M.A. (African Languages) / Poetry is an art form beyond other genres. It is superior because it is tied up with deep feelings. "It is an outflow of powerful feelings". Poetry is by and large, differentiated from prose by a mark of greater specialism. African poetry is twofold; viz. traditional poetry and modern poetry. Traditional poetry is derived from Africa; and modern poetry is developed largely from the west. A brief statement on Northern Sotho poetry was given attention. The abilities of Tseke as a poet were briefly discussed. Tseke's poems were divided according to themes and poetic forms. Russian Formalism as a literary theory was looked into. Imagery as a poetic device was discussed under headings such as: figures of speech, senses used to evoke images and repetition. Tseke's language was discussed to show his ability to coin new words. Structure as a poetic device included headings such as: structure of poems, what brings structural agreement between stanzas and elements which contribute to the achievement of unity in poems.

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Au vu du contexte actuel (mondialisation des échanges, concurrence, innovations technologiques…), les entreprises doivent trouver les moyens de proposer des produits et services toujours plus innovants pour se différencier. C’est pourquoi, elles font de plus en plus appel aux compétences des clients pour concevoir leurs offres qui correspondront davantage à leurs besoins. Cette pratique qui suscite un réel engouement auprès des managers est appelée « co-création ».Or, d’après la littérature, il semblerait que peu de recherches ne se sont intéressées aux raisons pour lesquelles certaines entreprises sont plus prédisposées que d’autres à co-créer des services dans le contexte interorganisationnel (Business-to Business, B to B). Pourtant, cette question est fondamentale. En effet, s’il est démontré que certains facteurs favorisent l’adhésion des clients et la gestion de projets de co-création, les organisations pourront mieux choisir des partenaires (candidats) à un projet de co-création. Ainsi, notre travail de recherche propose de répondre à la question suivante : Pourquoi certaines entreprises sont-elles plus disposées à co-créer un service alors que d’autres le sont moins ?Dès lors, après avoir réalisé un état de l’art sur la co-création de services, nous menons deux études qualitatives auprès de dirigeants et de clients B to B impliqués dans des démarches de co-création de services innovants. La troisième étude de nature quantitative est réalisée auprès d’un échantillon de prestataires de services destinés aux entreprises afin de tester nos hypothèses de recherche. Les résultats obtenus ont permis d’identifier des critères à la fois organisationnels (spécifiques à l’entreprise) et sectoriels (c’est-à-dire, relatifs au marché) explicatifs de la prédisposition et du degré d’implication des entreprises dans un processus de co-création. D’un point de vu managérial, cette recherche souligne les bonnes pratiques à mettre en place au sein des organisations avant d’initier cette démarche collaborative. / In the current world context (globalization, competition, technological innovations,.), companies must look for new ways to offer more innovative goods and services. Therefore, they require customer’s competencies to design offerings that meet their needs. This practice which is raising a great deal of enthusiasm from the managers is called “co-creation”.An examination of the existing literature on services suggests that little has been done on the reasons why some companies are more disposed to engage in a B to B service co-creation process while others are less disposed to do so. Yet, this is an important issue. Indeed, if we can show that there are some criteria which can be used to identify potential co-creators and that facilitate the management of co-creation projects, then organizations could use this knowledge to select their partners in a co-creation process.In the light of the foregoing, our research study seeks to answer the following question: Why are some B-to-B service providers more disposed to co-create services than others?After a literature review on service co-creation, we conduct two qualitative studies with leaders and B to B customers involved in innovative service co-creation projects. The third study that is quantitative surveys a number of service providers in order to test our research hypothesis.Our empirical results allow us to identify firm-level and industry-level criteria relevant for explaining businesses’ willingness to engage in a co-creation process as well as their level of involvement in this process. From a managerial perspective, the present research also underlines the best practices to implement in service organizations before starting such a collaborative approach.

