The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson’s disease. A novel intrastriatal rotenone model of Parkinson’s disease was used to examine the neuroprotective effects of valproic acid (VPA) and melatonin, both of which are known to induce neurotrophic gene expression in the central nervous system via mechanisms which may involve epigenetic modulation. In these studies, sham or lesioned rats were treated with either vehicle, VPA (4mg/mL), or melatonin (4µg/mL) in drinking water. Results from a forelimb asymmetry test indicated a significant decrease in use of the contralateral forelimb in rotenone-infused animals, in the third week post-surgery, which was abolished by VPA treatment. Apomorphine administration resulted in significantly higher ipsilateral rotation in rotenone-lesioned (12µg) animals, as compared to controls, which was attenuated by melatonin treatment. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-infused animals. VPA or melatonin treatment prevented this decrease in tyrosine hydroxylase in the striatum and substantia nigra. Stereological cell counting indicated a significant decrease in dopamine neurons within the substantia nigra of rotenone-treated animals. Importantly, this loss of dopamine neurons in rotenone-infused animals was blocked by chronic VPA or melatonin treatment. A third study explored whether rotenone infusion into the medial forebrain bundle and substantia nigra in mice could provide a model of Parkinson's disease. Densitometric analysis revealed a significant depletion of tyrosine hydroxylase immunofluorescence within the ipsilateral striatum and substantia nigra of lesioned animals, and a significant bilateral overexpression of α-synuclein in the substantia nigra, as compared to control animals. These novel findings support the use of intracranial rotenone as a Parkinsonian model, and provide a solid platform for future combinatorial therapeutic approaches with VPA and melatonin. / Dissertation / Doctor of Philosophy (PhD)

Despite the lack of robust clinical response, treatment strategies for cancer-induced depression (CID) are currently limited to those developed for non-cancer-related depression. The work presented in this dissertation conceptualizes CID as a pathophysiologically distinct form of depression. To investigate CID at the most basic level, we first developed a preclinical model that was validated by comparison to an established model of stress-induced depressive-like behaviours. The positive control model was developed by chronically treating female BALB/c mice with oral corticosterone (CORT). The CID model was developed using subcutaneous inoculation with 4T1 mammary carcinoma cells. Anhedonia, behavioural despair, and dendritic atrophy in the medial prefrontal cortex (mPFC) were observed in both models. Similar to many human cancer cell lines, 4T1 cells were shown to secrete significant amounts of glutamate, which was markedly attenuated using the system xc- inhibitor sulfasalazine (SSZ). In CID mice, oral treatment with SSZ was at least as effective as fluoxetine, a popular clinical antidepressant, at preventing depressive-like behaviours. This effect was primarily attributable to intact SSZ, rather than its anti-inflammatory metabolite. RNA-sequencing was performed on hippocampal samples from CID and CORT animals. Analysis of differential expressed genes (DEGs) revealed significant overlap between the two models. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological process gene ontologies (GO:BP) terms related to ion homeostasis and neuronal communication were enriched for both models. CID was associated with additional DEGs that were not identified in the CORT model. These DEGs were enriched in KEGG pathways and GO:BP terms related to neuronal development, intracellular signalling cascade, learning, and memory. These studies suggest that CID may involve a distinct aetiology, and that glutamate secretion by cancer cells presents a viable target for antidepressant treatment. The development of mechanism-based therapeutics for CID will dramatically improve the quality of life for cancer patients. / Thesis / Doctor of Philosophy (PhD) / Cancer patients are at a high risk of developing depression. In addition to the psychological stress caused by a cancer diagnosis, there is evidence that cancer causes depression through biological pathways. To investigate these pathways, a mouse model of cancer-induced depression (CID) was developed. This model showed comparable behavioural and structural brain deficits to those observed in a stress model of depression. Cancer cells secrete elevated levels of glutamate, a signalling molecule that is involved in depression. In CID mice, inhibiting glutamate release had an antidepressant effect similar to that of fluoxetine, a standard clinical antidepressant. A genetic analysis on brain samples from the CID model revealed significant overlap with the stress model of depression. CID mice had additional changes relevant to learning, memory, and brain cell development that were not detected in the stress model. A better understanding of CID will lead to better treatment strategies developed specifically for cancer patients.

