A learning task with thousands of training examples in Support Vector Machine (SVM) demands large amounts of memory and time requirements. SVMlight by Dr. Thorsten Joachims has been implemented in C using a fast optimizing algorithm for handling thousands of such support vectors. SVMlight solves the problem of classification, pattern recognition, regression and learning ranking function. The C code also provides methods for XiAlpha estimation of error rate and precision. Implementing these two methods leads to generalized performance of Support Vector Machine even for computation intensive text classification functions. SVMlight code allows users to define their own kernel functions. The SVMlight software employs an efficient algorithm and minimizes the cost, but it still takes considerable amount of time for computing thousands of support vectors and training examples. This time can be still reduced by parallelizing the code. In our work we refined the SVMlight code by removing unnecessary iterations and rewriting it as cost efficient. Then we parallelized the code individually using two different types, OpenMP and POSIX Threads shared memory parallelism. The code is parallelized for these two methods on Intel’s C compiler for Linux 7.1 using hyper threading technology. The parallelized code is tested for protein structure prediction. Different types of Protein Sequences are tested on these methods by varying the number of training examples and support vectors. The time consumption and speedup are calculated for both OpenMP and Pthreads. Implementation of OpenMP and Pthreads together showed good increase in speedup.

The object of this thesis is the revision of the exchange rate mechanisms ERM II from the point of his effect on the Czech Republic's integration process. In this thesis, there are analyzed benefits and risks cussed by ERM II participation and inferred conclusions relevant for the Czech Republic. This thesis is moreover dealing with hypothetic run of the participation of Czech koruna in ERM II and its incidence on fulfillment of exchange rate criterion. Except that there are analyzed reasons for current negative attitude of Denmark, Great Britain and the Northern Ireland and Sweden to third period of the Economy and monetary union.

Erythromycin is a macrolide antibiotic that inhibits not only mRNA translation but also 50S ribosomal subunit assembly in bacterial cells. An important mechanism of erythromycin resistance is the methylation of 23S rRNA by erm methyl transferase enzymes. A model for 50S ribosomal subunit formation suggests that the precursor particle which accumulates in erythromycin treated cells is the target for methyl transferase activity. Hybridization experiments identified the presence of 23S rRNA in the 50S precursor particle. The protein content of the 50S precursor particle was analyzed by MALDI-TOF mass spectrophotometry. These studies have identified 23 of 36 50S ribosomal proteins in the precursor. Methyltransferase assays demonstrated that the 50S precursor particle was a substrate for ermE methyltransferase. Competition experiments indicated that the enzyme could displace erythromycin from the 50S precursor particle and that the methyltransferase had a higher association constant for the precursor particle compared to that of erythromycin. Inhibition experiments showed that macrolide, lincosamide and streptogramin B compounds bound to the precursor particle with similar affinity and inhibited the ermE methyltransferase activity. These studies shed light on the interaction of ermE methyltransferase and erythromycin in this clinically important pathogen.

