[ES] Debido a la naturaleza (poli)iónica de los conjugados polipéptido-fármaco (PDC), su traslado a clínica puede ser una tarea complicada y costosa, que requiere técnicas de polimerización reproducibles y escalables, la implementación de herramientas analíticas sofisticadas, pasos de caracterización exhaustivos y la recopilación de datos detallados de seguridad y eficacia. Algunas técnicas clásicas implementadas en el control de calidad de los PDC no se pueden utilizar para el análisis cualitativo y cuantitativo de productos de degradación y metabolitos. Como alternativa, la espectrometría de masas (MS) y el análisis de fraccionamiento de flujo de campo de flujo asimétrico (AF4) se han posicionado de forma relevante en dicha caracterización de polipéptidos y PDC. Mediante el uso de métodos de LC-MS, se puede realizar el análisis tanto de fármacos como de productos o metabolitos de degradación. Además, dado que la separación en AF4 no se basa en la interacción del analito con la columna, como ocurre en SEC, sino aplicando el flujo cruzado en un canal vacío; en AF4 es posible una separación de moléculas "a medida" según su tamaño y peso molecular dando lugar a la mejora selectiva de la separación. Teniendo en cuenta lo descrito anteriormente con respecto al diseño de PDC y su caracterización, la investigación incluida en esta tesis se centra en el desarrollo de nuevos procedimientos analíticos que ayuden a la selección de candidatos PDC con las características adecuadas que les permitirán avanzar a su evaluación preclínica. Implementaremos una herramienta de inteligencia artificial, diseño de experimentos, para desarrollar métodos analíticos adecuados y determinar las condiciones óptimas en la síntesis de nanoconjugados polipeptídicos. Además, exploraremos técnicas relativamente nuevas, como AF4 para desarrollar nuevos nanoconjugados polipeptídicos simples y de combinación y además, generaremos imágenes de espectrometría de masas, para entender su comportamiento en modelos preclínicos relevantes, lo que nos permitirá identificar terapias eficaces para una gran variedad de patologías (tumores sólidos avanzados incluyendo cáncer de mama triple negativo, cáncer de próstata y cáncer de páncreas, así como, lesión medular). / [CAT] A causa de la naturalesa (poli)iònica i, de vegades, proteica dels conjugats polipèptid-fàrmac (PDC), el seu trasllat a clínica pot ser una tasca complicada i costosa, que requereix tècniques de polimerització reproduïbles i escalables, la implementació d'eines analítiques sofisticades, passos de caracterització exhaustius i la recopilació de dades detallades de seguretat i eficàcia. Algunes tècniques clàssiques implementades en el control de qualitat dels PDC no es poden utilitzar per l'anàlisi qualitativa i quantitativa de productes de degradació i metabòlits. Com a alternativa, l'espectrometria de masses (MS) i l'anàlisi del fraccionament de flux de camp de flux asimètric (AF4) han trobat el seu camí en la caracterització de PDC. Mitjançant l'ús de mètodes LC-MS, es pot realitzar l'anàlisi tant de fàrmacs com de productes/metabòlits de degradació. A més, atès que la separació en AF4 no es basa en la interacció de l'analit amb la columna com en SEC sinó aplicant el flux creuat en un canal buit, una separació de molècules "a mesura" segons la seua grandària i pes molecular i la millora selectiva de la separació és possible en l'instrument AF4. Tenint en compte tot el descrit anteriorment respecte al disseny de PDC i la seua caracterització, la investigació inclosa en aquest projecte es centra en el desenvolupament de nous procediments analítics que ajuden a la selecció de candidats PDC per als seu estudi preclínic posterior. Implementarem una eina d'intel·ligència artificial, disseny d'experiments, per a desenvolupar mètodes analítics i la síntesi de nanoconjugats basats en polipèptids de manera adequada. A més, explorarem tècniques relativament noves, com AF4, i generarem imatges d'espectrometria de masses, per a desenvolupar nous conjugats a la recerca de teràpies eficaces per a tractar una varietat de malalties (càncer de mama triple negatiu, càncer de pròstata, càncer de pàncrees, així com en la lesió de medul·la espinal). / [EN] Due to the (poly)ionic and proteinic nature of polypeptide-drug conjugates (PDCs), their translation "from