Happiness, anger, surprise, irritation… if we note down the emotions that we go through on a given day, the list will most probably be quite long. A surge of studies on the bidirectional interaction between emotion and cognition suggests that we need emotional appraisals in order to lead a successful life and maintain our personal, social and economic integrity (Bechara, 2005; Damasio, 1994; Fox, 2008; Gross & Thompson, 2007; Walter, 2005). And yet, we seldom ‘just’ experience emotions, but often try to influence them to best fit our current goals. Based on the assumption that emotional reactions entail changes on various levels, and that these changes happen in- or outside of our awareness, affective science has adopted emotion regulation as one of its major research topics (Beauregard, Levesque, & Paquette, 2004; Gross, 1999; Ochsner, 2007). In fact, neural (e.g. amygdala activation) and behavioral (e.g. feeling of negativity) correlates of emotional reactions are effectively reduced by top-down processes of explicit and implicit control (Drabant, McRae, Manuck, Hariri, & Gross, 2009; Levesque, et al., 2003; Ochsner, Ray, et al., 2004). Furthermore, evidence from studies investigating voluntary thought control suggests that control strategies may have lasting and paradoxical consequences (Abramowitz, Tolin, & Street, 2001; Wegner, 2009). In a very recent investigation, lasting effects of regulation were also shown after the cognitive control of emotions: the activation timecourse of the amygdala was significantly increased immediately following regulation, and this difference was also related to the activation of the amygdala to the same stimuli a few minutes later (Walter, et al., 2009). Aside from these contextual or qualitative influences, emotional processing also differs between individuals: genetic variation within the serotonergic system for instance is known to affect emotional reactivity both on the behavioral and on the neural level (Hariri, et al., 2005; Hariri, et al., 2002; Lesch, et al., 1996). In the present work, the temporal dynamics of volitional emotion regulation were investigated in three studies. It was hypothesized that both the subjective experience of negativity and the amygdala activation can be attenuated by the detachment from negative emotions, which in turn leads to an immediate neural aftereffect after the offset of regulation. Furthermore, volitional emotion regulation was expected to be capable of reducing or even obliterating genetically mediated amygdala hyperreactivity to negative emotional cues. Similar to previous investigations (Walter, et al., 2009), pictures of aversive or neutral emotional content were presented while participants were instructed to react naturally to half of the pictures, and to regulate their emotional response upon the other half of the stimuli. The first two studies of the present work were designed to further characterize the immediate aftereffect of volitional regulation in the amygdala: Study 1 included behavioral ratings of negativity at picture offset and at fixation offset in order to provide behavioral measures of experiential changes, while in Study 2, participants continued to experience or regulate their emotions during a “maintain” phase after picture offset. The primary goal of Study 3 was to evaluate whether volitional emotion regulation can reduce genetically mediated amygdala hyperreactivity to aversive emotional material in individuals with the short variant of the serotonin transporter genotype (Hariri, et al., 2005; Hariri, et al., 2002), and whether the immediate aftereffect is also influenced by the serotonin transporter genotype. In all three studies, the amygdala was significantly activated by aversive versus neutral stimuli, while cognitive emotion regulation attenuated the activation in the amygdala and increased the activation in a frontal-parietal network of regulatory brain regions. This neural effect was complemented by the behavioral ratings which show that the subjective experience of negativity was also reduced by detachment (Study 1). Also in all three studies, an immediate aftereffect was observed in the amygdala following the end of regulation. Moreover, the preoccupation with the previously seen pictures after the scanning session varied across the experimental conditions (Studies 2 and 3). Volitional regulation proved effective in reducing amygdala activation to negative stimuli even in 5-HTTLPR short allele carriers that show an increased reactivity to this type of cue. At the same time, functional coupling of the ventrolateral and medial orbital prefrontal cortex, the subgenual and the rostral anterior cingulate with the amygdala was higher in the s-group. However, in Study 3 the immediate aftereffect was found only in l/l-homozygote individuals following the regulation of fear. Taken together, the results of the three studies clearly show that volitional regulation is effective in reducing behavioral and neural correlates of the experience of negative emotions (Levesque, et al., 2003; Ochsner, Bunge, Gross, & Gabrieli, 2002; Ochsner, Ray, et al., 2004), even in the case of a genetically mediated hyperreactivity to such materials. Thus, it seems reasonable to assume that conscious will can effectively counteract genetic determinants of emotional behavior. Moreover, the present results suggest that the temporal dynamics of volitional emotion regulation are characterized by a paradoxical rebound in amygdala activation after regulation, and that the immediate aftereffect is a marker of the efficiency of the initial and the sustained effects of emotion regulation (Walter, et al., 2009). In summary, the successful replication of the immediate aftereffect of emotion regulation in all three studies of this dissertation opens up exciting new research perspectives: a comparison of the short- and long-term effects of different regulatory strategies, and the investigation of these effects also in positive emotions would complement the present results, since the neural mechanisms involved in these processes show some characteristic differences (Ochsner, 2007; Staudinger, Erk, Abler, & Walter, 2009). A comprehensive characterization of this neural marker and its implications for emotional experience might also be useful with respect to clinical applications. The detailed examination of the various time scales of emotional regulation might for instance inform the diagnostic and therapeutic interventions in affective disorders that are associated with emotional dysfunctions (Brewin, Andrews, & Rose, 2000; Johnstone, van Reekum, Urry, Kalin, & Davidson, 2007). Ultimately, we might thus come to understand the neural underpinnings of what the feelings we have today have to do with the feelings we had yesterday – and with the feelings with might have tomorrow.

