The graduation theses of the Scottish universities in the first half of the seventeenth century are at the crossroads of philosophical and historical events of fundamental importance: Renaissance and Humanist philosophy, Scholastic and modern philosophy, Reformation and Counterreformation, the rise of modern science. The struggle among these tendencies shaped the culture of the seventeenth century. Graduation theses are a product of the Scholasticism of the modern age, which survived the Reformation in Scotland and decisively influenced Scottish philosophy in the seventeenth century, including the reception of early modern philosophy. We can therefore speak of a ‘Scottish Scholasticism’, characterised by an original reception and interpretation of the long traditions of Scholastic philosophy and Aristotelianism. The aim of the thesis is the analysis of the general physics of the graduation theses: the two central theories are prime matter and movement. Natural philosophy is a particularly interesting case, and the main features of the graduation theses are the reception of Scholasticism alongside innovation within Scholasticism. Graduation theses adhere to the Scholastic tradition, especially Scotism, while being innovative in their opposition to Catholic forms of Scholasticism. Scottish Scholasticism can be then further qualified as an example of ‘Reformed Scholasticism’.

Les neutrophiles représentent une composante fondamentale du système immunitaire. En effet, il est bien connu qu'ils sont essentiels à la défense de l'organisme contre les agressions microbiennes. En plus de leurs fonctions anti-microbiennes classiques, les neutrophiles, via la sécrétion de cytokines (incluant les chimiokines), jouent un rôle prépondérant dans l'initiation et la modulation de la réponse immunitaire. Lors d'une infection ou d'une blessure, les neutrophiles agissent à titre de premier répondant et migrent rapidement au site de l'aggression. La production rapide de cytokines par les neutrophiles permet le recrutement additionnel de neutrophiles au site inflammatoire et celui d'autres populations leucocytaires, tout en modulant les fonctions de ces dernières. La génération de cytokines par les neutrophiles est induite par une vaste gamme de stimuli: agonistes d'origine microbienne, facteurs chimiotactiques, cytokines, chimiokines et facteurs de croissance. Ces signaux inflammatoires induisent l'activation de nombreuses voies de signalisation menant ultimement à l'activation de facteurs transcriptionnels. L'expression des gènes de cytokines inflammatoires doit être finement régulée afin qu'il y ait une production adéquate de ces médiateurs. Elle repose, en grande partie, sur le recrutement de facteurs transcriptionnels capables de se lier à des séquencescibles sur les promoteurs de ces gènes.Les travaux présentés dans cette thèse portent sur l'identification des facteurs de transcription impliqués, ainsi que des sentiers de signalisation en amont, dans l'expression de gènes encodant des cytokines chez le neutrophile humain. Dans le premier chapitre de la section résultats, nous avons montré que l'expression génique des cytokines dépend fortement de l'activation du facteur de transcription NF-[kappa]B. Celui-ci contrôle l'expression inductible de tous les gènes étudiés. De plus, nous avons montré que la génération de ces cytokines chez les neutrophiles dépend fortement de l'activation des voies p38 MAP kinases (aux niveaux transcriptionnel et traductionnel) et MEK/ERK (au niveau traductionnel seulement). Dans le deuxième chapitre, nous avons étudié l'expression et la localisation des différents facteurs de transcription de la famille C/EBP, de même que l'activation de C/EBP[bêta] via sa phosphorylation en Thr 235 chez les neutrophiles humains. Grâce à la surexpression d'un répresseur des C/EBP (A-C/EBP2N3T) chez les cellules PLB-985 granulocytiques, nous avons montré l'importance de la famille de C/EBP dans la production de MIP-1[alpha], de MIP-1[bêta] et d'IL-8 chez les neutrophiles humains.Les facteurs C/EBP ne semblent toutefois pas impliqués dans la production de TNF-[alpha] par ces cellules. La surexpression d'un mutant de C/EBP[bêta] (C/EBP[bêta] T235A) chez ces mêmes cellules nous a par ailleurs permis de déterminer que la phosphorylation de cet acide aminé