The aim of this study was to analyze number of incorporated T-DNA harbouring pmi and nptII transgenes and expression of the pmi gene in tomato transformants using Southern blot and Northern blot methods. The presence of a functional PMI protein was assesed using PMI-assay with Chlorophenol red dye. Mannose selection of tomato seeds was established and segregation patterns in T1 progeny were studied.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-08T22:40:13Z No. of bitstreams: 1 ThatianaCunhaNavarroDeSouza_TESE.pdf: 4253732 bytes, checksum: b88b33669e4903291d2e3da03d76f832 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-11T22:01:06Z (GMT) No. of bitstreams: 1 ThatianaCunhaNavarroDeSouza_TESE.pdf: 4253732 bytes, checksum: b88b33669e4903291d2e3da03d76f832 (MD5) / Made available in DSpace on 2016-04-11T22:01:06Z (GMT). No. of bitstreams: 1 ThatianaCunhaNavarroDeSouza_TESE.pdf: 4253732 bytes, checksum: b88b33669e4903291d2e3da03d76f832 (MD5) Previous issue date: 2015-03-13 / Um importante problema enfrentado pela ind?stria petrol?fera ? distribuir v?rios produtos derivados de petr?leo atrav?s de polidutos. Tal distribui??o ? feita atrav?s de uma rede composta por refinarias (n?s fonte), parques de armazenagem (n?s intermedi?rios) e terminais (n?s de demanda), interligados por um conjunto de polidutos que transportam petr?leo e derivados entre ?reas adjacentes. Restri??es relativas a limites de armazenamento, tempo de entrega, disponibilidade das fontes, limites de envio e recebimento, entre outras, t?m de ser satisfeitas. Alguns pesquisadores lidam com este problema sob o ponto de vista discreto onde o fluxo na rede ? visto como o envio de bateladas. Geralmente, n?o existem dispositivos de separa??o entre bateladas de produtos diferentes e as perdas devidas ? interface podem ser significativas. Minimizar o tempo de entrega ? um objetivo usual dos engenheiros durante a programa??o do envio de produtos em redes de polidutos. No entanto, os custos devidos ?s perdas geradas nas interfaces n?o podem ser desconsiderados. O custo do envio dos produtos tamb?m depende das despesas de bombeamento as quais s?o, em grande parte, devidas ao custo da energia el?trica. Uma vez que a tarifa industrial de energia el?trica varia ao longo do dia, o bombeamento em diferentes per?odos ter?o diferentes custos. Este trabalho apresenta uma investiga??o experimental de m?todos computacionais desenvolvidos para lidar com o problema do envio de bateladas de derivados de petr?leo considerando a minimiza??o simult?nea de tr?s fun??es objetivo: tempo de entrega, perdas devidas ?s interfaces e custo de energia el?trica. Tal problema ? NP- ?rduo e ser? abordado atrav?s de algoritmos evolucion?rios h?bridos. As hibridiza??es t?m como foco principal os Algoritmos Transgen?ticos e arquiteturas cl?ssicas de algoritmos evolucion?rios multi-objetivo como MOEA/D, NSGA2 e SPEA2. Tr?s arquiteturas denominadas MOTA/D, NSTA e SPETA, s?o aplicadas ao problema. ? apresentado um estudo experimental dos algoritmos propostos onde ? utilizado um conjunto de trinta casos teste. Para analisar os resultados obtidos com os algoritmos s?o empregados indicadores de qualidade Pareto concordantes e testes estat?sticos n?o param?tricos. / An important problem faced by the oil industry is to distribute multiple oil products through pipelines. Distribution is done in a network composed of refineries (source nodes), storage parks (intermediate nodes), and terminals (demand nodes) interconnected by a set of pipelines transporting oil and derivatives between adjacent areas. Constraints related to storage limits, delivery time, sources availability, sending and receiving limits, among others, must be satisfied. Some researchers deal with this problem under a discrete viewpoint in which the flow in the network is seen as batches sending. Usually, there is no separation device between batches of different products and the losses due to interfaces may be significant. Minimizing delivery time is a typical objective adopted by engineers when scheduling products sending in pipeline networks. However, costs incurred due to losses in interfaces cannot be disregarded. The cost also depends on pumping expenses, which are mostly due to the electricity cost. Since industrial electricity tariff varies over the day, pumping at different time periods have different cost. This work presents an experimental investigation of computational methods designed to deal with the problem of distributing oil derivatives in networks considering three minimization objectives simultaneously: delivery time, losses due to interfaces and electricity cost. The problem is NP-hard and is addressed with hybrid evolutionary algorithms. Hybridizations are mainly focused on Transgenetic Algorithms and classical multi-objective evolutionary algorithm architectures such as MOEA/D, NSGA2 and SPEA2. Three architectures named MOTA/D, NSTA and SPETA are applied to the problem. An experimental study compares the algorithms on thirty test cases. To analyse the results obtained with the algorithms Pareto-compliant quality indicators are used and the significance of the results evaluated with non-parametric statistical tests.

