The pituitary TGFb1 system as a novel target for the treatment of resistant prolactinomas

Prolactinomas are the most frequently observed pituitary adenomas and most of themrespond well to conventional treatment with dopamine agonists (DAs). However, a subsetof prolactinomas fails to respond to such therapies and is considered as DA-resistantprolactinomas (DARPs). New therapeutic approaches are necessary for these tumors.Transforming growth factor b1 (TGFb1) is a known inhibitor of lactotroph cell proliferationand prolactin secretion, and it partly mediates dopamine inhibitory action. TGFb1 is secretedto the extracellular matrix as an inactive latent complex, and its bioavailability is tightlyregulated by different components of the TGFb1 system including latent binding proteins,local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), andTGFb receptors. Pituitary TGFb1 activity and the expression of different components of theTGFb1 system are regulated by dopamine and estradiol. Prolactinomas (animal models andhumans) present reduced TGFb1 activity as well as reduced expression of several componentsof the TGFb1 system. Therefore, restoration of TGFb1 inhibitory activity represents a noveltherapeutic approach to bypass dopamine action in DARPs. The aim of this review is tosummarize the large literature supporting TGFb1 important role as a local modulator ofpituitary lactotroph function and to provide recent evidence of the restoration of TGFb1activity as an effective treatment in experimental prolactinomasFil: Recouvreux, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Cedars Sinai Medical Center; Estados UnidosFil: Camilletti, María Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rifkin, Daniel B.. University of New York; Estados UnidosFil: Diaz, Graciela Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Métodos prospectivos implementados en la vigilancia tecnológica y prospectiva de vehículos eléctricos (EVS) y tecnologías periféricas en Colombia

This paper presents prospective methodsimplemented during the development of Surveillance Technology in Electrical Vehicles and Prospective  technologies in Colombia. These methods are developed for identifying related lines of research and emerging technologies which foster innovation. Methodologies are Delphi rounds and the planning of future scenarios. Both methodologies are implemented as tools to identify research topics that revolve around EVs in Colombia. The topics selected following the development of technology forecasting, were discussed by a group of experts who contextualized the information obtained from Colombia. From this analysis, scenarios were constructed. Technologies hampering the incursion of EVs in Colombia were determined, as well as the technologies with the greatest trend to be consumed and the most influential regulatory aspects.En este artículo se presentan los métodos prospectivos implementados durante el desarrollo de la Vigilancia Tecnológica en Vehículos Eléctricos y Tecnologías Periféricas en Colombia. Estos métodos se desarrollan con el propósito de identificar las líneas de investigación relacionadas y las tecnologías emergentes que propendan por la innovación. Las metodologías aplicadas fueron las rondas Delphi y el planteamiento de escenarios futuros; ambas metodologías se implementaron como herramientas para identificar los principales temas de investigación que giran alrededor de los EVs en Colombia. Los temas seleccionados, posterior al desarrollo de la Vigilancia Tecnológica, fueron debatidos por un grupo de expertos que contextualizaron la información obtenida para Colombia. A partir de esto se construyeron los escenarios de análisis. Se determinaron las tecnologías que pueden obstaculizar la incursión de EVs en Colombia, así como las tecnologías con mayor tendencia al consumo y los aspectos regulatorios más influyentes

A push-pull unsymmetrical subphthalocyanine dimer

Unsymmetrical subphthalocyanine fused dimers have been prepared from appropriate ortho-dinitrile SubPc precursors. In particular, either electron-donating or electron-accepting substituents have been introduced on each SubPc constituent unit, resulting in unprecedented push–pull π-extended curved aromatic macrocycles. From fluorescence experiments in solvents of different polarity we conclude a dual fluorescence, namely a delocalized singlet excited state (1.73 eV) and a polarized charge transfer state (<1.7 eV). Pump probe experiments corroborate the dual nature of the fluorescence. On one hand, the delocalized singlet excited state gives rise to a several nanosecond lasting intersystem crossing yielding the corresponding triplet excited state. On the other hand, the polarized charge transfer state deactivates within a few picosesonds. Visualization of the charge transfer state was accomplished by means of molecular modeling with a slight polarization of the HOMO towards the electron donor and of the LUMO towards the electron acceptor

The effectiveness of national women’s mechanisms in Latin America: a window of opportunity to advance women’s equality or merely window-dressing?