No / A total of 107 antibiotic-resistant propionibacteria were isolated from the face of 102 Egyptian acne patients, dermatology staff and controls. Erythromycin-clindamycin-resistant propionibacteria were chosen to detect erm(X) gene and it was detected in 29 of 107 (27%) strains. However, just 7 strains had IS1249I, 3 of them had also Tn5432. The erm(X) gene which is not carried on Tn5432 confers inducible resistance to telithromycin by erythromycin or clindamycin. The DNA sequences of the PCR amplification products of this new erm(X)-mediated antibiotic resistance showed >99% identity to the erm(X) gene isolated from a Corynebacterium jeikeium. Southern blotting analysis of the erm(X)-specific probe shows that there were two copies of this resistance gene integrated within the chromosomal DNA. This is the first report of erm(X) being carried by Propionibacterium acnes outside Europe. Whilst the gene is associated with Tn5432 in some strains, the data suggests other genetic element carrying erm(X). The high carriage of erm(X) may affect the efficacy of clindamycin and macrolides for acne treatment in Egypt. / Egyptian Ministry of Higher Education

Le précurseur de la protéine amyloïde (APP) est une protéine transmembranaire qui, après coupure séquentielle par les sécrétases β et γ, produit des peptides Aβ trouvés dans les plaques séniles de patientsatteints d’Alzheimer. Par contre, la forme soluble de l’APP (sAPPα), produite après coupure par une sécrétase α, augmente la survie cellulaire, la croissance des neurites et la synaptogénèse. L’APP est coupéeau site α par 3 métalloprotéases : ADAM9, ADAM10 et ADAM17.Notre laboratoire a montré que la stimulation du récepteur purinergique P2X7 (P2X7R) provoque la coupure protéolytique du précurseur de la protéine amyloïde (APP). Le Dr Delarasse a établi que la voie non amyloïdogénique est mise en jeu et que c'est le fragment sAPPα, neuroprotecteur, qui est produit. Deplus, le laboratoire a précédemment démontré que ce ne sont pas les alpha-sécrétases ADAM9, 10 et 17 qui sont responsables du clivage protéolytique de l'APP après stimulation du P2X7R dans les cellules de neuroblastome Neuro2a.Durant mes travaux de thèse, nous avons étudié la voie biochimique menant à la libération du fragments APPα. L’activation du P2X7R stimule la phosphorylation et la translocation rapide à la membrane plasmique de protéines, appelées ezrine, radixine et moesine (ERM) qui ont la capacité d’établir un lien entre la région cytosolique du P2X7R et la F-actine. Les ERM jouent un rôle crucial dans la coupure protéolytique de l’APP par les métalloprotéases ADAM. En effet, l’inhibition de l’expression des ERM par RNA interférence aboutit à une absence de coupure de l’APP. Par ailleurs, nous avons observé que les MAPKERK1/2 et JNK et la ROCKinase sont nécessaires à la phosphorylation activatrice des ERM et jouent donc un rôle en amont des ERM. Enfin, nous avons mis en évidence le rôle de la PI3K en aval des ERM.Par ailleurs, nous avons démontré que l’activation du récepteur purinergique P2X7 entraînait la coupure protéolytique de la molécule NrCAM par ADAM17 aboutissant à la libération du fragment soluble del’ectodomaine de NrCAM. Les résultats obtenus indiquent que la coupure de NrCAM est dépendante de l’activation et de la fixation des ERM à NrCAM. Ces résultats suggèrent fortement que les ERM sont indispensables à la coupure protéolytique de différents substrats après stimulation du P2X7R.Les données obtenues mettent en évidence un mécanisme moléculaire original et important qui fait jouer aux ERM un rôle central de « liens moléculaires » dans le clivage protéolytique des protéines transmembranaires. A ce stade de notre étude, nous émettons l’hypothèse que les ERM agissent en aval du récepteur P2X7, en liant les substrats et/ou les protéases qu’ils regroupent à la membrane plasmique favorisant ainsi le clivage des substrats. / The amyloid protein precursor (APP) can be cleaved in neural cells by α-secretases to produce the soluble APP ectodomain (sAPPα), which is neuroprotective. We have shown previously that activation of the purinergic receptor P2X7 (P2X7R), a member of the P2X receptor family of ATP-gated cation channels, triggers sAPPα shedding from neural cells. Here, we demonstrate that theactivation of Ezrin/Radixin/Moesin proteins (ERM) is required for the P2X7R-dependent proteolyticprocessing of APP leading to sAPPα release. Indeed, the down regulation of ERM by siRNA blocksthe P2X7R-dependent shedding of sAPPα. We also show that P2X7R stimulation triggers thephosphorylation of ERM. Thus, ezrin translocates to the plasma membrane to interact with P2X7R.Using specific pharmacological inhibitors, we have established the order in which several enzymestrigger the P2X7R-dependent release of sAPPα. Thus, a Rho-kinase and the MAPK modules ERK1/2and JNK act upstream of ERM while a PI3Kinase activity is triggered downstream. This work for the first time identifies ERM as major partners in the regulated non-amyloidogenic processing of APP. Inaddition, we have recently established that the stimulation of P2X7R leads to the proteolytic cleavage of NrCAM by ADAM17 and the shedding of the soluble extracellular domain of NrCAM. Our results clearly show that the proteolytic cleavage of NrCAM is dependant of ERM activation and fixation tothe intracellular region of NrCAM. Thus, our results strongly suggest that ERM are required for the proteolytic cleavage of numerous substrates after P2X7R stimulation. Our findings suggest that ERM play a central role in the proteolytic cleavage of transmembrane proteins and act as molecular linkswhich aggregate ADAMs and substrates at the plasma membrane promoting the cleavage of substrates.