Regulatorische CD4+CD25+ T-Zellen (Tregs) stellen eine kleine Zellpopulation dar (1-5% der peripheren Blutzellen), die hauptsächlich für die Regulierung von Immunreaktionen verantwortlich ist. In der vorliegenden Arbeit wurden diese Zellen gemeinsam mit Stammzellen syngen und allogen kotransplantiert, um ihren Effekt auf das Anwachsen der Spenderzellen und die Rekonstitution der Hämatopoese nach Ganzkörperbestrahlung zu untersuchen. Es wurden humanisierte dreifach transgene Empfängermäuse (C57Bl/6-TTG) verwendet (human CD4+, murin CD4-, human HLA-DR+), wodurch sowohl bei syngener als auch bei allogener Transplantation eine Unterscheidung zwischen Spender- und Empfängerzellen möglich ist. Zunächst wurden CD4+CD25+ T-Zellen durch Separation aus Milzzellen bzw. Buffy Coats gewonnen und in vitro mittels Durchflusszytometrie und ELISpot charakterisiert. Anschließend fanden syngene und allogene Transplantationen mit einer Laufzeit von 61 Tagen statt. Überleben und Gewicht wurden täglich ermittelt und außerdem wurden wöchentlich Blutbilder erstellt und durchflusszytometrische Chimärismusanalysen (murines und humanes CD4, CD8, MHC (H2Db, H2Kd)) durchgeführt. Durch die magnetische Separation konnte die FoxP3-Expression der murinen Zellen (Transplantat) von 1,6% in der Ausgangspopulation auf 68,5% in der CD4+CD25+ Population gesteigert werden. In den ELISpot-Assays zeigten diese separierten Zellen, wie für Tregs typisch, keine Produktion von Interleukin-2. Nach syngener Transplantation (Spender: wildtyp C57Bl/6) von 2x106 Knochenmarkzellen und 1x106 CD4+CD25+ T-Zellen überlebten 100% der Tiere, wie zu erwarten war. Dabei setzte bei Tregs-kotransplantierten Tieren die Blutbildung nach bestrahlungsbedingter Leukozytopenie aufgrund bisher nicht bekannter Mechanismen früher wieder ein und der Donor-Zell-Chimärismus war an Tag 19 nach Transplantation signifikant höher als in der Kontrollgruppe. Dies zeigt, dass regulatorische T-Zellen im syngenen Transplantationsmodell einen positiven Effekt auf die Akzeptanz bzw. das Anwachsen des Transplantats haben. Dieses Modell entspricht klinisch einer autologen Transplantation. Nach einer knochenmarkzerstörenden Therapie werden dem Patienten eigene Stammzellen reinfundiert, um die Blutbildung und das Immunsystem wieder in Gang zu bringen. Der Zusatz von regulatorischen T-Zellen zum autologen Stammzelltransplantat könnte das Anwachsen der Zellen beschleunigen und die gefährliche Phase der Immunsuppression, in der es häufig zu Sekundärinfektionen kommt, verkürzen. Die Transplantation der gleichen Zahl von allogenen Spenderzellen (wildtyp Balb/c) führte überraschend zum Tod aller dreifach transgenen Empfängertiere. Der Vergleich zu Experimenten mit wildtyp C57Bl/6-Empfängertieren zeigte, dass dreifach transgene Mäuse sehr viel höhere Zellzahlen im Transplantat zum Überleben benötigen (Daten nicht gezeigt). Das Ausbleiben der Blutbildung nach der Bestrahlung führte zu vermindertem Allgemeinbefinden, gestörter Futter- und Wassseraufnahme und Exsikkose bis zum Tod bzw. aus Tierschutzgründen zur Euthanasie. Durch Erhöhung der Zellzahl im Transplantat auf 1x107 Knochenmark + 5x106 Milzzellen überlebten 25% der Mäuse, bei 3x107 Knochenmark + 5x106 Milzzellen waren es 50%. Anders als im syngenen Modell führte die Kotransplantation 1,5x106 allogener CD4+CD25+ T-Zellen zu 3x107 Knochenmark + 5x106 Milzzellen zum Versterben der Tiere. Dies verdeutlicht, dass regulatorische T-Zellen in diesem allogenen Transplantationsmodell das Anwachsen des Transplantats behindern (Transplantatversagen). Hier gilt es zu klären, ob dieser Effekt spezifisch für die gewählten Mausstämme ist und welche Mechanismen für das Transplantatversagen verantwortlich sind. In einem dreifach transgenen Mausmodell konnte ein positiver Effekt von regulatorischen T-Zellen auf die Rekonstitution der Hämatopoese bei syngener Kotransplantation nachgewiesen werden. Im allogenen Transplantationsmodell hingegen führte die Kotransplantation CD4+CD25+ T-Zellen zum Versterben der Empfänger. Der beschriebene und schon publizierte positive Effekt spenderspezifischer Tregs zur