The role of gamma-synuclein in mammary gland tumourigenesis

Abstract y-synuclein is the third and last discovered member of the synuclein family, it is expressed mostly in the nervous system and its physiological function is still unknown. y-synuclein has been claimed to play a role in mammary gland tumourigenesis as its overexpression in cancer cells was shown to inhibit apoptosis and stimulate growth, proliferation, survival, motility and metastasis. However, the role of endogenous y-synuclein in mammary gland tumourigenesis has not been studied in an appropriate in vivo model. The results obtained in this study show that y-synuclein is not required for the normal development of the mammary gland at any developmental stage - embryonic, pubertal or reproductive. Furthermore, ablation of y-synuclein did not prevent induction of mammary gland tumours by activated ErbB2 transgene in mammary gland epithelium. Unexpectedly, transgenic activated ErbB2 hemizygous, y-synuclein knockout female mice developed slightly more tumours with a significantly shorter tumour latency than the wild type littermates. These animals also exhibited similar tumour growth rates and metastases to the lungs, and a slightly shorter survival. Overall, a trend for accelerated tumourigenesis in the absence of y-synuclein was observed. Thus, it is feasible that the aberrant expression of y-synuclein reported in advance-stage tumours and metastases reflects activation of pathways aimed at repressing rather than enhancing tumourigenesis, as widely thought. Future studies will clarify the role of y-synuclein in ErbB2-induced mammary gland tumourigenesis

Interior landscapes: techniques for depicting the nuances of interracial relationships

This research explores techniques for depicting interracial relationships, and their accomanying racial and cultural tensions, in fiction with an emphasis on Native American literature. This includes an examination of assuming other ethnicities through character development, and the line between appropriating racial identity and demonstrating empathy for characters regardless of races. This research specifically addresses techniques for illustrating the post-Civil Rights tensions between Euroamericans and Native Americans within the Interior West. As a non-Native American author native to the American West, I also identify the obstacles and strategies for including interracial relationships within my own work, a novel titled A Delicate Divide, which is based on a historic event: The Confederated Salish & Kootenai Tribes’ water compact proposal that threatens to strip land owner —primarily white—of their water rights within reservation borders. This research discusses Cosmopolitan and Nationalist arguments in favor and against non-Native merican depiction of Indians1 in fiction, and traces the progression of Euroamerican characterization within Native American fiction of the twentieth and twenty-first centuries. Through its examination of this aspect of racial tension, this research illustrates the arc of sentiment toward the colonizing race from early in the twentieth century, through the Civil Rights Movement and Wounded Knee II in 1973 (a significant event in Indian history), and into contemporary literature. An important outcome of this research has been my own personal understanding of the methods used to create fictional characters with varying viewpoints on race, including extreme racism, without making the overall nature of the work racist. I examine authors whose work deals heavily in themes of racial identity, racism, and cultural tensions between the colonizing race and the oppressed races. These authors also clearly illuminate the hardships of race relations from each of their characters’ perspectives. This paper discusses my approach to interracial fiction through the use of a third-race or “outsider” perspective to tease out racial stereotypes and cultural differences; the concept of imperative racism as a way in which characters overcome racism; and the use of self-directed racism as a technique for dispelling racial biases. Lastly, I highlight the predominant depiction of reservation life in literature as that of addiction, abuse, and poverty, with methods for updating depictions to a modern industry- and education-focused community, which is present on many of today’s reservations

Mechanotransduction of Matrix Stiffness Regulates Cell Adhesion Strength: An Analysis Using Biomaterial Surfaces with Tunable Mechanical and Chemical Properties

Cells have the ability to sense the rigidity of the extracellular matrix which directly affects the control of cellular functions in development, wound healing and malignant transformation. Polydimethylsiloxane elastomers are useful model biomaterials for mechanotransduction studies because they possess several advantages including ease of fabrication, tunable elasticity and modifiable surface chemistry. In this work, we are investigating the influence of matrix stiffness on adhesion strength and the mechanosensory structures that regulate these processes. In addition, the effect of surface modifications to this elastic substrate system on other physical properties such as local stiffness and topography will be analyzed. Based on previous research, we hypothesized that cell adhesion dependent processes will be regulated by matrix stiffness, but that surface chemistry influences on protein adsorption could provide overriding regulatory signals. The results of this research will provide insight into the interconnected processes of mechanosensing and cell adhesion strengthening, and reveal criteria for designing instructive biomaterials with specific mechanical and chemical properties

Mechanotransduction of Matrix Stiffness Regulates Cell Adhesion Strength: An Analysis Using Biomaterial Surfaces with Tunable Mechanical and Chemical Properties

Cells have the ability to sense the rigidity of the extracellular matrix which directly affects the control of cellular functions in development, wound healing and malignant transformation. Polydimethylsiloxane elastomers are useful model biomaterials for mechanotransduction studies because they possess several advantages including ease of fabrication, tunable elasticity and modifiable surface chemistry. In this work, we are investigating the influence of matrix stiffness on adhesion strength and the mechanosensory structures that regulate these processes. In addition, the effect of surface modifications to this elastic substrate system on other physical properties such as local stiffness and topography will be analyzed. Based on previous research, we hypothesized that cell adhesion dependent processes will be regulated by matrix stiffness, but that surface chemistry influences on protein adsorption could provide overriding regulatory signals. The results of this research will provide insight into the interconnected processes of mechanosensing and cell adhesion strengthening, and reveal criteria for designing instructive biomaterials with specific mechanical and chemical properties

