Modulation of hepatic lipoprotein metabolism by dietary procyanidins

INTRODUCTIONDuring the past decade, Nutrition research has been subjected to a shift of focus, from epidemiology and physiology to the comprensión of the molecular basis of nutrients actions.Thus, the new "-omics" disciplines transcriptomics, proteomics or metabolomics, provide the tools to understand the molecular mechanisms involved in the modulation of gene expression by nutrients. The study of the beneficial properties of wine procyanidins has not avoided this shift of focus. Thus, from the initial studies which defined the "French paradox", to nowadays, a wide array of studies have been focused in defining the properties of the non-alcoholic components of red wine, mainly flavonoids, a family of polyphenolic compounds. The objectives of this thesis have been to define the molecular mechanisms by which grape procyanidins modulate the hepatic metabolism of lipoproteins, reducing the risk of cardiovascular disease and other pathologies which basis is found in the dysregulation of the lipoprotein metabolism.SUMMARYIn the present thesis, the effect of procyanidins in the hepatic lipoprotein metabolism has been studied. With this objective, HepG2, HeLa and CV-1 cells have been used as invitro models. In vivo studies have been performed in Wistar rats and C57BL6 mice, wild-type and transgenic mice lacking SHP (NR0B2) and FXR (NR5H1).RESULTS1. Procyanidins improve plasma lipid profile in the postprandial phase in rats. A single oral dose of procyanidins decreases plasma triglycerides and ApoB levels to 50% of control values. In addition LDL-Cholesterol is significantly reduced, thus improving the atherosclerotic risk index.2. Procyanidins display a triglyceride-lowering effect both in vivo and in vitro. In rat and mouse, procyanidin treatment triggers a hypotriglyceridemic response. In HepG2 cultures, procyanidins down-regulate the secretion of triglycerides and ApoB, thus showing that these flavonoids act directly on hepatic cells. This fact strongly suggests that, in vivo, a direct action of procyanidins on the liver contributes to their hypotriglyceridemic response.3. Nuclear receptor Small Heterodimer Partner (SHP) is a target of procyanidins in hepatic cells. Procyanidins modulate the expression of SHP, rapidly increasing its expression in rat liver as well as in HepG2 cultured cells.4. SHP mediates the triglyceride-lowering activity of procyanidins in vitro and in vivo. When SHP expression is silenced in HepG2 or abolished in SHP-null mice, procyanidins lose their hypotriglyceridemic activity. In contrast, in SHP-silenced HepG2 cells, procyanidins are still able to reduce apoB secretion. Hence, procyanidins reduce triglyceride via a SHP-dependent mechanism, whereas they reduce apoB in a SHPindependent manner.5. Nuclear receptor Farnesoid X Receptor (FXR) is an essential mediator of the hypotriglyceridemic action of procyanidins upstream SHP. Oral gavage of procyanidins to FXR-null mice have not a hypotriglyceridemic effect. Moreover, luciferase based in vitro assays showed that procyanidins increase the transcriptional activity of FXR. Thus, FXR is an essential component of the signalling pathway used by procyanidins to elicit the triglyceride lowering effect.6. Key genes of the inflammation process are targets of procyanidins in liver, in the postprandial phase. Oral administration of procyanidins to rats rapidly downregulates the expression, in liver, of transcription factor Egr1, a mediator of the hepatic inflammatory response, and several acute-phase proteins, namely haptoglobin, fibrinogen B and alpha-1 antitrypsin. In addition, expression of DUSP6, a component of the ERK1/2 subfamily of MAPK, is repressed by this treatment. Nfkbia, a repressor of NF-kB activity, is overexpressed upon procyanidin treatment. This expression pattern strongly suggests that procyanidins attenuate the pro-inflammatory state associated to the postprandial phase.INTRODUCCIÓNDurante la pasada década, la investigación en nutrición se ha visto sujeta a un cambio en sus objetivos, pasando de los estudios basados en la fisiología y la epidemiología a la comprensión de las bases moleculares implicadas en las acciones biológicas de los nutrientes. Así, las nuevas disciplinas, como la biología molecular o las "-omics", transcriptómica, proteómica o metabolómica, proporcionan las herramientas para el estudio de los mecanismos moleculares implicados en la modulación génica por nutrientes.El estudio de las propiedades beneficiosas del vino no ha evitado este cambio de foco. Así, desde los primeros estudios que definieron la "paradoja francesa", hasta la actualidad, una ámplia gama de estudios se han dedicado a definir las propiedades de los componentes no alcohólicos del vino, mayoritariamente, los Flavonoides, una familia de compuetos polifenólicos. El objetivo de esta tesis ha sido definir los mecanismos moleculares mediante los cuales las procianidinas de uva modulan el metabolismo de lipoproteínas en el hígado, disminuyendo así el riesgo cardiovascular y diferentes patologías cuya base se encuentra en la desregulación del metabolismo lipoproteico.MEMORIADurante esta tesis se ha estudiado el efecto de las procianidinas sobre el metabolismo lipoproteico en el hígado. Con este objetivo se han usado líneas celulares como modelo in vitro, tanto hepatocitos (HepG2) como líneas accesorias (HeLa y CV-1). Como modelos para el estudio de las procianidinas in vivo se han usado ratas de la cepa Wistar y ratones de la cepa C57BL6, tanto wild-type como dos líneas de transgénicos, Knockout para SHP (NR0B2) y FXR (NR5H1).RESULTADOSSe han obtenido los siguientes resultados:Las procianidinas de uva disminuyen los niveles de lipoproteínas ricas en triglicéridos, así como mejoran los índices de riesgo cardiovascular en ratas.Estos efectos se deben a la modulación de la expresión génica en el hígado, tejido adiposo y músculo entre otras acciones.El mecanismo por el cual las procianidinas disminuyen las lipoproteínas ricas en triglicéridos ha sido estudiado in Vitro (HepG2) e in vivo (C57BL6 wild-type y knockout para SHP). Se han definido dos mecanismos principales. El primero implica la señalización de las procianidinas por una vía dependiente de SHP (Small heterodimer partner, NR0B2), un receptor nuclear. El segundo mecanismo es independiente de SHP e inhibe la expresión de MTP (enzima controlador de la síntesis de lipoproteínas) y consecuente secreción de un menor número de lipoproteínas de muy baja densidad (VLDL).Por encima de SHP, se ha definido FXR (Farnesoid X receptor) como sensor de las procianidinas mediante el uso de ratones C57BL6 KO para FXR y sistemas reporter basados en luciferasa. Estableciendo que el mecanismo de señalización de las procianidinas pasa por FXR, que a su vez induce la expresión de SHP y este inhibe la expresión de SREBP1, factor de transcripción clave para la síntesis de lípidos, disminuyendo así la cantidad de lípidos hepáticos y, consecuentemente, la secreción de lipoproteínas.DISCUSIÓNLa modulación del metabolismo de lipoproteínas es el principal objetivo para el tratamiento de las diferentes patologías relacionadas con dislipemias. Así, la definición de las procianidinas de uva como agentes hipolipidémicos, las convierte en un componente de la dieta de alta importancia para prevenir y mejorar una ámplia gama de patologías, desde la aterogénesis hasta otros estados metabólicos alterados, causantes de la resistencia a la insulina o el síndrome metabólico.Por otro lado, el establecimiento de los mecanismos moleculares implicados en los efectos de las procianidinas de uva, aumenta el conocimiento sobre estos compuestos, así como su aplicabilidad en diferentes estados metabólicos alterados. De esta manera, se ha propuesto que la activación de FXR podría usarse como una estrategia en el tratamiento de la hiperlipidemia o la resistencia a la insulina. Así, las procianidinas emergen como un importante agente terapéutico, cuya importancia radica en la amplia presencia de estos compuestos en la dieta