The United Nations supported the idea of National Women´s Mechanisms (NWMs) since the 1970s. NWMs have been promoted internationally as the primary institutional tool to achieve women´s equality since the Beijing Platform for Action was adopted in 1995. Despite their widespread adoption, NWMs have been criticised in the academic literature and by practitioners as ineffective institutions that have not necessarily led to progressive change for women. This thesis examines the effectiveness of NWMs in Latin America. It asks, has their establishment produced potentially effective institutions, or have States been merely compliant with UN promoted global norms? The research uses a cross national survey study of the eighteen Latin American States based on three questionnaire surveys of three target groups –UN Women offices, NWMs and civil society organisations. Based on this survey, four case study countries - Chile, Uruguay, Nicaragua and Bolivia - were selected for in-depth analysis. The research was facilitated by my role in UN Women permitting me access to key informants, events and meetings. The result of the survey demonstrated that almost all NWMs in Latin America are ineffective entities indicating a fundamental flaw in either the design of the global norm or in its implementation. The research did not find a strong link between States´ compliance with the global norm and the effectiveness of NWMs. The Chilean NWM was compliant and effective while that of Nicaragua was also compliant but ineffective. Uruguay had an effective NWM in spite of a low level of compliance. In Bolivia the NWM was neither compliant nor effective. The conclusion to the thesis suggests that reforming this global norm may allow NWMs to become more effective institutions

Brain angiotensin II in dopaminergic imbalance-derived pathologies: Neuroinflammation and vascular responses

Brain angiotensin II (ANG II) as a pleiotropic player: Mental disorders have been commonly associated with an imbalance in many neurotransmitter systems, such as dopamine, glutamate, and gamma-aminobutyric acid. Considering the complexity of brain functioning, all components of the neurovascular unit should be considered in studies for a better comprehension of the physiopathology and possible therapeutics. ANG II is present in the brain and binds to AT1 receptors (AT1-R), located in the neurovascular unit and has a close relationship with the mentioned neurotransmitter systems. In pathological conditions, AT1-R expressed in astrocytes, microglia, and brain endothelial cells are key mediators in the development of an oxidative/inflammatory microenvironment, as well as in glial activation. Therefore, pharmacological intervention targeting AT1-R provides a holistic and moderated approach to modulate neurotransmission systems in addition to the glial and vascular responses [Figure 1]. This interaction is underscored by several studies that related brain ANG II to neurological disorders, such as Parkinson´s disease (PD) and attention deficit hyperactivity disorder (ADHD).Fil: Occhieppo, Victoria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Basmadjian, Osvaldo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Bregonzio Diaz, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentin

Syntheses, structures and reactivities of bis(thiophosphinoyl) metal complexes.

