INTRODUÇÃO: Apesar da fundamental importância da olfação para avaliação dos sabores dos alimentos ingeridos, percepção de vazamento de gases e de incêndios, sua avaliação clínica ainda não se encontra padronizada no Brasil. O Teste de Identificação do Olfato da Universidade da Pensilvânia (UPSIT) é um teste mundialmente utilizado e considerado por muitos como o padrão-ouro da avaliação olfatória. Originalmente em inglês, já foi traduzido para mais de 12 línguas. Esse trabalho se propôs a validar de forma inédita o UPSIT para outra cultura. O UPSIT versão em português foi validado para a população brasileira e tabelas normativas foram elaboradas para comparação do escore obtido segundo o sexo e idade do indivíduo. Secundariamente, procurou-se os fatores preditores de um melhor escore no teste. CASUÍSTICA E MÉTODOS: Estudo transversal realizado de dezembro de 2011 a agosto de 2012. A amostra utilizada foi não-probabilística por quotas e constituída por indivíduos presentes em uma instituição de atendimento público (Poupatempo São Paulo), de forma consecutiva, sem queixas olfatórias no dia do exame. Foi determinada a quota de 60 brasileiros(as) em cada faixa etária de cada sexo, a saber: 20-24, 25-30, 31-34, 35-40, 41-44, 45-50, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79 e >= 80 anos. Após responderem questionário referente a dados demográficos e critérios de inclusão e exclusão do estudo, fizeram o UPSIT 782 indivíduos do sexo masculino e 796 do sexo feminino. Nos pacientes com idade igual ou superior a 65 anos foi realizado o Mini Exame do Estado Mental e se excluíram aqueles pacientes com escore inferior a 24 pontos pela possibilidade de quadro demencial. A versão do UPSIT aplicada nesse estudo foi resultado de dois estudos prévios para melhorar a aplicabilidade desse teste para a população brasileira. RESULTADOS: 1820 voluntários participaram do estudo, 1578 foram incluídos nas tabelas normativas. 242 foram excluídos no dia da entrevista por estarem com infecção das vias aéreas superiores, terem história de trauma crânio-encefálico, queixa de perda de olfato ou paladar e um escore menor de 24 no Mini Exame do Estado Mental. Verificou-se que entre os 1578 indivíduos analisados, o escore de UPSIT variou de 9 a 40, obtendo-se escore médio de 32,1 (desvio padrão: 5,3) e escore mediano igual a 33. Pela análise univariada (p < 0,01) e multivariada - regressão linear múltipla- (p < 0,05), observou-se que a idade, sexo, número de anos de estudo e renda mensal da família influíram no escore do teste. CONCLUSÕES: O UPSIT está agora validado para utilização na população brasileira. Disponibilizou-se tabelas normativas para avaliação olfatória e um modo rápido de obtê-las. Fatores de correção são necessários para uma perfeita equivalência entre as normas de todos os continentes, utilizando como padrão-ouro as normas do país onde a versão original do teste foi desenvolvida. Pior status econômico e educacional interferem negativamente na performance olfatória / INTRODUCTION: Despite the fundamental importance of olfaction to assess the flavors of food, perception of gas leakage and fire, its clinical evaluation is not yet standardized in Brazil. The University of Pennsylvania Smell Identification Test of the (UPSIT) is a test used worldwide and considered by many as the gold standard of olfactory assessment. Originally in English, it has been translated into more than 12 languages. This study aimed to validate the UPSIT for another culture in a novel form. The portuguese version of UPSIT Portuguese version was validated for the Brazilian population and normative tables were prepared to compare the score obtained by sex and age of the individual. Secondarily, we sought the predictors of a better score on the test. PATIENTS AND METHODS: Cross-sectional study conducted from December 2011 to August 2012. The sample used was a non-probabilistic by quotas and consisted of individuals present in a public service institution (Poupatempo São Paulo), consecutively, without olfactory complaints on exam day. We determined the quota of 60 Brazilians in each age group for each sex, as follows: 20-24, 25-30, 31-34, 35-40, 41-44, 45-50, 50-54, 55 -59, 60-64, 65-69, 70-74, 75-79 and >= 80 years. After answering a questionnaire about demographics and inclusion and exclusion criteria of the study, 782 males and 796 females did the UPSIT. In patients aged over 65 years was held the Mini Mental State Examination and excluded those patients with a score less than 24 points for the possibility of dementia. The version of the UPSIT applied in this study was the result of two previous studies to enhance the applicability of this test for the Brazilian population. RESULTS: 1820 volunteers participated in the study, 1578 were included in the normative tables. 242 were excluded on the day of the interview for being with upper airway infection, having an history of head trauma, complaining of smell or taste losses and a score below 24 on the Mini Mental State Examination. It was found that among the 1578 subjects analyzed, the UPSIT scores ranged from 9 to 40, yielding a mean score of 32.1 (SD: 5.3) and a median 33. By univariate analysis (p < 0.01) and multivariate analysis - multiple linear regression-(p < 0.05), it was observed that the age, sex, years of schooling and family monthly income influenced the test scores. CONCLUSIONS: UPSIT is now validated for use in the Brazilian population. Normative tables for olfactory assessment and a fast way to obtain them were demonstrated. Correction factors are needed for a perfect equivalence between norms of all continents, using as gold standard norms of the country where the original version of the test was developed. Worse economic and educational status interfered negatively in olfactory performance

