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Bouvet, Alain. "Étude par diffusion inélastique de neutrons des propriétés magnétiques de borures de terre rare : CeB6, PrB6 et YbB12." Université Joseph Fourier (Grenoble ; 1971-2015), 1993. http://www.theses.fr/1993GRE10186.
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Cette thèse porte sur l'étude par diffusion inélastique de neutrons des propriétés magnétiques de borures de terre rare : ceb#6, prb#6 et ybb#1#2. La difficulté de réalisation des expériences, notamment la faiblesse des signaux due en partie à la forte absorption des neutrons par le bore, nous a conduit à inclure, dans un programme d'analyse, la correction d'absorption. La partie principale de cette thèse a été l'étude des interactions magnétiques dans les phases ordonnées de ceb#6 et prb#6. Nous avons confirmé la présence d'interactions magnétiques quadrupolaires importantes, grâce à la mesure des excitations magnétiques dans la phase quadrupolaire de ceb#6 en appliquant un champ magnétique dont la valeur était comprise entre 0 et 6 t, et dans les phases double-k et simple-k basse température de prb#6. De plus nous avons montré qu'il semble exister une compétition entre les interactions magnétiques quadrupolaires et les interactions magnétiques dipolaires dans le compose ceb#6, alors que les interactions quadrupolaires dans prb#6 semblent au contraire renforcer la structure magnétique dipolaire. Les mesures effectuées avec le compose ybb#1#2 nous ont permis de donner une valeur de 60 k pour l'énergie du gap, cette valeur étant conforme à celles obtenues par des mesures de résistivité et d'optique. De plus nous proposons un schéma de niveau de champ cristallin, avec le niveau fondamental #8 et les niveaux excites #7 et #6 a respectivement 18 et 39 mev. En annexe, nous présentons également les résultats obtenus par diffusion inélastique de neutrons avec le compose bidimensionnel xy bani#2(po#4)#2. Un programme a été développé pour déconvoluer les spectres mesures de la fonction de résolution instrumentale à 4 dimensions. Les largeurs intrinsèques, ainsi déterminées, de la diffusion magnétique critique ne montrent aucune caractéristique des excitations non linéaires prévues par la théorie, mais peut être expliqué uniquement par une renormalisation des ondes de spin
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Dagne, Carl. "Implementering av tillståndsmaskiner med PRBS." Thesis, Linköping University, Department of Electrical Engineering, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1841.
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Tillståndsmaskiner är vanliga komponenter i många digitala konstruktioner. En vanlig typ av tillståndsmaskin är räknare. Räknare är ofta ganska kostsamma att implementera, med avseende på antalet grindar. För att reducera denna kostnad kan istället en PRBS (Pseudo Random Binary Sequence) användas. Denna byggs upp av ett register där en xor - operation utförs mellan två positioner, som beror på längden av registret. Resultatet från denna operation skiftas sedan in i registret. På detta sätt fås en till synes slumpmässig sekvens. Talen är dock inte på något sätt slumpmässiga utan kan hela tiden förutsägas. I detta examensarbete har en undersökning för att konstruera en billig tillståndsmaskin med hjälp av PRBS:er gjorts i MatLab. Tre olika program har skrivits för att beräkna olika kostnader vid implementering av en tillståndsmaskin.
Finite state machines are common components in digital designs. A common type of finite state machine is a counter. Counters are often quite expensive to implement, with respect to the number of gates. To reduce this cost, a PRBS (Pseudo Random Binary Sequence) can be used. It is constructed of a register where a xor - operation is performed between two positions, which depend on the length of the register. The result from this operation is then shifted back into the register yielding a random-like sequence. The numbers are not random, but can always be predicted. In this thesis work finite state machine using PRBS are designed in MatLab. Three different programs have been written to calculate the costs for implementation of a PRBS.
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Newton, B. T. "Applied gas tracing or permeable reactive barriers (PRBs)." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602710.
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The aim of my thesis is to evaluate the use of applied dissolved noble gas tracers for the estimation of flow and transport parameters in permeable reactive barriers (PRBs) and for the assessment of changes in those parameters over time. PRBs consist of reactive materials that are p l aced in the subsurface to intercept a contaminant plume. PRBs have been proven to effectively remediate a variety of groundwater contaminants. The main limitation to the use PRBs as a remediation tool is the build up of mineral precipitates and gases that may inhibit water flow through the barrier, decrease the reactivity of the PRB medium, and reduce the residence time of contaminated water. Applied chemical tracers provide the most direct measurement of how water moves through PRBs to assess the effects of mineral precipitation and gas evolution on flow and transport parameters in PRBs. Tracer experiments in laboratory columns and full scale permeable reactive barriers are described in detail , highlighting advantages and disadvantages of using noble gases as applied tracers. The volatility of noble gases presents advantages and disadvantages. The retardation of dissolved gas tracers, as a result of interactions with gas bubbles trapped in pore spaces, provides information about the volume of a gas phase that is present in the system. However, the degassing of dissolved gas tracers during tracer injection, sampling , and sample preparation can result in many uncertainties with respect initial tracer concentrations. These uncertainties are best dealt with by using multiple noble gas tracers along with a "conservative" tracer such as Bromide or Chloride. This thesis demonstrates that noble gases can be used effectively as applied tracers to assess the long - term effectiveness of PRBs.
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ORRU', ROBERTO. "Sequenziamento e Analisi Molecolare di Varianti Alleliche del Gene PRB1." Doctoral thesis, Università degli Studi di Cagliari, 2016. http://hdl.handle.net/11584/266626.
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The aim of this work was the molecular characterization of gene PRB1 in three subjects with different salivary proteome profile. The PRB1 gene encodes a member of the heterogeneous family of Basic Proline rich Proteins (PRB), produced by the parotid gland and secreted in human saliva. The protein polymorphism resulting from post-translational modifications of the pre-protein PRB1, are further complicated by the gene allelic variants. Those variants involves the third exon of the gene, and are related to the presence or absence of a tandem repeat sequence 183 bp long. That tandem repeat may originate three different allelic forms, defined small, medium or large depending on the number of repeats inside the third exon.
The information reported in the literature about the class of PRP genes, and in particular PRB1 are, from the molecular point of view, fragmentary and difficult to reconstruct. In fact, the literature on this topic covers a time span ranging from the seventies (Azen & Oppenheim, 1973), when the associated peptides have been characterized for the first time, up to the end of the nineties (Stubbs et al., 1998). Since the eighties, there have been various attempts to characterize the PRB1 allelic variants, based on the resulting peptides. This approach has greatly complicated the classification of the gene, but also of his allelic variants and the deriving proteins (Maeda et al., 1985 ; Lyons et al., 1988a, b; Azen et al., 1993). Today we know that from PRB1, considering its allelic and splicing variants, are expressed six different proteins (Marconi et al., 2015). However, amongst the three allelic variants of this gene, the only of which we have the complete nucleotide sequence is the medium. Conversely, for the small and large we have so far only partial sequences, referring only to the third exon. Among the objectives of this study, there was the reconstruction of the complete sequences of the small and large variants, of which there have been previously characterized two putative bearers from the proteomic point of view. At the same time, we also sequenced the PRB1 gene from a putative homozygotic bearer of the medium variant.
While for the subject bearer of the small variant, we were able to identify and sequence the entire gene, the same was not possible for the subject bearer of the large variant. In fact, from our analysis this last subject has shown to be homozygous carrier of the medium variant. This result is incompatible with the presence in his saliva of Ps2 protein, which is characteristic of the large variant. In the absence of further mass spectrometric analysis, we cannot explain the reason for this discrepancy between genomic and proteomic data. The analysis of the complete sequences did not allow us to understand why it has not been identified to the mass spectrometer the peptide relative to the splice variant classified by Maeda with the acronym cP5 (Maeda et al., 1985), while in all the subject has been identified the peptide and the relative cP4 splice variant. Pk-o protein has so far been reported to be expressed from the large variant only, although the first classification of splice variants had been made from an individual carrying the medium variant. Since in none of the three sequenced subjects the splice acceptor site in 3' of the cP5 variant results to be altered, it is possible that the relative peptide has not been identified to the mass spectrometer. Otherwise, specific splicing factors, that recognize Splicing Regulatory Elements (SRES; Hernandez-Imaz et al., 2015) in the neighborhood of the two molecular acceptor sites, prevented the transcription of the cP5 in favor of cP4. In order to shed light on this aspect, there are some possible strategies in perspective. Recently, in fact, studies have been published in which extensive in vivo screening for the detection of SRES is coupled with RNA affinity purification and mass spectrometry, which allow also the identification of the splicing factors which bound to the SRES (Wang Y & Z Wang, 2014; Wang et al., 2013). This strategy could be effectively integrated with the analysis of minigenes (Hernandez-Imaz et al., 2015), specifically designed on the model of the third exon of PRB1, where alternative splicing takes place and where are probably placed the SRES.
Molecular analysis has also enabled us to identify a set of Single Nucleotide Polymorphims (SNPs), most of which have never been described so far, localized specially inside introns and some even within exons. In particular, for two of these, we have detected a non-synonymous substitution at the amino acid level, the role of which can only be clarified by means of appropriate functional studies. Although translationally silent, even synonymous SNPs may have an important function, especially in alternative splicing. In fact, these substitutions can determine the genesis or destruction of SRES, or strengthen cryptic donor /acceptor sites. Furthermore, they can result in the alteration of the secondary structure of the mRNA, important for the exons definition and the pause sites of RNA II. This could, in turn, alter the processivity of the polymerase, with possible consequences on the choice of splicing sites.
The reconstruction of the complete sequences and the comparison with the data available in the literature (Lyons et al., 1988) allowed us to produce an updated model, which allows to explain the generation of allelic variants small and large from the medium variant. Hopefully, the reconstruction also of the large allelic variation, and possibly the very large, will lay the basis for the validation of our model and possibly also its extension to other allelic variants of the PRB gene class.
The genotypic characterization of allelic variants of PRB1 may be, in the future, an important predictive tool about the subjective susceptibility towards a series of oral pathogens. In fact, polymorphic variations in the PRB1 peptides can build the basis for the prediction of individual differences at the level of the oral microflora, with repercussions on the susceptibility to infections and diseases in this body part (Newman et al., 1993 and 1996; O'Sullivan et al., 2000).
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Kalpathy, Venkiteswaran Venkatasubramanian. "Development of a Design Framework for Compliant Mechanisms using Pseudo-Rigid-Body Models." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1482232749828813.
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Sun, Ang. "Anti-cancer Functions and Mechanisms of a pRb2/p130 Peptide Fragment." Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/58962.
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BiologyPh.D.
The spacer region of pRb2/p130 was reported to be able to inhibit the kinase activity of Cdk2. The region responsible for the inhibitory effect was further narrowed down to a 39-amino-acid sequence, which was named as Spa310. In this dissertation, the anti-cancer functions and mechanisms of Spa310 were studied. The synthesized Spa310 peptide was able to inhibit the kinase activities of Cdk2/Cyclin E/A complexes. In vitro kinase assays showed the inhibition occurred in a dose-dependent manner. The half maximal inhibition concentration of the Spa310 in the kinase assay was 1.67mM. In addition, it has been shown that Spa310 peptide is able to inhibit the kinase activities of both Cdk2/Cyclin E and Cdk2/Cyclin A. Intra-cellular distribution study using fluorescein-labeled Spa310 peptide showed that Spa310 was able to localize to the nuclei of A549 cancer cells. Some data indicated the endoplasmic reticulum might play a role in transporting Spa310 peptide from cytoplasm to the nucleus. At high concentration, the treatment of Spa310 peptide was able to arrest cells at the G0/G1 phase of the cell cycle and reduce the growth of xenografted tumors in nude mice. Further studies indicated Spa310 peptide is not a specific inhibitor for Cdk2/Cyclin E/A. It is also able to inhibit the kinase activities of Cdk1/Cyclin B, Cdk4/Cyclin D and Cdk9/Cyclin T/K. Result of a binding assay using GST-Spa310 and in vitro transcribed/translated Cdk2 did not support a direct binding between Spa310 and Cdk2. Additionally, GST-Spa310 was unable to bind to the in vitro transcribed/translated Cyclin E. At first, co-immunoprecipitation experiments indicated a weak binding between Spa310 peptide and Cdk2. However, later this weak binding was proven to be unspecific and only occurred when the concentration of Spa310 peptide was high. Thus, the hypothesized mechanism of the inhibitory effect of Spa310 was not supported. After noticing three classic Cdk phosphorylation sites present in Spa310, it was proven that Spa310 is a substrate for Cdk1, 2, 4 and 9. Results of kinase assays supported the inhibitory effect of Spa310 on the different Cyclin-dependent kinases was resulted from a substrate-competitive mechanism. Although the data generated from this study does not support Spa310 is a potent peptide inhibitor for the Cdks, knowledge gained from and the approach used in this research can be applied to design and develop more potent and specific Cdk2 peptide inhibitors, which have their potentials to work as powerful anti-cancer reagents.
