Microglia, the resident immune cells of the central nervous system, can become activated following injury, disease, or infection. In vitro, they can be activated by stimuli, which determine the inflammatory phenotype they will develop. In this thesis, stimulating microglia with tumor necrosis factor- and interferon- resulted in classical activation, characterized by proliferation, increased transcription of complement receptor 3 and major histocompatibility class II molecules, and elevated production and transcription of interleukin-1 and nitric oxide. Stimulation with TNF and IFN also changed the intensity of phosphorylated (activated) cyclic adenosine monophosphate response element binding protein immunoreactivity in microglia. Specifically, cells differentiated into populations with high or low pCREB intensity. This was the first example of such a response in microglia and was representative of what occurred in vivo, after ICH. Thus, the characterization of this model will be useful for future studies of this and other intracellular pathways of classically activated microglia.

Tyrimo objektas – paslaugų kokybės vertinimas. Tyrimo tikslas: įvertinti paslaugų kokybę stovykloje „Gintaras“. Uždaviniai: 1. Apibrėžti paslaugų kokybę ir jų vertinimą. 2. Apžvelgti stovyklų teikiamas paslaugas; 3. Nustatyti tikėtiną paslaugų kokybę “Gintaro” stovykloje. 1. Paslaugos kokybė, tai objekto savybė, kuri įgalina tenkinti šiandieninius arba tikėtinus vartotojo poreikius. Kokybei tirti taikomi įvairūs kokybės tyrimo modeliai, kurie organizacijoms leidžia nustatyti paslaugų kokybės problemas ir paskatina, bei padeda gerinti jų tikėtiną ar jau įvertintą paslaugų kokybę. 2. Pagrindinės paslaugos be kurių stovyklos organizatoriai negalėtų vykdyti savo veiklos yra apgyvendinimas ir maitinimas. Teikiamos stovyklų paslaugos vyksmas yra neįmanomas be vadovų, kurie atsakingi už stovykloje vykdomas programas, stovyklautojų laisvalaikį bei kitus užsiėmimus vykstančius stovykloje. 3. Norint gerinti paslaugų kokybę „Gintaro“ stovykloje, pirmiausiai dėmesį reikėtų atkreipti į stovykloje vykdomą programą, jos įvairumą, programos tinkamumą, jos pritaikymą skirtingiems vartotojams, bei svarbiausia – jos naudingumą vartotojui, kuris aktualus ir labai svarbus mūsų augančiai jaunajai visuomenei, jos požiūriui į bendravimą, rezultatų siekimą bei bendrą pasaulėžiūrą. / Study object: service quality evaluation. Goal of the work: to assess quality in „Gintaras“ camp. Tasks of the work: 1. Define the service quality conception and quality evaluation. 2. Overview camp services. 3. Evaluate service quality in „Gintaras“ campo of consumer attitudes. Conslusion: 1. Servise quality is an object feature which allows to satisfy today or anticipated consumer needs. To assess servise quality there are various quality testing models that enables organizations to determine the quality of service issues, and encourages helps to improve their expected quality of services. 2. Basic services that childrens camp can not be organized is accommodation and nourishment. Providing camp services, process is not possible without the camp leaders who are responsible for camp programs, the campers leisure and other activities taking place in the camp. 3. In order to improve service quality, in the "Amber" camp, first consideration should be given to the camp running program and its diversity, relevance of programs, and adapt to different users, and most importantly - the utility of the user that is relevant and very important for our growing young society and its approach to communication, achievement of results and overall outlook.

Following the discovery of the DISC1 gene in 2000, subsequent research has led to DISC1 becoming one of the most promising candidate genes for psychiatric disorders. Acting as a scaffold protein, DISC1 has a large number of interacting proteins and is involved in a series of intracellular signalling pathways. Amongst these binding proteins are two enzymes, PDE4 and GSK3β, that were originally implicated in psychiatric disease by virtue of their inhibition by psychoactive drugs. PDE4 enzymes are inhibited by rolipram, which possesses anti-depressant and anti-psychotic activity, while GSK3β is one of the major targets of lithium, a potent mood stabiliser. Both these enzymes are intricately involved in the PI3K/AKT, cAMP, and MAPK signalling pathways, all of which have a number of downstream outcomes with potential relevance to psychiatric disorders. The Millar and Porteous laboratory had established that DISC1 modulates PDE4 activity, but this predated awareness of GSK3 as another DISC1 interactor whose binding site overlapped with that of PDE4. Since cAMP is a key regulator of signalling pathways in the brain, I hypothesised that not only DISC1, but also GSK3β may be involved in the regulation of PDE4 activity to control local cAMP levels and gradients. To investigate this hypothesis, I characterised SHSY5Y cells as a model for measuring PDE4 activity, and performed a series of genetic and pharmacological manipulations on this system. Inhibition of GSK3β resulted in a decrease of basal PDE4 activity that was amplified by DISC1 overexpression. Wild type cells that were treated with forskolin exhibited a significant increase in PDE4 activity, which was suppressed by GSK3β inhibition and both overexpression and knockdown of DISC1. Further experiments confirmed that none of these changes were a result of differences in PDE4 mRNA or protein expression. Thus I have provided evidence that suggests tonic activation of PDE4 by GSK3β and evidence for modulation of PDE4 activity by DISC1. I provide evidence for the localisation of PDE4B & PDE4D with key psychiatric associated receptors in structures resembling developing dendritic spines; furthermore, agonism of NMDA receptors results in a significant increase in PDE4 activity in primary neurons. These results are a simple demonstration of an emerging principle in psychiatric research: that none of the signalling pathways implicated in psychiatric disease are acting in isolation. There are likely to be multiple points of integration between these pathways, with the demonstrated DISC1-GSK3β-PDE4 interaction forming one of these points. My results add an important new element to the understanding of how the DISC1 complex may regulate intracellular signalling in response to extracellular cues.