<p>Kvalitetna postavka kombinacije internih kontrolnih mehanizama, u značajnoj meri oredeljuje i kvalitet samog kontrolnog okruženja preduzeća. Ovim istraživanjem je potvrđena činjenica da kvalitetno kontrolno okruženje značajno doprinosi dobrom upravljanju ciljevima i rizicima. Centralno mesto u procesu korporativnog upravljanja zauzimaju interni kontrolni mehanizmi koncentrisani u procesu upravljanja rizicima. Interni kontrolni mehanizmi upotrebom svojih kontrolnih &bdquo;alata&ldquo;, olakšavaju procenu rizika, njegovo prepoznavanje i merenje. Svako iz svog ugla: računovodstvo, kontroling, Fast Close, ERP (Enterprise Resource Planning ), IMS (Integrisani sistemi menadžmenta) , finansijsko upravljanje i kontrola, ERM (Enterprise Risk Management) i interna revizija, su značajni elementi internih kontrolnih mehanizama, u procesu</p> / <p>Creating a right combination of internal control mechanisms, to a large extent, also determines the quality of a company&rsquo;s control environment. This research has confirmedthe fact that an efficient control environment significantly contributes to proper management of goals and risks. The central place in the process of corporate governance belongs to internal control mechanisms centered in the process of risk management. Internal control mechanisms, by using their control &quot;tools&quot;, facilitate the risk assessment, its identification and measurement. Everyone from their own perspective: accounting, controlling, Fast Close, ERP (Enterprise Resource Planning), IMS (Integrated Management Systems), financial management and control, ERM (Enterprise Risk Management) and internal audit, are important elements of internal control mechanisms in the process of managing the key financial and operational risks.</p>

Made available in DSpace on 2016-03-15T19:32:54Z (GMT). No. of bitstreams: 1 Edmilson Casagrande Ricca_NAO AUTORIZADO PARA DIVULGACAO (2).pdf: 1604795 bytes, checksum: f06462c7036409e7701977bb66df9910 (MD5) Previous issue date: 2015-02-04 / In a global scenario, where transparency and trustworthiness have become more and more mandatory for financial institutions, the proper operational risk management has been the main concern of the financial sector due to the huge loss potential, the reputational risk and the consequences of financial scandals, with special mention to the financial crisis in 2008. Under these circumstances, this study s goal was to identify operational risks in a financial institution by setting a model of self-assessment for risks and controls - RCSA. The model was based on the concepts of ERM framework of COSO and was made feasible through the use of an interventionist approach. The research sought to diagnose the operational risks of the investigated company, providing data to the senior managers about each department, in order to enable them to do the proper mitigating actions in relation to those risks. As a consequence, an important supporting grind has been built for the corporation to strengthen its operational risks management before its headquarters and regulating offices. It is believed that the proposed stages applied during this study have contributed to the theoretical and practical model, making it a valuable tool for identifying the potential operational risks in the segment of the financial market. / Num cenário global, onde a demanda por transparência e confiabilidade em relação às instituições financeiras atinge proporções nunca antes alcançadas, o adequado gerenciamento de riscos operacionais tornou-se a maior preocupação deste segmento em razão do potencial de perdas elevado, risco de imagem e consequências de desastres financeiros recentes, com destaque para a crise de 2008. É nesse contexto que o presente estudo teve como objetivo principal fazer um diagnóstico de riscos operacionais em uma instituição financeira, através da construção de um modelo de autoavaliação de riscos e controles RCSA. O modelo foi fundamentado nos conceitos do framework ERM do COSO e viabilizado com a utilização da abordagem intervencionista. A pesquisa buscou identificar os riscos operacionais da empresa investigada, dando visibilidade à alta gerência sobre a exposição de cada departamento, permitindo que ações mitigadoras pudessem ser tomadas em relação àqueles. Consequentemente, foi construído um importante pilar de suporte para a instituição fortalecer seu gerenciamento de riscos operacionais perante sua matriz e regulador. Acredita-se que as etapas propostas aplicadas no decorrer do trabalho agregaram contribuição teórica e prática ao modelo, tornando esta uma valiosa ferramenta para identificar potenciais riscos operacionais no segmento do mercado financeiro.