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Στόχος της παρούσας διατριβής είναι η παρουσίαση ενός νέου μαθηματικού πλαισίου, βασιζόμενου στις γνωστές από τη Διαφορική Γεωμετρία κανονικές εξισώσεις (συντετμημένα ΚΕ) της καμπύλης. Όντας πολυωνυμικές εκφράσεις του μήκους τόξου s, οι ΚΕ παρέχουν ακριβέστερο έλεγχο της ταχύτητας πρόωσης σε σύγκριση με τους υπάρχοντες παραμετρικούς αλγορίθμους της ίδιας τάξης. Το ανωτέρω γεγονός, σε συνδυασμό με την εφαρμοσιμότητά τους σε όλες τις συνεχείς καμπύλες με συνεχείς παραγώγους, ανεξάρτητα από τον τρόπο αναπαράστασής τους, καθιστά τις ΚΕ ένα ιδανικό εργαλείο για την ανάπτυξη γενικών αλγορίθμων παρεμβολής, ικανών να εργάζονται επί οποιασδήποτε επίπεδης ή χωρικής καμπύλης σε πραγματικό χρόνο. Δοθέντος ότι οι συντελεστές των ΚΕ συναρτώνται με τις διαφορικές ιδιότητες της καμπύλης (δηλαδή την καμπυλότητα, τη στρέψη και τις παραγώγους τους ως προς το s), αναπτύσσονται αναλυτικές εκφράσεις για τον υπολογισμό των εν λόγω ιδιοτήτων, ανάλογα με τον εκάστοτε τρόπο αναπαράστασης της καμπύλης. Στα αντικείμενα της διατριβής συμπεριλαμβάνεται και ο υπολογισμός των διαφορικών ιδιοτήτων των επιφανειακών τομών, ενός δημοφιλούς τρόπου αναπαράστασης πολύπλοκων χωρικών καμπυλών στα συστήματα CAD. Επιπλέον, εξετάζεται η εισαγωγή διορθωτικών όρων στις ΚΕ, μέσω της οποίας επιτυγχάνεται η βελτίωση της ακρίβειας στον έλεγχο της ταχύτητας πρόωσης, χωρίς το επιπρόσθετο υπολογιστικό κόστος που επιφέρει η χρήση υψηλότερης τάξης όρων της σειράς Taylor. Σημαντικό πλεονέκτημα των προτεινόμενων αλγορίθμων είναι, επίσης, το γεγονός ότι για την εφαρμογή τους δεν απαιτείται η γνώση της αναλυτικής έκφρασης της παρεμβαλλόμενης καμπύλης. Κατά συνέπεια, επιτρέπουν την παρεμβολή πολύπλοκων γεωμετρικών τόπων, οι αναλυτικές εκφράσεις των οποίων είτε είναι δύσκολο να προσδιοριστούν με τις τρέχουσες μεθόδους απαλοιφής αγνώστων από μη γραμμικά συστήματα εξισώσεων, είτε είναι δύσχρηστες, εξ αιτίας της πολυπλοκότητάς τους. Στα πλαίσια της παρούσας διατριβής, μελετάται το πρόβλημα της παρεμβολής δύο γεωμετρικών τόπων με σημαντικές εφαρμογές στον τομέα του αριθμητικού ελέγχου των εργαλειομηχανών, καθώς χρησιμοποιούνται, μεταξύ άλλων, για την αντιστάθμιση της ακτίνας του κοπτικού εργαλείου και τον προγραμματισμό των διαδοχικών διαδρομών του κατά την κατεργασία θυλάκων: των καμπυλών offset και των ισαπεχουσών δύο επίπεδων καμπυλών. Πραγματοποιείται μία εκτενής εξέταση των διαφορικών ιδιοτήτων των προαναφερθέντων γεωμετρικών τόπων και παρουσιάζονται εκφράσεις για τον υπολογισμό τους, βασιζόμενες αποκλειστικά στις αντίστοιχες ιδιότητες των γενετειρών καμπυλών. Γίνεται, επίσης, μία ανασκόπηση των μεθόδων που έχουν προταθεί στη βιβλιογραφία για την αντιμετώπιση των τοπολογικών ιδιομορφιών τους (αυτοτομών και εσωτερικών βρόγχων), ώστε να εξασφαλιστεί η παραμονή των παραγόμενων σημείων επί του πραγματικού γεωμετρικού τόπου. Παράλληλα, συζητείται η επέκταση των προτεινόμενων μεθόδων παρεμβολής των καμπυλών offset για τον έλεγχο της διαδρομής του κέντρου ενός σφαιρικού εργαλείου, ώστε αυτό να διατηρείται σε μόνιμη επαφή