Wan, Chi Ling.Thesis (M.Phil.)--Chinese University of Hong Kong, 2009.Includes bibliographical references.Abstracts in English and Chinese.Table of Contents --- p.viAcknowledgement --- p.iAbstract --- p.ii摘要 --- p.ivList of Compounds Synthesized in This Work --- p.xAbbreviation --- p.xiChapter Chapter 1 --- Synthesis of Group 1 and 2 Metal Bis(thiophosphinoyl) ComplexesChapter 1.1 --- Introduction --- p.1Chapter 1.1.1 --- General Aspects of Thiophosphinoyl Ligands --- p.1Chapter 1.1.2 --- General Aspects of Group 1 and 2 Thiophosphinoyl Metal Complexes --- p.6Chapter 1.1.3 --- Objectives of This Work --- p.10Chapter 1.2 --- Results and Discussion --- p.11Chapter 1.2.1.1 --- Synthesis of Monoanionic Bis(thiophosphinoyl) Lithium Complex --- p.11Chapter 1.2.1.2 --- Spectroscopic Properties of 42 --- p.11Chapter 1.2.1.3 --- Molecular Structure of [Li{(S=PPh2)CH}(THF)(Et20)] (42) --- p.12Chapter 1.2.2.1 --- Synthesis of Dianionic Bis(thiophosphinoyl) Magnesium Complex --- p.14Chapter 1.2.2.2 --- Spectroscopic Properties of 43 --- p.14Chapter 1.2.2.3 --- Molecular Structure of [MgC(PPh2=S)(THF)]2.2THF (43) --- p.15Chapter 1.3 --- Experimental for Chapter 1 --- p.17Chapter 1.4 --- References for Chapter 1 --- p.19Chapter Chapter 2 --- Synthesis and Reactivity of Group 14 Metal Bis(thiophosphinoyl) ComplexesChapter 2.1 --- Introduction --- p.24Chapter 2.1.1 --- General Aspects of Low Valent Group 14 Organometallic Compounds --- p.24Chapter 2.2 --- Results and Discussion --- p.32Chapter 2.2.1.1 --- "Synthesis of 1,3-Distannacyclobutane and 1,3-Diplumbacyclobutane" --- p.32Chapter 2.2.1.2 --- Spectroscopic Properties of 74 and 75 --- p.33Chapter 2.2.1.3 --- Molecular Structures of [Sn{u2-C(Ph2P=S)2}]2.THF (74) and [Pb{u2-C(Ph2P=S)2}]2.THF(75) --- p.34Chapter 2.2.2.1 --- "Reaction of 1,3-Diplumbacyclobutane with Chalcogens" --- p.38Chapter 2.2.2.2 --- Spectroscopic Properties of 78 and 79 --- p.39Chapter 2.2.2.3 --- "Molecular Structures of [PbE{C(PPh2=S)2}] (E = S (78),Se (79))" --- p.39Chapter 2.2.3.1 --- Synthesis of Chlorogermylene and Chlorostannylene --- p.44Chapter 2.2.3.2 --- Spectroscopic Properties of 80 and 81 --- p.44Chapter 2.2.3.3 --- "Molecular Structures of [MCl{CH(PPh2=S)2}] (M = Ge (80),Sn (81))" --- p.45Chapter 2.2.4.1 --- Reaction of Chlorogermylene with Chalcogens --- p.49Chapter 2.2.4.2 --- Spectroscopic Properties of 82 --- p.50Chapter 2.2.4.3 --- Molecular Structure of [GeCl{CH(PPh2=S)2}(u-S)]2.4THF (82) --- p.51Chapter 2.2.4.4 --- Reaction of Chlorostannylene with Pb{N(SiMe3)2}2 --- p.53Chapter 2.3 --- Experimental for Chapter 2 --- p.54Chapter 2.4 --- References for Chapter 2 --- p.60Chapter Chapter 3 --- Synthesis of Group 13 Metal Bis(thiophosphinoyl) ComplexesChapter 3.1 --- Introduction --- p.65Chapter 3.1.1 --- General Aspects of Group 13 Organometallic Chemistry --- p.65Chapter 3.1.2 --- General Aspects of Group 13 Metal Complexes Bearing Phosphoranoimine or Phosphoranosulfide Ligands --- p.67Chapter 3.2 --- Results and Discussions --- p.72Chapter 3.2.1 --- Synthesis of Group 13 Metal Bis(thiophosphinoyl) Complexes --- p.72Chapter 3.2.2 --- Spectroscopic Properties of 108-110 --- p.72Chapter 3.2.3 --- "Molecular Structures of [MCl{C(PPh2=S)2}]2 (M = A1 (108),Ga (109), In (110))" --- p.73Chapter 3.3 --- Experimental for Chapter 3 --- p.79Chapter 3.4 --- References for Chapter 3 --- p.82Chapter Chapter 4 --- Synthesis of Group 4 Metal Bis(thiophosphinoyl) ComplexesChapter 4.1 --- Introduction --- p.86Chapter 4.1.1 --- General Aspects of Group 4 Early Transition Metal Complexes --- p.86Chapter 4.2 --- Results and Discussion --- p.92Chapter 4.2.1 --- Synthesis of Group 4 Metal Bis(thiophosphinoyl) Complexes --- p.92Chapter 4.2.2 --- Spectroscopic Properties of 125-128 --- p.93Chapter 4.2.3 --- Molecular Structures of [Hf(NMe2)3{CH(PPh2=S)2}] (126) --- p.94Chapter 4.3 --- Experimental for Chapter 4 --- p.97Chapter 4.4 --- References for Chapter 4 --- p.100Appendix IChapter A. --- General Procedures --- p.104Chapter B. --- Physical and Analytical Measurements --- p.104Chapter C. --- X-ray Crystallographic Determination --- p.105Appendix II"Table A.1. Selected Crystallographic Data for Compounds 42,43,74 and 75" --- p.108Table A.2. Selected Crystallographic Data for Compounds 77-80 --- p.109"Table A.3. Selected Crystallographic Data for Compounds 81,108-110 and 126" --- p.110Appendix IIIChapter A. --- Future Work --- p.11

Análisis de la función del gen SAV4194 sobre la exportación de metabolitos secundarios en Streptomyces avermitilis