Temple University--Theses
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STUCCHI, SIMONE. "Role of glucose and peroxiredoxin 6 in human chondrocytes and novel biomaterial for in vitro three-dimensional chondrocytes culture." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/261927.
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L’osteoartrite (OA) è una delle malattie reumatiche con più alta incidenza nel mondo moderno e rappresenta la pricipale cause di disabilità. L’OA è data da un disquilibrio tra degradazione e riparazione della cartilagine, a favore della degradazione, con un incremento dell’attivita degli enzimi catabolici come le matrici metalloproteinasiche. I condrociti sono responsabili della riparazione e della biosintesi degli elementi che compongono la ECM. Diversi studi supportano l’ipotesi che il diabete è uno dei fattori che causano l’osteoartrite. Sebbene non si conoscono ancor ai meccanismi molecolari che permettano l’associazione tra diabete e OA. Abbiano analizzato la crescita cellulare, i livelli dei ROS e l’apoptosi di condrociti posti in terreno con differenti concentrazioni di glucosio. I risultati mostrano che i condrociti preferiscono la concentrazione 2.5 mM di glucosio che è stata utilizzata come concentrazione normoglicemica; mentre 25 mM di glucosio è stata utilizzata come concentrazione iperglicemica. I livelli di ROS e la morte cellulare aumentano in condrociti cresciuti in alto glucosio, anche il citoscheletro si presenta disorganizzato in cellule C28/I2 cresciute in queste condizioni. Questo correla con lo stato di attivazione della GTPasi RalA, la cui attivazione è ridotta in condizioni iperglicemiche. Infatti questa GTPasi è coinvolta nella regolazione della riorganizzazione citoscheletrica. Inoltre sono stati effettuati esperimenti utilizzando medium contenenti ITS (Insulina, transferrina e selenio) che pruomuove il differenziamento a condrocita; mentre l’interleuchina-1β per simulare l’ambiente osteoartritico. Anche in uesto caso i livelli di RalA GTP diminuiscono in cellule cresciute in 25 mM glucosio e stimolate con IL-1β. Inoltre in queste condizioni diminuiscono ache i livelli di p-ERK1/2. Sono stati valutati anche i livelli di NF-κB, iNOS e LC3II. I risultati dimostrano che l’alto glucosio blocca l’autofagia nei condrociti. Inoltre sono stati valutati anche i pathways attivati dall’alto glucosio in condrociti primari umani dopo 24 h di trattamento. I risultati mostrano che la fosforilazione di ERK1/2, p38, Akt e p65 è alterata in condrociti cresciuti in condizioni iperglicemiche tale evento è correlato con un aumento di MMP-13. Per analizzare meglio il ruolo dei ROS nei condrociti ho lavorato per 6 mesi nel laboratorio del Dr. Loeser alla scuola di medicina presso l’università della north Carolina a Chapel Hill. Ho lavorato su PRX6 che è coinvolto nella detossificazione dai ROS. Lo stato di ossidazione di PRX6 è stato valutato nei condrociti trattati con diversi stimoli come H2O2, Fn-f, menadione (men) and DMNQ. Dopo questi esperimenti abbiamo voluto osservare se PRX6 potesse influenzare i pathway delle MAPK in cellule trattate con IGF-1, menadione, combinazione tra IGF-1 e menadione e con Fn-f. è stata valutata la localizzazione di PRX6 che si è visto essere sia nucleare che citoplasmatico. Inoltre ho lavorato in collaborazione con Prof. Laura Cipolla e Prof. Maddalena Collini per sviluppare e caratterizzare nuovi idrogel fatti di gelatina usando come agente cross-linkante lo squarato.Osteoarthritis (OA) is the most common rheumatic disease in the world and represents the first cause of disability in the world. OA results from the loss of balance between degradation and repair inside cartilage, in favor of degradation, with increased activity of catabolic enzymes such as matrix metalloproteinases and decreased production of ECM proteins. Chondrocytes are responsible for the repair and biosynthesis of elements of the extracellular matrix. Experimental findings support the hypothesis that diabetes is an independent risk factors for OA. However, correct molecular mechanisms underlying the diabetes-associated OA phenotype is still largely unknown. Firstly chondrocytes cell growth, ROS levels and apoptosis were analyzed using different glucose concentration. Results shown that chondrocytes prefer 2.5 mM of glucose which was used as normal glucose concentration and 25 mM of glucose was used as high glucose concentration. ROS levels and cell death increase in chondrocytes growth in high glucose environment. Also cytoskeletal network is more disorganized in C28/I2 cells growth at high glucose concentration, this correlates with different RalA-GTP levels which is involved in the regulation of cytoskeletal organization. Experiments were performed even using medium supplemented by ITS (Insulin-transferrin-selenium) to promote chondrocyte differentiation and IL-1β was used to simulate osteoarthritic cartilage environment. Ral A-GTP levels are lower in cells grown in 25 mM of glucose and stimulated with IL1β. Levels of p-ERK1/2 decrease in cells grown at high glucose concentration and in cells stimulated with IL1β. Furthermore, NF-κB, iNOS and LC3II levels were evaluated. Results demonstrate that high glucose media block autophagic process in chondrocytes. Effect of glucose concentration on human primary chondrocytes cells was evaluated after only 24 h to understand which signaling pathways is activated by high glucose environment. Phosphorylation of ERK1/2, p38, Akt and p65 is altered in chondrocytes growth at high glucose concentration and this correlates with an increase secretion of MMP-13. To better analyze the role of ROS levels in the chondrocytes I worked for 6 months in the Dr. Loeser Lab at the School of Medicine in the University of North Carolina at Chapel Hill; one of the best lab in the cartilage biology field. I worked on PRX6 which is involved in the recovery from H2O2. Oxidation state of PRX6 was evaluated in chondrocytes treated with different stimuli, like H2O2, Fn-f, menadione (men) and DMNQ. After this experiment, we wanted to see if PRX6 could impact the MAPK signaling pathways in cells treated with IGF-1, menadione, combination of menadione and IGF-1 and with Fn-f. Localization of PRX6 was analyzed using nuclear and cytoplasm extraction. Then I worked in collaboration with Prof. Laura Cipolla and Prof. Maddalena Collini to develop and characterized a new gelatin-based hydrogel using Diethylsquarate as crosslinker.
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Gong, Mingrui. "Multivariable system controller tuning techniques based on sensitivity measures." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312434.
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Kato, Gabriel Fukunaga. "Avaliação da expressão imuno-histoquímica das proteínas p53 e pRB em ameloblastomas e tumores odontogênicos queratocísticos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-19012016-155909/.
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Tumores odontogênicos constituem grupo abrangente de afecções tumorais, sendo ameloblastomas e tumores odontogênicos queratocísticos as lesões benignas de maior frequência, cujas características biológicas são pouco conhecidas. Objetivo do presente estudo foi avaliar o perfil imuno-histoquímico das proteínas pRB e p53 em ameloblastoma e tumor odontogênico queratocístico. Foram avaliadas amostras de material parafinado de 21 casos de ameloblastoma e de 20 casos de tumor odontogênico queratocístico para ensaio de imuno-histoquímica com os anticorpos anti-pRB e anti-p53. A contagem da imuno-marcação foi realizada a partir de fotografias de alta resolução processadas no software ImageJ para quantificação manual em campo de 1000 células. A localização da imuno-marcação para ambos anticorpos foi semelhante, sendo em ameloblastomas predominantemente nas células da periferia e, em tumores odontogênicos queratocísticos, nas camadas suprabasais. Quantitativamente, as porcentagens de células marcadas foram estatisticamente maior nos ameloblastoma para anti-p53 (p=0,01) e maior nos tumores odontogênicos queratocísticos para anti-pRB (p=0,04). Não houve correlação estatística entre a porcentagem de células marcadas para anti-p53 e anti-pRB nos ameloblastomas, porém, esta correlação foi positiva e moderada nos tumores odontogênicos queratocísticos (r=0,537; p=0,018). Nota-se ligeira diferença na quantificação das imuno-marcações para o anti-p53 e anti-pRB. Tais resultados devem ser ponderados pela reduzida casuística, porém, sugerem perfis distintos em mecanismos biológicos determinantes para ambos os tumores.Odontogenic tumors are a comprehensive group of tumor diseases, being ameloblastomas and keratocystic odontogenic tumors the most frequent benign odontogenic tumors. Their biological characteristics are little unknown. The aim of present study was to evaluate the immunohistochemical profile of pRB and p53 proteins in 21 cases of ameloblastomas and 20 cases of keratocystic odontogenic tumors for anti-pRB and anti-p53 antibodies. The quantification of immunostaining was performed manually with high-resolution photographs processed in the ImageJ software to quantify positive cells in a 1000 cells-field. The location of immunostaining for both antibodies was similar. In ameloblastomas, positive cells are located mainly in the peripheral layers, whereas in keratocystic odontogenic tumors the positive cells are located in the suprabasal layers. Quantitatively, the percentage of labeled cells was statistically higher in ameloblastomas for anti-p53 (p = 0.01) and higher in keratocystic odontogenic tumors for anti-pRB (p = 0.04). There was no statistical correlation between the percentage of labeled cells to anti-p53 and anti-pRB in ameloblastomas, however, its correlation was positive and moderate in keratocystic odontogenic tumors (r = 0.537; p = 0.018). It is possible to identify a slight difference in immuno-quantification for anti-p53 and anti-pRB among these lesions. These results must be pondered by the small sample, however, is suggests a different profile in a preponderant key biological mechanisms for odontogenic tumors.
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Chan, Ho Man. "Molecular basis of cell cycle control : p300 and pRb." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326430.
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Sajtar, Eric T. "Toolbox to evaluate treatment technologies for PRB CBM water." Laramie, Wyo. : University of Wyoming, 2008. http://proquest.umi.com/pqdweb?did=1594485851&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Lagerholm, Anton, and Staffan Molinder. "Parameter estimation on a closed loop nutrunner system by added PRBS disturbance signal." Thesis, KTH, Maskinkonstruktion (Inst.), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-168906.
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This thesis investigated how to perform parameter estimation on an electrical nutrunner operating in closed loop. The purpose for this was to create models that could later be used in design of controllers used in new tightening techniques. The system was divided into two models, one for the electrical motor and one for the driveline, that could be used separately in parameter estimation. Data was collected from both the control system and by an external data acquisition system while the nutrunner was operated in closed loop. A pseudo-random binary sequence signal was added as a disturbance in order to further excite the system such that the internal dynamics of the nutrunner wasforced to show up clearly in the output data.The MATLAB toolbox Simulink Design Optimization was used to perform the parameter estimations and the results were then validated. The validation showed that the sets of estimated parameters were able to simulate the system well, thus supporting the choice ofthe added disturbance signal.Detta examensarbete undersökte parameterskattning på en elektrisk skruvdragare som reglerades under återkoppling. Syftet med detta var att skapa modeller som senare ska kunna användas vid design av regulatorer för nya åtdragningsstrategier. Systemet delades in i två modeller, en för den elektriska motorn och en för drivlinan, som kunde parameterskattas separat. Data hämtade in dels från kontrollsystemet och med ett externt DAQ system vid körning av verktyget under återkoppling. En PRBS signal adderades till systemet som en störning i syfte att ytterligare excitera så att den interna dynamiken skulle synas i de uppmätta utsignalerna. MATLAB-vertyget Simulink Design Optimization användes för parameterskattningen och resultatet validerades sedan. Valideringen visade att systemet simulerades väl, detta visade på lämpligheten hos den adderade störsignalen.
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COMISSO, ELISA. "OCT4 promuove l'aggressività del tumore ovarico sieroso ad alto grado attraverso l'inattivazione di pRB e l'aumento della stabilità genomica." Doctoral thesis, Università degli Studi di Trieste, 2016. http://hdl.handle.net/11368/2908031.
