RADIC II : a fault tolerant architecture with flexible dynamic redundancy

The demand for computational power has been leading the improvement of the High Performance Computing (HPC) area, generally represented by the use of distributed systems like clusters of computers running parallel applications. In this area, fault tolerance plays an important role in order to provide high availability isolating the application from the faults effects. Performance and availability form an undissociable binomial for some kind of applications. Therefore, the fault tolerant solutions must take into consideration these two constraints when it has been designed. In this dissertation, we present a few side-effects that some fault tolerant solutions may presents when recovering a failed process. These effects may causes degradation of the system, affecting mainly the overall performance and availability. We introduce RADIC-II, a fault tolerant architecture for message passing based on RADIC (Redundant Array of Distributed Independent Fault Tolerance Controllers) architecture. RADIC-II keeps as maximum as possible the RADIC features of transparency, decentralization, flexibility and scalability, incorporating a flexible dynamic redundancy feature, allowing to mitigate or to avoid some recovery side-effects.La demanda de computadores más veloces ha provocado el incremento del área de computación de altas prestaciones, generalmente representado por el uso de sistemas distribuidos como los clusters de computadores ejecutando aplicaciones paralelas. En esta área, la tolerancia a fallos juega un papel muy importante a la hora de proveer alta disponibilidad, aislando los efectos causados por los fallos. Prestaciones y disponibilidad componen un binomio indisociable para algunos tipos de aplicaciones. Por eso, las soluciones de tolerancia a fallos deben tener en consideración estas dos restricciones desde el momento de su diseño. En esta disertación, presentamos algunos efectos colaterales que se puede presentar en ciertas soluciones tolerantes a fallos cuando recuperan un proceso fallado. Estos efectos pueden causar una degradación del sistema, afectando las prestaciones y disponibilidad finales. Presentamos RADIC-II, una arquitectura tolerante a fallos para paso de mensajes basada en la arquitectura RADIC (Redundant Array of Distributed Independent Fault Tolerance Controllers). RADIC-II mantiene al máximo posible las características de transparencia, descentralización, flexibilidad y escalabilidad existentes en RADIC, e incorpora una flexible funcionalidad de redundancia dinámica, que permite mitigar o evitar algunos efectos colaterales en la recuperación

Compiler assisted chekpointing of message-passing applications in heterogeneous environments

[Resumen] With the evolution of high performance computing towards heterogeneous, massively parallel systems, parallel applications have developed new checkpoint and restart necessities, Whether due to a failure in the execution or to a migration of the processes to different machines, checkpointing tools must be able to operate in heterogeneous environments. However, some of the data manipulated by a parallel application are not truly portable. Examples of these include opaque state (e.g. data structures for communications support) or diversity of interfaces for a single feature (e.g. communications, I/O). Directly manipulating the underlying ad-hoc representations renders checkpointing tools incapable of working on different environments. Portable checkpointers usually work around portability issues at the cost of transparency: the user must provide information such as what data needs to be stored, where to store it, or where to checkpoint. CPPC (ComPiler for Portable Checkpointing) is a checkpointing tool designed to feature both portability and transparency, while preserving the scalability of the executed applications. It is made up of a library and a compiler. The CPPC library contains routines for variable level checkpointing, using portable code and protocols. The CPPC compiler achieves transparency by relieving the user from time-consuming tasks, such as performing code analyses and adding instrumentation code

Shopping malls as ideological battlegrounds: discipline and power in Riyadh’s pseudo-public spaces

