Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. / Includes bibliographical references (p. 119-134). / How do cells sense their environment and decide whether to live or to die? This question has drawn considerable interest since 1972, when it was first discovered that cells have an intrinsic ability to self-destruct through a process called apoptosis. Since then, apoptosis has been shown to play a critical role in both normal physiology and disease. In addition, many of the basic molecular mechanisms that control apoptosis have been revealed. Yet despite the known list of interactions and regulators, it remains difficult to inspect the network of apoptosis-related proteins and predict how cells will behave. The challenge is even greater when one considers interactions with other networks that are anti-apoptotic, such as growth-factor networks. In this thesis, we develop an approach to measure, analyze, and predict how complex intracellular signaling networks transduce extracellular stimuli into cellular fates. This approach entails three interrelated aims: 1) to develop high-throughput, quantitative techniques that measure key nodes in the intracellular network; 2) to characterize the quantitative changes in network state and cell behavior by exposing cells to diverse fate-changing stimuli; and 3) to use data-driven modeling approaches that analyze large signaling-response datasets to suggest new biological hypotheses. / (cont.) These aims were focused on an apoptosis-survival cell-fate decision process controlled by one prodeath cytokine, tumor necrosis factor (TNF), and two prosurvival stimuli, epidermal growth factor (EGF) and insulin. We first developed radioactive- and fluorescence-based high-throughput assays for quantifying activity changes in the kinases that catalyze key phosphorylation events downstream of TNF, EGF, and insulin. By combining these assays with techniques measuring other important posttranslational modifications, we then compiled over 7000 individual protein measurements of the cytokine-induced network. The signaling measurements were combined with over 1400 measurements of apoptotic responses by using partial least squares (PLS) regression approaches. These signaling-apoptosis regression models predicted apoptotic responses from cytokine-induced signaling patterns alone. Furthermore, the models helped to reveal the importance of previously unrecognized autocrine cytokines in controlling cell fate. This thesis has therefore shown how cell decisions, like apoptosis-versus-survival, can be understood and predicted from the quantitative information contained in the upstream signaling network. / by Kevin A. Janes. / Ph.D.

Thesis (Ph. D. in Molecular Systems Toxicology and Pharmacology)--Massachusetts Institute of Technology, Biological Engineering Division, 2004. / Vita. / Includes bibliographical references. / High affinity antibody binding interactions are important for both pharmaceutical and biotechnological uses. However, designing higher affinity interactions has remained difficult. Both high affinity interactions from nature and the results from directed evolution affinity maturation processes may yield clues about the important structural and energetic contributions to attain these tight associations. In this Thesis, we investigate affinity maturation of antibodies for very high affinity binding. Two single chain antigen-binding fragment (scFv) antibody systems that were engineered to obtain higher affinity interactions through directed evolution were probed using biophysical techniques to illuminate affinity modulation in proteins. First, anti-c-erbB-2 antibodies and their binding partner, the extracellular domain of the glycoprotein tumor antigen c-erbB-2, were examined. Thermodynamic studies were carried out on the originally identified human scFv and three higher affinity mutants. Although the first two steps included either entropic or enthalpic gains to affinity, the third improvement came from both types. This study demonstrates that a single energetic component is not generally responsible for the increased affinity within a given protein-protein affinity maturation pathway. Second, a family of anti-fluorescein antibodies and their binding to the small molecule fluorescein-biotin were explored. The femtomolar affinity matured anti-fluorescein antibody, 4M5.3, was compared to its wildtype high affinity precursor, 4-4-20. Affinity, thermodynamic, kinetic, and structural characterization of the binding identified 4M5.3 as one of the highest engineered affinity protein binding interactions known and / (cont.) illuminated how subtle structural changes can lead to large consequences for the kinetics and free energy of binding. The affinity mechanisms were further studied by the creation of a series of partial mutants. Context dependent and independent mutational effects on binding affinity indicated the extent of complexity in higher affinity mechanisms attained through directed evolution affinity maturation processes. These studies emphasize the importance of a large number of residues working in concert to create a very high affinity binding molecule. Based on these results, both rational design and directed evolution studies will need to allow for mutations in a spatially broad range around the binding site and involve many biophysical contributions to the binding free energy to reach very high antigen binding affinities. / by Katarina S. Midelfort. / Ph.D.in Molecular Systems Toxicology and Pharmacology

