It is the goal of this body of work to research an assortment of different photoacid generators (PAGs) and quantify their ability to perform the decomposition of poly(propylene carbonate) (PPC). Adding PAGs to PPC allows for a decreased polymer decomposition temperature, which can in turn be used as a sacrificial polymer for the fabrication of various microelectromechanical and microfluidic devices. A focus will be placed on relating the properties of the PAG such as acid strength, acid volatility, and PAG activation to processing issues like percentage of total film decomposition, amount and composition of film residue, decomposition rate, decomposition temperature, and environmental dependencies. This research discovered that the use of superacid triflic and nonaflic based PAGs were not adequate for the decomposition of PPC due to the high vapor pressure of the acid. Furthermore, the non-fluorinated sulfonic acid based PAGs do not posses the super-acid level acidity needed to sufficiently decompose PPC. Conversely, a perfluorinated methide and a tetrakis(pentafluoropheyl)borate based PAG both demonstrated the capability for high level PPC decomposition. Building on the knowledge gained through experimentation with these individual PAGs, the creation of a novel Combination PAG was accomplished. The Combination PAG uses acid groups with different physical properties collectively working to achieve what neither could complete individually.

A utilização de amostras de leite para a realização do diagnóstico precoce de prenhez em bovinos tem se tornado uma alternativa relevante para propriedades produtoras de leite, principalmente nas quais o suporte técnico é limitado. Atualmente, muitas fazendas coletam amostras de leite para avaliação da sanidade da glândula mamária e/ou para controle nutricional. Eventualmente, a utilização desta mesma amostra para a realização do teste de prenhez, viabilizaria o processo de coleta e diminuiria os custos com materiais e transporte destas amostras. Porém, ainda não se tem conhecimento de como o processamento da amostra de leite, desde a coleta até a análise laboratorial, pode afetar os resultados do teste de prenhez. Desta forma, o objetivo do presente estudo foi avaliar os efeitos de estratégias de coleta, armazenamento, conservação e processamento das amostras de leite sobre os resultados do teste de prenhez. Para isso, foram realizados 5 experimentos. No experimento 1, que avaliou o efeito do período do dia no qual a amostra foi coletada, foram utilizadas amostras de 51 animais (duas amostras por animal, uma obtida na ordenha da manhã e outra na ordenha da tarde). No experimento 2, que avaliou a ocorrência do \"efeito de arraste\" no medidor de leite do equipamento de ordenha, foram utilizadas amostras de leite de 94 animais pertencentes a duas fazendas distintas. De cada animal foram obtidas duas amostras de leite, uma direto do teto antes do início da ordenha e outra do medidor de leite ao término desta. No experimento 3, que avaliou o impacto das condições e do tempo de armazenamento das amostras de leite, 40 amostras foram coletadas e divididas em 4 idades (0, 3, 6 e 9 dias entre a coleta e a análise) e 2 temperaturas de armazenamento (ambiente e refrigerado). No experimento 4, que avaliou o efeito do pré-aquecimento das amostras de leite, o teste de prenhez foi realizado em 14 amostras que haviam sido submetidas ao banho-maria. Enquanto que, no experimento 5, que avaliou a ocorrência do \"efeito de arraste\" nos equipamentos de análise laboratorial, amostras de leite de 11 animais foram submetidas primeiro à análise de qualidade e depois ao teste de prenhez. Para verificar a existência de impacto de todos estes fatores, o coeficiente kappa foi calculado utilizando o software R. Como resultado, a coleta da amostra de leite na ordenha da manhã ou na ordenha da tarde não afetou os resultados do teste de prenhez. As concentrações de PAG das amostras coletadas na fazenda 2 sofreram maior influência do \"efeito de arraste\" quando comparadas as amostras obtidas na fazenda 1. Os níveis de PAG não apresentaram variação quando analisadas até 9 dias após a coleta, armazenadas tanto na temperatura ambiente como na refrigerada. O pré-aquecimento das amostras no banho-maria e a submissão aos equipamentos laboratoriais para análise de