Using K5 Myc transgenic mice to delineate *Myc's apoptotic and tumorigenic pathways

The c-myc oncogene has the unusual ability to induce proliferation and apoptosis. Transgenic mice have been generated in which the expression of Myc is under the control of an epithelial-specific keratin 5 (K5) promoter. These mice have increased levels of proliferation and p53-dependent apoptosis, and are predisposed to developing spontaneous tumors in epithelial tissues. In this study, various knockout mice were bred to K5 Myc transgenic mice to identify factors involved in the aberrant apoptosis, hyperproliferation, and spontaneous tumorigenesis present in these mice. Consistent with in vitro studies, Myc-induced, p53-dependent apoptosis in transgenic epidermis was found to be partially dependent on p19ARF, a p53 regulator that inhibits mdm2. Additionally, the rate of tumorigenesis was increased when p19ARF was absent in Myc transgenic mice. Consistent with previous reports that some E2F family members may function as tumor suppressors, inactivation of either E2f1 or E2f2 was found to accelerate tumor development in the K5 Myc transgenic mice. Acceleration of tumorigenesis in the absence of E2F1 occurred despite the fact that apoptotic levels were increased in transgenic tissue and tumors null for E2f1 , whereas hyperproliferation was unaffected. In contrast, inactivation of E2f2 was found to increase hyperproliferation in the K5 Myc transgenic mice, while having no effect on apoptosis. The lack of E2f1 in the Myc transgenic mice increased the expression of several p53 transcription target genes, which may explain the increased apoptosis in these mice. In transgenic epidermis, p53 is phosphorylated at serine 18, a site of phosphorylation by ATM. Inactivation of ATM in K5 Myc transgenic mice impaired Myc-induced apoptosis, identifying ATM as having an important role in Myc-induced apoptosis. Moreover, the absence of ATM accelerates tumorigenesis in K5-expressing tissues. However, p53 accumulation and phosphorylation at serine 18 induced by Myc occurs independent of ATM. Therefore, another activity of ATM appears to be important for Myc-induced apoptosis. These findings show that acceleration of tumorigenesis in K5 Myc transgenic mice, as in the case of p53, p19ARF, E2F1, E2F2, and ATM absence, does not necessarily correlate with suppression of Myc-induced apoptosis, as seen only when p53, p19ARF or ATM was absent. ^

Molecular mechanism of the relaxin signaling pathways: Activation of cAMP, PI3K, and PKCzeta

Relaxin is a polypeptide hormone that has diverse effects on reproductive and non-reproductive tissues. Relaxin activates the G-protein coupled receptors, LGR7 and LRG8. Early studies described increased cAMP and protein kinase A activity upon relaxin treatment, but cAMP accumulation alone could not account for all of the relaxin-mediated effects. We utilized the human monocyte cell line THP-1 to study the mechanism of relaxin-stimulated CAMP production. ^ Relaxin treatment in THP-1 cells produces a biphasic time course in cAMP accumulation, where the first peak appears as early as 1–2 minutes with a second peak at 10–20 minutes. Selective inhibitors for phosphoinositide 3-kinase (P13K), such as wortmannin and LY294002, show a dose-dependent inhibition of relaxin-stimulated cAMP accumulation, specific for the second peak of the relaxin time course. Neither the effects of relaxin nor the inhibition of relaxin by LY294002 is mediated by the activity of phosphodiesterases. Furthermore, LY294002 blocks upregulation of vascular endothelial growth factor transcript levels by relaxin. ^ To further delineate relaxin signaling pathways, we searched for downstream targets of PI3K that could activate adenylyl cyclase (AC). Protein kinase C ζ (PKCζ) was a prime candidate because it activates types II and V AC. Chelerythrine chloride (a general PKC inhibitor) inhibits relaxin-induced cAMP production to the same degree as LY294002 (∼40%). Relaxin stimulates PKCζ translocation to the plasma membrane in THP-1, MCF-7, PHM1-31, and MMC cells, as shown by immunocytochemistry. PKCζ translocation is P13K-dependent and independent of cAMP production. Antisense PKCζ oligodeoxynucleotides (PKCζ-ODNs) deplete both PKCζ transcript and protein levels in THP-1 cells. PKCζ-ODNs abolish relaxin-mediated PKCζ translocation and inhibit relaxin stimulation of cAMP by 40%, as compared to mock and random ODN controls. Treatment with LY294002 in the presence of PKCζ-ODNs results in little further inhibition. Taken together, we present a novel role for PI3K and PKCζ in relaxin stimulation of cAMP and provide the first example of the PKCζ regulation of AC in an endogenous system. Furthermore, we have identified higher order complexes of AC isoforms and PKA anchoring proteins in attempts to explain the differential coupling of relaxin to cAMP and PI3K-signaling pathways in various cell types. ^