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2008. / Includes bibliographical references (leaves 87-89). / There are a lot of growth opportunities for multinational companies in emerging markets. These markets have a large consumer base but the market conditions in these regions are novel to these multinational companies. Various strategies evaluating government regulations, sales, marketing and supply chain have to be analyzed, isolated and implemented so that companies can quickly adapt to new market conditions. The purpose of this thesis is to review successful supply chain strategies adopted by multinationals catering to a large number of consumers in India. Based on the review, the thesis recommends insights for developing supply chains in emerging markets. To accomplish this, various strategies and literature on supplier, manufacturer and distributor partnerships were evaluated, compared and contrasted. Interviews with key management personnel across the supplier-manufacturer horizon were also conducted to gain insider perspective and information pertaining to supply chain issues. Current literature and public documents available have shown that successful supply chain strategies involved unique partnerships between local competitors and entering multinationals and also partnerships between local governments and direct source. Examples that stand out are the partnerships between PepsiCo and farmers in the state of Punjab, India or those of Project Shakti between women entrepreneurs from rural India and Hindustan Lever. This thesis recommends that such partnerships may hold the key to entering new markets in order to merge together different professional cultures without the risk of losing substantial investments in infrastructure. In addition, it also recommends the advantages of vertical integration for emerging markets like India. In addition, the findings on fragmentation within the echelons of supply chains propose opportunities for understanding developmental barriers. / by Don J. Palathinkal. / M.Eng.in Logistics

Thesis (M.Eng.)--Massachusetts Institute of Technology, Engineering Systems Division, 2000. / Includes bibliographical references (leaves 44-46). / The e-commerce boom has had a ripple effect on the way bricks-and-mortar retail stores operate their business. Bricks-and-mortar stores not only have to compete with one another in the physical world; they now have to compete with the pure Internet players. However, there are several issues that bricks-and-mortar stores must face before they can launch their online operations. The transformation strategy must be carefully planned. In addition, bricks-and-mortar stores must face certain challenges those pure Internet players seldom or never encounter. First, they have to recognize that e-commerce users have become an important segment of consumers; if they decide to go online, they must take the endeavor seriously. Second, they need to determine the best way to integrate online and physical operations. On the other hand, pure Internet players have also realized the benefits of a physical presence. Many have discovered that having outlets can improve their customers' overall shopping experience. For instance, Gateway Computers started as a catalog ordering company, but now the company has stores all over the country which serve as showrooms where customers can try out the computers. This combination has significantly increased Gateway's sales. This thesis will explore the factors that lead to the need for "clicks-and-mortar". Furthermore, it will point out the challenges facing clicks-and-mortar companies and discuss them in detail. It will then elaborate on the transition process and then create three clicks-and-mortar models. Finally, it will make a detailed comparison of the three models in order to determine their benefits and limitations. / by Ben Endy. / M.Eng.

Thesis: Ph. D., Massachusetts Institute of Technology, Engineering Systems Division, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 199-205). / This thesis explores the potential risk implications that a large penetration of intermittent renewable electricity generation -such as wind and solar power- may have on the future electricity generation technology mix, focusing on the anticipated new operating conditions of different thermal generating technologies and their remuneration in a competitive market environment. In addition, this thesis illustrates with an example how risk should be valued at the power plant level in order to internalize the potential risks to which the generators are exposed. This thesis first compares the impacts of three different bidding rules on wholesale prices and on the remuneration of units in power systems with a significant share of renewable generation. The effects of bidding rules are distinguished from the effects of regulatory uncertainty that can unexpectedly increase renewable generation by considering two distinct situations: 1) an 'adapted' capacity mix, which is optimized for any given amount of renewable penetration, and 2) a 'non-adapted' capacity mix, which is optimized for zero renewable penetration, but that operates with a certain non-zero renewable capacity, added on top of an already adequate system. The analysis performed stresses the importance of sound mechanisms that allow the full-cost recovery of plants in a system where the intermittency of renewables accentuates nonconvex costs, without over-increasing the cost paid by consumers for electricity. Additionally, the analysis quantifies the potential losses incurred by different thermal technologies if renewable deployment occurs without allowing for adaptation. Methodologically, this thesis uses a novel long-term generation investment model, the Investment Model for Renewable Electricity Systems (IMRES), to determine the minimum cost thermal capacity mix necessary to complement renewable generation to meet electricity demand, and to extract hourly wholesale prices. IMRES is a capacity expansion model with unit commitment constraints whose main characteristics are: 1) reflecting the impact of hourly resolution operation constraints on investment decisions and on total generation cost; 2) accounting for the chronological variability of demand and renewable output, and the correlation between the two; and 3) deciding on power plant investments at the individual plant level. These characteristics allow for a detailed analysis of the profits obtained by individual plants in systems with large renewable penetration levels. In addition, this thesis tests the performance of a heuristic method that selects four weeks from a full year series to optimally represent the net load duration curve (i.e., the difference between demand and renewable output, decreasingly ordered). For each application of this heuristic method, three metrics are proposed to reflect that the approximation also represents the chronological variability of the net load. Lastly, this thesis explores the role of risk in the valuation of electricity generating technologies and shows how to incorporate standard risk pricing principles into the popular Monte Carlo simulation analysis. The exposition is structured using the standard framework for a typical Monte Carlo cash flow simulation so that the implementation can be readily generalized. This framework stresses the necessity of an asset pricing approach to assess the relationship between the risk in the assets cash flows and the macroeconomic risk with which the financial investors are concerned. The framework provided is flexible and can accommodate many different structures for the interaction between the macroeconomic risk and the risks in the asset's cash flows (such as those from shocks in renewable deployment). / by Fernando J. de Sisternes. / Ph. D.