Farm Management - Bugger the roots, where is the future?

The Farm Management discipline has long been closely aligned with agricultural economics. The question we raise is not where either discipline came from but where is Farm Management going. The impact of globalisation, the rising tide of deregulation and chain reversal mean that farm management professionals who have traditionally focused on optimisation of activities at a farm level are now commonly expected to use sociology and management science to explain economic organisation and performance on farms. They also are required to look at relationships in the value chain(s) in which the farm sits. This paper will analyse the implications of such change for Farm Management professionals.Farm Management, value chains, Farm Management,

Factors constraining extension workers effectiveness in improving horticultural production: a case study from West Timor, Indonesia

The Indonesian government and the government of Nusa Tenggara Timur recognise that horticulture is economically important and is expected to become the leading agribusiness sector to overcome poverty for farmers. Hence, in the last 20 years, the government of Nusa Tenggara Timur through various agribusiness projects has encouraged the planting of more than 18,490 hectares of vegetables and 82,010 hectares of fruit. The major producing areas of both are in the Kupang district and in the Timor Tengah Selatan. However, productivity is low. If production can be increased, on-farm income may also increase, but this is dependent upon Agricultural Extension Workers performing their roles more effectively. This study investigates the constraints that impede the ability of Agricultural Extension Workers to effectively perform their roles. The results suggest that while Agricultural Extension Workers are not performing their roles effectively there are a number of reasons for this, many of them beyond the control of Agricultural Extension Workers. While the Nusa Tenggara Timur province is supposedly following the Training and Visits model Agricultural Extension Workers receive very little training. Other major constraints identified include the constant restructuring of the Agricultural Department, poor remuneration, oppressive authority, inadequate infrastructure, unclear job direction, geographical condition, and bureaucracy. Unless these constraints are addressed, the system will remain unable to deliver the information and skills necessary for farmers to overcome poverty