Los actinomicetos son un grupo de bacterias Gram positivas cuya importancia biotecnológica radica en su capacidad de producir un gran número de metabolitos secundarios, entre los que se encuentran los antibióticos. Streptomyces avermitilis produce 28 metabolitos secundarios entre los que destacan por su interés industrial las avermectinas y la oligomicina. Las avermectinas son empleadas en medicina y agricultura, debido a sus propiedades antiparasitarias y antihelmínticas, aunque también se han reportado con actividad antibacterial y antifúngica si se usan en altas concentraciones (Egerton et al., 1979; Chen et al., 2008). La oligomicina es un compuesto que muestra una amplia variedad de actividades biológicas, especialmente un fuerte efecto antifúngico por inhibición específica de la ATPasa mitocondrial, actividad inmunosupresora (Wei et al., 2006), y una potente actividad antitumoral contra hepatoma humano, leucemia mielógena crónica y varios tipos de células de carcinoma colónico (Xiuping et al., 2009). Debido a lo anterior se han incrementado los estudios para el mejoramiento genético de este microorganismo. Por otro lado, se han encontrado genes involucrados en la resistencia y exportación de los antibióticos propios de cada microorganismo productor. Se ha demostrado que puede presentarse un efecto tóxico propio de la actividad del antibiótico que sintetizan cuando las concentraciones del mismo son altas lo que marca un límite en la producción en cepas industriales de alta producción. En este sentido se han identificado en muchos actinomicetos proteínas de membrana que funciona como una bomba exportadora de antibiótico. Tal es el caso de Streptomyces pristinaespiralis, productor de pristinamicina en quien el gen ptr codifica una proteína responsable de la exportación de dicho antibiótico mediante un sistema antiport, pristinamicina/proton (Folcher et al., 2001). Con estos antecedentes, se buscó una proteína similar en S. avermitilis y mediante análisis insílico se encontró que el gen SAV4194 contiene 13 dominios transmembranales típicos de proteínas transportadoras además, se identificó que presenta 78% de similitud con el gen Ptr de S. pristinaespiralis y 74% con el gen RifP de A. mediterranei. Tanto el gen Ptr como el gen RifP codifican para proteínas transportadoras de antibióticos (Folcher et al., 2001; Absalón et al., 2007). En base a esta similitud es que consideramos que el gen SAV4194 también codifica para una proteína de transporte. Para probar la hipótesis, se plantearon dos estrategias. La primera fue interrumpir el gen SAV4194 mediante el transposón Tn5062. Para esto fue necesario en principio, amplificar el gen mediante PCR, posteriormente clonarlo en el plásmido pME6 e interrumpir con el transposón el gen ya clonado. Finalmente se trató de transformar a S. avermitilis con este nuevo vector para que mediante recombinación homóloga el gen interrumpido se integrara al cromosoma; con lo cual se obtendrían mutantes con el gen SAV4194 interrumpido. Sin embargo, no fue posible transformar por ninguna de las técnicas reportadas la cepa de S. avermitilis con la cual se trabajó lo que nos llevó a la conclusión de que el problema se debía a que se ha reportado que este microorganismo tiene un sistema de restricción muy fuerte (Macneil et al.,1998, Hwang et al., 2001, Gong et al., 2004). Por lo tanto, fue necesario implementar una estrategia alternativa para obtener información que nos permitiera responder la pregunta original del presente trabajo de tesis, sobre si este gen codifica o no para una proteína transportadora de avermectinas. Ésta consistió en evaluar la expresión del gen durante la trofofase e idiofase de S. avermitilis en diferentes medios de cultivo (medio semilla, medio de producción de oligomicina y medio de producción de avermectina). Las muestras de ARN se estudiaron mediante métodos cualitativos (RT-PCR) y cuantitativos (QRT-PCR). Tanto los resultados de RT-PCR como los de PCR en tiempo real mostraron que el gen SAV4194 no se expresa durante la producción de avermectinas pero si se expresa durante la producción de oligomicina. Por lo tanto, la no expresión del gen SAV4194 en el medio de producción de avermectina demuestra que este gen no está involucrado en su exportación. Y la expresión del gen SAV4194 en los medios donde hay producción de oligomicina sugiere que este gen podría estar implicado en el transporte de oligomicina hacia el exterior de la célula

Sex differences in the pituitary TGFβ1 system: the role of TGFβ1 in prolactinoma development

Prolactinomas are the most frequent functioning pituitary adenomas, and sex differences in tumor size, behavior and incidence have been described. These differences have been associated with earlier diagnosis in woman, as well as with serum estradiol levels. Experimental models of prolactinomas in rodents also show a higher incidence in females, and recent findings suggest that gender differences in the transforming growth factor beta 1 (TGFbeta1) system might be involved in the sex-specific development of prolactinomas in these models. The aim of this review is to summarize the literature supporting the important role of TGFbeta1 as a local modulator of pituitary lactotroph function and to provide recent evidencefor TGF1 involvement in the sex differences found in prolactinoma development in animal models.Fil: Recouvreux, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Faraoni, Erika Yanil. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Camilletti, María Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ratner, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Abeledo Machado, Alejandra Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rulli, Susana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Diaz, Graciela Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin