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Raval, Raju R. "Hypoxia-mediated pathways in cancer." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433331.
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Prado, Sánchez Judith. "Regulation of neuroinflammation by cGMP-mediated pathways." Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/96910.
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En el trabajo aquí presentado se investigó la participación de los niveles intracelulares de GMP-cíclico (CMPC) en la regulación de diferentes aspectos de la neuroinflamación. En el primer capítulo hemos observado que los cultivos de astrocitos y de celulas microgliales aisladas de rata expresan la maquinaria necesaria para sintetizar GMPc en repuesta a Péptidos Natriuréticos (PN) y también los enzimas necesarios para degradar el nucleótido. También se investigaron los efectos de la estimulación por PN en la expresión de la proteína pro-inflamatoria iNOS. Hemos observado que el pretratamiento con ANP hace disminuir los niveles de la proteína iNOS inducida por el agente pro-inflamatorio LPS a través de un mecanismo dependiente de NPR-A-PKG en células microgliales cultivadas de rata. Además hemos observado que esta regulación a la baja parece estar hecha a nivel de traducción, sin afectar a la transcripción o la tasa de degradación de la proteína. Sobre la base de datos obtenidos en nuestro laboratorio en cultivos de células gliales, se ha demostrado que las vías mediadas por GMPc regulan la dinámica del citoesqueleto, la expresión de GFAP en los astrocitos y la motilidad, así como la expresión de genes inflamatorios en la microglía que se demuestra en el primer capítulo, lo que sugiere un papel en la regulación del fenotipo reactivo glial. En el segundo capítulo, hemos querido verificar si el GMPc regula la respuesta inflamatoria glial in vivo después de un daño producido en el SNC causado por una criolesión focal en la corteza cerebral en ratas y ratones. Se investigó el efecto de 3 dosis de tratamiento con dos inhibidores de diferentes fosfodiesterasas de GMPc (PDE), zaprinast y sildenafilo. Hemos observado que el inhibidor no selectivo de PDE-GMPc zaprinast potencia la astrogliosis alrededor de la lesión, mientras que produce una disminución de la activación de macrófagos/microglía, el estrés oxidativo y muerte neuronal en la rata. Se observó también que el tratamiento con el inhibidor selectivo de la PDE5 sildenafilo reproduce en los ratones los cambios en la reactividad glial y los efectos antioxidantes y antiapoptóticos observados anteriormente con el zaprinast en ratas, indicando que la inhibición de la PDE5 es responsable de estas acciones neuroprotectoras. Sin embargo, los efectos de sildenafilo no se observaron en los ratones deficientes en MT-I/II. Asimismo, se muestra que el sildenafilo aumenta significativamente los niveles de las proteínas MT-I/II en homogenados corticales de ratones lesionados así como la inmunotinción de MT-I/II en las células gliales alrededor de la lesión, y disminuye la activación del factor transcriptor de STAT3, apoyando la participación de estas proteínas en los efectos neuroprotectores del sildenafilo en la lesión cerebral focal. Como resultado de los efectos antiinflamatorios y neuroprotectores observados por los inhibidores de la PDE5 en el modelo criolesión, en el tercer capítulo se investigó si el tratamiento con sildenafilo podría tener efectos beneficiosos en un modelo de EAE inducido por MOG35-55, un modelo animal de esclerosis múltiple, una enfermedad en la que existe una respuesta inflamatoria alterada. Se demuestra que el tratamiento con sildenafilo después del inicio de la enfermedad reduce notablemente los síntomas clínicos de la EAE mediante la prevención de la pérdida axonal y la promoción de la remielinización. Por otra parte, el sildenafilo disminuye la infiltración de leucocitos CD3+ así como la activación de microglia/macrófagos en la médula espinal, al tiempo que aumenta la presencia de Foxp3-Tregs. Además, el tratamiento con sildenafilo disminuye la expresión de ICAM-1 en las células infiltradas de la médula espinal. La presencia de astrocitos reactivos que forman estructuras similares a cicatrices alrededor de los infiltrados se potenció por el tratamiento con sildenafilo, sugiriendo un posible mecanismo para restringir la propagación de leucocitos en el parénquima sano. Se demuestra también que el tratamiento con sildenafilo al inicio de los síntomas clínicos, cuando el proceso inflamatorio es más fuerte, impide el avance de la enfermedad y regula la respuesta adaptativa inmune periférica y los niveles de la PDE5. Teniendo en cuenta todos los resultados obtenidos se demuestra que la modulación de los niveles intracelulares de GMPc tiene efectos beneficiosos en los procesos neuroinflamatorios y que estos beneficios están relacionados con la regulación de la gliosis reactiva, el estrés oxidativo, factores antioxidantes, la respuesta inmune adaptativa y la infiltración de células inmunes en el SNC que conducen a una disminuición en el daño neuronal.In the present work we investigated the involvement of intracellular cGMP levels in regulating different aspects of neuroinflammation. In the first chapter we observed that cultured rat astrocytes and microglial cells express the necessary machinery to synthesize cGMP in response NPs and to degrade the nucleotide. We also investigated the effects of NP stimulation in the expression of the pro-inflammatory protein iNOS. We observed that pretreatment with ANP down-regulates iNOS protein levels induced by the pro-inflammatory agent LPS by an NPR-A-PKG dependent mechanism in rat cultured microglial cells. In addition we found that this down-regulation seems to be done at translational level, without affecting transcription or protein degradation rate. Based on evidence obtained in our laboratory in cultured glial cells indicates that cGMP-mediated pathways regulate cytoskeleton dynamics, GFAP expression and motility in astrocytes, as well as inflammatory gene expression in microglia found in the first chapter, suggesting a role in the regulation of the glial reactive phenotype. In the second chapter we wanted to examine if cGMP regulates the glial inflammatory response in vivo following CNS damage caused by a focal cryolesion onto the cortex in rats and mice. We investigated the effect of 3 doses of treatment with two different cGMP-phosphodiesterase (PDE) inhibitors, zaprinast and sildenafil. We observed that the non-selective GMP-PDE inhibitor zaprinast enhances astrogliosis around the lesion while decreasing macrophage/microglial activation, oxidative stress and neuronal death in rat. We observed also that treatment with the selective PDE5 inhibitor sildenafil reproduces in mice the changes in glial reactivity and the antioxidant and antiapoptotic effects previously observed with zaprinast in rats indicating that inhibition of PDE5 is responsible for these neuroprotective actions. However, sildenafil effects were not observed in mice deficient in MT-I/II. We further show that sildenafil significantly increases MT-I/II protein levels in lesioned cortical homogenates and MT-I/II immunostaining in glial cells around the lesion, and decreases activation of the transcriptor factor STAT3, supporting the involvement of these proteins in the neuroprotective effects of sildenafil in focal brain lesion. As a result of the anti- inflammatory and neuroprotective effects observed by PDE5 inhibitors in the cryolesion model, in the third chapter we investigate if treatment with sildenafil could have beneficial effects in a MOG35-55-induced EAE model, an animal model of MS, a disease where an altered inflammatory response occurs. We show that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+-leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing Foxp3-Tregs. In addition, sildenafil treatment decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. We show also that treatment with sildenafil at the onset of clinical symptoms, when the inflammatory process is stronger, prevent disease advance and regulates peripheral adaptative immune response and PDE5 levels. Taking in account all the results obtained we evidenced that modulation of intracellular cGMP levels have beneficial effects in neuroinflammatory processes and that this benefits are related to regulation of reactive gliosis, oxidative stress, antioxidant factors, adaptative immune response and infiltration of immune cells into CNS leading to decrease neuronal damage.
