Pseudomonas aeruginosa (Pa) est un pathogène opportuniste responsable d’infections pulmonaires aigues graves chez les malades prédisposés. Devant l’émergence croissante de la résistance aux antibiotiques, le développement de thérapeutiques alternatives adjuvantes est indispensable et nécessite la compréhension des interactions hôte-pathogènes au cours de l’infection. La voie métabolique de dégradation du tryptophane appelée voie des kynurénines produit chez l’hôte des métabolites aux propriétés immunomodulatrices connues. Récemment, l’existence de cette voie a été mise en évidence chez Pa, bien que la nature et la quantité de métabolites produits ne soient pas parfaitement connus. La production bactérienne de kynurénines pourrait interférer avec la mise en place de la réponse immunitaire de l’hôte et sa régulation au cours des différentes phases de l’infection, altérant la balance immunitaire pulmonaire au profit du pathogène. A ce titre, la voie des kynurénines de Pa constituerait une cible thérapeutique potentielle. L’objectif de ce travail de thèse est d’étudier l’implication de la voie des kynurénines de Pa dans la virulence bactérienne et la réponse immune de l’hôte dans un modèle murin d’agression respiratoire aiguë. Pour cela, les souris sont infectées avec des souches sauvages de Pa, avec des souches mutantes ΔkynA, non productrices de kynurénines, et des souches ΔkynU, surproductrices de kynurénines. Les interactions potentielles avec la voie des kynurénines de l’hôte sont explorées en inhibant la première enzyme de la voie métabolique, l’indoleamine-2,3-dioxygenase (IDO). Enfin, le rôle du récepteur arylhydrocarbone (AhR), récepteur connu des kynurénines et impliqué dans l’immunité pulmonaire, est exploré en comparant la réponse à l’infection de souris AhR KO à celle des souris sauvages. Dans ce travail, nous décrivons tout d’abord la production des différents métabolites de la voie des kynurénines de Pa in vitro et in vivo dans le modèle d’infection respiratoire aigue, en décrivant pour la première fois la production d’acide kynurénique et de 3-hydroxy-kynurénine pour cette bactérie. Ensuite, nous montrons que les kynurénines bactériennes interfèrent avec la réponse immune de l’hôte, en majorant le recrutement cellulaire alvéolaire, tout en atténuant le niveau d’inflammation et l’activation des cellules présentatrices d’antigènes. Enfin, nous rapportons que l’IDO et l’AhR sont impliqués dans cette immunomodulation, faisant des kynurénines bactériennes des agents du dialogue hôte-pathogène au cours de l’infection respiratoire aigue. A la lumière de ces résultats, la voie des kynurénines pourrait constituer une cible thérapeutique d’intérêt dans les infections respiratoires à P. aeruginosa. / Pseudomonas aeruginosa (Pa) is a Gram-negative bacteria frequently involved in healthcare-associated pneumonia and considered as a « problem-pathogen ». To face the announced post-antibiotic era due to increasing resistance and lack of new antibiotics, new treatment strategies have to be developed. During pneumonia, lung injury results from both bacterial-mediated virulence and host response. Modulation of an overreacting host response could be an alternative therapeutic target in Pa-induced lung infection. Kynurenines are small molecules resulting from tryptophan degradation with reported immunomodulatory properties. Pa is known to produce kynurenine, but the functional enzymes, types and amounts of secreted metabolites are poorly known. Interestingly, many host cells also possess the kynurenine pathway, whose metabolites are known to control immune system homeostasis. The following experiments aim to determine whether bacterial metabolites can interfere with the host’s immune response, leading to a possible immunomodulatory interplay between bacteria and host kynurenine pathways, impacting on the pathophysiology of P. aeruginosa infection. To that goal, we use a murin model of acute lung injury. Mice were infected with WT strain of Pa, compared to mutant strains unable to produce kynurenine (ΔkynA), and mutant strains overproducing them (ΔkynU). Moreover, we studied the interactions between bacterial and host kynurenine pathways by inhibiting the first enzyme of the host pathway called indoleamine-2,3-dioxygenase (IDO). Finally, we assessed the role of the arylhydrocarbon receptor (AhR), a known receptor to kynurenine involved in lung immunity, using AhR KO mice. First, we assess types and levels of metabolites produced by Pa in an in vitro model, and the relevance of this production in vivo. We show for the first time that Pa is able to secrete kynurenine at clinically relevant levels, and other metabolites such as kynurenic acid and 3 OHkynurenine, what was unknown to date. Second, we show that bacterial metabolites were able to modulate the host innate immune response, by increasing alveolar recruitment of neutrophils, associated with decreased inflammatory cytokines levels and impairment of antigen-presenting cells activation. Finally, we report that IDO and AhR are involved in this kynurenine-mediated immunomodulation. These data suggest that pulmonary infection with a bacteria highly expressing the kynurenine pathway enzymes could lead to an imbalance in the immune response to infection, thus constituting a potential therapeutic target to improve Pa-induced pneumonia outcome.

Recent studies suggest that some cases of prenatal depression may be associated with reactivation of latent infections of the herpesvirus family. The possible relationships among stress, prenatal depression, and herpes viral reactivation in pregnancy are understudied and the molecular pathways such as the neuroimmune biogenic amine pathway are unidentified. Chronic stress shifts the T helper-1 cell (Th1) cytokine profile to a Th2 profile, which favors virus induced pathogenesis and survival. Pregnancy is also associated with a similar Th2 dominance. In non-pregnant individuals, exposure to psychological or physical stress may be associated with latent herpes viral reactivation and could result in behavioral deficits and depression. Normally, type-1 cytokines such as Interferon-gamma (IFN -gamma) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) induce indoleamine-2, 3-dioxygenase (IDO) activation which inhibits herpes virus replication and reactivation, decreases tryptophan production, and alters phenylalanine /tyrosine metabolism. Thus it is possible that prenatal depression may occur from tryptophan stealing through the IDO pathway which results in decreased serotonin as well as increased risk for latent herpes viral reactivation. The purpose of this study is to analyze the relationships among stress, herpes viral titers, depression, and metabolites of IDO activation, which involves tryptophan and guanosine-triphosphate-cyclohydrolase-1(GTP-CH1) pathways. This study builds on Influence of Lactation on Postpartum Stress and Immunity (Grant number: R01-NR05000) which investigated perinatal immune, endocrine, and inflammatory changes in pregnancy and the postpartum. A secondary data analysis was conducted on baseline data from women collected at 16 to 25 gestational weeks. This data set included some herpes viral titers, and additional ones were measured in stored plasma samples. The aim of this study is to examine relationships among stress, herpes viral reactivation, depression, and the IDO activation pathway. The results of this study provide information about the possible role of further relationships of prenatal stress, latent herpes viral reactivation, and depression mechanisms. The results will be important in health promotion and disease prevention during pregnancy.

No description available.

Submitted by Tatiana Oliveira (tsilva@icict.fiocruz.br) on 2012-06-06T12:23:16Z No. of bitstreams: 1 jorgenilce_s_sales_ioc_bp_0022_2010.pdf: 2120746 bytes, checksum: 319e0b7b0dce67008dbde7aeb9028520 (MD5) / Made available in DSpace on 2012-06-06T12:23:16Z (GMT). No. of bitstreams: 1 jorgenilce_s_sales_ioc_bp_0022_2010.pdf: 2120746 bytes, checksum: 319e0b7b0dce67008dbde7aeb9028520 (MD5) Previous issue date: 2010 / Fundação Oswaldo Cruz.Instituto Oswaldo Cruz. Rio de janeiro, RJ, Brasil / Os mecanismos que levam a ausência de resposta imune celular no pólo lepromatoso da hanseníase frente ao Mycobacterium leprae permanecem obscuros. Estudos anteriores mostraram que fatores secretados pelos macrófagos de pacientes lepromatosos inibem a proliferação de linfócitos de indivíduos saudáveis, sugerindo que fatores endógenos produzidos por células da linhagem mielóide podem exercer uma atividade supressora nas células T. Recentemente, diversos estudos têm demonstrado a participação da enzima indoleamina 2,3 dioxigenase (IDO) na supressão das células T, indicando que mudanças bioquímicas devido ao catabolismo do triptofano têm efeitos na proliferação dessas células. No presente trabalho nós demonstramos que os pacientes com a forma clínica lepromatosa apresentam uma maior expressão de IDO em biópsias de pele e maior atividade de IDO no soro quando comparados com pacientes com a forma tuberculóide e que o M. leprae induz a expressão e a atividade de IDO em monócitos de indivíduos saudáveis e de pacientes lepromatosos. Além disso, observamos que o M. leprae induz aumento na atividade de IDO nas células dendríticas derivadas de monócitos de indivíduos saudáveis e que esta atividade aumentada de IDO contribui para o aumento percentual de linfócitos expressando a molécula supressora CTLA-4, sugerindo que IDO participe na anergia T antígeno específico observada em pacientes com a forma lepromatosa da doença / The absence of cellular immune response to M. leprae in lepromatous pole of leprosy remains unclear. Previous studies showed that factors secreted by macrophages of lepromatous patients inhibit the proliferation of lymphocytes from healthy individuals, suggesting that endogenous factors produced by cells of myeloid lineage may have suppressive activity on T cells. Recently, several studies have been demonstrating the involvement of the enzyme indoleamine 2,3 dioxygenase (IDO) in the suppression of T cells, indicating that biochemical changes due to the catabolism of tryptophan affects on the proliferation of these cells. In this study we demonstrated that patients with lepromatous clinical form showed higher IDO expression in skin biopsies and increased IDO activity in serum when compared with patients with the tuberculoid form. In addition, M. leprae induces the expression and activity of IDO in monocytes of healthy subjects and lepromatous patients. Moreover, we observed that M. leprae induces increased activity of IDO in monocyte-derived dendritic cells of healthy individuals and that this increased IDO activity may contribute to the increase in percentage of T lymphocytes expressing CTLA-4, which suggest that IDO may play a role in T-specific anergy observed in lepromatous leprosy patients

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-07-17T13:05:36Z No. of bitstreams: 1 JuliaJensenDidonet_TESE.pdf: 2583824 bytes, checksum: 051c963d447673a358cc7bee29ee8629 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-07-18T13:26:56Z (GMT) No. of bitstreams: 1 JuliaJensenDidonet_TESE.pdf: 2583824 bytes, checksum: 051c963d447673a358cc7bee29ee8629 (MD5) / Made available in DSpace on 2017-07-18T13:26:56Z (GMT). No. of bitstreams: 1 JuliaJensenDidonet_TESE.pdf: 2583824 bytes, checksum: 051c963d447673a358cc7bee29ee8629 (MD5) Previous issue date: 2017-03-15 / A depress?o reduz a qualidade de vida do indiv?duo, compromete a funcionalidade profissional e social e ? considerada a principal causa para incapacidade em termos de anos perdidos no curso da doen?a. Apesar da severidade relatada, ainda n?o h? uma compreens?o clara dos substratos neurais alterados na depress?o, por isso o estudo de modelos animais que investiguem a etiologia deste transtorno torna-se extremamente necess?rio. Este trabalho buscou comparar altera??es bioqu?micas no soro, c?rtex pr?frontal (CPF) e hipocampo de camundongos submetidos a dois modelos animais de depress?o: desamparo aprendido e administra??o do lipopolissacar?deo de E.Coli (LPS). O teste de desamparo aprendido resultou em m?dia 70 % de animais desamparados, verificado pela falha em escapar aos choques 24 h e 48 h ap?s a sess?o de indu??o do desamparo. Os 30 % restantes foram considerados resilientes. Os animais desamparados apresentaram mais dano oxidativo no CPF e soro, quando comparados aos animais controles. N?o houve diferen?a entre desamparados e resilientes, por?m, foi observada correla??o positiva entre o dano oxidativo no soro e CPF e o comportamento desamparado. A concentra??o das citocinas pr?-inflamat?rias IL-1?, TNF?, IL-6 e antiinflamat?ria IL-10 no CPF e hipocampo dos animais submetidos ao desamparo e controles n?o foi diferente entre os grupos, por?m houve correla??o positiva entre a citocina IL-6 no hipocampo e o comportamento desamparado dos animais. A atividade da enzima indolamina 2,3-dioxigenase (IDO) n?o apresentou diferen?a significativa nos animais submetidos ao modelo do desamparo e controles. A administra??o sist?mica de LPS (0,8 mg/kg i.p.) induziu um comportamento doentio nos animais, caracterizado por diminui??o da ingest?o de ?gua e comida, perda de peso e altera??o da temperatura retal 6 h ap?s a inje??o. Em 24 h o estado doentio diminuiu, por?m, os animais que receberam LPS apresentaram imobilidade aumentada no teste de suspens?o pela cauda em compara??o aos animais que receberam salina. Foi observado mais dano oxidativo no soro, CPF e hipocampo do grupo LPS em compara??o aos grupos salina e controle. As citocinas IL-?, TNF? no soro, CPF e hipocampo n?o apresentaram nenhuma altera??o, indicando que a inflama??o induzida pela administra??o de LPS foi transit?ria. A citocina IL-6 mostrou-se elevada no CPF do grupo que recebeu LPS em compara??o ao grupo salina, correlacionada positivamente com o comportamento do tipo depressivo dos animais. Os n?veis de IL-10 no hipocampo correlacionaram-se negativamente com o comportamento do tipo depressivo e a atividade da IDO foi aumentada no CPF e diminu?da no hipocampo do grupo LPS. Os resultados apresentados corroboram a hip?tese da ativa??o do sistema imune no evento depressivo e consequente dano oxidativo, verificado em dois modelos animais de depress?o. A ativa??o da IDO variou entre as ?reas analisadas em cada modelo animal. / Major depression has a great impact on an individual?s quality of life and it is considered the leading cause of burden in terms of years lost due to disability. However, despite the severity of depression, the pathophysiology of the disease is still elusive. In this regard, the use of animal models plays an important role in research for the etiology of depression. This work compared biochemical alterations occurring on serum, prefrontal cortex (PFC) and hippocampus in two animal models of depression: learned helplessness and administration of lipopolyssaccharide from E.Coli (LPS). Learned helplessness protocol used in this work resulted in 70 % of helpless mice, assessed by the inability to escape from electroshocks given 24 h or 48 h after the helpless-induction session. The other 30 % of mice were considered resilient. Helpless animals showed more oxidative damage in PFC and serum when compared to controls. No difference was seen between helpless and resilient groups, but there was a positive correlation between the oxidative damage on serum and PFC and helpless behavior. There was no difference in the concentration of IL-1?, TNF?, IL-6 and IL-10 cytokines on PFC and hippocampus of the animals exposed to the learned helplessness test, but there was a significant positive correlation between IL-6 concentration and depressive-like behavior on hippocampus. Indoleamine 2,3-dioxygenase (IDO) enzyme activity was not altered on learned helplessness model. Systemic administration of LPS (0,8 mg/kg) induced sickness behavior on animals characterized by decreased food and water intake, bodyweight loss and altered body temperature 6 h after administration. Sickness behavior is over after 24 h, but LPS-treated mice displayed higher immobility time in the tail suspension test when compared to saline. There was more oxidative damage in serum, PFC and hippocampus of LPS group when compared to saline and controls. No differences on IL-1? and TNF? concentration on serum, PFC and hippocampus of the animals were detected, suggesting a transient nature of the LPS-induced inflammation. LPS-treated group displayed higher concentrations of IL-6 on PFC when compared to saline group, and IL-6 concentration positively correlated to depressive-like behavior. IL-10 concentrations on hippocampus were negatively correlated to depressive-like behavior and IDO activity was increased on PFC and decreased on hippocampus of LPS-treated mice. Data presented here corroborate for the hypothesis of immune activation during depressive episodes, then resulting in oxidative damage assessed in two animal models of depression. IDO activity behaved with some specificity in each animal model depending on the brain or systemic area.

La maladie du greffon contre l’hôte (GVHD) est la principale cause de mortalité et de morbidité suite aux greffes de cellules souches hématopoïétiques. Plusieurs patients demeurent réfractaires aux traitements actuels ce qui rend nécessaire le développement de nouvelles stratégies afin de combattre cette maladie. Dans l’étude qui suit, nous avons utilisé un nouvel agent thérapeutique, le TH9402, une molécule photosensible et démontré qu’elle permet, lorsqu’exposée à la lumière visible (514 nm), d’éliminer sélectivement les cellules T activées in vivo tout en préservant les cellules T au repos et les cellules T régulatrices (Tregs). Les Tregs ainsi préservés peuvent abroger la réponse alloréactive par la sécrétion d’IL-10 ou par contact cellule-cellule via un mécanisme impliquant le CTLA-4. Nous avons découvert que la signalisation du CTLA-4 était associée à une hausse de la population Treg in vitro. Cette hausse est due à la conversion de cellules T CD4+CD25- en Tregs et non à une prolifération sélective des Tregs. Dans la deuxième partie de cette étude, nous avons démontré que la signalisation de CTLA-4 était associée à une augmentation de l’expression de la protéine Indoleamine 2,3 dioxygenase (IDO). Ces effets nécessitent la déplétion du tryptophane ainsi que de la protéine de phase aigue GCN2. Finalement, nous avons observé que l’infusion de cellules traitées au TH9402 chez des patients souffrant de GVHD chronique est associée à une augmentation de la population Treg chez ces patients sans causer de lymphopénie ni de diminution de la réponse immunitaire dirigée contre les antigènes viraux. Ces résultats suggèrent que le traitement au TH9402 pourrait représenter une approche particulièrement intéressante pour le traitement de la GVHD chronique réfractaire aux traitements actuels. De plus, l’augmentation de l’expression d’IDO pourrait être utilisée comme valeur prédictive de la réponse du patient au traitement. Ceci pourrait permettre d’améliorer la qualité de soins ainsi que de la qualité de vie des patients souffrant de GVHD chronique. / Graft versus host disease (GVHD) is the primary cause of mortality and morbidity following hematopoietic stem cell transplantation. Many patients remain refractory to current treatments, emphasizing the need to develop new therapeutic strategies. In the present study, we have used a novel therapeutic agent, TH9402, and shown that once activated by visible light (514 nm), this photosensitizer becomes specifically cytotoxic toward activated T cells while preserving resting T cells and regulatory T cells (Tregs). Preserved Tregs can display anti GVHD activity through IL-10 and CTLA-4 dependent mechanisms. Furthermore, CTLA-4 signaling was associated with an increased Treg population. This increase resulted from FOXP3 induction in CD4+CD25- cells and not selective proliferation of Tregs. In the second part of this study, we showed that CTLA-4 signaling was associated with enhanced expression of indoleamine 2,3 dioxygenase (IDO). The expression of IDO results in the generation of anti GVHD activity and an increase in the Treg population following TH9402 treatment. This increased Treg population was mediated by tryptophan degradation and implied acute phase protein GCN2 activity. Finally, we show that the infusion of TH9402 treated cells in patients suffering from chronic GVHD resulted in an increase of the Treg population as early as 8 weeks after treatment initiation without causing lymphopenia or hyporesponsiveness toward viral antigens. Furthermore, the increase of IDO corresponded to patient response to treatment. These results suggest that TH9402 represents a most interesting therapeutic approach for patients with refractory chronic GVHD. IDO expression could also be used to predict patient responsiveness to the treatment. This could increase the quality of the treatment as well as the quality of life of patients suffering from refractory chronic GVHD.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2017-06-12T18:00:24Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2017-06-12T18:00:55Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) / Made available in DSpace on 2017-06-12T18:00:55Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) Previous issue date: 2016-12-30 / A depressao e uma doenca altamente incapacitante e que tem acometido um percentual crescente da populacao mundial. Ainda que varios antidepressivos estejam comercialmente disponiveis ha decadas, os efeitos colaterais destas drogas, aliados ao fato de que nem todos os pacientes respondem satisfatoriamente ao tratamento, levam a uma busca continua por novas alternativas para o tratamento ou complementacao do tratamento da depressao. Assim, expande-se cada vez mais o numero de estudos que avaliam compostos candidatos a antidepressivos. Neste contexto e que o efeito tipo-antidepressivo da crisina, um flavonoide natural abundante no maracuja do mato (Passiflora coerulea), em camundongos submetidos ao estresse cronico imprevisivel (UCS) foi demonstrado anteriormente por nosso grupo. No entanto, os fatores neuroquimicos associados a este efeito carecem de maiores investigacoes. Deste modo, o objetivo deste estudo foi avaliar os fatores neuroquimicos associados ao efeito tipo-antidepressivo do flavonoide crisina em dois modelos animais de depressao, o modelo do UCS e o modelo da bulbectomia olfatoria (OB), ambos em camundongos. No modelo do UCS foram avaliados o cortex pre-frontal (PFC) e o hipocampo (HP), enquanto no modelo da OB foi avaliado o HP. O UCS e a OB induziram um comportamento tipo-depressivo, caracterizado pela diminuicao no tempo de lambida no teste de borrifagem de sacarose e pelo aumento no tempo de imobilidade no teste de suspensao de cauda ou no teste de nado forcado. Ainda, a OB ocasionou alteracoes no teste de campo aberto, decorrentes da hiperatividade caracteristicamente induzida por este modelo. O tratamento oral com crisina (5 ou 20 mg/kg, durante 28 dias no modelo do UCS, e por 14 dias no modelo da OB), de forma semelhante a fluoxetina (10 mg/kg, controle positivo), culminou na prevencao destas alteracoes, confirmando a acao tipo-antidepressiva da crisina nos parametros comportamentais avaliados. O UCS ocasionou o aumento nos niveis plasmaticos do hormonio liberador de corticotrofina, do hormonio adrenocorticotrofico, e a atividade das caspases 3 e 9 nas estruturas cerebrais avaliadas, enquanto a OB ocasionou a reducao dos niveis hipocampais do fator neurotrofico derivado do encefalo. O UCS e a OB resultaram no aumento dos niveis de citocinas proinflamatorias nas estruturas cerebrais avaliadas, como fator de necrose tumoral-α, interferon- γ, interleucina-1β, interleucina-6, alem do aumento dos niveis de quinurenina. O UCS e a OB tambem induziram a diminuicao dos niveis de 5-hidroxitriptamina (5-HT) e o aumento da 11 atividade da enzima indoleamina-2,3-dioxigenase. O tratamento com crisina, de forma semelhante a fluoxetina, promoveu a atenuacao de todas estas alteracoes ocasionadas pelo UCS ou pela OB. Em suma, os resultados deste estudo vem a corroborar com a hipotese de que o flavonoide crisina e um alvo potencial no estudo de novas alternativas para o tratamento ou para a complementacao do tratamento da depressao. Adicionalmente, este trabalho indica a associacao das citocinas pro-inflamatorias, da via da quinurenina, do metabolismo da 5-HT, das neurotrofinas e da atividade das caspases na acao tipo-antidepressiva exercida pela crisina em camundongos expostos ao UCS ou a OB. Finalmente, o presente trabalho expoe o maracuja do mato como um importante alvo para o estudo dos produtos naturais no combate a depressao, mostrando a fundamentalidade da investigacao da funcionalidade e constituicao bioativa desta e outras plantas do bioma pampa. / Depression is a highly incapacitating disease that has affected a crescent percentage of the world population. Although various antidepressants have been commercially available for decades, the side effects of these drugs, together with the fact that not all patients respond satisfactorily to treatment, lead to continuous search for new alternatives for the treatment or supplementary treatment of depression. Thus, the number of studies evaluating compounds candidate to antidepressants expands increasingly. In this context, the antidepressant-like effect of chrysin, a natural flavonoid abundant in passion fruit bush (Passiflora coerulea), in mice subjected to unpredictable chronic stress (UCS) has been previously demonstrated by our group. However, neurochemical factors associated with this effect require further investigations. Thus, the objective of this study was to evaluate the neurochemical factors associated with the antidepressant-like effect of chrysin in two animal models of depression, the model of UCS and the model of olfactory bulbectomy (OB), both in mice. In the UCS model the prefrontal cortex (PFC) and the hippocampus (HP) were evaluated, in the OB model the HP was evaluated. The UCS and OB induced a depressive-like behavior, characterized by the decrease in the total time of grooming in the splash test and by increase on immobility time in the tail suspension test or forced swimming test. Still, OB induced changes in open field test, resulting from the hyperactivity characteristically induced by this model. The oral treatment with chrysin (5 or 20 mg/kg for 28 days in the UCS model and for 14 days in OB model), similarly to fluoxetine (10 mg/kg, positive control) resulted in the prevention of these changes, confirming the antidepressant-like action of chrysin in the behavioral parameters evaluated. The UCS led to an increase in plasma levels of corticotropin-releasing hormone, adrenocorticotropic hormone and activity of caspases 3 and 9 in the brain structures evaluated, while the OB caused a reduction of hippocampal levels of brain-derived neurotrophic factor. The UCS and OB resulted in increase of proinflammatory cytokines levels in the brain structures evaluated, such as tumor necrosis factor-α, interferon- γ, interleukin-1β, interleukin-6, and increase kynurenine levels. UCS and OB also induced the decrease in 5-hydroxytryptamine (5-HT) levels and the increase of the activity of indoleamine-2,3-dioxygenase enzyme. Treatment with chrysin, similarly to fluoxetine, 13 promoted the attenuation of all these changes caused by UCS or OB. In summary, results of this study come to corroborate the hyphotesis that the flavonoid chrysin is a potential target in the study of new alternatives for the treatment or complement treatment of depression. Additionally, this study indicates the association of pro-inflammatory cytokines, of kynurenine pathway, of 5-HT metabolism, of neurotrophins and of caspases activities in the antidepressant-like action exerted by chrysin in mice exposed to UCS or OB. Finally, this paper exposes the passion bush as an important target for the study of natural products to combat depression, showing the importance of research of functionality and bioactive constitution of this and other plants of the pampa biome.

With the exponential growth of virtualization and cloud computing over the last decade, many companies in the telecommunications sector have started their journey towards cloud migration by exchanging a lot of specialized hardware for virtualized solutions. With more and more applications running in a cloud environment, it became essential to run these applications on heterogeneous systems with shared underlying hardware and software resources. However, running these applications in a heterogeneous cloud environment often leads to  unpredictable and non-deterministic performance, as all the applications compete for the shared resources to improve their individual performance. This becomes a problem when the interference from the co-hosted applications starts affecting the performance of the critical applications running on the same server. Ericsson is therefore investigating a solution to dynamically manage the low-level hardware and software resources to get deterministic performance on applications deployed using Kubernetes.  In this thesis, the Intent Driven Orchestration (IDO) model developed by Intel is used as the baseline model. This model was then extended by adding another tool to the setup called Container Runtime Interface-Resource Manager (CRI-RM), which is used to manipulate low-level software and hardware resources managed by a Kubernetes cluster at runtime. The results achieved in this thesis suggest that it is possible to get deterministic performance for an application deployed using Kubernetes, by identifying and isolating the CPU cores in the cluster on which the application is running.

no / Vitiligo is characterized by a mostly progressive loss of the inherited skin color. The cause of the disease is still unknown, despite accumulating in vivo and in vitro evidence of massive oxidative stress via hydrogen peroxide (H2O2) and peroxynitrite (ONOO−) in the skin of affected individuals. The most favored hypothesis is based on autoimmune mechanisms. Since depletion of the essential amino acid l-tryptophan (Trp) severely affects various immune responses, we here looked at Trp metabolism and signaling in these patients. Our in vivo and in vitro data revealed total absence of epidermal Trp hydroxylase activities and the presence of H2O2/ONOO− deactivated indoleamine 2,3-dioxygenase. Aryl hydrocarbon receptor signaling is severely impaired despite the ligand (Trp dimer) being formed, as shown by mass spectrometry. Loss of this signal is supported by the absence of downstream signals (COX-2 and CYP1A1) as well as regulatory T-lymphocytes and by computer modeling. In vivo Fourier transform Raman spectroscopy confirmed the presence of Trp metabolites together with H2O2 supporting deprivation of the epidermal Trp pool by Fenton chemistry. Taken together, our data support a long-expressed role for in loco redox balance and a distinct immune response. These insights could open novel treatment strategies for this disease.—Schallreuter, K. U., Salem, M. A. E. L., Gibbons, N. C. J., Maitland, D. J., Marsch, E., Elwary, S., Healey, A. R. Blunted epidermal l-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H2O2/ONOO−-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling.

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