qualidade também não afetaram os níveis de PAG e nem os resultados do teste de prenhez. / The use of milk samples to perform the early pregnancy diagnosis in cattle has become an important alternative for dairy farms, especially when the technical support is limited. Currently, many farms use milk samples to evaluate the health of the mammary glands and the nutritional status of dairy cows. Eventually, the use of the same sample to make the pregnancy test could facilitate the collection process and decrease costs of materials and transport of samples. However, there is not enough knowledge about how processing the samples, from collection to laboratorial analysis, can affect the results of the pregnancy test. Therefore, the objective of the present study was to evaluate the effects of strategies of collecting, storing, conserving and processing milk samples on the results of the pregnancy test. For that purpose, five experiments were carried out. In experiment 1, the effect of the period of the day when the samples were collected is evaluated, samples of 51 animals were used (two samples per animal, one from the morning milking and another from the afternoon milking). In experiment 2, it was evaluated the carryover in the milk meter of the milking equipment, milk samples of 94 animals belonging to two different farms were used. Two samples were obtained from each animal, one collected directly from the tit before milking and the other by the meter at the end of milking. In experiment 3, it was evaluated the impact of different conditions: storage time and temperature of milk samples, 40 samples were collected and divided into four ages (0, 3, 6 and 9 days between collection and analysis) and two storage temperatures (ambient and refrigerated). In experiment 4, which evaluated the effect of pre-heating the milk samples, the pregnancy test was performed on 14 samples that had been subjected to water bath. In experiment 5, it was evaluated the occurrence of the carryover in laboratory analysis equipment, samples from 11 animals were first submitted to the milk quality analysis and after to the pregnancy test. To check the impact of all these factors, the kappa was calculated using the software R. The results show that sampling the milk in the morning or afternoon did not affect the results of the pregnancy test. PAG concentrations of samples collected on farm 2 had a greater influence on carryover compared to samples from farm 1. PAG levels did not show variation when analyzed until 9 days after collection, storage in ambient temperature or refrigerated. Preheating the samples in water bath and test in laboratory equipment of quality analysis also did not affect PAG levels or the results of the pregnancy test.

A técnica de Mobilização Neural (MOB) é um método não invasivo que demonstrou tanto na pesquisa básica, como na pesquisa clinica ser eficaz na redução da sensibilidade à dor. O presente, estudo visa examinar os efeitos da MOB na disfunção locomotora, na força muscular, nas alterações morfológicas no nervo isquiático e nas alterações moleculares induzida pela constrição crônica (CCI) do nervo isquiático de ratos Wistar. Para analisar a disfunção locomotora utilizamos o índice funcional do nervo Isquiático (IFC). Para analisar a força muscular, o sistema Biopac System. A ultraestrutura do nervo foi analisada pela técnica de microscopia eletrônica de transmissão e as alterações moleculares por meio de ensaios de Western blot. Ao finalizarmos os tratamentos com MOB os animais foram eutanasiados e os tecidos como, nervo isquiático, gânglios das raizes posteriores (DRG L4-L6) e Susbtância Cinzenta Periaquedutal (PAG) foram retirados. Os DRG´s foram processados pela técnica de Western Blot para a detecção da substância P (SP), receptor de potencial transitório vanilóide tipo I (TRPV1) e receptores opióides dos tipos µ (MOR), δ (DOR) e k (KOR). Com relação a PAG, analisamos somente os receptores opióides por Western Blot. Nossos resultados demonstraram uma reverção da disfunção locomotora induzida pela CCI após a MOB e aumentou 172% a força do músculo tibial anterior nos animais tratados quando comparado com os animais do grupo CCI. Nossos estudos sobre a ultraestrutura do nervo isquiático demonstraram intenso processo de degeneração Waleriana após a CCI e regeneração após a