Output complexity, environmental conditions, and the efficiency of municipalities

Over the last few years, many studies have analyzed the efficiency of local governments in different countries. An accurate definition of their output bundles—i.e., the services and facilities they provide to their constituencies—is essential to this research. However, several difficulties emerge in this task. First, since in most cases the law only establishes the minimum amount of services and facilities to provide, it may well be the case that some municipalities go beyond the legal minimum and, consequently, might have an uncertain effect on efficiency when compared to other municipalities which stick to the legal minimum. Second, municipalities face very different environmental conditions, which raises some doubts about the plausibility of an unconditional analysis. This study tackles these problems by proposing an analysis in which the efficiency of municipalities is evaluated after splitting them into clusters according to various criteria (output mix, environmental conditions, level of powers). We perform our estimations using order-m frontiers, given their robustness to outliers and immunity to the curse of dimensionality. We provide an application to Spanish municipalities, and results show that both output mix and, more especially, environmental conditions, should be controlled for, since efficiency differences between municipalities in different groups are notable

On the determinants of local government debt: Does one size fit all?

This paper analyzes the factors that directly influence levels of debt in Spanish local governments. Specifically, the main objective is to find out the extent to which indebtedness is originated by controllable factors that public managers can influence, or whether it hinges on other variables beyond managers’ control. The importance of this issue has intensified since the start of the crisis in 2007, due to the abrupt decline of revenues and, simultaneously, to the stagnation (or even increase) in the levels of costs facing these institutions face. Results can be explored from multiple perspectives, given that the set of explanatory factors is also multiple. However, the most striking result relates to the varying effect of each covariate depending on each municipality’s specific debt level, which suggests that economic policy recommendations should not be homogeneous across local governmen

Output complexity, environmental conditions, and the efficiency of municipalities: a robust approach

Over the last few years, many studies have analyzed the productive efficiency of local governments in different countries. An accurate definition of their output bundles -i.e., the services and facilities they provide to their constituencies- is essential to this research. However, several difficulties emerge in this task. First, since in most cases the law only establishes the minimum amount of services and facilities to provide, it may well be the case that some municipalities go beyond the legal minimum and, consequently, might be labeled as inefficient when compared to other municipalities which stick to the legal minimum. Second, municipalities face very different environmental conditions, which raises some doubts about the plausibility of an unconditional analysis. This study tackles these problems by proposing a metafrontier analysis in which the efficiency of municipalities is evaluated after splitting them into clusters according to various criteria (output mix, environmental conditions, size). We perform our estimations using order-m frontiers, given their robustness to outliers and immunity to the curse of dimensionality. We provide an application to Spanish municipalities, and results show that both output mix and, more especially, environmental conditions, should be controlled for, since efficiency differences between municipalities in different groups are notable.Durante los últimos años muchos trabajos han venido analizando la eficiencia productiva de las corporaciones locales de una gran variedad de países. Para este tipo de estudios resulta crucial una definición precisa de los servicios e infraestructuras que los municipios proporcionan a sus ciudadanos. Sin embargo, esta tarea presenta varias dificultades. En primer lugar, dado que en muchas circunstancias la ley únicamente establece los servicios mínimos que debe proporcionar un municipio, puede darse el caso de que algunos municipios vayan más allá de este mínimo legal y, consecuentemente, sean clasificados como ineficientes al compararlos con otros municipios que se ciñen al mínimo. En segundo lugar, las corporaciones locales operan en condiciones ambientales muy dispares, lo cual genera dudas acerca de la factibilidad de un análisis incondicional. Este trabajo aborda estas cuestiones proponiendo un análisis metafrontera en el que la eficiencia de las corporaciones locales se evalúa tras clasificarlas en distintos grupos de acuerdo con criterios múltiples (output mix, condiciones ambientales, tamaño). Las estimaciones son llevadas a cabo utilizando fronteras orden-m, debido a la robustez que presentan frente a observaciones atípicas y la inmunidad a la “maldición de la dimensionalidad” (curse of dimensionality). Llevamos a cabo una aplicación a los municipios españoles, y los resultados indican que tanto el output mix como, sobre todo, las condiciones ambientales, deberían ser tenidas en cuenta al evaluar la eficiencia, pues las diferencias en la eficiencia de los municipios en los distintos grupos son notables

SOK:young children’s cybersecurity knowledge, skills & practice: a systematic literature review

The rise in children’s use of digital technology highlights the need for them to learn to act securely online. Cybersecurity skills require mature cognitive abilities which children only acquire after they start using technology. As such, this paper explores the guidance and current curriculum expectations on cybersecurity aspects in Scotland. Additionally, a systematic review was undertaken of the literature pertaining to cybersecurity education for children on a wider scale including papers from around the world, with 27 peer reviewed papers included in the final review. We discovered that most research focused on assessing children’s knowledge or investigating the efficacy of interventions to improve cybersecurity knowledge and practice. Very few investigated the skills required to carry out the expected cybersecurity actions. For example, high levels of literacy, mature short- and long-term memory, attention, and established meta cognition are all pre-requisites to be able to carry out cybersecurity activities. Our main finding is that empirical research is required to explore the ages at which children have developed essential cognitive abilities and thereby the potential to master cybersecurity skills

Factors underpinning improved productivity in the WA wheat industry

Wheat yields in the Western Australian wheat industry have risen by about 3.9 percent per year over a period of 20 years. This has coincided with a decline in growing season rainfall over the grain belt. However, in the last few years yields have been highly variable because of fluctuations in rainfall and because two of the three driest years in the last 70 years have occurred during the last five years. Farm managers, consultants, researchers and research funders need to understand the key drivers of improvements in productivity. Researchers from the Department of Agriculture, Western Australia have conducted intensive research on wheat varieties and management practices needed to achieve high wheat yields. These have been combined into recommendations known as High Yield Packages (HYPs) for the regions of the state. The question addressed in this paper is which elements of these packages have been important and what other factors may have contributed to the improvements in productivity.Using graphical, statistical and regression analysis of benchmark data from PlanFarm Consulting group for 1995 to 2004, supported by in-depth qualitative analysis of 40 case study farmers, and a random telephone survey of 100 farmers, key factors associated with yield increases were investigated. The evidence suggests farmers have increased their water use efficiency since 1995 and that improvements in productivity are associated with nitrogen and phosphorous use, herbicide use, higher seeding rates and management performance. There is also qualitative evidence to suggest that the widespread adoption of one pass operations or no-tillage systems has been an important complementary factor

Appraisal of wine color and phenols from a non-invasive grape berry fluorescence method

[Aims] To investigate the relationships between the anthocyanin content of Vitis vinifera L. cvs. Tempranillo and Graciano grapes, determined in the vineyard and in the winery by a non-invasive fluorescence sensor, and the final wine color and phenolic traits.[Methods and results] Grape anthocyanin and phenol measurements were conducted with a hand-held, non-destructive fluorescence-based proximal sensor, in the vineyard (on clusters hanging on the vine) and at the winery (on harvested clusters in boxes) in two seasons. The anthocyanin fluorescence indices, ANTHRG and FERARI, were found to significantly correlate with the wine color density (R2 ranged from 0.51 to 0.82) and total phenol index (R2 ranged from 0.44 to 0.87), regardless that the measurements were made in the vineyard or in the winery. Similarly, the CIELAB parameters defining lightness (L*), hue angle (h*) and coordinate b* (yellow-blue component of the wine tonality) also showed significant relationships (R2 ranged from 0.55 to 0.74) with ANTHRG and FERARI indices in very young wines.[Conclusion] This preliminary study showed that satisfactory estimation of the final wine color and phenolic characteristics can be obtained from fast, non-destructive measurements in grapes, using a fluorescence-based sensor, either in the vineyard or in the winery.[Significance and impact of the study] This is the first work showing the capabilities of the chlorophyll fluorescence of grapes to estimate the final wine color and phenolic traits. This information could help the wine industry make more informed decisions regarding selective harvest and winemaking in a fast and cost-effective way. © Vigne et Vin Publications Internationales (Bordeaux, France).The authors want to thank Force-A and its team for their help and financial support.Peer Reviewe

Searching for the optimal territorial structure: the case of Spanish provincial councils

Modern states are organized in multi-level governance structures with economic and political authorities dispersed across them. However, although there is relatively widespread consensus that this form of organization is preferable to a centralized authority, the same cannot be said about its jurisdictional design—that is, how to transfer authority from central states to both supranational and subnational levels. This lack of consensus also exists in contexts with explicit initiatives to strengthen political ties such as the European Union (EU), and even within EU member countries, a situation that is aggravated by the relative scarcity of contributions that measure the advantages and disadvantages of different territorial organizations. We explore these issues through a study of one EU country, Spain, whose provincial councils (diputaciones) are often the subject of debate and controversy due to their contribution to increasing public spending and their purported inefficiencies, corruption, and lack of transparency. Specifically, we combine a variety of activity analysis techniques to evaluate how they impact on local government performance. Results suggest that, in general, the presence of a provincial council has a positive impact on local government performance, but when their activity levels are too high the effect can become pernicious