Behandlung von Graft versus Host Disease nach allogener Stammzelltransplantation widerspricht diesen Ergebnissen nicht, da es bei diesen Patienten schon zum Engraftment von hämatopoetischen Stammzellen gekommen ist. Dies hat weitreichende Konsequenzen für die therapeutische Anwendung regulatorischer T-Zellen bei hämatologischen Erkrankungen in der Human- und Veterinärmedizin. / Regulatory CD4+CD25+ T cells (Tregs) represent a small cell population (1-5% of peripheral blood cells) mainly responsible for the regulation of the immune system. In the present work, these cells were cotransplanted with syngeneic and allogeneic stem cells in order to analyze the effect of Tregs on the reconstitution of hematopoiesis after total body irradiation. Humanized triple transgenic hosts (C57Bl/6-TTG) (human CD4+, murine CD4-, human HLA-DR+) were applied allowing differentiation of donor and host cells in syngeneic and allogeneic transplantation settings. Murine and human CD4+CD25+ T cells were magnetically separated out of splenocytes or buffy-coats and characterized in vitro by means of flow cytometry and ELISpot. Afterwards syngeneic and allogeneic transplantation experiments were performed for a period of 61 days. Survival and weight were assessed daily and once a week blood parameters and chimerism analyses (murine and human CD4, CD8, MHC (H2Db/ H2Kd)) were carried out. FoxP3 expression increased from 1,6% in the initial murine cell fraction to 68,5% in the separated CD4+CD25+ T cells. ELISpot assays showed the typical lack of interleukin 2 production of Tregs. After syngeneic transplantation (donor: wildtype C57Bl/6) of 2x106 bone marrow cells and 1x106 CD4+CD25+ T cells, 100% of mice survived what was to be expected. Cotransplanted animals showed earlier reconstitution of hematopoiesis after leukocytopenia and significant higher donor-cell-chimerism on day 19 after transplantation. The mechanisms for this positive effect of Tregs in syngeneic transplantation on the engraftment have to be investigated. This model clinically correspond an autologous transplantation where patients are treated with their own stem cells after a myeloablative treatment (chemotherapy or irradiation). The addition of regulatory T cells to the transplant could accelerate the engraftment and shorten the risky period of immunosuppression. Injection of the same numbers of allogeneic cells (donor: wildtype Balb/c) did not preserve hosts from mortality. Compared to experiments with wildtype recipients, results showed that triple transgenic mice need much higher cell numbers in the transplant for survival (data not shown). The failure of hematopoiesis after irradiation led to reduced general condition, disordered ingestion and exsikkosis leading to death respectively to euthanasia for reasons of protection of animals. By scaling up the cell number in the inoculum to 1x107 bone marrow cells + 5x106 splenocytes 25% of mice survived, with 3x107 bone marrow cells + 5x106 splenocytes survival was 50%. In contrast to syngeneic experiments, cotransplantation of 1,5x106 allogeneic CD4+CD25+ T cells and 3x107 bone marrow cells + 5x106 splenocytes did not prevent animals from mortality. In this allogeneic transplantation model Tregs restrain engraftment (graft failure). It has to be clarified if this effect is specific for the utilized mouse strains and which mechanisms are responsible for the graft failure. In the syngeneic triple transgenic mouse model cotransplantation of CD4+CD25+ T cells showed a positive effect on reconstitution of hematopoiesis after irradiation. In the allogeneic setting however cotransplantation of allogeneic regulatory T cells avoided the engraftment of transplanted cells. The described and published effect of donor-specific Tregs for treatment of graft versus host disease after allogeneic transplantation does not contradict the presented results because treated patients already possessed engrafted hematopoietic stem cells. The results have wide consequences for the therapeutic appliance of regulatory T cells in hematological diseases in human and veterinary medicine.