με δύο προκαθορισμένες επιφάνειες – μία τεχνική που χρησιμοποιείται συχνά από τα συστήματα CAD/CAM για την επιφανειακή κατεργασία πολύπλοκων εξαρτημάτων. Το εργαλείο μπορεί να εφάπτεται οποιασδήποτε εκ των δύο επιφανειών είτε μέσω του ημισφαιρικού του άκρου, ή μέσω του κυλινδρικού του στελέχους. / The present dissertation aims at introducing a new mathematical framework, based on a curve’s canonical equations (abbreviated as CE), which are known from Differential Geometry. Being polynomial expressions of the curve’s arc length s, the CE provide greater feedrate accuracy, compared to the existing parametric algorithms of the same order. The above fact, combined with the canonical equations’ applicability on any continuous curve with continuous derivatives, regardless of its representation, renders them an ideal tool for the development of general-purpose real-time interpolation algorithms. Given that the CE coefficients consist of the curve’s differential properties (namely, the curvature, torsion and their arc length derivatives), the present dissertation deals with the expression of the aforementioned properties in closed form, depending on the chosen curve representation. This includes the study of surface intersections, which are frequently used by CAD systems in order to represent complex space curves. Moreover, it is proven that the proposed algorithms admit to corrections, supplying a means of improving feedrate accuracy, without the additional cost of employing higher order Taylor series terms. An additional, important advantage of the proposed algorithms, lies in the fact that they do not require knowledge of the curve’s analytic expression. Hence, they allow the interpolation of complex geometrical loci, whose analytic expressions are either difficult to deduce, using current elimination methods for non-linear equation systems, or are extremely impractical, due to their complexity. This dissertation addresses the problem of interpolating two such loci: offset curves and plane bisectors. Both of these entities play an important role in CNC machining, with applications that include the tool’s radius compensation and path planning during pocket clearing. It is shown that the differential properties of the above loci can be linked to the respective properties of their generators and may, hence, be easily computed through successive derivations of the generator curve’s position vector. In addition, previously suggested methods for the handling of possible topological irregularities (self-intersections and internal loops) are reviewed, so as to ensure that the generated points remain on the true locus. Furthermore, the presented offset interpolation methods are extended, in order to accommodate the path planning of a ball-end cutter, moving in constant contact with two given surfaces – a technique which is widely adopted by CAD/CAM systems to guide the tool through the surface machining of complex parts. The tool may contact any of the two surfaces through either its tip, or its cylindrical periphery.