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Vosten, Alexander. "Mathematical modelling of scaffold-mediated signalling pathways." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213225/1/Alexander_Vosten_Thesis.pdf.
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This thesis concerns the role of specialized molecules called scaffold proteins in the processing of signals in cellular protein networks. In particular, comprehensive mathematical models are developed of the mitogen-activated protein kinase cascade (MAPK) – an evolutionarily conserved signalling motif. Due to the complexity of the biological systems being modelled, an original method of algebraic analysis was used to ease computation time. These novel models and analysis provide new evidence that scaffold proteins have significant and unexpected potential to increase the possibility of switch-like responses known as bistability and ultrasensitivity.
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Wong, Tsz-yeung, and 王子揚. "IBDV-mediated antiviral responses by TLR3 signaling pathways." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41897201.
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Charlesworth, Amanda. "Signalling pathways mediated by the bombesin/GRP receptor." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244267.
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Zhu, Liang. "RAP1-TRIGGERED PATHWAYS FOR TALIN-MEDIATED INTEGRIN ACTIVATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1512580363343006.
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Wong, Tsz-yeung. "IBDV-mediated antiviral responses by TLR3 signaling pathways." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41897201.
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Boyer, Robert D. (Robert Damian) 1978. "Stress-mediated reaction pathways for dislocation nucleation in copper." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39550.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007.Includes bibliographical references (p. 111-119).
The ductile behavior of metals requires dislocation nucleation, from either homogeneous or heterogeneous sources, in order to produce the large number of dislocations necessary for extensive plastic deformation. As with the majority of the defect processes that comprise deformation and failure of materials, dislocation nucleation is well described in the framework of transition state theory as a stress-mediated, thermally activated process. We have used reaction pathway sampling methods and well-fit empirical potentials to determine the stress-dependent behavior of and atomistic mechanisms for dislocation nucleation at stresses much lower than typically accessible to atomistic techniques. We have shown that a significant range of stresses exist for which homogeneous dislocation loop nucleation is feasible because the critical nucleate transitions to an in-plane shear perturbation where the shear displacement of most particles is significantly less than the Burger's vector. We have also revealed that the common structural conception of activation volume for dislocation nucleation does not apply for all stresses and in general over-predicts the stress-dependence of activation by considering only the shear displacement of the critical defect.
(cont.) Furthermore, by considering the full reaction pathway for dislocation nucleation in perfect crystals and at a vacancy, we have provided a fully atomistic description of shear localization via an expanded one-dimensional chain analysis of the wave-steepening behavior. Lastly, both breaking the local atomic symmetry and increasing the extent of heterogeneous nucleation sites are shown to lower the activation energy for dislocation nucleation. In general we have applied reaction pathway sampling to the problem of dislocation nucleation in Cu not only for a perfect crystal, but also in the presence of point defects, vacancy clusters and nanowire surfaces. As a result the strength of a variety of nucleation sites in mediating activation as well as specific atomistic mechanisms for dislocation nucleation have been discussed from both structural and energetic perspectives.
by Robert D. Boyer.
Ph.D.
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Sickle, Eugene Stanford. "Cycloaddition-fragmentation mediated pathways to ring D modified 19-norsteroids." Doctoral thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/17967.
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Includes summary.Includes bibliographical references.
An efficient strategy for the synthesis of 14β-3'-oxobutyl 19-norsteroids has been developed and the intramolecular reactivity of the derived compounds has been investigated. The approach is based on cycloaddition of methyl vinyl ketone to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate which proceeded with a high degree of regio- and stereoselectivity to give 16α-acetyl-3-methoxy-14, 17α-ethenoestra-1 ,3,5(1 O)-trien-17β-yl acetate. The cycloadduct underwent base mediated fragmentation, affording an efficient and stereocontrolled synthesis of 3-methoxy-14β-3'-oxobutylestra-1,3,5(10),15-tetraen-17-one which in turn gave 3-methoxy-5',6'-dihydro-15αH-benzo[14,15]-14β-estra-1,3,5(1O)-trien-4'(3'H), 17-dione via an intramolecular Michael reaction. Regioselective deoxygenation of the dione at C-4', followed by standard functional group modifications provided the parent 14β-perhydrobenzo[14,15]-estradiol analogues. An alternative, more expedient, route to this novel steroidal ring system was developed which relied on an anionic oxy-Cope rearrangement as the key step. Thus methylenation of the cycloadducts derived from reaction of the dienyl acetate and selected dienophiles (acrolein and methyl vinyl ketone) gave after hydrolysis of the bridgehead ester, substrates which underwent [3,3]sigmatropic rearrangement to generate a series of 14β-perhydrobenzo[14,15]-17-ketones.
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Perens, Gregory S. "NMDA Receptor-mediated Synaptic Plasticity in Developing Mammalian Visual Pathways." VCU Scholars Compass, 1995. https://scholarscompass.vcu.edu/etd/5246.
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Precise connections in many mammalian nervous systems require a great deal of remodeling during development. In the visual system, many excess synapses are originally formed in the lateral geniculate nucleus and striate cortex. Only the correct set of axon terminals are retained during normal development, while imprecise ones withdraw. The mechanism by which only correct axons are retained requires neural activity, and may be regulated by specific receptors at synapses.
The transmission of neural signals at these synapses is carried out in part by the glutamate-activated NMDA receptor. It is hypothesized that NMDA receptor activation plays a crucial role in enhancing only those connections in the immature system which will form a retinotopically correct map in the LGN and cortex. NMDA receptor activation requires depolarization of the neuron membrane. Possibly, only neurons transmitting information from nearby areas in the retina summate to produce NMDA receptor- mediated currents. The result is an influx of Ca++ ions that has been shown to cause trophic effects within the cell that could enhance the synaptic connection. Thus, NMDA receptors may act to detect coincident neural activity in immature animals, thereby allowing only visuo-topically related axon terminals to undergo enhancement of synaptic transmission and structure. As development proceeds, NMDA receptor function decreases, possibly reducing these intracellular effects.
Blocking NMDA receptor activation experimentally does alter the normal set of connections in the visual system. Yet, is there a direct cause- and-effect relation between NMDA receptor activity and anatomical changes? Many cellular events probably result from NMDA-mediated currents. Intracellular changes in phosphorylation states and protein levels could eventually alter a synapse at the anatomical level. Study of the changing NMDA receptor subunit types making up the receptor within visual system structures could reveal, in part, the means by which plasticity is down-regulated. The experimental regulation of these subunits in vivo could reveal important information concerning their specific function if plasticity and development were to be altered as a result. A summary of previous studies, and proposals for further research concerning the role of the NMDA receptor and its various types in developing visual pathways are presented in this manuscript.