Memory monitoring, or the ability to accurately assess one’s memory retrieval success, is known to be declined for older adults. The behavioral decline has been well explored, and is specific to tasks of source monitoring; tasks involving item memory monitoring do not show age-related deficits. This study attempts to further characterize the decline by exploring neuroanatomical contributions to the decline, and genetic influences that may explain performance variability in older adults. Older adults were genotyped for the serotonin transporter (5-HTTLPR) gene, and those that are carriers of the low-expressing allele demonstrate the expected age-related decline of source monitoring performance when compared to younger adults. Interestingly, older adults who lack this allele did not display any decline in performance when compared to younger adults. Neuroanatomical correlates of task performance indicate that prefrontal regions in the inferior and lateral cortices support accurate source memory monitoring, likely through their role in the proper selection of memory cues and inhibition of irrelevant information. This relationship suggests that age-related atrophy occurring in these structures could be responsible for the performance deficits on source memory monitoring tasks. There was no direct relationship seen between genotype for the 5-HTTLPR gene and cortical volumes, however diffusion tensor imaging shows that older adults who carry this allele have altered connections between the medial temporal lobe, responsible for memory retrieval, and prefrontal cortex, which monitors the retrieval process. Through stronger connections of critical networks, older adults who lack the 5-HTTLPR short allele may be able to compensate for the age-related atrophy seen in the prefrontal cortex. Functional results further indicate that the older adult non-carriers recruit inferior and lateral frontal regions to a greater extent than the older adult carriers during accurate memory monitoring. These results begin to suggest a neuroprotective mechanism for the 5-HTTLPR genotype, wherein some older adults may be able to postpone the expected decline of memory monitoring by retaining the ability to recruit essential inferior frontal structures through more organized white matter pathways. / text

No description available.

