Une approche moléculaire pour mieux comprendre l'infertilité chez la vache laitière

Au cours des dernières années, une sélection génétique importante a été faite pour améliorer la production de lait des bovins, ceci au détriment des performances reproductives. Cette diminution de performance n’a cependant pas été rapportée chez la génisse présentant un même potentiel génétique. Cette immense production de lait et les changements métaboliques qui l’accompagnent ont donc un impact négatif sur l’efficacité reproductive des vaches laitières qui subissent un stress métabolique supérieur à celui des génisses. Le but de l’étude était d’acquérir une meilleure connaissance des différences moléculaires et métaboliques entre ces deux groupes d’animaux pour amener à une meilleure compréhension de la pathogenèse de l’infertilité chez la vache laitière. Pour ce faire, les vagues folliculaires de vaches en lactation (30-50 jours en lait; N = 12) et de génisses (N = 10) ont été synchronisées par ablation écho guidée des follicules et par traitement hormonal avec injection de prostaglandine et insertion d’un implant de progestérone. L’aspiration du liquide folliculaire et des cellules de la granulosa du follicule dominant a été faite au jour 6. Les paramètres métaboliques mesurés chez les animaux à partir de prises de sang, faites au jour 6, confirment un plus grand stress métabolique chez la vache, les niveaux de BHBA, acides biliaires et cholestérol étant plus élevés et le niveau de glucose plus bas chez celles-ci. Un total de six échantillons a été utilisé pour le séquençage d’ARN et des analyses bio-informatiques ont été effectuées. Plusieurs gènes et voies de signalisation ont présenté des différences entre les deux groupes d’animaux incluant le cycle cellulaire et la production d’hormones. Une confirmation des résultats par PCR en temps réel a été faite, mais la grande variation intragroupe a nui à l’obtention de résultats significatifs. Conjointement, une culture primaire de cellules de la granulosa a été réalisée pour évaluer l’effet des acides biliaires sur la stéroïdogenèse suite à la détection d’une plus grande quantité de ceux-ci chez la vache laitière. La présence d’acide biliaire dans la culture cellulaire cause une diminution de l’accumulation d’estradiol ainsi que de l’expression des gènes CYP19A1 et CYP11A1. Les résultats présentés dans ce mémoire indiquent une différence potentielle au niveau métabolique et moléculaire des follicules dominants entre la vache laitière et la génisse pouvant avoir une responsabilité dans la diminution de l’efficacité reproductive observée chez la vache laitière.

Rôle du microenvironnement apoptotique tissulaire et du MFG-E8 dans la modulation de la réponse inflammatoire

L’inflammation fait partie des processus réactionnels de défense dont dispose l’organisme en réponse aux agressions, assurant l’intégrité de l’hôte. En réponse au dommage tissulaire, plusieurs médiateurs inflammatoires interviennent dans le processus de l’inflammation. Lors de ces dommages, des signaux de dangers provenant de cellules endommagées sont relâchés dans l’environnement tissulaire, pouvant causer des dommages cellulaires et tissulaires. Les macrophages, tout comme d’autres cellules, peuvent être activés par ces signaux de danger, menant à la sécrétion de molécules telles que des cytokines et des chimiokines pouvant modifier le microenvironnement tissulaire. Les insultes au tissu sain peuvent entrainer la mort cellulaire telle que l’apoptose. Les molécules pouvant être relâchées lors de celle-ci contribuent au microenvironnement, notamment de par l’influence de celles-ci sur le macrophage. Parmi ces médiateurs, nous avons identifié le Milk Fat Globule-Epidermal growth factor 8 (MFG-E8), un acteur important dans la résolution de l’inflammation, comme étant relâché spécifiquement par les cellules apoptotiques. Nous avons émis l’hypothèse que le microenvironnement apoptotique tissulaire, via la relâche de MFG-E8, module le phénotype du macrophage, modifiant le microenvironnement, la réponse inflammatoire ainsi que le devenir de l’insulte tissulaire. Nos objectifs sont 1) de caractériser ce microenvironnement apoptotique tissulaire et la cinétique de relâche du MFG-E8 par les cellules apoptotiques, 2) d’en évaluer son rôle dans la modulation du phénotype du macrophage ainsi que 3) d’en étudier, in vivo, son influence sur l’environnement inflammatoire et le devenir tissulaire. Dans le premier article présenté, nous avons démontré que les cellules endothéliales apoptotiques relâchent le MFG-E8 de façon Caspase-3 dépendante. La stimulation des macrophages par l’environnement conditionné par les cellules endothéliales apoptotiques mène à l’adoption d’un profil macrophagien davantage anti-inflammatoire et moindrement pro-inflammatoire. Ce phénotype est réduit par l’inhibition de la Caspase-3 et il dépend de la présence de MFG-E8. De plus, le potentiel du MFG-E8 à la reprogrammation du macrophage pro-inflammatoire a été démontré via un modèle expérimental de péritonite. Ce changement phénotypique médié par MFG-E8 implique une signalisation STAT3. Ayant démontré que les cellules épithéliales apoptotiques, à l’instar des cellules endothéliales apoptotiques, relâchent elles aussi de façon apoptose-dépendante le MFG-E8, nous avons étudié plus exhaustivement un modèle in vivo riche en apoptose épithéliale, l’obstruction urétérale unilatérale. Dans ce deuxième article présenté, nous rapportons l’implication bénéfique de MFG-E8 dans ce modèle de pathologie rénale obstructive. Nous avons constaté que la présence ou l’administration de MFG-E8 réduit le dommage tissulaire et la fibrose. La protection conférée par MFG-E8 est médiée via la modulation de l’activation de l’inflammasome. De plus, nos résultats illustrent l’importance du phénotype anti-inflammatoire du macrophage médié par le MFG-E8 dans la régulation négative de l’activation de l’inflammasome rénal et du dommage tissulaire. Cette thèse présente la première description de la relâche Caspase-3-dépendante de MFG-E8 par les cellules apoptotiques. Elle démontre également l’importance du MFG-E8 dans le microenvironnement apoptotique inflammatoire dans l’atténuation du phénotype pro-inflammatoire du macrophage. De plus, nous avons démontré son rôle protecteur dans des modèles in vivo de transplantation aortique et de réparation tissulaire, de même que dans un modèle de maladie rénale chronique où nous avons montré que cette protection conférée par MFG-E8 est médiée par la régulation négative de l’inflammasome tissulaire. Nos résultats suggèrent ainsi que le MFG-E8 pourrait être considéré comme un interrupteur inflammatoire et ainsi comme une cible potentielle dans la modulation de maladies inflammatoires.

Research Ethics and Commercial Drug Development: When Integrity Threatens Profitability

Étude de cas / Case study

Performance of Supply Chain when using selected Coordination Mechanisms

Coordination among supply chain members is essential for better supply chain performance. An effective method to improve supply chain coordination is to implement proper coordination mechanisms. The primary objective of this research is to study the performance of a multi-level supply chain while using selected coordination mechanisms separately, and in combination, under lost sale and back order cases. The coordination mechanisms used in this study are price discount, delay in payment and different types of information sharing. Mathematical modelling and simulation modelling are used in this study to analyse the performance of the supply chain using these mechanisms. Initially, a three level supply chain consisting of a supplier, a manufacturer and a retailer has been used to study the combined effect of price discount and delay in payment on the performance (profit) of supply chain using mathematical modelling. This study showed that implementation of individual mechanisms improves the performance of the supply chain compared to ‘no coordination’. When more than one mechanism is used in combination, performance in most cases further improved. The three level supply chain considered in mathematical modelling was then extended to a three level network supply chain consisting of a four retailers, two wholesalers, and a manufacturer with an infinite part supplier. The performance of this network supply chain was analysed under both lost sale and backorder cases using simulation modelling with the same mechanisms: ‘price discount and delay in payment’ used in mathematical modelling. This study also showed that the performance of the supply chain is significantly improved while using combination of mechanisms as obtained earlier. In this study, it is found that the effect (increase in profit) of ‘delay in payment’ and combination of ‘price discount’ & ‘delay in payment’ on SC profit is relatively high in the case of lost sale. Sensitivity analysis showed that order cost of the retailer plays a major role in the performance of the supply chain as it decides the order quantity of the other players in the supply chain in this study. Sensitivity analysis also showed that there is a proportional change in supply chain profit with change in rate of return of any player. In the case of price discount, elasticity of demand is an important factor to improve the performance of the supply chain. It is also found that the change in permissible delay in payment given by the seller to the buyer affects the SC profit more than the delay in payment availed by the buyer from the seller. In continuation of the above, a study on the performance of a four level supply chain consisting of a manufacturer, a wholesaler, a distributor and a retailer with ‘information sharing’ as coordination mechanism, under lost sale and backorder cases, using a simulation game with live players has been conducted. In this study, best performance is obtained in the case of sharing ‘demand and supply chain performance’ compared to other seven types of information sharing including traditional method. This study also revealed that effect of information sharing on supply chain performance is relatively high in the case of lost sale than backorder. The in depth analysis in this part of the study showed that lack of information sharing need not always be resulting in bullwhip effect. Instead of bullwhip effect, lack of information sharing produced a huge hike in lost sales cost or backorder cost in this study which is also not favorable for the supply chain. Overall analysis provided the extent of improvement in supply chain performance under different cases. Sensitivity analysis revealed useful insights about the decision variables of supply chain and it will be useful for the supply chain management practitioners to take appropriate decisions.