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Venkateswaran, Anjli. "RET/PTC1-mediated phosphotyrosine signaling pathways involved in thyroid cell transformation." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1100117850.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xvi, 157 p.; also includes graphics (some col.) Includes bibliographical references (p. 146-157).
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Sukhai, Mahadeo A. "Cytokine-mediated pathways of mdr1 gene regulation in cultured rat hepatocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58862.pdf.
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Hartley, Strachan. "Prolactin mediated activation of survival pathways in human breast cancer cells." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29440.
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This study investigates the role of prolactin (PRL) as an autocrine/paracrine survival and/or growth factor in the human breast cancer cell line T47D and the signaling pathways that mediate this function. Utilizing an oligonucleotide antisense to human PRL (hPRL) mRNA to inhibit endogenous PRL production in T47D cells, we found that PRL contributes to the viability of the T47D cells. Furthermore, exogenous PRL stimulation mediates the activation of the protein kinase B/Akt (PKB/Akt) in the mammary epithelial cell lines HC11 and MCF-10, as well as T47D cells. PRL stimulation led to the phosphorylation of the pro-apoptotic protein Bad, a member of the Bcl-2 family, as well as the phosphorylation and subsequent cytoplasmic sequestration of FKHRL1, a member of the forkhead family of transcription factors. Utilizing the P13kinase inhibitor LY294002, the Jak2 inhibitor Ag490, and the Src kinase inhibitor PP2, we illustrated that PRL-mediated activation of PKB/Akt was dependent on both P13kinase and Src kinase activity, but independent of Jak2 kinase activity. (Abstract shortened by UMI.)
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Fosu, Stacy C. "Functionalization of Arenes, Amines, Alkenes, and Alkynes Mediated by Radical Pathways." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555514456659022.
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Wallace, Erin K. "Enzyme mediated reductive chemistry in plant flavonoid and monolignol biosynthetic pathways /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3167819.
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Guerra, Jillian. "Pathways to agroecology : mediated markets and credit access in Santa Catarina, Brazil." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58792.
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Agroecology applies ecological principles to the design and management of agricultural systems, while also seeking to improve the social and economic livelihoods of farmers and rural communities. Agroecology is defined both as a social movement and as an applied science, and is often operationalized as the adoption of a set of particular principles and agricultural practices. A call to transition to more sustainable agricultural practices in general, and agroecological practices more specifically, is endorsed by social movements, scholars and prominent international institutions. Identifying and evaluating pathways that facilitate the adoption of agroecological production practices, as part of a broader sustainable agricultural transition is thus necessary, but research specifically evaluating pathways that may facilitate the transition to agroecology is understudied. The problem is approached via two studies conducted in the context of Santa Catarina, Brazil. The first study uses agricultural census data to evaluate the relative significance of a specific set of economic, social and knowledge-related factors on the use of agroecological practices by family farmers. The analyses showed that credit access has a strong and enduring positive relationship with the use of agroecological practices, though it is also positively associated with an increase in agri-chemical use. These results suggest that the effect of credit access on agroecological management practices is undervalued in the agroecology literature. However, the characterization of the diverse agricultural systems that are represented by Brazilian agricultural census data reveals a need to further investigate contextual factors that may be driving the dominance of credit access in the results. The second study evaluates if and how public food procurement programs that include incentives for agroecology certification can mitigate common constraints to adopting agroecological practices. Drawing on interviews with participants in Brazil’s National School Feeding Program (PNAE) and key informants, we found that the PNAE offers an economic incentive to begin an agroecological transition by creating a price-differentiated market, which is otherwise absent in the regional context. However without broader participation in agricultural networks, including farmers’ associations, cooperatives and extension agencies that support agroecological practices, the PNAE’s influence was limited in stimulating the broader transition to agroecological production practices.Science, Faculty of
Resources, Environment and Sustainability (IRES), Institute for
Graduate
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Kennedy, Christopher R. J. "Signalling pathways of bradykinin-mediated arachidonic acid release in MDCK-D1 cells." Thesis, University of Ottawa (Canada), 1997. http://hdl.handle.net/10393/4074.
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An investigation was undertaken to elucidate the signal transduction pathways involved in bradykinin (BK)-mediated release of arachidonic acid (AA) from the D1 clone of Madin-Darby canine kidney cells (MDCK-D1) which display distal tubule- and cortical collecting duct principal cell-like characteristics. Prostaglandins (PG), generated subsequent to BK stimulation, are known to modulate arginine-vasopressin (AVP)-stimulated water flow across this portion of the nephron. The enzyme immediately responsible for AA release was determined to be the 85 kDa cytosolic phospholipase A$\sb2$ (cPLA$\sb2),$ since Western blots revealed the presence of this enzyme and its specific inhibition by an arachidonate analogue completely blunted BK-stimulated AA release. Additionally, in vitro PLA$\sb2$ activity could be significantly reduced by preincubating cell lysates with an antibody to this enzyme. Lastly, this in vitro activity met all the requirements specific to cPLA$\sb2,$ including activity at micromolar Ca$\sp{2+}$ concentrations and dithiotreitol (DTT)-insensitivity. The findings herein suggest the signalling route taken for BK-induced AA release involves phosphatidyicholine-specific phospholipase C (PC-PLC) as well as phospholipase D (PLD). Accordingly, production of sn-1,2-diacylglycerol (DAG) and to a lesser extent, phosphatidic acid (PA), both contribute to this release of AA by enhancing PLA$\sb2$ activity within the cellular membranes, whereas the activation of phosphatidylinositol-specific phopholipase C (PI-PLC) and subsequent inositol trisphosphate (InsP$\sb3$) production does not. While reports indicate the activation of protein kinase C (PKC) is required for epinephrine-mediated AA release in this cell line, inhibition of PKC failed to abrogate BK-stimulated AA release. On the other hand, down regulation of PKC levels via long-term incubation with phorbol ester (PMA) reduced both BK- and calcium ionophore (A23187)-induced AA release. However, both in vitro cPLA$\sb2$ activity and its phosphorylation, but not its expression, were significantly reduced subsequent to long-term PMA treatment, thereby demonstrating that this strategy falsely implicates immediate activation of PKC as being required for BK-mediated AA release. Extracellular calcium (Ca$\sp{2+})$ was also needed for AA release as blockade of receptor-operated Ca$\sp{2+}$ channels significantly decreased BK-induced AA release. In addition, a negative regulatory pathway in MDCK cells was demonstrated which diminishes BK-mediated AA release. Agents which cause elevations in adenosine-3$\sp\prime,5\sp\prime$-cyclic monophosphate (cAMP) levels, such as AVP or forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX), were found capable of significantly reducing BK-induced AA release and in vitro PLA$\sb2$ activity. This method of inhibition could represent a physiological mechanism of negative feedback promoted by agents which increase cAMP levels within the cells of the distal tubule and collecting duct. Possible targets for inhibition are suggested in light of results obtained in the present thesis and reported by others.
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Kennedy, Chris R. J. "Signalling pathways of bradykinin-mediated arachidonic acid release in MDCK-D1 cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq21003.pdf.
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Horner, Amy Jean. "Functional Roles of Crustacean Dual Antennular Chemosensory Pathways in Odor Mediated Behaviors." Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/biology_diss/18.
