Role of GPS2 in the regulation of adipocyte fate and function : a multi-omics approach

The escalating prevalence of obesity and its association with comorbidities like insulin resistance and type 2 diabetes have raised the interest in adipose tissue biology and its therapeutic potential. Adipose tissue remodeling during the development of obesity is an important regulator of systemic metabolic homeostasis, and dysfunctional adipose tissue is linked to the risk of developing type 2 diabetes. Adipocyte differentiation and function are orchestrated by a complex network of transcription factors and coregulators that transduce regulatory signals into epigenome alterations and transcriptional responses. While the role of transcription factors involved in adipogenic pathways is well established, the role of their associated coregulators remains poorly understood. Of particular interest is G protein pathway suppressor 2 (GPS2), a core subunit of the HDAC3 corepressor complex, which is downregulated in humans with obesity and implicated in regulating metabolic and antiinflammatory pathways in various tissues. The overall aim of this thesis was to identify hitherto unknown functions of GPS2 in the adipose tissue, with a particular emphasis on mechanisms underlying adipocyte dysfunction in the context of obesity and type 2 diabetes. In Paper I, by generating a unique loss-of-function model using human multipotent adiposederived stem cells, we showed that loss of GPS2 triggers the commitment of fibroblast-like progenitors towards the adipogenic lineage and induces hypertrophy of mature adipocytes associated with a deep remodeling of the adipocyte lipidome. Furthermore, we demonstrated that adipocyte hypertrophy was likely the consequence of the increased expression of ATPbinding cassette subfamily G member 1 (ABCG1) that mediates sphingomyelin efflux from adipocytes and modulates the activity of lipoprotein lipase (LPL). We validated the cellderived findings by gene expression analysis of an obese cohort, where GPS2 is downregulated in diabetic patients and negatively correlated with the expression of ABCG1. In Paper II, by characterizing adipocyte-specific Gps2 knockout mice, we discovered a hitherto unknown function of GPS2 in the induction of adipocyte hypertrophy, inflammation and mitochondrial dysfunction. The knockout phenotype was driven by over-activation of the transcription factor HIF1A that orchestrates an inadequate white adipose tissue remodeling and disrupts mitochondrial activity. The validation of the experimental mouse data in a human cohort of non-obese and obese individuals with or without diagnosed type 2 diabetes showed a negative correlation between the expression of GPS2 and HIF1A, adipocyte hypertrophy and insulin resistance. In Paper III, we found that the expression of GPS2 in the white adipose tissue of humans was strongly correlated with the insulin secretion rate. The causality of this relationship was confirmed using adipocyte-specific Gps2 knockout mice, in which adipocyte dysfunction caused by the loss of GPS2 triggered the secretion of factors that provoked pancreatic islet inflammation and impaired beta cell function. In conclusion, the research within this thesis revealed novel insights into the multifaceted regulatory roles of GPS2 in altering the epigenome and the transcriptome linked to adipose tissue metabolism and inflammation. These discoveries increase our understanding of the mechanisms underlying the development of obesity and its link with type 2 diabetes, and they may help to define novel potential targets for treating these metabolic diseases

Identifying New Approaches for U.S. Drug Policy using Ownership, Location, and Internalization Factors

Dunning’s Eclectic Paradigm is used to assess the effectiveness and impact of U.S. drug prohibition policy on economic growth and political stability in Latin American countries as well as the decision making of Latin American Transnational Criminal Enterprises (TCE) in the cocaine-coca market. Results showed U.S. drug prohibition policy reduces the on-site supply but does not significantly reduce the transportation of cocaine and coca. U.S. drug prohibition policy also generated political instability for the region and revealed policy externalities that facilitated TCE expansion. Tougher U.S. drug prohibition policy advances TCE by amplifying the impact that unemployment and local wages have on increases in cocaine-coca production, and by limiting the impact of control of corruption and economic freedom on coca eradication. Our results signal that a site-specific approach accompanied with policies that improve the farmers’ economic freedom, such as land formalization rights, and policies that lower unemployment rate facilitate effective U.S. drug prohibition policy

Identifying New Approaches for U.S. Drug Policy using Ownership, Location, and Internalization Factors