Since the 1950s, Riyadh has witnessed unprecedented urban growth that has put pressure on the fabric of the city and irreversibly changed its urban environment. The accelerated processes of urban modernisation and the car-centric development of Riyadh have created an environment in which urban public life and the human scale were often neglected. The shopping mall typology offered a solution that seemed to provide the city with the public spaces that it needed. Unlike their counterparts in European and North American cities — whose malls have been competing with the city and its urbanity — malls in Middle Eastern and East Asian contexts have been an integral part of the urban process as well as the socio-cultural fabric of cities; Riyadh is no exception. However, the mall typology was introduced at a time when the ideological struggles between economic powers — incentivised to ‘modernise’ the urban environment — and religious powers — which perceive processes of urban modernisation as a threat to the ‘integrity’ of Saudi society — reached its peak. This tension created an urban environment characterised by spatial control, which was absorbed by the mall and resulted in the development of an iteration of the typology that is essentially Saudi in its characteristics. This thesis aims to explore these characteristics and investigate the implications of the inherent tensions that are accentuated within the shopping mall. It aims to uncover the mechanisms that led to the emergence of the Saudi iteration of shopping malls and investigate how the typology has been re-adapted to respond to local requirements. The study of the mall in Riyadh offers a new understanding of the on-going evolution of the mall typology within a global context. More importantly, it is a vehicle through which the limitations that are imposed on urban spaces and public life in Riyadh are examined. The changing socioeconomic climate in Saudi Arabia today offers new opportunities for introducing sustainable and inclusive urban spaces. Understanding the limitations that have been imposed in public spaces in Riyadh — using the mall typology — is essential to efforts seeking to act on such opportunities

The molecular basis of the phenotype observed when normal cells recover from camptothecin and methyl pyruvate

A thesis submitted to the Faculty of Science under the School of Molecular and Cell Biology, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2017.Cancer has become a major cause of death in modern society. New cancer cases are estimated to increase to 22.2 million by 2030. Many chemotherapeutic drugs, such as irinotecan, target the p53 pathway in rapidly dividing cells. However, chemotherapeutic drugs possess little discrimination between normal and cancer cells since they target DNA replication, a normal physiological process. Many studies indicate that cancer and normal cells prefer different glucose metabolic pathways. Cancer cells rely mainly on glycolysis while normal cells prefer the oxidative phosphorylation (OXPHOS). We hypothesise that manipulating the known metabolic programme of cancer cells to follow the OXPHOS pathway experienced by normal cells may alleviate side effects experienced by normal cells and accelerate cancer cell death. In order to enhance OXPHOS optimal pyruvate levels were used. To investigate the effect of this on normal and cancer cell division, cell viability and cytotoxicity was measured in real-time using xCELLigence technology. Flow cytometry was then used to determine the mode of cell death and cell cycle changes induced by the various treatments. In order to characterise the molecular bases of this, differential gene expression upon treatment with the various drugs was measured by RT-PCR and Western blot analysis. Furthermore, we conducted microarray analyses using the Human Cancer PathwayFinder array to determine pathways affected by the drug combination in A549 lung fibroblast cancer and a normal lung fibroblast (MRC-5). Differentially expressed genes with a fold change ≥ 2 were analysed by PANTHER, GeneMania and Reactome. Overall, this study shows that the reversal of the metabolic program in A549 and MDA-MB 231 cancer cells with chemotherapeutic agents accelerates the death of cancer cells while promoting the survival of normal MRC-5 cells. However, in the breast cancer cell line, MDA-MB 231 with mutant p53, it is observed that inhibition of proliferation is by another cell death mechanism. RT-PCR and western blot analyses indicate that introduction of exogenous methyl pyruvate enhanced the p53/p21 axis of the apoptotic pathway resulting in cancer cell death. While promoting survival in MRC-5 normal lung fibroblast cells by turning off the p53/p21 axis of the apoptotic pathway. Furthermore, the introduction of exogenous methyl pyruvate promotes MRC-5 cell proliferation by modulating the expression of RBBP6 isoform 1 and isoform 3. Microarray analysis indicates alterations in specific genes promote the survival and growth of MRC-5 normal cells and death of A549 lung cancer cells. This knowledge may provide an opportunity to protect patients who undergo chemotherapy from the harsh side-effects and increase the success rate of chemotherapeutic drugs.LG201

Characterization of the protein interaction profile of the human kinase Nek4 and assignment of its functional context

