Tesis:

1

Röther, Jens. "Die Rolle von Orai1 in der Entwicklung und Aktivierung von T- und B- Lymphozyten und die Bedeutung von Mutationen in Orai1 für die Pathogenese schwerer kombinierter Immundefekte". Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-70949.

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Ein durch „Ca2+ Release Activated Ca2+ (CRAC)“-Kanal vermittelter Ca2+-Einstrom ist unverzichtbar für die vollständige Aktivierung von T-Zellen und eine produktive Immunantwort. Im Jahr 2006 führte die Entdeckung des transmembranen Proteins Orai1, einer porenbildenden Untereinheit des CRAC-Kanals, zu einem besseren Verständnis dieses Signalweges. Eine Mutation in Orai1 hat durch die Aufhebung der CRAC-Kanal Funktion eine schwere kombinierte Immundefizienz (SCID) zur Folge (Feske, S. et al. 2006). Die im Rahmen dieser Arbeit präsentierten Experimente hatten die nähere Erforschung der Rolle von Orai1 in Bezug auf die Aktivierung und Entwicklung von Lymphozyten sowie auf die pathogenetische Bedeutung für humane Immundefektsyndrome zum Ziel. So konnte hier durch das Sequenzieren genomischer DNA mehrerer SCID-Patienten eine neue Mutation in Orai1 aufgedeckt werden. Mithilfe intrazellulärer Durchflusszytometrie und Real-Time-PCR gelang es, die Expression von Orai1 auf humanen und murinen Immunzellen, einschließlich T- und B-Lymphozyten, nachzuweisen. Darüber hinaus wurden Orai1 „knock-in“ Mäuse analysiert, welche transgen für eine bei zwei SCID-Patienten gefundene Mutation (R91W) (Feske, S. et al. 2006) sind. Dadurch war es möglich die Funktion von Orai1 und die des CRAC-Kanal vermittelten Ca2+-Einstroms für die Entwicklung und Aktivierung von Lymphozyten zu analysieren. Diese transgenen Mäuse stellen das zu diesem Zeitpunkt erste Tiermodell dar, mit dessen Hilfe die Rolle von CRAC-Kanälen in vivo studiert werden kann.

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2

Jensen, Drake. "Functional Analysis of Calmodulin's Calcium Dependent Inactivation of Orai1". Thesis, Southern Illinois University at Edwardsville, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1589551.

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Calmodulin (CaM) plays an important role in calcium (Ca²⁺)-dependent signal transduction. Ca²⁺ binding to CaM triggers a conformational change, forming a hydrophobic patch that is important for target protein recognition. CaM regulates a Ca²⁺-dependent inactivation (CDI) process in store-operated Ca²⁺ entry (SOCE), by interacting with the N-terminus of the hexameric plasma membrane Ca²⁺ channel Orai1. To understand the relationship between Ca²⁺-induced hydrophobicity of CaM and the CaM/Orai interaction, chimera proteins constructed by exchanging EF-hands of CaM with those of Troponin C (TnC) were used as an informative probe to better understand the functionality of each EF-hand. ANS was used to assess the context of the induced hydrophobic surface on CaM and chimeras upon Ca²⁺ binding. The exchanged EF-hands from TnC to CaM resulted in reduced hydrophobicity compared with wild-type CaM, as depicted by ANS fluorescence and binding affinity. Such a conclusion is consistent with general concepts about the inadequacy of hydrophobic exposure for chimeras. However, such ANS responses exhibited no correlation with the ability to interact with Orai1. ANS lifetime measurements indicated that there are two types of ANS molecules with rather distinct fluorescence lifetimes, each specifically corresponding to one lobe of CaM or chimeras. Thermodynamic studies indicated the interaction between CaM and a 24-residue peptide corresponding to the CaM-binding domain of Orail1 (Orai-CMBD) is a 1:2 CaM/Orai-CMBD binding, in which each peptide binding yields a similar enthalpy change (ΔH = − 5.02 ± 0.13 kcal/mol) and binding affinity (K_a = 8.92 ± 1.03 x 105 M⁻¹). With the exchanged EF1 and EF2, the resulting chimeras noted as CaM(1TnC) and CaM(2TnC), displayed a two sequential binding mode with a one-order weaker binding affinity and lower ?H than that of CaM, while CaM(3TnC) and CaM(4TnC) had similar binding thermodynamics as CaM. Circular Dichroism studies suggested differences in binding most likely resulted from changes in chimera three-dimensional structure rather than secondary structure, as the extent of ?-helical content from apo-, Ca²⁺-, and Orai-CMBD-bound proteins remained similar. The dissociation rate constant for CaM/Orai-CMBD was determined to be 1.41 ± 0.08 s⁻¹ by rapid kinetics. Stern-Volmer plots of Orai-CMBD Trp76, indicated that the residue is located in a very hydrophobic environment but becomes more solvent accessible when EF1 and EF2 were exchanged. Here, the model of 1:2 binding stoichiometry of CaM/Orai-CMBD established in solution supports the unique, open binding mode suggested by already published structural studies.

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3

Lur, Gyorgy. "STIM1, Orai1 and store operated calcium entry in pancreatic acinar cells". Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539501.

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4

Bartoli, Fiona. "Le canal calcique Orai1 : nouvel acteur impliqué dans la physiopathologie cardiaque". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS027.

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Alors que l’entrée SOC (store-operated Ca2+ entry) portée par les canaux calciques TRPCs (transient receptor potential canonical) et Orai1 est essentielle dans les cellules non-excitables, son rôle physiologique dans les cardiomyocytes adultes reste à élucider. Néanmoins, il est largement admis qu’une entrée SOC exacerbée dépendante des canaux TRPCs et de la protéine régulatrice STIM1 participe à la pathogenèse de l’hypertrophie et de l’insuffisance cardiaque (IC) par induction de voies pro-hypertrophiques telles que la CaMKII (Ca2+/calmoduline-dépendante kinase II ) et la calcineurine (CaN)/NFAT (Nuclear factor of activated T-cells). Au contraire, une inhibition fonctionnelle ou une extinction génique des canaux TRPCs et de la protéine STIM1 serait cardioprotectrice contre le stress hypertrophique. Cependant, le rôle physiopathologique des canaux calciques Orai1 dans le cœur reste, à ce jour, méconnu et débattu puisque son extinction in vitro présente un effet bénéfique contre l’hypertrophie des cardiomyocytes alors que son extinction in vivo présente des effets délétères avec le développement d’une cardiomyopathie dilatée. De plus amples investigations quant au rôle d’Orai1 dans la physiopathologie cardiaque apparaissent donc primordiales. De ce fait, les objectifs de ma thèse sont d’explorer le rôle de la signalisation calcique dépendante d’Orai1 dans le cœur dans des conditions physiologiques et pathologiques grâce à un modèle de souris transgéniques exprimant un mutant non fonctionnel d’Orai1, spécifiquement dans le cœur (dn-Orai1R91W/tTa) et un inhibiteur pharmacologique sélectif, le JPIII. Tout d’abord, nous montrons que les souris dn-Orai1R91W/tTa présentent une fonction cardiaque normale et une homéostasie calcique impliquée dans le couplage excitation-contraction conservée suggérant qu’Orai1 n’a pas de rôle majeur dans le coeur adulte en condition physiologique. Cependant, nous avons démontré une augmentation de l’expression et de l’activité d’Orai1 dans un modèle murin d’hypertrophie cardiaque induite par surcharge de pression, qui serait délétère pour la fonction ventriculaire. Au contraire, l’inhibition fonctionnelle d’Orai1 par manipulation génétique ou par l’outil pharmacologique (JPIII) semble protéger le coeur des dysfonctions ventriculaires au cours de l’hypertrophie. Cet effet bénéfique passerait par une restauration de l’homéostasie calcique et notamment par un maintien de l’expression de la pompe ATPase SERCA2a. Nous avons également mis en évidence que la voie de l’aldostérone/récepteurs aux minéralocorticoïdes modulait l’expression des canaux TRPC1, -C4, -C5 et notamment Orai1 via la protéine SGK1 (Serum and Glucocorticoid-regulated Kinase 1) dans les cardiomyocytes ventriculaires de rat nouveaux-nés. L’activation de cette voie de signalisation pourrait être à l’origine de la surexpression des canaux TRPCs/Orai1 retrouvée au cours de l’hypertrophie cardiaque. Ces travaux décrivent donc Orai1 comme une cible thérapeutique potentielle dans le traitement de l’hypertrophie cardiaque et de l’IC
While the SOCE (store-operated Ca2+ entry), carried by TRPCs (transient receptor potential canonical) and Orai1 channels, is essential in non-excitable cells, its physiological role in adult cardiomyocytes remains elusive. Nevertheless, it is well established that exacerbated TRPCs/STIM1-dependent Ca2+ entry participates in the pathogenesis of hypertrophy and heart failure (HF) via the induction of pro-hypertrophic signaling pathways, such as CaMKII (Ca2+/calmodulin-kinase II) and calcineurin (CaN)/ NFAT (nuclear factor of activated T-cells). By contrast, functional inhibition or gene silencing of TRPCs and STIM1 is cardioprotective against hypertrophic insults. As for Orai1 Ca2+ channels, their pathophysiological roles in the heart remain unknown and under debate, since in vitro Orai1 silencing has a beneficial effect against cardiomyocyte hypertrophy, whereas in vivo silencing has deleterious effects with the development of dilated cardiomyopathy. Further investigations are necessary to determine the pathophysiological role of Orai1 in the heart. My thesis objectives are to explore the role of Orai1-dependent Ca2+ signaling in the heart under physiological and pathological conditions using a transgenic mouse model expressing a non functional mutant of Orai1, specifically in the heart (dn-Orai1R91W/tTa) and a selective pharmacological inhibitor, JPIII. First, we showed that dn-Orai1R91W/tTa mice have normal cardiac function and conserved Ca2+ homeostasis involved in the excitation-contraction coupling suggesting that Orai1 is not instrumental in regulating cardiac function under physiological conditions. However, we demonstrated an increased Orai1 expression and activity in a mouse model of cardiac hypertrophy induced by pressure overload, which is a maladaptive alteration involved in pathological ventricular dysfunction. By contrast, functional inhibition of Orai1 by genetic manipulation or by the pharmacological tool (JPIII) protects the heart from ventricular dysfunction after pressure overload-induced cardiac hypertrophy. This beneficial effect is related to a restoration of Ca2+ homeostasis and more specifically, is due to preserved ATPase SERCA2a pump expression. We also showed that the aldosterone/mineralocorticoid receptor signaling pathway modulates the expression of TRPC1, -C4, -C5 channels and also the Orai1 channels expression via the SGK1 (Serum and Glucocorticoid-regulated Kinase 1) protein, in neonatal rat ventricular cardiomyocytes. The activation of this signaling pathway could be the cause of the TRPCs/Orai1 channels overexpression found during cardiac hypertrophy. In conclusion, our studies highlighted that Orai1 Ca2+ channels could constitute potential therapeutic target in the treatment of cardiac hypertrophy and HF

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5

Gueder, Nahla. "sp²-Iminosugar-glucosidases inhibitor 1-C-octyl-2-oxa-3-oxocastanospermine - induced antiproliferative, apoptotic and necrotic effects in breast cancer cells via targeting GRP78, Stim1 and Orai1". Thesis, Amiens, 2018. http://www.theses.fr/2018AMIE0033/document.

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L'altération de glycosylation est l'une des caractéristiques du cancer du sein. Ainsi le défaut de glycosylation affecte différentes protéines glycosylées responsables des différents processus cancéreux. Les canaux SOC (Store operated channels) constituent la voie majeure de l'entrée du calcium dans les cellules et sont impliqués dans la prolifération, la migration et la survie des cellules cancéreuses du sein. CO-OCS est un nouvel inhibiteur de la glycosylation avec plus de sélectivité vis-à-vis des α-glucosidases, et montre des activités anticancéreuses des cellules cancéreuses du sein, sans affecter les cellules mammaires normales. L'objectif de ma thèse est d'étudier les mécanismes moléculaires par lesquels CO-OCS induit ses effets anti-tumoraux. CO-OCS inhibe la migration des cellules cancéreuses à fort potentiel métastatique. Cet effet anti-migratoire est dû à une réduction de l'expression de la β1-intégrine, de Stim1, et de l'activation des voies de signalisation FAK et ERK1/2 par CO-OCS. Dans les cellules cancéreuses peu invasives, CO-OCS diminue la prolifération et augmente la mortalité de ces cellules en affectant l'expression de 3 protéines : Stim1 et Orai1 : protéines N-glycosylées au niveau du réticulum endoplasmique (RE), et GRP78, protéine de stress du RE. Ainsi en supprimant complétement l'expression de Stim1, CO-OCS réduit la prolifération en accumulant les cellules dans les phases G1 et G2/M du cycle cellulaire. Alors que la réduction de l'expression de GRP78 et d'Orai1 par le CO-OCS augmente respectivement l'apoptose et la nécrose. Par ailleurs, l'invalidation de Stim1 atténue l'effet apoptotique induit par CO-OCS. CO-OCS réduit aussi le contenu calcique du RE. Cette réduction du calcium réticulaire est due à une fuite de calcium par le Translocon. En effet, l'Anisomycine, inhibiteur du Translocon, restore de contenu calcique réticulaire et antagonise l'apoptose induite par le CO-OCS. En conclusion, CO-OCS induit une accumulation de protéines mal-repliées dans le RE induisant ainsi un stress réticulaire. Trois cibles du CO-OCS ont été identifiées : l'expression de Stim1 favorise la prolifération tandis que celle d'Orai1 et de GRP78 protègent respectivement les cellules de l'apoptose et de la nécrose induites par CO-OCS. De plus, en diminuant l'expression de GRP78, CO-OCS induit une fuite du calcium du RE par le Translocon
Alteration in glycosylation pattern is one of the hallmarks of breast cancer. The levels and the abnormal expressions of glycan were found in breast cancer patients. Glycosylation defect can affect different glycosylated proteins which are implicated in cancerogenesis. Changes in intracellular Ca2+ levels can regulate different cellular processes. SOC channels are implicated in breast cancer proliferation, migration and survival. CO-OCS is a new glycosylation inhibitor with more selectivity toward theα- glucosidases exhibited anti-cancer activities in breast cancer cells without affecting the normal mammary cells. The objective of my thesis is investigating the related molecular mechanisms by which CO-OCS induced its anti-tumour effects.CO-OCS impaired breast cancer migration through decrease β1-integrin expression and the activation of FAK and ERK1/2 signalling pathways. CO-OCS also induced anti-migratory effect via Stim1 protein expression down-regulation leading to inhibition of SOCE. Additionally, CO-OCS affected the expression of both Orai1 and Stim1 proteins leading to anti-proliferative effects and cell cycle arrest in G1 and G2/M phase respectively. Moreover, CO-OCS affected the expression of Stim1 at the protein level without affecting its transcript level. GRP78 implicated in CO-OCS apoptotic death. The expression of Stim1 regulated the apoptosis induced by CO-OCS via modulating GRP78 expression. Orai1 down-regulation promoted CO-OCS necrotic effect. CO-OCS induced ER- calcium depletion due to increase in ER calcium leak via the Translocon; Anisomycin (Translocon inhibitor) decreased the apoptosis induced by CO-OCS. In conclusion, these results show that in breast cancer, by targeting Stim1, Orai1 and GRP78, CO-OCS reduced cell proliferation and induced apoptosis and necrosis cell death. Stim1 favours CO-OCS apoptotic effect while Orai1 protected from necrosis induced by CO-OCS. The inhibition of Translocon decreased CO-OCS apoptotic cell death via restoring the ER calcium homeostasis