INTRODUÇÃO: Apesar da fundamental importância da olfação para avaliação dos sabores dos alimentos ingeridos, percepção de vazamento de gases e de incêndios, sua avaliação clínica ainda não se encontra padronizada no Brasil. O Teste de Identificação do Olfato da Universidade da Pensilvânia (UPSIT) é um teste mundialmente utilizado e considerado por muitos como o padrão-ouro da avaliação olfatória. Originalmente em inglês, já foi traduzido para mais de 12 línguas. Esse trabalho se propôs a validar de forma inédita o UPSIT para outra cultura. O UPSIT versão em português foi validado para a população brasileira e tabelas normativas foram elaboradas para comparação do escore obtido segundo o sexo e idade do indivíduo. Secundariamente, procurou-se os fatores preditores de um melhor escore no teste. CASUÍSTICA E MÉTODOS: Estudo transversal realizado de dezembro de 2011 a agosto de 2012. A amostra utilizada foi não-probabilística por quotas e constituída por indivíduos presentes em uma instituição de atendimento público (Poupatempo São Paulo), de forma consecutiva, sem queixas olfatórias no dia do exame. Foi determinada a quota de 60 brasileiros(as) em cada faixa etária de cada sexo, a saber: 20-24, 25-30, 31-34, 35-40, 41-44, 45-50, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79 e >= 80 anos. Após responderem questionário referente a dados demográficos e critérios de inclusão e exclusão do estudo, fizeram o UPSIT 782 indivíduos do sexo masculino e 796 do sexo feminino. Nos pacientes com idade igual ou superior a 65 anos foi realizado o Mini Exame do Estado Mental e se excluíram aqueles pacientes com escore inferior a 24 pontos pela possibilidade de quadro demencial. A versão do UPSIT aplicada nesse estudo foi resultado de dois estudos prévios para melhorar a aplicabilidade desse teste para a população brasileira. RESULTADOS: 1820 voluntários participaram do estudo, 1578 foram incluídos nas tabelas normativas. 242 foram excluídos no dia da entrevista por estarem com infecção das vias aéreas superiores, terem história de trauma crânio-encefálico, queixa de perda de olfato ou paladar e um escore menor de 24 no Mini Exame do Estado Mental. Verificou-se que entre os 1578 indivíduos analisados, o escore de UPSIT variou de 9 a 40, obtendo-se escore médio de 32,1 (desvio padrão: 5,3) e escore mediano igual a 33. Pela análise univariada (p < 0,01) e multivariada - regressão linear múltipla- (p < 0,05), observou-se que a idade, sexo, número de anos de estudo e renda mensal da família influíram no escore do teste. CONCLUSÕES: O UPSIT está agora validado para utilização na população brasileira. Disponibilizou-se tabelas normativas para avaliação olfatória e um modo rápido de obtê-las. Fatores de correção são necessários para uma perfeita equivalência entre as normas de todos os continentes, utilizando como padrão-ouro as normas do país onde a versão original do teste foi desenvolvida. Pior status econômico e educacional interferem negativamente na performance olfatória / INTRODUCTION: Despite the fundamental importance of olfaction to assess the flavors of food, perception of gas leakage and fire, its clinical evaluation is not yet standardized in Brazil. The University of Pennsylvania Smell Identification Test of the (UPSIT) is a test used worldwide and considered by many as the gold standard of olfactory assessment. Originally in English, it has been translated into more than 12 languages. This study aimed to validate the UPSIT for another culture in a novel form. The portuguese version of UPSIT Portuguese version was validated for the Brazilian population and normative tables were prepared to compare the score obtained by sex and age of the individual. Secondarily, we sought the predictors of a better score on the test. PATIENTS AND METHODS: Cross-sectional study conducted from December 2011 to August 2012. The sample used was a non-probabilistic by quotas and consisted of individuals present in a public service institution (Poupatempo São Paulo), consecutively, without olfactory complaints on exam day. We determined the quota of 60 Brazilians in each age group for each sex, as follows: 20-24, 25-30, 31-34, 35-40, 41-44, 45-50, 50-54, 55 -59, 60-64, 65-69, 70-74, 75-79 and >= 80 years. After answering a questionnaire about demographics and inclusion and exclusion criteria of the study, 782 males and 796 females did the UPSIT. In patients aged over 65 years was held the Mini Mental State Examination and excluded those patients with a score less than 24 points for the possibility of dementia. The version of the UPSIT applied in this study was the result of two previous studies to enhance the applicability of this test for the Brazilian population. RESULTS: 1820 volunteers participated in the study, 1578 were included in the normative tables. 