MOB. Podemos sugerir um papel importante da MOB na modulação da expressão da SP e do TRPV 1. Sobre os receptores DOR e KOR no DRG, não encontramos alterações estatísticas entre os grupos, mas observamos um aumento da expressão de MOR após a MOB. Na PAG, nós observamos uma diminuição de DOR e KOR no grupo CCI e aumento após a MOB. Por outro lado, não encontramos alterações estatíticas para o receptor MOR. Baseado nestes achados, podemos sugerir que a MOB reverte a disfunção locomotora, aumenta a força muscular, induz a regeneração do nervo isquiático, modula a SP e TRPV 1 e aumentou a expressão de MOR no DRG´s. Sugerimos ainda que, a analsegia induzida pela técnica de MOB possa ter um envolvimento também com o sistema inibitório descendente de dor resultando na inibição da transmissão do estímulo nociceptivo aferente e assim, diminuindo a dor neuropática devido influência da MOB sobre os opióides na PAG. / Neural mobilization technique (MOB) is a noninvasive method that demonstrated to be effective in reducing pain sensitivity in both clinical and research study. The present study aims to examine the effects of MOB in locomotors dysfunction, muscle strength, morphological changes in sciatic nerve and molecular changes induced by chronic constriction (CCI) of the sciatic nerve in Wistar rats. To analyze locomotors dysfunction we used the Sciatic nerve functional index (SFI). To analyze muscle strength, was used Biopac System. The nerve morphology was analyzed using electron microscopy and molecular changes through western blot assays. After MOB treatments, animals were euthanized and tissues such as, sciatic nerve, the posterior root ganglions (DRG L4-L6) and substance periaqueductal gray (PAG) were removed. The DRG were processed by western blot for detection of substance P (SP), transient receptor potential vanilloid type I (TRPV1) and opioids receptors (MOR, DOR, KOR). Regarding PAG, we analyze only opioids receptors. Our results demonstrated a full reversal of locomotors dysfunction-induced by CCI after MOB treatment and an increase of 172% on maximal tetanic muscle strength in animals treated with MOB when compared to the CCI group. Our studies on photomicrography of sciatic nerve showed an intense Wallerian degeneration process in CCI animals and an intense regeneration of myelinated fibers. In western blot assays, we identified, in DRG, an increase of SP and TRPV1 expression after CCI and a decrease of optical density after MOB treatment. Regarding opioid receptor, we did not identify statistical changes on DOR and KOR in DRG, but we observed an increased expression of MOR in CCI after MOB treatment group. In PAG analyses, we observed a decrease in DOR and KOR expression after MOB treatment when compare with CCI animals. On the other hand, we did not identify any changes on MOR receptor. Based on our findings, we suggest that treatment with neural mobilization technique it is able to reverses the locomotors dysfunction and increases maximum tetanic force of the tibialis anterior muscle after CCI. Furthermore, the same treatment was also able to induce a severe regeneration in the sciatic nerve after treatment. Still, we can suggest an important role of MOB in modulating SP and TRPV 1 expression. We suggest that antinociceptive effect induced by MOB technique can also be involved with descending pain inhibitory system resulting in inhibition of the transmission of afferent nociceptive stimulus and thereby reducing neuropathic pain because of the influence of MOB opioids in the PAG.

A técnica de Mobilização Neural (MOB) é um método não invasivo que demonstrou tanto na pesquisa básica, como na pesquisa clinica ser eficaz na redução da sensibilidade à dor. O presente, estudo visa examinar os efeitos da MOB na disfunção locomotora, na força muscular, nas alterações morfológicas no nervo isquiático e nas alterações moleculares induzida pela constrição crônica (CCI) do nervo isquiático de ratos Wistar. Para analisar a disfunção locomotora utilizamos o índice funcional do nervo Isquiático (IFC). Para analisar a força muscular, o sistema Biopac System. A ultraestrutura do nervo foi analisada pela técnica de microscopia eletrônica de transmissão e as alterações moleculares por meio de ensaios de Western blot. Ao finalizarmos os tratamentos com MOB os animais foram eutanasiados