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Odor signals mediate a variety of behaviors in animals across a diversity of taxa. Despite dramatic morphological differences between animals from different taxa, several important features of olfactory system organization and processing are similar across animals. Because of this similarity, a number of different organisms including mammals, insects, and decapod crustaceans serve as valuable model systems for understanding general principles of olfactory processing. As in other organisms, including both vertebrates and insects, the chemosensory system of decapod crustaceans is organized into multiple anatomically distinct neuronal pathways. The two main pathways (the aesthetasc/ olfactory lobe pathway and non-aesthetasc/ lateral antennular neuropil pathway) originate in different populations of antennular sensilla and project to different neuropils in the brain. The functional significance of this parallel organization is not well understood in crustaceans or in many other species. Although in some insect species the functions of parallel pathways are clearly delineated by the types of odors processed by each, functional differences between parallel pathways in other organisms are much less distinct. A critical step towards understanding the functional significance of the multiple chemosensory pathways is to identify the specific behaviors that are driven by each pathway. Using spiny lobsters and crayfish as model organisms, the importance of each pathway was examined in three different behavioral contexts: (1) orientation to a distant food odor, (2) shelter selection in response to conspecific chemical signals, and (3) determination of conspecific social status. In each study, selective ablations of specific populations of antennular sensilla were performed, and the behavior of ablated animals was compared to that of intact controls. Results show that either the aesthetasc or non-aesthetasc pathway is capable of driving orientation to food odors, suggesting functional redundancy between the pathways in this behavior. In contrast social odors are processed preferentially by the aesthetasc pathway rather than the non-aesthetasc pathway, suggesting a unique role for the aesthetasc pathway in this context. As in other organisms possessing multiple chemosensory pathways, the dual antennular pathways in crustaceans display both unique and overlapping functions depending on the chemicals examined, and the behavioral context in which the signal is presented.
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Roux, Philippe P. "Signaling pathways implicated in p75 neurotrophin receptor-mediated neuronal survival and death." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38267.
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The neurotrophins are growth factors involved in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases, and the p75 neurotrophin receptor (p75NTR). In contrast to the rapid progress made in elucidating the mechanism of action of the Trk receptors, the physiological roles of p75NTR are uncertain, but two general functions have been ascribed to p75NTR. First, p75NTR can positively or negatively modulate Trk receptor signaling, and second, p75NTR can autonomously activate signaling cascades that results in cellular apoptosis. The signaling pathways employed by p75NTR to mediate its effects are unclear, but p75NTR was found to activate the NF-kappaB and JNK pathways, and to interact with several adaptor proteins, such as NRAGE, NADE, NRIF, TRAF proteins, and FAP-1.Nervous system injuries represent interesting models to study p75NTR because several types of injury induce p75NTR expression. In the first part of this thesis, we have used the pilocarpine model of seizure in the rat and found that this type of injury induces neuronal apoptosis and p75NTR expression. Apoptosis was tightly linked with p75NTR expression, suggesting that p75NTR may promote apoptosic cell death after seizure, and consistent with this, we have found that p75NTR can promote JNK activation and apoptosis in vitro. In the second study, we discovered that p75NTR can also facilitate survival under some cellular circumstances. The survival-promoting effect of p75NTR was accompanied with PI3-K-dependent Akt activation, and correlated with a reduction in cytosolic protein tyrosine phosphatase activity, suggesting that p75NTR may regulate a tyrosine phosphatase involved in the regulation of Akt and survival. In the last study, we have found that the related neuroprotective compounds, K252a and CEP 1347, are potent. MLK3 inhibitors, yet they simultaneously activated Akt and ERK, and survival through MLK3-independent mechanisms. These findings suggested that K252a and CEP1347 may act on a novel target responsible for their survival-promoting activities.
Taken together, the data in this thesis adds to our understanding of the physiological functions of p75NTR, and contributes to our knowledge of the cellular machinery that control neuronal cell survival and death.
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Ratcliffe, Marianne Jennifer. "Intercellular junctional proteins as targets for protein kinase c-mediated signalling pathways." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300471.
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Lam, Huy Hong. "Discrete Transition System Model and Verification for Mitochondrially Mediated Apoptotic Signaling Pathways." Thesis, Virginia Tech, 2007. http://hdl.handle.net/10919/33802.
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Computational biology and bioinformatics for apoptosis have been gaining much momentum due to the advances in computational sciences. Both fields use extensive computational techniques and modeling to mimic real world behaviors. One problem of particular interest is on the study of reachability, in which the goal is to determine if a target state or protein concentration in the model is realizable for a signaling pathway. Another interesting problem is to examine faulty pathways and how a fault can make a previously unrealizable state possible, or vice versa. Such analysis can be extremely valuable to the understanding of apoptosis. However, these analyses can be costly or even impractical for some approaches, since they must simulate every aspect of the model.
Our approach introduces an abstracted model to represent a portion of the apoptosis signaling pathways as a finite state machine. This abstraction allows us to apply hardware testing and verification techniques and also study the behaviors of the system without full simulation. We proposed a framework that is tailor-built to implement these verification techniques for the discrete model. Through solving Boolean constraint satisfaction problems (SAT-based) and with guided stimulation (Genetic Algorithm), we can further extract the properties and behaviors of the system.
Furthermore, our model allows us to conduct cause-effect analysis of the apoptosis signaling pathways. By constructing single- and double-fault models, we are able to study what fault(s) can cause the model to malfunction and the reasons behind it. Unlike simulation, our abstraction approach allows us to study the system properties and system manipulations from a different perspective without fully relying on simulation. Using these observations as hypotheses, we aim to conduct laboratory experiments and further refine our model.Master of Science
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Yamagishi, Kenji. "Studies on the cAMP-mediated signal transduction pathways in homobasidiomycete, Schizophyllum commune." Kyoto University, 2006. http://hdl.handle.net/2433/144347.
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Kyoto University (京都大学)0048
新制・論文博士
博士(農学)
乙第11785号
論農博第2591号
新制||農||923(附属図書館)
学位論文||H18||N4113(農学部図書室)
23840
UT51-2006-C707
(主査)教授 大東 肇, 教授 吉川 正明, 教授 永尾 雅哉
学位規則第4条第2項該当
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Shah, Bhavik P. "Targeting Fat-Sensitive Pathways In Enteroendocrine Cells Using Nanoparticle-Mediated Drug Delivery." DigitalCommons@USU, 2009. https://digitalcommons.usu.edu/etd/432.