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6

Noyer, Lucile. "Role of Orai1 in prostate cancer proliferation and cancer stem cell quiescence/activation transition". Thesis, Lille 1, 2019. http://www.theses.fr/2019LIL1S111.

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Le cancer de la prostate (CaP) est le cancer le plus fréquent et le troisième plus mortel chez l’homme en Europe. Les cellules souches cancéreuses (CSC) représentent une sous population de cellules cancéreuses possédant des propriétés de cellules souches qui les rendent résistantes aux thérapies et hautement tumorigènes. Les CSCs sont ainsi associées aux phénomènes de dormance tumorale, puis de rechute suite à leur réactivation. Les mécanismes régulant la transition dormance/prolifération constituent donc une question centrale dans la prise en charge du cancer. L’importance des protéines Orai dans le CaP a déjà été montrée dans de précédentes études, via leur implication dans les canaux de type SOC (store-operated calcium channel) et ARC (arachidonic acid-regulated channel). Cependant, le rôle du canal Orai1 dans la prolifération du CaP, ou son éventuelle implication dans la physiologie des CSC, restaient inconnus. Parallèlement, pour répondre aux limitations de son ciblage direct, nous avons cherché à identifier ses protéines partenaires. Nous nous sommes ainsi intéressés au récepteur Sigma 1 (S1R), une protéine chaperonne dont l’expression augmente dans le CaP, et qui possède de nombreux modulateurs pharmacologiques utilisés en clinique. Ce travail avait donc un double objectif : étudier le rôle d’Orai1 dans le CaP et les CSC prostatiques, et caractériser fonctionnellement le rôle du S1R en tant que nouveau partenaire du canal Orai1. Ces travaux ont tout d’abord permis de mettre en évidence l’importance d’Orai1 dans le contrôle de la transition entre la quiescence et la prolifération des CSCs prostatiques via la voie NFAT. De plus, ces résultats ont été confirmés dans les CSCs de mélanome, montrant que le rôle d’Orai1 serait généralisable au-delà du modèle prostatique. Nous avons également montré que le S1R interagit directement avec Orai1 et module positivement son activité, impactant ainsi la prolifération des cellules cancéreuses prostatiques. Enfin, nous avons mis en évidence la régulation de l’expression de ces protéines par les androgènes, ce qui est d’importance cruciale dans l’évolution du CaP. Nos résultats ont donc permis l’identification d’un acteur central du contrôle de la prolifération du CaP (Orai1), et la caractérisation d’une nouvelle protéine partenaire du canal Orai1 dans le CaP : le S1R. Ces travaux montrent que le S1R et Orai1 pourraient constituer de nouveaux marqueurs intéressants, ainsi que de potentielles nouvelles cibles thérapeutiques
Prostate cancer (PCa) is the most frequent and the third deadliest cancer in men in Europe. Cancer stem cells (CSC) are a rare subset of cancer cells possessing stem cell properties leading to a high resistance to therapy and an enhanced tumorigenicity. As a result, CSCs have been linked to tumor dormancy and relapse upon reactivation. Thus, the mechanisms regulating CSC dormancy/activation transition are of critical importance in PCa. Previous studies showed the importance of Orai proteins in PCa, through their roles in SOC (store-operated channel) and ARC (arachidonic acid-regulated calcium channel) channels. But the role of Orai1 in PCa proliferation and CSC physiology remained to be studied. Moreover, in order to bypass current targeting limitations for Orai1, we aimed to identify a partner protein able to regulate Orai1 in PCa. For this purpose, we focused on the Sigma 1 receptor (S1R), a chaperone protein capable of ion channel regulation. Interestingly, S1R expression is increased in PCa and this protein can bind many pharmacological compounds currently used for other clinical applications. This work thus aimed to first study the role of Orai1 in PCa and CSC physiology, and then characterize the role of S1R as a new regulator of Orai1 in PCa. Our results first show that Orai1 is a key regulator of CSC transition between quiescence and proliferation via the NFAT pathway. Moreover, this role is not limited to PCa, since these results were also confirmed in melanoma CSCs. We also show here that the S1R directly interacts with Orai1 and increases its activity, thus modulating PCa cell proliferation. Finally, we characterized the regulation of Orai1 and S1R expression by androgens, which is highly significant during PCa development. Our results therefore allowed the identification of a key regulator of PCa proliferation (Orai1), and propose an alternative method for its targeting via the identification of its partner protein (S1R). These results could lead to the development of new markers and innovative therapeutic strategies

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7

Clarysse, Lucie. "Régulation du canal SK3 par l'AMPc et le calcium extracellulaire dans les cellules cancéreuses du sein". Thesis, Tours, 2013. http://www.theses.fr/2013TOUR3312/document.

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Nous avons montré un rôle d’un canal K+, le canal SK3, dans la migration des cellules cancéreuses de sein MDA-MB-435s et le développement de métastases ostéolytiques du cancer du sein. Lors de l’ostéolyse, la [Ca²+]ext augmente dans le microenvironnement osseux. Nous avons voulu déterminer si cette élévation de [Ca²+]ext, pouvait moduler l’expression et l’activité du canal SK3. Nous avons montré que l’augmentation de la [Ca²+]ext: i) favorise l’expression du canal SK3. Cet effet fait intervenir le récepteur au calcium (CaSR), qui en diminuant la [AMPc]int réduit l’activité de la PKA et lève ainsi son inhibition de la transcription du gène KCNN3 (codant pour SK3) ; ii) favorise la migration cellulaire dépendante du canal SK3, mécanisme impliquant également le CaSR ; iii) active le canal SK3 qui, par ailleurs, voit son activité réduite par l’élévation d’AMPc intracellulaire. De plus, l’augmentation d’AMPc délocalise un canal calcique partenaire de SK3, le canal Orai1, et diminue l’entrée constitutive de Ca²+ et la migration dépendantes du canal SK3. En conclusion, nos résultats montrent que l’expression et l’activité de SK3 sont régulées par l’AMPc et le Ca2+ extracellulaire. Ceci permet d’envisager une nouvelle stratégie thérapeutique ciblant l’AMPc pour le traitement des métastases osseuses du cancer du sein
We showed that a K+ channel, SK3 channel, is a mediator of MDA-MB-435s breast cancer cells migration and of osteolytic bone metastasis development of breast cancer. Since [Ca²+]out rises during osteolysis, in bone microenvironment, we study if this [Ca²+]out elevation could modulate SK3 expression and activity. We show that [Ca²+]out elevation: i) increases SK3 expression threw CaSR activation which, in turn, decreases [cAMP]int and PKA activation, leading to loss of its inhibitory effect on KCNN3 transcription; ii) increases SK3-dependent migration threw CaSR activation; iii) increases SK3 channel activity that is in addition, decreased by [cAMP]int elevation. Furthermore, cAMP elevation moves the Ca2+ channel Orai1 (SK3 partner) outside of lipid rafts and reduces the SK3 dependent-constitutive Ca²+ entry and cell migration. Our results show that both SK3 expression and activity are regulated by cAMP and extracellular Ca²+. These results underscore an innovative opportunity to use therapeutic approaches targeting cAMP for the treatment of breast cancer bone metastasis

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8

Hassan, S. Faisal (Syed Faisal). "Pan-Orao and historical necessity : adjusted frames and optical settlement". Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/66769.

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Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Architecture, 1995.
Includes bibliographical references (leaves 79-84).
Large horizontally formatted images have frequently been preferred for urban portraiture. Totalizing and comprehensive such compositions depict an environment as landscape or prospect. In rendering an all-encompassing view they attempt an expansive topographic virtuality that warrants participation. As a fictive world modeled on a surface they allow the perceiving faculties to enter places where our bodies cannot follow. By securing and seaming the edges of multiple frames, by engaging peripheral vision, they extend the limits of normal vision. This thesis has chosen to study such images giving them the title Pan Orao. By considering them a phenomenon it invests them partially the status of a mode of expression and at same time acknowledges their role as apparatus. The latter also suggests that they serve as mechanical requisites, as machinery for viewing the expansive condition of urban portraiture. The research cuts are taken across boundaries of place, time, medium and type to speak of unbroken views or serial images passing before the mind and the eye. Distinctions of 'high' and 'low' old and new therefore are not entertained. Rather a wider scaffold is suggested. The project sustains two broad conceptual themes; immersion and mobility, which are used to organise the material which ranges from Wide Screen 3D Cinema to 17th century urban views. Detailed discussion of particular cases occurs with a simultaneous interest in the technology of the changing view, its sociological and cultural impact, and the spatial-visual component of the media and their role in providing immersive environments.
by S. Faisal Hassan.
M.S.

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9

Röther, Jens [Verfasser], Ulrich [Akademischer Betreuer] Sack, Stefan [Akademischer Betreuer] Feske y bekannt nicht bekannt [Gutachter] nicht. "Die Rolle von Orai1 in der Entwicklung und Aktivierung von T- und B- Lymphozyten und die Bedeutung von Mutationen in Orai1 für die Pathogenese schwerer kombinierter Immundefekte / Jens Röther ; Gutachter: nicht bekannt nicht bekannt ; Ulrich Sack, Stefan Feske". Leipzig : Universitätsbibliothek Leipzig, 2011. http://d-nb.info/1237894638/34.

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Giachini, Fernanda Regina Casagrande. "Contribuição da via STIM1/Orai1 para as diferenças relacionadas ao sexo na entrada de cálcio em miócitos vasculares durante a hipertensão arterial". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-28092010-170302/.

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Os distúrbios na regulação da concentração de cálcio (Ca2+) citoplasmático contribuem para a patogênese da hipertensão arterial. Evidências sugerem que as moléculas de interação estromal (STIM) atuam como sensores dos estoques intracelulares de Ca2+, enquanto as proteínas Orai representam as subunidades que formam os canais de Ca2+ ativados pela liberação de Ca2+ (CRAC). Neste estudo avaliamos a participação de STIM1/Orai1 na regulação das concentrações de Ca2+ citoplasmático e na ativação da contração vascular em aortas de ratos hipertensos. Nossos resultados sugerem que a ativação de STIM1/Orai1 pode representar um novo mecanismo que modula alterações vasculares nos níveis de Ca2+ intracelular na hipertensão arterial e que contribui para as diferenças sexuais de reatividade vascular em animais hipertensos.
Disturbance in the regulation of cytoplasmic calcium (Ca2+) concentration contributes to the pathogenesis of hypertension. Evidences suggest that the stromal interaction molecule (STIM) acts as a sensor of intracellular Ca2+ stores, whereas Orai proteins are the subunits that form CRAC channels. In this study, we evaluated the role of STIM1/Orai1 in the regulation of cytoplasmic Ca2+ concentrations and in the activation of contraction in aortas from hypertensive rats. We also studied how the differential activation of this pathway contributes to sex differences observed between hypertensive rats, as well as the protective effects of the female sex hormones in the vasculature. Our results suggest that activation of STIM1/Orai1 may represent a new mechanism that modulates intracellular Ca2+ concentration during hypertension and contributes to sex differences in the vascular reactivity of hypertensive animals.

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11

Zanotto, Camila Ziliotto. "Papel da O-glicosilação com N-acetil-glucosamina (O-GlcNAc) no influxo e recaptação de cálcio pelo retículo sarcoplasmático em aorta de ratos: análise funcional". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-09092013-133940/.

