Escrevendo do Uruguai para o mundo: Agrociencia Uruguai vinte e cinco anos

The article represents an approach to the trajectory of Agrociencia Uruguay, on the 25th anniversary of the publication of its first issue. A descriptive analysis on the journal’s evolution will be presented, based on an examination of the articles published, as well as five interviews with chief editors who have been associated with the publication since its creation.El artículo representa un acercamiento a la trayectoria de la revista Agrociencia Uruguay al cumplirse 25 años de la publicación de su primer número. Se intentará presentar un análisis descriptivo de la evolución de la revista a partir del examen de los artículos publicados y de cinco entrevistas a editores jefes que se vincularon con la publicación desde su fundación.O artigo representa uma aproximação à trajetória da revista Agrociencia Uruguay, no 25º aniversário da publicação de seu primeiro número. Tentar-se-á apresentar uma análise descritiva da evolução da revista a partir do exame dos artigos publicados e de cinco entrevistas com os editores-chefes associados à publicação desde a sua fundação

¿Innovar siempre es bueno? La reconversión vitivinícola uruguaya. Un estudio de caso (1974-2000)

A partir de los años noventa del siglo pasado, la vitivinicultura uruguaya ha sufrido una rápida reconversión que ha seguido las pautas generales del equivalente proceso a escala mundial: transformación de las diferentes fases productivas, concentración en grandes empresas, calidad de los caldos como indicador del éxito empresarial y comercial. En este marco, existe un consenso unánime en considerar que el proceso de reconversión fue consecuencia directa de la firma del Tratado de Asunción en 1991 y de la puesta en marcha del MERCOSUR y que las empresas que mejor supieron innovar terminaron triunfando en este nuevo contexto económico. Este trabajo, centrado en el análisis de la evolución de una empresa vitivinícola concreta, Bodega Faraut, pretende poner en discusión los postulados principales de esta interpretación. Asimismo, al hallar una firma que implementó todos los criterios adecuados para adoptarse favorablemente a los supuestos de la reconversión y que, sin embargo, terminó quebrando, intenta evidenciar algunos posibles problemas relacionados a la cuestión de la innovación en el ámbito de las empresas agropecuarias

Un conflicto sobre la hegemonía del sector. Técnicos y empresarios frente a la filoxera (1893-1900)

The work examines some debates that took place between the end of the XIX century and the beginning of the XX, about the characteristics that innovations in the agricultural field should have. The main hypothesis is that each confrontation, although disguised with scientific arguments and proposer as the best way for the common good, reveals the guidelines of a strategy (sectorial or personal) tending to take control of the policies of tecgnological change.Josep Collell, acrílico sobre cartón (1999) 40x40 cm El trabajo examina algunos debates que se registraron entre finales del siglo XIX y principios del XX,  sobre las características que debían tener las innovaciones en ámbito agrícola. La hipótesis principal es que cada enfrentamiento, aunque disfrazado con argumentaciones científicas y planteado como el mejor camino para el bien común revele los lineamientos de una estrategia (sectorial o personal), tendiente a hacerse con la dirección de las políticas de cambio tecnológico

The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

G PROTEIN-COUPLED RECEPTOR DESENSITISATION REGULATES STEM CELL DIFFERENTIATION

G-protein coupled receptors (GPCRs) play a key role in many complex biological processes, including regulation of stem cell pluripotency and differentiation. Signal transduction pathways that are activated during stem cell renewal and differentiation are shared, cross-activated or synergistic with GPCR stimulation [1]. Regulation of GPCR responses involved the activation of desensitization machinery, which started with phosphorylation of agonist-activated receptor by second messenger-dependent and/or GPCR kinases (GRKs)[1]. Besides controlling receptor responsiveness, GRKs can also act as agonist-regulated scaffolds assembling macromolecular signalosomes in the receptor environment, thereby contributing to signal propagation from cytosol to nucleus, and controlling gene transcription machinery [2]. Recent evidence suggests that the desensitization machinery fulfils a vital role in regulating cellular responses to GPCRs, and that changes in expression/functioning of these regulatory proteins may be crucial in the control of cell differentiation program [3]. These data are consistent with the notion that GPCR responsiveness may be differentially regulated during cell differentiation. In our hands, two different cellular models (oligodendrocyte precursor cells, OPCs, and mesenchymal stem cells, MSCs) were used to investigate the role of the GPCR desensitisation machinery in stem cell differentiation. During OPC differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impairs remyelination under demyelinating conditions [4]. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of p53 protein. In maturing OPCs, the inhibition of Mdm2-p53 interactions increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. In MSCs, the A2B adenosine receptor (A2BAR) has been recently emerged as the major AR involved in osteoblastogenesis [5]. Proinflammatory cytokines, such as Tumour Necrosis Factor- (TNF-, have been demonstrated to regulate MSC differentiation and bone remodelling. Herein, we show that TNF- diminished GRK2 levels in MSCs, thus blocking A2BAR desensitization. As a result, TNF- enhanced the A2BAR-mediated responses and favoured MSC differentiation to osteoblasts in response to receptor agonists. The findings get new insights for discovering of the signals at the basis of cell differentiation

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents

Paediatric Wolfram syndrome Type 1: should gonadal dysfunction be part of the diagnostic criteria?