Examining performance variables of nongovernmental organizations with Consultative Status with the United Nations

Nongovernmental organizations (NGOs) with Consultative Status with the United Nations (UN) continue to grow in numbers and in influence in the implementation of a global flood tide of activities and programs in the social, economic, political, public, and international policy arenas. However, there is a lack of information in literature and empirical research concerning variables considered relevant to their high performance. This dissertation examines two variables affecting NGOs performance; namely, examining the relationship between performance and the characteristics and strategies of NGOs with Consultative Status with the United Nations. In examining organizational variables influencing high performance of NGOs with Consultative Status with the UN, the following 16 operational factors/indicators that define the characteristics and strategies of NGOs are identified and rated in degree of importance by representatives of the responding NGOs. The 11 operational factors/indicators of the first independent variable, characteristics of NGOs, in the study are (a) goal setting, (b) goal clarity, (c) long-term decisions, (d) character of decision-making processes, (e) decision-making structure, (f) clarity of the day-to-day decision-making process, (g) organizational structure, (h) communication, (i) span of control, (j) task structure, and (k) overall effectiveness. The five operational factors/indicators of the second independent variable, strategies of NGOs, are (a) principal strategy, (b) intervening strategies, (c) interdependence in implementation, (d) determinants of performance effectiveness, and (e) survival. This study provides significant background data for future inquiries into issues related to the organizational design and structure of NGOs with Consultative Status with the UN. The findings add meaning to existing empirical research aiming at a better understanding of issues related to the assessment of NGOs performance. The focus on key organizational variables influencing high performance of NGOs and the factors that define them has significant implications in relation to NGO management, policymaking, and advancing empirical research in this area of study. In addition to taking few steps further in understanding some of the structural and strategic processes that may affect the performance of NGOs with Consultative Status with the UN, other contributions include: Establishing baseline-data references for future empirical research on examining performance variables of NGOs; Applying a design approach for mapping performance variables and their links to operational factors; and Setting performance indicators and benchmarks for assessment of performance

Contrasting effects of α-synuclein and γ-synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses.

In neuronal synapses, neurotransmitter-loaded vesicles fuse with presynaptic plasma membrane in a complex sequence of tightly regulated events. The assembly of specialized SNARE complexes plays a pivotal role in this process. The function of the chaperone cysteine string protein α (CSPα) is important for synaptic SNARE complex formation, and mice lacking this protein develop severe synaptic dysfunction and neurodegeneration that lead to their death within 3 months after birth. Another presynaptic protein, α-synuclein, also potentiates SNARE complex formation, and its overexpression rescues the phenotype of CSPα null mutant mice, although these two proteins use different mechanisms to achieve this effect. α-Synuclein is a member of a family of three related proteins whose structural similarity suggests functional redundancy. Here, we assessed whether γ-synuclein shares the ability of α-synuclein to bind synaptic vesicles and ameliorate neurodegeneration caused by CSPα deficiency in vivo. Although the N-terminal lipid-binding domains of the two synucleins showed similar affinity for purified synaptic vesicles, the C-terminal domain of γ-synuclein was not able to interact with synaptobrevin-2/VAMP2. Consequently, overexpression of γ-synuclein did not have any noticeable effect on the phenotype of CSPα null mutant mice. Our data suggest that the functions of α- and γ-synucleins in presynaptic terminals are not fully redundant

Contrasting effects of α-synuclein and γ-synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses.

In neuronal synapses, neurotransmitter-loaded vesicles fuse with presynaptic plasma membrane in a complex sequence of tightly regulated events. The assembly of specialized SNARE complexes plays a pivotal role in this process. The function of the chaperone cysteine string protein α (CSPα) is important for synaptic SNARE complex formation, and mice lacking this protein develop severe synaptic dysfunction and neurodegeneration that lead to their death within 3 months after birth. Another presynaptic protein, α-synuclein, also potentiates SNARE complex formation, and its overexpression rescues the phenotype of CSPα null mutant mice, although these two proteins use different mechanisms to achieve this effect. α-Synuclein is a member of a family of three related proteins whose structural similarity suggests functional redundancy. Here, we assessed whether γ-synuclein shares the ability of α-synuclein to bind synaptic vesicles and ameliorate neurodegeneration caused by CSPα deficiency in vivo. Although the N-terminal lipid-binding domains of the two synucleins showed similar affinity for purified synaptic vesicles, the C-terminal domain of γ-synuclein was not able to interact with synaptobrevin-2/VAMP2. Consequently, overexpression of γ-synuclein did not have any noticeable effect on the phenotype of CSPα null mutant mice. Our data suggest that the functions of α- and γ-synucleins in presynaptic terminals are not fully redundant