Ocean acidification weakens the immune response of blood clam through hampering the NF-kappa beta and toll-like receptor pathways

The impact of pCO2 driven ocean acidification on marine bivalve immunity remains poorly understood. To date, this impact has only been investigated in a few bivalve species and the underlying molecular mechanism remains unknown. In the present study, the effects of the realistic future ocean pCO2 levels (pH at 8.1, 7.8, and 7.4) on the total number of haemocyte cells (THC), phagocytosis status, blood cell types composition, and expression levels of twelve genes from the NF-kappa beta signaling and toll-like receptor pathways of a typical bottom burrowing bivalve, blood clam (Tegillarca granosa), were investigated. The results obtained showed that while both THC number and phagocytosis frequency were significantly reduced, the percentage of red and basophil granulocytes were significantly decreased and increased, respectively, upon exposure to elevated pCO2. In addition, exposure to pCO2 acidified seawater generally led to a significant down-regulation in the inducer and key response genes of NF-kappa beta signaling and toll-like receptor pathways. The results of the present study revealed that ocean acidification may hamper immune responses of the bivalve T. granosa which subsequently render individuals more susceptible to pathogens attacks such as those from virus and bacteria.

Reaction pathways in the solid state synthesis of multiferroic BiFeO 3

The obtaining of multiferroicBiFeO3 as a pure single-phase product is particularly complex since the formation of secondary phases seems to be unavoidable. The process by which these secondary impurities are formed is studied by analyzing the diffusion and solidstate reactivity of the Bi2O3–Fe2O3 system. Experimental evidence is reported which indicates that the progressive diffusion of Bi3+ ions into the Fe2O3 particles governs the solidstatesynthesis of the perovskite BiFeO3 phase. However a competition is established between the diffusion process which tends to complete the formation of BiFeO3, and the crystallization of stable Bi2Fe4O9 mullite crystals, which tend to block that formation reaction.

Sources and pathways of trace elements in urban environments: A multielemental qualitative approach

A geochemical model of an urban environment is presented in which multielemental tracers are used to characterise the circulation of trace elements in particulate matter_atmospheric aerosol, street dust and urban soil, within a city.

Reaction pathways in the solid state synthesis of multiferroic BiFeO3

The obtaining of multiferroic BiFeO3 as a pure single-phase product is particularly complex since the formation of secondary phases seems to be unavoidable. The process by which these secondary impurities are formed is studied by analyzing the diffusion and solid state reactivity of the Bi2O3?Fe2O3 system. Experimental evidence is reported which indicates that the progressive diffusion of Bi3+ ions into the Fe2O3 particles governs the solid state synthesis of the perovskite BiFeO3 phase. However a competition is established between the diffusion process which tends to complete the formation of BiFeO3, and the crystallization of stable Bi2Fe4O9 mullite crystals, which tend to block that formation reaction.

Teamwork, motivational profiles and academic performance in computer science engineering

The present work is aimed at discussing several issues related to the teamwork generic competence, motivational profiles and academic performance. In particular, we study the improvement of teamwork attitude, the predominant types of motivation in different contexts and some correlations among these three components of the learning process. The above-mentioned aspects are of great importance. Currently, the professional profile of engineers has a strong teamwork component and the motivational profile of students determines both their tendencies when they come to work as part of a team, as well as their performance at work. Taking these issues into consideration, we suggest four hypotheses: (H1) students improve their teamwork capacity through specific training and carrying out of a set of activities integrated into an active learning process; (H2) students with higher mastery motivation have a better attitude towards teamwork; (H3) students with different types of motivations reach different levels of academic performance; and (H4) students show different motivation profiles in different circumstances: type of courses, teaching methodologies, different times of the learning process. This study was carried out with Computer Science Engineering students from two Spanish universities. The first results point to an improvement in teamwork competence of students if they have previously received specific training in facets of that competence. Other results indicate that there is a correlation between the motivational profiles of students and their perception of teamwork competence. Finally, results point to a clear relationship between some kind of motivation and academic performance. In particular, four kinds of motivation are analyzed and students are classified into two groups according to them. After analyzing several marks obtained in compulsory courses, we perceive that those students that show higher motivation for avoiding failure obtain, in general, worse academic performance.