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2007. / Includes bibliographical references (leaf 63). / A large consumer package goods company would like to know the answer to the following question. What is the value to its customers of increased delivery frequency or reduced lead time? To answer this question, we collected shipment and inventory data for three customers: a mass merchandiser, a grocery store chain, and a drug store chain in the US. We examined the shipment histories to the customers' Distribution Centers (DCs) in the West, the Midwest, and the East for SKUs from three product families. We developed a continuous review QR inventory model to calculate the theoretical inventories for these high volume SKUs. We used this model to assess the theoretical inventory requirements for multiple scenarios entailing some form of increased frequency or decreased lead time. Some companies run heavy promotions during which time the majority of sales occur. If such a company is to benefit from reduced lead time from its supplier to their DCs, shipments from their DCs to stores must be frequent enough to respond to their stores' needs during a promotion. / (cont.) If this is not the case, the main opportunity to reduce inventory will be through better promotional planning. The data showed that there was a great amount of variability in the average inventory levels at the customers' DCs, which suggested that some DCs have large excesses of inventory for some SKUs. If customers could simply match their best in class inventory levels across all other products and locations, possibly $120 million could be saved annually in inventory carrying costs across all of this company's customers. The model also suggested that increasing delivery frequency provides a greater value than decreasing lead time. The methodology used to calculate the value of potential savings to customers could be applied to other locations or other industries. / by Joseph Sean Walkenhorst. / M.Eng.in Logistics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Engineering Systems Division, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Efforts to understand the determination of needs of new weapon systems must take into account inputs and actions beyond the formally documented requirements generation process. This study analyzes three recent historical cases of fighter aircraft development to identify decisions made independently from the documented requirements process, about the need for new systems. The primary inputs to those decisions are identified, and a qualitative model for understanding the undocumented inputs, and their role in determining weapon system needs, is presented. By analyzing data across the cases, which span a period of significant change in fighter design, the concept of a Dominant Mission Emphasis (DME) is introduced. The DME is defined as that mission which receives the most emphasis from the majority of participants in the needs determination process, and which the majority of other missions support, either directly or indirectly. It emerges when enough participants become convinced that it is appropriate to address the military, economic, political, social, and other needs that exist, and it serves as a means for bounding the intractable array of possibilities for weapon system needs. The convincing of participants occurs primarily through a social process, not a technical or an authoritative one. Over time, as conditions change, the appropriateness of the DME will decrease. The appropriateness over time can be modeled with a bell-shaped curve. Cues are identified which suggest the need to re-examine the DME. / (cont.) The strength of a DME can be measured by qualitative and quantitative indicators, including such things as verbal statements, military doctrine, intellectual and academic writings, organization within the military, resources committed, and promotion decisions. These indicators can also be used as controls to strengthen or weaken a DME in response to the perception of its appropriateness for existing conditions. The DME is constantly being questioned and challenged by individuals who seek to convince others that its appropriateness is not sufficient for existing conditions. Alternative missions are proposed and advocated as new DMEs. The roles of the primary means for convincing participants of the appropriateness of a DME are presented. / by Daniel Mark Gillespie. / Ph.D.