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OCT4 (POU5F1) appartiene alla famiglia dei fattori di trascrizione POU ed è noto svolgere un ruolo cruciale nel mantenimento dell’autorinnovamento e della pluripotenza delle cellule staminali embrionali (ESCs). Attualmente, diversi studi sottolineano l’importanza dell’espressione di OCT4 a livello tumorale nel mantenere le caratteristiche tumorigeniche simil-staminali. Nonostante il ruolo essenziale di OCT4 durante l’embriogenesi e la riprogrammazione di cellule somatiche, il suo preciso ruolo nella tumorigenesi non è stato ancora chiaramente definito. In questa tesi abbiamo trovato che OCT4 guida l’espressione dell’Inibitore Nucleare della Proteina Fosfatasi (NIPP1) e Ciclina F (CCNF) che insieme inibiscono la Proteina Fosfatasi 1 (PP1) nel tumore ovarico sieroso ad alto grado (HG-SOC). Questo causa l’iper-fosforilazione della proteina del Retinoblastoma (pRB), la proliferazione accelerata e l’aumento della tumorigenicità in vitro in cellule di tumore ovarico. In parallelo, OCT4 e NIPP1/CCNF causano l’aumento dell’espressione delle componenti del Chromosomal Passenger Complex (CPC), Borelin, Survivin e la chinasi mitotica Aurora B, che è essenziale per il mantenimento della stabilità genomica. Il CPC, infatti, promuove il meccanismo di raggruppamento dei centrosomi, chiamato “centrosomes clustering mechanism”, portando ad aumento della stabilità mitotica. La perdita di OCT4 o NIPP1/CCNF causa gravi difetti mitotici, fusi multipolari e centrosomi soprannumerari, portando alla fine all’induzione della senescenza e apoptosi. In particolare, l’attivazione di queste due vie parallele porta a una significativa riduzione della sopravvivenza in pazienti con HG-SOC. In conclusione abbiamo dimostrato che OCT4 aumenta l’aggressività del HG-SOC attraverso l’inattivazione della via di segnalazione di pRB e il miglioramento dell’accuratezza mitotica, sottolineando il ruolo di OCT4 quale regolatore della stabilità genomica e dell’attività oncosoppressiva di pRB. Quindi, bersagliare la via OCT4-NIPP1/CCNF-PP1 potrebbe essere una strategia promettente per gestire e trattare specificatamente una sottopopolazione aggressiva di HG-SOC.OCT4 (POU5F1) is a member of the POU family of transcription factors and is known to play a crucial role in the maintenance of self-renewal and pluripotency in Embryonic Stem Cells (ESCs). Nowadays, several studies highlight the importance of OCT4 expression in tumors in order to maintain the tumorigenic stem cell-like features. Despite the essential role of OCT4 during embryogenesis and reprogramming of somatic cells, its exact role in tumorigenesis is still not well defined. In this thesis we found that OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1) in High-Grade Serous Ovarian Cancer (HG-SOC). This cause Retinoblastoma protein (pRB) hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells. In parallel, OCT4 and NIPP1/CCNF drive the expression of the central Chromosomal Passenger Complex (CPC) components, Borealin, Survivin and the mitotic kinase Aurora B, that are essential for the maintenance of genomic stability. CPC, in fact, promoting the “centrosomes clustering mechanism”, leads to increased mitotic stability. Loss of OCT4 or NIPP1/CCNF results in severe mitotic defects, multipolar spindles and supernumerary centrosomes, finally leading to the induction of senescence and apoptosis. Importantly, activation of these parallel pathways leads to a dramatically reduced overall survival of HG-SOC patients. In conclusion we demonstrate that OCT4 increases HG-SOC aggressiveness by inactivating the Retinoblastoma tumorsuppressor pathway and enhancing mitotic fidelity in cancer cells, highlighting an unknown role of OCT4 as central regulator of genomic stability and RB tumorsuppressor pathway activity. Thus, targeting the OCT4-NIPP1/CCNF-PP1 pathway could be a promising strategy to manage and treat specifically an aggressive subpopulation of HG-SOC.
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Luczynski, Maciej Tomasz. "Structure-guided functional analysis of the pRb N-terminal domain." Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531336.
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Zarkowska, Tamara Anna. "Phosphorylation of the retinoblastoma protein, pRB, by CDK4-cyclin D1." Thesis, Institute of Cancer Research (University Of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321951.
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Franklin, Phoebe. "Are permeable reactive barriers (PRBS) a viable technology for remediation of diffuse nitrate pollution?" Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523068.
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Horton, Lynn Elizabeth. "Studies on cyclin structure and pRb phosphorylation in cell cycle control." Case Western Reserve University School of Graduate Studies / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=case1057684343.
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Cavallaro, Piera Maria Luisa. "Valutazione di materiali innovativi per l'allestimento di barriere reattive permeabili (PRB)." Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/1252.
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Le barriere reattive permeabili, che rappresentano un mezzo per prevenire e/o annulare l'inquinamento delle falde, sono oggetto di studio e continuo perfezionamento soprattutto per quanto riguarda la natura dei materiali reattivi. Secondo le nuove teorie, il materiale più efficiente è quello che agisce per adsorbimento e per catalisi delle reazioni di degradazione
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Yang, Zhongyu. "Performance Advantages of Maximum Likelihood Methods in PRBS-Modulated Time-of-flight Energy Loss Spectroscopy." Fogler Library, University of Maine, 2003. http://www.library.umaine.edu/theses/pdf/YangZ2003.pdf.
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Seibel, B. [Verfasser]. "Berechnungen von Röntgenabsorptionsspektren an YBa₂Cu₃O₇, PrBa₂Cu₃O₇ und Sr₂RuO₄ / B. Seibel." Karlsruhe : KIT-Bibliothek, 1997. http://d-nb.info/1108447422/34.
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Larrotta, Fabian Núñez. "Estudo e implementação de sinais de excitação aplicados em identificação de sistemas multivariáveis." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/3/3139/tde-21062016-135438/.
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Devido à crescente implementação do Controle Preditivo baseado em Modelo (MPC) em outros processos além de refino e plantas petroquímicas, que geralmente possuem múltiplas entradas e saídas, tem-se um aumento na demanda de modelos gerados por identificação de sistemas. Identificar modelos que representem fielmente a dinâmica do processo depende em grande medida das características dos sinais de excitação dos processos. Assim, o foco deste trabalho é realizar um estudo dos sinais típicos usados em identificação de sistemas, PRBS e GBN, em uma abordagem multivariável. O estudo feito neste trabalho parte das características da geração dos sinais individualmente, depois é feita uma análise de correlação cruzada dos sinais de entrada, observando a influência desta sobre os resultados de identificação. Evitar uma alta correlação entre os sinais de entrada permite determinar o efeito de cada entrada sobre a saída no processo de identificação. Um ponto importante no projeto de sinais de identificação de sistemas multivariáveis é a frequência dos mesmos para conseguir excitar os processos nas regiões de frequência de operação normal e assim extrair a maior informação dinâmica possível do processo. As características estudadas são avaliadas por meio de testes em três plantas simuladas diferentes, categorizadas como mal, medianamente e bem condicionadas. Estas implementações foram feitas usando sinais GBN e PRBS de diferentes frequências. Expressões para a caracterização dos sinais de excitação foram avaliadas identificando os processos em malha aberta e malha fechada. Para as plantas mal condicionadas foram implementados sinais compostos por uma parte completamente correlacionada e uma parte não-correlacionada, conhecido como método de dois passos. Finalmente são realizados experimentos de identificação em uma aplicação em tempo real de uma planta piloto de neutralização de pH. Os testes realizados na planta foram feitos visando avaliar os estudos de frequência e correlação em uma aplicaficção real. Os resultados mostram que a condição de sinais completamente descorrelacionados n~ao deve ser cumprida para ter bons resultados nos modelos identificados. Isto permite ter mais exibilidade na geração do conjunto de sinais de excitação.Due to the Predictive Control based on Model (MPC) rising in other process beyond refining and petrochemical plants, which in general have multiple inputs and outputs, there have been an increase in demand of models generated by system identification. Identify models that accurately represent the dynamics of the process depends largely on the characteristics of the processes excitation signals. Thus, the focus of this work is to perform a study of the typical signals used in identification systems, PRBS and GBN, in a multivariable approach. The study carried out in this work begins on the individual generation characteristics of the signals, and then an analysis is made of input signals cross-correlation, by observing the in uence of this on the identification results. Avoid a high correlation among the input signals allows to determine the effect of each input on the output of the identification process. An important point in the signals design for multivariable system identification is its frequency to get excite the processes in the normal operation frequency regions and thus extract the maximum dynamic information possible of the process. The studied characteristics are evaluated by testing three different simulated plants, categorized as well, medium and ill conditioned. These implementations were made using GBN and PRBS signals of dierent frequencies. Expressions to characterize the excitation signals were evaluated identifying the processes in open and closed-loop. For ill-conditioned plants were implemented signals composed by a fully correlated part and a non-correlated part, known as two-step method. Finally, identification experiments are performed on a real time application in a pilot pH neutralization plant. The tests were made in the plant in order to evaluate the frequency and correlation studies in a real application. The results show that the completely uncorrelated signals condition must not be satisfied to have good results on the identified models, which besides allows greater exibility in the generation of the excitation signals set.
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Ali-Khan, Nadeem. "Biochemical characterisation of the eukarytic cell cycle regulatory proteins, E2F and pRB." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270398.
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Simpson, Matthew Thomas W. "Caspace-3 deficiency rescues peripheral nervous system defect in pRb nullizygous mice." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6297.
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The retinoblastoma tumour suppressor protein, pRb, is a key regulator of cell cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by E14.5 from haematopoietic and neurological defects attributed to failed differentiation (Jacks et al., 1992; Lee et al., 1992; Clarke et al., 1992). Previous studies by Macleod et al., (1996) have demonstrated that the loss of p53 protects pRb-deficient central nervous system (CNS) neurons but not peripheral nervous system (PNS) neurons from cell death. Thus, the mechanisms by which PNS neurons undergo apoptosis in response to pRb deficiency remain unknown. In view of the pivotal role of caspase-3 in the regulation of neuronal apoptosis during development, we examined its function in the execution of the widespread neuronal cell death induced by pRb deficiency. Our results support a number of conclusions: First, we show that caspase-3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase-3 deficiency does not extend the life span of pRb null embryos, as double null mutants exhibit high rates of liver apoptosis resulting in erythropoietic failure. Third, pRb/caspase-3 double mutant neurons of the CNS exhibit widespread apoptosis similar to that seen in pRb mutants alone, thus caspase-3 deficiency does not protect this population from apoptosis. Finally, in contrast to the CNS, neurons of the PNS including those comprising the trigeminal ganglia (TG) and the dorsal root ganglia (DRG) are protected from apoptosis in pRb/caspase-3 double mutant embryos. Examination of the mechanistic differences between these two cell types revealed that CNS neurons invoke compensatory caspase activity that is not found in PNS neurons. These findings suggest that PNS neurons are dependent upon caspase-3 for the execution of apoptosis and that caspase-3 may serve as a key therapeutic target for neuroprotection following injury of this cell type.
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Banerji, Lolita. "The role and regulation of the pRB/E2F pathway in B-lymphocytes." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252407.
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Korah, Juliana. "Role of the pRb/E2F pathway in TGF beta-mediated tumour suppression." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123071.
