Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.

Women-led community development organizations (CDOs) in Miami-Dade County: A model of community development efforts impacting the economic security of women

Recent studies on the economic status of women in Miami-Dade County (MDC) reveal an alarming rate of economic insecurity and significant obstacles for women to achieve economic security. Consistent barriers to women's economic security affect not only the health and wellbeing of women and their families, but also economic prospects for the community. A key study reveals in Miami-Dade County, "Thirty-nine percent of single female-headed families with at least one child are living at or below the federal poverty level" and "over half of working women do not earn adequate income to cover their basic necessities" (Brion 2009, 1). Moreover, conventional measures of poverty do not adequately capture women's struggles to support themselves and their families, nor do they document the numbers of women seeking basic self-sufficiency. Even though there is lack of accurate data on women in the county, which is a critical problem, there is also a dearth of social science research on existing efforts to enhance women's economic security in Miami-Dade County. My research contributes to closing the information gap by examining the characteristics and strategies of women-led community development organizations (CDOs) in MDC, working to address women's economic insecurity. The research is informed by a framework developed by Marilyn Gittell, who pioneered an approach to study women-led CDOs in the United States. On the basis of research in nine U.S. cities, she concluded that women-led groups increased community participation and "by creating community networks and civic action, they represent a model for community development efforts" (Gittell, et al. 2000, 123). My study documents the strategies and networks of women-led CDOs in MDC that prioritize women's economic security. Their strategies are especially important during these times of economic recession and government reductions in funding towards social services. The focus of the research is women-led CDOs that work to improve social services access, economic opportunity, civic participation and capacity, and women's rights. Although many women-led CDOs prioritize building social infrastructures that promote change, inequalities in economic and political status for women without economic security remain a challenge (Young 2004). My research supports previous studies by Gittell, et al., finding that women-led CDOs in Miami-Dade County have key characteristics of a model of community development efforts that use networking and collaboration to strengthen their broad, integrated approach. The resulting community partnerships, coupled with participation by constituents in the development process, build a foundation to influence policy decisions for social change. In addition, my findings show that women-led CDOs in Miami-Dade County have a major focus on alleviating poverty and economic insecurity, particularly that of women. Finally, it was found that a majority of the five organizations network transnationally, using lessons learned to inform their work of expanding the agency of their constituents and placing the economic empowerment of women as central in the process of family and community development.

Contribution of lipophilic secondary metabolites to the toxicity of strains of freshwater cyanobacterial harmful algal blooms, identified using the zebrafish (Danio rerio) embryo as a model for vertebrate development

Cyanobacteria ("blue-green algae") are known to produce a diverse repertoire of biologically active secondary metabolites. When associated with so-called "harmful algal blooms", particularly in freshwater systems, a number of these metabolites have been associated—as "toxins", or commonly "cyanotoxins"—with human and animal health concerns. In addition to the known water-soluble toxins from these genera (i.e. microcystins, cylindrospermopsin, and saxitoxins), our studies have shown that there are metabolites within the lipophilic extracts of these strains that inhibit vertebrate development in zebrafish embryos. Following these studies, the zebrafish embryo model was implemented in the bioassay-guided purification of four isolates of cyanobacterial harmful algal blooms, namely Aphanizomenon, two isolates of Cylindrospermopsis, and Microcystis, in order to identify and chemically characterize the bioactive lipophilic metabolites in these isolates. ^ We have recently isolated a group of polymethoxy-1-alkenes (PMAs), as potential toxins, based on the bioactivity observed in the zebrafish embryos. Although PMAs have been previously isolated from diverse cyanobacteria, they have not previously been associated with relevant toxicity. These compounds seem to be widespread across the different genera of cyanobacteria, and, according to our studies, suggested to be derived from the polyketide biosynthetic pathway which is a common synthetic route for cyanobacterial and other algal toxins. Thus, it can be argued that these metabolites are perhaps important contributors to the toxicity of cyanobacterial blooms. In addition to the PMAs, a set of bioactive glycosidic carotenoids were also isolated because of their inhibition of zebrafish embryonic development. These pigmented organic molecules are found in many photosynthetic organisms, including cyanobacteria, and they have been largely associated with the prevention of photooxidative damage. This is the first indication of these compounds as toxic metabolites and the hypothesized mode of action is via their biotransformation to retinoids, some of which are known to be teratogenic. Additional fractions within all four isolates have been shown to contain other uncharacterized lipophilic toxic metabolites. This apparent repertoire of lipophilic compounds may contribute to the toxicity of these cyanobacterial harmful algal blooms, which were previously attributed primarily to the presence of the known water-soluble toxins.^

Theory development in humanitarian logistics : A framework and three cases

Purpose: There is a need for theory development within the field of humanitarian logistics to understand logistics needs in different stages of a crisis and how to meet these. This paper aims to discuss three dimensions identified in logistics and organization theories and how they relate to three different cases of humanitarian logistics operations - the regional concept of the International Federation of Red Cross Red Crescent Societies, the development and working of the United Nations Joint Logistics Centre and coordination challenges of military logistics in UN mandated peacekeeping operations. The purpose is to build a framework to be used in further studies. Design/methodology/approach: A framework for the study of humanitarian logistics along three dimensions is developed, followed by a discussion of the chosen cases in relation to these dimensions. The framework will be used as basis for the case studies to be undertaken for the purpose of understanding and identification of new questions and needs for other or revised concepts from theory. Findings: The paper shows the relevance of a wide literature to the issues pertinent to humanitarian logistics. There is considerable promise in extant literature on logistics, SCM and coordination, but this needs to be confronted with the particular issues seen in the humanitarian logistics setting to achieve further theory development. Originality/value: The major contribution of the paper lies in its breadth of theoretical perspectives presented and combined in a preliminary theoretical framework. This is applied more specifically in the three case studies described in the paper.

Women-led Community Development Organizations (CDOs) in Miami-Dade County: A Model of Community Development Efforts Impacting the Economic Security of Women

Recent studies on the economic status of women in Miami-Dade County (MDC) reveal an alarming rate of economic insecurity and significant obstacles for women to achieve economic security. Consistent barriers to women’s economic security affect not only the health and wellbeing of women and their families, but also economic prospects for the community. A key study reveals in Miami-Dade County, “Thirty-nine percent of single female-headed families with at least one child are living at or below the federal poverty level” and “over half of working women do not earn adequate income to cover their basic necessities” (Brion 2009, 1). Moreover, conventional measures of poverty do not adequately capture women’s struggles to support themselves and their families, nor do they document the numbers of women seeking basic self-sufficiency. Even though there is lack of accurate data on women in the county, which is a critical problem, there is also a dearth of social science research on existing efforts to enhance women’s economic security in Miami-Dade County. My research contributes to closing the information gap by examining the characteristics and strategies of women-led community development organizations (CDOs) in MDC, working to address women’s economic insecurity. The research is informed by a framework developed by Marilyn Gittell, who pioneered an approach to study women-led CDOs in the United States. On the basis of research in nine U.S. cities, she concluded that women-led groups increased community participation and “by creating community networks and civic action, they represent a model for community development efforts” (Gittell, et al. 2000, 123). My study documents the strategies and networks of women-led CDOs in MDC that prioritize women’s economic security. Their strategies are especially important during these times of economic recession and government reductions in funding towards social services. The focus of the research is women-led CDOs that work to improve social services access, economic opportunity, civic participation and capacity, and women’s rights. Although many women-led CDOs prioritize building social infrastructures that promote change, inequalities in economic and political status for women without economic security remain a challenge (Young 2004). My research supports previous studies by Gittell, et al., finding that women-led CDOs in Miami-Dade County have key characteristics of a model of community development efforts that use networking and collaboration to strengthen their broad, integrated approach. The resulting community partnerships, coupled with participation by constituents in the development process, build a foundation to influence policy decisions for social change. In addition, my findings show that women-led CDOs in Miami-Dade County have a major focus on alleviating poverty and economic insecurity, particularly that of women. Finally, it was found that a majority of the five organizations network transnationally, using lessons learned to inform their work of expanding the agency of their constituents and placing the economic empowerment of women as central in the process of family and community development.

Workaround motivation model (WAMM): an adaptation of the Theory of Interpersonal Behaviour

The study of workarounds (WA) has increased in importance due to their impact on patient safety and efficiency. However, there are no adequate theories to explain the motivation to create and use a workaround in a healthcare sitting. Although theories of technology acceptance help to understand the reasons to accept or reject technology, they fail to explain drivers for alternatives. Also workarounds involve creators and performers that have different motivations. Models such as Theory of Planned Behaviour (TPB) or Theory of Reasoned Action (TRA) can help to explain the role of workaround users, but lack explanation of workaround creators’ dynamics. Our aim is to develop a theoretical foundation to explain workaround motivation behaviour models with norms that relate to sanctions to provide an integrated Workaround Motivation Model; WAMM. The development of WAMM model is explained in this paper based on workaround cases as part of further research to establish the model.

Development of a simplified transmission line model directly in the phase domain

A transmission line digital model is developed direct in the phase and time domains. The successive modal transformations considered in the three-phase representation are simplified and then the proposed model can be easily applied to several operation condition based only on the previous knowing of the line parameters, without a thorough theoretical knowledge of modal analysis. The proposed model is also developed based on lumped elements, providing a complete current and voltage profile at any point of the transmission system. This model makes possible the modeling of non-linear power devices and electromagnetic phenomena along the transmission line using simple electric circuit components, representing a great advantage when compared to several models based on distributed parameters and inverse transforms. In addition, an efficient integration method is proposed to solve the system of differential equations resulted from the line modeling by lumped elements, thereby making possible simulations of transient and steady state using a wide and constant integration step. © 2012 IEEE.

Development of a Bayesian Joint Logistic Model to Better Study the Association between Haplotypes and Disease

In 2011, there will be an estimated 1,596,670 new cancer cases and 571,950 cancer-related deaths in the US. With the ever-increasing applications of cancer genetics in epidemiology, there is great potential to identify genetic risk factors that would help identify individuals with increased genetic susceptibility to cancer, which could be used to develop interventions or targeted therapies that could hopefully reduce cancer risk and mortality. In this dissertation, I propose to develop a new statistical method to evaluate the role of haplotypes in cancer susceptibility and development. This model will be flexible enough to handle not only haplotypes of any size, but also a variety of covariates. I will then apply this method to three cancer-related data sets (Hodgkin Disease, Glioma, and Lung Cancer). I hypothesize that there is substantial improvement in the estimation of association between haplotypes and disease, with the use of a Bayesian mathematical method to infer haplotypes that uses prior information from known genetics sources. Analysis based on haplotypes using information from publically available genetic sources generally show increased odds ratios and smaller p-values in both the Hodgkin, Glioma, and Lung data sets. For instance, the Bayesian Joint Logistic Model (BJLM) inferred haplotype TC had a substantially higher estimated effect size (OR=12.16, 95% CI = 2.47-90.1 vs. 9.24, 95% CI = 1.81-47.2) and more significant p-value (0.00044 vs. 0.008) for Hodgkin Disease compared to a traditional logistic regression approach. Also, the effect sizes of haplotypes modeled with recessive genetic effects were higher (and had more significant p-values) when analyzed with the BJLM. Full genetic models with haplotype information developed with the BJLM resulted in significantly higher discriminatory power and a significantly higher Net Reclassification Index compared to those developed with haplo.stats for lung cancer. Future analysis for this work could be to incorporate the 1000 Genomes project, which offers a larger selection of SNPs can be incorporated into the information from known genetic sources as well. Other future analysis include testing non-binary outcomes, like the levels of biomarkers that are present in lung cancer (NNK), and extending this analysis to full GWAS studies.

Examining the strategy development process through the lens of complex adaptive systems theory

The development of strategy remains a debate for academics and a concern for practitioners. Published research has focused on producing models for strategy development and on studying how strategy is developed in organisations. The Operational Research literature has highlighted the importance of considering complexity within strategic decision making; but little has been done to link strategy development with complexity theories, despite organisations and organisational environments becoming increasingly more complex. We review the dominant streams of strategy development and complexity theories. Our theoretical investigation results in the first conceptual framework which links an established Strategic Operational Research model, the Strategy Development Process model, with complexity via Complex Adaptive Systems theory. We present preliminary findings from the use of this conceptual framework applied to a longitudinal, in-depth case study, to demonstrate the advantages of using this integrated conceptual model. Our research shows that the conceptual model proposed provides rich data and allows for a more holistic examination of the strategy development process. © 2012 Operational Research Society Ltd. All rights reserved.

Development and validation of a risk model for prediction of hazardous alcohol consumption in general practice attendees : the PredictAL study

Background: Little is known about the risk of progression to hazardous alcohol use in people currently drinking at safe limits. We aimed to develop a prediction model (predictAL) for the development of hazardous drinking in safe drinkers. Methods: A prospective cohort study of adult general practice attendees in six European countries and Chile followed up over 6 months. We recruited 10,045 attendees between April 2003 to February 2005. 6193 European and 2462 Chilean attendees recorded AUDIT scores below 8 in men and 5 in women at recruitment and were used in modelling risk. 38 risk factors were measured to construct a risk model for the development of hazardous drinking using stepwise logistic regression. The model was corrected for over fitting and tested in an external population. The main outcome was hazardous drinking defined by an AUDIT score >= 8 in men and >= 5 in women. Results: 69.0% of attendees were recruited, of whom 89.5% participated again after six months. The risk factors in the final predictAL model were sex, age, country, baseline AUDIT score, panic syndrome and lifetime alcohol problem. The predictAL model's average c-index across all six European countries was 0.839 (95% CI 0.805, 0.873). The Hedge's g effect size for the difference in log odds of predicted probability between safe drinkers in Europe who subsequently developed hazardous alcohol use and those who did not was 1.38 (95% CI 1.25, 1.51). External validation of the algorithm in Chilean safe drinkers resulted in a c-index of 0.781 (95% CI 0.717, 0.846) and Hedge's g of 0.68 (95% CI 0.57, 0.78). Conclusions: The predictAL risk model for development of hazardous consumption in safe drinkers compares favourably with risk algorithms for disorders in other medical settings and can be a useful first step in prevention of alcohol misuse.

Genetic Programming meets Model-Driven Development

Genetic programming is known to provide good solutions for many problems like the evolution of network protocols and distributed algorithms. In such cases it is most likely a hardwired module of a design framework that assists the engineer to optimize specific aspects of the system to be developed. It provides its results in a fixed format through an internal interface. In this paper we show how the utility of genetic programming can be increased remarkably by isolating it as a component and integrating it into the model-driven software development process. Our genetic programming framework produces XMI-encoded UML models that can easily be loaded into widely available modeling tools which in turn posses code generation as well as additional analysis and test capabilities. We use the evolution of a distributed election algorithm as an example to illustrate how genetic programming can be combined with model-driven development. This example clearly illustrates the advantages of our approach – the generation of source code in different programming languages.

O modelo de integração econômico e social nas cooperativas agropecuárias do Paraná

Analisar o modelo de integração das cooperativas de produtores agropecuários no estado do Paraná foi o propósito deste estudo. Foram estudadas as características, os fatores que dificultam e as ações que facilitam a integração entre cooperados e suas cooperativas e destas entre si. As cooperativas têm características distintas dos outros atores do mercado, nos seus objetivos, na forma de gestão, na formação do capital e na sua identificação com a comunidade onde atuam. O desenvolvimento das cooperativas agropecuárias no Paraná é resultante dos Projetos Integrados de Cooperativismo (PICs), implementados a partir de 1972. O modelo previa cooperativas singulares, cada qual com sua área de ação, com o objetivo de proporcionar assistência técnica, creditícia e apoio logístico aos produtores associados, e centrais cooperativas, por região, para industrialização e comercialização da produção. Os resultados proporcionados pelos projetos integrados são evidentes, pois, quase 60% da produção agropecuária atual provém das cooperativas em todo o estado. Porém, ao longo do tempo, em razão do crescimento desigual das cooperativas, surgiram disputas por área de ação entre cooperativas e conflitos de interesses em relação às centrais que comprometeram o modelo de integração idealizado. Pesquisa de campo realizada para este estudo, mostra que 75% das pessoas que compõem o público interno das cooperativas – cooperados, dirigentes e funcionários, concordam que há concorrência entre cooperativas no Paraná. Trata-se de tema polêmico porém relevante para o desenvolvimento do cooperativismo paranaense, que concorre com grandes conglomerados econômicos nacionais e internacionais. A superação do dilema da integração constitui importante desafio às organizações cooperativas. Esta dissertação utiliza metodologia de análise de conteúdo, descrita por VERGARA (2007, p. 15) para extrair da bibliografia e da pesquisa de campo os resultados almejados. Com base na Teoria da Delimitação dos Sistemas Sociais, concebida por Guerreiro Ramos (1981), conclui-se que as cooperativas agropecuárias paranaenses são organizações de interesse econômico que apresentam características isonômicas de gestão. A maioria dos fatores que dificultam a integração nas cooperativas é originada de atitudes internas de cooperados e dirigentes, tais como: individualismo, falta de conhecimento sobre as cooperativas e falta de interesse em participar da cooperativa. Entre as ações que poderiam contribuir para a integração foi citada a necessidade de se constituir novo modelo de integração, apoiado por programas de educação, comunicação e capitalização em volumes compatíveis com as demandas dos projetos das cooperativas, tanto aos cooperados quanto para projetos integrados entre cooperativas.