Many rural communities in South Africa do not have running water or electricity. The fetching and heating of water is therefore a time consuming and expensive daily ritual. The use of energy sources such as wood or coal are not readily available and cause environmental pollution. Although solar water heaters are commonly available in South Africa, they are very seldom used in rural areas. Whilst this can mostly be attributed to a high system cost, current designs also do not cater for specific rural problems such as the transporting or purification of water. A prototype model, designed with such an approach in mind, has already been constructed by TEMM International (Pty.) Ltd. The Solar Heat Barrow (SHB) was developed in the 1992 to 2003 period with the intention of combining a number of functions at low cost. Specific requirements were: low cost, a suitable design and materials for manufacture in large volume, sufficiently durable taking into account the harsh conditions of use. suitability for cases where no in-house piped water supply was available, the use of appropriate technology and the improvement of quality of life. The unit combines the absorption of solar radiation, the heating of a relatively small volume of water, the transport of the water from the point of supply and the storage of the hot water until it is used. Untreated water sources such as surface waters (streams, rivers, lakes, etc.) or unprotected open wells are the vehicles for waterborne bacterial diseases such as cholera and typhoid fevers. In the case where water is collected from these sources, the SHB has a build-in Purification Dispenser that purifies the water in the collector against waterborne bacterial diseases. Certain research questions need to be answered. They will be answered by demonstrating the SHB in two communities where no in-house piped water supply is available and by establishing the socio-economic response of the users. The research questions are as follow: What are the responses of the users concerning the SHB, in comparison to those of a control group, regarding its operation, durability, utility and satisfaction of needs? What is the daily use of hot water and the reduction in energy use and cost? To what extent will the target community purchase the SHB at the full or subsidised commercial price? Is there a business case that can be developed for the large scale production, marketing. financing and Small, Medium and Micro Enterprises (SMME) development of the SHB? It was decided to choose a community in the Valley of Thousand Hills in KwaZulu Natal as the demonstration site. The name of the community is Mabedlane. It is a remote rural area 20 km's north of Botha's Hill and is situated along the Umgeni River. The community is dependent on the river for domestic water. Most families are headed by women. The area has low levels of infrastructure, poor roads, a high unemployment rate and poor health facilities. The first survey, which was conducted before the test period started, showed a very positive response from potential users. From 112 questionnaires that were given to the people of Mabedlane, all indicated that they were interested in a product that can transport and heat water for domestic use. The socio-economic study has shown that the price per unit needs to be adapted as 85% of the people who participated in the survey indicated that they would only pay less than R100 for the product. 15% indicated that they would pay between RlOO and R200. From the second and third questionnaires it was clear that the users were satisfied with the heating performances of the SHB. The community was very interested in purchasing a SHB. They have realised that a SHB will improve their standard of living and regard it as a necessity in their day to day activities. It is apparent that people, who will benefit from a SHB most, are those who will not be able to pay the full retail price. Therefore, new business strategies have to be researched when implementing the SHB to the target market in South Africa. The idea of considering ways to sponsorlfund the SHB must also be investigated. / Thesis (M.Ing. (Mechanical Engineering))--North-West University, Potchefstroom Campus, 2004.

Considerable evidence supports anandamide (AEA) as an important mediator in the regulation of nausea and vomiting. The present study investigates the effect of inhibiting a protein reported to mediate AEA transport, FLAT (FAAH-1-like AEA transporter), on nausea and vomiting and the neural correlates of AEA regulated nausea in the visceral insular cortex (VIC). The systemic administration of the AEA transport inhibitor ARN272 was evaluated in LiCl-induced conditioned gaping in rats, and vomiting in shrews. The effect of intra-cranial administration of ARN272 into the VIC was also investigated using LiCl-induced conditioned gaping in rats. Systemic administration of ARN272 dose-dependently suppressed LiCl-induced conditioned gaping in rats, and was reversed by CB1 receptor antagonism with SR141716. Systemic administration of ARN272 also attenuated vomiting in shrews. Delivery of ARN272 into the VIC produced no effect on LiCl-induced conditioned gaping in rats. These results suggest that preventing the cellular reuptake of AEA through transport inhibition tonically activates CB1 receptors to regulate toxin-induced nausea, but that this is not AEA regulated within the VIC. / This research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC-92057) to LAP.

The ATP-binding cassette (ABC) transporter, ABCA1, plays a pivotal role in reverse cholesterol transport, which is the elimination of excess sterols from peripheral cells and their transport to the liver for elimination. Early studies failed to detect significant ATPase activity, prompting the suggestion that ABCA1 was an ATP-regulated receptor, rather than an active transporter. We have provided evidence that ABCA1 can bind ATP and trap its hydrolysis product, ADP, in the presence of either ortho-vanadate or beryllium fluoride and Mg2+ or Mn2+. We have also shown that both nucleotide-binding domains (NBDs) trap nucleotide comparably, suggesting that ABCA1 is a functional ATPase. In addition, we have shown that ABCA1 can directly transport 25-hydroxycholesterol (25-OHC) in an ATP-dependent manner using a membrane vesicle uptake assay, and can do so when the physiological substrate acceptor apoA-I is replaced with BSA as a non-specific binding protein. Although more than 50 naturally occurring missense mutations and polymorphisms in ABCA1 have been identified in individuals with HDL-C levels within the lowest 5th percentile of the general population, the extent to which many of these mutations affect ABCA1 function is not known and cannot be predicted. Naturally occurring extracellular loop (ECL) mutations W590S and C1477R have both been shown to effectively eliminate the ability to mediate lipid efflux, despite the fact that the W590S mutant protein retains the ability to bind apoA-I. We show that neither mutant can transport nor efflux 25-OHC, whether in the presence of apoA-I or BSA, despite apparently full retention of the ability to bind and trap nucleotide. This suggests that these two ECL mutations inhibit transport by a mechanism that is independent of their effect on apoA-I binding. By introduction of naturally occurring mutations in the NBDs, we show that although some mutations associated with Tangier Disease, such as N935S, essentially eliminate nucleotide trapping and substrate translocation, other polymorphisms such as L1026P and T2073A associated with low HDL-C, appear to be fully functional. Lastly, we observed differences in the behaviour of both wild-type and mutant forms of ABCA1-GFP depending on whether they were expressed in insect or mammalian cell lines. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2010-02-12 11:14:11.381

No description available.

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action. In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 mg/kg/day, i.p.) or vehicle during adolescence (postnatal day 28-55). During adulthood (>77 days), DAT and NET functions in mPFC and OFC were determined as neurochemical mechanisms and locomotor sensitization to cocaine, and impulsivity under differential reinforcement of low rates 30-second (DRL30) schedule were evaluated as behavioral mechanisms associated with greater cocaine self-administration in methylphenidate-treated SHRs. Maximal velocity of [3H]dopamine uptake (Vmax) by DAT and DAT cellular distribution in mPFC and OFC did not differ between vehicle-control, adult SHR, Wistar-Kyoto and Wistar. Methylphenidate increased DAT Vmax, but not cell-surface expression, in SHR mPFC. In contrast, atomoxetine decreased Vmax and cell-surface expression in SHR OFC. Compared to control strains, norepinephrine uptake by NET in the OFC was increased in vehicle-administered SHR; methylphenidate during adolescence normalized NET function in SHR OFC. Locomotor sensitization was greater in SHR compared to control, and was not altered by methylphenidate. Under DRL30, methylphenidate increased burst responses in adult SHR compared to vehicle control as well as methylphenidate-treated Wistar-Kyoto and Wistar, indicating increased impulsivity. Increased OFC NET function, increased impulsivity and cocaine sensitivity may be the neurobehavioral mechanisms associated with the increased cocaine self-administration in SHR. Increased mPFC DAT function may underlie the enhanced impulsivity and cocaine self-administration in SHR administered methylphenidate during adolescence. Decreased OFC DAT function from atomoxetine-treated SHR may explain the reduced cocaine self-administration relative to methylphenidate. Thus, methylphenidate during adolescence in ADHD may increase risk for cocaine abuse, while atomoxetine may represent a therapeutic alternative for at-risk adolescents with ADHD.

Adenosine (ADO) is an endogenous neuroprotectant. Under ischemic conditions ADO levels rise in the brain up to 100-fold. ADO in the brain is dependent on the movement across cell membranes by equilibrative nucleoside transporters (ENT) or produced from membrane bound ecto-5’ nucleotidase (eN). We used transgenic neurons with neuronal specific expression of human ENT1 (hENT1) and eN knockout (CD73 KO) astrocytes. The aim of this research was to determine the role of ENT1 and eN in ADO release from ischemic-like conditions in primary cultured neurons, astrocytes or co-cultures. Neurons primarily release intracellular ADO via ENTs; this effect was blocked by transporter inhibitor, dipyridamole (DPR). Astrocytes primarily convert ADO extracellularly from eN; this effect was with eN inhibitor α, β-methylene ADP (AOPCP). Combined neuron and KO astrocytes produced less ADO, extracellular ADO was inhibited by DPR but not AOPCP. Overall these results suggest that eN is prominent in the formation of ADO but other enzymes or pathways contribute to rising ADO levels in ischemic conditions.