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Tumour formation is characterized by a series of well-defined events that occur in virtually all human cancers, including the ability of cells to attain immortalization, sustain proliferation and evade apoptosis. These cell growth and cytostatic processes are normally regulated by various growth factors that act in concert to maintain proper cellular homeostasis. As a result, deregulation of these growth factor signalling pathways leads to uncontrolled cell growth and tumour formation. In particular, transforming growth factor-β (TGFβ) exerts a central role in preventing tumour formation in virtually all cell types and tissues. TGFβ tumour suppressive effects are mainly illustrated by its ability to inhibit cell growth, induce cell death and prevent cell immortalization. TGFβ-mediated prevention of cell immortalization relies on inhibition of telomerase activity. While expression of hTERT, the protein component of telomerase, is increased in most cancer cells, studies from our laboratory revealed that TGFβ efficiently represses hTERT gene expression in both normal and cancer cells through multiple signalling pathways. We further found that the inhibition of hTERT by TGFβ requires the synthesis of an intermediate molecule that we identified as the transcription factor E2F1, and showed that interfering with E2F1 activity impedes the TGFβ inhibitory effect on telomerase activity. The E2F family of transcription factors plays a central role in regulating cell-cycle progression. Deregulation of these factors is a common event in most human cancers. Interestingly, E2F1 has been shown to have the ability to induce both cell cycle progression and apoptosis, though the mechanisms of E2F-mediated apoptosis have not been fully elucidated. TGFβ itself is a potent pro-apoptotic factor, as it modulates the expression of multiple apoptotic genes in various tissues. However, a common and central signalling pathway, acting downstream of TGFβ and leading to cell death, had yet to be uncovered. Interestingly, recent work from our laboratory highlighted E2F1 as a central factor downstream of TGFβ-induced apoptosis in cancer cells. Using the E2F1 knockout mouse model, we found E2F1 to be required for TGFβ-mediated apoptosis in normal cells as well. We further investigated the molecular mechanisms by which E2F1 contributes to TGFβ-mediated apoptosis and found that TGFβ treatment led to the formation of a transcriptionally active E2F1–pRb–P/CAF complex on multiple pro-apoptotic target gene promoters, thereby activating their transcription. These findings define a novel process of gene activation by the TGFβ-E2F1 signalling axis, and uncover the pRb/E2F1 pathway as a wide-ranging and critical mediator of the TGFβ apoptotic programme in multiple target tissues. We further determined that TGFβ induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes, potentially leading to autophagic cell death. Together, our studies support a role for the pRb/E2F pathway as a potent co-transducer of TGFβ signalling and highlight the pivotal role for pRb/E2F in mediating TGFβ tumour-suppressive effects.La formation de tumeurs est caractérisée par une série d'évènements bien définis qui sont communs à tous les cancers, notamment l'habileté des cellules à atteindre l'immortalisation, maintenir la prolifération, et éviter l'apoptose. Ces procédés cytostatiques et de croissance cellulaire sont normalement régulés par divers facteurs de croissance qui agissent de concert pour maintenir l'homéostasie cellulaire. De ce fait, un dérèglement dans la signalisation de ces facteurs mène à une croissance incontrôlée et à la formation de tumeurs. Plus particulièrement, le facteur de croissance β (TGFβ) exerce un rôle central en agissant comme suppresseur de tumeurs dans quasiment tous les types cellulaires et tissus. Les effets en tant que suppresseur de tumeurs du TGFβ sont illustrés par son habileté à inhiber la croissance cellulaire, induire la mort cellulaire, et prévenir l'immortalisation cellulaire. La capacité du TGFβ à prévenir l'immortalisation cellulaire s'appuie sur le fait qu'il inhibe l'activité de la télomérase. Bien que l'expression de hTERT, la protéine faisant partie du complexe de la télomérase, soit accrue dans la plupart des cellules cancéreuses, des études de notre laboratoire ont révélé que le TGFβ peut réprimer l'expression du gène codant pour hTERT dans les cellules autant normales que cancéreuses à travers des voies de signalisation multiples. Nous avons de plus trouvé que l'inhibition de hTERT par le TGFβ requiert la synthèse d'une molécule intermédiaire que nous avons identifié comme étant le facteur de transcription E2F1, et avons démontré que d'interférer avec l'activité du E2F1 empêche les effets inhibiteurs du TGFβ sur l'activité de la télomérase. La famille des facteurs de transcription E2F joue un rôle central dans la régulation de la progression du cycle cellulaire. La dérégulation de ces facteurs est un évènement commun dans la plupart des cancers. Il a été démontré que le E2F1 possède l'habileté d'induire autant la progression du cycle cellulaire que l'apoptose, cependant, le mécanisme par lequel le E2F1 induit l'apoptose n'est pas complètement élucidé. Le TGFβ est lui-même un facteur pro-apoptotique puissant, car il module l'expression de plusieurs gènes apoptotiques dans une variété de tissus. Cependant, une voie de signalisation commune et centrale, agissant en amont du TGFβ et amenant à la mort cellulaire, reste toujours à démontrer. Des travaux récents de notre laboratoire soulignent le E2F1 comme étant un facteur central en amont de l'apoptose médiée par le TGFβ dans les cellules cancéreuses. En utilisant un modèle de souris où le E2F1 a été inhibé, nous avons pu déterminer que le E2F1 est requis pour l'apoptose médiée par le TGFβ également dans les cellules normales. Nous avons investigué plus en profondeur les mécanismes moléculaires par lesquels le E2F1 contribue à l'apoptose médiée par le TGFβ et avons trouvé qu'un traitement par le TGFβ mène à la formation du complexe transcriptionellement actif E2F1-pRb-P/CAF sur le promoteur de plusieurs gènes pro-apoptotiques pour activer leur transcription. Ces découvertes définissent un nouveau procédé d'activation des gènes par l'axe de signalisation TGFβ-E2F1, et a permis d'élucider la voie pRb/E2F1 comme un médiateur critique et à grande portée du programme apoptotique du TGFβ et ce, dans plusieurs tissus cibles. Nous avons de plus déterminé que le TGFβ induit l'activation de la transcription de gènes autophagiques par le complexe pRb/E2F1. Collectivement, nos études supportent un rôle pour le complexe pRb/E2F1 dans la voie de signalisation du TGFβ et dans ses effets en tant que suppresseur de tumeurs.
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Moberg, Kenneth H. (Kenneth Harold) 1967. "Molecular analysis of the role of E2F proteins in the pRB pathway." Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/49676.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 1998.Includes bibliographical references.
The E2F family of transcription factors appear to represent the primary cellular target of the tumor suppressive properties of the retinoblastoma protein. E2F therefore functions in a pathway which is a frequent target in human cancer, and the tumorigenicity of these mutations may be mediated at the transcriptional level by E2F. E2F is also regulated by cell cycle-dependent interactions with the pRB-related proteins p107 and p130. Unlike pRB, mutations in p107 or p130 are not associated with cancer. The different properties of the pRB family may result from the manner in which each protein regulates E2F. To determine how individual E2Fs contribute to the cell cycle regulatory properties of pRB, p107 and p1 30, we have examined the regulation of individual members of the E2F family. Our data suggest that the induction of E2F responsive genes is primarily due to the loss of nuclear repressor complexes at G1/S. This loss correlates with the disappearance of nuclear forms of E2F-4 protein, which represents the majority of pRBbound nuclear E2F during G1. These data suggests that E2F-4, the most abundant E2F in vivo, acts primarily as the DNA-binding component of a G1 transcriptional repressor complex. In contrast, we find that E2F-1, -2 and -3 are present at low levels in vivo and localize to the nucleus by virtue of a nuclear localization signal sequence in the N-terminal domain of these proteins. Their constitutive nuclear localization suggests that these E2F family members will contribute to the activation of responsive gene transcription during S-phase. Together, these data suggest that induction of E2F-responsive genes at G1/S is triggered both by the loss of an abundant transcriptional repressor, E2F-4*pRB, and by the presence of nuclear forms of E2F capable of transcriptional activation. These functional differences among E2Fs may underlie the oncogenic consequences specifically associated with pRB loss. Inactivation of pRB is predicted to both abrogate repression of E2F-responsive genes, and relieve inhibition of nuclear, activatory E2Fs. The combined effect of these forms of transcriptional deregulation of the E2F pathway may be sufficient to promote transformation in vivo.
by Kenneth H. Moberg, Jr.
Ph.D.
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Tutton, Stephen Paul. "Repression of E2F-4 Mediated Transcription and Growth by Hypophosphorylated pRb2/p130 in Human Prostate Cancer Cells." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/138637.
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BiologyPh.D.
A fundamental property of tumor cells is the ability to proliferate in an unscheduled manner, circumventing the cues which would otherwise prevent entry into, and completion of, the cell cycle (Malumbres, Barbacid 2001). The retinoblastoma protein (pRb), and its homologues pRb2/p130 and p107, comprise a gene family which is central in maintaining appropriate cell proliferation and differentiation. The RB proteins bind to and modulate the activity of E2F transcription factors, by way of a unique binding motif termed the pocket domain; as such, RB family genes are often referred to as pocket proteins. E2F -1, -2, and -3 are considered transcriptional activators and have been shown mainly to bind pRB, whereas E2F -4 and -5 are considered transcriptional repressors, and primarily bind p107 and pRb2/p130 (Classon, Dyson 2001, Cobrinik 2005). The commonly accepted model of pRb2/p130 function is that, during quiescence, pRb2/p130, bound to E2F-4 and -5, is an active repressor of E2F responsive S-phase genes, which includes p107 and a number of cyclins (Figure 1). Upon entry into G1, the many phosphoacceptor sites of pRb2/p130 are progressively phosphorylated, disrupting the repressor complex, and allowing the transcription of downstream targets. pRb2/p130 is acted upon by the same early and late G1 kinases which phosphorylate pRb and p107, namely cyclin dependant kinases (cdk) 4 and 6, which partner with cyclin D, and later by cdk2, which requires cyclin E or A. pRb phosphorylation is required to prevent its inhibition of E2F transcription, which would otherwise halt cell cycle progression. E2F transcriptional activity permits the cell to traverse the G1/S restriction point by, among other effects, promoting cdk2 activity, which maintains pocket protein inactivation and E2F activity in a positive feedback fashion. By interacting with different sets of E2F proteins to repress transcription, pRb and pRb2/p130 act in a parallel manner to restrict cell proliferation (Classon, Dyson 2001, Cobrinik 2005, Bartek, Lukas 2001). Preliminary investigation of pRb2/p130 phosphorylation among individual cell lines grown to confluence revealed significant variation. The pattern observed suggests that, in quiescent cells, the state of pRb2/p130 phosphorylation, and thus its functionality, can vary significantly from one cell type to another. This variance likely has significant consequences on cell phenotype, dependant on the fine balance of upstream kinases and inhibitors which regulate pRb2/p130 activity. Further investigation revealed that prostate cancer cell lines which are judged to be more aggressive also resist contact inhibition, and also that there is a higher degree of pocket protein phosphorylation and E2F gene transcription in these cells. The expression and degree of pocket protein phosphorylation in these prostate cancer cells correlates with malignancy, and may impact E2F-mediated transcription and growth. Despite this increased phosphorylation, the more aggressive prostate cells did not appear to have excessive cdk2 or cdk4 expression or kinase activity. These cells did exhibit a progressive loss of cdk inhibitor (CKI) expression in comparison to less invasive cells, which might explain the greater degree of RB protein family phosphorylation. As a modestly invasive cell line containing abundant, hypophosphorylated pRb2/p130, LNCaP was selected for lentiviral infection with siRNA containing plasmids to generate knockdown subclones. Knockdown of pRb2/p130 resulted in increased E2F-dependant gene expression in these cells, supporting the idea that hypophosphorylated pRb2/p130 did in fact repress transcription in this context. However despite this derepression, a growth advantage was not conferred to these cells by pRb2/p130 knockdown.
Temple University--Theses
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Jayadeva, Girish. "B55alpha modulates the phosphorylation status of the pRb-related p107 and p130 proteins." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/64785.
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Molecular Biology and GeneticsPh.D.