Pour comprendre comment le cerveau inhibe l'appétit en dépit d'un besoin énergétique, nous avons étudié les mécanismes neuronaux qui sous-tendent l'effet hypophagique induit par la 3,4-N-méthylén édioxyméthamphétamine (MDMA : « ecstasie ») et le stress (immobilisation forcée) car ces facteurs réduisent la faim d'un animal, même s'il est affamé. Nous montrons que la stimulation intracérébrale des récepteurs 5-HT4 de la sérotonine (R5-HT4), ou leur plus forte expression (ectopique, physiologique) dans une aire de la récompense (noyau accumbens : NAc), réduit la faim en augmentant l'action anorexigène d'un peptide de l'addiction : CART. A l'encontre de l'équilibre énergétique, l'effet anorexigène induit par la stimulation des R5-HT4 dans le NAc s'accompagne d'une hyperactivité motrice, souvent décrite chez l'humain souffrant d'anorexie mentale. En supposant qu'un effet récompensant prévaut sur le danger d'un déséquilibre énergétique, nous montrons, qu'effectivement, l'injection d'un antagoniste des R5-HT4 dans le NAc réduit les effets anorexigène, hyperlocomoteur et récompensant de la MDMA. S'il est alors récompensant de se priver d'aliments, une souris surexprimant les R5-HT4 dans le NAc, devrait, après une faible et transitoire restriction alimentaire, continuer à s'auto-priver d'aliments même si l'aliment est fourni ensuite ad libitum. La réponse est positive. En revanche, les R5-HT4 du NAc ne contribuent pas, à priori, à l'hypophagie due au stress. Puisque le système de la récompense est inclut dans celui de la prise de décision contrôlée par le cortex préfrontal médian (CPFm), nous avons supposé que l'effet hypophagique provoqué par le stress utilise les R5-HT4 corticaux. L'injection de traitements nucléiques (siRNA, virus), dans le CPFm de souris sauvages et privées des R5-HT4, montre que seule l'activation des R5-HT4 du CPFm est à l'origine de l'effet hypophagique du stress. Nos résultats suggèrent que [1] le stress active les R5-HT4 du CPFm et réduit la densité du transporteur de capture de la 5-HT, favorisant [2] l'augmentation du taux de la 5-HT extracellulaire dans le noyau d u raphé dorsal d'où, [3] un contrôle inhibiteur de l'activité des neurones 5-HT par le R5-HT1A permettant d'éviter que l'hypophagie ne se prolonge en conduite anorexigène. L'ensemble de nos résultats étayent la possibilité que le réseau neuronal de l'addiction et de la prise de décision de manger après stress inclut celui de la conduite anorexigène, avec jusqu'alors, une contribution évidente des R5-HT4. / To understand how the brain inhibits appetite despite an energy demand, we study the neuronal mechanisms, which underlie the hypophagic effect induced by the 3,4-N-methylenedioxymethamphetamine (MDMA: « Ecstasy ») and stress (forced immobilization) because these factors reduce appetite in animals, even starved. We show that stimulating serotonin 4 receptors (5-HTR4), or their overexpression (ectopic, physiological) in a brain reward area (nucleus accumbens: NAc), reduced hunger in increasing the appetite-suppressant effect of an addiction peptide: CART. Against the energy balance, the appetite-suppressant effect induced by stimulating 5-HTR4 in the NAc comes along with hyperactivity, often described in human suffering from anorexia nervosa. Supposing that a rewarding effect prevails over the danger of an energy imbalance, we show indeed that injecting 5-HTR4 antagonist in the NAc reduced the appetite-suppressant effect, the hyperactivity and the rewarding effect provoked by MDMA. If food deprivation is rewarding, mouse overexpressing 5-HTR4 in the NAc, after a low and transient diet period, should continue to self-imposed food refusal even in the presence of food ad libitum. The answer is positive. In contrast, 5-HTR4 in the NAc does not contribute, à priori, to stress-induced hypophagia. Because the reward system is included in the neuronal network of the decision-making, mainly controlled by the medial prefrontal cortex (mPFC), we postulated that hypophagia following stress uses cortical 5-HTR4. Injecting nucleic treatments (siRNA, virus), in the mPFC of wild-type or 5-HTR4 null mice, shows that only the stimulation of 5-HTR4 in the mPFC sparks off the hypophagic effect of stress. Our results suggest that [1] stress activates 5-HTR4 in the mPFC and reduces density of the 5-HT transporter, promoting [2] increase of the extracellular 5-HT level in the dorsal raphe nucleus and thus [3] an inhibitory control of t he activity of 5-HT neurons by 5-HTR1A allowing to avoid that the period of food restriction persists (anorexia-like behavior). Colectively, our findings support the the neuronal network of addiction and decision-making to eat after stress include the neuronal pathway related to anorexia, with so far, a clear contribution of 5-HTR4.