est essentielle à la production des chimiokines MIP-1[alpha], MIP-1[bêta] et IL-8. Nous démontrons enfin une association constitutive de C/EBP[bêta] et de C/EBP[epsilon] avec le promoteur de l'IL-8 chez les neutrophiles primaires humains. Un des éléments déclencheurs de la transcription de ce gène serait probablement l'induction de la phosphorylation de C/EBP[bêta] sur les promoteurs géniques. Enfin, dans le troisième chapitre de la section résultats, nous explorons le rôle de la MAPK p38 dans la production de cytokines chez les neutrophiles. Nous y identifions quelques-uns de ses substrats impliqués dans la transcription et la traduction de cytokines inflammatoires. Ainsi, nous avons determiné que la MAPK p38 participe à l'activation des facteurs de transcription C/EBP[bêta] et CREB, probablement via l'activation des kinases MSK-1 et RSK. Nous avons également établi l'impact de la phosphorylation de la Ser 133 de CREB sur la production de cytokines chez les neutrophiles humains. Finalement, nous avons documenté l'activation de la kinase MNK1 par la MAPK p38, et son rôle dans la régulation traductionnelle des cytokines. L'ensemble de ces travaux a permis d'identifier des molécules-clés dans la génération de cytokines, plus particulièrement de chimiokines, chez le neutrophile humain. Nos travaux ont donc contribué de manière substantielle à nos connaissances des mécanismes transcriptionnels et traductionnels gouvernant l'expression de gènes précoces chez le neutrophile. Nos résultats permettront en outre l'identification de cibles thérapeutiques potentielles qui pourraient servir à atténuer l'inflammation chronique observée dans de nombreuses pathologies où les neutrophiles prédominent.

L’apoptose est un processus dont l’importance physiologique et pathophysiologique est de mieux en mieux appréciée. Si plusieurs mécanismes expliquant son initiation et son exécution ont été décrits, les détails de sa régulation fine restent à être précisés. Par ces travaux, nous démontrons une interaction directe entre la protéine pro-apoptotique Siva1 et la queue C-terminale de plusieurs récepteurs couplés aux protéines G, incluant TP, IP, PAF, AT?R et CHRM3. Pour TP, nous prouvons que la stimulation du récepteur par le U46619 entraîne une translocation et une accumulation cytoplasmique de Sival, ainsi qu’une modulation de ses interactions avec Mdm2, XIAP et TRAF2, résultant en une induction de l’apoptose. Nous rapportons également que l’expression de Siva1 potentialise l’ubiquitinylation de TP en réponse à une stimulation et que cette ubiquitinylation n’affecte ni la dégradation, ni l’internalisation du récepteur. Nous démontrons par ailleurs que la stimulation de TP diminue l’expression totale d’i?B?, l’inhibiteur principal de la voie NF?B et que cet effet corrèle avec le niveau d’expression de Siva1. En démontrant l’existence d’un complexe entre TP et TRAF2 suite à une stimulation réceptorielle, nous proposons que la modulation NF?B par TP pourrait résulter d’une signalisation dépendant de l’ubiquitine et analogue à celle des TNFR. D’autre part, nous présentons une interaction entre Siva1 et l’arrestine et apportons des données suggérant que l’expression de Siva1 pourrait moduler l’activation des MAPK. Nous proposons finalement un modèle réconciliant les fonctions anti- et pro-apoptotiques de TP et dans lequel le phénotype final d’une stimulation dépendrait de l’expression relative de Siva1. Les corolaires de ce modèle pourraient possiblement bonifier la prise en charge d’incidents ischémiques comme l’infarctus du myocarde ou l’accident vasculaire cérébral, et améliorer le traitement du cancer par une diminution de la toxicité d’agents chimiothérapeutiques et l’amélioration de la sensibilité tumorale.[symboles non conformes]