Double burden malnutrition of preschool children and its association with brain development and milk consumption

Protecting the quality of children growth and development becomes a supreme qualification for the betterment of a nation. Double burden child malnutrition is emerging worldwide which might have a strong influence to the quality of child brain development and could not be paid-off on later life. Milk places a notable portion during the infancy and childhood. Thus, the deep insight on milk consumption pattern might explain the phenomenon of double burden child malnutrition correlated to the cognitive impairments. Objective: Current study is intended (1) to examine the current face of Indonesian double burden child malnutrition: a case study in Bogor, West Java, Indonesia, (2) to investigate the association of this phenomenon with child brain development, and (3) to examine the contribution of socioeconomic status and milk consumption on this phenomenon so that able to formulate some possible solutions to encounter this problem. Design: A cross-sectional study using a structured coded questionnaire was conducted among 387 children age 5-6 years old and their parents from 8 areas in Bogor, West-Java, Indonesia on November 2012 to December 2013, to record some socioeconomic status, anthropometric measurements, and history of breast feeding. Diet and probability of milk intake was assessed by two 24 h dietary recalls and food frequency questionnaire (FFQ). Usual daily milk intake was calculated using Multiple Source Method (MSM). Some brain development indicators (IQ, EQ, learning, and memory ability) using Projective Multi-phase Orientation method was also executed to learn the correlation between double burden child malnutrition and some brain development indicator. Results and conclusions: A small picture of child double burden malnutrition is shown in Bogor, West Java, Indonesia, where prevalence of Severe Acute Malnutrition (SAM) is 27.1%, Moderate Acute Malnutrition (MAM) is 24.9%, and overnutrition is 7.7%. This phenomenon proves to impair the child brain development. The malnourished children, both under- and over- nourished children have significantly (P-value<0.05) lower memory ability compared to the normal children (memory score, N; SAM = 45.2, 60; MAM = 48.5, 61; overweight = 48.4, 43; obesity = 47.9, 60; normal = 52.4, 163). The plausible reasons behind these evidences are the lack of nutrient intake during the sprout growth period on undernourished children or increasing adiposity on overnourished children might influence the growth of hippocampus area which responsible to the memory ability. Either undernutrition or overnutrition, the preventive action on this problem is preferable to avoid ongoing cognitive performance loss of the next generation. Some possible solutions for this phenomenon are promoting breast feeding initiation and exclusive breast feeding practices for infants, supporting the consumption of a normal portion of milk (250 to 500 ml per day) for children, and breaking the chain of poverty by socioeconomic improvement. And, the national food security becomes the fundamental point for the betterment of the next. In the global context, the causes of under- and over- nutrition have to be opposed through integrated and systemic approaches for a better quality of the next generation of human beings.

