss origin. SWR and SJL mice developed minimal morbidity and no mortality in response to the pathogen, demonstrating resistance to disease. Furthermore, C3H mice developed severe diarrhea and gene expression changes comparable to those in infected FVB mice, suggesting common pathogenic mechanisms in susceptible strains. In conclusion, C. rodentium infection in FVB mice is a useful model for fatal infectious diarrhea. These studies contribute to our understanding of C. rodentium pathogenesis and identify possible candidates for susceptibility to fatal enteric bacterial infection. / by Diana Borenshtein. / Ph.D.

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2009. / Includes bibliographical references (leaf 53). / We explore the use of transportation relays, a somewhat unconventional transportation operations concept, in terms of improving private fleet management. A transportation relay is a shipment that is divided into two legs. With transportation relays, there is more ways to route freight with a private fleet. We use a linear program to find private fleet tours with and without relays for a large retailer. We find that relays increase private fleet use by 17% and reduce total transportation cost by 6%. Inbound relays increase the utilization of private fleet on the inbound lanes while outbound relays shift the private fleet capacity between neighboring DCs. Together, inbound and outbound relays better utilize existing private fleet resources and can be used to justify an investment in a larger private fleet through the purchase of addition tractors and trailers. / by John Tsu and Mayank Agarwal. / M.Eng.in Logistics

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2006. / Includes bibliographical references (leaves 70-72). / The upstream petroleum supply chain is inefficient and uneconomical because of the independence of the four complex and fragmented functions which comprise it. Crude oil exploration, trading, transportation, and refining are functions which may be integrated through unified decision-making facilitated by timely information exchange. This exchange has been problematic because the four business units with their disparate activities have not been able to capture and appropriately structure the required information. How can business executives in the oil industry assemble all of the required information to achieve system-wide optimization? To remove the silos which impede system-wide optimization, there is need to analyze people, systems and issues in the upstream section of the petroleum supply chain; as a background to understanding the current challenges faced in achieving integration. Hence, the use of secondary and primary data sources was used for this research. The secondary includes the review of relevant literature while the primary data were from two sources. The first came from an on-site interview with the heads of business units of a case study, a company which is a major player in the industry. / (cont.) The second is from telephone interviews with industry experts which include software providers, consultants and other major players in the industry. The findings are that on-time information exchange will maximize shareholders' value and improve process efficiency in the supply chain. This process efficiency makes the upstream supply chain more responsive to possible changes in the environment that affects its operation. This will allow supply chain managers to achieve both a reduction in the variability in price of end product will be obtained while achieving stable profit margins. This research concludes by advocating that the use of information systems that accurately support data exchange among the functions in the supply chain in a timely, coordinated fashion with minimal distortion is required to ensure consistency in optimal decision making. To achieve this, change management is necessary because it requires a shift to a holistic approach in making decisions. Finally, areas recommended for future research are stated. / by Beatrice N. Nnadili. / M.Eng.in Logistics

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2005. / Includes bibliographical references (leaves 67-69). / This thesis examines the benefit of postponement of fashion products by considering the overage cost of the intermediate product and the correlation between the demand for each end products produced from it. The benefit of postponement is measured by the percentage increase in maximum expected profit after demand is realized. the production process is modelled as a two stage newsvendor problem and the forecast update path follows an additive martingale. An optimal solution and a myopic solution are proposed to solve this problem. Numerical results indicate that the benefit of postponement decreases with the overage cost of the intermediate product and the correlation between demand for each end products. It becomes less sensitive to the overage cost of the intermediate product when end products are more negatively correlated. It is also less sensitive to the demand correlation between end products when the overage cost of the intermediate product is low. In addition, the benefit of postponement is sensitive to the additional unit costs introduced by postponement. A case study to NFL Jerseys purchase planning indicates that an increase of unit cost by 10% can reduce the benefit of postponement by over 50%. / by Huiling Gong. / M.Eng.in Logistics

Thesis (S.M. in Technology and Policy)--Massachusetts Institute of Technology, Engineering Systems Division, June 2013. / "June 2013." Cataloged from PDF version of thesis. / Includes bibliographical references (p. 75-77). / Firms seek to create a product that are both desired by consumers, and also minimize costs. These goals come into conflict, as minimizing costs leads firms toward mass production, and meeting consumer needs leads firms toward product differentiation. One strategy to resolve these conflicting goals is to share component parts across distinct product variants allowing firms to maintain differentiated products while obtaining some of the economies of scale. In this way, part sharing reduces the cost burden of maintaining multiple product variants. However, part sharing also reduces product differentiation by resulting in some feature sharing, as the requirements of component parts differ across different product variants. Though some sharing may add desirable features, there may also be negative impacts, such as unnecessary mass from overdesign, referred to as "scar mass." In products where low mass is an important feature, this scar mass may deter designers from implementing part sharing. A common way of reducing mass in products is to exchange the material used for a lighter-weight alternative. However, lighter materials may be more expensive to use due to higher unit price or more complicated forming. This research investigates combined part sharing and material substitution strategies and their implications on cost and product weight. Specifically, it seeks to evaluate whether there exist situations in which 1) the cost savings from part sharing outweigh the increased cost from material substitution, while simultaneously 2) the mass savings from material substitution outweigh the scar mass penalty from sharing. To address this problem, this research develops a framework for modeling the implementation of different part sharing and material substitution strategies. In this framework, design changes to products from material substitution and part sharing are estimated using equivalent structural performance. The cost implications of these design changes are then calculated using a Process-Based Cost Modeling approach. This framework is then used to address a case of a hypothetical generic product and finally is applied to a real case. The real case is based on three real vehicle bodies that share a common platform. The research findings identify situations in which material substitution and part sharing strategies can be combined to produce lower mass and lower cost products. Automotive manufacturers may benefit from using these findings to implement cost-effective lightweighting policies to help them meet fuel efficiency standards. / by Nathalie Marielle Rivest. / S.M.in Technology and Policy