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A O-glicosilação com N-acetil-glucosamina (O-GlcNAc) é uma modificação pós-translacional altamente dinâmica que modula diversas vias de sinalização. O processo de O-GlcNAc é controlado por duas enzimas: a enzima OGT é responsável por catalisar a adição de N-acetil-glucosamina no grupo hidroxila dos resíduos de serina e treonina, enquanto a OGA catalisa a remoção de O-GlcNAc das proteínas modificadas. Proteínas com importante papel na função vascular são alvo de O-GlcNAc e o aumento da expressão de proteínas modificadas por O-GlcNAc promove aumento da reatividade vascular para estímulos contráteis. Um dos mecanismos de extrema importância no controle do tônus vascular está ligado à regulação da concentração de cálcio (Ca2+) intracelular, onde destacamos a participação do sistema STIM1/Orai1. As moléculas de interação estromal (STIM) atuam como sensores dos estoques intracelulares de Ca2+ e as proteínas Orai representam as subunidades que formam os canais de Ca2+ ativados pela liberação de Ca2+ (CRAC). Neste estudo investigamos a hipótese de que o aumento dos níveis vasculares de proteínas glicosiladas aumenta a resposta contrátil em aorta de ratos, por mecanismos relacionados ao controle da concentração intracelular de Ca2+.Em nossos experimentos, utilizamos aortas torácicas de ratos incubadas com PugNAc (inibidor seletivo da OGA, ), por 24h. Utilizando protocolo experimental que permite avaliar contrações induzidas pelo influxo de Ca2+ e liberação de Ca2+ intracelular, demonstramos que a incubação com PugNAc aumentou a resposta contrátil à PE bem como a contração durante o período de influxo de Ca2+, induzida pela reintrodução de solução fisiológica contendo Ca2+ (1,56 mM). O bloqueio dos canais CRAC com 2-APB (100 ) e gadolíneo (Gd3+, 100 ) diminuiu significativamente as contrações induzidas pelo influxo de Ca2+ em aortas incubadas com PugNAc. Além disso, estas aortas apresentaram aumento da expressão protéica de STIM1, o que resultaria em maior influxo de Ca2+. A contração induzida por cafeína (20 mM) e serotonina (10 ), a qual reflete a capacidade funcional do retículo sarcoplasmático (RS) em captar Ca2+, foi maior em aortas incubadas com PugNAc. O papel da Ca2+-ATPase (SERCA) foi avaliado com a utilização de tapsigargina, bloqueador da SERCA. O efeito da tapsigargina foi semelhante em artérias incubadas com PugNAc e veículo, apesar do aumento de expressão proteica da SERCA em aortas incubadas com PugNAc. Como a proteína cinase C (PKC) é ativada por aumentos de Ca2+ intracelular, determinamos se a atividade de proteínas alvo da PKC estavam aumentadas. A incubação com PugNAc aumentou a expressão das formas fosforiladas da CPI-17, MYPT-1 e MLC. Em conjunto, estes resultados sugerem que a ativação de STIM1/Orai1, aumento da liberação de Ca2+ intracelular e ativação da via de sinalização da PKC podem representar mecanismos que modulam as alterações vasculares em resposta ao aumento de proteínas glicosiladas por O-GlcNAc.
Glycosylation with O-linked -N-acetyl-glucosamine (O-GlcNAc) is a highly dynamic post-translational modification. The process of O-GlcNAc is controlled by two enzymes: the OGT enzyme catalyses the addition of N-acetyl-glucosamine to the hydroxyl group of serine and threonine residues of a target protein, while OGA catalyzes the cleavage of O-GlcNAc from post-translationally-modified proteins. Proteins with an important role in vascular function are targets of O-GlcNAc and increased levels of proteins modified by O-GlcNAc increase vascular reactivity to contractile stimuli. The regulation of intracellular calcium (Ca2+) concentration, including the activation of STIM1/Orai1, is key in the control of vascular tone. The stromal interaction molecules (STIM) act as sensors of intracellular Ca2+ stores whereas the Orai proteins represent subunits of the Ca2+ release-activated Ca2+ channels (CRAC). We hypothesized that increased levels of vascular O-GlcNAc proteins augment vascular contractile responses by altering mechanisms that regulate the intracellular Ca2+. Rat thoracic aortas were incubated with PugNAc (OGA selective inhibitor, ) for 24h. Using an experimental protocol that evaluates contractions induced by Ca2+ influx and release, we demonstrated that incubation with PugNAc increases contractile responses to phenylephrine (PE) as well as the contraction induced by Ca2+ influx, after depletion of intracellular Ca2+ stores. The CRAC channel blockers, 2-APB (100 ) and gadolinium (Gd3+, 100 ), significantly reduced the contractions induced by Ca2+ influx in aortas incubated with PugNAc. Furthermore, these aortas showed increased STIM1 protein expression, which could result in increased influx of Ca2+ and, in turn, increase vascular contraction. The contraction induced by the release of intracellular Ca2+ stores, stimulated by caffeine (20 mM) and serotonin (10 ), was increased in aortas incubated with PugNAc. The Ca2+-ATPase (SERCA) inhibitor thapsigargin produced similar effects in arteries incubated with PugNAc or vehicle, despite the increased SERCA protein expression in aortas incubated with PugNAc. Since PKC is activated by increases in intracellular Ca2+ and arteries incubated with PugNAc show activation of PKC, we determined whether the activity of proteins that are targets of PKC was increased in PugNAc-treated aortas. Incubation with PugNAc increased the expression of phosphorylated forms of CPI-17, MYPT-1 and MLC. Together, these results suggest that activation of STIM1/Orai1, increased release of intracellular Ca2+ and PKC activation may represent mechanisms that modulate vascular responses upon increased O-GlcNAc proteins.

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12

Ansary, Dalia al [Verfasser] y Veith [Akademischer Betreuer] Flockerzi. "Regulatory mechanisms of the calcium selective ion channels TRPV6 and ORAI1 / Dalia Al-Ansary. Betreuer: Veith Flockerzi". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2011. http://d-nb.info/1051326214/34.

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13

Endo, Yukari. "Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca2+ channels". Kyoto University, 2015. http://hdl.handle.net/2433/198937.

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Latour, Simon. "Rôle des protéines Orai1 et STIM1 dans les lymphomes B non-Hodgkiniens, établissement d'un modèle d'étude en 3D". Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0038.

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Les lymphomes B non-Hodgkiniens (LNHB) représentent le type d’hémopathie maligne le plus fréquent. Ces pathologies sont traitées par l’association de chimiothérapies conventionnelles et d’immunothérapies dirigées contre le CD20. Bien qu’efficace, 40% des patients résistent ou rechutent après le traitement. Deux raisons peuvent expliquer ces échecs thérapeutiques : 1) l’absence de cibles thérapeutiques impliquées dans plusieurs processus oncogéniques et 2) l’absence de modèles pré-cliniques de LNHB pertinents pour le test de molécules thérapeutiques et la compréhension de la lymphomagenèse. Le calcium est un messager ubiquitaire qui est impliqué dans de nombreux processus cellulaires en condition physiologique et pathologique. La principale voie d’entrée de calcium dans les lymphocytes B est l’entrée capacitive de calcium médiée par Orai1 et STIM1. Ces deux protéines ont été largement décrites pour être impliquées dans les processus tumoraux de nombreux cancers, cependant leurs rôles dans la lymphomagenèse restait à élucider. Nos travaux ont révélé l'implication de la signalisation calcique dans la mort induite par le GA101, un anti CD20 de nouvelle génération actuellement en essai clinique. De plus, nous avons mis en évidence l’implication des protéines Orai1 et STIM1 dans la migration des cellules cancéreuses de LNHB. De manière intéressante, l’implication de ces deux protéines dans la migration cellulaire est calcium indépendante, suggérant donc un nouveau rôle de ces protéines. Enfin, grâce à la technologie des capsules cellulaires nous avons établi un nouveau modèle 3D de lymphome mimant la niche tumorale en incluant des cellules du microenvironnement et de la matrice extracellulaire. Ce modèle semble particulièrement pertinent pour le screening de molécules et la compréhension des mécanismes de la lymphomagenèse. Ce travail de thèse révèle ainsi le ciblage de Orai1 et STIM1 comme potentiellement intéressant dans le traitement du LNHB
B-cell non-Hodgkin lymphomas (BNHL) are the most common hematological malignancies, usually treated with a combination of chemotherapy and anti CD20 immunothérapie. However, 40% of patients are resistant or relapse after treatment. These therapeutic failures could be due to 1) lack of therapeutic targets implicated in several oncogenic processes, 2) lack of relevant preclinical BNHL models for drug screening and lymphomagenesis studies. Calcium is an essential second messenger involved in various cell functions. In B cells, calcium entry is mainly due to Orai1 and STIM1 proteins, both of which have been associated with oncogenesis on solid tumors. However, their role in lymphomagenesis still remains to be elucidated. Our work shows that calcium signaling in BNHL cells participates in cell death induced by GA101, a novel anti-CD20 monoclonal antibody. We also demonstrate that Orai1 and STIM1 play a role in BNHL cell migration. Interestingly, both proteins controlled cell migration in a calcium-independent manner, suggesting a new role for these proteins. Finally, using cellular capsule technology, we established a new BNHL 3D model mimicking tumoral niche by including extracellular matrix and stromal cells. This new model could be used for drug screening and understanding lymphomagenesis. In summary, this work suggests that targeting of Orai1 and STIM1 is promising for BNHL treatment

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15

Cabanas, Hélène. "Rôle de la signalisation calcique dans la leucémie myéloïde chronique". Thesis, Poitiers, 2016. http://www.theses.fr/2016POIT2302/document.

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La Leucémie Myéloïde Chronique (LMC) est une maladie clonale caractérisée par la présence du chromosome Philadelphie codant pour Bcr-Abl, une tyrosine kinase constitutivement active responsable de la leucémogenèse. Bien que très efficaces, les inhibiteurs de tyrosine kinase (ITKs) restent cependant inactifs sur les cellules souches leucémiques. Ce travail de thèse montre que la signalisation calcique, connue pour réguler de nombreux processus dans les cellules saines et cancéreuses, est importante dans la signalisation cellulaire au décours de la LMC. Le rôle des entrées calciques dépendantes des stocks (SOCEs) médiées par STIM1 (STromal Interaction Molecule 1) et les canaux Orai1 et TRPC1 ainsi que des entrées calciques induites par la thrombine a été étudié dans la leucémogenèse. Nous avons observé une diminution de ces entrées dans les cellules exprimant Bcr-Abl pouvant être expliquée par le changement de stœchiométrie Orai1/STIM1. Ceci entraîne la diminution de l'activation de NFAT (Nuclear Factor of Activated T-cells) ainsi que des conséquences sur la prolifération et la migration cellulaire mais pas sur l'apoptose. De plus, les SOCEs sont restaurées dans les cellules cancéreuses après traitement à l'Imatinib, le principal ITK. Nous proposons alors que l'expression de Bcr-Abl joue un rôle sur l'homéostasie calcique en entraînant une dérégulation générale des fonctions cellulaires dans les cellules leucémiques notamment via la voie PKC (Protein Kinase C). Ainsi, ces résultats montrent une dérégulation des entrées calciques dans les cellules exprimant Bcr-Abl, suggérant que la signalisation calcique puisse être une cible thérapeutique en parallèle avec les ITKs
Chronic Myeloid Leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia chromosome encoding for Bcr-Abl, a constitutively active tyrosine kinase responsible for leukemogenesis. Although Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized the therapy of Ph+ leukemia, the complete eradication of CML is limited by the emergence of resistance in hematopoietic stem cells. This thesis proposes that calcium (Ca2+) signaling pathways, known to govern a large number of functions in normal and cancer cells, may be important in CML cell signaling. Therefore, we studied the role of Store Operated-Calcium entry (SOCE) (i.e. STromal Interaction Molecule 1 (STIM1), Orai1 and TRPC1 channels) and thrombin induced Ca2+ entry in leukemogenesis. We found a decrease in both calcium entries in Bcr-Abl-expressing cells compared to normal cells. The reduced SOCE seems related to a change in stoichiometry of Orai1/STIM1. This leads to a reduction of the Nuclear Factor of Activated T-cells (NFAT) translocation and functional consequences on cell proliferation and migration but not on apoptosis. Moreover, we showed that SOCE is restored in malignant cells after treatment with Imatinib, the main TKI. We proposed that Bcr-Abl expression could impact on Ca2+ homeostasis enhancing a general disorganization of cell functions in leukemia cells notably via Protein Kinase C (PKC) pathway. Altogether this work shows a deregulation of Ca2+ entry in Bcr-Abl-expressing cells, suggesting that the Ca2+ signaling pathway could be a therapeutic target in parallel with TKIs

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16

Dramane, Gado. "Etude de la signalisation calcique dans les cellules gustatives lipidiques chez la souris". Thesis, Dijon, 2012. http://www.theses.fr/2012DIJOS035/document.