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The current epidemic of obesity has been linked to an increase in fat intake associated with the Western diet. Nutrient-induced stimulation of enteroendocrine cells in the small intestine leads to the release of hormones that contribute to satiety and the control of food intake. In particular, ingested fat, specifically in the form of free fatty acids, is potent activator of enteroendocrine cells in the proximal small intestine. However, the underlying signaling cascade that free fatty acids initiate in these enteroendocrine cells, which leads to secretion of satiety hormones, is not known. In general, my research is focused on identifying nutrient-responsive pathways in enteroendocrine cells involved with the release of satiety signals and using this information to begin to develop novel drug delivery strategies to reduce food intake. In general, my results revealed that activation of the fatty acid receptor GPR120 was ecessary for the linoleic acid-induced intracellular calcium rise, a necessary precursor for hormone release. Using patch clamp recording, I discovered that linoleic acid activated enteroendocrine cells by inducing membrane depolarization, a process requiring the calcium-activated, monovalent cation permeable channel TRPM5, which is activated downstream of GPR120. To validate the unexpected finding that TRPM5 was involved in fattyacid signaling, I performed experiments using bitter compounds, whose transduction pathway is known to involve TRPM5. Enteroendocrine cells express the bitter taste receptors and release cholecystokinin in response to bitter stimuli, suggesting the probable role of gut in initiation of protective behavior against ingestion of potentially harmful substances. Armed with the data on the specifics of the fatty acid transduction, I performed experiments using nanoparticles to determine their utility for delivering pharmaceuticals specifically to the enteroendocrine cells. I fabricated and characterized PLGA nanoparticles and performed intracellular uptake studies in order to optimally delivery payloads inside cells. Finally, I validated their use by using cell-based assays to determine the effects of internalized PLGA nanoparticles on ion channels and signaling pathways involved in CCK release. Taken together, this dissertation research has identified the signaling pathways (pharmacological targets) involved in fatty acid-mediated satiety hormone release and validated the potential therapeutic use of nanoparticle-mediated drug delivery for the eventual control of food intake.
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Catt, Samantha. "Light-activated nitrile imine mediated reaction pathways for the synthesis of bioinks." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/131122/1/Samantha_Catt_Thesis.pdf.
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This thesis combines two projects covering material development, characterization and standardization in the field of biofabrication. Novel materials pave the way towards more complex and biologically relevant tissue mimetic structures. The first project was a proof-of-concept study, developing and optimizing a novel synthesis pathway for light-activated initiator-free photocrosslinkable hydrogels to be used in spatiotemporally-controlled bioprinting. The second project focused on the challenge of reproducibility, particularly in natural polymer-based hydrogel systems. Molecular properties were determined through chemical and physical characterization methods and correlated to macromolecular effects observed during 3D-printing, allowing the determination of a window of printability.
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Pingguan, Belinda Bte Simon Jingking. "Calcium mediated signalling pathways for chondrocytes in 3D constructs subjected to cyclic loading." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426066.
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Buchmann, Cody. "Reversal of RNA-mediated gene silencing pathways by geminivirus AL2 and L2 proteins." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1221847080.
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Buckwalter, Tara Lynne Furminger. "Phosphotyrosine-mediated signal transduction pathways essential for RET/PTC-1-induced tumor formation /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu970163275.
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Traub, Oren. "Mechanisms of shear stress-mediated ERK1/2 modulating signal transduction pathways in endothelial cells /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6309.
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Newman, Alice Clare. "Autophagy- and TBK1-mediated regulation of TRAF2/3 in alternative NF-κB signalling." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25842.
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Autophagy is a core cytoplasmic degradation process. It is established that KRas-mutant lung cancer cells require basal autophagy for survival. However, the mechanisms that govern this are poorly understood. It has recently been suggested that selective autophagic degradation of signalling complexes may regulate downstream cell signalling pathways. Primarily, this thesis aims to uncover molecular mechanisms through which selective autophagy can regulate signalling pathways that may impact upon cancer cell proliferation. Previous work in the lab identified a putative interaction between the signalling protein TRAF3 and the autophagy protein Ndp52 via mass spectrometric screening. In this thesis I have identified TRAF3 as a target of selective autophagy in both KRas-mutant lung cancer cells and in in vitro transformed MEFs. TRAF3 is a negative regulator of a gene expression regulation pathway called alternative NF-κB. As such, autophagy of TRAF3 promotes basal activation of the alternative NF-κB signalling pathway. This basal activity supports the proliferation of cancer cells. Investigation of TRAF2, a protein closely related to TRAF3, revealed that it too associates with the autophagy pathway, but is not degraded. This is promoted by the activity of TBK1, which itself can phosphorylate TRAF2. Both TBK1 and TRAF2 promote alternative NF-κB signalling, and I investigate possible mechanisms underlying this, including changes in TRAF3 mRNA and protein levels and binding to other alternative NF-κB regulators. This thesis therefore identifies mechanisms through which basal alternative NF-κB signalling is regulated in KRas-mutant lung cancer cells, with implications for cell proliferation. Ultimately, this work provides valuable mechanistic insight to inform the use of autophagy and/or TBK1 inhibition in future cancer therapies.
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Mitchell, Dianne Courtenay. "Regulation and function of the Rho GTPase mediated signaling pathways in metastasis and lenticular differentiation." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/5845.
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Modulation of the actin-based cytoskeleton and transcription factor regulation are merely two essential functions in a wide array of cellular activities that the Rho family of small GTPases is responsible for mediating. Aberrations in, or loss of, Rho GTPase signaling has been found to lead to multiple pathologies, including both metastatic progression and lenticular differentiation leading to cataractogenesis. This study has examined the transcriptional regulation of the metastasis suppressor, KiSS-1. Although the mechanism by which KiSS-1 modulates an anti-metastatic effect is not entirely known, it is known that KiSS-1 mediates stress fiber formation, increased adhesion and reduced migratory and invasive properties through modulation of the Rho family of small GTPases. The loss of KiSS-1 that commonly occurs during metastatic progression, leads to a loss of proper Rho GTPase regulation. This study has examined how KiSS-1 is regulated in two tissue types, breast and skin, and how the loss of AP-2(alpha) and DRIP-130, respectively, leads to the progression of breast cancer and melanoma. In addition, this study has also looked at the importance of Rac1 expression and function in the lens epithelium. Activation of Rac1 and its downstream effector, SRF, have been shown to be key regulators in lens cell differentiation, possibly leading to lens opacification via its transcriptional control of the structural crystallins within the lens. The results of this dissertation research have made significant strides in understanding the nature of the anti-metastatic effects registered by the novel KiSS-1 peptide and its cognate GPCR. Additionally, it has shed light on the Rho family regulation of lens epithelial cell differentiation, indicating the elaborate involvement of Rac1 in mediating lens fiber development. In all, this research has determined previously unknown roles of small molecule GTPases in both the progression of metastasis, as well as in normal and abnormal lens cell differentiation.
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Püschel, Gerhard, C. Kirchner, A. Schröder, and Kurt Jungermann. "Glycogenolytic and antiglycogenolytic prostaglandin E₂ actions in rat hepatocytes are mediated via different signalling pathways." Universität Potsdam, 1993. http://opus.kobv.de/ubp/volltexte/2010/4585/.
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Prostaglandin E₂ has been reported both to stimulate glycogen-phosphorylase activity (glycogenolytic effect) and to inhibit the glucagon-stimulated glycogen-phosphorylase activity (antiglycogenolytic effect) in rat hepatocytes. It was the purpose of this study to resolve this apparent contradiction and to characterize the signalling pathways and receptor subtypes involved in the opposing prostaglandin E₂ actions.