e os tecidos como, nervo isquiático, gânglios das raizes posteriores (DRG L4-L6) e Susbtância Cinzenta Periaquedutal (PAG) foram retirados. Os DRG´s foram processados pela técnica de Western Blot para a detecção da substância P (SP), receptor de potencial transitório vanilóide tipo I (TRPV1) e receptores opióides dos tipos µ (MOR), δ (DOR) e k (KOR). Com relação a PAG, analisamos somente os receptores opióides por Western Blot. Nossos resultados demonstraram uma reverção da disfunção locomotora induzida pela CCI após a MOB e aumentou 172% a força do músculo tibial anterior nos animais tratados quando comparado com os animais do grupo CCI. Nossos estudos sobre a ultraestrutura do nervo isquiático demonstraram intenso processo de degeneração Waleriana após a CCI e regeneração após a MOB. Podemos sugerir um papel importante da MOB na modulação da expressão da SP e do TRPV 1. Sobre os receptores DOR e KOR no DRG, não encontramos alterações estatísticas entre os grupos, mas observamos um aumento da expressão de MOR após a MOB. Na PAG, nós observamos uma diminuição de DOR e KOR no grupo CCI e aumento após a MOB. Por outro lado, não encontramos alterações estatíticas para o receptor MOR. Baseado nestes achados, podemos sugerir que a MOB reverte a disfunção locomotora, aumenta a força muscular, induz a regeneração do nervo isquiático, modula a SP e TRPV 1 e aumentou a expressão de MOR no DRG´s. Sugerimos ainda que, a analsegia induzida pela técnica de MOB possa ter um envolvimento também com o sistema inibitório descendente de dor resultando na inibição da transmissão do estímulo nociceptivo aferente e assim, diminuindo a dor neuropática devido influência da MOB sobre os opióides na PAG. / Neural mobilization technique (MOB) is a noninvasive method that demonstrated to be effective in reducing pain sensitivity in both clinical and research study. The present study aims to examine the effects of MOB in locomotors dysfunction, muscle strength, morphological changes in sciatic nerve and molecular changes induced by chronic constriction (CCI) of the sciatic nerve in Wistar rats. To analyze locomotors dysfunction we used the Sciatic nerve functional index (SFI). To analyze muscle strength, was used Biopac System. The nerve morphology was analyzed using electron microscopy and molecular changes through western blot assays. After MOB treatments, animals were euthanized and tissues such as, sciatic nerve, the posterior root ganglions (DRG L4-L6) and substance periaqueductal gray (PAG) were removed. The DRG were processed by western blot for detection of substance P (SP), transient receptor potential vanilloid type I (TRPV1) and opioids receptors (MOR, DOR, KOR). Regarding PAG, we analyze only opioids receptors. Our results demonstrated a full reversal of locomotors dysfunction-induced by CCI after MOB treatment and an increase of 172% on maximal tetanic muscle strength in animals treated with MOB when compared to the CCI group. Our studies on photomicrography of sciatic nerve showed an intense Wallerian degeneration process in CCI animals and an intense regeneration of myelinated fibers. In western blot assays, we identified, in DRG, an increase of SP and TRPV1 expression after CCI and a decrease of optical density after MOB treatment. Regarding opioid receptor, we did not identify statistical changes on DOR and KOR in DRG, but we observed an increased expression of MOR in CCI after MOB treatment group. In PAG analyses, we observed a decrease in DOR and KOR expression after MOB treatment when compare with CCI animals. On the other hand, we did not identify any changes on MOR receptor. Based on our findings, we suggest that treatment with neural mobilization technique it is able to reverses the locomotors dysfunction and increases maximum tetanic force of the tibialis anterior muscle after CCI. Furthermore, the same treatment was also able to induce a severe regeneration in the sciatic nerve after treatment. Still, we can suggest an important role of MOB in modulating SP and TRPV 1 expression. We suggest that antinociceptive effect induced by MOB technique can also be involved with descending pain inhibitory system resulting in inhibition of the transmission of afferent nociceptive stimulus and thereby reducing neuropathic pain because of the influence of MOB opioids in the PAG.