Zebrafish, Danio rerio, are able to survive exposure to extreme acidity (pH 4). Because previous studies demonstrated that disruption of ionic balance during exposure to acidic water is the major cause of mortality in acid-sensitive freshwater species, the focus of this thesis was to characterize the molecular mechanisms enabling zebrafish to maintain their Na+ homeostasis following exposure to acidic water. Initial findings (Chapter 2) demonstrated that branchial mRNA expression of selected isoforms of claudins, major components of tight junctions, are altered in an isoform-dependent manner, suggesting the potential regulation of epithelial permeability to minimize ion loss. Concurrently, a marked stimulation of Na+ uptake was observed in adults and larvae following acid-exposure. Because of the uniqueness of this response (increasing Na+ uptake in acidic water) among freshwater teleosts, the mechanisms related to Na+ uptake and its stimulation were investigated further (Chapters 3 - 7). Pharmacological treatments and gene knockdown approaches revealed that a functional metabolon consisting of an apically expressed Na+-H+-exchanger (NHE3b) in association with an apically expressed ammonia-conducting channel (Rhcg1), enables Na+ uptake in acidic water. During chronic (>1 day) exposure to acidic water, cortisol (via glucocorticoid receptors) and catecholamines (via β-adrenergic receptors) are involved in stimulating Na+ uptake. Although catecholamines may act on both NHE3b and Na+-Cl- co-transporter (NCC), the effects of cortisol on Na+ uptake are mediated primarily by activation of NHE3b. On the other hand, during acute (<3 h) exposure to acidic water, cortisol does not appear to affect Na+ uptake; rather, the stimulation of Na+ uptake appears to be mediated by angiotensin II and catecholamines. Cyclic AMP (cAMP), a signalling molecule synthesized following the activation of β-adrenergic receptors, is critically involved in stimulating Na+ uptake, likely via activation of NHE3b and NCC. In agreement with this idea, ionocytes that express NHE3b also express high levels of β-adrenergic receptor (propranolol binding sites) as well as trans-membrane adenylyl cyclase (forskolin binding sites). Taken together, the results of this thesis provide fresh insight into the mechanisms of osmoregulation in freshwater (FW) fish. In particular, the data reveal the presence of complex pathways regulating Na+ uptake in zebrafish exposed to acidic water. The relative importance of the various pathways depends in part on the duration of exposure; acute versus chronic.

The segregation of disabled people is often perceived of as a form of oppression that acts as a means of exclusion from mainstream society. Disability rights activists and theorists have worked to end segregation as a form of oppression using the social model of disability and drawing on feminist theory. Feminist use of disengagement as a tool for empowerment is one component of feminist theory that has been left unexplored as it relates to disability. This work explores the role of segregation within the disability rights movement and within the development of the activist identity for disabled people. Based on the individual and collective experiences of six participants, all of whom are activists who attended segregated summer camps, I use a thematic analysis to reframe segregation as Empowering Exclusivity. This reframing has the potential to shift the strategic goals of the disability rights movement away from binary understandings of integration and segregation and towards a critical analysis of full inclusion and empowerment. / Graduate / 0700 / 0453 / julia.munk@gmail.com