Prostaglandin E₂ (10 μM) increased glucose output, glycogen-phosphorylase activity and inositol trisphosphate formation in hepatocyte cell culture andor suspension. In the same systems, prostaglandin E₂ decreased the glucagon-stimulated (1 nM) glycogen-phosphorylase activity and cAMP formation.
The signalling pathway leading to the glycogenolytic effect of PGE₂ was interrupted by incubation of the hepatocytes with 4P-phorbol 12-myristate 13-acetate (100 nM) for 10 min, while the antiglycogenolytic effect of prostaglandin E₂ was not attenuated.
The signalling pathway leading to the antiglycogenolytic effect of prostaglandin E₂ was interrupted by an incubation of cultured hepatocytes with pertussis toxin (100 ng/ml) for 18 h, whereas the glycogenolytic effect of prostaglandin E₂ was enhanced.
The EP₁/EP₃ prostaglandin-E₂-receptor-specific prostaglandin E₂ analogue Sulproston had a stronger glycogenolytic potency than the EP₃ prostaglandin-E₂-receptor-specific prostaglandin E₂ analogue Misoprostol. The antiglycogenolytic potency of both agonists was equal.
It is concluded that the glycogenolytic and the antiglycogenolytic effects of prostaglandin E₂ are mediated via different signalling pathways in hepatocytes possibly involving EP₁ and EP₃ prostaglandin E₂ receptors, respectively.
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Schilling, Ramon [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Identification of novel molecular components in Ripoptosome-mediated signaling pathways / Ramon Schilling ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180617096/34.
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Pathak, Ashutosh K. "A proteomics based approach of IgE-receptor mediated signalling pathways in a mast cell line." Thesis, University of Sheffield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427236.
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Aldossary, Sara Abdulrahman M. "The sensitisation of TRPV1 mediated responses by prostaglandin and bradykinin and the signalling pathways involved." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/33359.
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TRPV1 ion channels have crucial roles in inflammatory hyperalgesia as TRPV1-/- mice show reduced thermal hyperalgesia response in response to tissue inflammation. The activity of TRPV1 is upregulated in the case of inflammation due to the release of different inflammatory mediators which can modulate the function of TRPV1. Bradykinin is an algogenic substance which is released at the site of inflammation and it’s known to produce thermal hyperalgesia. However, the mechanism underlying the sensitising effect of bradykinin has not been full elucidated. The aim of present project is to investigate how bradykinin mediates the sensitisation of capsaicin evoked calcium responses in DRG neurons. With the use of immunocytochemical and morphometric techniques, the present study has demonstrated the expression and distribution of EP4, TRPV1, COX-1 and B2 proteins mainly in small diameter (<1,000μm2) cell bodies of rat DRG neurons which are typically nociceptors. Cultured rat DRG neurons were utilised to elucidate the direct and sensitising effects of bradykinin on sensory neurons. Following direct application of bradykinin, a group of cells evoked calcium responses which were mediated via the B2 receptor. In addition, bradykinin showed the ability to sensitise TRPV1 in the presence of thapsigargin, conditions under which bradykinin does not elicit a Ca2+ responses on its own. With the use of various pharmacological ligands that modulate prostaglandin biosynthesis, the formation of the second messenger, PGE2, acting through EP4 receptors was identified as a key signalling pathway mediating the effect of bradykinin on sensory neurons. The present study provides evidence for a novel signalling pathway through which bradykinin can regulate the TRPV1 ion channel function.
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Pu, Qiaoxue, and 浦峤雪. "Investigation of the regulatory pathways involved in NO- and EDHF-mediated relaxations in porcine coronary arteries." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B50712652.
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Background
Nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) are both important relaxing factors. Their synthesis, release and downstream signaling pathways are controlled by a number of proteins, such that alteration in the activity of these proteins may disturb vascular tone.
Aim
This study was aimed to investigate the role of some of the regulatory proteins in NO- and EDHF-mediated relaxations. The regulatory proteins that were examined include: 1) calcium-calmodulin dependent protein kinase II (CaMK II), 2) mitogen-activated protein kinase (MAPK), 3) adenosine monophosphate-activated protein kinase (AMPK), 4) phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) and 5) phosphoprotein phosphatase.
Experimental approach
Organ chamber system was used for measuring isometric tension of porcine coronary arteries. The role of the regulatory proteins was investigated by using their activators or inhibitors. In the contraction study, arterial rings without endothelium were contracted with U46619 (0.1 nM to 10 μM) or phorbol 12,13-dibutyrate (PDBu, 0.1 nM to 1 μM). In the relaxation study, arterial rings with and without endothelium were contracted with U46619 (30 or 100 nM). They were incubated with indomethacin (cyclooxygenase inhibitor, 10 μM) and TRAM-34 plus UCL1684 (intermediate- and small-conductance calcium-activated potassium channel blockers, respectively; 1 μM each) or L-NAME (NO synthase inhibitor, 30 μM) for the study of NO and EDHF components of bradykinin (0.1 nM to 10 μM)-induced relaxations. Moreover, endothelium-independent relaxations by sodium nitroprusside (SNP, exogenous NO donor, 0.1 nM to 100 μM) and diazoxide (ATP-sensitive potassium channel activator, 1 nM to 1 mM) were examined in arteries without endothelium.
Key findings
1. NO and EDHF are both involved in endothelium-dependent relaxation in porcine coronary arteries, in which NO is the dominant relaxing factor.
2. KN-93 (CaMK II inhibitor, 30 μM) significantly reduced contractions to U46619 and PDBu. On the other hand, CaMK II partly involved in EDHF signaling but not in the NO-mediated relaxations.
3. Calyculin A (phosphoprotein phosphatase inhibitor, 30 nM) greatly inhibited both endothelium-dependent and –independent relaxations.
4. PD98059 (MAPK inhibitor, 30 μM) significantly potentiated bradykinin-induced relaxation that was mediated by EDHF but not that mediated by NO. On the other hand, it potentiated SNP-induced but not diazoxide-induced endothelium-independent relaxations.
5. AMPK and Akt do not play a role in regulating vascular tone as compound C (AMPK inhibitor, 30 μM), AICAR (AMPK activator, 1 mM) and wortmannin (PI3K inhibitor, 100 nM) did not affect contractions to U46619 and PDBu, and relaxations to bradykinin, SNP and diazoxide in porcine coronary arteries.
Conclusions and implications
Different regulatory proteins (CaMKII, MAPK, AMPK, Akt, phosphoprotein phosphatase) have different effects on the regulation of vascular tone. While the present study has the limitation of using pharmacological agents at only one concentration to examine the role of these proteins, it still produces scientific information for the development of therapeutic agents. In considering CaMK II, MAPK and phosphoprotein phosphatase as potential therapeutic targets, the vascular effects (which can be therapeutic or adverse) of the compounds acting on these proteins should be taken into account.published_or_final_version
Pharmacology and Pharmacy
Master
Master of Medical Sciences
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Wilkinson, Meredyth Grace Llewellyn. "Investigating novel pathways in B cell mediated autoimmunity in the context of the disease juvenile dermatomyositis." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10048930/.