Repetitive Störungen manifestieren sich als Leitsymptom in der Zwangsstörung und dem Tourette-Syndrom. Die Symptome werden als enthemmte Stereotypien eines desinhibierten Basalganglien-thalamo-kortikalen (BGTC) Regelkreises verstanden. Überdies wird als neurochemisches Korrelat ein dysregulatives Dopamin (DA)-System innerhalb dieser Kerngebiete nahegelegt, welches über ein überaktives Dopamintransporter (DAT)-System erklärt werden könnte. In der Induktion repetitiver Erkrankungen ist die Interaktion des BGTC Regelkreises und des DA-Systems dennoch unklar. In der vorliegenden Arbeit wurden daher anhand von zwei Pathologiemodellen (Ratte) mit unterschiedlich induzierter Dysregulation des DA-Systems (transgen versus pharmakologisch) die dysfunktionalen Einheiten im BGTC Regelkreises vergleichend untersucht. Im transgenen Modell führte die zentralnervöse DAT-Überexpression: (1) zu einer verstärkten Genexpression des vesikulären Monoamintransporter 2 (VMAT2) sowie des DA-Rezeptors 1 und DA–Rezeptors 2 (DRD1, DRD2), (2) zu einem reduzierten DA-Spiegel mit erhöhter DA-Umsatzrate und veränderten serotonergen- und GABAergen-System, und (3) zu perserverativen Verhalten. Im Gegensatz dazu zeigte die chronische Applikation mit dem D2-Agonisten Quinpirol im pharmakologischen Modell: (1) eine Reduktion des DAT, VMAT2 und DRD2, (2) eine reduzierte DA-Umsatzrate und (3) zwanghaftes Kontrollverhalten. Die Ergebnisse legen nahe, dass die unterschiedlichen klinischen Subtypen der Zwangsstörung unterschiedlichen neurobiologischen Veränderungen zugrunde liegen könnten. Ferner bietet das hier vorgestellte transgene Modell erfolgsversprechende Ansatzpunkte um als neues valides Tiermodell der repetitiven Störungen etabliert zu werden. / Repetitive disorders manifest as the cardinal symptom in obsessive-compulsive disorder and Tourette syndrome. The symptoms are understood as disinhibited stereotypies of a basal ganglia-thalamo-cortical (BGTC) circuit. Furthermore, it is suggested that a dysregulated dopamine (DA) system within this circuit is the underlying neurochemical correlate which could be explained by an overactive dopamine transporter (DAT). At this point, it is still unclear how the BGTC circuit and the DA system interact in the induction of repetitive disorders. Therefore we investigated the dysfunctional unities within the BGTC circuit by comparing two pathological rat models (transgenic versus pharmacologic) with different induced dopaminergic dysregulation. The DAT overexpressing rat model showed: (1) increased gene expression of the vesicular monoamine transporter 2 (VMAT2), DA receptor D1 (DRD1) and DA receptor D2 (DRD2), (2) lower levels of DA with an increased DA metabolism and alterations in the serotonin- and GABA system, and (3) perseverative behavior. In contrast, the chronic application of the D2 receptor agonist quinpirole resulted in the pharmacologic model in: (1) lower gene expressions of the DAT, VMAT2 and DRD2, (2) reduced DA-turnover and (3) compulsive control behavior. These results suggest that different clinical subtypes of obsessive-compulsive disorder caused by different neurobiological alterations. In addition, the presented transgenic model provides the opportunity to be established as a new valid animal model of repetitive disorders.

No description available.

Made available in DSpace on 2014-12-17T15:47:55Z (GMT). No. of bitstreams: 1 SilviaMDM_DISSERT.pdf: 1535044 bytes, checksum: 925f2f885f42335d55c35aa64bb4d026 (MD5) Previous issue date: 2011-02-17 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The Multiobjective Spanning Tree is a NP-hard Combinatorial Optimization problem whose application arises in several areas, especially networks design. In this work, we propose a solution to the biobjective version of the problem through a Transgenetic Algorithm named ATIS-NP. The Computational Transgenetic is a metaheuristic technique from Evolutionary Computation whose inspiration relies in the conception of cooperation (and not competition) as the factor of main influence to evolution. The algorithm outlined is the evolution of a work that has already yielded two other transgenetic algorithms. In this sense, the algorithms previously developed are also presented. This research also comprises an experimental analysis with the aim of obtaining information related to the performance of ATIS-NP when compared to other approaches. Thus, ATIS-NP is compared to the algorithms previously implemented and to other transgenetic already presented for the problem under consideration. The computational experiments also address the comparison to two recent approaches from literature that present good results, a GRASP and a genetic algorithms. The efficiency of the method described is evaluated with basis in metrics of solution quality and computational time spent. Considering the problem is within the context of Multiobjective Optimization, quality indicators are adopted to infer the criteria of solution quality. Statistical tests evaluate the significance of results obtained from computational experiments / A ?rvore Geradora Multiobjetivo ? um problema de Otimiza??o Combinat?ria NP-?rduo. Esse problema possui aplica??o em diversas ?reas, em especial, no projeto de redes. Nesse trabalho, prop?e-se uma solu??o para o problema em sua vers?o biobjetivo por meio de um Algoritmo Transgen?tico, denominado ATIS-NP. A Transgen?tica Computacional ? uma t?cnica metaheur?stica da Computa??o Evolucion?ria cuja inspira??o est? na coopera??o (e n?o na competi??o) como fator de maior influ?ncia para a evolu??o. O algoritmo proposto ? a evolu??o de um trabalho que j? originou dois outros algoritmos transgen?ticos. Nesse sentido, os algoritmos previamente desenvolvidos tamb?m s?o apresentados. Essa pesquisa compreende ainda uma an?lise experimental que visa obter informa??es quanto ao desempenho do ATIS-NP quando comparado a outros algoritmos. Para tanto, o ATIS-NP ? comparado aos dois algoritmos anteriormente implementados, bem como a outro transgen?tico proposto na literatura para o problema tratado. Os experimentos computacionais abrangem ainda a compara??o do algoritmo desenvolvido a duas abordagens recentes da literatura que obt?m excelentes resultados, um GRASP e um gen?tico. A efici?ncia do m?todo apresentado ? avaliada com base em medidas de qualidade de solu??o e tempo computacional despendido. Uma vez que o problema se insere no contexto da Otimiza??o Multiobjetivo, indicadores de qualidade s?o utilizados para inferir o crit?rio de qualidade de solu??es obtidas. Testes estat?sticos avaliam a signific?ncia dos resultados obtidos nos experimentos computacionais

Made available in DSpace on 2014-12-17T14:55:03Z (GMT). No. of bitstreams: 1 IloneideCOR.pdf: 1010601 bytes, checksum: 76bbc04aa0a456f079121fb0d750ea74 (MD5) Previous issue date: 2005-03-03 / The problems of combinatory optimization have involved a large number of researchers in search of approximative solutions for them, since it is generally accepted that they are unsolvable in polynomial time. Initially, these solutions were focused on heuristics. Currently, metaheuristics are used more for this task, especially those based on evolutionary algorithms. The two main contributions of this work are: the creation of what is called an -Operon- heuristic, for the construction of the information chains necessary for the implementation of transgenetic (evolutionary) algorithms, mainly using statistical methodology - the Cluster Analysis and the Principal Component Analysis; and the utilization of statistical analyses that are adequate for the evaluation of the performance of the algorithms that are developed to solve these problems. The aim of the Operon is to construct good quality dynamic information chains to promote an -intelligent- search in the space of solutions. The Traveling Salesman Problem (TSP) is intended for applications based on a transgenetic algorithmic known as ProtoG. A strategy is also proposed for the renovation of part of the chromosome population indicated by adopting a minimum limit in the coefficient of variation of the adequation function of the individuals, with calculations based on the population. Statistical methodology is used for the evaluation of the performance of four algorithms, as follows: the proposed ProtoG, two memetic algorithms and a Simulated Annealing algorithm. Three performance analyses of these algorithms are proposed. The first is accomplished through the Logistic Regression, based on the probability of finding an optimal solution for a TSP instance by the algorithm being tested. The second is accomplished through Survival Analysis, based on a probability of the time observed for its execution until an optimal solution is achieved. The third is accomplished by means of a non-parametric Analysis of Variance, considering the Percent Error of the Solution (PES) obtained by the percentage in which the solution found exceeds the best solution available in the literature. Six experiments have been conducted applied to sixty-one instances of Euclidean TSP with sizes of up to 1,655 cities. The first two experiments deal with the adjustments of four parameters used in the ProtoG algorithm in an attempt to improve its performance. The last four have been undertaken to evaluate the performance of the ProtoG in comparison to the three algorithms adopted. For these sixty-one instances, it has been concluded on the grounds of statistical tests that there is evidence that the ProtoG performs better than these three algorithms in fifty instances. In addition, for the thirty-six instances considered in the last three trials in which the performance of the algorithms was evaluated through PES, it was observed that the PES average obtained with the ProtoG was less than 1% in almost half of these instances, having reached the greatest average for one instance of 1,173 cities, with an PES average equal to 3.52%. Therefore, the ProtoG can be considered a competitive algorithm for solving the TSP, since it is not rare in the literature find PESs averages greater than 10% to be reported for instances of this size. / Os problemas de otimiza??o combinat?ria t?m envolvido um grande n?mero de pesquisadores na busca por solu??es aproximativas para aqueles, desde a aceita??o de que eles s?o considerados insol?veis em tempo polinomial. Inicialmente, essas solu??es eram focalizadas por meio de heur?sticas. Atualmente, as metaheur?sticas s?o mais utilizadas para essa tarefa, especialmente aquelas baseadas em algoritmos evolucion?rios. As duas principais contribui??es deste trabalho s?o: a cria??o de uma heur?stica, denominada Operon, para a constru??o de cadeias de informa??es necess?rias ? implementa??o de algoritmos transgen?ticos (evolucion?rios) utilizando, principalmente, a metodologia estat?stica - An?lise de Agrupamentos e An?lise de Componentes Principais -; e a utiliza??o de an?lises estat?sticas adequadas ? avalia??o da performance de algoritmos destinados ? solu??o desses problemas. O Operon visa construir, de forma din?mica e de boa qualidade, cadeias de informa??es a fim de promover uma busca -inteligente- no espa?o de solu??es. O Problema do Caixeiro Viajante (PCV) ? focalizado para as aplica??es que s?o realizadas com base num algoritmo transgen?tico, denominado ProtoG. Prop?e-se, tamb?m, uma estrat?gia de renova??o de parte da popula??o de cromossomos indicada pela ado??o de um limite m?nimo no coeficiente de varia??o da fun??o de adequa??o dos indiv?duos, calculado com base na popula??o. S?o propostas tr?s an?lises estat?sticas para avaliar a performance de algoritmos. A primeira ? realizada atrav?s da An?lise de Regress?o Log?stica, com base na probabilidade de obten??o da solu??o ?tima de uma inst?ncia do PCV pelo algoritmo em teste. A segunda ? realizada atrav?s da An?lise de Sobreviv?ncia, com base numa probabilidade envolvendo o tempo de execu??o observado at? que a solu??o ?tima seja obtida. A terceira ? realizada por meio da An?lise de Vari?ncia n?o param?trica, considerando o Erro Percentual da Solu??o (EPS) obtido pela percentagem em que a solu??o encontrada excede a melhor solu??o dispon?vel na literatura. Utiliza-se essa metodologia para a avalia??o da performance de quatro algoritmos, a saber: o ProtoG proposto, dois algoritmos mem?ticos e um algoritmo Simulated Annealing. Foram realizados seis experimentos, aplicados a sessenta e uma inst?ncias do PCV euclidiano, com tamanhos de at? 1.655 cidades. Os dois primeiros experimentos tratam do ajuste de quatro par?metros utilizados no algoritmo ProtoG, visando melhorar a performance do mesmo. Os quatro ?ltimos s?o utilizados para avaliar a performance do ProtoG em compara??o aos tr?s algoritmos adotados. Para essas sessenta e uma inst?ncias, conclui-se, sob testes estat?sticos, que h? evid?ncias de que o ProtoG ? superior a esses tr?s algoritmos em cinq?enta inst?ncias. Al?m disso, para as trinta e seis inst?ncias consideradas nos tr?s ?ltimos experimentos, nos quais a avalia??o da performance dos algoritmos foi realizada com base no EPS, observou-se que o ProtoG obteve EPSs m?dios menores que 1% em quase metade das inst?ncias, tendo atingido a maior m?dia para uma inst?ncia composta por 1.173 cidades, com EPS m?dio igual a 3,52%. Logo, o ProtoG pode ser considerado um algoritmo competitivo para solucionar o PCV, pois n?o ? raro serem reportados, na literatura, EPSs m?dios maiores que 10% para inst?ncias desse porte.

Zusammenfassung Thure Adler Der Streptozotozin-induzierte Diabetes in der transgenen CD4/DR17-Maus Aus dem Institut für Immunologie der Veterinärmedizinischen Fakultät und dem Institut für Klinische Immunologie und Transfusionsmedizin der Medizinischen Fakultät der Universität Leipzig, 80 Seiten, 24 Abbildungen, 20 Tabellen, 217 Literaturangaben Die Verwendung transgener Tiere, die humane Moleküle exprimieren, gewinnt zunehmend an Bedeutung bei der Erforschung der Funktionen solcher Moleküle in Krankheitsprozessen und bei der experimentellen Erprobung neuartiger Therapieverfahren, in denen solche Moleküle die Zielstrukturen darstellen. In der vorliegenden Arbeit wurde die CD4/DR17-Maus, welche das humane CD4- und das DR17-Molekül exprimiert, im MLD-STZ-induzierten Diabetes, einem Tiermodell für den Typ 1 Diabetes, eingesetzt. Die funktionelle Beteiligung der Transgene wurde durch einen Vergleich mit Segreganten untersucht, denen die Transgene teilweise fehlen. Als klinische Parameter sind Blutglukose und Glukosetoleranz erfaßt worden, histopathologisch wurden Insulitis und Insulingehalt der Inselzellen bestimmt. Ferner wurde getestet, ob sich durch Verabreichung von monoklonalen Antikörpern, die gegen das transgene hCD4- oder gegen das CD8-Molekül gerichtet sind, dieser STZ-induzierte Diabetes beeinflussen läßt. Mit Hilfe der durchflußzytometrischen Immunfluoreszenzanalyse von Blutzellen wurde zusätzlich überprüft, ob Veränderungen auf T-Zellen hinsichtlich der Expression der Aktivierungsmarker CD25, CD69 und CD71 während des STZ-induzierten Diabetes auftreten. Es wurde gezeigt, dass die CD4/DR17-transgene Maus nach der Behandlung mit mehrfachen subdiabetogenen Dosen von Streptozotozin eine transiente Hyperglykämie entwickelt, die mit einer verringerten Glukosetoleranz sowie Insulitiden und einem Rückgang des Insulingehaltes in den Langerhans’schen Inseln einhergeht. Vergleiche mit Segreganten zeigen, dass die Expression beider transgener Merkmale zur maximalen Ausprägung einer schwergradigen Insulitis beiträgt. Die Anwendung von monoklonalen Antikörpern gegen das transgene hCD4-Molekül nach Beginn der STZ-Behandlung hat den Diabetes nicht wirkungsvoll verzögert. Dagegen milderte eine Behandlung mit Antikörpern, die gegen das CD8-Molekül gerichtet sind, den Diabetesverlauf. Während des STZ-Diabetes veränderte sich die Expression von Aktivierungsmarkern auf Lymphozyten des peripheren Blutes nicht signifikant. Die Arbeit belegt, dass die CD4/DR17-Maus suszeptibel gegenüber der Induktion eines experimentellen Diabetes mit mehrfachen subdiabetogenen Dosen von Streptozotozin ist. Die transgenen Moleküle hCD4 und DR17 sind dabei am Krankheitsprozeß beteiligt. / Summary Thure Adler The streptozotocin-induced diabetes in the transgenic CD4/DR17 mouse From the Institute of Immunology, Faculty of Veterinary Medicine and the Institute of Clinical Immunology and Transfusion Medicine, Faculty of Medicine, University of Leipzig 80 pages, 24 figures, 20 tables, 217 references Today, transgenic animals that express human molecules are getting important tools in functional studies and experimental, therapeutical attempts, that target these molecules. In this study, the CD4/DR17 mouse expressing the human CD4 and the human DR17 molecules and with a defective murine CD4 gene, was used in the multiple low-dose streptozotocin-induced (MLD-STZ) diabetes model, a model for type 1 diabetes. The functional involvement of the transgenic molecules in the development of the MLD-STZ-diabetes was analysed by comparing CD4/DR17 mice and segregants that lack one or more of the transgenes. The described parameters included the measurement of blood glucose levels and oral glucose tolerance tests, histopathologically grading of insulitis and determination of the content of insulin in pancreatic islets by immunohistological methods. In addition, the model was used to test the potential therapeutic effect of the administration of monoclonal antibodies against hCD4 or CD8. Furthermore, alterations of the expression of the activation markers CD25, CD69 and CD71 during the experimentally induced diabetes has been measured by FACS analysis. The study shows, that CD4/DR17 mice develop a transient hyperglycemia after MLD-STZ treatment, accompanied by a reduced tolerance to oral glucose, insulitis and the reduction of the content of insulin in the pancreatic islets. The full incidence of insulitis requires the expression of both transgenes. The treatment performed with monoclonal antibodies against the transgenic hCD4 after STZ-treatment could not meliorate the diabetic course, while the treatment with anti CD8 antibodies moderated the diabetic process. After STZ-treatment the expression of activation marker of peripheral T-cells did not alter significantly. Thus, the CD4/DR17 mouse is shown to be susceptible to the induction of experimental diabetes with MLD-STZ. The transgenic molecules CD4 and DR17 are involved in the pathogenesis of the disease.

Made available in DSpace on 2014-12-17T15:46:59Z (GMT). No. of bitstreams: 1 PauloHAS_TESE.pdf: 9268945 bytes, checksum: 08c0c5f93ed7b964b99c6df2ee26ab1b (MD5) Previous issue date: 2011-12-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The Car Rental Salesman Problem (CaRS) is a variant of the classical Traveling Salesman Problem which was not described in the literature where a tour of visits can be decomposed into contiguous paths that may be performed in different rental cars. The aim is to determine the Hamiltonian cycle that results in a final minimum cost, considering the cost of the route added to the cost of an expected penalty paid for each exchange of vehicles on the route. This penalty is due to the return of the car dropped to the base. This paper introduces the general problem and illustrates some examples, also featuring some of its associated variants. An overview of the complexity of this combinatorial problem is also outlined, to justify their classification in the NPhard class. A database of instances for the problem is presented, describing the methodology of its constitution. The presented problem is also the subject of a study based on experimental algorithmic implementation of six metaheuristic solutions, representing adaptations of the best of state-of-the-art heuristic programming. New neighborhoods, construction procedures, search operators, evolutionary agents, cooperation by multi-pheromone are created for this problem. Furtermore, computational experiments and comparative performance tests are conducted on a sample of 60 instances of the created database, aiming to offer a algorithm with an efficient solution for this problem. These results will illustrate the best performance reached by the transgenetic algorithm in all instances of the dataset / O Problema do Caixeiro Alugador (CaRS) ? uma variante ainda n?o descrita na literatura do cl?ssico Problema do Caixeiro Viajante onde o tradicional tour de visitas do caixeiro pode ser decomposto em caminhos cont?guos e que podem ser realizados em diferentes carros alugados. O problema consiste em determinar o ciclo hamiltoniano que resulte em um custo final m?nimo, considerando o custo da rota adicionado ao custo de uma prov?vel penaliza??o paga em cada troca de ve?culos na rota, penaliza??o devida ao retorno do carro descartado at? a sua cidade base. Sem perda para a generalidade do caso, os custos do aluguel do carro podem ser considerados embutidos nos custos da rota do carro. O presente trabalho introduz o problema geral e o exemplifica, caracterizando igualmente algumas variantes associadas. Uma an?lise geral da complexidade desse problema combinat?rio ? descrita, visando justificar sua classifica??o na classe NP-dif?cil. Um banco de inst?ncias para o problema ? apresentado, descrevendo-se a metodologia de sua constitui??o. O problema proposto tamb?m ? objeto de um estudo algor?tmico experimental baseado na aplica??o de seis metaheur?sticas de solu??o, representando adapta??es do melhor do estado da arte em programa??o heur?stica. Novas vizinhan?as, procedimentos construtivos, operadores de busca, agentes evolucion?rios, coopera??o por multiferom?nios, s?o criados para o caso. Experimentos computacionais comparativos e testes de desempenho s?o realizados sobre uma amostra de 60 inst?ncias, visando oferecer um algoritmo de solu??o competitivo para o problema. Conclui-se pela vantagem do algoritmo transgen?tico em todos os conjuntos de inst?ncias

Made available in DSpace on 2015-03-03T15:48:41Z (GMT). No. of bitstreams: 1 MatheusSM_TESE.pdf: 3657538 bytes, checksum: 05bf71663b044728a1e70b6db57b834e (MD5) Previous issue date: 2014-03-21 / This paper introduces a new variant of the Traveling Car Renter Problem, named Prizecollecting Traveling Car Renter Problem. In this problem, a set of vertices, each associated with a bonus, and a set of vehicles are given. The objective is to determine a cycle that visits some vertices collecting, at least, a pre-defined bonus, and minimizing the cost of the tour that can be traveled with different vehicles. A mathematical formulation is presented and implemented in a solver to produce results for sixty-two instances. The proposed problem is also subject of an experimental study based on the algorithmic application of four metaheuristics representing the best adaptations of the state of the art of the heuristic programming.We also provide new local search operators which exploit the neighborhoods of the problem, construction procedures and adjustments, created specifically for the addressed problem. Comparative computational experiments and performance tests are performed on a sample of 80 instances, aiming to offer a competitive algorithm to the problem. We conclude that memetic algorithms, computational transgenetic and a hybrid evolutive algorithm are competitive in tests performed / Este trabalho apresenta uma nova variante do problema do Caixeiro Alugador ainda n?o descrita na literatura, denominada de Caixeiro Alugador com Coleta de Pr?mios. Neste problema s?o disponibilizados um conjunto de v?rtices, cada um com um b?nus associado e um conjunto de ve?culos. O objetivo do problema ? determinar um ciclo que visite alguns v?rtices coletando, pelo menos, um b?nus pr?-de nido e minimizando os custos de viagem atrav?s da rota, que pode ser feita com ve?culos de diferentes tipos. ? apresentada uma formula??o matem?tica e implementada em um solver produzindo resultados em sessenta e duas inst?ncias. O problema proposto tamb?m ? objeto de um estudo algor?tmico experimental baseado na aplica??o de quatro metaheur?sticas de solu??o, representando adapta??es do melhor do estado da arte em programa??o heur?stica. Nesse trabalho tamb?m apresentamos a constitui??o de novos operadores que exploram as vizinhan?as do problema, procedimentos construtivos e adapta??es, criados especifi camente para o problema abordado. Experimentos computacionais comparativos e testes de desempenho s?o realizados sobre uma amostra de 80 inst?ncias, visando oferecer um algoritmo de solu??o competitivo para o problema. Conclui-se que algoritmos com abordagem mem?tica, transgen ?tica e evolucion?ria h?brida obtiveram resultados competitivos nos testes efetuados. Palavras-chave: Caixeiro Alugador com Coleta de Pr?mios. Metaheur?sticas. GRASP/VNS. Algoritmo Mem?tico. Transgen?tica Computacional. Computa??o Evolucion?ria