Herzinsuffizienz ist ein weltweites Gesundheitsproblem mit hoher Morbidität und Mortalität und immer noch schlechter Prognose. Ein charakteristisches Merkmal der molekularen und damit verbundenen strukturellen Veränderungen, die der terminalen Insuffizienz vorangehen ist die durch Desensitivierungsmechanismen vermittelte Abnahme des beta-adrenergen (β-AR) Signalmoleküls zyklisches Adenosinmonophosphat (cAMP) auf der einen Seite und der gleichzeitigen Zunahme des von natriuretischen Peptiden (NP) und Stickstoffmonoxid (NO) generierten zyklischen Guanosinmonophosphat (cGMP) auf der anderen Seite. Während hohe cAMP-Spiegel im Herzen als schädlich gelten, werden cGMP-abhängige Signalkaskaden vorwiegend als protektiv verstanden. Amplitude, Lokalisation und Halbwertszeit beider Signalmoleküle werden durch spezifische Enzyme, den Phosphodiesterasen (PDE) reguliert. Unter der PDE-Superfamilie wird die Isoform PDE2 als einzige von cGMP aktiviert, um dann verstärkt cAMP abzubauen und steht damit im Zentrum eines negativen Crosstalks dieser beiden Signalwege. PDE2 ist sowohl in der humanen als auch der experimentellen Herzinsuffizienz hochreguliert und scheint dort am β-AR Desensitivierungsprozess beteiligt zu sein. Im Rahmen dieser Arbeit wurde die pathophysiologische Rolle der PDE2 im Herzen näher charakterisiert. Es wird gezeigt, dass die PDE2 nicht nur in Kardiomyozyten, sondern auch in kardialen Fibroblasten exprimiert wird. In Fibroblasten inhibieren cAMP/cGMP-Signalwege die Transformation von kardialen Fibroblasten (CF) zu Myofibroblasten (MyoCF), einem zellulären Phänotyp, der unter anderem mit der persistenten Fibrotisierung des erkrankten Herzgewebes in Verbindung gebracht wird. In CF führte eine Überexpression von PDE2 zu eine starken Abnahme der basalen und β2-AR-vermittelten cAMP-Synthese und war ausreichend, um in Abwesenheit exogener, pro-fibrotischer Stimuli die Transformation zum MyoCF zu induzieren. In Übereinstimmung zeigten funktionale Analysen mit künstlich hergestelltem Bindegewebe aus PDE2-überexprimierenden CF eine deutliche Zunahme der Gewebssteifigkeit. PDE2 übte keinen Einfluss auf basale oder durch das atriale NP generiertes cGMP aus und reduzierte nur partiell die NO-induzierte cGMP-Akkumulation. Interessanterweise waren beide Stimuli in der Lage, trotz niedriger cAMP-Spiegel die PDE2-induzierte CF-Transformation zum MyoCF zu verhindern und lassen daher eine Redundanz dieser beiden sonst so gegensätzlichen Signalwege vermuten. Zur Untersuchung von PDE2 in Kardiomyozyten wurde ein transgenes (TG) Mausmodell mit spezifischer kardialer Überexpression herangezogen. Die Basalcharakterisierung zeigte eine erniedrigte Herzfrequenz (HR) mit kompensatorisch erhöhter, basaler Kontraktionskraft, sowie eine verminderte Maximalantwort bezüglich der HR nach akuter β-AR Stimulation. Auf molekularer Ebene war dieser Phänotyp mit einer verminderten Phosphorylierung verschiedener β-AR Zielstrukturen wie Troponin I, Phospholamban und Ryanodinrezeptor-2 assoziiert. Langzeitstudien belegten, dass eine Überexpression von PDE2 keine pathologischen Konsequenzen hat, sondern im Gegenteil die durchschnittliche Lebensspanne der Tiere eher verlängerte. Erste Studien im Herzinsuffizienzmodel der transversalen Aortenkonstriktion (TAC) zeigten bisher eine beständig erniedrigte HR und verminderte Wanddicken bei allerdings vergleichbarer Abnahme der kardialen Kontraktionskraft. Trotz der klaren Befunde und neuen Erkenntnisse über die vielfältige Rolle der PDE2 im Herzen lässt sich bisher noch nicht klar belegen, ob eine zusätzliche Aktivierung von myokardialen PDE2 tatsächlich im Sinne einer intrazellulären β-AR-Blockade die Progression zur Herzinsuffizienz verlangsamen oder verhindern könnte. Weitere darauf aufbauende Untersuchungen, wie z.B. eine akut induzierbare Aktivierung bzw. Deaktivierung in experimentellen Herzinsuffizienzmodellen könnten den Weg für die Entwicklung klinisch anwendbarer Ansätze zur therapeutischen Modulation dieser viel versprechenden Zielstruktur ebnen.

Microglia, the resident immune cells of the central nervous system, can become activated following injury, disease, or infection. In vitro, they can be activated by stimuli, which determine the inflammatory phenotype they will develop. In this thesis, stimulating microglia with tumor necrosis factor- and interferon- resulted in classical activation, characterized by proliferation, increased transcription of complement receptor 3 and major histocompatibility class II molecules, and elevated production and transcription of interleukin-1 and nitric oxide. Stimulation with TNF and IFN also changed the intensity of phosphorylated (activated) cyclic adenosine monophosphate response element binding protein immunoreactivity in microglia. Specifically, cells differentiated into populations with high or low pCREB intensity. This was the first example of such a response in microglia and was representative of what occurred in vivo, after ICH. Thus, the characterization of this model will be useful for future studies of this and other intracellular pathways of classically activated microglia.

Camps provide an avenue for examining positive youth development. Camps represent environments where children can develop their social capital and emotional intelligence insofar as camp activities teach children how to build positive relationships and to relate to others emotionally that lead to positive outcomes. Little research has examined children’s social capital and emotional intelligence and the relationship between them. Using a longitudinal dataset, this study examined the change of social capital and emotional intelligence experienced by campers. Findings revealed that increases in social capital caused increases in emotional intelligence. Differences were found based on gender. Furthermore, residential camps were found to have a stronger effect on the relationship between social capital and emotional intelligence than day camps. This study lends itself to furthering the understanding of the development of emotional intelligence and the importance of camp in children’s development.

El objetivo principal es el estudio exhaustivo de la conducta nidificadota de los chimpancés de Kanyawara, teniendo en cuenta una amplia lista de variables (sexo, edad, variaciones estacionales, características del hábitat.) que podrían incidir sobre la mencionada conducta. Se completa el trabajo con la colaboración de mapas de macro-distribución de los sitios de nidificación en el área de estudio y micro-distribución de los nidos en las zonas de descanso, así como con el seguimiento de la dinámica de reutilización.Finalmente, los resultados conseguidos se quieren comparar con otros estudios, sobre este comportamiento en grandes simios salvajes, con el fin de establecer semejanzas y diferencias ecológicas, sociales y/o culturales.La metodología utilizada es la usual en los trabajos etológicos de campo. El trabajo de campo va a suponer el seguimiento de la comunidad de chimpancés estudiada durante un año. El procedimiento empleado implicó el seguimiento diario (desde el amanecer hasta el crepúsculo) y el seguimiento de episodios nidificadores de los subgrupos de estudio, registrando sistemáticamente las conductas y variables relacionadas con la construcción de camas nocturnas y diurnas, además de la toma de medidas acerca de los nidos y de los sitios de anidaje conocidos, en ausencia de chimpancés, para su posterior análisis. Se presenta una amplia muestra, tanto por el número de nidos estudiados como por el número de episodios nidificadores nocturnos y diurnos observados.Entre las aportaciones de esta investigación cabe destacar el extenso y rico conjunto de datos descriptivos sobre la construcción de nidos de los chimpancés de la comunidad de Kanyawara.

The purpose of this thesis is to understand why the Arab-Israeli conflict has remained irreconcilable for sixty-one years. While the details and forms of the conflict have changed over time, the central factors dividing Zionists and Arabs in the Middle East have altered little. In this thesis I examine what these factors are and why they have been so effective in frustrating every peace effort. To understand the fundamental factors which keep the dispute alive I have conducted a comparative study of the two major peace initiatives which frame it diplomatically. The first formal peace conference between Israel and her Arab adversaries took place in Lausanne in 1949. The issues of borders, Jerusalem and refugees would not be seriously engaged with again until the last peace effort to date, the Camp David talks of 2000. Through a detailed comparative analysis of both conferences I seek to understand the positions taken by the warring parties towards these issues and the broader motivating factors separating them and preventing them from achieving peace. As the most important third party and supposed ??honest broker?? in both talks, I also closely examine the behaviour and policy of the US at each case. I find that the positions taken towards each issue by Israel, on the one hand, and the Arab party, on the other, were remarkably consistent in 1949 and 2000. Israel was not fully committed to peace in either instance, while the Arabs twice refused to sign what amounted to documents of surrender. These consistent positions starkly contrasted with that of the US, which completely changed its positions in ways which, by 2000, had almost wholly aligned it with Zionist demands. I conclude that future peace will rest on the ability of each party to re-examine its past in order to produce a spirit of reconciliation. For Israel, this will mean honestly revisiting Zionism in order to confront what its triumph meant for the Palestinian inhabitants of the land. The Arabs must also seek a broader understanding of their role in the dispute and demonstrate forcefully to Israelis that they seek peace rather than retribution. Above all, if the US is to retain its role as mediator it must abandon its ??special relationship?? with Israel and return to a more genuinely?? even handed alignment with the broader international consensus on the dispute. As it stands, the US??s more or less unconditional support of Israel has the effect of leading Israelis and Palestinians ever further from peace even as an ever more empty ??peace process?? is rhetorically trumpeted abroad.