My diploma thesis designs a suitable alternace of shifting a production for Havlík Opal Ltd. company. This step should fulfil the firms requierements to lower the costs, savings creation, modersination of technology, production atuomation and help to generate higher profit.

This diploma thesis serves as a basis for a changes in the marketing mix for company BTR Group Ltd., which focuses on the distribution of handmade cymbals from Turkey. Results of this diploma thesis are suggestions and recommendations for changes in the marketing mix based on analyzes and observations. I believe that my ideas and insights will lead company to acquire a new customers, strengthen market posiotion a business succes.

[ES] Las cerámicas son cada vez más utilizadas como materiales estructurales con aplicaciones biomédicas debido a sus propiedades mecánicas, biocompatibilidad, características estéticas y durabilidad. En concreto, los compuestos a base de óxido de circonio se utilizan comúnmente para desarrollar restauraciones sin metal en implantes dentales. La consolidación de las cerámicas suele realizarse a través de polvos mediante procesos que requieren de mucha energía, ya que se necesitan largos tiempos de procesado y altas temperaturas (mayores de 1000 C). Nuevas investigaciones se están desarrollando en este campo para reducir tanto el consumo energético como el tiempo del procesado de polvos cerámicos. Una de las técnicas más prometedoras en cuanto a la sinterización de cerámicas es la tecnología de calentamiento rápido por microondas. El principal objetivo de esta tesis doctoral es la obtención de compuestos circona-alúmina con densidades próximas a las teóricas mediante una técnica de sinterización no convencional, conocida como tecnología de microondas. Concretamente, los materiales que se van a estudiar en este trabajo son: 10Ce-TZP/Al2O3 y 3Y-TZP/Al2O3 (ATZ). Tras su sinterización, los materiales son caracterizados con el fin de determinar si las propiedades finales cumplen con los requisitos mecánicos para sus aplicaciones finales, ortopedia y/o dentales. Además, se ha estudiado la resistencia al desgaste de los composites sinterizados para comprobar su durabilidad. Finalmente, se ha investigado la degradación hidrotermal a baja temperatura, cuyo proceso consiste en la transformación de fase espontánea de la circona, dando lugar a un envejecimiento del material. Los resultados de este trabajo indican que los composites circona-alúmina pueden ser consolidados mediante la tecnología de microondas, obteniéndose materiales con propiedades mecánicas comparables a los obtenidos mediante métodos convencionales, pero con una reducción en el tiempo de procesado del 90 %. Por otro lado, la resistencia al desgaste de dichos composites también es del mismo orden de magnitud para ambas técnicas de sinterización. Respecto a la degradación hidrotermal a baja temperatura, los resultados obtenidos sugieren que las muestras consolidadas mediante microondas tienen una mayor resistencia a la degradación (para el composite 3Y-TZP/Al2O3), mientras que para el composite el 10Ce-TZP/Al2O3, no se observa un envejecimiento significativo para ninguna de las muestras. Esto es consecuencia de la adición de la ceria como estabilizador de fase tetragonal de la circona, aumentando la resistencia de la degradación hidrotermal a baja temperatura. En resumen, la sinterización por microondas ha demostrado ser una alternativa excepcional para la sinterización de composites circona-alúmina, debido a la microestructura obtenida y a las excepcionales propiedades mecánicas de los materiales resultantes. Además, esta tecnología requiere temperaturas de sinterización y tiempos de permanencia más bajos que la sinterización convencional, lo que conlleva una reducción de los costes energéticos y de los tiempos de procesamiento y, en consecuencia, la técnica de calentamiento por microondas tiene un menor impacto medioambiental. / [CA] Les ceràmiques són cada vegada més utilitzades com a materials estructurals amb aplicacions biomèdiques a causa de les seues propietats mecàniques, biocompatibilitat, característiques estètiques i durabilitat. En concret, els compostos a base d'òxid de zirconi s'utilitzen comunament per a desenvolupar restauracions sense metall i implants dentals. La consolidació de les ceràmiques sol realitzar-se a través de pols mitjançant processos