Thesis (Ph. D. in Molecular and Systems Toxicology and Pharmacology)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. / Includes bibliographical references. / Tetracyclines, a broad-spectrum class of antibiotics, were discovered in the late 1940s, and became widely used because of their important advantages: they are inexpensive, safe, demonstrate good oral absorption, and are active against a broad range of bacterial pathogens. Unfortunately, as with most antibiotics, the emergence of microbial resistance to tetracyclines has become a serious problem. Today, most genera examined have tetracycline-resistant isolates, although the percentage varies according to species and geographic location. Due to the emergence of resistance, tetracyclines are no longer the antibiotics of choice in treatment of many conditions, although they are still extensively used to treat a variety of bacterial infections. Substantial research efforts have been directed towards reversing tetracycline resistance in bacteria. This work describes the development of a novel anti-bacterial treatment for diseases caused by bacteria resistant to tetracycline. It was found that tetracycline-resistant bacteria expressing the TnlO gene of tetracycline resistance, upon induction with tetracycline, became extremely susceptible to destruction by the DNA-damaging anti-cancer drug cisplatin. Tetracycline-resistant bacteria grown in tetracycline and subsequently treated with cisplatin in the presence of tetracycline were killed about 10⁵-fold more effectively than wild-type bacteria and tetracycline-resistant bacteria not exposed to tetracycline. This phenomenon was observed in different strains of tetracycline-resistant E. coli. Other antibiotics tested with respective antibiotic-resistant bacteria did not produce the same effect of sensitization to cisplatin, suggesting a unique relationship among cisplatin, tetracycline and the tetracycline resistance / (cont.) gene. It was determined that levels of platinum DNA damage were higher in sensitized tetracycline-resistant cells than in wild-type cells, although total cellular platinum levels in sensitized tetracycline-resistant cells were not increased. At this time, the mechanism of increased DNA damage formation and the mechanism underlying sensitization to cisplatin are still matters of speculation. The experiments reported here, however, demonstrate that cells expressing the genes of tetracycline resistance actually became primary targets for destruction by cisplatin. Based on this study, it is suggested that the therapeutic power of the tetracyclines could be restored and enhanced by using a complementary drug that, in combination with tetracycline, would induce selective destruction of tetracycline-resistant bacteria. / by Doriana Froim. / Ph.D.in Molecular and Systems Toxicology and Pharmacology

Thesis: M. Eng. in Logistics, Massachusetts Institute of Technology, Engineering Systems Division, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages [72]-[74]). / The handicraft sector in Morocco represents more than 9% of the nation's GDP and employs 2.3 million people. However, despite their talent and expertise, Morocco's artisans are struggling to reach markets other than local regional or national markets. The main distribution model used so far has been the classic retail distribution model, which does not add value to the artisans' work, with most downstream actors playing the role of the middlemen. Other Ecommerce models such as the marketplace model or the crowdfunding model did not solve all the issues faced by artisans and customers. This paper provides the framework for a new distribution channel for Moroccan artisans to improve the efficiency of the value chain linking them to the American consumer by eliminating all unnecessary steps, overhead, and overall inefficiencies of the current distribution models. We first identify the models that are currently used to bring the artisans' crafts to the end consumer in developed markets: the market place (used by the platform Etsy), the crowdfunding model and the classic retail distribution model involving middlemen. We assessed the benefits of all the models by developing a new framework allowing to score each one of them. We then switched our focus to a hybrid model: a crowdfunding platform where the company partners with the artisans to align the different stakeholders' interests. To the extent of our knowledge, this model has not been used yet. It was found that our methodology could help artisans access international markets more efficiently. We finished by determining the optimal strategy using social media to market this platform and engage more efficiently potential customers. Keywords: handicraft, supply chain, crowdfunding, retail, social network marketing. / by Zyad El Jebbari. / M. Eng. in Logistics

Thesis (S.M. in Technology Policy)--Massachusetts Institute of Technology, Engineering Systems Division, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 109-125). / Mercury is a toxic pollutant that endangers human and ecosystem health. Especially potent in the form of methyl mercury, exposure is known to lead to adverse neurological effects, and, a growing body of evidence suggests, cardiovascular ones. Mercury's health impacts have economic consequences, and benefit-cost analyses focusing on these health benefits are used to motivate regulatory action in the United States and elsewhere. However, many existing valuation studies of the health impacts of mercury have substantial limitations, both from a scientific and economic perspective. Because they do not fully model mercury's path from emissions to impacts, they do not fully reflect the spatial and temporal dimensions of the mercury problem. In addition, many do not consider uncertain, but potentially policy-relevant health effects like cardiovascular disease. This thesis develops an integrated assessment framework that more completely represents mercury's emissions-to-impacts path, and then evaluates its policy relevance. The assessment framework integrates chemical transport modelling, exposure and health impacts modelling, and general equilibrium modelling of the US economy. As a case study, the framework is used to evaluate the benefits of the Mercury and Air Toxics Standards-a recent US regulation that targets emissions from coal-fired power plants-until 2050. I estimate the annual benefit of MATS to be 13 million 2005 USD, compared to a scenario that includes stringent air quality policy, and 414 million 2005 USD when compared to a no policy scenario. I find that the estimate is highly sensitive to uncertainties along the emissions-to-impacts path-in particular, dose-response parameterization, ecosystem lag times, and discount rate. The analysis suggests that given the large ranges of uncertainty involved, more fully representing the emissions-to-impact chain does not lead to substantially different aggregate benefits estimates, compared to those existing in the literature. However, because this approach does provide more insight into the controlling influences behind benefits, it can inform decisions about where policies should be implemented, and of what type, as well as best practices for transparently assessing mercury-related policies. / by Amanda Giang. / S.M.in Technology Policy