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Les personnes en surcharge pondérale semblent préférer une alimentation riche en graisse. Face à l'épidémie d'obésité qui touche nos Sociétés tant urbaines que rurales, élucider les mécanismes de la détection des lipides alimentaires devient un enjeu majeur. Il avait précédemment été admis que la glycoprotéine CD36 exprimée dans les papilles caliciformes de souris, est impliquée dans la perception oro-gustative des lipides alimentaires. Dans ce travail, nous avons montré que l'acide linoléique (LA), en activant les phospholipases A2, sPLA2, cPLA2 et iPLA2 via CD36, produit de l'acide arachidonique (AA) et la lyso-phosphatidylcholine (lyso-PC). LA déclenche un influx calcique dans les cellules CD36-positives et induit la production du facteur CIF (Calcium Influx Factor). CIF, AA et lyso-PC exercent différentes actions sur l'ouverture des canaux SOC (Stored Operated Calcium Channel) constitués de protéines Orai et contrôlés par STIM1. Stim1 est un senseur calcique situé sur la membrane du réticulum endoplasmique activé par la déplétion du calcium intracellulaire. Nous avons utilisé la technologie siRNA et des modèles de souris transgéniques pour montrer que CIF et lyso-PC activent des canaux calciques homodimériques composés de protéines Orai1 tandis qu’AA active des canaux hétéro-pentamériques composés d’Orai1 et Orai3. Nous avons également montré que STIM1 régule la production de CIF dans les cellules stimulées par la thapsigargine et l’acide linoléique ainsi que l'ouverture de deux types de canaux calciques. Par ailleurs les souris au phénotype Stim1-/- perdent la préférence spontanée pour les lipides observé chez les animaux de type sauvage. D’un autre côté les cellules CD36-positive de souris Stim1-/- sont incapables de libérer la sérotonine dans l'environnement extracellulaire. Nos résultats suggèrent que des acides gras à longue chaine (AGLC) induisent la signalisation calcique régie par STIM1 via CD36. La perception oro-gustative des lipides alimentaires détermine la préférence spontanée pour les lipides observée chez les mammifères
The lipid-binding glycoprotein CD36, expressed by circumvallate papillae (CVP) of the mouse tongue, has been shown to be implicated in oro-gustatory perception of dietary lipids. We demonstrate that linoleic acid (LA) by activating sPLA2, cPLA2 and iPLA2 via CD36, produced arachidonic acid (AA) and lyso-phosphatidylcholine (Lyso-PC) which triggered Ca2+ influx in CD36-positive taste bud cells (TBC), purified from mouse CVP. LA induced the production of Ca2+ influx factor (CIF). CIF, AA and Lyso-PC exerted different actions on the opening of store-operated Ca2+ (SOC) channels, constituted of Orai proteins and regulated by STIM1, a sensor of Ca2+ depletion in the endoplasmic reticulum. We used siRNA technology and transgenic mice models and observed that CIF and Lyso-PC opened Orai1 channels whereas AA-opened Ca2+ channels were composed of Orai1/Orai3. STIM1 was found to regulate LA-induced CIF production and opening of both kinds of Ca2+ channels. Furthermore, Stim1–/– mice lost the spontaneous preference for fat, observed in wild-type animals. The CD36-positive TBC from Stim1–/– mice also failed to release serotonin into extracellular environment. Our results suggest that fatty acid-induced Ca2+ signaling, regulated by STIM1 via CD36, might be implicated in oro-gustatory perception of dietary lipids and the spontaneous preference for fat

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17

Usui, Ryota. "GPR40 activation initiates store-operated Ca²⁺ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells". Kyoto University, 2020. http://hdl.handle.net/2433/253196.

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18

Hyväri, S. (Sampsa). "The value-creation of the business model of Finnish residential REITs as observed through the annual statement:evidence from Orava Residential REIT plc". Master's thesis, University of Oulu, 2017. http://urn.fi/URN:NBN:fi:oulu-201706062555.

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The thesis evaluates the value creation of the business model of Finnish residential real estate investment trusts (REITs) by observing the annual statement of Orava Residential REIT Plc. for the financial year ending 2016. The theoretical framework discusses peculiarities of REITs, company and its management and financial accounting. Different concepts and aspects have been highlighted in all of the chapters of the theoretical framework. The empirical research is qualitative and done by selective coding. The research method has been abductive. The most important research findings are related to fair value accounting, corporate governance and their role in real estate investment trusts. It seems that fair values are related to all different aspects of the operations of a REIT, the uncertainty related to it possibly enables the management to practice real earnings management. Moreover, unrealized gains and due to the changes in fair values play a significant role in the net income of the company. Considering corporate governance, major concern was raised from the independence of the board of directors. The board has assessed majority of its members to be independent, still, evidence is found to justify that majority of the board members cannot be considered to be truly independent. Also, the cash flows from the realized gains, from the point of view of private investor, have been discussed. More research should be conducted to validate the findings of the research. For example, corporate governance, real earnings manipulation or leverage and capital structure could be inspected more.

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19

Peche, Georges Arielle. "Physiopathologie de la myopathie à agrégats tubulaires". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ008/document.

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La myopathie à agrégats tubulaires (TAM) est une maladie génétique qui se caractérise par la présence d’agrégats tubulaires dans les biopsies musculaires de patients. Notre équipe a identifié pour la première fois des mutations dans STIM1 comme étant à l’origine de cette maladie. STIM1 (stromal interaction molecule 1) est le senseur calcique du réticulum sarco/endoplasmique (RE/RS). En effet, en cas de diminution du calcium (Ca2+) dans le RE/RS, STIM1 se déplie, oligomérise et migre à proximité de la membrane plasmique (MP) pour activer le canal calcique ORAI1 et permettre le remplissage des stocks. Ce mécanisme est le «store-operated Ca2+ entry» (SOCE). D’autres équipes ont rapporté une mutation dans STIM1 (p.R304W) conduisant à une TAM associée à d’autres symptômes, ou encore syndrome de Stormorken. Ainsi, ce travail a eu pour but d’étudier et de comparer l’impact des mutations TAM et Stormorken à différents niveaux du SOCE. Nous avons ainsi montré que les mutations TAM et Stormorken conduisent à une augmentation de l’expression de STIM1, à la formation de clusters constitutifs de STIM1 à proximité de la MP, ainsi qu’au recrutement du canal ORAI1 et à l’activation de la voie du NFAT, dépendante du Ca2+
Tubular aggregate myopathy (TAM) is a genetic disorder characterized by tubular aggregates in muscle biopsies of patients. Our team identified for the first time mutations in STIM1 as causative of this disease. STIM1 (stromal interaction molecule 1) is the main calcium (Ca2+) sensor of the endo/sarcoplasmic reticulum (ER/SR). Following Ca2+ depletion of the ER/SR, STIM1 unfolds, oligomerizes and migrates close to the plasma membrane (PM) to activate the Ca2+ channel ORAI1, leading to Ca2+ entry. This mechanism is the «store-operated Ca2+ entry» (SOCE). Several teams report a mutation in STIM1 (p.R304W) leading to TAM associated with other symptoms, described as Stormorken syndrome. Therefore, this work aims to assess and compare the impact of TAM and Stormorken mutations at different stages of the SOCE pathway. We show that TAM and Stormorken mutations lead to an increase expression of the protein, a constitutive STIM1 clustering near the PM, to ORAI1 constitutive recruitment and to the activation of a Ca2+ -dependent pathway: the NFAT pathway

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20

Campbell, Joan Cecelia. "All testimonies are not equal, a study of the use of [orao] in the Fourth Gospel". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq25197.pdf.

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21

EHSANI, SCHAROKH. "Approccio multidisciplinare al trattamento parodontale del PZ con bisogni speciali: la telemedicina quale strumento innovativo nell'ambito dell'organizzazione a rete delle attività odontoiatriche territoriali (ORAOT)". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/28399.

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The definition of patients with special needs includes patients who have or are at increased risk for a chronic physical, developmental, behavioral, or emotional condition and who also require health and related services of a type or amount beyond that required by patients generally. 13% of the U.S.A. Patients are estimated to have been diagnosed with some special health care need. Periodontal disease is the most common chronic disease In geriatric patients with special needs .many problems related to the condition of this type of patients prevent them from accessing care.we studied the problem of this population in relation to periodontal disease in the territory of Monza and Brianza and evaluated the benefits of using telemedicine in this area. The results were that telemedicine helps geriatric patients with special needs to access health and periodontal qulità increasing the safety of these treatments in addition to increasing the number of accesses.

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22

Eylenstein, Anja [Verfasser] y Florian [Akademischer Betreuer] Lang. "Regulierung des speicherabhangigen Ca2+-Kanals Orai1 und des Ca2+-sensitiven Proteins STIM1 durch die Serum- und Glukokortikoid induzierbare Kinase 1 / Anja Eylenstein ; Betreuer: Florian Lang". Tübingen : Universitätsbibliothek Tübingen, 2011. http://d-nb.info/1160309620/34.

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23

Castro, Kraftchenko Joel y kraf0005@flinders edu au. "STORE OPERATED Ca2+ CHANNELS IN LIVER CELLS: REGULATION BY BILE ACIDS AND A SUB-REGION OF THE ENDOPLASMIC RETICULUM". Flinders University. Medicine, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20080826.135311.

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Cholestasis is an important liver pathology. During cholestasis bile acids accumulate in the bile canaliculus affecting hepatocyte viability. The actions of bile acids require changes in the release of Ca2+ from intracellular stores and in Ca2+ entry. The target(s) of the Ca2+ entry pathway affected by bile acids is, however, not known. The overall objective of the work described in this thesis was to elucidate the target(s) and mechanism(s) of bile acids-induced modulation of hepatocytes calcium homeostasis. First, it was shown that a 12 h pre-incubation with cholestatic bile acids (to mimic cholestasis conditions) induced the inhibition of Ca2+ entry through store-operated Ca2+ channels (SOCs), while the addition of choleretic bile acids to the incubation medium caused the reversible activation of Ca2+ entry through SOCs. Moreover, it was shown that incubation of liver cells with choleretic bile acids counteracts the inhibition of Ca2+ entry caused by pre-incubation with cholestatic bile acids. Thus, it was concluded that SOCs are the target of bile acids action in liver cells. Surprisingly, despite the effect of choleretic bile acids in activating SOCs, the Ca2+ dye fura-2 failed to detect choleretic bile acid-induced Ca2+ release from intracellular stores in the absence of extracellular Ca2+. However, under the same conditions, when the sub-plasma membrane Ca2+ levels were measured using FFP-18 Ca2+ dye, choleretic bile acid induced a transient increase in FFP-18 fluorescence. This evidence suggested that choleretic bile acids-induced activation of Ca2+ entry through SOCs, involving the release of Ca2+ from a region of the endoplasmic reticulum (ER) located in the vicinity of the plasma membrane.

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24

Lesca, Elena [Verfasser], Robert [Akademischer Betreuer] Huber y Sonja Alexandra [Akademischer Betreuer] Dames. "Structural analysis of the human Fibroblast Growth Factor Receptor 4 kinase - Expression and purification of the human calcium channel ORAI1 / Elena Lesca. Gutachter: Robert Huber ; Sonja Alexandra Dames. Betreuer: Robert Huber". München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1064694985/34.

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25

Agostini, Mario. "Exploring Orai2 function in alzheimer's disease models based on presenilin 2 and amyloid precursor protein mutants". Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3425360.

