Pc3-4 waves are recorded as geomagnetic pulsations with periods of 6-100s. They are generated at the bowshock and propagate to mid and auroral latitudes as Alfvén waves along closed magnetic field lines. At these latitudes Pc3-4 waves have been studied on the ground using magnetometers and in the ionosphere using HF radar. These waves have also been observed using magnetometers at polar latitudes even though there is no known propagation mechanism to the “open” field lines of the polar cap regions. In this work we used PolarDARN stations at Rankin Inlet and Inuvik to attempt the first study of Pc3-4 waves in the polar cap regions using radar. In ground scatter data, Doppler velocity oscillations with frequencies in the Pc3-4 range were found to be a common daytime occurrence. The oscillations are spatially coherent and in phase along the beam’s line of sight, matching lower latitude observations. However, upon further study it became apparent that the characteristics of the oscillations are different from those known for Pc3-4 waves. The observed oscillations have a diurnal trend that shows peaks in activity at 7:00 and 14:00MLT, where Pc3-4 oscillations have a diurnal peak at 10:30-11:00 MLT. In addition, poor coherence was observed between oscillations in radar and ground magnetic field variations at the nearby Taloyoak magnetometer. Further confounding the problem, we found that although the oscillations were coherent along the line-of-sight of the radar, poor coherence is observed when comparing oscillations in different beams separated by similar spatial scales. This finding counters both the spatial coherence observed along the beam’s line of sight and the spatial coherence of Pc3-4 waves at auroral latitudes. We conclude that it is unlikely that the observed oscillations are the result of Pc3-4 ULF waves. We instead propose that the observed Doppler velocity oscillations are caused by a change in the ionization along the ray’s path due to auroral particle precipitation.

Tesis para optar al grado de Magíster en Control de Gestión / Autor no autoriza el acceso a texto completo de su documento. / En un contexto de interconexión globalizado de economías cada vez más abiertas como es el actual, los directivos de empresas públicas y privadas se ven enfrentados a tomar decisiones en entornos cada vez más complejos. En este escenario, se plantea una metodología para el diseño e implementación de un Sistema de Control de Gestión basado en la herramienta de gestión denominada Cuadro de Mando Integral y muestra una aplicación práctica del modelo propuesto en la empresa CAP Minería, perteneciente al grupo siderúrgico nacional CAP S.A. El objetivo principal de este sistema es facilitar el complimiento de los objetivos estratégicos generales, para lo cual primeramente se hace análisis crítico de las declaraciones estratégicas actuales y de los elementos internos y externos que influyen en la organización, para derivar en una propuesta de valor actualizada, que este alineada con el propósito de generar valor sustentable para los accionistas y demás grupos de interés. Luego se desarrolló un Cuadro de Mando Integral, siguiendo el modelo de Kaplan y Norton, basado en un mapa estratégico que consta de tres ejes estratégicos definidos por los atributos de la nueva propuesta de valor. Con esto se logra visualizar de manera sencilla y gráfica la estrategia y los objetivos de la empresa. Para hacer llegar la estrategia a los áreas operativas de la unidad, se hace una bajada en cascada mediante el desdoblamiento de objetivos hacia dos gerencias de segunda línea (operacional y desarrollo minero), este ejercicio permite hacer operativa la estrategia y definir con claridad las distintas áreas de responsabilidad de los gerentes. Finalmente y en base a los tableros de control de cada una de las gerencias responsables (operacional y desarrollo minero), se diseñó un esquema de incentivos económicos para alinear sus comportamientos en dirección al cumplimiento de la Estrategia General definida para la Unidad Estratégica de Negocios elegida.

The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.