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 49-51). / The objective of this thesis is to improve the accuracy of individual freight train run time predictions defined as the time between departure from an origin node to arrival at a destination node not including yard time. A correlation analysis is conducted to identify explanatory variables that capture predictable sources of delay and influence run times for use in a regression model. A regression model is proposed utilizing the following explanatory variables: rolling historical average, congestion window, meets, passes, overtakes, direction, arrival headway, and departure headway to predict train run times. The performance of the proposed regression model is compared against a baseline simple historical averaging technique for a two year period of actual train operational data. The proposed regression model, though subject to specific limitations, offers substantial improvements in accuracy over the baseline technique and is recommended as justifying further exploration by the railroad to ultimately enable more accurate train schedules with subsequent improvements in railroad capacity, customer service, and asset utilization. / by Kunal Bonsra and Joseph Harbolovic. / M.Eng.in Logistics

Thesis (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division, 2007. / Includes bibliographical references (p. 153-158). / As a large-scale, long-term transportation project, the Chuo Shinkansen Maglev Project in Japan includes various uncertainties. Among them, two major uncertainties are identified in this thesis: the uncertainty of demand and the risk of R&D. Because each Maglev train requires a dedicated Power Conversion System (PCS) but a different one as it moves along the route, it is required to estimate the future demand accurately to determine the number of PCSs to construct. At the same time, the R&D to advance the technologies of PCS has the possibility of improving the project value by enabling staged flexible system development strategies. Since it is difficult to correctly estimate demand and R&D results, a framework that can evaluate projects with explicit considerations of these uncertainties is needed. In the light of the above background, this thesis develops a quantitative model that is appropriate for evaluating the Chuo Shinkansen Project. More specifically, this thesis applies the hybrid real options model, which is suitable for appraising projects with both market risks and R&D risks, in an innovative manner, addressing four major complexities that arise when applying the model to the project: / (cont.) the difficulty of estimating the demand of a new train system, identification of the possible system designs that vary depending on R&D results, necessity to incorporate capacity constraints into analysis, and the selection of the appropriate discount rate. Analyzing the data and the characteristics of the Chuo Shinkansen Project, this thesis develops an evaluation model that addresses above issues. Using the quantitative analytic model developed herein and assuming reasonable estimates of R&D costs, probability of success in R&D project, demand growth, volatility of demand, and the discount rate, this thesis estimates the value of the Chuo Shinkansen Project and concludes that it will be advantageous to invest in the R&D of the PCS technology despite its large cost. The thesis also conducts sensitivity analyses to demonstrate how the evaluation model developed in this thesis can be used to analyze the effects, on the project value, of changes in the probability of R&D success (in relation to R&D costs), demand growth and its volatility, and the discount rate, to obtain implications for the development strategies for the Chuo Shinkansen Project. / by Masaki Ishii. / S.M.

Thesis: M. Eng. in Logistics, Massachusetts Institute of Technology, Engineering Systems Division, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 90-91). / Supply chain resiliency is a relatively new field within supply chain management. Many quantitative and qualitative resiliency frameworks are available. However, there is a need for a hybrid framework that provides a more comprehensive resiliency assessment. In this thesis, we attempt to synthesize important features from different assessment frameworks and develop a hybrid resiliency assessment framework that more comprehensively addresses resiliency assessment. Our proposed framework combines quantitative assessment with a qualitative assessment to create a single Balanced Scorecard of Resiliency (BSR). We deployed the quantitative assessment of the BSR framework in a single commodity supply chain of ABC Company, and were able to compute the expected business impact risk of each node. We also aggregated across multiple nodes to assess the expected business impacts of each of the facilities, suppliers and locations of ABC Company's supply chain, and identify the critical entities in the supply chain for mitigation planning. For the critical facilities, suppliers, and locations, we developed response curves of the expected business impact for key parameters to identify the best mitigation options and the extent of investments. Lastly, we used a supply chain visualization tool called Sourcemap to visualize the expected business impact risk in both a map view and supply network view. Our quantitative assessment of resiliency allowed us to gain insights and generate recommendations for improving ABC Company's supply chain resiliency. / by Jaspar Siu and Santosh Stephen. / M. Eng. in Logistics