Yes / Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n = 8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p < 0.05), motor cortex (p < 0.01), orbital cortex (p < 0.01), olfactory bulb (p < 0.05), retrosplenial cortex (p < 0.001), frontal cortex (p < 0.01), parietal cortex (p < 0.01), CA1 (p < 0.05) and polymorphic layer of dentate gyrus (p < 0.05) of the hippocampus and the central (p < 0.01), lateral (p < 0.05) and basolateral (p < 0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p < 0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25003号 / 医博第5037号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 後藤 慎平, 教授 平井 豊博, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Neuromesodermal progenitors (NMPs) are bipotent progenitors, located at the caudal end of the embryo and are essential for axis formation. These stem cell-like progenitors possess the ability to self-renew and differentiate to both mesodermal and neural lineages, such as skeletal muscle and spinal cord derivatives. These progenitors arise at E8.5 and are localised in the caudal lateral epiblast (CLE), a posterior region of the embryo near the primitive streak. Later in development, they reside in the tail bud until cessation of axial elongation at E13.5. Throughout these stages NMPs are characteristically marked by co-expression of T(Bra) (Brachyury) and Sox2. This characteristic is also present in in vitro NMPs, which can be derived from Epiblast Stem Cells (EpiSCs) through treatment with Wnt/β-catenin signalling agonists and Fgf2, which simulates their in vivo environment. Protein and mRNA profiling of NMPs and mutant phenotypes in vivo supports the hypothesis that a non-canonical Wnt pathway, the Wnt/Planar Cell Polarity pathway (PCP) could be involved in NMP fate decision and/or maintenance. This thesis focuses on understanding more about the role of PCP by aiming to identify the spatio-temporal profile of Wnt/PCP pathway components in NMP regions during axial elongation, as well as determining its role in NMP behaviour through manipulation of this pathway via in vivo and in vitro assays Employing in situ hybridisation and immunohistochemistry techniques, key Wnt/PCP components, including Pk1, Vangl2 and Ptk7, were confirmed to be present in in vivo and in vitro NMPs, thus, providing strong evidence that Wnt/PCP may be involved regulating NMP behaviour. Disruption of Wnt/PCP signalling through overexpression of Wnt/PCP components was tested in refined in vivo and in vitro assays. Overexpression of Vangl2 and Ptk7, but not Pk1 in NMPs regions in vivo resulted in loss of contribution to neural lineages, as well as lower contribution to NMP regions themselves. Similarly, Wnt/PCP components were disrupted in vitro through generation of dox-inducible overexpression cells lines for Wnt/PCP components. These lines were used to generate NMPs from an optimised novel alternative source Epiblast-Like Cells (EpiLCs), however no clear affect to lineage was observed. Overall this work has successfully advanced our knowledge of Wnt/PCP mediated control of NMP differentiation and maintenance, and provided a finer grained description of the relationships between them.

L’asymétrie Droite-Gauche (DG) est responsable de l’empaquetage et l’enroulement stéréotypé des organes internes au cours du développement. Chez la Drosophile, l’intestin postérieur adulte (AHG) se développe asymétriquement selon l’axe DG en formant une boucle dextrale. Comme pour tous les organes asymétriques DG de la Drosophile, la mise en place de l’axe DG nécessite l’expression de la myosine non conventionnelle de type I : MyoID. Cette myosine se lie à la DE-Cadherine au niveau des jonctions adhérentes (AJ) pour mettre en place l’axe DG, mais le mécanisme moléculaire qui transforme la chiralité de MyoID en une morphogenèse asymétrique DG est totalement inconnu. Le AHG est un long tube situé au milieu de l’abdomen, qui présente une boucle dextrale dans sa partie proximale. Il se développe à partir d’un groupe de progéniteurs formés de deux populations de cellules : H1 et H2. Dans cette étude, nous avons mis en évidence que MyoID contrôle la formation de la boucle dextrale du AHG grâce à son interaction avec la cadhérine atypique Dachsous dans les cellules H1. De plus, nous avons pu mettre en évidence que la signalisation Dachsous-Fat est activée à travers les cellules H2 entrainant leur polarisation du coté droit, et ainsi formant l’enroulement du AHG. Les cellules H1 sont transitoires, elles disparaissent lors des premières heures de la métamorphose. Cependant, l’information dextrale générée dans les cellules H1 perdure dans les cellules H2 grâce à l’action coordonnée des composants de la polarité planaire. Nous montrons que la polarité planaire contrôle l’établissement de l’asymétrie DG en aval de MyoID, en transmettant l’information DG dans le AHG. / Stereotyped left right (LR) asymmetry ensures proper looping of internal organs. In Drosophila, the adult hindgut (AHG) has a clear stereotypical dextral loop and, like all LR asymmetric organs, require MyoID for correct orientation. MyoID is an unconventional myosin type I that binds to DE-Cadherin, this association is required for proper LR establishment; however the mechanism that translates MyoID chirality into proper morphogenesis remains unknown. The AHG is a long tube coiled dextrally and located in the middle of the abdominal region. It develops from a cluster of progenitors containing two different populations of cells, H1 and H2. Here, we show that MyoID controls the AHG dextral loop by binding to the atypical cadherin Dachsous in H1 cells. Further, Ds-Fat signaling propagates towards the H2 cells which in turn become polarized towards the right and consequently loop. H1 is a transient population of cells that wear off in the first hours of metamorphosis; nevertheless the dextral information generated in H1 is maintained in H2 cells due to the cooperative action of PCP components. We demonstrate that the molecular basis of the LR establishment downstream of MyoID action lies in the PCP system, which has a double role transmitting and maintaining a dextral signal in the AHG. Thus, we provide for the first time a link in L/R morphogenesis between Drosophila and vertebrates in which PCP mutants result in L/R defects. Furthermore, in our attempts to better understand the evolution of L/R morphogenesis we found the recently co-Appearance of a myoID cis-Regulatory element and the AHG dextral loop, during Drosophila evolution, suggesting that changes in myoID express.