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Alzheimer's disease (AD) is the most common form of dementia among elderly population. More than twenty years ago the so-called amyloid hypothesis was formulated based on the major histopathological hallmarks of AD, among which the amyloid plaques are the most known and studied. This hypothesis was prompted by the discovery of three genes that, whereas mutated, are associated with the familial forms of the disease (FAD). One of these genes encodes for the amyloid precursor protein (APP), a single-pass type I transmembrane protein that undergoes sequential cleavages operated by the secretase family of enzymes. The last and key secretase, called gamma-secretase, is composed of four proteins, among which we found either presenilin 1 (PS1) or presenilin 2 (PS2), encoded by other two genes (PSEN1/PSEN2) that are responsible for FAD pathogenesis. Autosomic dominant mutations in either APP, PSEN1 or PSEN2 cause accelerated Abeta deposition due to an increased Abeta42/Abeta40 ratio. While the vast majority of AD cases are sporadic, FAD patients bearing PS2 mutations show a clinical course much similar to that of sporadic patients. By many groups it was found that PSs are capable of perturbing cellular Ca2+ homeostasis, and, particularly, our group demonstrated that PS2, either bearing FAD-linked mutations or wild-type (WT), lowers endoplasmic reticulum (ER) and Golgi apparatus Ca2+ content, interacts with SERCA pump, dampening its function, and tethers ER and mitochondria; all of these pleiotropic effects are independent of its gamma-secretase activity. Recently another group identified PS2 as a regulator of the ER Ca2+ content, together with Orai2, a plasma membrane channel implicated in the Store-Operated Ca2+ Entry (SOCE). This latter phenomenon is impaired in AD, and specifically it is down-tuned in mutant PS-bearing cells. Taken together this body of information offered an interesting background to study the interplay between ER Ca2+ levels, SOCE defects and APP processing/Abeta production. Taking advantage of the PS2-based AD mouse models available in our laboratory, namely the homozygous single transgenic (TG) line expressing the FAD-linked mutant PS2-N141I (line PS2.30H) and the homozygous double transgenic (2TG) line expressing PS2-N141I together with the Swedish double mutant APP-K670M/N671L (line B6.152H), we could investigate the expression pattern of Orai2 in the nervous tissue. Western blot analyses on cortices and hippocampi revealed that Orai2 was overexpressed in cortices from TG and 2TG mice, when compared to C57BL/6 (WT) mice. This overexpression was mainly due to the neuronal contribution since it was even higher in cortical neuronal cultures and in situ Orai2 was found only in neurons, as assayed by immunohistochemical analysis of brain slices. Orai2 up-regulation, that is the condition found in TG and 2TG neurons, is capable of perturbing cellular Ca2+ homeostasis. Particularly, when overexpressed it caused a significant decrease in IP3-induced ER Ca2+ release in both H4-APPswe and HEK29T cells; these results are consistent with a decreased ER Ca2+ level, as measured with the ER-targeted probe G-CEPIA1er. In addition to this, Orai2 revealed to be a less efficient mediator of SOCE than Orai1, since it dampened SOCE when overexpressed alone and it produced a much smaller SOCE when overexpressed with STIM1 as compared with Orai1 plus STIM1 overexpression. Conversely to our expectations, Orai2 downregulation had a noticeable effect neither on IP3-induced ER Ca2+ release nor on total store Ca2+ content; it however improved Ca2+ entry upon store depletion. As far as subcellular localization goes, Orai2 overexpression did not increase the fraction of protein present in the ER and it appeared that most of the protein was found at the early endosomal level, as revealed by immunofluorescence staining of various subcellular compartments. This holds true moving to cortical neurons, where Orai2 was preferentially found in Rab5-EEA1 positive endosomes in primary cultures from WT mice, with a dramatic accumulation at this level in neurons from 2TG mice, possibly reflecting the increased early-endosome compartment that characterizes the AD phenotype. Orai2 localization is, however, dynamic, meaning that it moves in and out of endosomes when properly stimulating neurons with compounds able to induce neuronal activity or to stimulate SOCE. This behaviour is anyway different among the three genotypes, with TG neurons showing a greater tendency to retrieve Orai2 in endosomes upon cell stimulation, and 2TG neurons being unable to properly tune their endosome pool, possibly because of its higher accumulation level. Whether these changes involve also Orai1 has still to be evaluated and it will give us a better picture of this unknown phenomenon. Finally, evidence is provided that a down-tuning of SOCE is associated with increased levels of secreted Abeta42, as measured by ELISA performed on conditioned media from mutant APP-expressing cells such as CHO-7PA2 and H4-APPswe.
La malattia di Alzheimer (AD) costituisce la forma di demenza più comune nella popolazione anziana. Ormai più di vent'anni fa è stata formulata la cosiddetta ipotesi della cascata amiloide, la quale si basa sulle placche amiloidi, uno dei principali marker di AD, tra i più conosciuti e studiati. La formulazione di quest'ipotesi fu permessa dalla scoperta di tre gene i quali, allorché mutati, sono associati con la forma familiare di AD (FAD). Uno di questi geni codifica per la proteina precursore dell'amiloide (APP), la quale è una proteina di tipo I a singolo dominio transmembrana che viene tagliata in maniera sequenziale dagli enzimi della famiglia delle secretasi. L'ultima secretasi a tagliare APP, nonché la più importante nell'AD, è chiamata gamma-secretasi ed è composta da quattro proteine, che comprendono o la presenilina 1 (PS1) o la presenilina 2 (PS2), codificate dagli altri due geni (PSEN1/PSEN2) responsabili della patogenesi di FAD. Mutazioni autosomiche dominanti in APP, PSEN1 o PSEN2 causano una deposizione più veloce di Abeta dovuta ad un aumentato rapporto Abeta42/Abeta40. La maggior parte dei casi di AD, tuttavia, è sporadica; i pazienti FAD con mutazioni in PS2 mostrano un decorso clinico della malattia molto più simile a quello dei pazienti sporadici. Molti gruppi di ricerca hanno dimostrato la capacità delle PSs di perturbare l'omeostasi cellulare del Ca2+, e in particolare il nostro gruppo ha dimostrato che PS2, sia nella forma mutata associata a FAD che nella forma wild-type (WT), abbassa il contenuto di Ca2+ del reticolo endoplasmatico (ER) e dell'apparato di Golgi. Inoltre essa interagisce con la pompa SERCA, diminuendone il funzionamento, e modula la vicinanza fra ER e mitocondri; tutte queste funzioni pleiotropiche sono indipendenti dalla sua attività gamma-secretasica. Recentemente un altro gruppo ha identificato PS2 come un regolatore del contenuto di Ca2+ del ER, insieme ad Orai2, il quale è un canale della membrana plasmatica implicato nell'entrata di Ca2+ dipendente dallo svuotamento del ER (SOCE). Quest'ultimo fenomeno è alterato nell'AD, e in particolare è ridotto nelle cellule che esprimono PS mutate. Questa serie di informazioni rappresenta una base interessante per lo studio dell'interazione fra contenuto di Ca2+ del ER, diminuzione di SOCE e metabolismo di APP/produzione di Abeta. Grazie ai modelli murini di AD basati su PS2 presenti in laboratorio, specificatamente il modello singolo transgenico (TG), esprimente il mutante FAD PS2-N141I (linea PS2.30H) e il modello doppio transgenico (2TG), esprimente PS2-N141I insieme al mutante Swedish APP-K670M/N671L (linea B6.152H), abbiamo potuto investigare il pattern di espressione di Orai2 nel tessuto nervoso. Nei Western blot di cortecce ed ippocampi abbiamo notato come Orai2 sia sovra-espressa nella corteccia dei topi TG e 2TG se confrontati con topi di controllo C57BL/6 (WT). Quest'aumento di espressione è dovuto principalmente ad un contributo neuronale, sia in quanto è maggiore in colture neuronali pure, sia perché Orai2 è presente solamente nei neuroni in situ, come rivelato dall'analisi immunoistochimica di fettine di cervello. L'aumentata espressione di Orai2, così come si ritrova nei neuroni TG e 2TG, è in grado di alterare l'omeostasi cellulare del Ca2+. In particolare, quando sovra-espressa, Orai2 causa una riduzione significativa del rilascio di Ca2+ indotto da IP3, sia in cellule H4-APPswe che HEK293T; questi risultati sono in accordo con una riduzione del contenuto di Ca2+ del ER, condizione osservata utilizzando la sonda G-CEPIA1er, direzionata al ER. Inoltre, Orai2 si è rivelato essere un mediatore di SOCE meno efficiente di Orai1, infatti diminuisce SOCE quando espresso da solo e, se co-espresso con STIM1, dà vita ad un SOCE meno ampio di quello prodotto da Orai1 co-espresso con STIM1. Contrariamente a quanto atteso la riduzione di Orai2 non produce alcuna diminuzione né del rilascio di Ca2+ indotto da IP3, né del contenuto totale di Ca2+ dei depositi intracellulari; essa tuttavia produce un lieve aumento dell'ingresso di Ca2+ causato dalla deplezione dei depositi. Per quanto riguarda la localizzazione subcellulare, la sovra-espressione di Orai2 non aumenta la frazione di questa proteina presente nel ER, la maggior parte di Orai2 è infatti presente a livello degli 'early endosomes', come dimostrato marcando numerosi compartimenti subcellulari in immunofluorescenza. Ciò resta vero anche nei neuroni corticali in coltura. Nei neuroni WT, Orai2 si trova preferenzialmente negli endosomi positivi per Rab5 ed EEA1, a questo livello la localizzazione aumenta nei neuroni 2TG, un accumulo causato probabilmente dallaumento degli 'early endosomes' tipico del fenotipo AD. Nonostante sia presente a livello endosomiale, la localizzazione di Orai2 è dinamica, e cioè cambia fra dentro e fuori dagli endosomi a seconda dello stimolo usato per aumentare l'attività neuronale o per indurre SOCE. Questo dinamismo appare diverso fra i tre genotipi, dove i neuroni TG mostrano una maggior tendenza ad accumulare Orai2 negli endosomi dopo stimolazione della cellula, mentre i neuroni 2TG risultano incapaci di modulare questo aspetto, probabilmente perché in queste cellule l'accumulo di endosomi è prossimo alla saturazione. Resta da valutare se questi cambi di localizzazione interessano anche Orai1, un'informazione che ci permetterà di avere un'idea più precisa di questo fenomeno sconosciuto. Infine vi è evidenza che la diminuzione di SOCE è associata ad un aumento dei livelli di Abeta42 secreta, così come misurato tramite saggio ELISA sui terreni condizionati provenienti da cellule che esprimono una forma mutata di APP, quali le CHO-7PA2 e le H4-APPswe.

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26

Tian, Geng. "On the Generation of cAMP Oscillations and Regulation of the Ca2+ Store-operated Pathway in Pancreatic Islet α- and β-cells". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-191852.

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Insulin and glucagon are released in pulses from pancreatic β- and α-cells, respectively. Both cell types are electrically excitable, and elevation of the cytoplasmic Ca2+ concentration ([Ca2+]i) due to depolarization with voltage-dependent entry of the cation is the main trigger of hormone secretion. Store-operated Ca2+ entry (SOCE) also contributes to the [Ca2+]i elevation and this process has been suggested to be particularly important for glucagon secretion. cAMP is another important messenger that amplifies Ca2+-triggered secretion of both hormones, but little is known about cAMP dynamics in islet cells. In type-2 diabetes, there is deteriorated β-cell function associated with elevated concentrations of fatty acids, but the underlying mechanisms are largely unknown. To clarify the processes that regulate insulin and glucagon secretion, cAMP signalling and the store-operated pathway were investigated in β- and α-cells, primarily within their natural environment in intact mouse and human islets of Langerhans. Fluorescent biosensors and total internal reflection microscopy were used to investigate signalling specifically at the plasma membrane (PM). Adrenaline increased and decreased the sub-PM cAMP concentration ([cAMP]pm) in immuno-identified α-cells and β-cells, respectively, which facilitated cell identification. Glucagon elicited [cAMP]pm oscillations in α- and β-cells, demonstrating both auto- and paracrine effects of the hormone. Whereas glucagon-like peptide 1 (GLP-1) consistently elevated [cAMP]pm in β-cells, only few α-cells responded, indicating that GLP-1 regulates glucagon secretion without changes of α-cell [cAMP]pm. Both α- and β-cells responded to glucose with pronounced oscillations of [cAMP]pm that were partially Ca2+-dependent and synchronized among islet β-cells. The glucose-induced cAMP formation was mediated by plasma membrane-bound adenylyl cyclases. Several phosphodiesterases (PDEs), including the PDE1, -3, -4, and -8 families, were required for shaping the [cAMP]pm signals and pulsatile insulin secretion. Prolonged exposure of islets to the fatty acid palmitate deteriorated glucose-stimulated insulin secretion with loss of pulsatility. This defect was associated with impaired cAMP generation, while [Ca2+]i signalling was essentially unaffected. Stromal interacting molecule 1 (STIM1) is critical for activation of SOCE by sensing the Ca2+ concentration in the endoplasmic reticulum (ER). ER Ca2+ depletion caused STIM1 aggregation, co-clustering with the PM Ca2+ channel protein Orai1 and SOCE activation. Glucose, which inhibits SOCE by filling the ER with Ca2+, reversed the PM association of STIM1. Consistent with a role of the store-operated pathway in glucagon secretion, this effect was maximal at the low glucose concentrations that inhibit glucagon release, whereas considerably higher concentrations were required in β-cells. Adrenaline induced STIM1 translocation to the PM in α-cells and the reverse process in β-cells, partially reflecting the opposite effects of adrenaline on cAMP in the two cell types. However, cAMP-induced STIM1 aggregates did not co-cluster with Orai1 or activate SOCE, indicating that STIM1 translocation can occur independently of Orai1 clustering and SOCE.

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Dramane, Gado y Gado Dramane. "Etude de la signalisation calcique dans les cellules gustatives lipidiques chez la souris". Phd thesis, Université de Bourgogne, 2012. http://tel.archives-ouvertes.fr/tel-00833888.

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Les personnes en surcharge pondérale semblent préférer une alimentation riche en graisse. Face à l'épidémie d'obésité qui touche nos Sociétés tant urbaines que rurales, élucider les mécanismes de la détection des lipides alimentaires devient un enjeu majeur. Il avait précédemment été admis que la glycoprotéine CD36 exprimée dans les papilles caliciformes de souris, est impliquée dans la perception oro-gustative des lipides alimentaires. Dans ce travail, nous avons montré que l'acide linoléique (LA), en activant les phospholipases A2, sPLA2, cPLA2 et iPLA2 via CD36, produit de l'acide arachidonique (AA) et la lyso-phosphatidylcholine (lyso-PC). LA déclenche un influx calcique dans les cellules CD36-positives et induit la production du facteur CIF (Calcium Influx Factor). CIF, AA et lyso-PC exercent différentes actions sur l'ouverture des canaux SOC (Stored Operated Calcium Channel) constitués de protéines Orai et contrôlés par STIM1. Stim1 est un senseur calcique situé sur la membrane du réticulum endoplasmique activé par la déplétion du calcium intracellulaire. Nous avons utilisé la technologie siRNA et des modèles de souris transgéniques pour montrer que CIF et lyso-PC activent des canaux calciques homodimériques composés de protéines Orai1 tandis qu'AA active des canaux hétéro-pentamériques composés d'Orai1 et Orai3. Nous avons également montré que STIM1 régule la production de CIF dans les cellules stimulées par la thapsigargine et l'acide linoléique ainsi que l'ouverture de deux types de canaux calciques. Par ailleurs les souris au phénotype Stim1-/- perdent la préférence spontanée pour les lipides observé chez les animaux de type sauvage. D'un autre côté les cellules CD36-positive de souris Stim1-/- sont incapables de libérer la sérotonine dans l'environnement extracellulaire. Nos résultats suggèrent que des acides gras à longue chaine (AGLC) induisent la signalisation calcique régie par STIM1 via CD36. La perception oro-gustative des lipides alimentaires détermine la préférence spontanée pour les lipides observée chez les mammifères

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Goswamee, Priyodarshan. "The Role of Orai-Mediated Ca²⁺ Entry in Migration in a Gastroenteropancreatic Neuroendocrine Tumor Model". University of Toledo Health Science Campus / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438280470.

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Arunachalam, Sasi. "The Role of store operated calcium channels in human carcinoid cell lines". University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1279216983.

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Abdoul-Azize, Souleymane. "Implication de la signalisation calcique et des MAP kinases dans la perception gustative lipidique". Phd thesis, Université de Bourgogne, 2013. http://tel.archives-ouvertes.fr/tel-01018378.