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The Inflammatory Idiopathic Myopathies (IIM) are a rare group of myopathic autoimmune diseases diagnosed in both adults and children. Patients present with proximal muscle weakness and Gottron’s papules. Immunohistochemical analysis of muscle tissue from these patients has identified immune cell infiltrate and the expression of pro-inflammatory cytokines however, little is known about the peripheral immunological profile in juvenile and adult patient groups. There are three aims: Firstly, to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in the blood of Juvenile Dermatomyositis (JDM) patients. Secondly, to identify specific immune cell signatures and cytokine profiles for myositis disease subtypes and correlate this data with measurements of disease activity. Finally, to delineate a correlation between the up-regulated type I interferon signature and dysfunction of cholesterol homeostasis in immune cells. Using a combination of cell culture, flow cytometry, RNA-seq, q-PCR and ELISA techniques this study has assessed the immune cell signature, B cell biology and IFN related mechanisms in patients with IIM. The results identified that JDM patients with active disease have a significantly expanded immature B cell population which was correlated with a type I IFN signature. Activation through TLR7 and IFN- may drive the expansion of immature B cells in JDM and skew the cells towards a more pro-inflammatory phenotype. There are unique immune signatures in adult disease sub-types, one example was an expanded Th17 population seen in adult dermatomyositis (ADM). Lastly, IFN- stimulation of T and B cells does change the expression of some genes that are part of the Hallmark cholesterol homeostasis pathway. In conclusion, the work undertaken during my thesis provides further evidence that anti- IFN biologics could be efficacious in the treatment of JDM. Also, the need for further investigation for the use of IL-17A inhibitors in the treatment of IIM.
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Rush, Craig Michael. "Crosstalk between the Jak-Stat and Wingless pathways is mediated by Mad in Drosophila melanogaster larval hematopoiesis." Ohio University Art and Sciences Honors Theses / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ouashonors1367508013.
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Kleveman, Jan Alexander Verfasser], and Martin [Akademischer Betreuer] [Korte. "Neurotrophin mediated signaling pathways common to the immune and nervous system / Jan Alexander Kleveman ; Betreuer: Martin Korte." Braunschweig : Technische Universität Braunschweig, 2018. http://d-nb.info/1175816302/34.
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Jindra, Peter Thomas. "Anti-MHC class I antibody-mediated activation of cell proliferation and survival signaling pathways in endothelial cells." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1495958881&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Jessop, Lea. "Architecture of the synaptic intermediates of the site-specific recombination pathways mediated by the bacteriophage Lambda integrase /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9981973.
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Sagi, Sarah Ann. "G alpha q- and G alpha 12-mediated signaling pathways activated by G protein-coupled thrombin receptors /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9992384.
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Foraker, Amy Beth. "Characterization of the endocytic pathways regulating riboflavin (vitamin B2) absorption and trafficking in human epithelial cells." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172865566.
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Oliveira, Mateos Cristina. "Epigenetic regulation mediated by antisense non-coding RNAs and its impact on oncogenic pathways: the HMGA2/RPSAP52 locus." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/669259.
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The vast majority of the human genome is transcribed giving rise to non-coding RNAs. Antisense transcripts are one of the most abundant types of long non-coding RNAs and many of them have regulatory roles in the transcription of the nearby genes. Specifically, we study gene pairs with divergent transcription and a GC skew in the promoter region that allows the formation of an R-loop by the antisense. The HMGA2/RPSAP52 pair was selected for further investigation due to the aberrant expression of HMGA2 in a multitude of cancers. In this case, the R-loop formed by RPSAP52 reduces chromatin compaction, which has a positive impact on HMGA2 transcription.
Both genes are overexpressed in some human cancers, with a positive correlation in breast cancer patients and cell lines; and hypermethylation of their promoter correlates with their repression. On the other hand, RPSAP52 enrichment in the cytoplasm, its polyadenylation and its association with polysomes indicate a possible function in translation. In this sense, we described the binding of RPSAP52 to IGF2BP2 protein, a transcriptional target of HMGA2 that regulates the translation of mRNAs such as IGF1R and RAS. RPSAP52 depletion resulted in an increase of let-7 expression that correlated with low levels of the proteins IGF2BP2, IGF1R and RAS, whose mRNAs are let-7 targets. LIN28B is not expressed in MCF10A cells and LIN28A does not change with RPSAP52 depletion. Thus, it is not possible to explain these results by alterations in the levels of LIN28 proteins, the main negative regulators of let-7 biogenesis.
The phenotypic impact of RPSAP52 depletion in breast cancer cell lines includes a decrease in cell proliferation, migration and clonogenicity. Also, the protein levels of the stemness markers NANOG and OCT4 are reduced in these cells. Similarly, the weight and volume of subcutaneous tumors is lower in immunosuppressed mice injected with RPSAP52-depleted cells.
Given the role played by the HMGA2-IGF2BP2-NRAS axis in embryonic rhabdomyosarcoma, the study was extended to sarcomas using A673 cell line as a model. As seen in MCF10A, an increase in let-7 expression was observed in RPSAP52-depleted clones, and the interaction between IGF2BP2 and RPSAP52 was confirmed. In this case, IGF2BP2 and RAS proteins remain unchanged, but the pathway is affected downstream
with the decrease of p-ERK. It is noteworthy to mention the reduction of LIN28B protein in the clones, which is abundantly expressed in A673 cells. The reduction in tumor formation was the consequence of RPSAP52 depletion in vivo.
Importantly, we described the binding of IGF2BP2 to LIN28B mRNA, and confirmed the interaction using iCLIP-Seq. RPSAP52 knockdown caused a specific loss of IGF2BP2 affinity for particular mRNAs, influencing the translational efficiency of HMGA2 and LIN28B. Moreover, RPSAP52 mediates IGF2BP2 recruitment to polysomes. This could be the mechanism by which RPSAP52 controls the expression of LIN28B and, therefore, let-7 levels.
An expression array was performed to study the genome-wide impact of RPSAP52 silencing. The increase of some tumor suppressor genes was detected in the clones, as well as the decrease of genes usually overexpressed in cancer. In support of the influence that RPSAP52 has in tumorigenicity, high expression levels imply a worse survival rate in sarcoma patients.
