Role of IkappaB kinase beta in inflammation-mediated breast cancer development

Breast cancer is the second most common farm of cancers and the second leading cause of cancer death for American women. Clinical studies indicate inflammation is a risk factor for breast cancer development. Among the cytokines and chemokines secreted by the infiltrating inflammatory cells, tumor necrosis factor a (TNFα) is considered one of the most important inflammatory factors involved in inflammation-mediated tumorigenesis. ^ Here we found that TNFα/IKKβ signaling pathway is able to increase tumor angiogenesis through activation of mTOR pathway. While investigating which molecule in the mTOR pathway involved in TNFα/IKKβ-mediated mTOR activation, our results showed that IKKβ physically interacts with and phosphorylates TSC1 at Ser487 and Ser511 in vitro and in vivo. Phosphorylation of TSC1 by IKKβ inhibits its association with TSC2, alters TSC2 membrane localization, and thereby activates mTOR. In vitro angiogenesis assays and orthotopic breast cancer model reveals that phosphorylation of TSC1 by IKKβ enhances VEGF expression, angiogenesis and culminates in tumorigenesis. Furthermore, expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. ^ Furthermore, dysregulation of tumor suppressor FOXO3a contributes to the development of breast cancer. We found that overexpression of IKKβ led to inhibition of FOXO3a-mediated transactivation activity. While investigating the underlying mechanisms of IKKβ-mediated dysregulation of FOXO3a, our results showed that IKKβ physically associated with FOXO3a and phosphorylated FOXO3a at Ser644 in vitro and in vivo. The phosphorylation of FOXO3a by IKKβ altered its subcellular localization from nucleus to cytoplasm and promoted its degradation through ubiquitin-proteasome pathway. Mutation of FOXO3a at Ser644 prevented IKKβ-induced ubiquitination and degradation. In vitro cell proliferation assay and orthotopic breast cancer model revealed that phosphorylation of FOXO3a by IKKβ overrode FOXO3a-mediated repression of tumor progression. ^ In conclusion, our findings identify IKKβ-mediated suppressions of both TSC1 and FOXO3a are critical for inflammation-mediated breast cancer development through increasing tumor angiogenesis and evading apoptosis, respectively. Understanding the role of IKKβ in both FOXO3a and TSC/mTOR signaling pathways provides a critical insight of inflammation-mediated diseases and may provide a target for clinical intervention in human breast cancer. ^

Transcriptional and translational regulators of gene expression in germ cell development

Germ cell development is a highly coordinated process driven, in part, by regulatory mechanisms that control gene expression. Not only transcription, but also translation, is under regulatory control to direct proper germ cell development. In this dissertation, I have focused on two regulators of germ cell development. One is the homeobox protein RHOX10, which has the potential to be both a transcriptional and translational regulator in mouse male germ cell development. The other is the RNA-binding protein, Hermes, which functions as a translational regulator in Xenopus laevis female germ cell development. ^ Rhox10 is a member of reproductive homeobox gene X-(linked (Rhox) gene cluster, of which expression is developmentally regulated in developing mouse testes. To identify the cell types and developmental stages in which Rhox10 might function, I characterized its temporal and spatial expression pattern in mouse embryonic, neonatal, and adult tissues. Among other things, this analysis revealed that both the level and the subcellular localization of RHOX10 are regulated during germ cell development. To understand the role of Rhox10 in germ cell development, I generated transgenic mice expressing an artificial microRNA (miRNA) targeting Rhox10. While this artificial miRNA robustly downregulated RHOX10 protein expression in vitro, it did not significantly reduce RHOX10 expression in vivo. So I next elected to knockdown RHOX10 levels in spermatogonial stem cells (SSCs), which I found highly express both Rhox10 mRNA and RHOX10 protein. Using a recently developed in vitro culture system for SSCs combined with a short-hairpin RNA (shRNA) approach, I strongly depleted RHOX10 expression in SSCs. These RHOX10-depleted cells exhibited a defect in the ability to form stem cell clusters in vitro. Expression profiling analysis revealed many genes regulated by Rhox10, including many meiotic genes, which could be downstream of Rhox10 in a molecular pathway that controls SSC differentiation. ^ RNA recognition motif (RRM) containing protein, Hermes is localized in germ plasm, where dormant mRNAs are also located, of Xenopus oocytes, which implicates its role in translational regulator. To understand the function of Hermes in oocyte meiosis, I used a morpholino oligonucleotide (MO) based knockdown approach. Microinjection of Hermes MO into fully grown oocytes, which are arrested in meiotic prophase, caused acceleration of oocytes reentry into meiosis (i.e., maturation) upon progesterone induction. Using a candidate approach, I identified at least three targets of Hermes: Ringo/Spy, Xcat2, and Mos. Ringo/Spy and Mos are known to have functions in oocyte maturation, while Ringo/Spy, Xcat2 mRNA are localized in the germ plasm of oocytes, which drives germ cell specification after fertilization. This led me to propose that Hermes functions in both oocyte maturation and germ cell development through its ability to regulate 3 crucial target mRNAs. ^