que requereixen de molta energia, ja que es necessiten llargs temps de processament i altes temperatures (majors a 1000 C). Noves investigacions s'estan desenvolupant en aquest camp per a reduir tant el consum energètic com el temps del processament de pols ceràmiques. Una de les tècniques més prometedores quant a la sinterització de ceràmiques és la tecnologia de calfament per microones. El principal objectiu d'aquesta tesi doctoral és l'obtenció de compostos circonaalúmina altament densificats mitjançant una tècnica de sinterització no convencional, coneguda com a tecnologia de microones. Concretament, els materials que s'estudiaran en aquest treball són: 10Ce-TZP/Al2O3 i 3Y-TZP/Al2O3 (ATZ). Després de la seua sinterització, els materials són caracteritzats amb la finalitat de determinar si les propietats finals compleixen amb els requisits mecànics per a les seues aplicacions finals, ortopèdia i/o dentals. A més, s'ha estudiat la resistència al desgast dels composites sinteritzats per a comprovar la seua durabilitat. Finalment, s'ha investigat la degradació hidrotermal a baixa temperatura, la qual consisteix en la transformació de fase espontània de la circona, donant lloc a un envelliment del material. El resultats d'aquest treball indiquen que els composites circona-alúmina poden ser consolidats mitjançant la tecnologia de microones, obtenint-se materials amb propietats mecàniques comparables als obtinguts mitjançant mètodes convencionals. A més, la resistència al desgast dels composites també és del mateix ordre de magnitud per a les dues tècniques de sinterització. Respecte a la degradació hidrotermal a baixa temperatura, els resultats obtinguts suggereixen que les mostres consolidades mitjançant microones tenen una major resistència a la degradació (per al composite ATZ), mentre que per al composite el 10Ce-TZP/Al2O3, no s'observa un envelliment significatiu per a cap de les mostres. Això és conseqüència de l'addició de la ceria com a estabilitzador de fase tetragonal de la circona, augmentant la resistència de la degradació hidrotermal a baixa temperatura. En definitiva, la sinterització per microones ha demostrat ser una alternativa excepcional per a la sinterització de compostos circona-alúmina, a causa de la fina microestructura i a les excepcionals propietats mecàniques dels materials resultants. A més, aquesta tecnologia requereix temperatures de sinterització i temps de permanència més baixos que la sinterització convencional, la qual cosa comporta una reducció dels costos energètics i dels temps de processament i, en conseqüència, la tècnica de calfament per microones té un menor impacte mediambiental. / [EN] Ceramics are increasingly used as structural materials with biomedical applications due to their mechanical properties, biocompatibility, aesthetic characteristics and durability. Specifically, zirconia-based compounds are commonly used to develop metal-free restorations and dental implants. The consolidation of ceramics is usually carried out through powders by means of processes that require a lot of energy, as long processing times and high temperatures (over 1000oC) are required. New research is being developed in this field to reduce both energy consumption and processing time of ceramic powders. One of the most promising techniques for sintering ceramics is microwave heating technology. The main objective of this doctoral thesis is to obtain highly densified zirconia-alumina compounds by means of a non-conventional sintering technique, known as microwave technology. Specifically, the materials to be studied in this work are: 10Ce-TZP/Al2O3 and 3Y-TZP/Al2O3 (ATZ). After sintering, the materials are characterized in order to determine whether the final properties meet the mechanical requirements for their final applications, orthopaedics and / or dental. In addition, the wear resistance of sintered composites has been studied to test their durability. Finally, hydrothermal degradation at low temperature has been investigated, the process of which consists in the spontaneous phase transformation of the zirconia, leading to an ageing of the material. The results of this work indicate that zirconia-alumina composites can be consolidated by means of microwave technology, obtaining materials with mechanical properties comparable to those obtained by conventional methods. In addition, the wear