<p>Natural IgM (nIgM) is constitutively present in the serum, where it aids in the early control of viral and bacterial expansions. nIgM also plays a significant role in the prevention of autoimmune disease by promoting the clearance of cellular debris. However, the cells that maintain high titers of nIgM in the circulation had not yet been identified. Several studies have linked serum nIgM with the presence of fetal-lineage B cells, and others have detected IgM secretion directly by B1a cells in various tissues. Nevertheless, a substantial contribution of undifferentiated B1 cells to nIgM titers is doubtful, as the ability to produce large quantities of antibody (Ab) is a function of the phenotype and morphology of differentiated plasma cells (PCs). No direct evidence exists to support the claim that a B1-cell population directly produces the bulk of circulating nIgM. The source of nIgM thus remained uncertain and unstudied.</p><p>In the first part of this study, I identified the primary source of nIgM. Using enzyme-linked immunosorbent spot (ELISPOT) assay, I determined that the majority of IgM Ab-secreting cells (ASCs) in naïve mice reside in the bone marrow (BM). Flow cytometric analysis of BM cells stained for intracellular IgM revealed that nIgM ASCs express IgM and the PC marker CD138 on their surface, but not the B1a cell marker CD5. By spinning these cells onto slides and staining them, following isolation by fluorescence-activated cell sorting (FACS), I found that they exhibit the typical morphological characteristics of terminally differentiated PCs. Transfer experiments demonstrated that BM nIgM PCs arise from a progenitor in the peritoneal cavity (PerC), but not isolated PerC B1a, B1b, or B2 cells. Immunoglobulin (Ig) gene sequence analysis and examination of B1-8i mice, which carry an Ig knockin that prohibits fetal B-cell development, indicated that nIgM PCs differentiate from fetal-lineage B cells. BrdU uptake experiments showed that the nIgM ASC compartment contains a substantial fraction of long-lived plasma cells (LLPCs). Finally, I demonstrated that nIgM PCs occupy a survival niche distinct from that used by IgG PCs.</p><p>In the second part of this dissertation, I characterized the unique survival niche of nIgM LLPCs, which maintain constitutive high titers of nIgM in the serum. By using genetically deficient or Ab-depleted mice, I found that neither T cells, type 2 innate lymphoid cells, nor mast cells, the three major hematopoietic producers of IL-5, were required for nIgM PC survival in the BM. However, IgM PCs associate strongly with IL-5-expressing BM stromal cells, which support their survival in vitro when stimulated. In vivo neutralization of IL-5 revealed that, like individual survival factors for IgG PCs, IL-5 is not the sole supporter of IgM PCs, but is likely one of several redundant molecules that together ensure uninterrupted signaling. Thus, the long-lived nIgM PC niche is not composed of hematopoietic sources of IL-5, but a stromal cell microenvironment that provides multiple redundant survival signals.</p><p>In the final part of my study, I identified and characterized the precursor of nIgM PCs, which I found in the first project to be resident in the PerC, but not a B1a, B1b, or B2 cell. By transferring PerC cells sorted based on expression of CD19, CD5, and CD11b, I found that only the CD19+CD5+CD11b- population contained cells capable of differentiating into nIgM PCs. Transfer of decreasing numbers of unfractionated PerC cells into Rag1 knockouts revealed an order-of-magnitude drop in the rate of serum IgM reconstitution between stochastically sampled pools of 106 and 3x105 PerC cells, suggesting that the CD19+CD5+CD11b- compartment comprises two cell types, and that interaction between the two necessary for nIgM-PC differentiation. By transferring neonatal liver, I determined that the early hematopoietic environment is required for nIgM PC precursors to develop. Using mice carrying a mutation that disturbs cKit expression, I also found that cKit appears to be required at a critical point near birth for the proper development of nIgM PC precursors.</p><p>The collective results of these studies demonstrate that nIgM is the product of BM-resident PCs, which differentiate from a PerC B cell precursor distinct from B1a cells, and survive long-term in a unique survival niche created by stromal cells. My work creates a new paradigm by which to understand nIgM, B1 cell, and PC biology.</p> / Dissertation