The Role of Succession Planning in Leadership Development

In progressive companies succession planning plays a vital role in leadership development. Some companies have neither succession planning nor ways to fill leadership gaps. On the academic side of research, this Capstone Project focuses on the role of succession planning in leadership development through various approaches and theories. The purpose of this Capstone Project is to provide HR professionals with solid mechanisms for identifying and preparing leaders for leadership roles through proper succession mapping within a company. Through the analysis of case studies and research, recommendations are made on the formulation of a decision tree so that succession planning may take a new place in leadership development in an organization.

Thinking Local About Self-Driving Cars: a Local Framework for Autonomous Vehicle Development in the United States

Thesis (Master's)--University of Washington, 2016-06

Is ICT key to development?

Using panel data for 52 developed and developing countries over the period 1998-2006, this article examines the links between information and communication technology diffusion and human development. We conducted a panel regression analysis of the investments per capita in healthcare, education and information and communication technology against human development index scores. Using a quantile regression approach, our findings suggest that changes in healthcare, education and information and communication technology provision have a stronger impact on human development index scores for less developed than for highly developed countries. Furthermore, at lower levels of development education fosters development directly and also indirectly through their enhanced effects on ICT. At higher levels of development education has only an indirect effect on development through the return to ICT.

Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

Transdisciplinarity and reflective practice in sustainable development learning

Using various extracts from the reflective commentaries of MSc students, this article explores how transdisciplinarity and reflective practice operate in the programme. It shows how learners managed the uncertainties of sustainable development through regular critical and evaluative reflections. Students were able to apprehend the several worlds making up the sustainable development project and their own personal learning journey through the various competing, complementary and occasionally contradictory perspectives, modes of learning, sources of knowledge and information. One conceptual device facilitating this process was offering an understanding of sustainable development as constituting a ‘dialogue of values’, an approach that effectively invites students to square the metaphorical circle - i.e. broadly reconciling (ecological) sustainability with (economic) development.

Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

The experiences of Cuban American women attending a Hispanic serving institution and the influences on identity development

The purpose of this study was to gain an understanding and gather insight into the experiences of Cuban American women attending a 4-year, public, Hispanic Serving Institution and how those experiences influenced their identity development. This was accomplished by conducting in-depth interviews and focus groups with 12 self-identified Cuban American women who were classified as sophomores, juniors, seniors, or graduate students. All of the participants had attended Florida International University for at least 1 year. The women had varying degrees of on and off campus academic and campus involvement activities. Participants were asked about six topics: (a) family, (b) cultural influences, (c) gender, (d) ethical and moral development, (e) education, and (f) ethnic identity. Based on the coding of the data provided by the participants, several interconnected themes emerged including the importance of family, familial support, cultural pride, expected gender roles, core values, decision making, biculturalism, and the value of attending a Hispanic Serving Institution. These themes were found to be all related to the identity development of the participants. It was found that looking at identity through a multidimensional lens is essential. Looking at personal growth and development through anthropological, sociological, and psychosocial lenses gave greater insight to a population of students who have been largely underrepresented in the literature. The findings of this case study are that culture is contextual and identity development is complex for first and second generation Cuban American women attending a Hispanic Serving Institution in a majority minority city. It was found that several factors, including the importance of family and gender roles, were not found to be more important than one another; rather they supported each other in regards to the participants' identity development. The notion of biculturalism as it has been presented in the literature was challenged in this study as it was found that the participants' experiences living and attending a school in a majority minority city presented a new way of understanding what it might mean to be bicultural. For professionals in the field, the findings of this study may lead to a broader understanding of nuances within the Hispanic community and a better understanding of the distinctiveness of what it means to be a Cuban American woman.

