A Grammatical Paradigm

Avram Noam Chomsky is known for his work at Massachusetts Institute of Technology, for his political pursuits, and most importantly, for his theories in the discipline of linguistics. Chomsky linguistic pursuits aimed to answer the following linguistic studies: how a person learns and develops a language, how a person structures and understands a sentence, and what the purpose of linguistics is as a whole. His theories dramatically changed the linguistic paradigm. Due to this change, this paper also attempts to illustrate the correlation between scientific philosopher Thomas Kuhn’s belief in ‘paradigm shifts’ and the subsequent change in linguistic thought spurred by Chomsky’s grammatical theories

Estimating long-term growth-rate changes of southern bluefin tuna (Thunnus maccoyii) from two periods of tag-return data

Southern bluefin tuna (SBT) (Thunnus maccoyii) growth rates are estimated from tag-return data associated with two time periods, the 1960s and 1980s. The traditional von Bertalanffy growth model (VBG) and a two-phase VBG model were fitted to the data by maximum likelihood. The traditional VBG model did not provide an adequate representation of growth in SBT, and the two-phase VBG yielded a significantly better fit. The results indicated that significant change occurs in the pattern of growth in relation to a VBG curve during the juvenile stages of the SBT life cycle, which may be related to the transition from a tightly schooling fish that spends substantial time in near and surface shore waters to one that is found primarily in more offshore and deeper waters. The results suggest that more complex growth models should be considered for other tunas and for other species that show a marked change in habitat use with age. The likelihood surface for the two-phase VBG model was found to be bimodal and some implications of this are investigated. Significant and substantial differences were found in the growth for fish spawned in the 1960s and in the 1980s, such that after age four there is a difference of about one year in the expected age of a fish of similar length which persists over the size range for which meaningful recapture data are available. This difference may be a density-dependent response as a consequence of the marked reduction in the SBT population. Given the key role that estimates of growth have in most stock assessments, the results indicate that there is a need both for the regular monitoring of growth rates and for provisions for changes in growth over time (possibly related to changes in abundance) in the stock assessment models used for SBT and other species

Tumor cell migration in complex microenvironments

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.National Science Foundation (U.S.) (Graduate Research Fellowship)Charles Stark Draper Laboratory (Research and Development Program (N.DL-H-550151))National Cancer Institute (U.S.) (R21CA140096

Microfluidic model of monocyte extravasation reveals the role of hemodynamics and subendothelial matrix mechanics in regulating endothelial integrity

Extravasation of circulating cells is an essential process that governs tissue inflammation and the body's response to pathogenic infection. To initiate anti-inflammatory and phagocytic functions within tissues, immune cells must cross the vascular endothelial barrier from the vessel lumen to the subluminal extracellular matrix. In this work, we present a microfluidic approach that enables the recreation of a three-dimensional, perfused endothelial vessel formed by human endothelial cells embedded within a collagen-rich matrix. Monocytes are introduced into the vessel perfusate, and we investigate the role of luminal flow and collagen concentration on extravasation. In vessels conditioned with the flow, increased monocyte adhesion to the vascular wall was observed, though fewer monocytes extravasated to the collagen hydrogel. Our results suggest that the lower rates of extravasation are due to the increased vessel integrity and reduced permeability of the endothelial monolayer. We further demonstrate that vascular permeability is a function of collagen hydrogel mass concentration, with increased collagen concentrations leading to elevated vascular permeability and increased extravasation. Collectively, our results demonstrate that extravasation of monocytes is highly regulated by the structural integrity of the endothelial monolayer. The microfluidic approach developed here allows for the dissection of the relative contributions of these cues to further understand the key governing processes that regulate circulating cell extravasation and inflammation

Mechanotransduction of interstitial fluid stresses and effects on tumor cell migration