Abstract Dunning’s Eclectic Paradigm is used to assess the effectiveness and impact of U.S. drug prohibition policy on economic growth and political stability in Latin American countries as well as the decision making of Latin American Transnational Criminal Enterprises (TCE) in the cocaine-coca market. Results showed U.S. drug prohibition policy reduces the on-site supply but does not significantly reduce the transportation of cocaine and coca. U.S. drug prohibition policy also generated political instability for the region, and revealed policy externalities that facilitated TCE expansion. Tougher U.S. drug prohibition policy advances TCE by amplifying the impact that unemployment and local wages have on increases in cocaine-coca production, and by limiting the impact of control of corruption and economic freedom on coca eradication. Our results signal that a site-specific approach accompanied with policies that improve the farmers’ economic freedom, such as land formalization rights, and policies that lower unemployment rate facilitate effective U.S. drug prohibition policy

How can Big Data contribute to improve the financial performance of companies?

Objective: We propose a comprehensive methodology that combines a set of Big Data Analytics tools (BDA) with prospective analysis, risk analysis and strategic analysis with the aim to improve the firm’s financial performance measured through Key Performance Indicators (KPIs).Methodology: The methodology consists of five (5) stages: financial modeling, prospective analysis, risk analysis that includes BDA, strategic analysis and monitoringResults: This methodology allows directing the BDA towards the characterization of the critical variables that create value for the company, designing contingent strategies and evaluating their impact on the selected financial indicators (KPI) all this in a multidimensional wayRecommendations: We require constant monitoring to generate different forms of innovation and flexibility in the company and improve its financial performance.Limitations: The success of the methodology depends on the company's ability to improve, adapt, adjust, or innovate to gain, sustain, or reconfigure a competitive advantage. This skill is called process-oriented dynamic capabilities (PODC)Originality: The proposed methodology is comprehensive since it allows the inclusion of various areas of the company in order to improve its financial performance represented by the KPIs. Furthermore, the analysis can be performed for specific areas and business units.Conclusions: The proposed methodology promotes innovation and flexibility that will improve the financial performance of the company as long as there is a good fit among Big Data activities, the organizational structure, the commitment of senior management and support for the development of PODC.¿Cómo puede contribuir el Big Data a mejorar el rendimiento financiero de las empresas?Objetivo: Proponemos una metodología integral que combina un conjunto de herramientas del análisis de Big Data (BDA) con el análisis prospectivo, análisis de riesgo y análisis estratégico con la finalidad de mejorar el desempeño financiero de la empresa medido a través de Key Performance Indicators (KPI)}Metodología: La metodología está compuesta por cinco (5) etapas: modelación financiera, prospectiva, análisis de riesgo que incluye BDA, análisis estratégico y monitoreoResultados: Esta metodología permite dirigir el BDA hacia la caracterización de las variables críticas que crean valor para la empresa, diseñar estrategias contingentes y evaluar su impacto en los indicadores financieros seleccionados (KPI) todo esto de forma multidimensional.Recomendación: Se requiere un monitoreo constante del modelo para generar diferentes formas de innovación y flexibilidad en la empresa y mejorar su desempeño financiero.Limitación: El éxito de la metodología depende de la habilidad de la empresa para mejorar, adaptarse, ajustarse o innovar para ganar, sostener o reconfigurar una ventaja competitiva. A esta habilidad se le denomina capacidades dinámicas orientadas a procesos (PODC)Originalidad: La metodología propuesta es integral ya que permite la inclusión de diversas áreas de la empresa con el objetivo de mejorar su desempeño financiero representado por los KPIs. Asimismo, el análisis se puede realizar para áreas específicas y unidades de negocio.Conclusión: La metodología propuesta promueve la innovación y la flexibilidad que mejorarán el desempeño financiero de la compañía siempre que exista un buen ajuste entre las actividades de Big Data, la estructura organizacional, el compromiso de la alta gerencia y el apoyo para el desarrollo de PODC

Bold leadership is needed for transforming health care.

Health care in the United States is going through significant changes and is at the forefront of the political landscape. While the health care debate rages on, leaders need to forge ahead and continue to work towards population-based health care and investing in their communities in a fiscally conscious way. Many innovations are happening but more needs to be done, especially in upstream services improving the health of the community. Research shows that investing in social care services and community-based investments results in lower health care expenditures and better health outcomes. Efforts should be placed on exploring a blended medical/social model of care while considering blended funding sources wherein the community needs to be active participants in this explorative process