resistance of these composites is also of the same order of magnitude for both sintering techniques. Regarding hydrothermal degradation at low temperature, the results obtained suggest that the samples consolidated by microwave have a higher resistance to degradation (for composite ATZ), while for composite 10Ce-TZP/Al2O3, no significant aging is observed for any of the samples. This is a consequence of the addition of ceria as a tetragonal phase stabilizer of zirconia, increasing the resistance of hydrothermal degradation at low temperature. In short, microwave sintering has proven to be an exceptional alternative for sintering zirconia-alumina compounds, due to the fine microstructure and the exceptional mechanical properties of the resulting materials. In addition, this technology requires lower sintering temperatures and residence times than conventional sintering, which leads to a reduction in energy costs and processing times and, consequently, the microwave heating technique has a lower environmental impact. / A la Generalitat Valenciana, por la concesión del proyecto PROMETEO para grupos de excelencia (PROMETEO/2016/040), del cual ha sido financiado mi contrato predoctoral para la realización de esta Tesis Doctoral. / Gil Flores, L. (2020). DISEÑO Y DESARROLLO DE BIOCERÁMICAS BASE CIRCONA OBTENIDAS MEDIANTE TECNOLOGÍA DE MICROONDAS [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/141086 / TESIS

Synapses can be altered due to experiences in a process called synaptic plasticity, which causes memory formations. Synapses can be strengthened through methods known as long-term potentiation (LTP) or weakened through long-term depression (LTD). Stresses can cause changes by altering synapses through either LTP or LTD. Rats were used to study the effects of post-traumatic stress disorder (PTSD)-like symptoms and a prophylactic treatment using pharmaceuticals. The first model used was the single prolonged stress (SPS) with two weeks of chronic light, which was not as effective for causing changes in synaptic plasticity. The second model, seven days of social defeat (SD) with two weeks of chronic light was more effective at inducing PTSD-like behavior symptoms and causing changes in LTP levels in the ventral hippocampus, amygdala, and prefrontal cortex between stressed and non-stressed rats. For the prophylactic treatment, propranolol and mifepristone were administered one week prior to and throughout the two weeks of the social defeat protocol. The drugs were able to prevent the changes due to stress on LTP in the three aforementioned brain regions, but did not change the anxious behavior of the rats. An enzyme-linked immunosorbent assay (ELISA) was used to determine corticosterone and norepinephrine levels between the different groups of rats. No significant differences were detected between SD and control rats, but SD injected rats were different from controls indicating that the injections were causing added stress. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was used to detect changes in the adrenergic, corticoid, AMPA, and NMDA receptors. There were a few significant changes to some of the targets indicating that the stress protocol and drugs were having an effect on the mRNA expression. Propranolol and mifepristone could possibly be used as a prophylactic treatment for traumatic stress. In a separate study, techniques were used to determine the negative effects chronic stress (non-PTSD-like) has on synaptic plasticity in the dorsal hippocampus and to show how exercise was able to mitigate some of those negative stress effects. Electrophysiology showed differences in LTP between four groups of mice: sedentary no stress (SNS), sedentary with stress (SWS), exercise with stress (EWS), and exercise no stress (ENS). SWS had the lowest amount of LTP, whereas ENS had the highest. SNS and EWS had similar levels of LTP, which were in between the SWS and ENS groups. Corticosterone blood levels measured by an ELISA showed significant increases in the stressed groups compared to the non-stressed groups. The radial arm maze showed that both groups of exercise mice made fewer reference memory errors the second week of testing compared to the sedentary groups. RT-qPCR determined that brain-derived neurotrophic factor (BDNF) and corticoid and dopamine 5 receptors were likely causing some of the memory changes.