Protein kinases ERK1 and ERK2 are one of the most studied proteins in cell signalling. Both proteins are involved in a plethora of processes, such as phosphorylation and activation of kinases as part of signalling pathways. Enzymes ERK1 and ERK2 are part of MAPK/ERK signalling cascade, connected to many cellular including cell proliferation, cell growth or differentiation. The MAPK/ERK signalling cascade is often activated in different types of tumors, making it a candidate for developing new chemical inhibitors. One of the important questions in fundamental research of ERK1 and ERK2 protein kinases is the search for difference between these proteins. Current knowledge points to redundancy of both proteins, howver several examples suggest otherwise. Recently, the work presented in Casanova et al. 2012 indirectly suggests divergent effect of ERK1 and ERK2 on cap-independent translation initiation. In the Laboratory of RNA biochemistry we focus on HCV IRES (Hepatitis C Virus Internal Ribosome Entry Site) dependent translation initiation. This diploma thesis lead to establish RNA interference method in our laboratory and to establish reporter system to study ERK1 and ERK2 effect on HCV IRES dependent translation initiation. Based on our data acquired during our research, we present in this work...

This dissertation thesis is a critical assessment of the relationship of rural development policy within the second pillar of the EU CAP framework to aspects of territorial cohesion. The main aim is to analyse if the tools of rural development policy applied within the Czech Republic are in accordance with EU territorial cohesion goals and to assess the importance of the differences in the extent of regional support in accordance to the problems in rural areas. Within the main aim four hypotheses are formulated which are analysed in detail. For the verification of the hypotheses, introductory theoretical-methodological analysis of approaches to agriculture and rural development were prepared and their critical assessment was focused on historical issues of the EU CAP. The next part of the thesis is aimed at the verification of the rural development policy within the framework of the second pillar of the EU CAP to aspects of territorial cohesion using the example of the implementation of the EU Territorial Agenda in the programming period of 2007 -- 2013 in the Czech Republic. These issues are further studied in more depth with an institutional analysis of the EU CAP rural development policy role and its importance in the realisation of the EU Territorial Agenda in the Czech Republic, especially within the framework of urban-rural relations. For defining the territorial cohesion goals a methodological approach from the research project conducted by Prof. Mark Shucksmith (project ESPON, Shucksmith et al., 2005) was used who dealt with an assessment of the second pillar of the EU CAP in relation to aspects of territorial cohesion. In his research project the territorial cohesion goals were assessed by levels of selected indicators and their relevance to support from the second pillar of the EU CAP. This approach was adjusted and studied in depth by the author of this thesis according to the conditions of the Czech Republic. For the verification of the hypotheses, statistical data of the Horizontal Rural Development Plan CR was used which represented 73 % of the total expenditure of the second pillar of the EU CAP in the Czech Republic during the period 2004 -- 2006. With regards to scientific contribution, the main benefit of this thesis is in delivering an analytical framework of the rural development policy in relation to aspects of territorial cohesion by way of the EU Territorial Agenda and its implementation in the Czech Republic. The analysis and assessment of the HRDP programme in the Czech Republic and its relationship to socio economic indicators presents a concrete verification of the implementation of the second pillar of the EU CAP in the period 2004 -- 2006 with aspects of territorial cohesion. The results of this thesis will contribute to current research projects also aimed at the analysis of this theme.