Title: Complexity Theory in Feasible Mathematics Author: Ján Pich Department: Department of Algebra Supervisor: Prof. RNDr. Jan Krajíček, DrSc., MAE Abstract: We study the provability of statements and conjectures from Complex- ity Theory in Bounded Arithmetic. First, modulo a hardness assumption, we show that theories weaker in terms of provably total functions than Buss's theory S1 2 cannot prove nk -size circuit lower bounds for SAT formalized as a Σb 2-formula LB(SAT, nk ). In particular, the true universal first-order theory in the language containing names for all uniform NC1 algorithms denoted TNC1 does not prove LB(SAT, n4kc ) where k ≥ 1, c ≥ 2 unless each function f ∈ SIZE(nk ) can be approximated by formulas Fn of subexponential size 2O(n1/c) with subexponential advantage: Px∈{0,1}n [Fn(x) = f(x)] ≥ 1/2 + 1/2O(n1/c) . Unconditionally, V 0 does not prove quasipolynomial nlog n -size circuit lower bounds for SAT. Considering upper bounds, we prove the PCP theorem in Cook's theory PV1. This includes a formalization of the (n, d, λ)-graphs in PV1. A consequence of the result is that Extended Frege proof system admits p-size proofs of tautologies encoding the PCP theorem. Keywords: Circuit Lower Bounds, Bounded Arithmetic, The PCP theorem

La voie de signalisation WNT/PCP, couramment associée à la polarité planaire cellulaire, joue un rôle fondamental dans la morphogenèse chez les vertébrés. Parmi les différents composants protéiques de la voie WNT/PCP, on retrouve la protéine tyrosine kinase 7 (PTK7), dont les fonctions restent encore très peu décrites. Au cours de ma thèse, j’ai montré que PTK7 interagissait avec le récepteur tyrosine kinase ROR2. Ce complexe, après fixation du ligand WNT5A, induit la migration de fibroblastes embryonnaires murins via l’activation de JNK. Au cours du développement embryonnaire du xénope, Ptk7 interagit de manière fonctionnelle avec Ror2, et contrôle l’expression de la protocadhérine Papc ainsi que la morphogénèse. De plus, en utilisant une approche de Tissue MicroArray, réalisée sur des patients atteints de cancers colorectaux, j’ai pu montrer que PTK7 était retrouvé surexprimé chez 34% des patients, et que cette surexpression était un facteur de mauvais pronostic. Dans des lignées cellulaires issues de cancers colorectaux, la suppression de PTK7 par shRNA entraine une diminution de la migration des cellules tumorales, mais n’impacte pas leur prolifération et leur résistance aux drogues anticancéreuses. Dans un modèle de xénogreffe murin, la suppression de PTK7 induit une diminution du développement tumoral et l’expression de ce dernier, dans des cellules négative pour PTK7, entraine une augmentation de l’apparition de métastases chez les animaux injectés. Ce travail apporte de nouveaux éclaircissements sur le du récepteur PTK7 dans la voie de signalisation WNT/PCP, et le définit comme potentiel biomarqueur et cible thérapeutique dans le cancer colorectal. / The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. We show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells and physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, Ptk7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that Ptk7 is required for papc activation induced by Wnt5a and that Wnt5a stimulates the release of the Ptk7 intracellular domain, which can translocate into the nucleus and activate papc expression. Moreover, using a Tissue MicroArray produced from CRC patients we correlated PTK7 expression with pathological features and patient outcome. PTK7 was significantly up-regulated in CRC tissue, and its overexpression was found in 34% of patients. In CRC cell lines, shRNA PTK7 reduced migration, but did not affect cell proliferation and resistance to drugs. In a xenograft mouse model, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. This work reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements and define PTK7 expression as a potential prognostic biomarker and a novel therapeutic target in CRC.

The human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) initially emerged in the 1980s and ever since, a battle has been underway with regard to understanding some of the root issues attributed to behavior and HIV/AIDS. AIDS is prevalent in the men sleeping with men (MSM) community. There is lack of studies evaluating the quality and quantity of communication between MSM and medical professionals, which can be a catalyst to help reduce HIV/AIDS within this community. The aim of this quantitative study was to evaluate the relationship between quantity and quality of medical professionals' communication and regular HIV screening and testing, as well as modifying high-risk behaviors attributing to HIV/AIDS MSM behaviors, controlled for race/ethnicity, educational level, and income. Universal precautions theory and health belief model were the theoretical framework of this study. A total of 126 MSM were evaluated via survey research. Chi-square analysis revealed that MSM who have ever visited a medical professional about HIV/AIDS were tested in significantly higher frequency compared with those that did not visit medical professional for this reason (51.5% vs. 18.5%, respectively, p < .001). Also, significantly more participants changed their sexual behavior during the last 5 years and considered that the approach of the medical professional contributed in this change, compared with those who changed their sexual behavior but did not consider this approach helpful (73.7% vs. 26.7%, p < .001). This research can provide positive social change to the MSM community as well as medical professionals, by encouraging MSM to seek more information pertaining to safe sexual health practices, prevention, and awareness.

No description available.

Secondary hypothyroidism is caused by treatment for hyperthyroidism and is a chronic condition. After adequate treatment, people can continue to experience persistent physical and depressive symptoms. There is a lack of research into the psychological factors involved in the condition, such as how people adjust to hypothyroidism. The study used Kelly’s (1955) Personal Construct Theory to explore the way in which patients construe (appraise) themselves with hypothyroidism and how this relates to coping, depression and hypothyroid symptoms. Twenty participants were recruited from an endocrinology clinic and online, through thyroid support organisations. Participants completed a semi-structured interview called a repertory grid and self-report measures of coping (Brief COPE), depression (HADS) and hypothyroid symptoms (ThySRQ). Repertory grid measures were extracted such as distances between different views of the self. The results showed that how unfavourably the self now was viewed compared to self before a thyroid disorder was positively correlated with depression, dysfunctional coping and hypothyroid symptoms. Identification with a negative view of hypothyroidism was associated with poorer mental and physical health and with dysfunctional coping. Polarized (i.e. black-and-white) construing and tight (i.e. rigid) construing were significantly and positively related to depression scores. Tightness of construing was also related to the number of hypothyroid symptoms experienced. Dysfunctional coping was positively correlated with depression and hypothyroid symptoms. Those with a history of depression experienced significantly more hypothyroid symptoms. Exploratory multiple regression analyses uncovered that how unfavourably the person viewed themselves now compared with before any thyroid problem, hypothyroid symptom frequency and dysfunctional coping accounted for 82.9% of the variance in depression. This highlights the importance of understanding how people construe the experience of hypothyroidism and their coping strategies and therefore psychological interventions may be helpful. Limitations include a small sample size and a correlational design, whereby cause and effect conclusions cannot be drawn.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2014-10-01T14:18:43Z No. of bitstreams: 2 Dissertação - José Luciano Pereira Neto - 2013.pdf: 1133662 bytes, checksum: e8e6cb0e84e39329916ff784344430f7 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2014-10-01T15:32:52Z (GMT) No. of bitstreams: 2 Dissertação - José Luciano Pereira Neto - 2013.pdf: 1133662 bytes, checksum: e8e6cb0e84e39329916ff784344430f7 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-10-01T15:32:52Z (GMT). No. of bitstreams: 2 Dissertação - José Luciano Pereira Neto - 2013.pdf: 1133662 bytes, checksum: e8e6cb0e84e39329916ff784344430f7 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-10-09 / This is a research on the performance of the Portuguese Communist Party front of the decolonization process in Africa seeks to understand the role of the party in relation to the colonial question of the Provisional Government of Portugal in the years 1974-75. For this research is based on the reading of periodicals of the time, in case the Avante mainly and then the serial Movimento 25 de Abril. Both newspapers bring the discussion about the direction to take regarding decolonization, placing the positioning of the MFA, which makes positioning the PCP with regard to decolonization, and the ways that the Government should proceed to completion of the decolonization process of Portuguese Africa. / A pesquisa sobre a atuação do Partido Comunista Português, frente ao processo de descolonização em África, busca compreender a atuação do partido em relação à questão colonial dentro do Governo Provisório de Portugal nos anos de 1974-75. Para tanto, a pesquisa baseia-se na leitura dos periódicos da época, no caso, o Avante, principalmente, e, posteriormente, o folhetim das Forças Armadas, o Movimento 25 de Abril. Ambos os jornais trazem a discussão acerca dos rumos referentes à descolonização, colocando o posicionamento do Movimento das Forças Armadas (MFA), que se torna o posicionamento do PCP no que se refere à descolonização, e às formas que o Governo deveria prosseguir para a conclusão do processo de descolonização da África portuguesa.