Synapses can be altered due to experiences in a process called synaptic plasticity, which causes memory formations. Synapses can be strengthened through methods known as long-term potentiation (LTP) or weakened through long-term depression (LTD). Stresses can cause changes by altering synapses through either LTP or LTD. Rats were used to study the effects of post-traumatic stress disorder (PTSD)-like symptoms and a prophylactic treatment using pharmaceuticals. The first model used was the single prolonged stress (SPS) with two weeks of chronic light, which was not as effective for causing changes in synaptic plasticity. The second model, seven days of social defeat (SD) with two weeks of chronic light was more effective at inducing PTSD-like behavior symptoms and causing changes in LTP levels in the ventral hippocampus, amygdala, and prefrontal cortex between stressed and non-stressed rats. For the prophylactic treatment, propranolol and mifepristone were administered one week prior to and throughout the two weeks of the social defeat protocol. The drugs were able to prevent the changes due to stress on LTP in the three aforementioned brain regions, but did not change the anxious behavior of the rats. An enzyme-linked immunosorbent assay (ELISA) was used to determine corticosterone and norepinephrine levels between the different groups of rats. No significant differences were detected between SD and control rats, but SD injected rats were different from controls indicating that the injections were causing added stress. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was used to detect changes in the adrenergic, corticoid, AMPA, and NMDA receptors. There were a few significant changes to some of the targets indicating that the stress protocol and drugs were having an effect on the mRNA expression. Propranolol and mifepristone could possibly be used as a prophylactic treatment for traumatic stress. In a separate study, techniques were used to determine the negative effects chronic stress (non-PTSD-like) has on synaptic plasticity in the dorsal hippocampus and to show how exercise was able to mitigate some of those negative stress effects. Electrophysiology showed differences in LTP between four groups of mice: sedentary no stress (SNS), sedentary with stress (SWS), exercise with stress (EWS), and exercise no stress (ENS). SWS had the lowest amount of LTP, whereas ENS had the highest. SNS and EWS had similar levels of LTP, which were in between the SWS and ENS groups. Corticosterone blood levels measured by an ELISA showed significant increases in the stressed groups compared to the non-stressed groups. The radial arm maze showed that both groups of exercise mice made fewer reference memory errors the second week of testing compared to the sedentary groups. RT-qPCR determined that brain-derived neurotrophic factor (BDNF) and corticoid and dopamine 5 receptors were likely causing some of the memory changes.

L’objectif principal de mon projet de thèse a été d’identifier les mécanismes neuronaux adaptatifs se mettant en place au niveau des circuits de la récompense et des circuits activés en réponse à un stress aigu. Plus spécifiquement, nous avons étudié le rôle du noyau du lit de la strie terminale (BNST) au sein de ces deux circuits. Mon hypothèse est que le BNST appartient à un circuit de structures interconnectées dans lequel il intègre des informations contextuelles (hippocampe ventral) et des informations émotionnelles (cortex préfrontal médian) afin, d’une part, de réguler les niveaux d’anxiété innés ainsi que les réponses induites par les centres du stress suite à un épisode de stress aigu mais également, d’adapter l’activité des neurones dopaminergiques de l’aire tegmentale ventrale (VTA) en vue de motiver ou d’empêcher la reproduction d’un comportement associé à un stimulus récompensant ou aversif. Afin de tester cette hypothèse, nous avons mis en place et développé différents projets de recherche combinant des approches d’électrophysiologie in vivo, anatomiques et comportementales. Dans un premier temps, nous nous sommes intéressés au BNST en tant que structure clef participant à la régulation des centres de stress. Grâce à l’utilisation d’approches d’électrophysiologie in vivo chez la souris anesthésiée, nous avons montré qu’après l’exposition à un stress aigu, les neurones du BNST adaptent leur réponse suite à la stimulation du cortex préfrontal médian et passent d’une dépression à long terme (LTD) en situation contrôle à une potentialisation à long terme (LTP) après un stress aigu. Nous avons disséqué une partie des mécanismes permettant l’élaboration de ces plasticités grâce à l’utilisation de souris génétiquement modifiés pour le récepteur aux endocannabinoïdes de type 1 (CB1-R). Ainsi, nous avons trouvé que la LTD et la LTP mis en place dans le BNST sont médiées par le système endocannabinoïde via les récepteurs