Can the brain register the emotional valence of brief exposures of complex natural stimuli under conditions of forward and backward masking, and under conditions of attentional competition between foveal and peripheral stimuli? To address this question, three experiments were conducted. The first, a behavioural experiment, measured subjective valence of response (pleasant vs unpleasant) to test the perception of the valence of natural images in brief, masked exposures in a forward and backward masking paradigm. Images were chosen from the International Affective Picture System (IAPS) series. After correction for response bias, responses to the majority of target stimuli were concordant with the IAPS ratings at better than chance, even when the presence of the target was undetected. Using functional magnetic resonance imaging (fMRI), the effects of IAPS valence and stimulus category were objectively measured on nine regions of interest (ROIs) using the same strict temporal restrictions in a similar masking design. Evidence of affective processing close to or below conscious threshold was apparent in some of the ROIs. To further this line of enquiry, a second fMRI experiment mapping the same ROIs and using the same stimuli were presented in a foveal (‘attended’) peripheral (‘to-be-ignored’) paradigm (small image superimposed in the centre of a large image of the same category, but opposite valence) to investigate spatial parameters and limitations of attention. Results are interpreted as showing both valence and category specific effects of ‘to-be-ignored’ images in the periphery. These results are discussed in light of theories of the limitations of attentional capacity and the speed in which we process natural images, providing new evidence of the breadth of variety in the types of affective visual stimuli we are able to process close to the threshold of conscious perception.

The main theme of this thesis is the non-banking- loans- companies and its medial portrait. The thesis formulates the basic hypotheses related to social status and reputation of non-banking companies. As the research method there was chosen the quantitative content analysis. The research sample consists of the daily papers Hospodářské noviny, MF DNES and some selected economic and political magazines. The research period was divided in two parts: March - June 2010 and September - December 2010. The thesis contents two analysis: the first one contents the results of surveys of the company called Provident Financial. The second one is an analysis of advertising in the daily papers MF DNES and Hospodářské noviny. The results of the analysis of advertising didn't confirm one of the main hypotheses assuming that the non-banking -loans- companies have any impact on the content of investigated media. And vice versa, other hypotheses were confirmed by results of the quantitative content analysis. The result of the analysis is that the non-banking-loans- companies are presented as companies working within the standards of law and which are entitled to a place in the financial market.

Jaroslav Šimáček - Diploma Thesis Abstract The diploma thesis "Presidents of the Czech Republic - Medial representations of Václav Havel and Václav Klaus" analyses media images of presidents of Czech Republic Václav Havel and Václav Klaus in magazine Týden. After delimination president's role in czech political system and introducing to concrete heads of the state in the biographical part, author deals with media's role and function in contemporary world. At the same time he brings out medial communication manners and generation media images. Consequently he examines new technological possibilities in medial world plus procedure at media content analysis, which is chosen as main method. In methodology part author links hypotheses, concerning with media images of czech presidents, also describes concrete working methods and characterizes choice of medium. Select experimental period is the second presidential term of both presidents. In practical part author tries to prove or disprove given hypotheses. The research proceeds first of all in the internet archive of magazine Týden, that contains data since 1994 and is relatively well - aranged. The aim of this diploma thesis is creation of media images of Václav Havel and Václav Klaus in chosen medium. Key words: president, Czech Republic, Václav Havel, Václav...