A pilot investigation of the relationship between climate variability and milk compounds under the bootstrap technique

This study analyzes the linear relationship between climate variables and milk components in Iran by applying bootstrapping to include and assess the uncertainty. The climate parameters, Temperature Humidity Index (THI) and Equivalent Temperature Index (ETI) are computed from the NASA-Modern Era Retrospective-Analysis for Research and Applications (NASA-MERRA) reanalysis (2002–2010). Milk data for fat, protein (measured on fresh matter bases), and milk yield are taken from 936,227 milk records for the same period, using cows fed by natural pasture from April to September. Confidence intervals for the regression model are calculated using the bootstrap technique. This method is applied to the original times series, generating statistically equivalent surrogate samples. As a result, despite the short time data and the related uncertainties, an interesting behavior of the relationships between milk compound and the climate parameters is visible. During spring only, a weak dependency of milk yield and climate variations is obvious, while fat and protein concentrations show reasonable correlations. In summer, milk yield shows a similar level of relationship with ETI, but not with temperature and THI. We suggest this methodology for studies in the field of the impacts of climate change and agriculture, also environment and food with short-term data.

When a data set can be considered compositional?

Traditionally, compositional data has been identified with closed data, and the simplex has been considered as the natural sample space of this kind of data. In our opinion, the emphasis on the constrained nature of compositional data has contributed to mask its real nature. More crucial than the constraining property of compositional data is the scale-invariant property of this kind of data. Indeed, when we are considering only few parts of a full composition we are not working with constrained data but our data are still compositional. We believe that it is necessary to give a more precise definition of composition. This is the aim of this oral contribution

Regression analysis of compositional data when both the dependent variable and independent variable are components

It is well known that regression analyses involving compositional data need special attention because the data are not of full rank. For a regression analysis where both the dependent and independent variable are components we propose a transformation of the components emphasizing their role as dependent and independent variables. A simple linear regression can be performed on the transformed components. The regression line can be depicted in a ternary diagram facilitating the interpretation of the analysis in terms of components. An exemple with time-budgets illustrates the method and the graphical features

When zero doesn't mean it and other geomathematical mischief

There is almost not a case in exploration geology, where the studied data doesn’t includes below detection limits and/or zero values, and since most of the geological data responds to lognormal distributions, these “zero data” represent a mathematical challenge for the interpretation. We need to start by recognizing that there are zero values in geology. For example the amount of quartz in a foyaite (nepheline syenite) is zero, since quartz cannot co-exists with nepheline. Another common essential zero is a North azimuth, however we can always change that zero for the value of 360°. These are known as “Essential zeros”, but what can we do with “Rounded zeros” that are the result of below the detection limit of the equipment? Amalgamation, e.g. adding Na2O and K2O, as total alkalis is a solution, but sometimes we need to differentiate between a sodic and a potassic alteration. Pre-classification into groups requires a good knowledge of the distribution of the data and the geochemical characteristics of the groups which is not always available. Considering the zero values equal to the limit of detection of the used equipment will generate spurious distributions, especially in ternary diagrams. Same situation will occur if we replace the zero values by a small amount using non-parametric or parametric techniques (imputation). The method that we are proposing takes into consideration the well known relationships between some elements. For example, in copper porphyry deposits, there is always a good direct correlation between the copper values and the molybdenum ones, but while copper will always be above the limit of detection, many of the molybdenum values will be “rounded zeros”. So, we will take the lower quartile of the real molybdenum values and establish a regression equation with copper, and then we will estimate the “rounded” zero values of molybdenum by their corresponding copper values. The method could be applied to any type of data, provided we establish first their correlation dependency. One of the main advantages of this method is that we do not obtain a fixed value for the “rounded zeros”, but one that depends on the value of the other variable. Key words: compositional data analysis, treatment of zeros, essential zeros, rounded zeros, correlation dependency

Comparing methods for dimensionality reduction when data are density functions

Functional Data Analysis (FDA) deals with samples where a whole function is observed for each individual. A particular case of FDA is when the observed functions are density functions, that are also an example of infinite dimensional compositional data. In this work we compare several methods for dimensionality reduction for this particular type of data: functional principal components analysis (PCA) with or without a previous data transformation and multidimensional scaling (MDS) for diferent inter-densities distances, one of them taking into account the compositional nature of density functions. The difeerent methods are applied to both artificial and real data (households income distributions)

Lectures 17 and 18 - Exceptions - when it all goes wrong

Exceptions An Example The Throws keyword Try and Catch The flow Multiple exceptions Finally How exceptions are thrown What the complier checks Handle or Defer Recovery Writing your own

It will be succesful to have a commercial relation between France and Colombia focus on the milk sector ?