Our findings provide new knowledge about NATs-mediated regulatory mechanisms and highlight their impact on cancer-related genes and on tumor progression itself. According to our results, RPSAP52 regulates HMGA2 expression through the formation of an R-loop and IGF2BP2 function through the binding to this protein. We also demonstrated that LIN28B mRNA constitutes a new target of IGF2BP2. Thus, RPSAP52 affects LIN28B/let-7 balance and promotes tumorigenesis. In conclusion, our work establishes RPSAP52 as a master regulator with oncogenic properties.La gran mayoría del genoma humano se transcribe, dando lugar en muchos casos a RNAs no codificantes. Los transcritos antisentido son uno de los tipos más abundantes de RNAs no codificantes largos y muchos poseen importantes funciones en la regulación de los genes cercanos. Este es el caso de RPSAP52, transcrito antisentido del gen codificante HMGA2. La expresión de ambos genes es elevada en varios cánceres humanos y correlaciona positivamente como consecuencia de la regulación que RPSAP52 ejerce sobre HMGA2. RPSAP52 forma un R-loop en la región promotora de los dos genes, lo que modifica la conformación de la cromatina y favorece la transcripción de HMGA2. RPSAP52 desempeña funciones adicionales en el citoplasma gracias a su unión a la proteína IGF2BP2, cuya transcripción es regulada por HMGA2. IGF2BP2 promueve la traducción de genes relacionados con importantes rutas proliferativas, y su interacción con RPSAP52 afecta su unión a algunos RNAs mensajeros, así como su reclutamiento a polisomas. En este trabajo demostramos que LIN28B, uno de los principales reguladores negativos de la maduración del miRNA let-7, es uno de sus targets. De este modo, RPSAP52 aumenta la traducción de LIN28B y reduce los niveles del supresor tumoral let-7. La regulación mediada por RPSAP52 tiene un importante impacto en rutas génicas relacionadas con el cáncer. Su depleción afecta negativamente las características tumorigénicas de las células in vitro y disminuye la progresión tumoral in vivo. Además, RPSAP52 puede ser considerado como un biomarcador en sarcomas, ya que sus altos niveles se asocian a un peor pronóstico. En resumen, el presente trabajo propone un modelo regulador mediado por RPSAP52 con dos niveles diferentes de acción. Este transcrito antisentido promueve la activación transcripcional de HMGA2 y, a su vez, regula la función de la proteína IGF2BP2. Dado que HMGA2 e IGF2BP2 están en la misma vía proliferativa, RPSAP52 refuerza la función de HMGA2 tanto sobre IGF2BP2 como sobre sus efectores posteriores, lo que afecta la progresión del cáncer. Debido a los importantes roles desempeñados por RPSAP52 y a sus propiedades oncogénicas, podría ser una potencial diana terapéutica para el desarrollo de nuevos tratamientos contra el cáncer.
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Franco, Alier J. "Functional and anatomical basis for corticotropin releasing factor mediated analgesia covergence of parallel pathways on the periaqueductal gray /." Cincinnati, Ohio : University of Cincinnati, 2005. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin.
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Thesis (Ph. D.)--University of Cincinnati, 2005.Title from electronic thesis title page (viewed Mar. 6, 2006). Includes abstract. Keywords: rat, corticotropin, stress, pain, analgesia. Includes bibliographical references.
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Kavuri, Megha Shyam [Verfasser]. "Molecular analysis of death receptors mediated apoptotic and non-apoptotic signalling pathways in human keratinocytes / Megha Shyam Kavuri." Magdeburg : Universitätsbibliothek, 2011. http://d-nb.info/104720276X/34.
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Seeliger, Christine. "Spatial and stochastic modeling of TrkB mediated signaling pathways involved in long term potentation in the dendritic spine." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708013.
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FRANCO, ALIER J. "FUNCTIONAL AND ANATOMICAL BASIS FOR CORTICOTROPIN RELEASING FACTOR MEDIATED ANALGESIA: COVERGENCE OF PARALLEL PATHWAYS ON THE PERIAQUEDUCTAL GRAY." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1122923847.
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Karthik, A. G. "Effect of hexadecylglycerol supplementation on protein kinase C-mediated signaling pathways in a murine macrophage-like cell line." Thesis, Boston University, 2005. https://hdl.handle.net/2144/37161.
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Thesis (Ph.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
All mammalian membranes contain ether-linked glycerolipids in which the sn-1 position of the glycerol backbone is occupied by an alkyl chain attached through either an ether, or vinyl ether linkage (plasmalogens). Plasmalogens and ether lipids have been implicated in important cellular functions such as (i) mediating membrane-fusion events, (ii) serving as endogenous antioxidants and (iii) modulating protein kinase C (PKC) and/or phosphatidylinositol-3-kinase (PI3-K)-mediated cellular responses to stimuli. sn -1-hexadecylglycerol (HG) is a simple ether lipid precursor that is able to enter cells and then enter the biosynthetic pathway for ether lipids. We have used HG and ether lipid-deficient animal cell mutants to examine ether lipids' cellular roles. We have examined three cellular events thought to be influenced by cellular ether lipid levels and mediated by both PKC and PI3-K, namely, the generation of superoxide anion (respiratory burst), the release of arachidonic acid (AA) and fragment crystallizable γ (Fcγ) receptor-mediated phagocytosis, three processes essential for neutrophil and macrophage immune functions. When the ether lipid-deficient murine macrophage-like cell line, RAW.108, was treated with HG prior to simulation, superoxide production in response to either a soluble stimulus (phorbol ester, PMA) or particulate stimulus (zymosan), was reduced by >90%. HG supplementation also inhibited PMA-induced but not zymosan-induced AA release, suggesting that two different pathways exist for the release of AA in these cells depending on the stimulus. Fcγ receptor-mediated phagocytosis was also inhibited by HG supplementation. This inhibition was not related to changes in plasmalogen levels as HG was also effective in inhibiting the respiratory burst in the mutant cell line, RAW.12, which cannot form plasmalogens even with HG supplementation. The mechanism of inhibition of these events by HG was likely due to inhibition of PKC and not PI3-K, which was verified independently using other inhibitors of these enzymes.
2031-01-01
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Lemaitre, Philippe. "Early role of IL-17 and calcineurin inhibitor-mediated Th2- and Th17-polarization of chronic trachea allograft rejection pathways." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209243.
Full textAbstract:
Lung transplantation is the only therapeutic approach for patients presenting end-stage pulmonary failure. Despite progress made in organ preservation and immunosuppression, primary graft dysfunction and obliterative bronchiolitis still hamper short-term and long-term outcomes, respectively. Interleukin-17 recently emerged as a major actor in several immuno-inflammatory disorders. Clinical and experimental evidence also suggest the implication of interleukin-17 or type 17 CD4+ T cells in lung rejection. We therefore investigated the contribution of this cytokine to graft pathology in a murine model of tracheal transplantation that recapitulates pathological features of lung rejection including the development of obliterative airway disease.We first demonstrated that interleukin-17 contributes to inflammatory lesions in the early phase post-transplantation. Interleukin-17 was found to be produced by &61543;&61540;+ T cells and CD4+ T cells infiltrating the graft and interleukin-17 neutralization significantly reduced the development of epithelial lesions together with inhibition of interleukin-6 and heat-shock-protein 70 gene transcription.
We then investigated the contribution of interleukin-17 to obliterative airway disease. Although interleukin-17 did not play a dominant role in absence of immunosuppression, it was found to contribute to airway pathology in animals receiving cyclosporin A. Under this treatment, we first observed dramatic changes in the composition of the lymphocyte populations infiltrating the graft: the numbers of CD8+ T cells producing interferon-&61543; and type 1 CD4+ T cells were dramatically decreased while the numbers of type 17, and also type 2 CD4+ T cells were unaffected. The pathological relevance of these findings was first demonstrated by the prolongation of graft survival afforded by the depletion of CD4+ T cells in cyclosporin A-treated animals. Furthermore, graft rejection was also delayed in mice genetically deficient in either interleukin-17 or interleukin-4, providing evidence that type 17 and type 2 CD4+ T cells actively contribute to graft rejection in cyclosporin A-treated recipients. On the other hand, parallel experiments in interferon-&61543;-deficient mice revealed that interferon-&
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished