The last two glacial terminations represent the most recent, and best documented, periods of Earth warming in the geological record. During these terminations atmospheric CO\textsubscript{2 }rose by approximately 100 ppm and global mean temperatures increased by 4-6\textsuperscript{o}C. Whilst the driver for these deglaciations ultimately derives from changes in the insolation forcing at the edge of the atmosphere, feedbacks within the Earth\textquoteright s climate system act to amplify these small external forcings tipping the Earth from a cold glacial climate state to a warm interglacial climate state. A key question in Quaternary climate science is understanding which feedbacks are important in regulating global climate on glacial-interglacial timescales. On this topic, the Southern Ocean has long been considered to be an important player in regulating atmospheric CO\textsubscript{2 } on glacial-interglacial timescales. This thesis investigates some of the hypothesised drivers of changes in atmospheric CO\textsubscript{2 } on glacial-interglacial timescales by generating high-resolution multi-proxy records from the Southern Ocean spanning the last two glacial terminations. In particular, I focus on changes in the structure, circulation and biological productivity within the sub-Antarctic zone. A change in the deep ocean density structure has been hypothesised to have resulted in the release of CO\textsubscript{2 } from the deep ocean. Centennial records from the sub-Antarctic are used to reconstruct deep and intermediate water density for the first time. I demonstrate that timing of the major breakdown in the density gradient of the ocean significantly lagged the breakdown in the chemical gradient, suggesting that changes in the deep ocean density structure were not the major driver of the deglacial rise in atmospheric CO\textsubscript{2 }. Changes in the density structure of the Southern Ocean likely had significant implications for global circulation. In particular, the flow of low salinity water through the Drake Passage is thought to be important in setting the strength and geometry of Atlantic Overturning Circulation. Drake Passage through-flow speed was reconstructed from two sites in the central and northern margins of the Antarctic Circumpolar Current downstream of Drake Passage. These records suggest a very different structure of Antarctic Circumpolar flow through Drake Passage during glacial periods, and evidence significant changes in ocean temperature as a result of pronounced reductions in Drake Passage through-flow. The strength of the biological pump has long been identified as an important player in regulating atmospheric CO\textsubscript{2 }. In particular, a strong glacial increase in sub-Antarctic productivity has been observed at open ocean sites in the South Atlantic and Indian Ocean. However, the glacial-interglacial changes in productivity in sub-Antarctic shelf settings are less well-documented. The new high-resolution records presented here from the sub-Antarctic southwest Atlantic suggest a significant change in the CaCO\textsubscript{3}:C\textsubscript{org} ratio which likely has implications for the surface ocean\textquoteright s ability to uptake CO\textsubscript{2 }.

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Creating a scientifically literate society appears to be the major goal of recent science education reform efforts (Abd-El-Khalick, Boujaoude, Dushl, Lederman, Hofstein, Niaz, Tregust, & Tuan, 2004). Recent national reports in the U.S, such as Shaping the Future, New Expectations for Undergraduate Education in Science, Mathematics, Engineering, and Technology (NSF,1996), Inquiry in Science and In Classroom,. Inquiry and the National Science Education Standards (NRC, 2001), Pursuing excellence: Comparison of international eight-grade mathematics and science achievement from a U.S. perspective (NCES, 2001), and Standards for Science Teacher Preparation (NSTA 2003) appear to agree on one thing: the vision of creating a scientifically literate society. It appears from science education literature that the two important components of being a scientifically literate individual are developing an understanding of nature of science and ability to conduct scientific inquiries. Unfortunately, even though teaching science through inquiry has been recommended in national reports since the 1950's, it has yet to find its way into many science classrooms (Blanchard, 2006; Yerrick, 2000). Science education literature identfies several factors for this including: 1)lack of content knowledge (Anderson, 2002; Lee, Hart Cuevas, & Enders, 2004; Loucks-Horsely, Hewson, Love, & Stiles, 1998; Moscovici, 1999; Smith & Naele, 1989; Smith, 1989); 2)high stake tests (Aydeniz, 2006); 3) teachers' conflicting beliefs with inquiry-based science education reform (Blanchard, 2006; Wallace & Kang, 2004) ; and, 4) lack of collaboration and forums for communication (Anderson, 2002; Davis, 2003; Loucks-Horsely, Hewson, Love, & Stiles, 1998; Wallace & Kang, 2004). In addition to the factors stated above this study suggest that some of the issues and problems that have impeded inquiry instruction to become the primary approach to teaching science in many science classrooms might be related to teachers NOS conceptions. Developing desired understanding of nature of science conceptions and having an adequate experience with inquiry learning is especially important for science teachers because science education literature suggests that the development of teachers' nature of science conceptions is influenced by their experiences with inquiry science (Akerson et. al. 2000) and implementation of science lessons reflect teachers' NOS conceptions (Abd-EL-Khalick & Boujaoude, 1997; Matson & Parsons, 1998; Rosenthal, 1993; Trowbridge, Bybee & Powell, 2000; Turner & Sullenger, 1999). Furthermore, the impediments to successful integration of inquiry based science instruction from teachers' perspective are particularly important, as they are the implementers of inquiry based science education reform. The purpose of this study is to understand the relationship between the teachers' NOS conceptions and their inquiry beliefs and practices in their classrooms and how this relationship impedes or contributes to the implementation of inquiry based science education reform efforts. The participants of this study were in-service teachers who were accepted into the online Masters Program in science education program at a southern university. Three online courses offered in the summer semester of 2005 constituted the research setting of this study: (1) Special Problems in the Teaching of Secondary School Science: Nature of Science & Science Teaching, (2) Curriculum in Science Education, and (3) Colloquium. Multiple data sources were used for data triangulation (Miles & Huberman, 1984; Yin, 1994) in order to understand the relationship between participants' NOS views and their conceptions and beliefs about inquiry-based science teaching. These include: (1) VNOS questionnaire, (2) Electronic postings, (3) Semi-structured interviews, (4) email correspondence, and (5) videotapes. The study revealed that the relationship between the teachers' NOS conceptions and their inquiry beliefs and practices is far from being simple and linear. Data suggests that the teachers' sophistication of NOS conceptions influence their perception of inquiry science instruction in variety of ways. In a nutshell, these include: 1) The teachers become more confident in their ability to implement inquiry-based science classes; 2) Better understanding of NOS conceptions assists the teachers develop a higher appreciation of inquiry science instruction; 3) The teachers' misconceptions about nature of science appear to be connected to their misconceptions about inquiry science instruction; 4) A better understanding of NOS concepts seems to have stimulate the teachers to put more emphasis on some aspects of inquiry more than others; and 5) Sophistication of teachers' NOS conceptions influences their decisions about the type of inquiry they plan to incorporate in their instruction. This study also suggests that enhancing teachers' NOS conceptions should be among the main objectives of inquiry-based professional development programs and courses that are taught in science education programs. Science education literature suggests that teachers' resistances to adopting inquiry-based science instruction may be related to their inadequate or inappropriate knowledge of the nature of science (Lederman & O' Malley, 1990; Lederman, 1992; Ryan & Aikenhead, 1992). This study reveals that enhancing NOS conceptions helps teachers in their efforts to integrate inquiry into their instruction by boosting their confidence in their abilities to teach science through inquiry. This study reveals that especially teachers who lack strong science backgrounds and prior experience with inquiry science are at risk. Not having a strong background in science and lacking extensive experience with inquiry science negatively influences the teachers' confidence and thus delays their efforts to implement inquiry-based science lessons. / A Dissertation submitted to the Department of Middle & Secondary Education in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Degree Awarded: Fall Semester 2007. / Date of Defense: June 21, 2007. / Nature of Science Conceptions, Reform in Science Education, Professional Development, Online learning, Inquiry learning / Includes bibliographical references. / Alejandro J. Gallard, Professor Directing Dissertation; Jeff Chanton, Outside Committee Member; Nancy Davis, Committee Member; Janice Flake, Committee Member.