242 were excluded on the day of the interview for being with upper airway infection, having an history of head trauma, complaining of smell or taste losses and a score below 24 on the Mini Mental State Examination. It was found that among the 1578 subjects analyzed, the UPSIT scores ranged from 9 to 40, yielding a mean score of 32.1 (SD: 5.3) and a median 33. By univariate analysis (p < 0.01) and multivariate analysis - multiple linear regression-(p < 0.05), it was observed that the age, sex, years of schooling and family monthly income influenced the test scores. CONCLUSIONS: UPSIT is now validated for use in the Brazilian population. Normative tables for olfactory assessment and a fast way to obtain them were demonstrated. Correction factors are needed for a perfect equivalence between norms of all continents, using as gold standard norms of the country where the original version of the test was developed. Worse economic and educational status interfered negatively in olfactory performance

The purpose of the senses of animals (and humans) is to translate information available in the external environment into internal information that can be processed by the brain. In the case of the olfactory sense -- the sense of smell -- this is information about the type and concentration of odourants. In the last 15 years major progress has been made in the experimental understanding of the first two stages of the olfactory sense: the signal transduction inside the cilia of the olfactory receptor neurons and the first 'relay station' in the brain, the olfactory bulb, as well as the connection between these two. Theoretical studies that classify the experimentally achieved knowledge or help in testing different biological hypotheses are only starting to be developed. The present work aims to contribute to the theoretical understanding of the first two stages of the olfactory sense. The first processing of the olfactory information, the olfactory signal transduction, is accomplished by a complex chemical network in the sensory cells with the task of coding the available information reliably over a wide range of stimulus strength. In the present work, methods from nonlinear dynamics combined with network theory (namely stoichiometric network analysis) are used to identify a specific negative feedback mechanism that accounts for a number of recently measured experimental results, e.g. oscillations in calcium concentration or the adaptation of the cell towards strong stimuli. This feedback is an experimentally well-established inhibition of cationic channels by the calcium-loaded form of the protein calmodulin. The results of the set of coupled nonlinear deterministic differential equations describing these dynamics agree quantitatively with experimental data. A bifurcation analysis of the system considered shows the robustness of the oscillatory solution against changes in parameters used. It also gives predictions that could serve as an experimental test of the proposed mechanism. Further abstraction and simplification of this specific signal transduction unit leads to a stochastic two-level system with negative feedback, that can not only be found in signalling systems but also in other branches of cell biology, e.g. regulated enzyme activity or in transcription dynamics. Whereas the description outlined above is fully deterministic, here the model system is intrinsically noisy. The influence of the feedback on the intrinsic noise as well as on the signalling properties of the module are analysed in detail by computing mean values, correlation and response functions of the two dynamical system variables using different analytical approaches. Common to all of them is that the intrinsic noise of the system is calculated from its dynamics rather than being introduced by hand. A master equation is used to get generally valid expressions for the mean values. Correlation and response functions for weak feedback are calculated within a path-integral description, and an easier self-consistent method with restricted validity is developed for future extensions of the module such as, e.g., the inclusion of diffusion. The results of the analytical methods are compared to each other and to the results of extended numerical simulations. The considered quantities allow for statements regarding the quality of the signal transduction properties of this module and the positive and negative effects of feedback on it. Going one step up in the information processing in the olfactory sense, another system is found that shows interesting dynamics during development and is influenced by stochastic effects: the formation of the neural map on the surface of the olfactory bulb -- stage two in the olfactory system. The dynamics of this very complex biological pattern formation process is studied mostly numerically focusing on three different aspects of axonal growth. Possible chemical guidance cues and the reaction of axonal growth cones to them are described using different levels of detail. There is strong experimental evidence for interactions among growing axons which is implemented in different ways into models. Finally, axon turnover is considered and used in the most promising simulation approach, where many axons grow as interacting directed random walkers. For each of these aspects, qualitative features of respective experiments are reproduced. / Die Sinne der Tiere (und Menschen) dienen dazu, Informationen über die Aussenwelt in neuronale, ' interne' Information zu 'übersetzen'. Im Falle des Geruchssinns sind dies Informationen über die Art und Konzentration von Geruchsstoffen. In den letzten 15 Jahren wurden grosse Fortschritte im experimentellen Verständnis der ersten beiden Stufen des Geruchssinns gemacht, sowohl was die Signaltransduktion in den Zilien der Geruchszellen betrifft, als auch bezüglich der ersten 'Schaltstelle' im Gehirn, dem olfaktorischen Bulbus (sowie in der Verbindung dieser beiden Stufen). Die Entwicklung theoretischer Studien, die die experimentell gewonnenen Daten klassifizieren können, befindet sich dagegen erst am Anfang. Ziel der vorliegenden Arbeit ist es, zum theoretischen Verständnis dieser ersten beiden Stufen beizutragen. Die erste Verarbeitung der olfaktorischen Information, die olfaktorische Signaltransduktion, wird durch ein komplexes chemisches Netzwerk in den Sinneszellen bewerkstelligt. In dieser Dissertation werden Methoden der nichtlinearen Dynamik, kombiniert mit Netzwerktheorie (stöchiometrische Netzwerkanalyse) benutzt, um einen negativen Rückkopplungsmechanismus zu identifizieren, der einige in neuerer Zeit gewonnene experimentelle Ergebnisse erklären kann, u.a. Oszillationen der Kalziumkonzentration oder die Anpassung der Zelle an starke Reize. Bei dieser Rückkopplung handelt es sich um eine experimentell gut bestätigte Hemmung eines Kationenkanals durch den Kalziumkomplex des Proteins Calmodulin. Das Ergebnis der vier gekoppelten nichtlinearen deterministischen Differenzialgleichungen, die das dynamische Verhalten des Systems beschreiben, stimmt quantitativ mit experimentellen Daten überein. Eine Bifurkationsanalyse zeigt die Robustheit der oszillierenden Lösung gegenüber Veränderungen der verwendeten Parameter und macht Vorhersagen möglich, die als experimentelle Tests des vorgeschlagenen Mechanismus dienen können. Eine weitere Abstrahierung der oben beschriebenen Signaltransduktionseinheit führt zu einem stochastischen Zweiniveausystem mit negativer Rückkopplung, das nicht nur in Signalsystemen gefunden werden kann, sondern auch in anderen Bereichen der Zellbiologie. Im Gegensatz zu der oben beschriebenen, komplett deterministischen Beschreibung zeigt das hier betrachtete Modellsystem intrinsisches Rauschen. Der Einfluss der Rückkopplung auf das Rauschen sowie auf die Signalübertragungseigenschaften des Moduls werden detailliert analysiert, indem mit Hilfe verschiedener analytischer Methoden Mittelwerte, Korrelations- und Antwortfunktionen des Systems ausgerechnet werden. Diese Methoden habe alle gemein, dass das intrinsische Rauschen des Systems aus der Dynamik selbst berechnet wird und nicht ' von Hand' eingefügt wird. Um allgemeingültige Ausdrücke für die Mittelwerte zu bekommen, wird eine Mastergleichung aufgestellt und gelöst. Die Korrelations- und Antwortfunktionen werden für schwache Rückkopplung mit Hilfe einer Pfadintegralmethode ausgerechnet, und eine einfachere, selbstkonsistente Methode begrenzter Gültigkeit wird für mögliche Erweiterungen des Systems, z.B. die Berücksichtigung von Diffusion, entwickelt. Die Ergebnisse der verschiedenen analytischen Methoden werden miteinander und mit den Ergebnissen ausführlicher numerischer Simulationen verglichen. Die betrachteten Grössen ermöglichen Aussagen über die Qualität der Signaltransduktion dieses Moduls sowie über die positiven und negativen Effekte der Rückkopplung auf diese. Ein weiteres Beispiel für interessante und von stochastischen Effekten beeinflusste Dynamik findet man einen Schritt weiter in der olfaktorischen Signalverarbeitung: Die während der Entwicklung stattfindende Ausbildung der neuronalen Karte auf der Oberfläche des olfaktorischen Bulbus, der zweiten Stufe des olfaktorischen Systems. Die Dynamik dieser sehr komplexen biologischen Musterbildung wird mittels numerischer Simulationen untersucht, wobei der Schwerpunkt auf drei verschiedene Aspekte axonalen Wachstums gesetzt wird. Die Reaktion axonaler Wachstumskegel auf mögliche chemische Signalstoffe wird verschieden detailliert beschrieben. Es gibt deutliche experimentelle Hinweise auf Wechselwirkung zwischen Axonen, was in den Modellen auf verschiedene Arten implementiert wird. Schliesslich wird die Erneuerung der Axone betrachtet und im vielversprechendsten Modell, in dem viele Axone als wechselwirkende gerichtete random walkers simuliert werden, berücksichtigt und analysiert. Für jeden dieser drei Aspekte können entsprechende experimentelle Ergebnisse qualitativ reproduziert werden.

No description available.

La neurogenèse persiste à l’âge adulte dans deux régions du système nerveux central (SNC) des mammifères : la zone sous-ventriculaire (SVZ) du cerveau antérieur et la zone sous-granulaire (SGZ) de l’hippocampe. Cette neurogenèse est possible grâce à la capacité de prolifération des cellules souches présentes dans les niches de la SVZ et la SGZ, mais en vieillissant, le cerveau subit une diminution dramatique du nombre de cellules souches neurales adultes (CSNa), une diminution de la prolifération cellulaire et une altération des niches de neurogenèse. Cependant, une importante question reste sans réponse : comment la perte tardive des CSNa est temporellement reliée aux changements de l’activité de prolifération et de la structure de la principale niche de neurogenèse (la SVZ)? Afin d’avoir un aperçu sur les événements initiaux, nous avons examiné les changements des CSNa et de leur niche dans la SVZ entre le jeune âge et l’âge moyen. La niche de la SVZ des souris d’âge moyen (12 mois) subit une réduction de l’expression des marqueurs de plusieurs sous-populations de précurseurs neuraux en comparaison avec les souris jeunes adultes (2 mois). Anatomiquement, cela est associé avec des anomalies cytologiques, incluant une atrophie générale de la SVZ, une perte de la couche de cellules sousépendymaires par endroit et l’accumulation de gouttelettes lipidiques de grande taille dans l’épendyme. Fonctionnellement, ces changements sont corrélés avec une diminution de l’activité de la SVZ et une réduction du nombre de nouveaux neurones arrivant aux bulbes olfactifs. Pour déterminer si les CSNa de la SVZ ont subi des changements visibles, nous avons évalué les paramètres clés des CSNa in vivo et in vitro. La culture cellulaire montre qu’un nombre équivalent de CSNa ayant la capacité de former des neurosphères peut être isolé du cerveau du jeune adulte et d’âge moyen. Cependant, à l’âge moyen, les précurseurs neuraux semblent moins sensibles aux facteurs de croissance durant leur différenciation in vitro. Les CSNa donnent des signes de latence in vivo puisque leur capacité d’incorporation et de rétention du BrdU diminue. Ensemble, ces données démontrent que, tôt dans le processus du vieillissement, les CSNa et leur niche dans la SVZ subissent des changements significatifs, et suggèrent que la perte de CSNa liée au vieillissement est secondaire à ces événements. / Neurogenesis persists throughout the adulthood in two regions of the mammalian central nervous system (SNC): the sub-ventricular zone (SVZ) of the forebrain and the sub-granular zone (SGZ) of the hippocampus. Neurogenesis is possible due to the proliferation capacity of stem cells present within both the SVZ and SGZ niches, but with aging, the forebrain undergoes a drastic reduction in its number of adult neural stem cells (aNSCs), a decrease of cell proliferation and an alteration of the neurogenic niches. However, a key unresolved question remains: how the onset of aNSC loss is temporally related to changes of proliferating activity and to structural alterations within the principal stem cell niche (the SVZ)? To gain insights into the initial events leading to aging-associated aNSC loss, we investigated the changes occurring to aNSCs and the SVZ niche between young adulthood and middle-age. The SVZ niche of middle-aged mice (12-months-old) was found to display reduced expression of markers for multiple neural precursor sub-populations when compared to young adult mice (2-months-old). Anatomically, this was associated with significant cytological aberrations, including an overall atrophy of the SVZ, loss of sub-ependymal cells, and accumulation of large lipid droplets within the ependyma. Functionally, these changes correlated with diminished SVZ activity and reduced number of newly born neurons reaching the principal target tissue: the olfactory bulbs. To determine whether changes were evident at the level of the SVZ stem cells, we evaluated key in vitro and in vivo parameters of aNSCs. Tissue culture experiments showed that equal numbers of neurosphere-forming aNSCs could be isolated from young adult and middle-aged forebrains. However, at middle-age, neural precursors seemed to be less sensitive to growth factors during their in vitro differentiation and displayed signs of increased quiescence in vivo. Collectively, these findings demonstrate that, with early aging, aNCS and their SVZ niche go through significant changes, and suggest that aging-associated aNSC loss is secondary to these events.

The purpose of the senses of animals (and humans) is to translate information available in the external environment into internal information that can be processed by the brain. In the case of the olfactory sense -- the sense of smell -- this is information about the type and concentration of odourants. In the last 15 years major progress has been made in the experimental understanding of the first two stages of the olfactory sense: the signal transduction inside the cilia of the olfactory receptor neurons and the first 'relay station' in the brain, the olfactory bulb, as well as the connection between these two. Theoretical studies that classify the experimentally achieved knowledge or help in testing different biological hypotheses are only starting to be developed. The present work aims to contribute to the theoretical understanding of the first two stages of the olfactory sense. The first processing of the olfactory information, the olfactory signal transduction, is accomplished by a complex chemical network in the sensory cells with the task of coding the available information reliably over a wide range of stimulus strength. In the present work, methods from nonlinear dynamics combined with network theory (namely stoichiometric network analysis) are used to identify a specific negative feedback mechanism that accounts for a number of recently measured experimental results, e.g. oscillations in calcium concentration or the adaptation of the cell towards strong stimuli. This feedback is an experimentally well-established inhibition of cationic channels by the calcium-loaded form of the protein calmodulin. The results of the set of coupled nonlinear deterministic differential equations describing these dynamics agree quantitatively with experimental data. A bifurcation analysis of the system considered shows the robustness of the oscillatory solution against changes in parameters used. It also gives predictions that could serve as an experimental test of the proposed mechanism. Further abstraction and simplification of this specific signal transduction unit leads to a stochastic two-level system with negative feedback, that can not only be found in signalling systems but also in other branches of cell biology, e.g. regulated enzyme activity or in transcription dynamics. Whereas the description outlined above is fully deterministic, here the model system is intrinsically noisy. The influence of the feedback on the intrinsic noise as well as on the signalling properties of the module are analysed in detail by computing mean values, correlation and response functions of the two dynamical system variables using different analytical approaches. Common to all of them is that the intrinsic noise of the system is calculated from its dynamics rather than being introduced by hand. A master equation is used to get generally valid expressions for the mean values. Correlation and response functions for weak feedback are calculated within a path-integral description, and an easier self-consistent method with restricted validity is developed for future extensions of the module such as, e.g., the inclusion of diffusion. The results of the analytical methods are compared to each other and to the results of extended numerical simulations. The considered quantities allow for statements regarding the quality of the signal transduction properties of this module and the positive and negative effects of feedback on it. Going one step up in the information processing in the olfactory sense, another system is found that shows interesting dynamics during development and is influenced by stochastic effects: the formation of the neural map on the surface of the olfactory bulb -- stage two in the olfactory system. The dynamics of this very complex biological pattern formation process is studied mostly numerically focusing on three different aspects of axonal growth. Possible chemical guidance cues and the reaction of axonal growth cones to them are described using different levels of detail. There is strong experimental evidence for interactions among growing axons which is implemented in different ways into models. Finally, axon turnover is considered and used in the most promising simulation approach, where many axons grow as interacting directed random walkers. For each of these aspects, qualitative features of respective experiments are reproduced. / Die Sinne der Tiere (und Menschen) dienen dazu, Informationen über die Aussenwelt in neuronale, ' interne' Information zu 'übersetzen'. Im Falle des Geruchssinns sind dies Informationen über die Art und Konzentration von Geruchsstoffen. In den letzten 15 Jahren wurden grosse Fortschritte im experimentellen Verständnis der ersten beiden Stufen des Geruchssinns gemacht, sowohl was die Signaltransduktion in den Zilien der Geruchszellen betrifft, als auch bezüglich der ersten 'Schaltstelle' im Gehirn, dem olfaktorischen Bulbus (sowie in der Verbindung dieser beiden Stufen). Die Entwicklung theoretischer Studien, die die experimentell gewonnenen Daten klassifizieren können, befindet sich dagegen erst am Anfang. Ziel der vorliegenden Arbeit ist es, zum theoretischen Verständnis dieser ersten beiden Stufen beizutragen. Die erste Verarbeitung der olfaktorischen Information, die olfaktorische Signaltransduktion, wird durch ein komplexes chemisches Netzwerk in den Sinneszellen bewerkstelligt. In dieser Dissertation werden Methoden der nichtlinearen Dynamik, kombiniert mit Netzwerktheorie (stöchiometrische Netzwerkanalyse) benutzt, um einen negativen Rückkopplungsmechanismus zu identifizieren, der einige in neuerer Zeit gewonnene experimentelle Ergebnisse erklären kann, u.a. Oszillationen der Kalziumkonzentration oder die Anpassung der Zelle an starke Reize. Bei dieser Rückkopplung handelt es sich um eine experimentell gut bestätigte Hemmung eines Kationenkanals durch den Kalziumkomplex des Proteins Calmodulin. Das Ergebnis der vier gekoppelten nichtlinearen deterministischen Differenzialgleichungen, die das dynamische Verhalten des Systems beschreiben, stimmt quantitativ mit experimentellen Daten überein. Eine Bifurkationsanalyse zeigt die Robustheit der oszillierenden Lösung gegenüber Veränderungen der verwendeten Parameter und macht Vorhersagen möglich, die als experimentelle Tests des vorgeschlagenen Mechanismus dienen können. Eine weitere Abstrahierung der oben beschriebenen Signaltransduktionseinheit führt zu einem stochastischen Zweiniveausystem mit negativer Rückkopplung, das nicht nur in Signalsystemen gefunden werden kann, sondern auch in anderen Bereichen der Zellbiologie. Im Gegensatz zu der oben beschriebenen, komplett deterministischen Beschreibung zeigt das hier betrachtete Modellsystem intrinsisches Rauschen. Der Einfluss der Rückkopplung auf das Rauschen sowie auf die Signalübertragungseigenschaften des Moduls werden detailliert analysiert, indem mit Hilfe verschiedener analytischer Methoden Mittelwerte, Korrelations- und Antwortfunktionen des Systems ausgerechnet werden. Diese Methoden habe alle gemein, dass das intrinsische Rauschen des Systems aus der Dynamik selbst berechnet wird und nicht ' von Hand' eingefügt wird. Um allgemeingültige Ausdrücke für die Mittelwerte zu bekommen, wird eine Mastergleichung aufgestellt und gelöst. Die Korrelations- und Antwortfunktionen werden für schwache Rückkopplung mit Hilfe einer Pfadintegralmethode ausgerechnet, und eine einfachere, selbstkonsistente Methode begrenzter Gültigkeit wird für mögliche Erweiterungen des Systems, z.B. die Berücksichtigung von Diffusion, entwickelt. Die Ergebnisse der verschiedenen analytischen Methoden werden miteinander und mit den Ergebnissen ausführlicher numerischer Simulationen verglichen. Die betrachteten Grössen ermöglichen Aussagen über die Qualität der Signaltransduktion dieses Moduls sowie über die positiven und negativen Effekte der Rückkopplung auf diese. Ein weiteres Beispiel für interessante und von stochastischen Effekten beeinflusste Dynamik findet man einen Schritt weiter in der olfaktorischen Signalverarbeitung: Die während der Entwicklung stattfindende Ausbildung der neuronalen Karte auf der Oberfläche des olfaktorischen Bulbus, der zweiten Stufe des olfaktorischen Systems. Die Dynamik dieser sehr komplexen biologischen Musterbildung wird mittels numerischer Simulationen untersucht, wobei der Schwerpunkt auf drei verschiedene Aspekte axonalen Wachstums gesetzt wird. Die Reaktion axonaler Wachstumskegel auf mögliche chemische Signalstoffe wird verschieden detailliert beschrieben. Es gibt deutliche experimentelle Hinweise auf Wechselwirkung zwischen Axonen, was in den Modellen auf verschiedene Arten implementiert wird. Schliesslich wird die Erneuerung der Axone betrachtet und im vielversprechendsten Modell, in dem viele Axone als wechselwirkende gerichtete random walkers simuliert werden, berücksichtigt und analysiert. Für jeden dieser drei Aspekte können entsprechende experimentelle Ergebnisse qualitativ reproduziert werden.

博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

El objetivo de esta Tesis Doctoral es estudiar diferentes herramientas para el manejo de plagas y enfermedades del cultivo de la platanera. Entre las herramientas que vamos a desarrollar, se van a analizar los compuestos orgánicos volátiles (COVs) fúngicos derivados de hongos entomopatógenos (HE) y nematófagos, como fuente de metabolitos con actividad antagónica contra el picudo negro (PN) de la platanera, Cosmopolites sordidus, para su control y manejo en el campo. Así mismo, vamos a estudiar las respuestas de cultivares de plataneras a quitosano, un polisacárido biodegradable, para evaluar su posible uso en el campo como estimulante y protector de las plantas frente a plagas y patógenos, como Fusarium oxysporum f. sp. cubense. El conjunto de capítulos de esta tesis pretende sentar las bases de una estrategia de manejo sostenible de plagas y enfermedades del cultivo de la platanera, basada en el uso de COVs derivados de hongos presentes de forma natural en los cultivos, en combinación con la suplementación de quitosano en el riego, para un efecto de protección y activación de las defensas de las plataneras antes de cualquier infección de plagas y/o enfermedades. El objetivo principal de esta Tesis Doctoral es encontrar nuevas fórmulas para la gestión integrada de plagas como Cosmopolites sordidus y enfermedades de la platanera en condiciones de campo. En esta Tesis Doctoral hemos ideado enfoques sostenibles para la gestión de las plagas y enfermedades de las plataneras. Nuestros objetivos son: a) Cosmopolites sordidus (picudo negro de la platanera, PN), la principal plaga de los cultivos de plátano y, b) el hongo del marchitamiento Fusarium oxysporum f. sp. cubense Raza Tropical 4 (FocTR4), agente causante de una nueva variante extremadamente virulenta de la enfermedad del “Mal de Panamá”, que se está extendiendo rápidamente por todo el mundo. Nuestras herramientas de gestión sostenible son: a) los hongos entomopatógenos (HE, conocidos por su uso como agentes de control biológico, ACBs) aislados de campos comerciales de plátanos, b) sus compuestos orgánicos volátiles (COVs) y, c) el quitosano, un compuesto biodegradable y elicitor de la inmunidad de las plantas con actividad antimicrobiana. Damos evidencia de que los COVs de los hongos agentes de control biológico son repelentes del PN. Pueden utilizarse en los cultivos de platanera mediante estrategias de push and pull para gestionar la plaga de forma sostenible. El quitosano puede utilizarse en el riego para prevenir las defensas de la platanera local y sistémicamente. Por lo tanto, este polímero, con probada actividad antimicrobiana frente a otros patógenos de marchitamiento de Fusarium spp., podría utilizarse contra la actual pandemia en las plataneras causada por FocTR4. La capacidad de inducir reguladores del crecimiento de las plantas sostiene también el papel fertilizante del quitosano. La inducción de compuestos relacionados con la respuesta sistémica adquirida (RSA) hace que el riego con quitosano sea una herramienta para manejar también las plagas de las plataneras sobre el suelo (PN) y las enfermedades (Sigatoka). De esta manera, los COVs y el quitosano podrían ayudar a reducir el uso de agroquímicos tóxicos en los cultivos de platanera en todo el mundo.

Anxiety disorders are the most prevalent psychiatric conditions within primary care, affecting up to 29% of people across their lifetime. Generalized Anxiety disorder (GAD) is frequently comorbid with Major Depressive Disorder (MDD), resulting in greater functional impairment. Gut microbiota have been shown to modulate brain chemistry and function, possibly also playing a role in the genesis of anxiety. Bacteria are also able to produce, or interact with the host metabolism of neuroactive substances, including classical neurotransmitters and trace amines, like octopamine, which although found in trace concentrations in the mammalian brain, can affect CNS function. Specifically, trace amines can affect catecholamine release, reuptake and biosynthesis, and modulate dopamine and serotonin metabolism. We investigated whether microbiota from patients with GAD with no signs of immune activation can alter behaviour in gnotobiotic mice and whether this is accompanied by changes in metabolites within the gastrointestinal tract. Germ-free NIH Swiss mice (n=35) were colonized with microbiota from either a GAD patient (n=18) with severe anxiety, comorbid depression, and low serum and fecal octopamine, or an age and sex-matched healthy control (HC) (n=17). Three weeks post- colonization, mouse behaviour was assessed by standard psychometric tests. Emotionality z-scores were calculated to provide a robust integrated behavioural assessment. Microbiota profiles were assessed by 16S rRNA based Illumina, fecal β-defensin-3 level was measured by ELISA. After sacrifice, mouse brain BDNF and GDNF expression was assessed by immunofluorescence, and gene expression in the hippocampus, amygdala, and olfactory bulbs was assessed by Nanostring. Stool and cecum metabolites were measured in all colonized mice by multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). There were no differences in fecal β-defensin levels between mice colonized with GAD microbiota as compared to mice colonized with HC microbiota. However, GAD mice exhibited greater anxiety and depressive-like behavior compared to HC mice in the digging and tail suspensions tests. Behavioural z-scoring across all six standard psychometric tests showed a significant increase in group emotionality score means of GAD-colonized mice compared to HC-colonized mice. Mice colonized with microbiota from a GAD patient had distinct bacterial profiles from mice colonized with HC microbiota. Compared to HC mice, GAD mice had lower levels of dopamine, octopamine and acetylcholine in cecum contents. Furthermore, GAD mice had higher expression of BDNF in the amygdala, lower expression of BDNF in the hippocampus, and lower expression of GDNF in the midbrain. GAD mice also had lower expression of CCR2 in the hippocampus, higher Cnlp/CAMP in the amygdala and olfactory bulb, and higher Nfkb1 in the olfactory bulb compared to HC mice. Our results suggest that microbiota from a selected patient with GAD has the ability to induce anxiety and depressive-like behavior, by mechanisms independent of immune system, likely by altered production of biogenic amines and neurotransmitters. / Thesis / Master of Science (MSc)

Die paläarktische omnivore Weichwanze Dicyphus errans Wolff (Heteroptera, Miridae, Bryocorinae) zeichnet sich durch ein ausgesprochen breites Spektrum an besetzten Wirtspflanzen und konsumierten Beutetieren aus. Über 150 von D. errans akzeptierte Pflanzenarten sind erstmalig belegt worden. Der erfolgreiche Verzehr von 15 Beute-tierarten wurde quantitativ nachgewiesen. Eine weitere Besonderheit der Wanze besteht in der Präferenz für glandulär behaarte Pflanzen. Die Weichwanze besetzt somit von vielen anderen Insekten gemiedene Nischen. Untersuchungen im Botanischen Garten der Technischen Universität Dresden (2000 bis 2002) ließen auf eine bemerkenswerte räuberische Aktivität und Anpassungsfähigkeit an unterschiedliche Habitate, Beutetiere und Klimabedingungen schließen. Die fortführenden Studien im Rahmen der vorliegenden Dissertation (2002 bis 2005) erbrachten umfassende Erkenntnisse über die Art D. errans im Hinblick auf deren Morphologie, Vermehrung und Haltung, Bionomie und Ökologie (Fekundität und Ontogenese in Abhängigkeit von ausgewählten Einflussfaktoren, Dormanz), Aufenthalt und Fortbewegung (räumliche Orientierung und strukturanalytische Studien zu den Interaktionen zwischen Wanze und Pflanzenoberflächen), den Nahrungserwerb (Verzehrleistung und Omnivorie) sowie Videodokumentationen der Lebensweise und des Verhaltens. Der Generalist und Opportunist D. errans integriert sich als Pflanzensaftsauger regulierendes Kompartiment neben echten Räubern und Parasitoiden in Biozönosen. Als omnivores Insekt übernimmt die Wanze eine intermediäre und supplementäre Position in Nahrungsnetzen. Die Lebensweise dieser Weichwanzenart erscheint sehr komplex. Die enge Assoziation mit Pflanzen tritt stark in den Vordergrund. Sie ist in jeglichen Betrachtungen von D. errans unbedingt zu berücksichtigen und bietet außerdem als ein Modellsystem ein spannendes Forschungsfeld im Hinblick auf die Adaptation partiell räuberisch lebender Insekten an behaarte Pflanzen. / The omnivorous mirid bug Dicyphus errans Wolff (Heteroptera, Miridae, Bryocorinae) lives on a wide range of host plants and feeds on various preys. Over 150 plant species accepted by the mirid bug have been identified. It was experimentally shown that 15 prey species are efficiently consumed. Another characteristical features of D. errans is that it preferes hairy plants. Thus, the mirid bug occupies unique niches avoided by many other insects. Investigations, carried out at the Botanical Garden of the Technical University of Dresden (2000-2002) gave evidence for a remarkable predatory activity and ability to adaptation to different habitats, preys and climate conditions. The studies presented in the dissertation (2002-2005) gave the comprehensive knowledge about the species D. errans, especially its morphology, rearing, bionomy and ecology (fecundity and ontogenesis depending on selected factors, dormancy), habitat preference and locomotion (spatial orientation and structural-analytical studies of the interactions between the bug and plant surfaces), foraging and food ingestion (predatory capacity and omnivory). In addition, video documentation of the modus vivendi and the behavior was performed. The generalist and opportunist D. errans lives together with predators and parasitoids and takes part in a biological control of phytophagous insects in biocenoses. The life history of this bug species appeared to be very complex. The close association to plants has to be considered. Dicyphus errans offers a model system for further research on omnivorous predatory insects connected with hairy plants.