Memoria para optar al título de Químico Farmacéutico / Las vacunas de ADN son una terapia alternativa altamente atractiva para combatir el cáncer. Esta estrategia consiste en la entrega in vivo de ADN plasmidial codificante de antígenos tumorales que son expresados y presentados por células dendríticas (DC) con el fin de activar linfocitos T capaces de eliminar específicamente células tumorales. Un importante paso hacia la aplicación clínica de las vacunas de ADN ha sido el uso de la electroporación in vivo, un método de entrega altamente eficiente y clínicamente aplicable, que aumenta considerablemente el ingreso de plásmidos al interior de las células. Sin embargo, la mayoría de los antígenos tumorales son antígenos propios expresados en células normales, por lo que el sistema inmune es incapaz de discriminar a los tumores como agentes potencialmente peligrosos. Es así como los esfuerzos para resolver estos inconvenientes se han enfocado, en parte, en la búsqueda y elaboración de nuevas estrategias que sean capaces de promover eficientemente la inducción de linfocitos T específicos contra estos antígenos tumorales poco inmunogénicos. El ADN usado en las vacunas puede ser reconocido por numerosos receptores de la inmunidad innata, los cuales al ser activados, señalizan a través del factor de transcripción NF-κB, induciendo la expresión de citoquinas proinflamatorias e interferones de tipo I. NF-κB es un regulador maestro de la función de las DC y de la inducción de linfocitos T mediada por vacunas de ADN, por lo tanto, el desarrollo de adyuvantes que modulen su actividad representa una estrategia interesante para promover la inducción eficiente de linfocitos T antitumorales. IκBα es uno de los principales inhibidores de NF-κB, el cual además es un gen blanco de NF-κB, por lo que actúa en un sistema de retroalimentación negativa para detener la activación de esta vía. Por otro lado, el uso de shARN que silencian la expresión de reguladores negativos de las DC ha demostrado su capacidad como adyuvantes génicos en vacunas de ADN, al inducir una respuesta inmune antitumoral más potente. Por tanto, nuestra hipótesis plantea que un shARN contra IκBα es capaz de potenciar la activación de la inmunidad innata mediada por NF-κB y, como consecuencia, la magnitud de la respuesta inmune adaptativa específica contra el antígeno tumoral codificado. En este proyecto se utilizaron plásmidos codificantes de un shARN contra IκBα como adyuvantes génicos para ser administrado junto a una vacuna de ADN que codifica para el antígeno tumoral TRP2. Se evaluó el efecto del silenciamiento de IκBα sobre la migración de las células dendríticas de la piel, particularmente sobre las células de Langerhans y sobre las células dendríticas dermales CD103+. La generación de linfocitos T específicos contra TRP2 se analizó en ratones vacunados mediante citometría de flujo y el efecto antitumoral in vivo se evaluó usando un modelo de profiláctico de melanoma metastásico y un modelo terapéutico de melanoma subcutáneo. Los resultados de este trabajo indican que la administración de ADN plásmidial en la piel incrementa la migración de células dendríticas hacia los nódulos linfáticos drenantes y que la inhibición de la expresión de IκBα con un shARN en el sitio de vacunación incrementa la migración de células dendríticas dermales CD103+ hacia el nódulo linfático drenante. Además se observó que la coadministración del shARN contra IκBα en conjunto con una vacuna de ADN dirigida contra el antígeno tumoral TRP2 potencia la generación de linfocitos T CD8 específicos e incrementa la respuesta inmune antitumoral en ensayos de metástasis pulmonar y crecimiento tumoral utilizando el modelo de melanoma murino B16F10. Dada la gran capacidad de las células dendríticas dermales CD103+ para activar linfocitos T CD8 es posible correlacionar su incremento en los nódulos linfáticos drenantes del sitio de vacunación con una mayor generación de linfocitos T CD8 específicos contra TRP2 y con un incremento en la respuesta inmune antitumoral contra melanoma cuando se coadministra el shARN contra IκBα junto con una vacuna de ADN dirigida contra el antígeno tumoral TRP2 / DNA vaccines are a highly attractive therapeutic alternative to treat cancer. This strategy consists of in vivo delivering plasmid vectors encoding tumor antigens, which are expressed and presented by dendritic cells (DC) in order to activate T cells capable of specifically eliminating tumor cells. An important step towards the clinical