Stem cell marker Nestin is an intermediate filament protein that plays an important role in cell integrity, migration and differentiation. Nestin expression occurs in approximately one-third of pancreatic ductal adenocarcinoma (PDAC) cases, and its expression positively correlates with tumor stage and peripancreatic invasion. Little is known of the mechanisms by which Nestin influences PDAC progression. We showed that Nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition in vitro, conversely, knockdown of endogenous Nestin expression reduced the migration rate and cells reverted to a more epithelial phenotype. In vivo mice studies showed that knockdown of Nestin significantly reduced tumor incidence and volume in xenografts. Expression of the Nestin protein was associated with Smad4 status in PDAC cells, hence Nestin expression might be regulated by the TGF-b1/SMAD4 pathway in PDAC. We examined Nestin expression after TGF-b1 treatment in human pancreatic cancer PANC-1, and PANC-1 shSmad4 cells. The TGF-b/SMAD pathway induced Nestin protein expression in PDAC cells through Smad4 in a dependent manner. Moreover, increased Nestin expression caused a positive feedback loop in the TGFb/SMAD signaling system. Finally, we demonstrated that 2 anti-microtubule inhibitors, Cytochalasin D (CD) and Withaferin A (WFA), exhibited anti-Nestin activity; these inhibitors might be potential anti-metastatic drugs. Our findings uncovered a novel role of Nestin in regulating TGF-b1-induced EMT. Anti-Nestin therapeutics are under development as a potential treatment for PDAC metastasis.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 177-196). Also available in print.

The mechanical behaviour of cells is essential in ensuring continued physiological function, and deficiencies therein can result in a variety of diseases. Also, altered mechanical response of cells can in certain cases be an indicator of a diseased state, and even actively promoting progression of pathology. In this thesis, methods to model cell and cytoskeletal mechanics are developed and analysed. In Paper A, a constitutive model for the response of transiently cross-linked actin networks is developed using a continuum framework. A strain energy function is proposed and modified in terms of chemically activated cross-links. In Paper B, a finite element framework was used to assess the influence of numerous geometrical and material parameters on the response of cross-linked actin networks, quantifying the influence of microstructural properties and cross-link compliance. Also, a micromechanically motivated constitutive model for cross-linked networks in a continuum framework was proposed. In Paper C, the discrete model is extended to include the stochastic nature of cross-links. The strain rate dependence observed in experiments is suggested to depend partly on this. In Paper D, the continuum model for cross-linked networks is extended to encompass more composite networks. Favourable comparisons to experiments indicate the interplay between phenomenological evolution laws to predict effects in biopolymer networks. In Paper E, experimental and computational techniques are used to assess influence of the actin cytoskeleton on the mechanical response of fibroblast cells. The influence of cell shape is assessed, and experimental and computational aspects of cell mechanics are discussed. In Paper F, the filament-based cytoskeletal model is extended with an active response to predict active force generation.  Importantly, experimentally observed stiffening of cells with applied stress is predicted. / <p>QC 20151209</p>

Thesis (Ph. D.)--University of Oregon, 2008. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 159-164). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.