Orientador: Jörg KobargTese (doutorado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: As Neks são proteínas quinases similares a NIMA, proteína que é indispensável para a entrada em mitose de células de Aspergillus nidulans. Em humanos foram identificadas 11 Neks (1-11) e, estudos crescentes vêm demonstrando a participação destas em diversas funções celulares além do controle do ciclo e divisão celular. A Nek4 é um dos maiores membros dessa família e sua relação com a manutenção ciliar e resposta ao DNA danificado já foi demonstrada. Contudo, seus parceiros de interação e substratos são ainda desconhecidos. Para melhor compreender o papel da Nek4 foi realizado um estudo de interatoma para identificar novos processos biológicos com os quais a Nek4 está envolvida. Inicialmente foi identificada uma nova isoforma para a Nek4 e assim, realizou-se o estudo de interatoma para as duas isoformas com a finalidade de comparar o perfil de interação das duas proteínas. As duas isoformas da Nek4 foram expressas em células humanas e após imunoprecipitação seguida de identificação por espectrometria de massas, foram identificadas 474 proteínas que interagem com a isoforma 1 da Nek4, Nek4.1 e 149 para a isoforma 2, Nek4.2. Dentre as proteínas identificadas, 102 interagem com ambas isoformas da Nek4. Nossos resultados confirmam o envolvimento da Nek4 com a resposta ao DNA danificado, função ciliar, estabilização dos microtúbulos e ainda sugerem o envolvimento da Nek4 em funções completamente novas, como processamento de RNAm, resposta ao estresse, controle de qualidade das proteínas e apoptose. Entre os parceiros de interação encontramos importantes proteínas como TRAP-1, Whirlin, PCNA, 14-3-3?, Btf, PARP-1, SRSF1, PAI-RBP1 e KAP-1. As duas isoformas compartilham funções que não foram ainda descritas para os membros da família Nek e a isoforma 1 ainda apresenta funções que já foram descritas para outros membros da família. Aliado ao resultado da imunoprecipitação ainda foram realizadas imunofluorescências que permitiram verificar a localização da Nek4 em diferentes estruturas celulares, como os speckles nucleares e a mitocôndria, corroborando com a função no processamento de RNAm e apoptose. O experimento de imunoprecipitação seguido de identificação por espectrometria de massas também apontou para a possibilidade de autofosforilação e dimerização da Nek4. Além disso, foi possível observar diferenças entre o perfil de interação das duas isoformas da Nek4, sendo que a isoforma 1 interage com proteínas que mantém funções biológicas similares a outras Neks, que a isoforma 2 não apresentaAbstract: Neks are serine-threonine kinases that are similar to NIMA, a protein found in Aspergillus nidulans which is essential for cell division. In humans there are eleven Neks (1-11) which are involved in different biological functions besides the cell cycle control. Nek4 is one of largest members of the Neks family and has been related to the primary cilia formation and in DNA damage response. However, its substrates and interaction partners are still unknown. Thus in an attempt to better understand the role of Nek4 we performed an interactomics study to find new biological processes in which Nek4 is involved. Besides, we described here a novel Nek4 isoform and compared the interactomics profile of these two Nek4 proteins. Isoform 1 and isoform 2 of Nek4 were expressed in human cells and after an immunoprecipitation followed by mass spectrometry, 474 interacting proteins were identified for isoform 1 and 149 for isoform 2 of Nek4. 102 proteins are common interactors between both isoforms. Our results confirm Nek4 involvement in the DNA damage response, cilia maintenance and microtubules stabilization, and raise the possibility of new functional contexts including mRNA processing, apoptosis signaling, stress response, translation and protein quality control. Among the interaction partners, we found important proteins such as TRAP-1, Whirlin, PCNA, 14-3-3?, Btf, PARP-1, SRSF1, PAI-RBP1 and KAP-1. We could observe that both isoforms share functions that are new to the Nek family, and isoform 1 apparently has also maintained functions which have already been established to other Nek family members. From our immunoprecipitation followed by mass spectrometry experiment a possible site for Nek4 autophosphorylation and dimerization was identified. This study provides new insights into Nek4 functions, identifying new interaction partners, localization to new cellular compartment and further suggests an interesting difference between isoform 1 and the novel isoform 2 of Nek4. Nek4 isoform 1 may have maintained similar roles compared to other Neks and these roles are not related to isoform 2DoutoradoBioquimicaDoutora em Biologia Funcional e Molecula