CB1. Ensuite, nous avons étudié le rôle du ventral subiculum (vSUB) dans la régulation des neurones du BNST ainsi que l’impact de l’activation de cette voie vSUB-BNST sur l’autre voie glutamatergique ILCx-BNST. Tout d’abord, nous avons montré par des approches électrophysiologiques et anatomiques, qu’un même neurone du BNST est capable d’intégrer des informations provenant à la fois du ventral subiculum et du cortex infralimbic (ILCx). Nous avons induit in vivo une LTP NMDA dépendante dans la voie vSUB-BNST suite à un protocole de stimulation haute fréquence dans le vSUB alors qu’en parallèle ce même protocole induit une LTD sur ces mêmes neurones dans la voie ILCx–BNST. Deplus, nous avons noté que ces adaptations plastiques se mettant en place dans le BNST suiteà une simple stimulation haute fréquence dans le vSUB permettent à long terme de diminuerles niveaux d’anxiété innés chez le rat. Enfin, nous avons mis en évidence que le BNST est un relai excitateur entre le vSUBet la VTA. Nous avons montré qu’une stimulation à haute fréquence dans le vSUBpotentialise in vivo l’activité des neurones dopaminergiques (DA) de la VTA. Or le vSUBne projette pas de manière directe sur les neurones DA de la VTA. Nous avons observé quece protocole de stimulation haute fréquence dans le vSUB induit dans un premier temps uneLTP NMDA dépendante dans les neurones du BNST projetant à la VTA qui est nécessairepour observer cette potentialisation des neurones DA. En dernier lieu, nous avons montréque cette potentialisation des neurones DA de la VTA augmente la réponse locomotrice à unchallenge avec de la cocaine.Ainsi, l’ensemble de ces projets nous ont permis de confirmer et de préciser lafonction majeure du BNST dans la régulation du stress et de l’anxiété ainsi que dans lecircuit de la motivation. / The main goal of my PhD was to identify the adaptive neuronal mechanismsdeveloping in the reward circuit and in the circuit implicated in the regulation of stressresponses. More specifically, we have studied the function of the bed nucleus of the striaterminalis (BNST) in both circuits.My hypothesis was that, the BNST belongs to interconnected circuits in whichintegrates contextual (from ventral hippocampus) and emotional informations (from medialprefrontal cortex). Thus, the BNST diffuses these informations in order to regulate the basalinnate level of anxiety and stress centers responses induced after acute stress exposure, butalso to adapt the activity of dopaminergic neurons of the ventral tegmental area (VTA) thatcan promote or prevent a behavioral task associated with a rewarding or aversive stimulus.To test this hypothesis, we decided to develop several research projects usingelectrophysiological, anatomical and behavioral approaches.Firstly, we focused our interest on the stress circuit in which the BNST is a keystructure which participates in regulating the responses of stress centers after acute stressexposure. By using in vivo electrophysiology approach in anesthetized mice, we haveshown that after acute restraint stress, BNST neurons adapt their plastic responses inducedby the tetanic stimulation of the medial prefrontal cortex: switch from long term depression(LTD) under control condition to long term potentiation (LTP) after acute stress condition.Furthermore, we demonstrated that both LTD and LTP are endocannabinoid dependent byusing genetic modified mice for the type 1 endocannabinoid receptors and localpharmacological approach in the BNST.In a second step, we studied the function of the ventral subiculum (vSUB) in theregulation of BNST neurons and the impact of the vSUB-BNST pathway activation on theother glutamatergic ILCx-BNST pathway. In a first set of experiments, we showed that asame single BNST neuron could integrate informations from both vSUB and the infralimbiccortex. By using high frequency stimulation (HFS) protocols, we induced in vivo NMDAdependentLTP in the vSUB-BNST pathway whereas the same protocol led to LTD in thesame BNST neurons in the ILCx-BNST pathway. Moreover, we noted single application ofHFS protocol in the vSUB induced a long term decrease of the basal innate level of anxietyin rats.Lastly, we presented the BNST as a key excitatory relay between the vSUB and theVTA. Here, we have shown that in vivo HFS protocols in the vSUB potentiate the activity ofdopaminergic (DA) neurons of the VTA. However, the vSUB does not directly project to theVTA. We observed that a HFS protocol in the vSUB first induce NMDA-dependent LTP inBNST neurons that project to the VTA, which is necessary to promote the potentiation of7VTA DA neurons. In the last step, we demonstrated in vivo that the potentiation of VTA DAneurons increases the locomotor response to cocaine challenge.All together, these projects allow us to confirm and detail the major function of theBNST in the regulation of stress and anxiety and also in the motivational circuit.

As a medium-sized life insurance company Assupol Life provide life insurance products to clients within government departments, although the company entered the broader private market. The enactment of the Financial Advisory and Intermediary Services Act, 2002 and the Financial Intelligence Centre Act, 2001 impacted financial service providers and the research analysed the influence of regulation on managerial decision making, marketing and sales, finance, human resources, training and the structures within the organisation to comply with the legislation. The study endeavoured to determine the influence of regulation on the company and the measures implemented by the management of Assupol Life. The research results confirmed that the primary challenge faced by the company is to find a balance between compliance, managing human capital and creating value for shareholders. The major impact of the legislation involves the human resource- and training functions and the study illustrated that other influences was less severe. / Business Administration / M. Tech. (Business Administration)

Thesis (MBA (Business Management))--University of Stellenbosch, 2008. / ENGLISH SUMMARY: The onset of globalisation has brought major shifts in business conduct where stakeholder expectations and business priorities and obligation are concerned, bringing a whole new meaning to the issue of sustainable development. In the past, sustainable development essentially concerned the environment, particularly the safeguarding of ecological interests through more responsible business practices. However, over the years, this perspective has evolved to give equal priority to economic, ecological, as well as social interests. The shift in business priorities and obligation has increased the significance of corporate social responsibility (CSR), or the discretionary contribution of corporate resources towards social, environmental and economic development, as defined by the study. The practice of CSR, too, has evolved over time – from being mostly once-off, random philanthropic donations, to a more strategic approach that aligns CSR initiatives with national and corporate objectives. Today, CSR has become an item on many corporate agendas worldwide and hence, the study seeks to explore the concept of corporate social responsibility to gain a deeper understanding of the issue. The aims of the study are to gain an understanding of Corporate Social Responsibility and its dynamics, to establish the nature and scope of CSR at NAMDEB Diamond Corporation, and to establish how CSR at NAMDEB aligns with current global approaches and practices. These will be achieved through an analytical study of CSR literature, an exploration of Government’s expectations of the private sector with regard to CSR, and by exploring NAMDEB’s CSR initiatives and practices. In Chapter 2, the meaning of CSR is explored and defined, followed by a discussion of the history, trends, approaches and practices in CSR. The chapter also presents global initiatives relevant to sustainable development and CSR. Following the literature review, Chapter 3 explores the Government’s expectations of the private sector in terms of its support and involvement in socioeconomic development in Namibia. NAMDEB Diamond Corporation (Pty) Ltd was selected for the case study, being a leading mining company in Namibia. The Company is the second-largest employer in Namibia, only second to Government, and the country’s largest single taxpayer. In Chapter 4, the study explores the Company’s CSR initiatives and practices to establish the scope and nature of CSR at NAMDEB. The study then seeks to determine the approach adopted by the Company in implementing CSR, and how it aligns with global approaches and practices. The main conclusions of the study and recommendations to the Company are laid down in Chapter 5. / AFRIKAANSE OPSOMMING: Die aanvang van globalisering het ‘n groot verskuiwing veroorsaak aangaande die besigheidspraktyk van belangstellendes, hul besigheidsprioriteite, verantwoordelikhede en ‘n heel nuwe betekenis vir volhoubare ontwikkeling. In die verlede was volhoubare ontwikkeling meer gemoeid met die omgewing, veral die beskerming van sekere ekologiese belange deur middel van meer verantwoordelike besigheidspraktyke. Oor die jare het die konsep van volhoubare ontwikkeling soveel verander en gee nou ook gelyke aandag aan ekonomiese, ekologiese sowel as sosiale belange. Die verskuiwing in besigheidsprioriteite en verantwoordelikhede het die belang van korporatiewe-sosiale verantwoordelikhede (KSV) verhoog, of te wel die oordeelkundige bydrae van korporatiewe hulpbronne vir sosiale-, omgewings en ekonomiese ontwikkeling, soos deur die studie gedefineer. Die praktyk van KSV het ook mettertyd ontwikkel – van eenmalige, willekeurige filantrofiese donasies, na ‘n meer strategiese benadering wat nasionale sowel as korporatiewe objektiewe met KSV inisiatiewe inskakel. Deesdae is KSV ‘n item op agendas van baie wêreldwye korporasies, en gevolglik is die studie se doel om die konsep van KSV te eksploreer en te ontleed om sodoende dit beter te verstaan. Die doel van die studie is om KSV en sy dinamika beter te verstaan asook die omvang van KSV te NAMDEB Diamand Korporasie, en om vas te stel hoe KSV te NAMDEB met huidige wêreldwye benaderings en uitvoerings inskakel. Dié word bereik met ‘n analitiese studie van KSV literatuur, ‘n eksplorasie van die regering se verwagting van die private sektor aangaande KSV, en met die ondersoek van NAMDEB se KSV inisiatiewe en praktyke. In Hoofstuk 2 word die betekenis van KSV eksploreer en gedefineer. Hierop volg ‘n bespreking oor die geskiedenis, tendens, benaderings en uitvoering van KSV. Die hoofstuk beeld ook wêreldwye inisiatiewe wat relevant is tot KSV en volhoubare ontwikkeling. Die literatuur oorsig word deur Hoofstuk 3 gevolg, wat die regering se verwagting van die private sektor in terme van dié se ondersteuning en betrokkenheid by die sosio-ekonomiese ontwikkeling in Namibie eksploreer. NAMDEB is vir hierdie gevalstudie geselekteer omdat dit ‘n leidende korporasie in die mynwese van Namibia is. Die Maatskappy is die tweede grootste werkverskaffer in Namibie, naas die regering, en is ook die grootste enkel belastingbetaler in die land. Hoofstuk 4 kyk na die Maatskappy se KSV inisiatiewe en praktyke om sodoende die omvang en natuur van KSV té NAMDEB te bepaal. Die studie probeer verder om die benadering wat deur NAMDEB aangeneem is met die implementering van KSV te bepaal en hoe dit met wêreldwye benaderings en praktyke inskakel. Die hoofafleidings van die studie en voorstelle oor KSV aan die Maatskappy word in Hoofstuk 5 bespreek.

La déficience intellectuelle affecte de 1 à 3% de la population mondiale, ce qui en fait le trouble cognitif le plus commun de l’enfance. Notre groupe à découvert que des mutations dans le gène SYNGAP1 sont une cause fréquente de déficience intellectuelle non-syndromique, qui compte pour 1-3% de l’ensemble des cas. À titre d’exemple, le syndrome du X fragile, qui est la cause monogénique la plus fréquente de déficience intellectuelle, compte pour environ 2% des cas. Plusieurs patients affectés au niveau de SYNGAP1 présentent également des symptômes de l’autisme et d’une forme d’épilepsie. Notre groupe a également montré que SYNGAP1 cause la déficience intellectuelle par un mécanisme d’haploinsuffisance. SYNGAP1 code pour une protéine exprimée exclusivement dans le cerveau qui interagit avec la sous-unité GluN2B des récepteurs glutamatergique de type NMDA (NMDAR). SYNGAP1 possède une activité activatrice de Ras-GTPase qui régule négativement Ras au niveau des synapses excitatrices. Les souris hétérozygotes pour Syngap1 (souris Syngap1+/-) présentent des anomalies de comportement et des déficits cognitifs, ce qui en fait un bon modèle d’étude. Plusieurs études rapportent que l’haploinsuffisance de Syngap1 affecte le développement cérébral en perturbant l’activité et la plasticité des neurones excitateurs. Le déséquilibre excitation/inhibition est une théorie émergente de l’origine de la déficience intellectuelle et de l’autisme. Cependant, plusieurs groupes y compris le nôtre ont rapporté que Syngap1 est également exprimé dans au moins une sous-population d’interneurones GABAergiques. Notre hypothèse était donc que l’haploinsuffisance de Syngap1 dans les interneurones contribuerait en partie aux déficits cognitifs et au déséquilibre d’excitation/inhibition observés chez les souris Syngap1+/-. Pour tester cette hypothèse, nous avons généré un modèle de souris transgéniques dont l’expression de Syngap1 a été diminuée uniquement dans les interneurones dérivés des éminences ganglionnaires médianes qui expriment le facteur de transcription Nkx2.1 (souris Tg(Nkx2,1-Cre);Syngap1). Nous avons observé une diminution des courants postsynaptiques inhibiteurs miniatures (mIPSCs) au niveau des cellules pyramidales des couches 2/3 du cortex somatosensoriel primaire (S1) et dans le CA1 de l’hippocampe des souris Tg(Nkx2,1-Cre);Syngap1. Ces résultats supportent donc l’hypothèse selon laquelle la perte de Syngap1 dans les interneurones contribue au déséquilibre d’excitation/inhibition. De manière intéressante, nous avons également observé que les courants postsynaptiques excitateurs miniatures (mEPSCs) étaient augmentés dans le cortex S1, mais diminués dans le CA1 de l’hippocampe. Par la suite, nous avons testé si les mécanismes de plasticité synaptique qui sous-tendraient l’apprentissage étaient affectés par l’haploinsuffisance de Syngap1 dans les interneurones. Nous avons pu montrer que la potentialisation à long terme (LTP) NMDAR-dépendante était diminuée chez les souris Tg(Nkx2,1-Cre);Syngap1, sans que la dépression à long terme (LTD) NMDAR-dépendante soit affectée. Nous avons également montré que l’application d’un bloqueur des récepteurs GABAA renversait en partie le déficit de LTP rapporté chez les souris Syngap1+/-, suggérant qu’un déficit de désinhibition serait présent chez ces souris. L’ensemble de ces résultats supporte un rôle de Syngap1 dans les interneurones qui contribue aux déficits observés chez les souris affectées par l’haploinsuffisance de Syngap1. / Intellectual disability affects 1-3% of the world population, which make it the most common cognitive disorder of childhood. Our group discovered that mutation in the SYNGAP1 gene was a frequent cause of non-syndromic intellectual disability, accounting for 1-3% of the cases. For example, the fragile X syndrome, which is the most common monogenic cause of intellectual disability, accounts for 2% of all cases. Some patients affected by SYNGAP1 also showed autism spectrum disorder and epileptic seizures. Our group also showed that mutations in SYNGAP1 caused intellectual disability by an haploinsufficiency mechanism. SYNGAP1 codes for a protein expressed only in the brain which interacts with the GluN2B subunit of NMDA glutamatergic receptors (NMDAR). SYNGAP1 possesses a Ras-GAP activating activity which negatively regulates Ras at excitatory synapses. Heterozygote mice for Syngap1 (Syngap1+/- mice) show behaviour abnormalities and learning deficits, which makes them a good model of intellectual disability. Some studies showed that Syngap1 affects the brain development by perturbing the activity and plasticity of excitatory neurons. The excitatory/inhibitory imbalance is an emerging theory of the origin of intellectual disability and autism. However, some groups including ours, showed that Syngap1 is expressed in at least a subpopulation of GABAergic interneurons. Therefore, our hypothesis was that Syngap1 happloinsufficiency in interneurons contributes in part to the cognitive deficits and excitation/inhibition imbalance observed in Syngap1+/- mice. To test this hypothesis, we generated a transgenic mouse model where Syngap1 expression was decreased only in GABAergic interneurons derived from the medial ganglionic eminence, which expresses the transcription factor Nkx2.1 (Tg(Nkx2,1-Cre);Syngap1 mouse). We showed that miniature inhibitory postsynaptic currents (mIPSCs) were decreased in pyramidal cells in layers 2/3 in primary somatosensory cortex (S1) and in CA1 region of the hippocampus of Tg(Nkx2,1-Cre);Syngap1 mice. Those results suggest that Syngap1 haploinsufficiency in GABAergic interneurons contributes in part to the excitation/inhibition imbalance observed in Syngap1+/- mice. Interestingly, we also observed that miniature excitatory postsynaptic currents (mEPSCs) were increased in cortex S1 but decreased in CA1 region of the hippocampus. We further tested whether synaptic plasticity mechanisms that are thought to underlie learning and memory were affected by Syngap1 haploinsufficiency in GABAergic interneurons. We showed that NMDAR-dependent long-term potentiation (LTP) but not NMDAR-dependent long-term depression (LTD) was decreased in Tg(Nkx2,1-Cre);Syngap1 mice. We also showed that GABAA receptor blockade rescued in part the LTP deficit in Syngap1+/- mice, suggesting that a disinhibition deficit is present in these mice. Altogether, the results support a functional role of Syngap1 in GABAergic interneurons, which may in turn contributes to the deficit observed in Syngap1+/- mice.

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