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Dans ce travail, nous démontrons que STIM1, un senseur calcique activé par la déplétion du Ca2+ intracellulaire du réticulum endoplasmique, est indispensable pour la signalisation calcique et la préférence oro-sensorielle du gras. Nous observons que l'acide linoléique (LA), en activant les phospholipases A2 via CD36, produit de l'acide arachidonique (AA) et de la lyso-phosphatidylcholine (lyso-PC). Cette activation déclenche un influx calcique dans les cellules CD36-positives, et induit la production du facteur CIF (Ca2+ Influx Factor). CIF, AA et lyso-PC exercent différentes actions sur l'ouverture des canaux SOC (Stored Operated Calcium Channel) constitués de protéines Orai et contrôlés par STIM1. Par ailleurs, les souris au phénotype Stim1-/- perdent la préférence spontanée pour les lipides et la libération de la sérotonine à partir des cellules gustatives dans le milieu extracellulaire chez les animaux sauvages. Nous demontrons aussi que la signalisation calcique médiée via CD36 est doublement modulée lors de l'obésité. L'augmentation de la [Ca2+]i dans les cellules gustatives observée chez le Psammomys obesus, un modèle d'obésité nutritionelle, est fortement diminuée chez les souris rendues obèses par un regime hyperlipidique. Nous avons constaté également que l'interaction de LA avec le CD36 induit l'activation des MAP Kinases de la voie MEK1/2/ERK1/2/Elk-1 qui est non seulement à l'origine de l'activation des aires cérébrales telles que le NTS, le noyau arqué, l'hippocampe mais aussi indispensable pour la préférence spontanée pour les lipides alimentaires. Nos résultats suggèrent pour la prémière fois, que la voie ERK1/2 des MAPK et la signalisation calcique lipidique controlée par STIM1 sont impliquées dans la perception oro-gustative des lipides

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31

Terrie, Élodie. "Rôle de la signalisation calcique dépendante des Store-Operated Channels (SOC) dans les cellules souches neurales adultes et les cellules souches cancéreuses de glioblastomes". Thesis, Poitiers, 2019. http://www.theses.fr/2019POIT2322.

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Des cellules souches neurales (CSN) persistent dans le cerveau adulte et produisent des neurones et des cellules gliales tout au long de la vie de l’individu. Les CSN suscitent un intérêt considérable pour la médecine régénératrice mais leur utilisation thérapeutique potentielle nécessite au préalable d’approfondir les connaissances sur leurs mécanismes de régulation. Les glioblastomes, quant à eux, sont les tumeurs cérébrales les plus fréquentes chez l’adulte et les plus mortelles. Au sein de ces tumeurs, les cellules souches de glioblastomes (CSG) seraient issues de la transformation maligne des CSN et seraient responsable de l’initiation, de la propagation et de la résistance aux traitements des tumeurs. Des analyses transcriptomiques ont suggéré un rôle majeur de la signalisation calcique au sein des CSN et des CSG. Représentant une des voies principales d’entrée du calcium dans la cellule, les canaux calciques SOC (Store-Operated Channels) régulent de nombreux processus cellulaires, y compris la progression tumorale. L’objectif des travaux de cette thèse est d’évaluer le rôle des SOC dans les CSN et les CSG.Nous avons établi par des approches in vitro et in vivo, que les CSN de souris adulte expriment des SOC fonctionnels et que leur inhibition pharmacologique diminue la prolifération et l’autorenouvellement des CSN, propriété indispensable au maintien de la population souche. La deuxième partie de nos travaux montre que les CSG issues de cultures primaires de patients expriment des SOC dont l’inhibition altère la prolifération et l’autorenouvellement de ces cellules.Ainsi, les résultats obtenus lors de cette thèse mettent en évidence un rôle essentiel des SOC dans la régulation de l’autorenouvellement des CSN et des CSG. Les CSG étant responsables de la résistance aux traitements dans le glioblastome, ces travaux ouvrent des perspectives thérapeutiques ciblant les canaux calciques pour contrer cette pathologie au pronostic sombre
Neural stem cells (NSC) persist in the brain of adult mammals and fuel the brain with new neurons and glial cells all lifelong. Recruited by brain injuries, NSC are considered with great interest by regenerative medicine. However, the development of new therapeutic approaches based on the use of NSC requires an in-depth knowledge of the mechanism regulating these cells. Glioblastomas are the most frequent and deadliest form of adult brain tumors. Within the tumor, glioblastoma stem cells (GSC) form a subpopulation of cells that is considered as responsible of tumor initiation, propagation and relapse, as these cells are particularly resistant to anti-tumoral treatments. GSC and NSC share key characteristics and numerous studies suggest that GSC arise from transformed NSC. Transcriptomic analysis of NSC and of GSC revealed an enrichment of calcium signaling transcripts in these two cell populations. Representing a major way of calcium influx into cells, Store-Operated Channels (SOC) are mobilized in response to a wide range of extracellular factors. SOC regulate many cellular processes and are often hijacked in cancer to promote tumor progression.The aim of this thesis is to evaluate potential SOC involvement in NSC and GSC regulation.The first part of this work, relying on in vitro and in vivo studies, demonstrates that NSC from adult mice express functional SOC whose inhibition by pharmacological agents reduces NSC proliferation and self-renewal. In the second part of this thesis, we demonstrate that GSC from primary cultures derived from patients express SOC, as do NSC, and that SOC inhibition reduces GSC ability to proliferate and self-renew.Accordingly, the results of this thesis demonstrate that SOC regulate NSC and GSC self-renewal, a property that is essential to maintain stem cells pool. As GSC are responsible for glioblastomas treatment resistance, our studies point to a potential new therapeutic way, via calcium channels, against this deadly pathology

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32

Jesenský, Marcel. "Between Realpolitik and Idealism: The Slovak-Polish Border, 1918-1947". Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22796.

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My doctoral dissertation examines the delimitation of the Slovak - Polish border in the interwar period and the impact of the cession of the parts of the Slovak districts in Orava and Spiš to Poland on the relations between Czecho-Slovakia and Poland, Czechoslovakia and Poland, and Slovakia and Poland. The Tešín question dominated the border delimitation and the relations and the Orava and Spiš questions and the delimitation of the Slovak - Polish border received much less scholarly attention. While acknowledging the complexity of the issue under consideration, this work attempts to make small contribution towards filling existing gap in historiography. The majority of research work occurred at the diplomatic archives in Prague, Paris and Warsaw (Archives of the Foreign Ministry, Archives diplomatiques and Archiwum Akt Nowych). Some primary research also took place in Bratislava, Warsaw, Washington and Ottawa. This work seeks to interpret primary sources in an innovative way which demonstrates influence exerted by the Orava and Spiš questions on the relations between Czecho-Slovakia and Poland, Czechoslovakia and Poland, Slovakia and Poland, Slovaks and Poles, Slovaks and Czechs, and Czechs and Poles. Effectiveness of the Orava and Spiš questions to carve out their own constituencies and to communicate the message of their populations were limited or enhanced by contemporary configuration of international and internal factors. The Orava and Spiš border delimitations in the Slovak-Polish border and their consequences for the Slovak-Czech-Polish relations, remain largely neglected by the scholars in the English and French historiographies. The Orava and Spiš border delimitations play an important role in understanding of Slovak-Polish-Czech relations and international relations in the interwar and post World War II periods. The questions posed by examining the Orava and Spiš border delimitations are as relevant in Schengen Europe as they were almost a century ago.

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Camponeschi, Francesca, Sabine Annemarie Elisabeth Heider, Simone Ciofi-Baffoni y Lucia Banci. "Characterization of pathways for the Fe-S protein biogenesis in the human cytoplasm". Doctoral thesis, 2020. http://hdl.handle.net/2158/1217050.

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Human cytosolic monothiolglutaredoxin-3 (GLRX3) is a protein essential for the maturation of cytosolic [4Fe−4S] proteins. We show here that dimeric cluster-bridged GLRX3 transfers its [2Fe−2S]2+ clusters to the human P-loop NTPase NUBP1, an essential early component of the cytosolic iron−sulfur assembly (CIA) machinery. Specifically, we observed that [2Fe−2S]2+ clusters are transferred from GLRX3 to monomeric apo NUBP1 and reductively coupled to form [4Fe−4S]2+ clusters on both N-terminal CX13CX2CX5C and C-terminal CPXC motifs of NUBP1 in the presence of glutathione that acts as a reductant. In this process, cluster binding to the C-terminal motif of NUBP1 promotes protein dimerization, while cluster binding to the N-terminal motif does not affect the quaternary structure of NUBP1. The cluster transfer/assembly process is not complete on both N- and C-terminal motifs and indeed requires a reductant stronger than GSH to increase its efficiency. We also showed that the [4Fe−4S]2+ cluster formed at the N-terminal motif of NUBP1 is tightly bound, while the [4Fe−4S]2+ cluster bound at the C-terminal motif is labile. Our findings provide the first evidence for GLRX3 acting as a [2Fe−2S] cluster chaperone in the early stage of the CIA machinery. Iron-sulfur (Fe-S) clusters are among the most versatile cofactors in biology. Although Fe-S clusters formation can be achieved spontaneously in vitro with inorganic iron and sulfur sources, the in vivo behaviour is more complex and requires the so-called Fe-S biogenesis machineries. In the cytosol, the biogenesis of Fe-S proteins is assisted by the cytosolic Fe-S protein assembly machinery, which comprises at least thirteen known proteins, among which there are human ORAOV1 and YAE1. A hetero-complex formed by the two latter proteins facilitates Fe-S cluster insertion in the human ABC protein ABCE1 within a chain of binding events that are still not well understood. In the present work, ORAOV1 and the YAE1-ORAOV1 complex were produced and their structural and cluster binding properties spectroscopically investigated. It resulted that both ORAOV1 and the YAE1-ORAOV1 complex are characterized by well-structured alpha-helical regions and by unstructured, flexible regions, and are both able to bind a [4Fe-4S]2+ cluster. Bioinformatics and site-directed mutagenesis studies indicated that ORAOV1, and not YAE1, is the protein involved in [4Fe-4S]2+ cluster binding in the hetero-complex. ORAOV1 has indeed a conserved cluster-binding motif able to coordinate a [4Fe-4S] cluster. Overall, our data suggested that the YAE1-ORAOV1 complex might actively participate in the Fe-S cluster insertion into ABCE1 thanks to the [4Fe-4S]2+ cluster binding properties of ORAOV1.

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34

Röther, Jens. "Die Rolle von Orai1 in der Entwicklung und Aktivierung von T- und B- Lymphozyten und die Bedeutung von Mutationen in Orai1 für die Pathogenese schwerer kombinierter Immundefekte". Doctoral thesis, 2010. https://ul.qucosa.de/id/qucosa%3A11227.

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Ein durch „Ca2+ Release Activated Ca2+ (CRAC)“-Kanal vermittelter Ca2+-Einstrom ist unverzichtbar für die vollständige Aktivierung von T-Zellen und eine produktive Immunantwort. Im Jahr 2006 führte die Entdeckung des transmembranen Proteins Orai1, einer porenbildenden Untereinheit des CRAC-Kanals, zu einem besseren Verständnis dieses Signalweges. Eine Mutation in Orai1 hat durch die Aufhebung der CRAC-Kanal Funktion eine schwere kombinierte Immundefizienz (SCID) zur Folge (Feske, S. et al. 2006). Die im Rahmen dieser Arbeit präsentierten Experimente hatten die nähere Erforschung der Rolle von Orai1 in Bezug auf die Aktivierung und Entwicklung von Lymphozyten sowie auf die pathogenetische Bedeutung für humane Immundefektsyndrome zum Ziel. So konnte hier durch das Sequenzieren genomischer DNA mehrerer SCID-Patienten eine neue Mutation in Orai1 aufgedeckt werden. Mithilfe intrazellulärer Durchflusszytometrie und Real-Time-PCR gelang es, die Expression von Orai1 auf humanen und murinen Immunzellen, einschließlich T- und B-Lymphozyten, nachzuweisen. Darüber hinaus wurden Orai1 „knock-in“ Mäuse analysiert, welche transgen für eine bei zwei SCID-Patienten gefundene Mutation (R91W) (Feske, S. et al. 2006) sind. Dadurch war es möglich die Funktion von Orai1 und die des CRAC-Kanal vermittelten Ca2+-Einstroms für die Entwicklung und Aktivierung von Lymphozyten zu analysieren. Diese transgenen Mäuse stellen das zu diesem Zeitpunkt erste Tiermodell dar, mit dessen Hilfe die Rolle von CRAC-Kanälen in vivo studiert werden kann.

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KŘÍŽOVÁ, Adéla. "Electrophysiology Studies Providing Insights into the STIM1/ORAI1 Machinery". Master's thesis, 2017. http://www.nusl.cz/ntk/nusl-263344.

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"Role of ORAI1 in modulating hypertrophy of human embryonic stem cell-derived cardiomyocytes". 2015. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291954.

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Wang, Yan.
Thesis Ph.D. Chinese University of Hong Kong 2015.
Includes bibliographical references (leaves 144-160).
Abstracts also in Chinese.
Title from PDF title page (viewed on 07, December, 2016).

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37

"Minority groups and NGOs in Northwestern Bangladesh: an anthropological study of the Santal and the Oraon". 2004. http://library.cuhk.edu.hk/record=b5892081.

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Islam Md. Saiful.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2004.
Includes bibliographical references (leaves 175-181).
Abstracts in English and Chinese.
Abstract
Abstract in Chinese --- p.ii
Acknowledgements --- p.iii
Note --- p.iv
List of Figures --- p.ix
List of Plates --- p.x
Chapter Chapter One --- Introduction --- p.1
Statement of the Problem
Literature Review
Chapter - --- "Minority Groups, NGOs and Development Issues"
Chapter - --- Education Among Minority Groups
Chapter - --- Minority Groups as Discriminated and Stigmatized
Chapter - --- Fighting Against Discrimination: The Art of Resistance
Methodology
Chapter - --- Selecting the NGOs
Chapter - --- Finding the Field Site
Chapter - --- Settling
Chapter - --- From Padri through Sir to Dada: Rapport Buildup
Chapter - --- How I Collected Data
Chapter - --- Pains and Pleasures of Fieldwork
Chapter - --- Limitations of the Study
Structure of the Thesis
Chapter Chapter Two --- "Barind Tract of Northwest Bangladesh: The Villages Studied, Ecology and Cultural Mosaic" --- p.37
The Study Villages: A Brief Profile
Chapter - --- Ruposhi: A Santal Village
Chapter - --- Fulpur: An Oraon Village
Northwest Bangladesh: Ecology and Implications
People of Barind Tract: The Cultural Mosaic
The Santal and the Oraon: From Historical Context to the Present Situation
Chapter Chapter Three --- "NGOs in Bangladesh: Growth, Rhetoric and Realities" --- p.56
The Growth of NGOs in Bangladesh: A Brief Overview
Chapter - --- NGOs and Their Achievements
Chapter - --- The Rhetoric Behind the Reality: Challenges and problems of the NGOs
Prochesta: A Minority-run NGO
Chapter - --- "Goals, Objectives and Programmes of Prochesta"
Chapter - --- Organizational Structure of Prochesta
Unnoyan: A Bengali-run NGO
Chapter - --- "Vision, Mission and Programmes of Unnoyan"
Chapter - --- Unnoyan: Organizational Structure
Chapter Chapter Four --- "Minority Groups, Economic Livelihood and NGOs" --- p.79
Agrarian Economy with Single Crop Cultivation
Land Ownership and Patterns of Tenancy
Agriculture and Food Sufficiency: A General Calculation
Supplementing Household Income
Economic Support: The Santal and Prochesta
The Oraon and Unnoyan in Promoting Economic Livelihood
"Minority Groups, Economic Livelihood and the Role of NGOs"
Chapter Chapter Five --- "Education Among Minority Groups: The Santal, The Oraon and The NGOs" --- p.114
The General Situation of Education Among Minority People in the Study Villages
Dropout From the School: Minority Point of View
Medium of Instruction for Minority Students: The Dilemmas of Monolingualism
The Santal and Prochesta in Promoting Education
"The Oraon, Unnoyan and Education"
Chapter - --- Primary Education for the Oraon Children
Chapter - --- Lahanti: The Adult Education Programme
Chapter - --- Preparing Curriculum in Oraon Language: The Action Research Project
"Minority Groups, Education and the NGOs"
Chapter Chapter Six --- Minority Groups and Fighting Against Discrimination: The Art of Resistance and the Involvement of NGOs --- p.144
Everyday Discrimination Encountered by Minority People: Nature and Pervasiveness
Fighting Against Discrimination and the Involvement of NGOs
Chapter - --- The Santal and Prochesta in Fighting Against Discrimination
Chapter - --- The Oraon and Unnoyan in Fighting Against Discrimination
Minority Groups and the Role NGOs in Fighting Against Discrimination
Chapter Chapter Seven --- Conclusion --- p.164
Bibliography --- p.175

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38

Jans, R., L. Mottram, D. L. Johnson, A. M. Brown, Stephen K. Sikkink, K. Ross y N. J. Reynolds. "Lysophosphatidic Acid Promotes Cell Migration through STIM1- and Orai1-Mediated Ca2+i Mobilization and NFAT2 Activation". 2013. http://hdl.handle.net/10454/7256.

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no
Lysophosphatidic acid (LPA) enhances cell migration and promotes wound healing in vivo, but the intracellular signaling pathways regulating these processes remain incompletely understood. Here we investigated the involvement of agonist-induced Ca2+ entry and STIM1 and Orai1 proteins in regulating nuclear factor of activated T cell (NFAT) signaling and LPA-induced keratinocyte cell motility. As monitored by Fluo-4 imaging, stimulation with 10 μM LPA in 60 μM Ca2+o evoked Ca2+i transients owing to store release, whereas addition of LPA in physiological 1.2 mM Ca2+o triggered store release coupled to extracellular Ca2+ entry. Store-operated Ca2+ entry (SOCE) was blocked by the SOCE inhibitor diethylstilbestrol (DES), STIM1 silencing using RNA interference (RNAi), and expression of dominant/negative Orai1R91W. LPA induced significant NFAT activation as monitored by nuclear translocation of green fluorescent protein-tagged NFAT2 and a luciferase reporter assay, which was impaired by DES, expression of Orai1R91W, and inhibition of calcineurin using cyclosporin A (CsA). By using chemotactic migration assays, LPA-induced cell motility was significantly impaired by STIM1, CsA, and NFAT2 knockdown using RNAi. These data indicate that in conditions relevant to epidermal wound healing, LPA induces SOCE and NFAT activation through Orai1 channels and promotes cell migration through a calcineurin/NFAT2-dependent pathway.

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39

Islam, Md Rafiul. "Culture, economy and identity: a study of the Oraon ethnic community in the Barind region of Bangladesh". Thesis, 2014. https://researchonline.jcu.edu.au/41601/1/41601-islam-2014-thesis.pdf.

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Culture, Economy and Identity: A Study of the Oraon Ethnic Community in the Barind Region of Bangladesh concerns identity politics among Oraons in Bangladesh. The Oraons are an ethnic community who live in the North-West region of Bangladesh. Bangladesh is a multi-cultural, multi-religious and multi-lingual country. While Bengalis are the majority, the country has a large number of marginalised ethnic communities with distinct languages, religions, cultures and identities. These peoples are not well addressed in the development process of the country and face many socio-cultural changes in their lives. This thesis examines the present economic condition of the Oraons and how this affects their socio-cultural life and their identity. Although past literature has portrayed the marginalisation and socio-economic alienation of the ethnic communities in Bangladesh, it has not provided insights into the specific problem of the connection between economic conditions and identity politics. The comparative literature on other societies also falls short in depicting the relationship between economy and identity in relation to ethnic groups that are socio-economically marginalised. Thus, my study focuses on Oraon identity in Bangladesh to see how it is structured by their present economic condition. Through ethnographic fieldwork in Bangladesh, this research explores the factors that have led to the present economic condition of the Oraons. The literature on the Oraon community shows that they had a prosperous life in their settlement in parts of India before British colonisation in 1765. They were self-sufficient in livelihood as agriculturalists and forest food gatherers. However, their livelihood activities were interrupted by the Hindu, Muslim and British administrators in India. The Oraons were taken away from Chotonagpur in India and were settled in Bangladesh by the British India Government (1765-1947). Over time, socio-political factors, including the partition of Bengal in 1947, the abolition of the zamindary (land tenancy) act in 1951, economic differentiation and the rise of Bengali Muslim peasants during 1950s, communal uprising/war between India and Pakistan in 1965 and the independence of Bangladesh in 1971, have caused economic deterioration among the Oraons. According to oral histories and other empirical data gathered during field research in Barind, the Oraons faced economic crisis and led a hard life. This research study reveals that the Oraons have lost land to local influential Bengali Muslim peasants and money-lenders. At present, almost all of the Oraons are landless agricultural day labourers and less than self-sufficient in terms of livelihood. Oraon economic practices include inter-household reciprocity of resources or sharing with kin outside the family performing festivals and ceremonies in the community. Thus, although the Oraons are landless agricultural day labourers, Oraon socio-cultural practices contribute to understanding of their domestic moral economy. In addition to their domestic economic practice, the Oraons sell their physical labour to rich Bengali Muslim peasants and are dependent on the wider Bengali society for subsistence, but are exploited. Although the Oraons face economic exploitation, they maintain strategic relations of indebtedness with rich Bengali Muslim peasants for survival. Some Oraons turn to religious conversion and assistance to survive against local Bengali Muslim peasants' domination and socio-economic exploitation. I explore the processes that have promoted internal Oraon diversity through conversion in Barind. The Oraons are divided into groups embracing Christianity, Hinduism, Buddhism or Islam because of their economic crises over time. My thesis, thus, identifies the processes of Oraonisation that help define the Oraons as Oraon.Although the Oraons face changes in economic activity and are divided into groups based on world religious views, they nevertheless assert their identity as Oraon, with particular socio-cultural features. In addition, the socio-economic relationships of the Oraons with the local Bengali Muslim peasants have contributed to processes of Oraonisation. Oraon socio-economic exploitation contributes to the constitution of their identity as Oraon, an ethnic minority group in Bangladesh. My study, thus, focuses on the processes of marginalisation of Oraons in Bangladesh and their resistance to such marginalisation. Although the Government of Bangladesh does not recognise their distinct identity as adibashis (indigenous peoples) and has banned celebration of the international day of the world's indigenous peoples, the Oraons are deeply engaged socio-politically concerning their rights and recognition in the country. The Oraons maintain strategic networks with adibashi groups from both Bangladesh and abroad for their identity as adibashis or indigenous peoples to escape from local Bengali domination and state oppression. The Oraons' demands for socio-economic change and equal participation in mainstream Bangladeshi society and culture, described in this study, are partly framed in terms of indigeneity. The Oraons, thus, respond to the discourse of global indigeneity, although they live in remote parts of the Barind region in Bangladesh. In exploring the changing problems of Oraons, this thesis contributes strategically as well as theoretically to the literature on ethnicity. This research demonstrates a relationship between economy and identity in the case of the Oraons. Significantly, this study explores peoples' choices and interests in shaping their livelihood and survival strategies. I hope that, in exploring the problems of indigeneity in Bangladesh, my study also demonstrates the importance of devising policies for the adibashis. I also highlight the need to develop policies for those who live in the plains regions, such as Barind, because most development programmes in Bangladesh focus only on the ethnic groups of the Chittagong Hill Tracts (CHTs).

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40

Fu, Ou-Yang y 歐陽賦. "Breast cancer-associated high-order SNP-SNP interaction of ORAI1 and CXCL12/CXCR4 related genes by bioinformatics analyses". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/j5c3x9.

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博士
高雄醫學大學
醫學研究所博士班
104
Although many disease/cancer-associated SNPs have been reported, the impact of more rare or non-significant SNPs is underestimated and this may partly contribute to “missing heritability”. Lack of a detailed inspection of gene-gene (SNP-SNP) interactions is one of the common reason of “missing heritability” effects. In my thesis, I use the bioinformatics analyses to investigate the possible SNP-SNP interaction for ORAI1 gene and CXCL12/CXCR4 related genes in breast cancer association studies. There are two parts in my thesis: Part I focuses on the SNP interaction within ORAI1 gene using particle swarm optimization (PSO) algorithm and Part II focuses on SNP-SNP interaction of CXCL12/CXCR4 related genes by an improved multifactor dimensionality reduction (MDR-ER). In Part I, the ORAI calcium release-activated calcium modulator 1 (ORAI1) has been proven to be an important gene for breast cancer progression and metastasis. However, the protective association model between the single nucleotide polymorphisms (SNPs) of ORAI1 gene was not investigated. Based on a published data set of 345 female breast cancer patients and 290 female controls, we used a PSO algorithm to identify the possible protective models of breast cancer association in terms of the SNPs of ORAI1 gene. Results showed that several PSO-generated models 2-7 SNPs interactions displayed low values of odds ratios (0.409–0.425) for breast cancer association. These results suggested that our proposed PSO strategy is powerful to identify the combinational SNPs of rs12320939, rs12313273, rs7135617, rs6486795, and rs712853 of ORAI1 gene with a strongly protective association in breast cancer. The joint effect of SNP-SNP interactions and the problem of imbalanced data between cases and controls are frequently ignored in association studies. In part II, we used an improved multifactor dimensionality reduction (MDR) approach namely MDR-ER to detect the high order SNP-SNP interaction in an imbalanced breast cancer data set containing seven SNPs of chemokine CXCL12/CXCR4 pathway genes. Most individual SNPs were not significantly associated with breast cancer. After MDR-ER analysis, six significant SNP-SNP interaction models with seven genes (highest cross-validation consistency = 10, classification error rates = 41.3–21.0, and prediction error rates = 47.4–55.3) were identified. CD4 and VEGFA genes were associated in a 2-loci interaction model (classification error rate = 41.3, prediction error rate = 47.5, odds ratio (OR) = 2.069, 95% bootstrap CI = 1.40–2.90; P = 1.71E-04) and it also appeared in all best 2–7-loci models. When the loci number increased, the classification error rates and P values decreased. The powers in 2–7-loci in all models were higher than 0.9. The minimum classification error rate of the MDR-ER-generated model was shown with the 7-loci interaction model (classification error rate = 21.0, OR = 15.282; 95% bootstrap CI = 9.54–23.87; P = 4.03E-31). In epistasis network analysis, the overall effect with breast cancer susceptibility was identified and the SNP order of impact on breast cancer was identified as follows: CD4 = VEGFA > KITLG > CXCL12 > CCR7 = MMP2 > CXCR4. In conclusion, the MDR-ER can effectively and correctly identify the best SNP-SNP interaction models in an imbalanced data set for breast cancer. Taken together, the breast cancer-associated high-order SNP-SNP interaction of ORAI1 and CXCL12/CXCR4 related genes are improved by using bioinformatics analyses. These SNP-SNP interaction algorithms may be potential to other association studies to predict the disease/cancer risk.

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41

Deng, Yi-Han y 鄧伊涵. "EGFR and ORAI1 genetic polymorphisms associ-ate with serum TNF-alpha and blood lead levels among lead workers and controls". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/41350711049616584727.