La morphogenèse cellulaire représente l’ensemble des évènements qui dictent la forme et la structure d’une cellule. Ces changements morphologiques sont importants pour de nombreux mécanismes vitaux, comme le développement embryonnaire, la réaction inflammatoire ou encore la cicatrisation. Pour cela, la morphogénèse cellulaire dépend principalement du remodelage du cytosquelette cellulaire qui, une fois associé à la membrane plasmique, forme l’armature de la cellule. L’ezrine, la radixine et la moésine appartiennent à la famille de protéines ERM et lient la membrane plasmique au cytosquelette d’actine et aux microtubules. De ce fait, les protéines ERM sont impliquées dans différents processus fondamentaux nécessitant un remodelage du cortex cellulaire tels que la mitose et la migration. Dans un contexte pathologique, la surexpression et/ou la sur-activation des protéines ERM corrèlent avec un haut potentiel métastatique et un pauvre pronostic chez les patients. Une meilleure compréhension de la régulation de ces trois protéines pourrait ainsi aider au développement de nouvelles solutions thérapeutiques. L’objectif de mon doctorat portait sur l’identification et la caractérisation de nouvelles voies de signalisation régulant les protéines ERM. Dans un premier temps (i), j’ai participé au développement et la caractérisation de sondes BRET2 permettant de suivre l’activité de chaque protéine ERM en temps réel. Ces sondes BRET2 sont d’ailleurs compatibles avec des études à grande échelle ce qui nous permettra de réaliser des cribles génomiques et chimiques dans le but d’identifier, respectivement, de nouveaux régulateurs et inhibiteurs pharmacologiques des protéines ERM. Ensuite (ii), grâce aux sondes BRET2, nous avons identifié les microtubules en tant que nouveaux régulateurs négatifs des protéines ERM. Nous avons alors montré que la dépolymérisation des microtubules d’interphase à l’entrée en mitose participe à l’activation des protéines ERM et à l’arrondissement cellulaire. Enfin (iii), nous avons montré que le récepteur couplé aux protéines G TPα régule l’activité des protéines ERM dans des cellules de cancer du sein triple négatif. Cette régulation est d’ailleurs importante pour la motilité de ces cellules. Pour conclure, en plus d’avoir développé de nouveaux outils utiles pour des études à grande échelle, mon travail de doctorat a permis de mettre en lumière deux nouvelles voies de signalisation régulant les protéines ERM au cours de la mitose et la migration cellulaire. Sans compter l’apport de nouvelles informations sur un aspect fondamental, mon travail a apporté de nouvelles pistes de réflexion quant aux rôles des protéines ERM dans le développement des métastases. / Cell morphogenesis represents the set of events that dictate the shape and structure of a cell. These morphological changes are important for many vital mechanisms such as embryonic development, inflammatory response, or wound healing. Cell morphogenesis depends mainly on the remodeling of the cell cytoskeleton which forms the framework of the cell when associated with the plasma membrane. Ezrin, radixin and moesin belong to the ERM family and crosslink the plasma membrane to the actin cytoskeleton and microtubules. Therefore, ERMs are involved in various fundamental processes requiring remodeling of the cell cortex such as mitosis and migration. In a pathological context, overexpression and/or overactivation of ERMs correlate with high metastatic potential and poor prognosis in patients. Thus, a better understanding of the regulation of these three proteins could help in the development of new therapeutic solutions. The aim of my PhD work was to identify and characterize novel signaling pathways regulating ERMs. In a first step (i), I participated in the development and characterization of BRET2 biosensors allowing to follow the activity of each ERM protein in real time. These BRET2 biosensors are compatible with large-scale studies which will allow us to perform genomic and chemical screens to identify, respectively, new upstream regulators and pharmacological inhibitors of ERMs. Secondly (ii), based on BRET2-chemical screen, we identified microtubules as new negative regulators of ERMs. We then showed that depolymerization of interphase microtubules at mitosis entry triggers ERM activation and cell rounding. Finally (iii), we showed that the G protein-coupled receptor TPα regulates the activity of ERMs in triple negative breast cancer cells. This regulation is important for the motility of these cells. To conclude, in addition to having developed new tools useful for large-scale studies, my PhD work has uncovered two new signaling pathways regulating ERMs during mitosis and cell motility. In addition to providing new information on a fundamental aspect, my work has provided new insights into the roles of ERMs in the development of metastasis.

Antibiotic resistance threatens to throw mankind back into an era when infectious disease was the predominant cause of death. In an effort to mitigate this danger, we targeted ErmC’ and KsgA. Both methylate N6-adenosine of ribosomal RNA, though each serve different roles in their bacterial host. ErmC’ dimethylates A2058 on 23S rRNA, conferring resistance to MLSB antibiotics (macrolides, lincosamides, streptogramin B). KsgA aids in ribosome assembly, binding inactive 30S until dimethylating A1518/A1519 of 16S rRNA. Like most methyltransferases, ErmC’ and KsgA use cofactor S-adenosylmethionine (SAM) as their methyl source, which binds adjacent to their specific adenosine substrate. ErmC’ inhibitors could restore MLSB antibiotics against infections with this resistance mechanism. KsgA inhibitors could form novel antibiotics that stall 30S assembly. Previous studies reported a potent ErmC’ inhibitor, N6-cyclopentyl adenosine (1), binding to the substrate pocket with cyclopentyl bridging into the SAM pocket. We expanded this study by synthesizing 1 and 22 other N6-substituted analogs to explore more favorable interactions within the SAM pocket. When these compounds (1mM) were screened against ErmC’ and KsgA, some showed greater inhibition than 1. Two of these inhibitors that were crystallized with ErmC’, N6-8-octylamine adenosine (2.60Å) and N6-phenethyl adenosine (2.40Å), unexpectedly docked into the SAM pocket with their 5’-C pointing towards the substrate pocket. New compounds were made to exploit this orientation by adding substituents off the 5’-C to probe the substrate pocket. Through a five step synthesis, the 5’-OH of 1 was substituted with an amine linked to benzyl (30), phenethyl (31), propylphenyl (32) or butylphenyl (33). When 30-33 were screened using 20μM SAM, ErmC’ showed greater inhibition (relative to 1), while KsgA showed virtually none. However, when ErmC’ was tested using 0.5μM SAM, inhibition from 30-33 was nearly unchanged, whereas 1 became significantly more potent than 30-33, suggesting 30-33 were not binding to the SAM pocket. Preliminary data showed that raising 23S concentrations lowered inhibition from 32-33, while inhibition from 1, 30 and 31 was nearly unchanged, suggesting that at least 32-33 bound within the substrate pocket.

A Gestão de Riscos Corporativos (ERM), a partir das publicações da ISO 31000 em 2009 e do guia do COSO em 2007, vem sendo aplicada e adaptada às especificidades de múltiplos mercados. O contexto hospitalar, caracterizado pela necessidade de avanços em sistemas e métodos gerenciais que permitam maior acurácia de informações e sustento na orientação à tomada de decisão, passou a, também, interessar-se pelo valor da ERM. Influenciado pelos programas de qualidade e segurança do paciente e de gestão de riscos assistencial, presentes na cultura hospitalar mundial, gestores estratégicos à frente de organizações de saúde começaram a procurar por metodologias que possam ser adaptadas à complexidade de um hospital e apoiem a implementação da ERM. A literatura prévia ao desenvolvimento desta tese não apresenta um modelo que consolida e orienta a operacionalização da ERM em organizações de saúde, mas destaca em múltiplas publicações a necessidade que os hospitais têm de atentar a metodologias que permitam gerir de forma proativa e estratégica seus negócios, que estão expostos a riscos internos e externos. Motivada pela lacuna descrita, esta tese explorou o mercado brasileiro e norte americano através de entrevistas, estudos de caso e survey, e propôs um modelo global de ERM para organizações de saúde: o E2RMhealthcare. Este sugere requisitos para a operacionalização global da ERM e é fragmentado em 4 níveis: risk baseline, education, quantitative e governance que orientam uma implementação gradual, considerando a maturidade de gestão da organização. Formas de como explorar as características do hospital e capital humano para exercer a ERM também foram estudadas, sendo proposto uma relação entre as equipes de avaliação de tecnologias de saúde hospitalar e de ERM no processo de criação de valor da organização através de um mapa de causa e efeito. Como destaque do negócio saúde, essa tese inova propondo o primeiro inventário de riscos corporativos orientado a organizações de saúde que foi validado por gestores de múltiplos países, identificando o risco de ataques cibernéticos como o principal. Por fim, o uso de métodos de análise multicriterial e de custeio por atividade são aplicados como soluções inovadoras para a priorização e avaliação econômica de riscos ao longo dos níveis Baseline e Quantitative do E2RMhealthcare. O avanço do E2RMhealthcare com estas metodologias incorporadas para um software com capacidade de inteligência artificial é deixado como sugestão de trabalhos futuros além da sua real aplicação em múltiplos casos. / Since the ISO 31000 publication in 2009 and the COSO guide in 2007 Enterprise Risk Management (ERM) has been applied and adapted to the specificities of different business markets. The hospital context characterized by the demand for advances in management systems and methods that allow to improve information accuracy and to support the decision-making process, also became interested in the value of ERM. Influenced by quality and patient safety and healthcare risk management programs presents in the global hospital culture, managers at the top of healthcare organizations started to look for methodologies that can be adapted to the hospital management complexity to support the ERM implementation. The literature, prior to the development of this thesis, does not present a model that consolidates a guide to operationalize ERM in healthcare organizations. Although emphasizes, in multiple publications, the urgency for methodologies that enable proactive and strategic management of healthcare businesses, which are exposed to internal and external risks. Motivated by the described gap, this thesis explored the Brazilian and American healthcare market through interviews, case studies and survey, and proposed a global ERM model for healthcare organizations: E2RMhealthcare. It suggests requirements for global operationalization of the ERM and is organized in 4 levels: risk baseline, education, quantitative and governance that guide a gradual implementation, considering the maturity of the organization management. Different manners to explore the features of the hospital and human capital to operate the ERM were also studied, and it was proposed a relation between the hospital healthcare technology assessment teams and the ERM in the value creation process of the organization through a cause and effect map. Focusing on the healthcare business, this thesis innovates by proposing the first enterprise risk inventory aimed at healthcare organizations that was confirmed by risk managers from different countries. Cyber-attack was identified as the main enterprise risk in healhtcare. Finally, the use of multicriterial analysis methods and activity-based costing are applied as innovative solutions for prioritization and economic assessment of risks throughout the Baseline and Quantitative levels of E2RMhealthcare. The progress of E2RMhealthcare with these incorporated methodologies for a software with artificial intelligence capacity is left as a suggestion for future studies, in addition to its actual application in multiple cases.