Memoria para optar al Titulo Profesional de Médico Veterinario / La endotelina-1 (ET-1) es un péptido vasoactivo producido principalmente por el endotelio vascular. La ET-1 estimula la contracción y tiene acción mitogénica en la célula muscular lisa vascular al unirse a su receptor ETA muscular, mientras que la unión del péptido al receptor ETB endotelial promueve vasodilatación, participando ambos receptores en la regulación del tono vascular. La alteración del sistema ET-1 y de sus receptores puede tener un profundo impacto en la regulación de la presión arterial pulmonar durante la transición desde la vida fetal a la vida extrauterina, bajo condiciones de hipoxia crónica. Hipótesis: existiría una mayor expresión del precursor de ET-1, preproendotelina-1 (PPET-1) y del receptor ETA y una menor expresión del receptor ETB en pulmón de ovejas recién nacidas crónicamente hipóxicas, gestadas y nacidas en tierras altas, que desarrollan hipertensión arterial pulmonar, en comparación con ovejas recién nacidas gestadas y nacidas en tierras bajas. Estos cambios no se observarían en llamas recién nacidas, especie tolerante a la hipoxia crónica, en la que la gestación y nacimiento en tierras altas no genera hipertensión arterial pulmonar. Objetivo: comparar la expresión de PPET-1 y receptores ETA y ETB en pulmón de ovejas y llamas recién nacidas de tierras bajas y altas. Método: evaluar la expresión de PPET-1 y de receptores ETA y ETB a nivel de mRNA por RT-PCR semicuantitativo y a nivel proteico para ambos receptores por inmunoblot, en pulmón de ovejas recién nacidas de tierras bajas (n=5) y altas (n=6) y de llamas recién nacidas de tierras bajas (n=6) y altas (n=5). Resultados: a nivel de mRNA, la expresión de PPET-1 y de los receptores ETA y ETB aumentó en ovejas recién nacidas de tierras altas en comparación con el grupo de tierras bajas. Por otra parte, no hubo diferencias en la expresión de estos mRNA entre llamas recién nacidas de tierras bajas y altas. La expresión de estos receptores a nivel de proteína no pudo ser determinada debido a que los anticuerpos ensayados no permitieron la detección específica de los receptores en los pulmones de ambas especies. Conclusión: el aumento de expresión pulmonar del sistema de ET-1 podría estar implicado en el desarrollo de la hipertensión arterial pulmonar observado en ovejas recién nacidas crónicamente hipóxicas, mientras que la capacidad de mantener sin cambios este sistema en las llamas recién nacidas contribuiría a prevenir el desarrollo de hipertensión arterial pulmonar en esta especie / Proyectos FONDECYT 1010636 y 1050479 (Investigador responsable: Doctor Jorge Aníbal Llanos Mansilla y coinvestigador: Víctor Roberto Reyes Catalán) y 1020599 (Investigador responsable: Víctor Roberto Reyes Catalán y coinvestigador: Doctor Aníbal Llanos Mansilla) de Chile y The Wellcome Trust CRIG 072256 (Investigador responsable: Doctor Jorge Aníbal Llanos Mansilla y coinvestigador: Víctor Roberto Reyes Catalán) de Reino Unido

Seminario para optar al título de Ingeniero Comercial, Mención Administración / El surgimiento de una tendencia, que enmarca una nueva forma de hacer negocios, en la cual cada una de las organizaciones que optan por este camino, se preocupan de ser social y ambientalmente responsables con cada uno de los involucrados en el desarrollo de su actividad, buscando generar un triple impacto, ha llegado para quedarse, esta tendencia se refiere a las Empresas B. Como día a día se va propagando y masificando el tema en Chile y Latinoamérica, este trabajo entrega información sobre de qué se trata ser una empresa B, cómo es posible conseguir la acreditación necesaria para adquirir este título, qué motivaciones que pueden llevar a un emprendedor a tomar este vía, cómo se relacionan con la Responsabilidad Social Empresarial y con el contexto social chileno desde 2006 en adelante, entre otras cosas. Lo anterior se obtiene gracias a la revisión bibliográfica y al análisis cualitativo de contenido de entrevistas semi estructuradas realizadas a cinco empresas que ya consiguieron certificarse como empresa B. Con los resultados de las entrevistas es posible realizar una comparativa entre el antes y el después de que cada una de las organizaciones consultadas obtuvieron la acreditación B. De ello es posible colegir cuánto impacta en términos de resultados percibidos por las empresas el hecho de haber conseguido la certificación. Se espera que este trabajo también sea una contribución a la bibliografía académica sobre el tema, pues dado lo reciente del concepto en la región, se hace necesario engrosar el listado de documentos referidos al tema en investigación.

The non-obese diabetic (NOD) mouse is widely used model Type 1 diabetes (T1D), a chronic inflammatory disease characterized by destruction of the insulin producing β cells in the islets of Langerhans by immune cells. The classical symptoms include increased glucose levels in urine and blood, frequent urination and enhanced thirst. The disease has a strong genetic component and is also influenced by the environment. NOD mice develop T1D spontaneously. The disease occurs in two phases; insulitis - the infiltration of immune cells in the islets of Langerhans and overt diabetes caused by the destruction of insulin producing β cells. Several disease associated gene regions or loci [termed insulin dependent diabetes (Idd) loci] have been associated with T1D development. Although, T1D is recognized as a T cell mediated disease in both mouse and man, many studies have shown the importance of B cells in the pathogenesis of the disease. Autoantibodies appear prior to islet infiltration and several molecular and cellular events precede this beta-cell autoimmunity. Although the pathogenesis of T1D is well characterized, less is known about the environmental and immunological factors that trigger the disease. In this thesis, we studied the contribution of B cell anomalies to the skewed immune response observed in the NOD mouse. In our studies covered in the thesis we observed that NOD mice display enhanced IgE in the serum already at one week of age. In addition, upon treatment of pre-diabetic NOD mice with anti-IgE antibodies, diabetes incidence was delayed. We hypothesize that the presence of IgE in the system may be explained due to enhanced class switching. Antibody feedback however, is an essential component of the immune response and can lead to either enhanced or dampened responses. Thus, increased IgE may provide positive feedback that might sustain an immune response. We also aimed to analyze the biological consequence of this feature. In vitro stimulation of B cells by the TACI ligand APRIL resulted in enhanced plasma cell differentiation accompanied with increased class switching and IgG production. In addition, TACI+ cells were observed in NOD germinal centers facilitating increased BAFF uptake and subsequent escape of low affinity antibody producing clones. NOD mice elicited an enhanced and prolonged immune response towards T-dependent antigens such as hen-egg lysozyme (HEL). Serum HEL-specific IgG level was significantly increased and was predominantly of the IgG1 isotype. Immunofluorescence analysis of NOD spleen revealed the presence of spontaneous germinal centers which others have perceived to provide a ready niche for the entry of naïve B cells that encountered novel antigen. Adoptive transfer experiments of purified B and T cells from NOD into NOD.Rag2-/- (NOD-RAG) mice illustrated the importance of B cell intrinsic defects in the reproduction of the original phenotype as observed in NOD.

Bakgrund: Blodburna smittor är omgivna av tabu och stigma. Sjuksköterskan kan därför känna osäkerhet inför att möta denna patientgrupp, vilket kan resultera i ett dåligt bemötande från sjuksköterskan sida. Sjuksköterskan har även risk att genom en olyckshändelse i arbetet, själva bli smittade av dessa sjukdomar vilket också kan skapa osäkerhet och rädsla för att möta denna patientgrupp. Syfte: Syftet med studien var att beskriva sjuksköterskornas upplevelse av att möta patienter med blodburna smittor. Metod: Studien var en litteraturstudie med kvalitativ ansats. Till resultatet valdes sex artiklar ut och analyserades med en innehållsanalys som var inspirerad av Graneheim och Lundmans (2004) sammanställning av innehållsanalyser. Resultat: Resultatet i litteraturstudien visar på att attityder och fördomar fortfarande förekommer, även om sjuksköterskorna är väl medvetna om hur ett patientmöte borde gå till och vad sjuksköterskan har för yrkesroll. Användning av skyddsutrustning brister vid många tillfällen på grund av att sjuksköterskor upplever tidspress av att använda dem samt att det inte alltid finns tillgängligt. Även om fördomar och attityder förekom släppte dessa känslor med tiden när sjuksköterskorna fått mer erfarenhet och kunskap om blodsmittor. Sjuksköterskorna kände då medkänsla och empati för patientgruppen.  Slutsats: Det förekommer än idag fördomar, attityder samt rädsla för patienter med blodburen smitta, även om det idag finns större medvetenhet om sjukdomarna. För att öka vårdkvaliten för patienter med blodsmittor behövs mer forskning om hur sjuksköterskor upplever mötet med denna patientgrupp.

<p>Organelle transport in eukaryotic cells is regulated by a precisely coordinated activity of phosphoinositide lipids, small GTPases, and molecular motors. Despite the extensive study of functional activities of individual regulators, how these activities promote precise deliveries of particular membrane proteins to specific cellular locations remained unclear. Ankyrin-B, which is previously well recognized as a plasma membrane adaptor that assembles diverse specialized plasma membrane domains, exhibited an unexpected role in intracellular transport. This thesis establishes ankyrin-B as a master integrator of the polarized long range organelle transport via direct interactions with Rab GTPase Activating Protein 1 Like (RabGAP1L), phosphatidylinositol 3-phosphate (PI3P) and dynactin 4. In Chapter 2, I identified an ankyrin-B death domain binding partner, RabGAP1L, that specifically interacts with ankyrin-B on intracellular organelles and requires ankyrin-B for its proper localization. In Chapter 3, I demonstrated that ankyrin-B is a PI3P-effector in mouse embryonic fibroblasts (MEFs) and promotes the polarized transport of associated organelles in migrating cells in a RabGAP1L-dependent manner. I continued to investigate what membranes/membrane-associated proteins utilize the ankyrin-B/RabGAP1L pathway in Chapter 4 and identified α5β1-integrin as a cargo whose polarized transport and recycling are ankyrin-B-dependent. I further presented that ankyrin-B, through recruiting RabGAP1L to PI3P-positive/Rab22A-associated endosomes containing α5β1-integrin, promotes polarized recycling of α5β1-integrin in migrating mouse embryonic fibroblasts. In collaboration with James Bear (UNC Chapel Hill), we further demonstrated that this ankyrin-B/RabGAP1L-mediated pathway is required for haptotaxis along fibronectin gradients. In Chapter 5, I elucidated the in vivo interaction between ankyrin-B and RabGAP1L. I demonstrated that ankyrin-B specifically interacts with RabGAP1L at long axon tracts in the brain and at costameres in the skeletal muscle. I also show the phenotypic analysis of ankyrin-B floxDD mice as an initial attempt to determine the physiological function of the ankyrin-B death domain in vivo. Together, this thesis dissects an ankyrin-B-mediated molecular mechanism for polarized endosomal trafficking and α5β1-integrin recycling during directional cell migration, and provides new insights into how phosphoinositide lipids, Rab GTPases, and molecular motor activities are coordinated to control the directional transport of specialized membrane cargos.</p> / Dissertation

Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, VEGF-A. Studies demonstrated VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about VEGF-B function in pathological processes, compare probable mechanisms of action and elude to its potential as a homeostatic protective factor to increase mitochondrial function in the setting of neurological disease and cardiovascular disease.