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碩士
高雄醫學大學
公共衛生學研究所
101
Background and Purpose: Lead are one of the most toxic heavy mentals.The mental lead is widely used in our life and in the industry.Popele may expose to lead not only in the job but also in the life.Exposed to lead is harmful various organs in human.Several lines of evidence have indicated that Pb is able to stimulate the expression of tumor of necrosis factor-alpha(TNF-α).Previous reports indicate that Pb2+ can entry into cells by activating mediators of inflammation vis the plasma membrane EGFR,and by store-operated Ca2+ channel(SOC).Thus,we investigate the association among EGFR/ORAI1(the key subunit of store-operated Ca2+ channel) gene polymorphisms,blood lead levels,and serum TNF-alpha. Materials and Methods: The present study included 426 lead-exposed subjects and controls in Taiwanese population.The questionnaire and blood sample collected information about demographic characteristics,biochemical data,blood lead levels,and serum TNF-α levels.DNA was also extracted for Genotyping. Genotyping was performed using TaqMan® SNP Genotyping Assays.The EGFR 3 SNPs (rs763317,rs2280653,rs2072454) and ORAI1 5 SNPs (rs712853,rs6486795,rs12313273,rs12320939,rs7135617) were genotyped in all subjects. Results: First,we divided blood lead levels into four groups (0≦BPb≦5, 5< BPb≦10, 10< BPb≦30 ,and BPb>30).After analysing,we found that serum TNF-α levels increased with blood lead levels.And then,using multiple regression analysis.After adjusting potential confounder,the association with blood lead levels and serum TNF-α levels was found.When blood lead levels increased 1μg/dL,serum TNF-α levels increased 0.34~0.38pg/mL.Two of ORAI1 SNPs(rs712853 and rs12313273)effected the lead-induced TNF-α expression. After adjusting blood lead levels and other confounder,the CT genotype of rs712853 polymorphism had significantly decreased the level of TNF-α 3.20(SE=1.39)pg/mL compared with the TT genotype. The CC genotype of rs712853 polymorphism had decreased the level of TNF-α 3.32(SE=2.15)pg/mL compared with the TT genotype.The CT genotype of rs12313273 had significantly increased the level of TNF-α 2.77(SE=1.36)pg/mL compared with the TT genotype. The CC genotype of rs12313273 polymorphism had increased the level of TNF-α 1.07(SE=2.18)pg/mL compared with the TT genotype.But all three EGFR SNPs were not. Conclusions: We showed that two of ORAI1 SNPs were associated with blood lead levels and serum TNF-α levels in Taiwanese population.

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42

Pham, Elizabeth. "Development of Protein-based Tools to Image and Modulate Ca2+ Signaling". Thesis, 2011. http://hdl.handle.net/1807/31898.

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Optogenetics has emerged as a branch of biotechnology that combines genetic engineering with optics to observe intracellular changes as well as control cellular function. Despite recent progress, there still remains the need for an optogenetic tool that can specifically control Ca2+. Such a tool would greatly facilitate the study of highly Ca2+-dependent cellular processes that are regulated both spatially and temporally. Ca2+ signaling regulates many cellular processes in both healthy and diseased cells. The ability to modulate the shape, duration, and amplitude of Ca2+ signaling is important for elucidating mechanisms by which endogenous Ca2+ concentrations are maintained. In this thesis, we used optogenetic approaches to explore a number of strategies to control Ca2+ influx through store-operated Ca2+ entry (SOCE) mediated by Stim1 and Orai1. To better study Ca2+ signaling in live cells, protein-based biosensors can be developed to monitor intracellular Ca2+ changes. To aid in this, we developed a computational modeling tool called FPMOD to improve both new and existing biosensor designs. Although FPMOD was initially intended for evaluating biosensor designs, other research groups have since used it to construct models of other proteins to answer questions related to protein conformation. We next studied the modulation of SOCE by using drug-inducible fusion proteins to study the regulation of Stim1 puncta formation. Interestingly, recruiting a Ca2+-buffering protein to Stim1 led to puncta formation, a previously unknown means of inducing puncta. These results suggest Stim1 may additionally be regulated by cytoplasmic Ca2+ levels. Finally, we developed LOVS1K, an optogenetic tool to directly activate Orai1 channels and specifically control Ca2+ influx. Photo-sensitive LOVS1K was used to generate both local Ca2+ influx at the membrane and global cytoplasmic Ca2+ signals. As proof of concept, LOVS1K was further used to modulate engineered Ca2+-dependent proteins. Ca2+ is a remarkably versatile intracellular messenger. The combination of high spatiotemporal control of irradiation and the ability of LOVS1K to generate both local and global Ca2+ changes provides a promising platform to study cellular processes that are highly dependent on different Ca2+ signals. Together, biosensors and engineered Ca2+-modulating tools can be used to study the many different aspects of Ca2+ signaling and controllably manipulate endogenous Ca2+ signaling pathways.

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43

Singh, Suman K., Richard Baker, Stephen K. Sikkink, C. Nizard, S. Schnebert, R. Kurfurst y Desmond J. Tobin. "E-Cadherin mediates UVR- and calcium-induced melanin transfer in human skin cells". 2017. http://hdl.handle.net/10454/12481.

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yes
Skin pigmentation is directed by epidermal-melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously we reported that MC:KC contact is required for melanosome transfer, that this can be enhanced by filopodial and by UVR/UVA irradiation, which can up-regulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca2+-dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca2+, while ultraviolet radiation (UVR) raises intra-MC Ca2+ via calcium selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear, and here we evaluated the role of E-Cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-Cadherin, Cdc42, VASP and β-catenin, all of which were upregulated by UVR/UVA in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased β-catenin, Cdc42, Myosin X, and E-Cadherin expression in these skin cells. Together these data suggest that filopodial proteins and E-Cadherin, which are upregulated by intracellular (UVR-stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation.

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44

Šejvl, Jaroslav. "Vznik a vývoj prvních zařízení s léčebnými programy pro pacienty závislé na alkoholu v Českých zemích, na Moravě a Slezsku: analýza historického a institucionální rámce a kontextu vzniku, vývoje a zániku těchto programů do roku 1945". Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-415779.

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Background: The tradition of specialised institutional alcohol treatment in what is now the Czech Republic dates back over a hundred years. The first modern institution aimed at treating alcohol dependency began to operate on 7 September 1948. While formally constituting an organisational unit of the Psychiatric Clinic, the "U Apolináře" facility, headed by Dr. Jaroslav Skála, was an independent workplace which gave rise to a distinct treatment approach. Becoming known as the "Apolinar" treatment model, this approach was adopted by all the residential alcohol treatment facilities which came into existence or operated in Czechoslovakia from 1948 to 1989. Before the establishment of this department, three similar treatment facilities existed on the historical territory of Czechoslovakia - Velké Kunčice (1911 to 1915), Tuchlov (1923 to 1938), and Istebné nad Oravou (1937 to 1939/1949). Aim: The aim of the dissertation thesis was to describe the analysis of the conditions which had an influence on the origin, development, operation, and dissolution of the three oldest specialised alcohol treatment institutions on the historical territory of what is now the Czech Republic and Slovakia from 1900 to 1945. Methods: The research involved qualitative content analysis of historical materials, mainly written...

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45

Šejvl, Jaroslav. "Vznik a vývoj prvních zařízení s léčebnými programy pro pacienty závislé na alkoholu v Českých zemích, na Moravě a Slezsku: analýza historického a institucionálního rámce a kontextu vzniku, vývoje a zániku těchto programů do roku 1945". Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-446019.

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Background: The tradition of specialised institutional alcohol treatment in what is now the Czech Republic dates back over a hundred years. The first modern institution aimed at treating alcohol dependency began to operate on 7 September 1948. While formally constituting an organisational unit of the Psychiatric Clinic, the "U Apolináře" facility, headed by Dr. Jaroslav Skála, was an independent workplace which gave rise to a distinct treatment approach. Becoming known as the "Apolinar" treatment model, this approach was adopted by all the residential alcohol treatment facilities which came into existence or operated in Czechoslovakia from 1948 to 1989. Before the establishment of this department, three similar treatment facilities existed on the historical territory of Czechoslovakia - Velké Kunčice (1911 to 1915), Tuchlov (1923 to 1938), and Istebné nad Oravou (1937 to 1939/1949). Aim: The aim of the dissertation thesis was to describe the analysis of the conditions which had an influence on the origin, development, operation, and dissolution of the three oldest specialised alcohol treatment institutions on the historical territory of what is now the Czech Republic and Slovakia from 1900 to 1945. Methods: The research involved qualitative content analysis of historical materials, mainly written...

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46

Movsisyan, Naira. "The implication of Kv10.1 in the regulation of G2/M progression". Doctoral thesis, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0005-139E-4.

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47

Łoziński, Maciej. "Zastosowanie badań anizotropii podatności magnetycznej w rekonstrukcji środowisk sedymentacji i ewolucji strukturalnej basenu orawskiego (neogen, Karpaty Zachodnie)". Doctoral thesis, 2017. https://depotuw.ceon.pl/handle/item/2311.

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Basen orawski stanowi nieckę śródgórską znajdującą się na granicy Karpat Wewnętrznych i Zewnętrznych. Powstała ona w miocenie środkowym jako neoalpejski element strukturalny uformowany po zasadniczym etapie tworzenia się struktur fałdowo-nasunięciowych pasa Karpat Zewnętrznych. Wypełnienie klastyczne basenu stanowi kluczowy materiał badawczy z punktu widzenia odtworzenia historii aktywności tektonicznej, wypiętrzania i erozji jego obszarów alimentacji: jednostki magurskiej, pienińskiego pasa skałkowego, paleogenu centralno-karpackiego oraz bloku Tatr. Odczytanie tego zapisu geologicznego, co jest tematem niniejszej pracy, wymaga interpretacji wypełnienia basenu, które stanowią przeważnie utwory drobno- i bardzo drobnoklastyczne. Dotychczasowe badania w basenie orawskim wskazują na lądowe warunki sedymentacji w środowiskach koryt rzecznych, równi zalewowych, bagien oraz w mniejszym stopniu także jezior. Obok klasycznych badań sedymentologicznych oraz strukturalnych w niniejszej pracy zastosowanie znalazła metoda anizotropii podatności magnetycznej (AMS). Stanowi ona uznane narzędzie w badaniach geologicznych, pozwalające na zobrazowanie struktury osadu pod kątem kierunkowości ułożenia minerałów cechujących się anizotropią magnetyczną. Przeprowadzone badania dyfrakcji rentgenowskiej oraz uzyskane pomiary podatności, krzywe nasycania magnetycznego oraz testy Lowrie’ego pokazały, że w basenie orawskim za podatność magnetyczną odpowiadają w większości paramagnetyczne minerały ilaste oraz w mniejszym stopniu ferromagnetyki (siarczki żelaza oraz magnetyt). Pomiary AMS przeprowadzone zostały w osadach różnych środowisk sedymentacji w sposób, który pozwolił scharakteryzować poszczególne wydzielone litofacje. Otrzymane duże zróżnicowanie parametrów anizotropii pozwoliło na wydzielenie 12 facji AMS odnoszących się do charakteru sedymentacji oraz zgeneralizowanego stopnia deformacji. Do ich zdefiniowania posłużono się stopniem (P) oraz kształtem (T) anizotropii oraz ich rozkładem statystycznym w serii prób. Obserwacje sedymentologiczne uzupełnione o facje AMS pozwoliły na opracowanie mapy rozkładu facji w basenie orawskim. Zbliżone kierunki osi elipsoidy podatności w dużej części basenu oraz ich porównanie do kierunków transportu sedymentacyjnego pozwalają przypuszczać, iż kierunki AMS powstały w wyniki deformacji tektonicznych. Opracowana mapa strukturalna basenu zawiera położenia warstw, kierunki osi największej kompresji tektonicznej oraz orientacyjny stopień deformacji utworów. Wyróżniono przy tym pięć stref silnie zdeformowanych tektonicznie, wskazujących m.in. na aktywność tektoniczną pienińskiego pasa skałkowego po miocenie środkowym. Analiza rozkładu facji i deformacji tektonicznych pozwoliła potwierdzić obecność i określić zasięg przestrzenny inwersji południowej części basenu. Jej obecność wraz z charakterem facji w południowej części basenu świadczą o jego dawnym istotnie większym zasięgu na południe. Inwersja ta zachodziła przy kompresji zorientowanej na N-NE, co powiązano z ruchem jednostki ALCAPA ku NNE.
The Orava Basin constitutes an intramontane depression located at the Inner/Outer Carpathian border. It originated as a neoalpine structure which postdates the main stage of Outer Carpathian thrust-and-fold belt forming. The siliciclastic basin infilling is crucial for reconstruction of tectonic activity, uplift and erosion of basin’s source area: Magura Unit, Pieniny Klippen Belt, Central Carpathian Paleogene, and Tatra block. Deciphering of this geological record was the aim of this thesis which required the interpretation of basin infilling consisting of mostly fine and very fine deposits. Previous studies had revealed that sedimentation could have taken place in terrestrial environments: river, floodplain, swamp and lacustrine settings. Besides classic sedimentary and structural investigations the anisotropy of magnetic susceptibility (AMS) method was involved in this study. This method, which has been widely approved to be useful in a range of geological applications, allows for the interpretation of sediment structure in terms of orientation of mineral grains having magnetic anisotropy. The XRD survey, magnetic susceptibility measurements, magnetic saturation curves, and Lowrie tests carried out during this study revealed that magnetic susceptibility is determined mostly by paramagnetic clay minerals and subordinately by ferromagnetic minerals (iron sulphides and magnetite). The AMS measurements were carried out in a lithofacies-oriented manner to reflect magnetic properties of individual defined lithofacies. The obtained considerable variety of anisotropy parameters allowed for defining 12 AMS facies with respect to sedimentary environment and general degree of deformation. The AMS facies definition was based on the anisotropy degree (P) and shape (T) parameters and their statistical distribution within a group of specimens. The sedimentological data supplemented by AMS facies were utilized to create a facies map of the Orava Basin. Similar directions of AMS ellipsoid axes in the large area of the basin and their comparison with sedimentary transport directions allowed for the assumption that the AMS directions originated tectonically. A new structural map containing bedding orientations, directions of strongest compression and general deformation degree of deposits was presented. Five zones of strong deformation were identified and the tectonic activity within Pieniny Klippen Belt after Middle Miocene was suggested. The analysis of distribution of facies and deformations indicated the area of the basin inversion within its southern part. It also suggested that the basin spread significantly more to the south during deposition. The inversion could have occurred in the N-NE trending compression, which could have been related with the NNE-directed ALCAPA unit advance.

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