Queering Human Resource Development

Societal norms for gender and sexual identity and practices tend to be heteronormative or homonormative, often privileging individuals belonging to the normative population. Viewing human resource development through a queer lens can suggest ways to support work environments that welcome all identities.

Fertilisation and larval development in an Antarctic bivalve, Laternula elliptica, under reduced pH and elevated temperatures

Elevated temperatures associated with ocean warming and acidification can influence development and, ultimately, success of larval molluscs. The effect of projected oceanic changes on fertilisation and larval development in an Antarctic bivalve, Laternula elliptica, was investigated through successive larval stages at ambient temperature and pH conditions (-1.6°C and pH 7.98) and conditions representative of projections through to 2100 (-0.5°C to +0.4°C and pH 7.80 to pH 7.65). Where significant effects were detected, increased temperature had a consistently positive influence on larval development, regardless of pH level, while effects of reduced pH varied with larval stage and incubation temperature. Fertilisation was high and largely independent of stressors, with no loss of gamete viability. Mortality was unaffected at all development stages under experimental conditions. Elevated temperatures reduced occurrences of abnormalities in D-larvae and accelerated larval development through late veliger and D-larval stages, with D-larvae occurring 5 d sooner at 0.4°C compared to ambient temperature. Reduced pH did not affect occurrences of abnormalities in larvae, but it slowed the development of calcifying stages. More work is required to investigate the effects of developmental delays of the magnitude seen here in order to better determine the ecological relevance of these changes on longer term larval and juvenile success.

Art + Bioéthique : quand la recherche en bioéthique quitte les murs de l’université

Éditoral / Editorial

Art + Bioéthique : quand la recherche en bioéthique quitte les murs de l’université

Éditoral / Editorial

The Open Data Smart City: A Case Study of Smart City Progress through Open Data Initiatives

Smart cities, cities that are supported by an extensive digital infrastructure of sensors, databases and intelligent applications, have become a major area of academic, governmental and public interest. Simultaneously, there has been a growing interest in open data, the unrestricted use of organizational data for public viewing and use. Drawing on Science and Technology Studies (STS), Urban Studies and Political Economy, this thesis examines how digital processes, open data and the physical world can be combined in smart city development, through the qualitative interview-based case study of a Southern Ontario Municipality, Anytown. The thesis asks what are the challenges associated with smart city development and open data proliferation, is open data complimentary to smart urban development; and how is expertise constructed in these fields? The thesis concludes that smart city development in Anytown is a complex process, involving a variety of visions, programs and components. Although smart city and open data initiatives exist in Anytown, and some are even overlapping and complementary, smart city development is in its infancy. However, expert informants remained optimistic, faithful to a technologically sublime vision of what a smart city would bring. The thesis also questions the notion of expertise within the context of smart city and open data projects, concluding that assertions of expertise need to be treated with caution and scepticism when considering how knowledge is received, generated, interpreted and circulates, within organizations.

On gathering in Art therapy: a way to understand and build the discipline with the other

In the present article I try to share some reflections on a case study of an attachment disorder child I worked with for two years through art therapy in a day hospital. Those reflections let me go deeply in some specific elements concerning the discipline which let us delimit its theoretical and methodological possible scope. In this way, from the specific of the case study on propose to reflect on those elements that conform a methodology related to the art therapist way of doing, in order to concrete and evaluate other possible interventions to develop in similar cases and contexts.