Made available in DSpace on 2014-06-12T15:56:43Z (GMT). No. of bitstreams: 2 arquivo2966_1.pdf: 1666666 bytes, checksum: 973dda346a6f1998a4dcfea9706b94a5 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010 / A Common Intermediate Language (CIL), linguagem intermediária definida pelo padrão ECMA-335, provou ser uma representação alvo eficiente para muitas linguagens de alto nível, permitindo a portabilidade de programas para diversas plataformas. Entretanto, os compiladores de linguagem CIL disponíveis nas implementações existentes do padrão ECMA-335 não são adequados para o desenvolvimento de sistemas que executem diretamente sobre o hardware, como sistemas em tempo real, sistemas embarcados e novos sistemas operacionais específicos, porque exigem o suporte de uma máquina virtual (VES Virtual Execution System) para o funcionamento dos programas compilados. Este fato confina a seleção de linguagens às tradicionais C e C++ como opções para o desenvolvimento de tais sistemas. Face a esse confinamento, apresentamos a construção de um compilador estático de código CIL chamado CILCompiler, que transforma um subconjunto da linguagem em uma imagem executável que funciona com acesso direto ao hardware, sem a necessidade de uma máquina virtual. No intuito de tornar didático o compilador, facilitando a construção, compreensão e extensão do mesmo, foi adotada a abordagem incremental para a construção de compiladores, que sugere a utilização de pequenos passos incrementais para obter um compilador funcional logo nos estágios primitivos de desenvolvimento

Abstract The role of vacuolar H+-ATPase (V-ATPase) in exocytic and endocytic membrane transport processes was studied by using its specific inhibitor, bafilomycin A1 (Baf A1), as a tool. On the exocytic pathway, both brefeldin A- and nocodazole-induced retrograde transport of Golgi proteins to the endoplasmic reticulum (ER) were inhibited by Baf A1. Furthermore, p58/ERGIC-53, which normally cycles between the ER, the intermediate compartment (IC), and cis-Golgi, was arrested in pre-Golgi tubules and vacuoles, and the number of p58-positive 80-nm Golgi (COPI) vesicles was reduced, suggesting that the drug inhibits the vesicle-mediated retrieval of the protein from post-ER compartments. The small GTPase rab1p was efficiently recruited to the tubules, accumulating in the presence of Baf A1. In contrast, these tubules showed no enrichment of anterogradely transported proteins, indicating that they participate in retrograde transport. Interestingly, acidic lumenal pH could only be detected in the more central pre-Golgi elements. The forward (anterograde) transport of newly synthesized Semliki Forest virus (SFV) and vesicular stomatitis virus (VSV) glycoproteins from the ER to the cis-Golgi was largely unaffected by Baf A1. However, maturation processes occurring in the trans-Golgi were inhibited, and the amounts of viral glycoproteins appearing at the cell surface were reduced. Newly synthesized VSV glycoprotein accumulated into rab1p-positive Golgi membranes in the presence of Baf A1, indicating that the transport from cis-Golgi was affected. Furthermore, O-glycosylation of the expressed CD8 chimeras and lectin cytochemistry experiments indicate that Baf A1 affects the transport from cis-Golgi. Instead, Baf A1 did not affect the transport of viral glycoproteins from the trans-Golgi network to the cell surface. We propose, that anterograde intra-Golgi traffic may be affected indirectly by Baf A1, as it inhibits retrograde vesicle-mediated transport and thus cisternal maturation. Baf A1 inhibited the entry of SFV into BHK-21 cells. Thus, V-ATPase was responsible for the acidification of the endosomes needed for virus entry. In cells infected with VSV and subsequently treated with Baf A1, virus particles were found to be accumulated in tubular membrane structures, which also contained endocytosed BSA-gold. Neither VSV nor BSA-gold particles were detected in lysosomal glycoprotein (lgp) 120-positive lysosomes, however. Thus, secreted and further endocytosed virus particles accumulate into tubulated endocytic organelles, apparently early endosomes, in Baf A1-treated cells. We conclude that the transport from endosomes to lysosomes is inhibited by Baf A1. The bulk of rab7 GTPase, which participates in vesicle fusion to late endosomes, was localized to the ruffled border (RB) membrane of bone-resorbing osteoclast. This indicates that the membrane has some characteristics of late endosomal membranes and that endocytic membrane transport is oriented towards the RB. Consistently, both endocytosed lumenal horseradish peroxidase and receptor-bound transferrin were delivered to the RB. The delivery of membrane-associated transferrin to the RB further indicates that the RB has some endosomal characteristics and suggests that the endocytic pathway contributes to the maintenance of functional RB. The endocytic pathway could act in balancing the membrane traffic associated with transcytosis from the RB to the basal plasma membrane. Endocytic processes in osteoclasts appeared to be very sensitive to Baf A1. Thus, blocking of the endocytic membrane traffic towards the RB could explain the inactivation of cells by low concentrations of the drug.