bench to bedside" represents a complex and expensive undertaking, requiring reproducible and scalable polymerization techniques, the implementation of sophisticated analytical tools, exhaustive characterization steps, and the collection of detailed safety and efficacy data. Classical techniques, such as liquid chromatography (LC) - UV/Vis and size exclusion chromatography (SEC) implemented in the quality control of PDCs during and after synthesis, cannot always support a qualitative and quantitative analysis of degradation products and metabolites. As an alternative, mass spectrometry (MS) and asymmetric flow field flow fractionation (AF4) have grown in influence on polypeptide and PDC characterization. The analysis of drug and degradation products/metabolites can take advantage of LC when coupled to MS. Meanwhile, AF4-mediated separation does not suffer from problems related to the interaction of the analyte with the column like in SEC; instead, AF4 applies a cross flow in an empty channel, which supports the "tailor-made" separation of molecules according to size and molecular weight. The research included in this Ph.D. thesis focuses on developing new analytical procedures that will aid the selection of PDC candidates for further preclinical studies. We implemented an artificial intelligence tool (design of experiments) to develop analytical methods and optimize the synthesis of genipin-crosslinked PDCs. Moreover, we explored relatively new techniques, such as AF4 and mass spectrometry imaging, in developing novel single and combination PDCs and studying their biological fate in the search for efficient therapies for a range of diseases (advanced solid tumors, including triple negative breast, prostate, and pancreatic cancer, as well as spinal cord injury). / Dordevic, S. (2023). Development of Analytical Procedures for the Characterization of Polypeptide-Based Nanoconjugates [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/194554

Electrical machines with more than three phases are usually called multiphase electrical machines and they can have several advantages compared to conventional three-phase electrical machines such as a lower content of space-harmonics, lower torque ripple and better fault tolerance. This degree project involves rewinding of a three-phase induction machine into an asymmetrical six-phase machine. The winding design is based on simulations of a machine model in a finite element method software and the method "the star of the slot" that computes winding layouts. A six-phase drive is developed based on an existing printed circuit board prototype that is not operating according to its original specifications. Debugging of the prototype is performed and solutions to the problems are identified. Design and layout improvements for better electromagnetic compatibility are also implemented. The drive including the electrical machine is tested and confirmed to be working according to the specifications. Speed control based on indirect rotor field orientation is implemented and tested for the six-phase induction machine as well with the machine connected as a standard three-phase induction machine. / Elektriska maskiner med fler än tre faser kallas vanligtvis flerfasiga elektriska maskiner och kan ha flera fördelar jämfört med konventionella trefasiga elektriska maskiner, som lägre innehåll av övervågor, lägre rippel i vridmomentet och bättre feltolerans. Detta examensarbete involverar omlindning av en trefasig asynkronmaskin till en asymmetrisk sexfasig asynkronmaskin. Lindningsdesignen baseras på simuleringar av en maskinmodell i mjukvara baserat på finita element metoden och metoden kallad the star of the slotsom räknar ut lindnings ritningar. En sexfasig drivlina utvecklas baserat på en existerande kretskorts prototyp som inte fungerar enligt dess ursprunliga specifikationer. Felsökning av prototypen utförs och lösningar till problemen identifieras. Design- och layoutförbättringar för bättre elektromagnetisk kompatibilitet implementeras också. Drivlinan med den elektriska maskinen inkluderad testas och bekräftas fungera enligt dess specifikationer. Hastighetsreglering baserad på indirekt rotorfälts orientering implementeras och testas för den sexfasiga asynkronmaskinen samt även med maskinen kopplad som en standard trefas asynkronmaskin.