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2013."September 2013." Cataloged from PDF version of thesis.Includes bibliographical references (pages 93-106).Breast cancer incidence in the United States is I in 8, and over 90% of breast cancer related deaths are due to metastases, secondary tumors at a site distant from the primary tumor. Metastasis formation requires carcinoma cells to navigate through the tumor microenvironment and invade the surrounding stroma. Migration is a highly orchestrated process in which cells are guided by both internal signals and signals from the microenvironment. Hence, understanding the mechanisms that guide cell migration in response to various stimuli in the tumor and stromal microenvironments is key to developing therapies that prevent tumor cell migration and render cancer more treatable. Osmotic and hydrostatic pressure gradients within the extracellular matrix (ECM) drive flow of interstitial fluid through the ECM. Elevated osmotic pressure, lymphatic collapse, solid stress, and increased microvascular permeability contribute to elevated interstitial fluid pressure (IFP) during carcinoma progression, and high intratumoral IFP leads to pressure gradients at the tumor margin, which drive fluid flow that emanates from the tumor core to drain in the surrounding stroma. In this thesis, we explore the effect of interstitial flow (IF) on tumor cell migration. We developed a microfluidic platform to apply repeatable, robust IF through tissue constructs consisting of human metastatic breast cancer cells embedded within a 3D collagen type I matrix. We implemented the microfluidic device to validate CCR7-mediated autologous chemotaxis as a mechanism that guides downstream migration in response to IF. However, we identified a separate competing pathway that drives cell migration upstream (rheotaxis). Rheotaxis results from asymmetry in matrix adhesion stress that is required to balance fluid drag imparted by IF on tumor cells. Thus, autologous chemotaxis, mediated by chemical transport, and rheotaxis, mediated by fluid stresses, compete to direct cell migration downstream or upstream in response to IF. Our results provide insight into mechanotransduction in 3D porous media and into the mechanisms by which asymmetries in matrix adhesion tension guide cell migration. Furthermore, our results demonstrate that the consideration of IF is crucial for understanding and treating metastatic disease. Key words: Interstitial flow, mechanotransduction, tumor cell migration, microfluidics.by William J. Polacheck.Ph. D

Effects of interstitial flow on tumor cell migration

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 80-84).Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. However, due to limitations in experimental procedures and apparatuses, the mechanism by which cells detect flow and the details and dynamics of the cellular response remain largely unknown. We developed a microfluidic cell culture system in which we can apply stable pressure gradients and fluid flow, and in which we can observe transient responses of breast cancer cells seeded in a 3D collagen type I scaffold. We employed this system to examine cell migration in the presence of interstitial flow to address the hypothesis that interstitial flow increases the metastatic potential of breast cancer cells. By varying the concentration of chemoattractants, we decoupled the mechanisms that provide the migratory stimulus and the directional stimulus to migrating breast cancer cells in the presence of a flow field. We found that cells migrated along streamlines in the presence of flow and that the strength of the flow field determined directional bias of migration along the streamline. We provide evidence that CCR7-dependent autologous chemotaxis is the mechanism by which cells migrate with the flow, while a competing CCR7-independent mechanism leads to migration against the flow. Furthermore, we demonstrate these competing mechanisms are a powerful migrational stimulus, which likely play an important role in development of metastatic disease.by William J. Polacheck.S.M

Engineering of In Vitro 3D Capillary Beds by Self-Directed Angiogenic Sprouting

In recent years, microfluidic systems have been used to study fundamental aspects of angiogenesis through the patterning of single-layered, linear or geometric vascular channels. In vivo, however, capillaries exist in complex, three-dimensional (3D) networks, and angiogenic sprouting occurs with a degree of unpredictability in all x,y,z planes. The ability to generate capillary beds in vitro that can support thick, biological tissues remains a key challenge to the regeneration of vital organs. Here, we report the engineering of 3D capillary beds in an in vitro microfluidic platform that is comprised of a biocompatible collagen I gel supported by a mechanical framework of alginate beads. The engineered vessels have patent lumens, form robust ~1.5 mm capillary networks across the devices, and support the perfusion of 1 µm fluorescent beads through them. In addition, the alginate beads offer a modular method to encapsulate and co-culture cells that either promote angiogenesis or require perfusion for cell viability in engineered tissue constructs. This laboratory-constructed vascular supply may be clinically significant for the engineering of capillary beds and higher order biological tissues in a scalable and modular manner.Singapore-MIT Alliance for Research and Technolog