AimsWolfram Syndrome Spectrum Disorder (WFS1-SD), in its “classic” form, is a rare autosomal recessive disease with poor prognosis and wide phenotypic spectrum. Insulin dependent diabetes mellitus (DM), optic atrophy (OA) diabetes insipidus (DI) and sensorineural deafness (D) are the main features of WFS1-SD. Gonadal dysfunction (GD) has been described mainly in adults with variable prevalence and referred to as a minor clinical feature. This is the first case series investigating gonadal function in a small cohort of paediatric patients affected by WFS1-SD.MethodsGonadal function was investigated in eight patients (3 male and 5 female) between 3 and 16 years of age. Seven patients have been diagnosed with classic WFS1-SD and one with non-classic WFS1-SD. Gonadotropin and sex hormone levels were monitored, as well as markers of gonadal reserve (inhibin-B and anti-Mullerian hormone). Pubertal progression was assessed according to Tanner staging.ResultsPrimary hypogonadism was diagnosed in 50% of patients (n=4), more specifically 67% (n=2) of males and 40% of females (n=2). Pubertal delay was observed in one female patient. These data confirm that gonadal dysfunction may be a frequent and underdiagnosed clinical feature in WFS1-SD.ConclusionsGD may represent a frequent and earlier than previously described feature in WFS1-SD with repercussions on morbidity and quality of life. Consequently, we suggest that GD should be included amongst clinical diagnostic criteria for WFS1-SD, as has already been proposed for urinary dysfunction. Considering the heterogeneous and elusive presentation of WFS1-SD, this clinical feature may assist in an earlier diagnosis and timely follow-up and care of treatable associated diseases (i.e. insulin and sex hormone replacement) in these young patients

Historia de la viña y el vino de Uruguay : el viñedo y su gente (1870-1930). Tomo I

Prólogo / Jean-Marie Aurand. -- Prefacio / José Lezz. -- Presentación / Alcides Beretta Curi .-- Capítulo 1 La vitivinicultura en la región austral de América / Alcides Beretta Curi.-- Capítulo 2 Agricultura y vitivinicultura (1870-1930) / Daniele Bonfanti.-- Capítulo 3 La temprana vitivinicultura en el Uruguay : surgimiento y consolidación (1870-1930) / Belén Baptista.-- Capítulo 4 La inmigración europea en la construcción del viñedo uruguayo / Alcides Beretta Curi.-- Capítulo 5 La acción de una elite empresarial desde la Asociación Rural del Uruguay : el caso de la vitivinicultura (1871-1900) / Alcides Beretta Curi.-- Capítulo 6 La vitivinicultura: un atractivo camino para la diversificación empresarial / Alcides Beretta Curi.-- Capítulo 7 A vueltas con la cuestión de las relaciones entre elites y producción vitivinícola. Los políticos productores (1875-1930) / Daniele Bonfanti.-- Capítulo 8 Los caminos de innovación en el agro: inmigración, redes de agricultores, elites y viticultura en el Uruguay de la modernización (1870-1900) / Alcides Beretta Curi. -- Capítulo 9 El ojo del amo engorda el ganado. Reglamentos de trabajo, dispositivos para el control social de la mano de obra asalariada dentro del sector vitivinícola uruguayo / Andrea Bentancor Bossio. -- Capítulo 10. Trabajadoras de la vid y el vino: Significaciones y lugares del quehacer subalterno / Mariana Viera Cherro.-- Capítulo 11. Discursos, imaginarios y condiciones laborales de niños y adolescentes en el sector vitivinícola Uruguayo (1870-1930) / Andrea Bentancor Bossio. -- Capítulo 12. Procesos asociativos en el sector vitivinícola uruguayo (1870-1935). Las organizaciones gremiales, orígenes y desafíos / Andrea Bentancor Bossio. -- Capítulo 13. La Asociación Rural del Uruguay: entre el saber técnico agronómico y el viticultor uruguayo (1872-1900) / Verónica Sanz Bonino. -- Capítulo 14. Un acercamiento al estudio léxico-terminológico de las enfermedades de la vid (1870-1888) / Ana Clara Polakof. -- Conclusiones. -- Fuentes y Bibliografía. -- Los autores

Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination

The aim of this study was to investigate the potential of surface plasmon resonance (SPR) spectroscopy for the measurement of real-time ligand-binding affinities and kinetic parameters for GPR17, a G protein-coupled receptor (GPCR) of major interest in medicinal chemistry as potential target in demyelinating diseases. The receptor was directly captured, in a single-step, from solubilized membrane extracts on the sensor chip through a covalently bound anti-6x-His-antibody and retained its ligand binding activity for over 24h. Furthermore, our experimental setup made possible, after a mild regeneration step, to remove the bound receptor without damaging the antibody, and thus to reuse many times the same chip. Two engineered variants of GPR17, designed for crystallographic studies, were expressed in insect cells, extracted from crude membranes and analyzed for their binding with two high affinity ligands: the antagonist Cangrelor and the agonist Asinex 1. The calculated kinetic parameters and binding constants of ligands were in good agreement with those reported from activity assays and highlighted a possible functional role of the N-terminal residues of the receptor in ligand recognition and binding. Validation of SPR results was obtained by docking and molecular dynamics of GPR17-ligands interactions and by functional in vitro studies. The latter allowed us to confirm that Asinex 1 behaves as GPR17 receptor agonist, inhibits forskolin-stimulated adenylyl cyclase pathway and promotes oligodendrocyte precursor cell maturation and myelinating ability