A utilização de amostras de leite para a realização do diagnóstico precoce de prenhez em bovinos tem se tornado uma alternativa relevante para propriedades produtoras de leite, principalmente nas quais o suporte técnico é limitado. Atualmente, muitas fazendas coletam amostras de leite para avaliação da sanidade da glândula mamária e/ou para controle nutricional. Eventualmente, a utilização desta mesma amostra para a realização do teste de prenhez, viabilizaria o processo de coleta e diminuiria os custos com materiais e transporte destas amostras. Porém, ainda não se tem conhecimento de como o processamento da amostra de leite, desde a coleta até a análise laboratorial, pode afetar os resultados do teste de prenhez. Desta forma, o objetivo do presente estudo foi avaliar os efeitos de estratégias de coleta, armazenamento, conservação e processamento das amostras de leite sobre os resultados do teste de prenhez. Para isso, foram realizados 5 experimentos. No experimento 1, que avaliou o efeito do período do dia no qual a amostra foi coletada, foram utilizadas amostras de 51 animais (duas amostras por animal, uma obtida na ordenha da manhã e outra na ordenha da tarde). No experimento 2, que avaliou a ocorrência do \"efeito de arraste\" no medidor de leite do equipamento de ordenha, foram utilizadas amostras de leite de 94 animais pertencentes a duas fazendas distintas. De cada animal foram obtidas duas amostras de leite, uma direto do teto antes do início da ordenha e outra do medidor de leite ao término desta. No experimento 3, que avaliou o impacto das condições e do tempo de armazenamento das amostras de leite, 40 amostras foram coletadas e divididas em 4 idades (0, 3, 6 e 9 dias entre a coleta e a análise) e 2 temperaturas de armazenamento (ambiente e refrigerado). No experimento 4, que avaliou o efeito do pré-aquecimento das amostras de leite, o teste de prenhez foi realizado em 14 amostras que haviam sido submetidas ao banho-maria. Enquanto que, no experimento 5, que avaliou a ocorrência do \"efeito de arraste\" nos equipamentos de análise laboratorial, amostras de leite de 11 animais foram submetidas primeiro à análise de qualidade e depois ao teste de prenhez. Para verificar a existência de impacto de todos estes fatores, o coeficiente kappa foi calculado utilizando o software R. Como resultado, a coleta da amostra de leite na ordenha da manhã ou na ordenha da tarde não afetou os resultados do teste de prenhez. As concentrações de PAG das amostras coletadas na fazenda 2 sofreram maior influência do \"efeito de arraste\" quando comparadas as amostras obtidas na fazenda 1. Os níveis de PAG não apresentaram variação quando analisadas até 9 dias após a coleta, armazenadas tanto na temperatura ambiente como na refrigerada. O pré-aquecimento das amostras no banho-maria e a submissão aos equipamentos laboratoriais para análise de qualidade também não afetaram os níveis de PAG e nem os resultados do teste de prenhez. / The use of milk samples to perform the early pregnancy diagnosis in cattle has become an important alternative for dairy farms, especially when the technical support is limited. Currently, many farms use milk samples to evaluate the health of the mammary glands and the nutritional status of dairy cows. Eventually, the use of the same sample to make the pregnancy test could facilitate the collection process and decrease costs of materials and transport of samples. However, there is not enough knowledge about how processing the samples, from collection to laboratorial analysis, can affect the results of the pregnancy test. Therefore, the objective of the present study was to evaluate the effects of strategies of collecting, storing, conserving and processing milk samples on the results of the pregnancy test. For that purpose, five experiments were carried out. In experiment 1, the effect of the period of the day when the samples were collected is evaluated, samples of 51 animals were used (two samples per animal, one from the morning milking and another from the afternoon milking). In experiment 2, it was evaluated the carryover in the milk meter of the milking equipment, milk samples of 94 animals belonging to two different farms were used. Two samples were obtained from each animal, one collected directly from the tit before milking and the other by the meter at the end of milking. In experiment 3, it was evaluated the impact of different conditions: storage time and temperature of milk samples, 40 samples were collected and divided into four ages (0, 3, 6 and 9 days between collection and analysis) and two storage temperatures (ambient and refrigerated). In experiment 4, which evaluated the effect of pre-heating the milk samples, the pregnancy test was performed on 14 samples that had been subjected to water bath. In experiment 5, it was evaluated the occurrence of the carryover in laboratory analysis equipment, samples from 11 animals were first submitted to the milk quality analysis and after to the pregnancy test. To check the impact of all these factors, the kappa was calculated using the software R. The results show that sampling the milk in the morning or afternoon did not affect the results of the pregnancy test. PAG concentrations of samples collected on farm 2 had a greater influence on carryover compared to samples from farm 1. PAG levels did not show variation when analyzed until 9 days after collection, storage in ambient temperature or refrigerated. Preheating the samples in water bath and test in laboratory equipment of quality analysis also did not affect PAG levels or the results of the pregnancy test.