Mon travail de thèse s’est focalisé sur l’étude fonctionnelle de deux méthyltransférases (MTases) de la structure coiffe des ARNs, les protéines nsp14 et nsp16, chez le coronavirus responsable du syndrome respiratoire du Moyen-Orient (MERS-CoV). Notre étude a démonté un processus de méthylation séquentiel. La coiffe est d’abord méthylée en position N7 par nsp14 formant la coiffe-0 (7mGpppN). La coiffe-0 est ensuite méthylée en position 2’OH du premier nucléotide de l’ARN par nsp16 stimulée par nsp10 formant une coiffe 1 (7mGpppN2’Om). De plus, nos résultats suggèrent un mécanisme de régulation allostérique de l’activité de nsp16 par nsp10. Nos résultats indiquent que l’interaction nsp10/nsp16 est régulée par la variation de concentration du SAM et/ou de SAH. Le SAM présent à une concentration physiologique, environ 100 µM dans les cellules, favorise l’assemblage du complexe nsp10/nsp16. La faible concentration intracellulaire du SAH produit accélère la dissociation du complexe nsp10/nsp16 permettant le « turnover » de la réaction enzymatique. Par ailleurs, nous avons cartographié les résidus essentiels au recrutement de l’ARN par nsp16. Les méthylations étudiées jouent un rôle important dans la réplication virale. Nous avons donc criblé des inhibiteurs des deux MTases nsp14 et nsp10/nsp16 respectivement à partir des chimiothèques « Prestwick » et « 2P2I3D ». En résumé, mon travail de thèse a décortiqué les bases moléculaires de méthylation de la coiffe chez le MERS-CoV et a permis d’identifier des inhibiteurs de MTases représentant un point de départ crucial pour le développement d’antiviraux contre les CoV. / My PhD work focused on the functional study of two cap RNA methyltransferases (MTases), nsp14 and nsp16, of the Middle-East respiratory syndrome coronavirus (MERS-CoV). Our study demonstrates a sequential methylation process. The cap is first methylated at the N7 position by nsp14 forming a cap-0 (7mGpppN). It is next methylated at the 2’OH position of the first transcribed nucleotide by nsp16 stimulated by nsp10 forming a cap-1 (7mGpppN2’Om). Furthermore, our results suggest an allosteric regulation mechanism of the nsp16 activity by nsp10. Moreover, our results indicate that the nsp10/nsp16 interaction is regulated by the variation of SAM and/or SAH concentration. SAM present at physiologic concentration, around 100µM in cells, enhances the assembly of nsp10/nsp16. The weak intracellular concentration of SAH by-product speeds up the dissociation of nsp10/nsp16 allowing the enzymatic reaction turnover. In addition, we have mapped the essential residues for the recruitment of the RNA by nsp16. The methylations studied in this work play an important role for viral replication. We have therefore screened inhibitors of nsp14 and nsp10/nsp16 MTases respectively from chemical libraries « Prestwick » and « 2P2I3D ». In summary, my PhD work deciphers the molecular bases of cap RNA methylation of MERS-CoV and identifies MTase inhibitors that represent a crucial starting point for the development of antivirals against CoV.

L’épilepsie survient à tout âge, mais les causes, l’expression clinique, les complications et le retentissement social, sont fonction de l’âge des sujets. En Afrique subsaharienne, les données épidémiologiques, les données portant sur la scolarisation et le retentissement de l’épilepsie de l’enfant sont peu accessibles. Afin d’évaluer les aspects socioculturels et thérapeutiques de l’épilepsie de l’enfant au Gabon, nous avons réalisé une revue de la littérature sur l’épilepsie de l’enfant en Afrique subsaharienne et deux enquêtes transversales, l’une sur les connaissances, attitudes et pratiques et les représentations socioculturelles de l’épilepsie de l’enfant auprès des enseignants et des personnels de santé, l’autre sur la qualité de vie des enfants souffrant d’épilepsie et de leurs parents. En Afrique subsaharienne, les données sur l’épilepsie de l’enfant sont diluées dans les études étendues à la population entière. La prévalence de l’épilepsie de l’enfant varie de 2 à 297 ‰ et son incidence de 17 à 930 / 100 000 personnes-années. Les facteurs périnataux, les crises fébriles et les facteurs infectieux sont les plus décrits alors que les facteurs génétiques demeurent peu étudiés. La prise en charge de l’enfant reste limitée à cause de l’insuffisance des ressources humaines, des moyens diagnostics et de l’accès aux traitements