The retinoblastoma family of phosphoproteins consisting of the retinoblastoma protein (pRB) and the two structurally related proteins p130 and p107 play an important role in the negative regulation of cell cycle progression. Hypophosphorylated pocket proteins interact with the different members of the E2F family and repress the transcription of E2F-dependent genes and consequently suppress cell cycle progression through the G0/G1 transition and the restriction point in G1. Mitogenic stimulation results in sequential activation of cyclin/CDK complexes in mid to late G1, leading to subsequent hyperphosphorylation at multiple Ser/Thr sites of pocket proteins triggering dissociation of pocket protein/E2F complexes. This disruption leads to de-repression of many E2F dependent genes whose products are essential for cell cycle progression. The traditional view has been that pocket proteins continue to be hyperphosphorylated through the S and G2 phases and following cyclin/CDK inactivation during mitotic exit become dephosphorylated by action of PP1. However, our lab observed that upon treatment of asynchronously growing cells with the CDK inhibitor Flavopiridol or CHX, pocket proteins, are rapidly dephosphorylated correlating with the inactivation of G1/CDKs and down regulation of D-type cyclins, respectively. Pocket protein dephosphorylation was prevented by pre-treating these cells with phosphtase inhibitors at a concentration selective for PP2A, implicating PP2A or PP2A-like serine/threonine phosphatase in this iii process. The involvement of PP2A on pocket protein dephosphorylation was further strengthened by the observation that SV40 small t antigen (ST) delays/prevents p107 dephosphorylation. Moreover, a physical association between PP2A/C and p130/p107 was observed throughout the cell cycle that was not affected by CHX treatment, strongly suggesting that CHX-induced dephosphorylation is not the result of increased pocket protein targeting by PP2A, but rather that a dynamic equilibrium between CDKs and PP2A is shifted to dephosphorylation when CDK activity is compromised. This dynamic equilibrium operates throughout the cell cycle. PP2A is a trimeric enzyme complex consisting of a catalytic C, a structural A and substrate specific B subunit. There are four families of regulatory B subunits designated B, B’, B’’ and B’’’, each with several members encoded by genes with multiple splice variants that mediate substrate specificity and subcellular localization. It has been reported recently that in excess of 200 functional distinct PP2A holoenzymes can assemble with distinct specificities. Therefore, to gain insight into the mechanisms that regulate the steady state phosphorylation of pocket proteins throughout the cell cycle, it was essential to identify the specific holoenzyme complexes involved. To this end, it was identified that a PP2A trimeric holoenzyme containing B55α specifically targets and dephosphorylates p107/p130 both in vitro and in mammalian cells. B55α associates directly with the spacer of p107 and this interaction seems to be indirectly enhanced by the C-terminus of p107. The decreased association of p107 with PP2A/C of the B55α/PP2A holoenzyme complex upon treatment with ST further confirmed the role of B55α in mediating p107-PP2A/C interaction. Our data also revealed an interaction between B55α and p130, but not pRb, which appears to prefer a PR70, suggesting selectivity in the interaction of pocket proteins with distinct PP2A holoenzymes. In accordance with this, recombinant purified B55α dephosphorylates p107 in vitro. Limited ectopic expression of B55α but not other subunits, result in ST sensitive dephosphorylation of p107 and p130 in cells. Further shRNA mediated knockdown of B55α results in hyperphosphorylation of p107 and p130. This suggests that the cellular levels of B55α are critical in modulating the phosphorylation status of p107/p130 rather than just catalyzing the dephosphorylation of these proteins when the activity of CDKs is compromised. Since ST disrupts the B55α/PP2A holoenzyme complex by binding to the PP2A-A-C dimer and leads to hyperphosphorylation of pocket proteins it is conceivable that ST mediates its effects on cell proliferation at least in part, via inactivation of the PP2A holoenzymes that activates pocket proteins. Given the sensitivity of p107 phosphorylation to the cellular levels of B55α, future analyses should ascertain if deregulation of B55α leads to hyperphosphorylation of pocket proteins and abnormal cell cycle progression.
Temple University--Theses
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Meza, Maria I. "The use of PRBs (permeable reactive barriers) for attenuation of cadmium and hexavalent chromium from industrial contaminated soil." Muncie, Ind. : Ball State University, 2009. http://cardinalscholar.bsu.edu/432.
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Norman, Per-Gustaf. "Cloning, Purification and Crystallization of Low PSII Accumultation 19 (LPA19) and Peroxiredoxin-6 (Prx6): A Thorny Road to Diffracting Crystals." Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-111548.
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Penglong, Tipparat. "Molecular Basis of Erythroid Cell Proliferation and Differentiation." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T022.
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Pour assurer la production de milliards de globules rouges, l’érythropoièse doit parfaitement contrôler les processus de prolifération et de différenciation. Ces deux processus sont régulés par l’expression de gènes spécifiques dépendant d’une coordination entre l’activité des facteurs de transcription (FT) et les fonctions épigénétiques portées par exemple par les protéines à bromodomaine. Cette étude se concentre sur les conséquences de l’association ou la dissociation du FT clef de l’érythropoièse GATA-1 avec les FT déterminant pour le cycle cellulaire, pRb et E2F. Dans la première partie de ma thèse, j’ai participé à l’étude du rôle de l’association/dissociation de GATA-1 et FOG-2 avec pRb/E2F dans le contrôle la balance prolifération/différenciation cellulaire. Nos résultats montrent que les souris exprimant une mutation de GATA-1 sur la sérine 310 (GATA-1S310A), qui a la capacité accrue à séquestrer E2F-2, présentent une anémie létale lorsqu’un mécanisme de compensation de production de E2F-2 induit par l’IGF-1 est inhibé. Puis, nous avons trouvé que les propriétés décrites pour GATA-1 sont partagées par le FT FOG-2 et montré que l’abrogation de sa fixation avec pRb induit une perturbation de l’adiposité dans des souris FOG-2pRb-. Dans la deuxième partie, l’expression de c-Myc étant régulé différentiellement par GATA-1 et E2F, j’ai testé si la drogue « JQ1 », premier inhibiteur épigenétique chimique de l’expression de c-Myc, pouvait contrôler l’érythropoièse. Pour cela, j’ai utilisé la ligné érythroleucémique UT7 qui prolifère sans se différencier en présence d’érythropoiétine (stade proérythroblaste). Les résultats montrent que le traitement par JQ1 bloque la prolifération des cellules UT7 et permet de réinitier le programme de différentiation érythroide terminale. J’ai alors recherché les mécanismes moléculaires impliqués dans cette régulation et trouvé que l’inhibition transcriptionnelle de c-Myc par JQ1 est associée à l’inhibition de l’activité transcriptionnelle de STAT5 sans modification de son état de phosphorylation. Enfin, j’ai montré que JQ1 pouvait avoir une activité comparable à celle du TGF-b mais sans implication les voies Smad. Des études in vivo montre que JQ1 augmente la viabilité cellulaire et accélère la maturation des cellules érythroides à la fois chez les souris sauvages et thalassémiques. Cette différence d’action de JQ1 sur l’érythropoièse normale et pathologique implique des modifications épigénétiques différentielles entre ces deux types cellulaires et sont à la base de nouvelles stratégies du traitement du cancer. Le rôle clef de la régulation de l’association/dissociation de GATA-1 ou FOG-2 avec pRb/E2F dans l’érythropoièse et l’adipogénèse, nous a conduit, dans une troisième partie, à déterminer in vivo, les conséquences physiologiques de la séquestration de E2F par pRb. Pour cela nous avons crée une souris transgénique exprimant de façon conditionnelle un peptide contenant la partie N terminale de GATA-1 qui se fixe à pRb (GATA-1Nter). In vitro, ce peptide séquestre E2F dans le complexe GATA-1Nter/pRb et inhibe la prolifération cellulaire de façon irréversible. In vivo, aucune souris transgéniques exprimant le peptide GATA-1Nter n’a pu être sélectionnée et une mortalité au stade embryonnaire est observée. Une expression induite de ce peptide au stade adulte ne produit que des souris chimériques avec une fréquence de recombinaison du transgène GATA-1Nter importante. L’établissement de lignées stables de souris exprimant le peptide GATA-1Nter permettra de déterminer les conséquences physiologiques de la séquestration de E2F dans le complexe GATA-1Nter/pRbTo ensure the generation of billions of erythrocytes daily, erythropoiesis must be well controlled by proliferation and differentiation processes. These two processes are regulated by expressions of specific genes, coordinated by transcription factors (TFs) and epigenetic factors, such as bromodomain proteins. This study focused on the effects of the binding and dissociation of a key erythroid TF, GATA-1, to the crucial cell cycle TFs, pRb and E2F. In the first part of this thesis, the role of GATA-1 and FOG-2 binding to pRb/E2F in a control balances between cell proliferation and differentiation was studied. Mice bearing a GATA-1 mutation (GATA-1S310A) displayed higher levels of E2F2 sequestration and suffered from fatal anemia when the compensatory pathway of E2F2 production via IGF-1 signaling was also inhibited. The properties described for GATA-1 were found to be common to FOG-2, and the abolition of FOG-2 binding to pRb led to obesity resistance in FOG-2pRb- mice. In the second part of this work, as c-Myc is regulated by GATA-1 and E2F, the first chemical epigenetic inhibitor repressing c-Myc expression to be described, JQ1, was investigated to see if it could control erythropoiesis. The UT7 erythroleukemia cell line, which proliferates without differentiating was used. This cell line stops differentiation at the proerythroblast stage, in response to erythropoietin. JQ1 treatment inhibited UT7 proliferation and restored terminal erythroid differentiation. The molecular mechanism underlying this regulation by JQ1 was shown that the inhibition of c-Myc expression was associated with the inhibition of STAT5 transcription, with no change in the phosphorylation of this protein. It was found that JQ1 had a putative TGF--like activity, which did not involve the Smad pathway. It was shown in the ex vivo studies that JQ1 increased the viability of erythroid cells and accelerated the maturation of these cells in both WT and thalassemic mice. The observed differences between leukemic and normal erythropoiesis involved differential epigenetic modifications that could be at the basis of new strategies regarding cancer treatment.The key role of the association of GATA-1 or FOG-2 had with pRb/E2F, and the dissociation of these factors, in erythropoiesis and adipogenesis, respectively, led us to investigate, in vivo, the physiological consequences of E2F sequestration by pRb. As a result, transgenic mice displaying conditional expression of a peptide containing the N-terminal part of GATA-1 that binds to pRb (GATA-1Nter) were developed. In vitro, this peptide traps E2F in a GATA-1Nter/pRb complex, resulting in the irreversible inhibition of cell proliferation. The yield of transgenic mice expressing the GATA-1Nter peptide in vivo was unsuccessful, as this expression lead to lethality at the embryonic stage. Using an alternative approach, based on the inducible expression of the peptide in adults, chimeric mice with a high frequency of recombination of the GATA-1Nter transgene were obtained for this study. The establishment of a stable mouse line expressing the GATA-1Nter peptide should make it possible to determine the pathophysiological consequences of E2F sequestration in the GATA-1Nter/pRb complex
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Luo, Ping. "Quantification of morphological changes in zero valent iron (ZVI) : effect on permeable reactive barrier (PRB) longevity." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503921.
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Permeable Reactive Barriers (PRBs) have been used world-wide to remediate chlorinated solvents, metals and radionuclides from contaminated groundwater by precipitation, sorption, ion exchange and biodegradation in the last two ;ades. There is still however limited information regarding the formation of byproducts and subsequent pore clogging with respect to attaining the predicted, significant life spans (>50 years), even on the most popular PRE materials such as ZVI. This project aimed to visually examine and quantify morphological :hanges on ZVI barriers and subsequently to quantify the PRE longevity due to the occlusions.
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Doherty, R. D. "Modelling of a permeable reactive barrier (PRB) in a manufactured gas plant site, Portadown, Northern Ireland." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269086.
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Thunberg, Billy, and Kalle Kurttio. "Radardetektering av stålämnen med hjälp av UWB-radar." Thesis, Högskolan i Gävle, Elektronik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-22538.
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Stålindustrierna Sandvik, Sandviken och SSAB, Borlänge tillverkar billets (kvadratiska ochlångsmala stålämnen). Vid tillverkningen av billets förflyttas stålämnena stegvis i ugnensamtidigt som de hettas upp. När stålämnena når slutet av ugnen lyfts de ur av en externmaskin. För att tids- och energieffektivisera den sista etappen krävs positionsbestämning avämnena då de når slutet av ugnen. Dessa aspekter är viktiga ur en ekonomisk såväl sommiljövänlig synpunkt då induktiva ugnar använder en stor mängd energi. Tillämpningen ärtänkt att användas av stålindustrin. UWB-radarns bredbandiga karakteristisk gör den till en lämplig ersättare till dagens sensorersom kräver håltagning i ugnens valv. Det breda frekvensspektrat hos en UWB-radarmöjliggör ytmonterade enheter i kontrast till de konventionella sensorer som används idag.Underhållsstopp för rengöring av sensorhålen kan då undvikas. Arbetet började med teoretisk studie rörande UWB-teknik och radar i allmänhet. Därefterutformades testscenarion för att studera radarvågen under varierande förhållanden. Denradaruppställning som användes under testscenariorna var framåtspridande radar. Deresulterande mätningarna signalbehandlades i Matlab. Resultatet visar att det är möjligt att detektera objekt av olika dimensioner och former på olikaavstånd, med hjälp av UWB-radar. Denna metod fungerar även som ett passagelarm, vilkenkan användas inom fler områden.The steel industries Sandvik, Sandviken and SSAB, Borlänge, produces billets (quadratic,long steel units). Billets travelling through the furnace will heat up. At the end of the furnace,the billets will require precision measurements regarding its position, due to the extractingdevice. Sensors that are used today require an unobstructed view, which is achieved by holesin the furnace walls. Maintenance is needed in order to ensure that no impurities are cloggingthe holes. The goal with this thesis is to investigate whether it is possible to detect rectangular billets byusing an UWB-radar system. The broadband characteristics of an UWB-unit makes it asuitable successor, as free sight is not a requirement. This will decrease downtown due tomaintenance and optimize the time required for billets extraction.This involves economic and environmental aspects as well, due to lower energy consumption. This will be tested by collecting radar measurements for further signal processing. The usedradar system is forward scattering radar. The work started with a theoretical study aboutUWB-technique and basics about radar. Thereafter test scenarios were designed to study howthe radar wave is affected by changing environments. The resulting measurements were latersignal processed in Matlab. This work shows that it is possible to detect billets with various dimensions, using UWBradar.The algorithm can also be used as a passage alarm, which can be used in other areasthan furnaces.