Globalization has led to a drastic change on the international trade, this has caused that many countries such as France and Colombia find new business partners. This is the raison because I develop the investigation about How these countries can be integrated commercially in the dairy sector? Colombia and France had active trade relations for more than 8 years, but this has been declining for several factors. In the case of France, it has found that Germany is an excellent producer of raw milk, which can supply domestic demand and can export large quantities with a low price to European countries because of its proximity. For this reason, Colombia is a country that can not compete with Germany directly in raw milk, but I concluded that Colombia could become a major competitor with organic milk. This is the result of a research of the way they raise and feed the cows in the two countries, Colombia is generally on open country and Germany is on cow housing. In Colombia, the country found that Venezuela could offer many benefits in the processing of raw milk, and other processes that require high technology. But today Colombia has had several disputes with Venezuela and many Colombian companies are affected in this sector. Additionally, France is one of the largest producers and distributors of processed milk and its derivatives; it launches annually many manufactured products with high technology. At this point, Colombia can take out the best advantage because it can create an strategic alliance with French companies to bring most innovative and processed products such as cheese and yoghurts. The theoretical framework of this thesis consists on the analysis of competitiveness, because it is relevant to see if these two countries are competitive or if one has the comparative advantage over the other. The related authors are: Michael Porter, Adam Smith and David Ricardo. To complete the theoretical part, we found that France has a comparative advantage over Colombia in this sector thanks to its high technology, and Colombia is not currently competitive in the area of raw milk because the milk price is higher and the distance is a barrier, and it has no technology. But this research indicates that Colombia could become a competitive country selling organic milk.

El impacto del TLC con la Unión Europea en el sector lácteo colombiano

En un mundo globalizado como en el que se vive hoy, se necesitan crear acuerdos comerciales e integraciones económicas que ayuden a la expansión comercial de los países que participan en dichos tratados. Por este motivo es que Colombia durante varias décadas ha buscado relaciones comerciales con diferentes países para facilitar la comercialización de los productos colombianos con el resto del mundo. Al entrar en un acuerdo económico como el Tratado del Libre Comercio se necesita tener productos competitivos, de buena calidad y diferenciados para que puedan mantenerse en un mercado internacional. Este es el caso del sector lácteo colombiano, que se ve amenazado por la firma del TLC con la Unión europea, ya que la Unión Europea es exportador neto de leche, y esto hace que el sector este preocupado el bienestar de pequeños productores, lo que traería como consecuencia un problema en la economía del país. Por este motivo el gobierno ha tomado medidas para proteger este sector y evitar repercusiones que pongan en peligro la estabilidad del sector y que se darán ayudas a este sector para que pueda mejorar sus procesos, renovación tecnológica, mejora de la productividad y demás campos en los que están mal para poder competir con los productores europeos, la ayuda es de 30 millones de euros durante los próximos 5 años; también el gobierno ha puesto restricciones a las cantidades que los países europeos puedan comercializar en Colombia con el fin de garantizar el bienestar de este sector.

Tools to use when writing a thesis in Word 2010/2013 (PC)

This collection of videos shows you how to use a range of time-saving tools when writing a thesis in MS Word 2010/2013. See the full SupportGuide at http://www.go.soton.ac.uk/thesispc. There are videos on using styles; creating tables of contents and tables of figures; using the Navigation Pane; using the Browse Object tool and many more. There is an equivelent collection for use with Word 2011 which is for use with Apple computers.

Tools to use when writing a thesis using Word 2011 (for Apple computers)

A collection of videos on time saving features when using MS Word 2011 to write a thesis. Learn how to use styles, make table of contents, make table of figures, use the document map, use the browse object tool and keep a count of the words in your file and many more useful features of Word 2011. Word 2011 is for Apple computers, there is a collection of similar video for use with the PC version Word 2010.