L’explosion de la nanotechnologie a permis l’intégration d’une multitude de nanoparticules dans des produits de consommation. Les nanoparticules d’argent (nAg) sont les plus utilisées à ces fins, selon les derniers recensements disponibles. La plupart des études toxicologiques, à ce jour, ont fait état de l’implication très évidente de l’ion Ag+ dans la toxicité aigüe des nAg; cependant, quelques études ont mis en évidence des effets toxicologiques dus aux nAg. Il y a un certain consensus à propos d’un risque de contamination des eaux douces via leur rejet par les effluents des réseaux d’aqueducs. Puisque les concentrations en Ag+ sont généralement très faibles dans les eaux douces (de l’ordre du pg L-1), de par la formation de complexes non-labiles avec des thiols (organiques et inorganiques) et des sulfures, la toxicité inhérente aux nAg pourrait ne pas être négligeable- comparativement aux tests en laboratoires. Cette étude s’intéressait donc aux mécanismes de bioaccumulation d’argent par l’algue verte C. reinhardtii suite à l’exposition à des nAg de 5 nm (enrobage d’acide polyacrylique). La bioaccumulation d’argent pour l’exposition à Ag+ servait de point de comparaison; également, les abondances de l’ARNm de l’isocitrate lyase 1 (ICL1) et de l’ARNm de Copper Transporter 2 (CTR2) étaient mesurées comme témoins biologiques de la bioaccumulation de Ag+. Les expériences ont été menées en présence d’un tampon organique (NaHEPES, 2 x 10-2 M; Ca2+, 5x 10-5 M) à pH de 7,00. Pour des expositions à temps fixe de 2 heures, la bioaccumulation d’argent pour nAg était supérieure à ce qui était prédit par sa concentration initiale en Ag+; cependant, il n’y avait pas de différence d’abondance des ARNm de ICL1 et de CTR2 entre nAg et Ag+. D’un autre côté, pour une exposition à temps variables, la bioaccumulation d’argent pour nAg était supérieure à ce qui était prédit par sa concentration initiale en Ag+ et une augmentation de l’abondance de l’ARNm de ICL1 était notée pour nAg. Cependant, il n’y avait aucune différence significative au niveau de l’abondance de l’ARNm de CTR2 entre nAg et une solution équivalente en Ag+. L’ajout d’un fort ligand organique (L-Cystéine; log K= 11,5) à une solution de nAg en diminuait radicalement la bioaccumulation d’argent par rapport à nAg-sans ajout de ligand. Par contre, l’abondance des ARNm de ICL1 et de CTR2 étaient stimulées significativement par rapport à une solution contrôle non-exposée à nAg, ni à Ag+. Les résultats suggéraient fortement que les nAg généraient des ions Ag+ au contact de C. reinhardtii. / The recent developments in nanotechnology have given rise to a new and increasing economical market where nanoparticles are at the forefront. Recent inventories of the nanoparticles-containing products have shown that silver nanoparticle- containing products are the most frequently used consumer nanomaterial. Due to the fear of a large scale contamination-and even pollution- of the aquatic environment from silver nanoparticles (nAg), studies have been conducted to assess their toxicities, which, in many cases, have been found to be mediated by the concomitant presence of Ag+. Notably, few studies have found evidence of toxicity due to the nAg, per se. Since numerous non-labile complexes are formed with Ag+ in freshwaters- especially with thiols and sulfides-, nAg toxicity might be more relevant in comparison to laboratory tests where the Ag+ tends to dominate toxicity studies. Therefore, this study investigated the mechanisms underlying silver bioaccumulation by the green alga, C. reinhardtii upon exposure to solutions of nAg (nominal size of 5 nm; poly-acrylate coating). Silver bioaccumulation upon exposures to the free ion alone served for comparison. In parallel, the abundance of two mRNAs- ICL1 and CTR2- were used to better understand the mechanisms underlying the bioaccumulation of Ag+ (and potentially nAg). The experiments were conducted in pH buffered solutions (NaHEPES, 2 x 10-2 M; Ca2+, 5x 10-5 M) at pH 7.00. For 2-hour exposures, the silver bioaccumulation for solutions of nAg exceeded what was expected from their Ag+ content only; however, no differences were noticed in the abundance of the expression of ICL1 and CTR2. For variable time exposures, the silver bioaccumulation for solutions of nAg exceeded what was expected from their Ag+ content only. Moreover, the expression of ICL1 was significantly higher for nAg than what was expected based upon an exposure to Ag+ only. When exposed to nAg, expression levels of CTR2 could be predicted from levels based solely on the Ag+ concentrations. The addition of a large excess of L-Cysteine, which is a very strong silver ligand (log K =11.5), to a nAg solution largely decreased silver bioaccumulation, however, bioaccumulation remained significant and the expression of both ICL1 and CTR2 were significantly higher than that of the control solutions (without Ag+). The results strongly suggest that nAg generated Ag+ ions when in contact with C. reinhardtii and that the nAg released to freshwaters might exert its toxicity through organism-contact-dependant release of Ag+.