Pathways towards the integration of periurban agrarian ecosystems into the spatial planning system

The potential of periurban agrarian ecosystems is recognized as one of the cornerstones for improving urban sustainability; however, this potential has been disregarded in spatial planning and decision making. The main goal of the PAEc-SP project was to assess the feasibility of integrating periurban agricultural areas into spatial planning by developing a viable ecosystem services-based methodology

Business, development and inclusive supply chains. Exploring pathways for the sustainable incorporation of the poor as suppliers in agrifood supply chains

El panorama global está cambiando, y esto influye sobre la forma en la que entendemos y tratamos de alcanzar un desarrollo humano sostenible. El crecimiento de la población conlleva una mayor presión sobre los recursos, pero también supone una mayor cantidad de mano de obra y de talento; la concentración en áreas urbanas está cambiando las dinámicas sociales y desafiando los canales de comercialización tradicionales, pero también genera nuevos mercados y fomenta la innovación; los cambios en la economía global están reduciendo los tradicionales desequilibrios de poder entre los países occidentales y el resto del mundo; y las crecientes interconexiones crean nuevos riesgos pero también oportunidades para lanzar iniciativas de alcance global. Todas estas tendencias nos están obligando a repensar qué es el desarrollo humano y de qué manera deberíamos afrontar el reto de la pobreza. Es comúnmente aceptado que la globalización implica interdependencia y que, para conseguir un desarrollo humano sostenible, la colaboración entre actores de distintos ámbitos es necesaria. Se observa una creciente convergencia de temas, intereses y soluciones en torno al desarrollo sostenible, incluso en diferentes países y sectores, lo que está facilitando la colaboración estratégica entre empresas, gobiernos y sociedad civil. Existen pocas duda a día de hoy sobre el papel fundamental que las empresas deben desempeñar en la transición mundial hacia la sostenibilidad ambiental y la erradicación de la pobreza. Las empresas están evolucionando desde un enfoque tradicional centrado en la maximización de beneficios económicos hacia un enfoque holístico que integra la sostenibilidad y la responsabilidad social como parte del núcleo de negocio de las compañías. En el ámbito medioambiental, muchas empresas ya han comenzado a actuar y tratan de reducir sus emisiones, sus desechos y su consumo de energía. Sin embargo la contribución de las empresas a la reducción de la pobreza no está tan clara. Actualmente en torno a 1,2 miles de millones de personas viven en situación de extrema pobreza. La mayoría de estas personas aún vive en zonas rurales donde la mayor parte de la población activa trabaja en el sector agrícola. Por lo tanto, mejorar las oportunidades y reducir los riesgos de los productores más vulnerables en el sector de la agricultura puede ser un motor de desarrollo rural y reducción de la pobreza, especialmente en países de bajo nivel de desarrollo cuyas economías están fundamentalmente basadas en la agricultura. Algunas empresas comienzan a incluir a los pobres en sus operaciones como consumidores, proveedores y emprendedores. Esta tesis se centra en las potenciales oportunidades relacionadas con la incorporación sostenible de los pobres como proveedores de productos y/o de mano de obra. La colaboración entre empresas y productores vulnerables de países en desarrollo es un tema relativamente nuevo y todavía poco estudiado. La pregunta que guía esta tesis es: “¿Cómo pueden las empresas facilitar la inclusión sostenible en cadenas de suministro de productores vulnerables de los países menos desarrollados?”. Para responder a la pregunta anterior, la autora ha aplicado una metodología de casos de estudio. Esta metodología se considera apropiada porque la investigación sobre cadenas de suministro inclusivas es todavía escasa y porque es necesario entender en profundidad un fenómeno de la vida real, y para ello es fundamental conocer su contexto. En primer lugar, se realiza una revisión de literatura para identificar las proposiciones y los constructos teóricos que guiarán la posterior recogida de datos. La revisión de literatura se divide en dos partes: una más general que explora la dimensión social de la sostenibilidad en cadenas de suministro, y una más específica que se centra en la incorporación de los pobres como proveedores en cadenas de suministro. A lo largo de la última década, ha habido un crecimiento exponencial de los estudios académicos sobre la sostenibilidad de las cadenas de suministro, pero la mayoría de los esfuerzos se han dirigido hacia la dimensión medioambiental de la sostenibilidad. Por lo tanto la revisión de literatura, que se presenta en la Sección 3.1 (página 35) y que profundiza en la sostenibilidad social de las cadenas de suministro, puede considerarse una contribución en sí misma. Esta revisión de literatura revela que la investigación sobre aspectos sociales en cadenas de suministro está cobrando impulso en distintas áreas de conocimiento, principalmente en los ámbitos de investigación sobre “gestión de cadenas de suministro”, “responsabilidad social corporativa” y “estudios del desarrollo”. La investigación existente sobre sostenibilidad social de cadenas de suministro se centra en tres temas: aclarar la definición de sostenibilidad social; analizar la implementación de estrategias de sostenibilidad social en cadenas de suministro; y estudiar el apoyo de las em presas líderes a proveedores vulnerables para facilitar su transición hacia la sostenibilidad. Un marco conceptual que resume los principales hallazgos de esta primera parte de la revisión de literatura es planteado en la Figura 7 (página 48). No obstante, en el área de investigación que está emergiendo en torno a la sostenibilidad social de las cadenas de