The experiments reported in this thesis studied the contributions of opioid and NMDA receptors to predictive fear learning, as measured by freezing in the rat. The first series of experiments (Chapter 2) used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct action of predictive error on Pavlovian association formation. Systemic administrations of the opioid receptor antagonist naloxone or intra-vlPAG administrations of the selective μ-opioid receptor antagonist CTAP prior to Stage II training prevented one-trial blocking. These results show for the first time that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation. The second series of experiments (Chapter 3) then studied temporal-difference prediction errors during Pavlovian fear conditioning. In Stage I rats received CSA ?? shock pairings. In Stage II they received CSA/CSB ?? shock pairings that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB → CSA, was followed by shock. The change in intra-trial durations supported fear learning to CSB but reduced fear of CSA, revealing the selective operation of temporal-difference prediction errors. This bi-directional change in responding was prevented by systemic NMDA receptor antagonism prior to Stage III training. In contrast opioid receptor antagonism differentially affected the learning taking place during Stage III, enhancing learning to CSB while impairing the loss of fear to CSA. The final series of experiments (Chapter 4) then examined potential neuroanatomical loci for the systemic effects reported in Chapter 3. It was observed that intra-BLA infusion of ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, prevented all learning during Stage III, whereas intra-vlPAG infusion of the μ-opioid receptor antagonist CTAP facilitated learning to CSB but impaired learning to CSA. These results are consistent with the suggestion that opioid receptors in the vlPAG provide an important contribution to learning. Importantly, this contribution of the vlPAG is over and above its role in producing the freezing conditioned response. Furthermore, the findings of this thesis identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG μ-opioid receptors in predictive fear learning.

The experiments reported in this thesis studied the contributions of opioid and NMDA receptors to predictive fear learning, as measured by freezing in the rat. The first series of experiments (Chapter 2) used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct action of predictive error on Pavlovian association formation. Systemic administrations of the opioid receptor antagonist naloxone or intra-vlPAG administrations of the selective μ-opioid receptor antagonist CTAP prior to Stage II training prevented one-trial blocking. These results show for the first time that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation. The second series of experiments (Chapter 3) then studied temporal-difference prediction errors during Pavlovian fear conditioning. In Stage I rats received CSA ?? shock pairings. In Stage II they received CSA/CSB ?? shock pairings that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB → CSA, was followed by shock. The change in intra-trial durations supported fear learning to CSB but reduced fear of CSA, revealing the selective operation of temporal-difference prediction errors. This bi-directional change in responding was prevented by systemic NMDA receptor antagonism prior to Stage III training. In contrast opioid receptor antagonism differentially affected the learning taking place during Stage III, enhancing learning to CSB while impairing the loss of fear to CSA. The final series of experiments (Chapter 4) then examined potential neuroanatomical loci for the systemic effects reported in Chapter 3. It was observed that intra-BLA infusion of ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, prevented all learning during Stage III, whereas intra-vlPAG infusion of the μ-opioid receptor antagonist CTAP facilitated learning to CSB but impaired learning to CSA. These results are consistent with the suggestion that opioid receptors in the vlPAG provide an important contribution to learning. Importantly, this contribution of the vlPAG is over and above its role in producing the freezing conditioned response. Furthermore, the findings of this thesis identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG μ-opioid receptors in predictive fear learning.

Les lymphomes B non-Hodgkiniens sont caractérisés par des altérations génétiques à l’origine du syndrôme néoplasique. Dans ce travail, nous démontrons que l’association dans les microdomaines rafts de la membrane de Lyn, une kinase de la famille Src, avec l’adaptateur PAG, participe également au processus néoplasique. Dans les cellules B non-néoplasiques, Lyn et PAG sont des molécules impliquées dans la signalisation du récepteur des cellules B en réponse à une stimulation antigénique. Dans ce contexte, l’adaptateur PAG est décrit comme un inhibiteur de l’activité kinase de Lyn. Au contraire, dans les rafts des lymphomes B non-Hodgkiniens, nous avons mis en évidence que PAG retient la kinase Lyn sous une conformation active. Au sein des rafts, la kinase Lyn semble responsable de l’activation oncogénique de la voie de signalisation PI3K/Akt et de la voie de signalisation STAT3. L’inhibition pharmacologique et génétique de la kinase Lyn induit l’apoptose et l’inhibition de la prolifération de lignées cellulaires dérivées de lymphomes B non-Hodgkiniens. Ce résultat est révélateur d’une dépendance des lignées cellulaires à l’association oncogénique de Lyn avec PAG. Le ciblage thérapeutique du complexe Lyn/PAG constitue donc une opportunité pour le traitement des lymphomes B non-Hodgkiniens. / Non Hodgkin B lymphomas are caracterized by genetic alerations that condition their neoplastic development. In this work, we demonstrate that an association between the Src family kinase Lyn and the PAG adaptor in rafts is also involved in the neoplastic phenotype. In normal B cells, Lyn and PAG contribute to BCR signalling, where PAG functions as a Lyn kinase inihibitor. In contrast, we demonstrate that Lyn remains active when associated with PAG in B non Hodgkin lymphomas rafts. In those rafts, the Lyn kinase participates in the oncogenic activation of the PI3K/Akt and STAT3 signaling pathways. Pharmacologic and genetic inhibition of the Lyn kinase leads to apoptosis induction and proliferation inhibition of B non Hodgkin lymphoma cell lines. Our results reveal the dependence (or addiction) of these cell lines to the Lyn and PAG complex in rafts. The Lyn/PAG complex therefore constitutes an appropriate therapeutic target in certain non Hodgkin B lymphoma treatment.

Depuis les années 60, la génération d’acide fort de Brönsted par un processus photoinduit à un photon est utilisée dans des nombreux domaines de recherche de plus en plus nombreux. Cependant, de tels acides peuvent-être facilement obtenus par voie biphotonique ce qui présente de nombreux avantages comme par exemple : une meilleure réactivité via une excitation direct du photoacide, l’utilisation possible d’une atmosphère non contrôlée, l’utilisation de microlasers à impulsions sub-nanosecondes peu couteux, mais aussi l’augmentation de la résolution spatiale des micro-objets 3D fabriqués. La génération d’acide se fait généralement par transfert d’électron entre un sensibilisateur et un générateur de photoacide (PAG). Une approche prometteuse consiste à associer, sur une même molécule, un PAG et un chromophore actif à deux photons. Il a donc semblé intéressant de développer de nouveaux PAG capables, par excitation biphotonique, d’amorcer directement la photopolymérisation. Nous avons choisi de préparer des systèmes capto-datifs stilbéniques, de nature neutre ou ionique. Aussi, une série de PAG neutres substitués par des groupements diphénylamino- donneur et iminosulfonates -cyanés accepteurs a été synthétisée. Nous avons également commencé, mais non achevé, la synthèse de PAG neutres portant des groupements iminosulfonates -trifluorométhylés. Puis, nous avons cherché à synthétiser des PAG ioniques substitués soit par un groupement éthoxy soit par un groupement diphénylamino soit par un groupement julolidine. Néanmoins, la dernière étape de la synthèse est pour l’instant un verrou synthétique. / Since the 60’s, the generation of strong Brönsted acids by a one-proton photoinduced process has been used in more and more research areas. Recently, it has been shown, that such acids are easily obtained by a two-photon process. This offers many advantages such as: i) a better reactivity owing to a direct excitation of the photoacid, ii) the possible use of a non-controlled atmosphere, iii) the use of inexpensive microlasers with sub-nanosecond impulsions, iv) the increase of spatial resolution in 3D microfabrication. The acid generation generally proceeds through a photo-induced electro transfer from an excited sensitizer to the photoacid generator (PAG). A promising approach should be the introduction on a single molecule of both a PAG and a two-photon active chromophore moiety. In this context, we have developed new PAGs able to initiate photopolymerisation through a two-photon activation process. The syntheses were focused on stilbenic push-pull systems having either a neutral or an ionic nature. A series of neutral PAGs bearing a diphenylamino donor group and an α-cyano iminosulfonate acceptor moiety has been synthesized. The preparation of neutral PAGs bearing iminosulfonate α-trifluoromethylated groups were not yet completed. The syntheses of ionic PAGs substituted by an ethoxy group, a diphenylamino group or a julolidine one, could not be completed either.

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