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Barnes, James Douglas. "The role of the pRb/BAG-1 complex in the regulation of apoptosis in colorectal epithelial cells." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414356.
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Contu, Simone Santana. "Expressão imunohistoquímica da proteína pRb na mucosa esofágica de indivíduos sob risco para carcinoma epidermóide de esôfago." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2001. http://hdl.handle.net/10183/5078.
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O câncer de esôfago é a sexta neoplasia maligna mais comum no mundo. No Rio Grande do Sul, Brasil, o carcinoma epidermóide de esôfago apresenta coeficientes de mortalidade elevados e com tendência ascendente com, pelo menos, o dobro dos coeficientes padronizados de mortalidade encontrados em outros estados brasileiros ou em países do cone sul da América latina. O diagnóstico tardio parece ser o principal responsável pelo mau prognóstico. Nos últimos anos, diversos estudos têm demonstrado a possibilidade de identificação das lesões precursoras do câncer esofágico, mas sem repercussão no prognóstico, até o momento. Considera-se, atualmente, que a carcinogênese esofágica está relacionada a uma interação entre fatores ambientais e anormalidades genéticas Recentemente, estudos em biologia molecular têm demonstrado a influência dos fatores reguladores do ciclo celular no prognóstico de diversas moléstias, inclusive o câncer. O Rb é um gene supressor tumoral envolvido no mecanismo de controle do ciclo celular, cuja expressão tem sido demonstrada no câncer do esôfago. O objetivo deste estudo foi determinar a prevalência da perda da expressão da proteína pRb na mucosa esofágica de indivíduos sob risco para o carcinoma epidermóide de esôfago, bem como relacionar esta expressão com o consumo de tabaco, álcool e chimarrão, achados histopatológicos e cromoscopia com lugol. Foram estudados 170 casos e 20 controles através de reação imunohistoquímica utilizando anticorpo monoclonal anti-pRb em amostras teciduais fixadas em formalina e armazenadas em parafina. Um total de 33 casos demonstrou perda da expressão imunohistoquímica da proteína pRb, determinando uma prevalência de 19,4% na amostra estudada. Não houve associação estatisticamente significativa entre a perda da expressão da proteína pRb e as variáveis idade, raça, exposição ao fumo, álcool e chimarrão, bem como a cromoendoscopia com lugol. Foi demonstrada uma associação significativa entre a perda da expressão da pRb com a história de câncer na família. Da mesma forma, foi demonstrada uma associação linear significativa entre a perda da pRb e o grau histopatológico das lesões. Estes resultados demonstraram uma influência da proteína pRb na evolução da carcinogênese esofágica e permitem sugerir que os indivíduos expostos aos fatores de risco estudados sejam candidatos a uma maior vigilância.
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Moriéras, Angéline. "Rôle de RBF1, l’homologue de la protein oncosuppressive pRb, dans l’apoptose et l’homéostasie tissulaire chez drosophila melanogaster." Versailles-St Quentin en Yvelines, 2013. http://www.theses.fr/2013VERS0034.
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PRb est le premier suppresseur de tumeur identifié chez l’Homme. Si son rôle vis-à-vis de la régulation du cycle cellulaire est bien caractérisé, celui vis-à-vis de l’apoptose et de la prolifération en réponse à l’apoptose l’est moins. Nous avons généré un mutant ponctuel de RBF1. Celui-ci conserve l’effet pro-apoptotique dépendant de la voie JNK de RBF1 et a une capacité spécifique à entrainer la formation de tissu ectopique dans l’aile. Cela est dû à un excès de prolifération dans le disque imaginal d’aile, et dépend de l’activation de la voie JNK. Ces résultats montrent pour la première fois que RBF1 serait important pour le contrôle de l’homéostasie tissulaire en régulant la prolifération induite en réponse à l’apoptose. Parallèlement, j’ai identifié par MS/MS un nouveau partenaire potentiel de RBF1 : PABP, impliquée dans la stimulation de la traduction. Cette interaction suggère que RBF1 pourrait exercer une partie de son rôle d’oncosuppresseur via un contrôle de la traductionPRb is the first tumor suppressor identified in Human. While its role during cell cycle is well characterized, little is known about its properties on apoptosis regulation and apoptosis-induced cell responses. We generated a punctual mutant form of RBF1. This mutant form conserved the JNK-dependent pro-apoptotic properties of RBF1 and gained the ability of inducing overgrowth phenotypes in adult wings. We show that this overgrowth is a consequence of an abnormal proliferation in wing imaginal discs, which depends on the JNK pathway activation. These results show for the first time that RBF1 could be important to control tissue homeostasis via the regulation of apoptosis induced-proliferation. In parallel, I have used MS/MS to identified a new potential RBF1 partner: PABP, which is implicated in translation activation. This interaction suggests that RBF1 could act as a tumor suppressor in part by regulating translation
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Bertin, Joséphine. "Impact des voies pRb/E2F1 et p53 dans la réponse à l'ABT-737 dans les cellules cancéreuses." Nantes, 2011. https://archive.bu.univ-nantes.fr/pollux/show/show?id=2767bce7-a3c4-4dcd-b8eb-25d280da3795.
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L'ABT-737 est un analogue fonctionnel de l'ABT-263 (Navitoclax), un agent anticancéreux inhibiteur de différentes protéines de la famille Bcl-2, pour lequel une cytotoxicité a été enregistrée, dans certains contextes, lorsqu'il est utilisé en agent simple. L'ABT-737 en mimant la structure du domaine BH3 de Bad, inhibe la formation des complexes entre les protéines pro- et anti-apoptotiques de la famille Bcl-2 pour favoriser l'apoptose. Dans notre étude, nous avons identifié un mécanisme additionnel, dépendant de la transcription, qui contribue à la sensibilité à l'ABT-737. Dans des cellules cancéreuses ayant un p53 non fonctionnel, on observe une induction de Noxa, protéine BH3-seul, dépendante des caspases, sous traitement à l'ABT-737. Cette induction est dépendante du facteur de transcription E2F1, présent sur le promoteur de Noxa, et, plus surprenant, de la protéine régulatrice d'E2F1, pRb, clivé par les caspases, lors du traitement à l'ABT-737. De plus, nous avons montré que, dans des cellules cancéreuses ayant un p53 sauvage, la sensibilité à l'ABT-737 était dépendante de p53 et non d'E2F1. Dans ce cas, le rôle de p53, dans l'induction de l'apoptose par l'ABT-737, n'engage pas sa fonction transcriptionnelle. Nous concluons que des facteurs de transcription, notamment p53 et E2F1, favorisent la sensibilité des cellules cancéreuses à l'ABT-737. L'utilisation, en clinique, de combinaisons composées de l'ABT-263 et de molécule activant les voies pRb/E2F1 ou p53, telle que la Nutlin-3, pourrait s'avérer particulièrement prometteuseABT-737 is a functional analogue of ABT-263 (Navitoclax), an anticancer agent inhibitor of some Bcl-2 homologues, for which monotherapy cytotoxicity has been reported in certain instances. ABT-737 by mimicking the BH3 domain structure of the BH3-only Bad, inhibits the formation of complexes between pro- and anti-apoptotic Bcl-2 family members to trigger apoptosis. In our study, we identify an additional, transcription dependent, mechanism that contributes to sensitivity to ABT-737. In cancer cells lacking functional p53, we observe a caspase dependent induction of Noxa, a BH3-only protein, upon treatment with ABT-737. This induction is dependent upon the transcription factor E2F-1 that occupied of the Noxa promoter and, strikingly, upon the E2F-1 regulatory protein pRb, cleaved by caspases upon ABT-737 treatment. Moreover, we have shown that, in cancer cells with functional p53, the sensitivity to ABT-737 is dependent upon p53 and no upon E2F1. In this case, the role of p53, in apoptosis induction by ABT-737, does not require its transcriptional function. Our data suggest that transcription factors, as p53 and E2F1, may allow to sensitive cancer cells to ABT-737. Thus, the use of drug that induced the pRb/E2F1 or p53 pathway, as Nutlin-3a, may have clinical utility in treatment of patient when combined with orally bioavailable compound ABT-263
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Lamichhane, Suman. "Physiological and Molecular Dissection of Salinity Tolerance in Arabidopsis and Maize and Nitrogen Uptake in Wheat." Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/97843.
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The PROTEOLYSIS 6 (PRT6) branch of the N-end rule pathway is a well-characterized negative regulator of flooding and low oxygen tolerance in plants. This study investigated the role of this pathway in adaptation to salinity stress in Arabidopsis and maize via physiological and molecular characterization of Arabidopsis prt6-1 and maize prt6 MU insertion mutants, respectively. Our study demonstrated that the loss of function mutation of prt6 in Arabidopsis activated hormonal and transcriptional responses associated with adaptation to salinity stress, enhancing high salt tolerance at seed germination, seedling, and adult plant stages. Our data also indicated that salinity tolerance conferred by the prt6 mutation is attributed to increased mRNA abundance of key transcriptional factors in ABA-dependent (AREB/ABFs) and independent (DREBs) pathways, together with the dominant expression of downstream dehydrins. Furthermore, this study revealed that the prt6 mutation enhances ethylene and brassinosteroid responses, resulting in restricted Na+ accumulation in roots and shoots as well as increased expression of dehydrin genes such as RD29A and RD29B. Maize prt6 mutant plants, contrary to our observation in Arabidopsis, showed lower seed germination, primary root elongation, and shoot biomass growth along with increased malondialdehyde (MDA) accumulation under high salt. Moreover, maize prt6 mutants exhibited reduced grain yield and yield-related components under high salt. These results indicate that PRT6 functions as a negative regulator for salinity tolerance in Arabidopsis, whereas this gene plays a positive role in salinity tolerance in maize. In wheat, we compared two genotypes with contrasting nitrogen-use-efficiency (NUE), VA08MAS-369 and VA07W-415, to dissect physiological and molecular mechanisms underlying NUE regulation. Our agronomic data revealed that line 369 maintained yield and yield-related parameters and exhibited greater NUE indexes relative to line 415 under N deficient conditions. Furthermore, our analyses suggested that the significantly higher nitrogen use efficiency (NUE) in line 369 could be attributed to the greater N uptake efficiency in this genotype. In fact, line 369 was able to maintain the development of root systems under N limitation. Consistently, genes encoding high-affinity nitrate transporters such as TaNRT2.1 and TaNRT2.2 were expressed more abundantly in the roots of line 369 than line 415 at limited N. Overall, the results of this study characterized physiological and molecular phenotypes associated with high N uptake efficiency in line 369. This is useful information for the development of new wheat accessions with improved NUE.Doctor of Philosophy
In coastal areas, sea-level rise increases the chances of saltwater intrusion into cultivable lands, making a hostile environment for crop growth and production by imposing flooding and salinity stresses simultaneously. Identification of central regulators that regulate the adaptation to both flooding and salinity is a critical step for the development of new crop genotypes with enhanced tolerance to these stresses. Previous studies have characterized the function of the PROTEOLYSIS 6 (PRT6) gene in adaptation to flooding stress in plants. This study assessed whether this gene is involved in adaptation to salinity stress in Arabidopsis and maize by evaluating the growth and survival of their respective prt6 mutants under high salt. Consistent with the flooding tolerance data, our study showed that the PRT6 gene also functions as a negative regulator of salinity stress tolerance in Arabidopsis. The prt6 mutation in Arabidopsis activated the key transcriptional and hormone response pathways associated with adaptation to both salinity/osmotic stress and sodium toxicity, expressed as enhanced tolerance to excess salt at seed germination, seedling, and adult plant stages. In maize, disruption of the PRT6 gene decreased seed germination, primary root elongation, and shoot biomass growth under high salt, which is opposite to our observations in Arabidopsis. Additionally, the maize mutant plants encountered more oxidative stress, as demonstrated by the higher accumulation of malondialdehyde (MDA) under high salt. Moreover, maize prt6 mutants exhibited reduced grain yield under high salt. Overall, these results indicate that disruption of the PRT6 gene confers increased tolerance to high salt in Arabidopsis, whereas it conversely reduced salinity tolerance in maize. In wheat, we compared two genotypes with distinct nitrogen use efficiency (NUE), VA08MAS-369 and VA07W-415, to determine critical traits involved in NUE regulation. Our study showed that grain yield and yield-related parameters were significantly higher in line 369 than line 415 under low N. Moreover, high NUE in line 369 was attributed to efficient N uptake in this genotype under limited N. Our root architecture analysis demonstrated that line 369 was able to maintain root depth, volume, and thickness even under N limitation. Consistently, line 369 highly induced expression of genes associated with nitrogen transport at low N. Altogether, this study identified key traits involved in high NUE in wheat, facilitating the breeding of new wheat genotypes with enhanced NUE.