suministro, los estudios relacionados con la reducción de la pobreza son aún escasos. Además se aprecia una falta de contribuciones desde y sobre los países menos desarrollados, así como una clara tendencia a reflejar la visión de las empresas líderes de las cadenas de suministro, olvidando la perspectiva de los proveedores. La segunda parte de la revisión de literatura presentada en la Sección 3.2 (página 51) profundiza en tres líneas de investigación que exploran, desde distintas perspectivas, la inclusión de los pobres en cadenas de suministro. Estas líneas son “Global Value Chains” (GVC), “Base of the Pyramid” (BoP) y “Sustainable Supply Chain Management” (SSCM). La investigación en GVC analiza las cadenas de suministro desde la perspectiva de la globalización económica y el comercio internacional, poniendo especial énfasis en las implicaciones para los países en desarrollo y las comunidades vulnerables. GVC caracteriza las cadenas de suministro según la forma en la que son gobernadas, las oportunidades de mejora que existen para los productores que forman parte de la cadena y el grado de inclusión o exclusión de las comunidades más pobres y vulnerables. La investigación en BoP explora las relaciones comerciales entre empresas y comunidades pobres. La premisa fundamental del concepto BoP es la posibilidad de combinar la generación de beneficios con la reducción de la pobreza. La propuesta original es que mediante la venta de productos y servicios a las comunidades pobres de países en desarrollo, la pobreza puede ser reducida al tiempo que las empresas incrementan sus beneficios, especialmente las grandes empresas multinacionales. Esta idea ha ido evolucionando y, a día de hoy, los investigadores BoP consideran la incorporación de los pobres no sólo como consumidores sino también como empleados, proveedores y co-creadores. La investigación en SSCM ha estado fundamentalmente orientada al estudio de la dimensión medioambiental de la sostenibilidad de cadenas de suministro. Sin embargo, la creciente externalización de la producción a países en desarrollo y las demandas de los grupos de interés para que las empresas aborden todos los aspectos de la sostenibilidad han llevado a los académicos de SSCM a reconocer la importancia de integrar asuntos relacionados con la reducción de la pobreza en sus investigaciones. Algunos estudios comienzan a apuntar los principales retos a los que se enfrentan las empresas para colaborar con productores vulnerables en sus cadenas de suministro. Estos retos son: falta de comunicación, altos costes de transacción y el incremento de la complejidad de las operaciones. Las contribuciones de estas tres líneas de investigación son complementarias para el estudio de las cadenas de suministro inclusivas. Sin embargo, raramente han sido consideradas conjuntamente, ya que pertenecen a ámbitos de conocimiento distintos. Esta tesis integra las aportaciones de GVC, BoP y SSCM en un marco conceptual para la creación y gestión de cadenas de suministro inclusivas. Este marco conceptual para cadenas de suministro inclusivas queda representado en la Figura 9 (página 68). El marco conceptual refleja las motivaciones que llevan a las empresas a colaborar con productores vulnerables, los retos a los que se enfrentan al hacerlo, y los caminos o estrategias que están siguiendo para construir y operar cadenas de suministro inclusivas de manera que sean beneficiosas tanto para la empresa como para los productores vulnerables. A fin de validar y refinar el marco conceptual propuesto, tres casos de estudio se llevan a cabo. Las cadenas de suministro analizadas por los casos de estudio pertenecen al sector agrícola y sus principales proveedores se encuentran en países de África subsahariana. Múltiples métodos de recolección de datos y triangulación son utilizados para mejorar la fiabilidad de los datos. La autora desarrolló trabajos de campo en Senegal, Etiopía y Tanzania. Estos viajes permitieron enriquecer el proceso de recogida de información mediante entrevistas semiestructuradas y conversaciones informales con los principales actores de la cadena de suministro y mediante la observación directa de los procesos y las interacciones entre productores vulnerables y empresas. El Caso de estudio A (Sección 5.1 en página 96) es un caso de estudio único. Analiza la cadena de suministro local de verduras en Senegal. La organización focal es Manobi, una empresa senegalesa que provee servicios de bajo coste a emprendedores locales del sector agrícola. El Caso de estudio A proporciona un interesante análisis del funcionamiento de una cadena de suministro local en un país en desarrollo y muestra como la provisión de servicios profesionales puede mejorar el desempeño de productores vulnerables. El Caso de estudio B (Sección 5.2 en página 122) es un caso de estudio único. Analiza la cadena de suministro global de flor cortada con origen en Etiopía. La organización focal es EHPEA, la Asociación Etíope de Productores y Exportadores Hortícolas, cuya misión es promover y salvaguardar la posición competitiva del sector agrícola etíope en el mercado global. El Caso de estudio B ayuda a comprender mejor la perspectiva de los proveedores respecto a los requerimiento de sostenibilidad del mercado global. También muestra cómo la inclusión de los productores en el proceso de desarrollo de un estándar privado facilita su implementación posterior. El Caso de estudio C (Sección 5.3 en página 143) es un caso de estudio múltiple. Analiza la cadena de suministro global de café especial con origen en Tanzania. Las organizaciones focales son comerciantes que conectan de manera directa a pequeños agricultores de café en países en desarrollo con empresas tostadoras de café en países desarrollados. El Caso de estudio C muestra cómo un pequeño agricultor puede proveer un producto “premium” al mercado global, y participar en un segmento diferenciado del mercado a través de una cadena de suministro transparente