antiépileptiques mais aussi à cause de la persistance des préjugés et des croyances négatives sur l’épilepsie communément retrouvées parmi les enseignants, les enfants en âge scolaire et dans la population. Les enfants épileptiques sont une source d’angoisse, de perturbations socioprofessionnelles et scolaires pour leurs parents et de leur fratrie. Les enquêtes ont retrouvé un niveau de connaissance bas, une persistance de croyances négatives, notamment celles qui considèrent l’épilepsie comme une affection contagieuse ou transmissible, une maladie psychiatrique ou un retard mental ou encore une maladie surnaturelle. Ces considérations rencontrées indifféremment en milieu urbain ou rural semblent tenir leur explication dans la conception culturelle de l’épilepsie qui renvoie cette maladie à une cause extérieure ; un animal ou un mauvais esprit. En milieu rural, les enfants n’ont généralement pas d’avis médical, mais la scolarisation reste supérieure à 50 % indépendamment de leur milieu de vie. La non-scolarisation est liée aux comorbidités, à l’attitude réfractaire des parents et de certains chefs d’établissements scolaires. L’anxiété, les troubles du comportement, les troubles cognitifs et les troubles de la sociabilité restent élevés. La qualité de vie des parents de l’enfant épileptique est altérée. Ce travail sera étendu à d’autres localités du Gabon pour inclure plus d’enfants épileptiques et mettre en place une cohorte. Cette cohorte pourra servir à l’évaluation de la fraction attribuable des infections (notamment celle du paludisme grave) dans la survenue de l’épilepsie ; l’évaluation du stigma chez l’enfant épileptique et leurs parents et à la mise en place de programmes d’éducation thérapeutique et de promotion de la santé auprès des familles, des enseignants et des personnels de santé. / Epilepsy occurs at any age, but the causes, clinical manifestations, complications and social impact, depend on the age of the subjects. In Sub-Saharan Africa epidemiological data, data on enrollment and the impact of the child's epilepsy are difficult to access. To assess the socio-cultural and therapeutic aspects of the child's epilepsy in Gabon, we conducted a review of the literature on child epilepsy in SSA and two cross-sectional surveys, one on knowledge, attitudes, practices and socio-cultural representations of childhood epilepsy in teachers and health workers, the other on the impact of epilepsy on the children with epilepsy and their parent. In SSA, the data on child epilepsy drowned in studies extended to the general community. The prevalence of childhood epilepsy varies from 2.04 to 297/1000 and its incidence from 17 to 930/100.000 person-years. Perinatal factors, febrile seizures and infectious factors are most described while genetic factors remain poorly studied. The care of the child remains limited due to the lack of human resources, diagnostic means and access to AEDs but also because of the persistence of prejudices and negative beliefs about epilepsy commonly found in teachers, school children and in the community. Children with epilepsy are a source of anxiety, disruption of socio-professional and academic activities for parents and their siblings. The surveys found a low level of knowledge, persistence of negative beliefs, including those that consider epilepsy as a contagious or communicable disease, psychiatric illness or mental retardation or a supernatural disease. These considerations found in urban and rural areas could be explained by the cultural conception of epilepsy that links the disease to an external cause, to an animal, or an evil spirit. In rural areas, children usually have no medical advice, but enrollment is still above 50% regardless of their living environment. Non-enrollment is related to comorbidities, the refractory attitude of parents and some school heads. Anxiety, behavioral disorders, cognitive disorders and disorders of sociability remain high. The quality of life of epileptic children's parents is impaired. This work will be extended to other areas to include more children with epilepsy and build a cohort. This cohort will be used to assess the attributable fraction of infections (including that of severe malaria) in the occurrence of epilepsy; to assess the stigma of epileptic children and their parents and to implement the therapeutic education programs and health promotion with families, teachers and health workers.

Thesis advisor: Lawrence T. Scott / This dissertation describes the work that has been carried out towards accessing a C3v [6,6] nanotube end-cap through rational chemical synthesis. Continued advancement in carbon nanotube research has driven scientists to develop a successful route to usable quantities of nanotubes that are homogeneous in structure. Due to the current inability to separate nanotube mixtures efficiently, researchers in fields ranging from chemistry to computer science have been unable to exploit fully all that these unique molecules have to offer. Our envisioned approach to this obstacle involves elongation of a template endcap using iterative growth chemistry. The final stage of the proposed end-cap synthesis involves the execution of a six fold cyclodehydrogenation reaction. To carry out this desired transformation, a new microwave assisted variant of the anionic cyclodehydrogenation reaction has been developed. Through this chemistry we have been able to access a variety of both known and novel polycyclic aromatic hydrocarbons, often in impressively high yields. We hope that this chemistry will be useful to us in accessing the target nanotube end-caps, and to others in providing a new route to accessing a variety of polycyclic aromatic hydrocarbon cores. / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Atmospheric mass is transported in and out of the stratospheric polar cap region by a wave-driven meridional circulation. Using composites of polar cap pressure anomalies, defined as deviations from the average annual cycle, it is shown that this stratospheric mass flux is accompanied by a similar mass flux near the surface. This 'tropospheric amplification' of the stratospheric signal is introduced as a new way to quantify stratosphere-troposphere coupling. Regression analysis is used to create a vertical profile of atmospheric pressure during a tropospheric amplification event, and the regression slope profile is used as a tool to quantify the amplification. Using data from 5 reanalysis datasets and 11 climate models, it is shown that high-top models, with a model lid of above 1 hPa, are significantly better at reproducing tropospheric amplification than low-top models, due to having more detailed parameterisations of stratospheric processes. However, the regression slope profiles of all models, bar one, are significantly different to the profile of reanalysis data at a 95% confidence level. Tropospheric amplification is also investigated in historical and future simulations from these models, and it is concluded that there is not expected to be a large change in the phenomenon over the next 100 years. The processes needed to reproduce tropospheric amplification can be identified by comparing idealised models of different complexity. A simple dry-core model is not able to reproduce tropospheric amplification, while a model with a comprehensive radiation scheme does produce the basic regression slope profile under certain configurations. The associations between pressure change and mass flux are further investigated using primitive equations. It is found that vertical and horizontal contributions to mass flux act to mostly cancel each other out, leaving a poorly-conditioned residual, and that the horizontal mass flux across the polar cap boundary has both geostrophic and ageostrophic components.

Introduction: Streptococcus pneumoniae (pneumococci) is most common and has the highest mortality in community-acquired pneumonia (CAP). In vitro many antibiotics are effective against pneumococci, but recent studies suggest a favor for narrow-spectrum antibiotics. Aim: To investigate difference in mortality from pneumococcal CAP if betalactam antibiotics in monotherapy with a narrow or broad spectrum are selected initially. Methods: A retrospective national register study with cases of pneumococcal CAP 2008-2015. Cohorts of CAP were divided by severety, 0-2 and 3-4 CRB-65-points. Antibiotics and background factors were analyzed. A logistic regression model analyzed potential factors for mortality <30 days. Results: There were 34.299 cases, of which 1592 cases were included, n=1509 with 0-2 CRB-65 and n=83 with 3-4 CRB-65. Overall mortality was 2.5%. 17 out of 1025 (1.7%) died after narrow-spectrum betalactam monotherapy (NSBM), and 23 out of 567 (4.1%) died after broad-spetrum betalactam monotherapy (BSBM). In CAP with 0-2 CRB-65-points, NSBM were associated with less mortality than BSBM (p=0.007, OR 0.39; 95 % CI 0.20-0.78). Age<65 and kidney disease were associated with higher mortality, but in the logistic regression model, these factors were not associated with selected antibiotics and thus not confounders. In CAP with 3-4 CRB-65-points, no significant results were found. Conclusion: NSBM, like penicillins, seems to be safe choice and associated with less mortality than BSBM in less severe pneumococcal CAP. The reasons are unknown, but maybe because of less severe side-effects, better property to the bacteria or better empirical dosage.