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Khan, Shireen S. "Analysis of the roles of p53, pRb and p19ARF in promoting cell cycle arrest and maintaining genetic stability /." 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?p9952660.
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Queiroz, Leila Brito de. "Avaliação da expressão das proteínas p53 e prb em cacarcinoma escamocelular e papilomas orais pelo método imuno –histoquímico." Instituto de Ciências da Saúde, 2006. http://repositorio.ufba.br/ri/handle/ri/20017.
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A progressão do ciclo celular é regulada por uma variedade de proteínas, como as quinases dependentes de ciclinas, inibidores de quinases dependente de ciclinas e proteínas supressoras de tumor, como a p53 e pRb. Alterações na expressão de proteínas supressoras de tumor podem ser responsáveis pelo desenvolvimento de processos neoplásicos malignos. O HPV, vírus epiteliotrópico, considerado agente causal do câncer de colo de útero produz oncoproteínas E6 e E7 capazes de modificar o comportamento celular das proteínas p53 e pRb, respectivamente. A proposta deste estudo foi avaliar a expressão imuno-histoquimica das proteínas p53 e pRb de biópsias em blocos parafinados (n=56) de carcinoma escamocelular (n=31), papiloma orais (n=19) e tecido histologicamente normal (n=6) e associar os achados à detecção do HPV pelo método de PCR. A imunoexpressão foi avaliada de acordo com a marcação nuclear protéica, em escores 0,1, e 2 (imunoexpressão até 10%; entre 10% e 50% e acima de 50%, respectivamente). Nos Carcinomas, a p53 estava expressa em 61,3% dos casos, assim como para pRb. Nas 19 amostras de papilomas, 5,3% e 26,3%% foram positivos para expressão imuno-histoquímica das proteínas p53 e pRb, respectivamente. Nos tecidos normais, em 50% houve imunoexpressão da p53 e em 16,7% da pRb. Foi estatisticamente significante a correlação entre a detecção da proteína p53 e a natureza da neoplasia (p=0,000), assim como para análise da proteína pRb foi estatisticamente significante a diferença entre os ranks médios do epitélio normal e carcinoma (p=0,014) e papilomas e carcinomas (p=0,003). De acordo com o grau de expressão, o escore 2 (superexpressão) para p53 e pRb foi associado ao desenvolvimento de neoplasias malignas, não sendo este escore detectado nas lesões papilomatosas ou em tecidos histologicamente normais. O presente estudo não permitiu definir o associação do HPV com a imunoexpressão das proteínas p53 e pRb em lesões malignas e benignas na cavidade oral, em função do pequeno número de amostra com resultados positivos.
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Ndabambi, Nonkululeko. "Recombinant expression of the pRb- and p53-interacting domains from the human RBBP6 protein for in vitro binding studies." Thesis, University of the Western Cape, 2004. http://etd.uwc.ac.za/index.php?module=etd&.
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The aim of this thesis was to produce DNA expression constructs and use them to investigate the feasibility of recombinantly expression proteins for future interaction studies between human RBBP6 and p53 and pRb proteins.
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Svoboda, Devon. "The Role of Pocket Proteins pRb and p107 in Radial Migration and Axon Guidance through Cell Cycle Independent Mechanisms." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32954.
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Pocket proteins (pRb, p107 and p130) are well studied in the role of regulating cell proliferation by controlling progression through the G1/S phase of the cell cycle. Increasing genetic and anatomical evidence suggests that these proteins also control early differentiation and even later stages of cell maturation including neural migration. However, the multifaceted functions of pocket proteins in the regulation of cell proliferation and cell death has complicated our interpretation of their role during development. As a result, the mechanisms through which pocket proteins regulate neuronal migration and neural maturation remain unknown. Using a pRb and p107 double knock out model, we show that a population of upper layer cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and have exited the cell cycle. In addition, the role of pocket proteins in radial migration is independent cell death, since this migration defect cannot be rescued by eliminating ectopic cell death through Bax deletion. We also show a novel role of pRb and p107 in development of the dorsal midline and guidance of callosal axons. In the absence of pRb and p107, the structures of the commissural plate are highly disorganized and the callosal axons fail to cross the midline. We identify primary defects in axon extension and expression of multiple guidance cues, which can be observed prior to the disorganization of the midline axon guidance structures. Through the use of in vitro cortical explants and in utero electroporation, we identify defects in the rate of axon extension and directional guidance independent from the midline. In addition, protein levels of Netrin and Neuropilin-1 are decreased in the absence of pRb and p107, which could mediate the function of pocket proteins in guiding callosal axons. Indeed, we identify a previously undescribed population of Netrin expressing cells in the cingulate cortex of control embryos which is lost in the pRb/p107 deficient littermates. We propose that these cells play a significant role in callosal axon guidance during normal development. The results presented in this dissertation define multiple novel roles of pRb and p107 in the regulation of radial migration and axon guidance, independent from the role of these pocket proteins in cell death and proliferation.
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Engel, Brienne E. "Mechanisms and Molecular Biology of Major Tumor Suppressors." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5357.
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This dissertation is devoted to the study of the molecular biology of major tumor suppressors, defined as those that prevent the cellular processes identified as the hallmarks of cancer. Specifically, the major tumor suppressors pRb and STK11 are explored in the context of osteosarcoma and lung cancer, respectively.
RB1 was the first tumor suppressor gene discovered. Over four decades of work have revealed that the Rb protein (pRb) is a master regulator of biological pathways influencing virtually every aspect of intrinsic cell fate including cell growth, cell-cycle checkpoints, differentiation, senescence, self-renewal, replication, genomic stability and apoptosis. While these many processes may account for a significant portion of RB1's potency as a tumor suppressor, a small, but growing stream of evidence suggests that RB1 also significantly influences how a cell interacts with its environment, including cell-to-cell and cell-to-extracellular matrix interactions. Chapter 2 highlights pRb's role in the control of cell adhesion and how alterations in the adhesive properties of tumor cells may drive the deadly process of metastasis.
Chapter 3 defines a role for pRb as a suppressor of the progression to metastasis by upregulating integrin α10. Transcription of this integrin subunit is herein found to be pRb-dependent in mouse osteoblasts. Classic pRb partners in cell cycle control, E2F1 and E2F3, do not repress transcription of integrin α10 and phosphorylation of pRb is not necessary for activation of the integrin α10 promoter. Promoter deletion revealed a pRb responsive region between -108bp to -55bp upstream of the start of the site of transcription. pRb activation of transcription also leads to increased levels of integrin α10 protein and a greater concentration of the integrin α10 protein at the cell membrane of mouse osteoblasts. These higher levels of integrin α10 correspond to increased binding to collagen substrate. Consistent with our findings in mouse osteoblasts, we found that integrin α10 is significantly underexpressed in multiple solid tumors that have frequent inactivation of the pRb pathway. Bioinformatically, we identified data consistent with an 'integrin switch' that occurs in multiple solid tumors consisting of underexpression of integrins α7, α8, and α10 with concurrent overexpression of integrin β4. pRb promotes cell adhesion by inducing expression of integrins necessary for cell adhesion to a substrate. We propose that pRb loss in solid tumors exacerbates aggressiveness by debilitating cellular adhesion, which in turn facilitates tumor cell detachment and metastasis.
Lung cancer is the leading cause of cancer-related death in the U.S. and additional targeted therapies are desperately needed to treat these patients. STK11 is the third most frequently mutated gene in lung adenocarcinoma following only KRAS and TP53, yet its mutational status is not currently clinically evaluated and no therapies have been approved to specifically target its pathway. A deep understanding of the complex pathways controlled by STK11 and their alterations in cancer are required to develop effective therapies for patients with loss-of-function mutations. In Chapter 4 we present the current understanding of STK11, focusing on its molecular biology and therapeutic implications, including a compilation of studies evaluating STK11 somatic mutations in human lung cancer tissue and how the frequency of these mutations varies across histological subtypes and patient populations. Finally, we review the strategies being used to target STK11-deficient cancers at the clinical trial, pre-clinical, and basic science levels as well as proposing potential new therapies that might benefit this patient population.
STK11 is a tumor-suppressor commonly mutated in lung adenocarcinoma (LuAd). There are a number of agents that may selectively target the deregulated pathways in STK11 mutated tumors, and thus, identifying the subset of adenocarcinomas that harbor these mutations could have significant clinical benefit. In Chapter 5, we characterized a cohort of 442 adenocarcinoma patients with respect to STK11 mutation status and subset of this cohort using immunochemistry, gene expression, and western blotting. We found that measuring STK11 mutation status is complicated by the fact that many STK11 mutations lead to expression of a stable protein that is indistinguishable from wild type (WT) via immunohistochemistry. To circumvent this, we used published cell line mutation and gene expression data to derive a signature correlating with STK11 mutation status. This signature was validated in the cohort of 442 lung adenocarcinomas and strongly correlates with mutation status (ROC curve AUC = 85.29). These data suggest that STK11; mutation status may be best assessed by measuring the downstream targets included in our signature.
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Khan, Junaid Ali. "Progesterone Receptor Isoforms : functional Selectivity and Pharmacological Targeting." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00769945.
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Progesterone receptor (PR) is an essential pharmacological target for contraception, female reproductive disorders as well as for hormone-dependent breast and uterine cancers. Human PR is expressed as two major isoforms PRA and PRB which behave as distinct transcriptional factors. PRA vs PRB expression is often altered under pathological conditions notably breast cancer through unknown mechanisms. In this thesis we demonstrate that down-regulations of PRB and PRA proteins are negatively controlled by key phosphorylation events involving distinct MAP kinase signaling. PRA is selectively stabilized by p38 MAPK whereas p42/44 MAPK specifically controls PRB stability leading to unbalanced PRA/PRB ratios in a ligand sensitive manner. In cancer cells, elevated extracellular stimuli such as epidermal growth factors or pro-inflammatory cytokines that preferentially activate p42/44 or p38 MAPK respectively may result in opposite variations in PRA/PRB expression ratio. These results may explain altered PRA/PRB ratios often associated with breast tumors. To get a mechanistic understanding of how varied PRA/PRB ratio contributes in cell signaling, we generated an original bi-inducible PR-isoform cell model allowing selective, reversible and dose-dependent expression of PRA and/or PRB, enabling fine-tune adjustment of PRA/PRB ratio in the same cells. Using this cell-based system, we undertook genome-wide transcriptomic studies to investigate transcriptional regulation driven by unliganded and liganded PR isoforms. We report that several aspects of PR signaling such as target gene selection/transcriptional regulation, cross-talk with growth factors and antiproliferative efficacy of antiprogestin are highly dependent upon variation in PRA/PRB ratio. A new potential therapeutic strategy in PR-dependent pathological conditions may rely on the use of PR antagonists. Most of the currently available antiprogestins such as mifepristone present partial agonist activity and are not selective to PR leading to undesirable side effects. Therefore, in a collaborative project we have synthesized and characterized several new PR antagonist compounds named as APRn. Structure-activity relationship studies allowed identification of the key substitutions in steroidal skeleton responsible for agonist/antagonist character of these molecules. Several selected APRn lack partial agonist effect, are PR specific and inhibit PR transcriptional properties through a new passive mechanism of action i.e. impaired recruitment of transcriptional coregulators. Such PR selective antagonists devoid of partial agonist character might provide important therapeutic perspectives for various reproductive tract abnormalities and hormone-dependent uterine and breast cancers. Altogehter, our results provide mechanistic insights into the functional selectivity of PR isoforms and their pharmacological targeting by the use of PR antagonists.
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Savvidis, Charalampos, and Zeyang Geng. "Onboard Impedance Diagnostics Method of Li-ion Traction Batteries using Pseudo-Random Binary Sequence." Thesis, Linköpings universitet, Tekniska fakulteten, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-118970.