y eficiente. Las aportaciones empíricas de los casos de estudio ayudan a validar y mejorar el marco conceptual sobre cadenas de suministro inclusivas (ver discusión en el Capítulo 6 en página 170). El resultado es la propuesta de una nueva versión del marco conceptual representado en la Figura 40 (página 195). Los casos de estudio también proporcionan interesantes aportaciones en relación a la gestión de cadenas de suministro inclusivas y muestran las perspectivas de distintos actores implicados. Esta tesis arroja luz sobre el papel de las empresas en la creación y la gestión de cadenas de suministro inclusivas llevando a cabo una revisión de literatura multidisciplinar y analizando tres casos de estudio en países africanos. Como resultado, esta tesis presenta una serie de contribuciones empíricas y teóricas al ámbito de investigación emergente en torno a las cadenas de suministro inclusivas (Capítulo 7). Esta tesis también pretende ser útil a profesionales que deseen facilitar la incorporación de los pobres como proveedores en condiciones justas y beneficiosas. ABSTRACT The global outlook is changing, and this is influencing the way we understand and try to achieve sustainable human development. Population growth entails increasing pressure over resources, but it also provides greater workforce and talent; concentration in urban areas is changing social dynamics and challenging traditional marketing channels, but also creating news markets and driving innovation; the global economy shift is rebalancing the traditional power imbalance between Western countries and the rest of the world, making new opportunities to arise; and interconnections and global interdependence create new risks but also opportunities for launching initiatives with a global reach. All these trends are impelling us to rethink what development is and in which way poverty alleviation should be approached. It is generally agreed that globalization implies interdependence and, in order to achieve sustainable human development, collaboration of all actors is needed. A convergence of issues, interests and solutions related to sustainable development is being observed across countries and sectors, encouraging strategic collaboration among companies, governments and civil society. There is little doubt nowadays about the crucial role of the private sector in the world’s path towards environmental sustainability and poverty alleviation. Businesses are evolving from a “business as usual” stance to a more sustainable and responsible approach. In the environmental arena, many companies have already “walk the talk”, implementing environmental management systems and trying to reduce emissions and energy consumption. However, regarding poverty alleviation, their contribution is less clear. There are around 1.2 billion people living in extreme poverty. Most of this people still live in rural areas where the agricultural sector employs a big part of the active population. Therefore, improving opportunities and reducing risks for vulnerable producers in the agri-food sector can be a primary engine of rural development and poverty alleviation, particularly in the poor, agriculture-based economies of least developed countries. Some companies are beginning to include the poor into their operations as consumers, suppliers and entrepreneurs. This thesis focuses specifically on the potential opportunities related to the sustainable incorporation of the poor as suppliers of products and/or labor. Business collaboration with vulnerable producers in developing countries is a relatively new trend and it is still understudied. The overall question guiding this thesis is: “How can businesses facilitate the sustainable inclusion of vulnerable producers from least developed countries into supply chains?”. In order to answer the research question, the author has applied a case study research strategy. This methodology is considered appropriate because research about inclusive supply chains is still at an early stage, and because there is a need to understand a real-life phenomenon in depth, but such understanding encompasses important contextual conditions. First, a literature review is conducted, in order to identify the research propositions and theoretical constructs that will guide the data collection. The literature review is divided in two parts: a more general one that explores the social dimension of sustainability of supply chains, and a more specific one that focuses on the incorporation of the poor as suppliers in supply chains. During the last decade, there has been an exponential growth of studies in the field of supply chain sustainability, but research efforts have traditionally been directed towards the analysis of the environmental dimension. Therefore, the literature review presented in Section 3.1 (page 35) that delves into social sustainability of supply chains can be considered a contribution in itself. This literature review reveals that the investigation of social issues in supply chains is gaining momentum and comes from different academic disciplines, namely Supply Chain Management, Corporate Social Responsibility and Development Studies. Existing research about social sustainability of supply chains focuses on three issues: clarify the definition of social sustainability; analyze the implementation of social sustainability strategies in supply chains; and study lead companies’ support to vulnerable suppliers in their transition towards sustainability. A conceptual framework that outlines the main findings that emerge from this first part of literature review is proposed in Figure 7 (page 48). Nevertheless, in this nascent field of social sustainability of supply chains, studies related to poverty alleviation are still scarce. Moreover, a lack of contributions from and about least developed countries has been observed, as well as a tendency to reflect on the lead firms’ standpoint, neglecting the suppliers’ perspective. The second part of the literature review (Section 3.2 in page 51) delves into three research streams that are exploring the inclusion of the poor into supply chains from different viewpoints. These research streams are Global Value Chains (GVC), Base of the Pyramid (BoP) and Sustainable Supply Chain Management (SSCM). GVC research discusses the dynamics of economic globalization and international trade, putting special emphasis in the implications for developing countries and vulnerable communities. GVC characterizes supply chains by the way they are governed, the upgrading opportunities that exist for producers in the chain and the degree of inclusion or exclusion of impoverished communities. BoP research explores trading relationships between businesses and impoverished communities. The core premise of the BoP concept is the possibility to combine profits with poverty alleviation. The original BoP proposition is that by marketing innovative products and services to poor communities in developing countries, poverty would be reduced and companies would increase their benefits, especially multinational companies. This idea has evolved to consider the incorporation of the poor to business activities not only as consumers, but also as employees, entrepreneurs and co-creators. The SSCM school of thought has mainly focused on studying the environmental dimension of supply chain sustainability, neglecting the consideration of the social perspective. However, in recent years, increasing outsourcing of production to developing countries and stakeholders’ demands for a more holistic approach to business sustainability have led SSCM scholars to acknowledge the importance of integrating poverty concerns in this field’s research agenda. Some SSCM studies identify the main operational challenges for companies which engage with vulnerable suppliers in their supply chains: missing communication, higher transactional and operational costs and increased complexity. Contributions from these three research streams are complementary for the study of inclusive supply chains. However, they have been rarely considered together, since they belong to different research areas. This thesis seeks to play a dovetailing role in this scenario by proposing a conceptual framework for creating and operating inclusive supply chains that builds on contributions from GVC, SSCM and BoP research. This framework for inclusive supply chains is depicted in Figure 9 (page 68), and explains the motivations that drive businesses to collaborate with vulnerable suppliers, the chal lenges they face in doing so, and the pathways they are following in order to build and operate inclusive supply chains profitably for both buying companies and vulnerable suppliers. In order to validate and refine the proposed framework, three case studies are carried out. The supply chains analyzed by the case studies belong to the agri-food sector and source from Sub-Saharan African countries. Multiple data collection methods and triangulation are used in order to improve reliability of findings. The author carried out field work in Senegal, Ethiopia and Tanzania. These travels enriched the data collection process, providing semi-structured interviews and informal conversations with the main actors in the supply chains, as well as direct observation of processes and interactions among companies and vulnerable suppliers. Case study A (Section 5.1 in page 96) is a single case study. It analyzes a local supply chain in Senegal providing vegetables to the local market. The focal organization is Manobi, a Senegalese inclusive business which provides affordable ICT services to local entrepreneurs in the agri-food sector. Case study A provides interesting insights into the dynamics of local supply chains and how professional services can help to improve their performance. Case study B (Section 5.2 in page 122) is a single case study. It analyzes a global supply chain with origin in Ethiopia providing cut flowers to the global commodity market. The focal organization is EHPEA, Ethiopian Horticulture Producers and Exporters Association, whose mission is to promote and safeguard the competitive position of the Ethiopian horticulture sector within the global market. Case study B helps to better understand the suppliers’ perspective regarding global market sustainability requirements and shows how the inclusion of suppliers in the process of development of a private standard has a positive impact in its implementation. Case study C (Section 5.3 in page 143) is a multiple case study. It analyzes a global supply chain with origin in Tanzania providing coffee to the global niche market of specialty coffee. The focal organizations are traders who are directly connecting smallholder coffee farmers in developing countries to coffee roasters in developed countries. Case study C shows how smallholder farmers can supply a premium product and be incorporated in a differentiated market segment through a transparent and efficient supply chain. The empirical findings from the case studies help to validate and refine the conceptual framework (see discussion in Chapter 6). The proposal of a new version of the conceptual framework is depicted in Figure 40 (page 195). The case studies also provide interesting insights related to the management of inclusive supply chains and show the perspectives of the different actors involved. This thesis sheds some light on the role of businesses in the creation and operation of inclusive supply chains by carrying out a cross-disciplinary literature review and analyzing three case studies in African countries. In doing so, this thesis presents a series of theoretical and empirical contributions to the emerging academic field of inclusive supply chains (Chapter 7). This thesis also intends to be useful to practitioners willing to improve the incorporation of the poor as suppliers in fair and profitable conditions.

An Evening with Dr. Venus Opal Reese, Motivational Speaker, Business Woman, and Author

This Droppin' Knowledge Lecture Series will challenge the audience to "defy the impossible". Dr. Venus Opal Reese will offer insight on how to achieve success on Thursday, September 17, at 6:30pm in Martin Luther King Hall-Thomas Pawley Theature, 812 E. Dunklin Street. Reese, an inspirational speaker, business mentor and marketing strategist, offers training to professionals, particularly entrepreneurs and executives, on how to "defy their impossible" to reach million-dollar success. Reese has consulted for O Magazines, and appeared on ABC and CBS News. For more information on Dr. Venus Opal Reese, please visit http://defyimpossible.com.

Cell adhesion and the integrin-linked kinase regulate the LEF-1 and β-catenin signaling pathways

The integrin-linked kinase (ILK) is an ankyrin repeat containing serine-threonine protein kinase that can interact directly with the cytoplasmic domains of the β1 and β3 integrin subunits and whose kinase activity is modulated by cell–extracellular matrix interactions. Overexpression of constitutively active ILK results in loss of cell–cell adhesion, anchorage-independent growth, and tumorigenicity in nude mice. We now show that modest overexpression of ILK in intestinal epithelial cells as well as in mammary epithelial cells results in an invasive phenotype concomitant with a down-regulation of E-cadherin expression, translocation of β-catenin to the nucleus, formation of a complex between β-catenin and the high mobility group transcription factor, LEF-1, and transcriptional activation by this LEF-1/β-catenin complex. We also find that LEF-1 protein expression is rapidly modulated by cell detachment from the extracellular matrix, and that LEF-1 protein levels are constitutively up-regulated at ILK overexpression. These effects are specific for ILK, because transformation by activated H-ras or v-src oncogenes do not result in the activation of LEF-1/β-catenin. The results demonstrate that the oncogenic properties of ILK involve activation of the LEF-1/β-catenin signaling pathway, and also suggest ILK-mediated cross-talk between cell–matrix interactions and cell–cell adhesion as well as components of the Wnt signaling pathway.

Cooperation between the activin and Wnt pathways in the spatial control of organizer gene expression

The normal expression pattern of the Wnt responsive homeobox gene Siamois is restricted to the dorso-vegetal region of the Xenopus embryo. Because the Wnt signaling pathway (via β-catenin) is active on the entire dorsal side of the early embryo, we have asked why Siamois expression is not seen in the dorsal ectoderm. Only Wnt signaling, via activation of β-catenin, can induce directly Siamois, and signaling via the SMAD1 (BMP2/4) or SMAD2 (activin/Vg-1) pathways cannot. We now directly show that the SMAD2 pathway can cooperate with the Wnt pathway to induce expression of Siamois much more strongly than the Wnt pathway alone, in normal embryos. We demonstrate the significance of this cooperation in normal embryos by blocking the SMAD2 signaling pathway with a dominant negative activin receptor. The activin dominant negative receptor blocks this cooperative effect and reduces the expression of Siamois by threefold in early embryos. Furthermore, we find that this cooperative relationship between the SMAD2 and Wnt pathways is reciprocal. Thus, in normal embryos, the Wnt pathway can enhance induction, by the SMAD 2 pathway, of the organizer genes Gsc and Chd but not the pan-mesodermal marker genes Xbra and Eomes. We conclude that the Wnt and SMAD2 signaling pathways cooperate to induce the expression of Spemann-organizer specific genes and so help to localize their spatial expression.

Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment

Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 μm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.

Prominence of the dopamine D2 short isoform in dopaminergic pathways

As a result of alternative splicing, the D2 gene of the dopamine receptor family exists in two isoforms. The D2 long is characterized by the insertion of 29 amino acids in the third cytoplasmic loop, which is absent in the short isoform. We have produced subtype-specific antibodies against both the D2 short and D2 long isoforms and found a unique compartmentalization between these two isoforms in the primate brain. The D2 short predominates in the cell bodies and projection axons of the dopaminergic cell groups of the mesencephalon and hypothalamus, whereas the D2 long is more strongly expressed by neurons in the striatum and nucleus accumbens, structures targeted by dopaminergic fibers. These results show that the splice variants of the dopamine D2 receptor are differentially distributed and possess distinct functions. The strategic localization of the D2 short isoform in dopaminergic cell bodies and axons strongly suggests that this isoform is the likely dopamine autoreceptor, whereas the D2 long isoform is primarily a postsynaptic receptor.

Differential roles of Ca2+/calmodulin-dependent kinases in posttetanic potentiation at input selective glutamatergic pathways

The electrosensory lateral line lobe (ELL) of the electric fish Apteronotus leptorhynchus is a layered medullary region receiving electroreceptor input that terminates on basal dendrites of interneurons and projection (pyramidal) cells. The molecular layer of the ELL contains two distinct glutamatergic feedback pathways that terminate on the proximal (ventral molecular layer, VML) and distal (dorsal molecular layer) apical dendrites of pyramidal cells. Western blot analysis with an antibody directed against mammalian Ca2+/calmodulin-dependent kinase 2, α subunit (CaMK2α) recognized a protein of identical size in the brain of A. leptorhynchus. Immunohistochemistry demonstrated that CaMK2 α expression in the ELL was restricted to fibers and terminals in the VML. Posttetanic potentiation (PTP) could be readily elicited in pyramidal cells by stimulation of either VML or DML in brain slices of the ELL. PTP in the VML was blocked by extracellular application of a CaMK2 antagonist (KN62) while intracellular application of KN62 or a CaMK2 inhibitory peptide had no effect, consistent with the presynaptic localization of CaMK2 α in VML. PTP in the dorsal molecular layer was not affected by extracellular application of KN62. Anti-Hebbian plasticity has also been demonstrated in the VML, but was not affected by KN62. These results demonstrate that, while PTP can occur independent of CaMK2, it is, in some synapses, dependent on this kinase.