This dissertation is a focused analysis of the origins, organization, training, politics, and combat capability of the Army of the Republic of Viet Nam (ARVN) from 1954 to 1963, the leading military instrument in the national counterinsurgency plan of the government of the Republic of Viet Nam (RVN). Other military and paramilitary forces that complemented the army in the ground war included the Viet Nam Marine Corps (VNMC), the Civil Guard (CG), the Self-Defense Corps (SDC) and the Civil Irregular Defense Groups (CIDG) which was composed mainly of the indigenous populations in the Central Highlands of South Vietnam. At sea and in the air, the Viet Nam Air Force (VNAF) and the Viet Nam Navy (VNN) provided additional layers of tactical, strategic and logistical support to the military and paramilitary forces. Together, these forces formed the Republic of Viet Nam Armed Forces (RVNAF) designed to counter the communist insurgency plaguing the RVN. This thesis argues the following. First, the origin of the ARVN was rooted in the French Indochina War (1946-1954). Second, the ARVN was an amalgamation of political and military forces born from a revolution that encompassed three overlapping wars: a war of independence between the Vietnamese and the French; a civil war between the Vietnamese of diverse social and political backgrounds; and a proxy war as global superpowers and regional powers backed their own Vietnamese allies who, in turn, exploited their foreign supporters for their own purposes. Lastly, the ARVN failed not because it was organized, equipped, and trained for conventional instead of counterinsurgency warfare. Rather, it failed to assess, adjust, and adapt its strategy and tactics quickly enough to meet the war’s changing circumstances. The ARVN’s slowness to react resulted from its own institutional weaknesses, military and political problems that were beyond its control, and the powerful and dangerous enemies it faced. The People’s Army of Viet Nam (PAVN) and the People’s Liberation Armed Forces (PLAF) were formidable adversaries. Not duplicated in any other post-colonial Third World country and led by an experienced and politically tested leadership, the Democratic Republic of Viet Nam (DRVN) and the National Front for the Liberation of Southern Viet Nam (NFLSVN) exploited RVN failures effectively. Hypothetically, there was no guarantee that had the US dispatched land forces into Cambodia and Laos or invaded North Vietnam that the DRVN and NFLSVN would have quit attacking the RVN. The French Far East Expeditionary Corps (FFEEC)’ occupation of the Red River Delta did not bring peace to Cochinchina, only a military stalemate between it and the Vietnamese Liberation Army (VLA). Worse yet, a US invasion potentially would have unnerved the People’s Republic of China (PRC) which might have sent the PLAF to fight the US in Vietnam as it had in Korea. Inevitably, such unilateral military action would certainly provoke fierce criticism and opposition amongst the American public at home and allies abroad. At best, the war’s expansion might have bought a little more time for the RVN but it could never guarantee South Vietnam’s survival. Ultimately, RVN’s seemingly endless political, military, and social problems had to be resolved by South Vietnam’s political leaders, military commanders, and people but only in the absence of constant PAVN and PLAF attempts to destroy whatever minimal progress RVN made politically, militarily, and socially. The RVN was plagued by many problems and the DRVN and NFLSVN, unquestionably, were amongst those problems.