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Environmental and economic reasons have lead automotive companies towards the direction of EVs and HEVs. Stricter emission legislations along with the consumer needs for more cost-efficient and environmental friendly vehicles have increased immensely the amount of hybrid and electric vehicles available in the market. It is essential though for Li-ion batteries, the main propulsion force of EVs and HEVs, to be able to read the battery characteristics in a high accuracy manner, predict life expectancy and behaviour and act accordingly. The following thesis constitutes a concept study of a battery diagnostics method. The method is based on the notion of a pseudo-random binary signal used as the current input and from its voltage response, the impedance is used for the estimation of parameters such as the state of charge and more. The feasibility of the PRBS method at a battery cell has been examined through various tests, both in an experimental manner at the lab but also in a simulation manner. The method is compared for validation against the electrochemical impedance spectroscopy method which is being used as a reference. For both the experimental and the simulation examinations, the PRBS method has been validated and proven to work. No matter the change in the parameters of the system, the method behaves in a similar manner as in the reference EIS method. The level of detail in the research and the performed experiments is what makes the significance of the results of high importance. The method in all ways has been proven to work in the concept study and based on the findings, if implemented on an EV’s or HEV’s electric drive line and the same functionality is observed, be used as a diagnostics method of the battery of the vehicle.
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Soares, Rosilene Calazans. "Estudo da detec??o do DNA do papiloma v?rus humano (HPV) e da express?o imuno-histoqu?mica de prote?na do ciclo celular no carcinoma epiderm?ide oral." Universidade Federal do Rio Grande do Norte, 2005. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17157.
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Previous issue date: 2005-11-04Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
Oral squamous cell carcinoma (OSCC) is the most common malignancy in oral cavity and human papillomavirus (HPV) may have an important role in its development. The aim of this experiment was to investigate the HPV DNA and viral types in 90 cases of OSCC. Moreover, a comparative analysis between the cases of OSSC with and without HPV DNA was performed by using cell cycle markers p21 and pRb in order to detect a possible correlation of these proteins and HPV infection. DNA was extracted from paraffin embedded tissue and amplified by PCR (polymerase chain reaction) with primers PCO3+ e PCO4+ for a fragment of human β-globin gene. After this procedure, PCR for HPV DNA detection was realized using a pair of generic primers GP5+ e GP6+. Immunohistochemical study was performed by streptoavidin-biotin technique and antibodies against p21 and pRb proteins were employed. Eighty-eight cases were positive for human β-globin gene and HPV DNA was found in 26 (29.5%) of then. It could not be detected significant correlation between HPV and age, sex and anatomical sites of the lesion. The most prevalent viral type was HPV 18 (80.8%). Regarding the immunohistochemical analysis, it was detected significant association between HPV presence and pRb immunoexpression (p=0,044), nevertheless, the same was not observed in relation to p21 protein (p =0,416). It can be concluded that the low detection of HPV DNA in OSCC by the present experiment suggests a possible role of the virus in the development and progression in just a subset of this disease
O carcinoma epiderm?ide oral ? a neoplasia maligna mais freq?ente da cavidade oral e o papilomav?rus humano (HPV) parece ter um relevante papel na indu??o desta les?o. Neste trabalho investigou-se o DNA do HPV e tipos virais em 90 casos de carcinoma epiderm?ide oral (CEO). Realizou-se tamb?m uma an?lise comparativa entre os grupos de CEO com DNA do HPV e sem o DNA do v?rus, empregando-se os marcadores do ciclo celular p21 e pRb, a fim de estabelecer poss?vel correla??o entre a express?o imuno-histoqu?mica dessas prote?nas e a infec??o pelo HPV. O DNA foi extra?do de tecido emblocado em parafina e amplificado por PCR (rea??o em cadeia da polimerase) com um par de primers designados PCO3+ e PCO4+ para um fragmento do gene da β-globina humana. Posteriormente, realizou-se PCR para detec??o do DNA de HPV utilizando-se um par de primers gen?ricos designados GP5+ e GP6+. A tipagem viral foi realizada pela hibridiza??o dot blot. No m?todo imuno-histoqu?mico utilizou-se a t?cnica da streptavidina-biotina com um painel de anticorpos monoclonais para as prote?nas p21 e pRb. Dos 88 casos positivos para o gene da β-globina humana, em 26 (29,5%) foi detectado o DNA do HPV. N?o houve associa??o significativa entre o HPV e as vari?veis idade e sexo dos pacientes e localiza??o anat?mica da les?o. O tipo viral prevalente foi o HPV 18 (80,8%). Quanto ? an?lise imuno-histoqu?mica, foi observada associa??o estatisticamente significativa entre a presen?a do HPV e a express?o imunohistoqu?mica de pRb (p=0,044), entretanto, n?o houve qualquer diferen?a estatisticamente significativa entre a express?o da prote?na p21 e a presen?a do v?rus (p =0,416). P?de-se concluir que o baixo percentual de detec??o do DNA do HPV no carcinoma epiderm?ide oral no presente trabalho, sugere uma poss?vel participa??o do HPV no desenvolvimento e progress?o de apenas um subgrupo dessas les?es
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Rekštytė, Toma. "Pienarūgščių bakterijų įtaka akrilamido formavimuisi pusruginės duonos gaminiuose bei kvietinių kepinių kokybės pagerinimo galimybės deaktyvuotų mielių priedu." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130618_094636-54626.
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Darbo tikslas – įvertinti pienarūgščių bakterijų įtaką akrilamido formavimuisi pusruginės duonos gaminiuose, kurių gamybai naudotos skirtingos PRB (Lactobacillus delbruecki, Pediococcus acidilactici, Pediococcus pentosaceus ir Lactobacillus sakei), bei įvertinti RS 190 deaktyvuotų mielių įtaką kvietinių miltų technologinėms savybėms ir kvietinių kepinių kokybei.
Nustatyta, kad akrilamido kiekis kepiniuose kito nuo 37,87 ± 0,55 iki 74,64 ± 0,36 µg/kg. Pusruginės duonos kepiniuose, fermentuotose L. delbruecki nustatytas mažiausias akrilamido kiekis, lyginant su kitais pusruginės duonos kepiniais, kurių gamyboje buvo naudotos PRB. PRB proteolitinis aktyvumas yra tiesiogiai susijęs su akrilamido kiekio mažinimu duonos kepiniuose. Kepiniuose, pagamintuose su L. delbruecki (su didžiausiu proteolitiniu aktyvumu) susidarė mažiausias akrilamido kiekis (37,87 ± 0,55 µg/kg), o kepiniuose fermentuotuose P. pentosaceus ir P. acidilactici (su mažiausiu proteolitiniu aktyvumu) nustatytas didžiausias akrilamido kiekis, atitinkamai, 74,64 ± 0,36 ir 63,38 ± 0,98 µg/kg.
Atlikus kvietinių miltų su deaktyvuotų mielių priedu ir be priedo farinografinį tyrimą, nustatyta, kad didžiausiu vandens įgėrimu (59,1 ± 1,18 %) ir tešlos stabilumu (5 kartus didesnis) pasižymėjo kvietiniai miltai su priedu, tačiau jų tešlos susidarymo trukmė 1,3 karto ilgesnė. Deaktyvuotų mielių priedas turi teigiamos įtakos kepinių savitajam tūriui, minkštimo akytumui ir drėgniui.
Pagal gautus tyrimo rezultatus galima... [toliau žr. visą tekstą]The aim of this study was to investigate acrylamide formation in semi rye bread fermented with Lactobacillus delbruecki, Pediococcus acidilactici, Pediococcus pentosaceus and Lactobacillus sakei, and, to investigate the influence of RS 190 deactivated yeast on wheat flour technological properties and wheat bread quality. Results show that the amount of acrylamide in bread samples ranged from 37.87 ± 0.55 to 74.64 ± 0.36 µg/kg. Lactofermentation reduce acrylamide formation in semi rye bread. L. delbruecki was found to have a higher effect on acrylamide reduction in bread samples in compare with P. acidilactici, P. pentosaceus and L. sakei. Also, proteolytic activity of LAB have a influence on acrylamide content reduction in bread. Bread made with L. delbruecki (the highest proteolytic activity) contained lower acrylamide content (37.87 ± 0.55 µg/kg), while breads prepared with P. pentosaceus and P. acidilactici (lower proteolytic activity) contained higher acrylamide contents (74.64 ± 0.36 and 63.38 ± 0.98 µg/kg, respectively). Pharinographic analysis of wheat flour with deactivated yeast and without deactivated yeast results shows that the higher water absorbtion have wheat flour with deactivated yeast (59.1 ± 1.18 %) and higher dough stability (5 times higher) but longer dough formation time (1,3 times longer). The addition of deactivated yeast in wheat flour have a significant effect of bread specific volume, porosity and moisture content. In conclusion we could say... [to full text]
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Fritah, Asmaà. ""P21WAF1 régule l'activité transcriptionnelle du récepteur des oestrogènes à l'interface prolifération / différenciation"." Paris 6, 2006. http://www.theses.fr/2006PA066173.
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Nous avons montré que p21WAF1, un inhibiteur des complexes cycline/CDKs, se comporte comme un coactivateur transcriptionnel gène-spécifique de ER impliqué dans la différenciation épithéliale mammaire. L'expression de p21WAF1, dans les cellules MCF-7, augmente l'expression oestrogéno-dépendante du récepteur à la progestérone B et de hWISP-2/CCN5 alors qu'elle diminue la cycline D1. Le mécanisme d'action passe par le recrutement sélectif de p21WAF1 de manière oestrogéno-dépendante et concomitante du recrutement de ER et de CBP sur les promoteurs du récepteur à la progestérone B et de hWISP-2/CCN5. L'expression de p21WAF1, dans les cellules MCF-7, induit un arrêt de la prolifération et des changements caractéristiques de la différenciation épithéliale mammaire. Nous avons aussi montré que hWISP-2/CCN5 est une cible directe de ER, dont l'expression oestrogéno-dépendante nécessite la présence d'un ERE fonctionnel entre –581 et –569 dans le promoteur du gène hWISP-2/CCN5.
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Ferraz, de Sá Beltrão Monique. "Estudo clínico e genético do Papilomavírus humano sorotipo 16/ Monique Ferraz de Sá Beltrão." Universidade Federal de Pernambuco, 2011. https://repositorio.ufpe.br/handle/123456789/1738.
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Previous issue date: 2011Faculdade de Amparo à Ciência e Tecnologia do Estado de Pernambuco
O câncer cervical é o segundo tipo de neoplasia que mais acomete as mulheres no Brasil, com alta prevalência em Pernambuco. A associação desta patologia como o papilomavírus humano (HPV) já está bem estabelecida e atualmente, sabe-se que o HPV pode ser encontrado em vários outros locais de infecção, além da região genital. Com o intuito de apontar a distribuição corpórea do HPV pelo corpo humano foi realizada uma revisão da literatura buscando por sítios corpóreos em que o DNA viral já tinha sido identificado. Dentre os tipos virais de alto risco que mais acometem a população brasileira, sabe-se que o HPV16 aparece associado a mais de 50% dos achados. Baseado nisso, uma busca pela presença do DNA do HPV e pelos variantes virais do HPV16 foi realizada em mulheres de Pernambuco que apresentavam lesões genitais. Complementarmente, sabe-se que sistemas de expressão são amplamente utilizados para produção de diversas moléculas biológicas, sendo o bacteriano o mais rápido e fácil de ser utilizado. Visando melhor utilização do sistema de expressão em bactéria, desenvolvemos um método para detectar a produção de -galactosidase em cepas heterólogas de Escherichia coli. Esse sistemas bacterianos vem sendo utilizados para produção de diversas moléculas virais, como oncoproteínas virais. Baseado no levantamento bibliográfico realizado foi possível identificar DNA viral nos mais diferentes sítios corpóreos, inclusive com ausência de lesões clínicas, apontando para a possibilidade do HPV agir como um oportunista. Da população estudada, mais de 50% foram positivas para o HPV, com achados de múltiplas infecções com tipos virais distintos, onde o variante Europeu foi o mais frequente nos casos de HPV16 positivo. A linhagem Origami (DE3) de E.coli demonstrou-se eficiente no ensaio colorimétrico expressando o gene da -galactosidase com baixa produção de proteínas bacterianas. Baseado nisso, esse modelo bacteriano foi utilizado no processo de sub-clonagem do gene E7 do HPV16 permitindo após indução do promotor visualizar uma banda de 15 KDa na eletroforese de proteínas totais, banda provavelmente referente a oncoproteína viral. No entanto, faz-se necessário emprego de testes imunológicos com anticorpos específicos para confirmar sua produção e posterior purificação. A tipagem da população a respeito do variante do HPV mais predominante e produção da proteína E7 permitem o aumento nos conhecimentos dos diferentes mecanismos de interação do vírus com o hospedeiro e favorecem ao desenvolvimento de métodos diagnósticos e terapêuticos mais eficientes e específicos para as diferentes regiões do mundo