application of DNA vaccines has been the use of in vivo electroporation, a highly efficient delivery method that is clinically applicable and considerably increases plasmid uptake in cells. However, most of tumor antigens are self-antigens expressed by normal cells, so that the immune system is unable to recognize tumors as potentially dangerous agents. Thus, the efforts to solve these inconvenient have been focused on developing new strategies to promote the induction of T cells responses specific against such poorly immunogenic tumor antigens. DNA used for vaccines can be recognized by several innate immune receptors that, upon activation, signal through the transcription factor NF-κB which induces the expression of proinflamatory cytokines and type I interferons. NF-κB is a master regulator of both DC function and DNA vaccine-mediated induction of T cell responses, therefore the development of adjuvants that modulate NF-κB activity represents an interesting strategy to promote the efficient induction of antitumor T cell responses. IκBα is one of the major inhibitors and downstream target genes of NF-κB, therefore acting in a negative feedback loop to stop NF- κB activation. The use of shRNA silencing negative regulators of DC function has demonstrated its potential as genetic adjuvants for DNA vaccines by inducing enhanced antitumor immune responses. Hence, our hypothesis states that a shRNA targeting IκBα is able to promote the NF-κB innate immune activation and, as a consequence, the magnitude of tumor antigen-specific adaptive immune responses. In this project, plasmid-encoded shRNA targeting IκBα were generated as genetic adjuvants to be coadministrated with a DNA vaccine encoding the tumor antigen TRP2.The effect of IκBα silencing was analyzed over the migration of skin dendritic cells, particularly Langerhans cells and CD103+ dermal dendritic cells. Generation of TRP2-specific T cells was studied in vaccinated mice by flow cytometry and the in vivo antitumor effect was evaluated using prophylactic model of metastatic melanoma and a subcutaneous model of melanoma. The results obtained in this work shows that the inhibition of IκBα using a shRNA increases the migration of CD103+ dermal dendritic cells to the skin draining lymph nodes. Also the coadministration of the shRNA against IκBα and a DNA vaccine against TRP2 enhance the generation of TRP2 specific CD8 T cells increasing the antitumor immune response against melanoma. Finally due to the high ability of CD103+ dermal dendritic cells to cross-present antigens and activate CD8 T cell is possible to correlate their increase in the migration with higher levels of TRP2 specific CD8 T cells and higher antitumor immune response when the shRNA against IκBα is coadministered with a DNA vaccine against TRP2

A b-coloring of G is a proper vertex coloring such that there is a vertex in each color class, which is adjacent to at least one vertex in every other color class. Such a vertex is called a color-dominating vertex. The b-chromatic number of G is the largest k such that there is a b-coloring of G by k colors. Moreover, if for every integer k, between chromatic number and b-chromatic number, there exists a b-coloring of G by k colors, then G is b-continuous. Determining the b-chromatic number of a graph G and the decision whether the given graph G is b-continuous or not is NP-hard. Therefore, it is interesting to find new results on b-colorings and b-continuity for special graphs. In this thesis, for several graph classes some exact values as well as bounds of the b-chromatic number were ascertained. Among all we considered graphs whose independence number, clique number, or minimum degree is close to its order as well as bipartite graphs. The investigation of bipartite graphs was based on considering of the so-called bicomplement which is used to determine the b-chromatic number of special bipartite graphs, in particular those whose bicomplement has a simple structure. Then we studied some graphs whose b-chromatic number is close to its t-degree. At last, the b-continuity of some graphs is studied, for example, for graphs whose b-chromatic number was already established in this thesis. In particular, we could prove that Halin graphs are b-continuous.:Contents 1 Introduction 2 Preliminaries 2.1 Basic terminology 2.2 Colorings of graphs 2.2.1 Vertex colorings 2.2.2 a-colorings 3 b-colorings 3.1 General bounds on the b-chromatic number 3.2 Exact values of the b-chromatic number for special graphs 3.2.1 Graphs with maximum degree at most 2 3.2.2 Graphs with independence number close to its order 3.2.3 Graphs with minimum degree close to its order 3.2.4 Graphs G with independence number plus clique number at most number of vertices 3.2.5 Further known results for special graphs 3.3 Bipartite graphs 3.3.1 General bounds on the b-chromatic number for bipartite graphs 3.3.2 The bicomplement 3.3.3 Bicomplements with simple structure 3.4 Graphs with b-chromatic number close to its t-degree 3.4.1 Regular graphs 3.4.2 Trees and Cacti 3.4.3 Halin graphs 4 b-continuity 4.1 b-spectrum of special graphs 4.2 b-continuous graph classes 4.2.1 Known b-continuous graph classes 4.2.2 Halin graphs 4.3 Further graph properties concerning b-colorings 4.3.1 b-monotonicity 4.3.2 b-perfectness 5 Conclusion Bibliography

Hepatitis B virus (HBV) infection is an important global health concern and chronic carriers of the virus are at high risk of developing hepatocellular carcinoma (HCC) and cirrhosis. Current therapies are only partially effective, which emphasises the need for improved treatment strategies. Harnessing the RNA interference (RNAi) pathway as a treatment strategy against HBV has shown great promise. However, there are obstacles that need to be overcome before RNAi-based treatment of HBV infection is realised. These include problems of liver tissue targeting and dose regulation. This study investigated the use of a liver specific and mifepristone-inducible RNA polymerase (Pol) II promoter system for the specific and precise regulation of anti-HBV sequence expression. The inducible system used consists of two expression cassettes; one containing the regulator/transactivator protein and another containing the transgene. Natural primary microRNA (pri-miR) mimics, pri-miR-31/5 and pri-miR-31/5/8/9, were used as anti-HBV sequences. Firefly luciferase gene expression was used to test modulation by the inducible system and to determine optimal induction conditions. The pri-miR-31/5, pri-miR-31/5/8/9 and luciferase encoding fragments were incorporated into the plasmid vector pRS17 that bears the inducible promoter, creating pRS-31/5, pRS-31/5/8/9 and pRS-Luc respectively. Firefly luciferase expression with this system was shown to be inducible and mifepristone dose-dependent. Effective knockdown of HBV gene expression was achieved with both pRS-31/5 and pRS-31/5/8/9 in vitro and in vivo. However, with high vector amounts, similar efficiency in silencing of HBV gene expression was observed in the presence and absence of the inducer mifepristone suggesting leaky expression of the pri-miRs. To confirm this, knockdown studies were carried out with the pri-miR-31/5/8/9-expressing cassette separated from the transactivator cassette. HBV gene expression knockdown was observed with the pri-miR-31/5/8/9 cassette alone confirming leaky expression from the inducible system. Leakiness appears to be as a result of the E1B promoter driving the expression of the pri-miRs in the absence of mifepristone. However, reducing the vector amounts decreased basal expression and improved the inducibility of the system in cell culture studies. Successful propagation of an inducible and liver-specific RNAi-activating expression system will address the difficulty of achieving dose control of RNAi effectors and contribute to advancing the use of RNAi for HBV treatment.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / A 24-year-old pregnant woman arrived at the emergency service at 34 weeks of gestational age with intermittent right upper abdominal pain. An abdominal ultrasound was performed showing signs of hepatopathy with multiple neo-formative nodules with mild ascites and fetal biometry confirmed at 34 weeks gestation. During her hospitalization, an emergency caesarean was induced with favorable result in the survival of the mother and the baby. / Revisión por pares

La leishmaniose viscérale est une maladie tropicale négligée et létale en l’absence de traitement. L’Amphotéricine B (AmB) est une molécule efficace mais sa forme conventionnelle, Fungizone®, conduit à une toxicité limitant les doses tandis que les formulations lipidiques moins toxiques telles que l’Ambisome® sont très coûteuses. Ainsi, le besoin de nouvelles formes thérapeutiques à la fois non toxiques et peu coûteuses subsiste actuellement. Dans ce travail, nous avons étudié deux solutions possibles : la Fungizone® chauffée (H-AmB) et une microémulsion chargée en AmB (MEAmB). En ce qui concerne la microémulsion, une forme lyophilisée est souhaitable afin de s’affranchir des risques d’hydrolyse et de contamination microbienne. Les objectifs de la thèse étaient de développer les deux nouvelles formes, d’évaluer la toxicité et l’efficacité de H-AmB et MEAmB contre Leishmania donovani (souche LV9) in-vitro et in-vivo et également d’optimiser la lyophilisation de la microémulsion.La microémulsion MEAmB est composée de gouttelettes sphériques dont le diamètre moyen est proche de 35 nm et a montré un comportement rhéologique de type newtonien. L’analyse spectroscopique de H-AmB a révélé la formation de super-agrégats qui sont moins toxiques que d’autres états d’agrégation. La MeAmB ainsi que l’H-AmB ont montré une activité antiparasitaire équivalente à celle d’AmBisome® sur les formes axénique et intramacrophagique de L. donovani. L’indice de sélectivité pour ces deux formulations est élevé, en contraste avec celui de la Fungizone® native. De plus, à la différence d’AmBisome®, elles ont montré une activité importante sur des souches résistantes à l’AmB. L’activité anti-leishmanienne in-vivo des nouvelles formulations est comparable aux formulations de référence. De même, aucune différence significative des marqueurs de toxicité rénale et hépatique n’a pu être observée. Ainsi, l’H-AmB et la MEAmB pourraient être considérées comme des traitements alternatifs de la leishmaniose viscérale, avec l’avantage d’être moins onéreuses à produire que l’Ambisome®.Afin d’optimiser le procédé de lyophilisation de la MEAmB, un plan d’expérience a été mis en œuvre. Ainsi, la taille des gouttelettes est minimisée par l’utilisation de 5% de maltose comme cryoprotectant, avec une température de congélation de -80°C et un temps total de lyophilisation de 24h. Par ailleurs, aucune modification significative de la teneur en AmB n’a été observée après la lyophilisation. Ainsi, la MEAmB lyophilisée est stable et pourrait éviter la dégradation due à la présence d’eau. / Visceral leishmaniasis is a neglected tropical disease that can be fatal if left untreated. Amphotericin B (AmB) is effective in the treatment of this disease, but the conventional formulation, Fungizone® has dose-limiting toxicity while the less toxic lipid-based forms such as Ambisome® are expensive. Therefore, the need for new therapeutic systems remains. In this respect, the heating of the Fungizone® formulation (H-AmB), and the development of a microemulsion (ME) containing AmB (MEAmB) are possible solutions. In addition, it is desirable to remove water from microemulsion systems in order to reduce instability due to microbiological contamination and hydrolysis. Therefore, the objective of this work was to develop and to evaluate the activity and toxicity in vitro and in vivo of H-AmB and MEAmB against Leishmania donovani (strain LV9) and, furthermore, to optimize a lyophilized microemulsion system containing AmB. Rheological, size and morphology studies showed that MEAmB presented average droplet sizes of 35 nm, a Newtonian behavior and spherical morphology. Spectroscopic characterization of H-AmB showed the formation of superaggregates, which are less toxic than the other states of aggregation. In-vitro evaluation on both the axenic and intramacrophagic amastigote forms showed that H-AmB and MEAmB showed similar activity to Ambisome®. A high selectivity index of H-AmB and MEAmB was observed compared with unheated Fungizone®. Furthermore, both new formulations showed high activity against AmB-resistant strains compared with Ambisome®. In-vivo experiments designed to evaluate their activity and toxicity did not reveal significant differences in activity between the new and reference formulations. There were no significant differences either in indicators of renal and hepatic toxicity. Therefore, both H-AmB and MEAmB can be used as an alternative for the treatment of LV9, presenting an advantage over Ambisome® in their lower costs of production. Therefore, a complete experimental design was performed in order to optimize the lyophilisation of the microemulsion system. It was observed that microemulsions with smaller droplet sizes were obtained using maltose as a cryoprotectant at a concentration of 5%, with freezing at -80 ° C, and a lyophilization process period of 24 h. Furthermore, it was observed that ME containing AmB showed no significant changes in drug content before and after the lyophilization process. Therefore, in its lyophilized form, the ME can remain stable and avoid degradation due to the presence of water.

Synthetic routes toward a B-alkylthiolanthionine derivative, as found in the quinomycin depsipeptide antibiotics, have been studied through a sequence involving as the key intermediates and steps (a) (S) - Z-[(benzyloxycarbonyl)amino]-3,3-dimethoxy-l-propanol (2), prepared from N-benzyloxycarbonyl-L-serine in 3 or 4 steps, (b) N-benzyloxycarbonyl- 0 - tetrahydropyranyl-B,B-(ethylsulfinylethylthio)-alaninol (4a), converted from 2, and (c) attempted Lewis acid catalyzed replacement of alkylsulfinyl function by thiol moiety of cysteine, which gave undesired products. Stability of protecting groups used in this study, which are N,0-isopropylidenyl and tetrahydropyranyl functions in N-protected-L-serinol 20 or 26, under acidic conditions was found to play an important role in determining the optical purity obtained in 2. Jone's oxidation and methylation of 2 led to the formation of N-benzyloxycarbonyl-B,B-(dimethoxy)alanine methyl ester (3) in low yield. Swern oxidation or Moffat oxidation of Z-L-Ser-Val-OMe dipeptide (5), which was expected to be converted to aldehyde 34, were carried out with unsuccessful results. Swern oxidation was applied to various N-protected amino alcohols derived from a-amino acids to give the corresponding aldehydes with excellent yields and optical purities.

Esta tesis está basada en un ensayo clínico, simple-ciego y no aleatorizado, realizado en el servicio de Cirugía Oral y Maxilofacial del Hospital Nacional Hipólito Unanue, cuyo objetivo fue determinar si la terapia con diclofenaco más vitaminas B es superior a la terapia con sólo diclofenaco en pacientes sometidos a cirugía electiva de tercera molar inferior. Se formaron 2 grupos, un grupo recibió diclofenaco más vitaminas B y el otro diclofenaco solo. La variable principal fue la intensidad de dolor medida luego de 1, 3, 6, 9, 12 y 24 horas de finalizada la cirugía mediante una escala gráfica verbal del 0-100; las variables secundarias fueron el tiempo para analgesia de rescate y la cantidad de analgésicos consumidos en el postoperatorio. Treinta pacientes completaron el estudio, quince de ellos recibieron diclofenaco (75 mg) más una mezcla de vitaminas B (B1: 100 mg, B6: 100 mg y B12: 10 mg) y los otros quince solamente diclofenaco (75 mg). Ambas terapias fueron administradas por vía intramuscular al finalizar la cirugía. Los resultados mostraron que la adición de vitaminas B al diclofenaco mejoró la eficacia analgésica del diclofenaco en la variable principal pero no de manera estadísticamente significativa (p > 0.05). Palabras clave: diclofenaco - vitaminas b - cirugía dental - tercera molar impactada / --- This thesis is based on a single-blind, non-randomized clinical trial which took place in the oral and maxillofacial surgery service of the Hipólito Unanue National Hospital, of which objective was to determine if the therapy using diclofenac plus B vitamins is better than the therapy using only diclofenac in patients subjected to elective surgery of inferior third molar. Two groups were formed, a group received diclofenac plus B vitamins and the other group received diclofenac only. The main variable was the intensity of pain measured after 1, 3, 6, 9, 12 and 24 hours the surgery had finished using a verbal graphic scale (0-100); the secondary variables were the time for rescue analgesics consumption and the amount of rescue analgesics taken in the postoperative period. Thirty patients completed the study, fifteen of them received diclofenac (75 mg) plus B vitamins (B1: 100 mg, B6: 100 mg and B12: 10 mg) and other fifteen patients received only diclofenac (75 mg). Both therapies were administered by intramuscular route once the surgery was finished. The results showed that by adding B vitamins to diclofenac improved the analgesic effectiveness of diclofenac in the main variable but there were no statistically significant differences. Keywords: diclofenac – b vitamins – dental surgery – impacted third molar / Tesis