This dissertation is a focused analysis of the origins, organization, training, politics, and combat capability of the Army of the Republic of Viet Nam (ARVN) from 1954 to 1963, the leading military instrument in the national counterinsurgency plan of the government of the Republic of Viet Nam (RVN). Other military and paramilitary forces that complemented the army in the ground war included the Viet Nam Marine Corps (VNMC), the Civil Guard (CG), the Self-Defense Corps (SDC) and the Civil Irregular Defense Groups (CIDG) which was composed mainly of the indigenous populations in the Central Highlands of South Vietnam. At sea and in the air, the Viet Nam Air Force (VNAF) and the Viet Nam Navy (VNN) provided additional layers of tactical, strategic and logistical support to the military and paramilitary forces. Together, these forces formed the Republic of Viet Nam Armed Forces (RVNAF) designed to counter the communist insurgency plaguing the RVN. This thesis argues the following. First, the origin of the ARVN was rooted in the French Indochina War (1946-1954). Second, the ARVN was an amalgamation of political and military forces born from a revolution that encompassed three overlapping wars: a war of independence between the Vietnamese and the French; a civil war between the Vietnamese of diverse social and political backgrounds; and a proxy war as global superpowers and regional powers backed their own Vietnamese allies who, in turn, exploited their foreign supporters for their own purposes. Lastly, the ARVN failed not because it was organized, equipped, and trained for conventional instead of counterinsurgency warfare. Rather, it failed to assess, adjust, and adapt its strategy and tactics quickly enough to meet the war’s changing circumstances. The ARVN’s slowness to react resulted from its own institutional weaknesses, military and political problems that were beyond its control, and the powerful and dangerous enemies it faced. The People’s Army of Viet Nam (PAVN) and the People’s Liberation Armed Forces (PLAF) were formidable adversaries. Not duplicated in any other post-colonial Third World country and led by an experienced and politically tested leadership, the Democratic Republic of Viet Nam (DRVN) and the National Front for the Liberation of Southern Viet Nam (NFLSVN) exploited RVN failures effectively. Hypothetically, there was no guarantee that had the US dispatched land forces into Cambodia and Laos or invaded North Vietnam that the DRVN and NFLSVN would have quit attacking the RVN. The French Far East Expeditionary Corps (FFEEC)’ occupation of the Red River Delta did not bring peace to Cochinchina, only a military stalemate between it and the Vietnamese Liberation Army (VLA). Worse yet, a US invasion potentially would have unnerved the People’s Republic of China (PRC) which might have sent the PLAF to fight the US in Vietnam as it had in Korea. Inevitably, such unilateral military action would certainly provoke fierce criticism and opposition amongst the American public at home and allies abroad. At best, the war’s expansion might have bought a little more time for the RVN but it could never guarantee South Vietnam’s survival. Ultimately, RVN’s seemingly endless political, military, and social problems had to be resolved by South Vietnam’s political leaders, military commanders, and people but only in the absence of constant PAVN and PLAF attempts to destroy whatever minimal progress RVN made politically, militarily, and socially. The RVN was plagued by many problems and the DRVN and NFLSVN, unquestionably, were amongst those problems.

Notre projet de recherche porte sur l’enseignement/apprentissage de l’oral en FLE aux étudiants russes de deuxième – et en partie de troisième - année de la faculté de langues de l’université pédagogique. Nous sommes notamment centrés sur l’agir de l’enseignant, celui-ci étant la figure clé assurant la progression du processus de l’apprentissage organisé dans une situation exolingue, en milieu hétéroglotte. Son rôle est plurifonctionnel, ses manifestations sont variables. Les polylogues pédagogiques se trouvent au cœur de nos analyses, dont le but est d’optimiser le processus d’enseignement/apprentissage par l’intermédiaire des modifications de l’agir de l’enseignant en y appliquant notre thèse du « naturel didactique » censée créer des conditions d’expression naturelles dans une situation didactique en motivant ainsi la parole des apprenants, d’une part, et en diminuant la dissymétrie des relations enseignant-apprenants, d’autre part.Les analyses quantitatives ont permis de dégager les particularités discursives des interactions verbales en groupe de FLE de l’université pédagogique russe, notamment la manière spécifique d’agir de l’enseignant. Les éléments dégagés de cette observation permettent d’ouvrir une réflexion sur la pédagogie à concevoir en contexte de la Russie. / Our research project is concerned with the teaching/apprentiship of oral French in the « French as a Foreign Language » (FLE) program for Russian students in the second and, in part, third years in the Faculty of Languages of the teaching university of Vologda. We concentrated in particular on the action of the teacher, since the teacher is the key actor who ensures progress in the learning process in a situation using a non-native language in a foreign language context. The teacher assumes multiple functions with varying manifestations. Pedagogical polylogues are at the heart of our analyses. They aim to optimize the process of teaching/learning by modifying the action of the teacher via the application of our hypothesis of « natural didactics ». This method favors the creation of conditions allowing natural expression in a didactic situation by motivating the learners to speak on the one hand, and by reducing the asymmetry of the teacher-student relation on the other. Quantitative analyses allowed us to isolate particular aspects of verbal interaction in a FLE group within the Russian teaching university and in particular the specific action of the teacher. The results of these observations open up the possibility of a study of pedagogical methods appropriate for use in Russia.

This dissertation is a focused analysis of the origins, organization, training, politics, and combat capability of the Army of the Republic of Viet Nam (ARVN) from 1954 to 1963, the leading military instrument in the national counterinsurgency plan of the government of the Republic of Viet Nam (RVN). Other military and paramilitary forces that complemented the army in the ground war included the Viet Nam Marine Corps (VNMC), the Civil Guard (CG), the Self-Defense Corps (SDC) and the Civil Irregular Defense Groups (CIDG) which was composed mainly of the indigenous populations in the Central Highlands of South Vietnam. At sea and in the air, the Viet Nam Air Force (VNAF) and the Viet Nam Navy (VNN) provided additional layers of tactical, strategic and logistical support to the military and paramilitary forces. Together, these forces formed the Republic of Viet Nam Armed Forces (RVNAF) designed to counter the communist insurgency plaguing the RVN. This thesis argues the following. First, the origin of the ARVN was rooted in the French Indochina War (1946-1954). Second, the ARVN was an amalgamation of political and military forces born from a revolution that encompassed three overlapping wars: a war of independence between the Vietnamese and the French; a civil war between the Vietnamese of diverse social and political backgrounds; and a proxy war as global superpowers and regional powers backed their own Vietnamese allies who, in turn, exploited their foreign supporters for their own purposes. Lastly, the ARVN failed not because it was organized, equipped, and trained for conventional instead of counterinsurgency warfare. Rather, it failed to assess, adjust, and adapt its strategy and tactics quickly enough to meet the war’s changing circumstances. The ARVN’s slowness to react resulted from its own institutional weaknesses, military and political problems that were beyond its control, and the powerful and dangerous enemies it faced. The People’s Army of Viet Nam (PAVN) and the People’s Liberation Armed Forces (PLAF) were formidable adversaries. Not duplicated in any other post-colonial Third World country and led by an experienced and politically tested leadership, the Democratic Republic of Viet Nam (DRVN) and the National Front for the Liberation of Southern Viet Nam (NFLSVN) exploited RVN failures effectively. Hypothetically, there was no guarantee that had the US dispatched land forces into Cambodia and Laos or invaded North Vietnam that the DRVN and NFLSVN would have quit attacking the RVN. The French Far East Expeditionary Corps (FFEEC)’ occupation of the Red River Delta did not bring peace to Cochinchina, only a military stalemate between it and the Vietnamese Liberation Army (VLA). Worse yet, a US invasion potentially would have unnerved the People’s Republic of China (PRC) which might have sent the PLAF to fight the US in Vietnam as it had in Korea. Inevitably, such unilateral military action would certainly provoke fierce criticism and opposition amongst the American public at home and allies abroad. At best, the war’s expansion might have bought a little more time for the RVN but it could never guarantee South Vietnam’s survival. Ultimately, RVN’s seemingly endless political, military, and social problems had to be resolved by South Vietnam’s political leaders, military commanders, and people but only in the absence of constant PAVN and PLAF attempts to destroy whatever minimal progress RVN made politically, militarily, and socially. The RVN was plagued by many problems and the DRVN and NFLSVN, unquestionably, were amongst those problems.