Green computing, an emerging field of research that seeks to reduce excess power consumption in high performance computing (HPC), is gaining popularity among researchers. Research in this field often relies on simulation or only uses a small cluster, typically 8 or 16 nodes, because of the lack of hardware support. In contrast, System G at Virginia Tech is a 2592 processor supercomputer equipped with power aware components suitable for large scale green computing research. DIRECT is a deterministic global optimization algorithm, implemented in the mathematical software package VTDIRECT95. This thesis explores the potential energy savings for the parallel implementation of DIRECT, called pVTdirect, when used with a large scale computational biology application, parameter estimation for a budding yeast cell cycle model, on System G. Two power aware approaches for pVTdirect are developed and compared against the CPUSPEED power saving system tool. The results show that knowledge of the parallel workload of the underlying application is beneficial for power management. / Master of Science

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La cytokinèse est un processus fondamental prenant place à la fin de la mitose et permettant la séparation des deux cellules filles. Un défaut de cytokinèse peut mener à une ségrégation anormale des chromosomes et engendrer des phénomènes de cancer. Dans beaucoup d'organismes eucaryotes, la cytokinèse nécessite l'assemblage et la contraction d'un anneau d'actomyosine permettant la formation d'un sillon et la réorganisation de la membrane cellulaire au site de clivage. Dans la plupart de ces organismes, des protéines du cytosquelette appelées septines participent à la cytokinèse. Chez la levure bourgeonnante, Saccharomyces cerevisiae, cinq septines sont exprimées durant la mitose (Cdc3, Cdc10, Cdc11, Cdc12 et Shs1). Ces protéines ont la capacité de s'assembler en un anneau au niveau du site de bourgeonnement, lieu de séparation entre la cellule mère et la cellule fille. Cet anneau de septines permet la fixation et le recrutement de nombreuses protéines intervenant dans la cytokinèse. La dynamique des septines change durant le cycle cellulaire, ce qui a une importance dans la régulation de la cytokinèse. La stabilisation de cet anneau est accompagnée d'un changement du niveau de phosphorylation des septines, mais les kinases responsables de ces modifications restent inconnues. Les travaux de l'équipe de Simonetta Piatti ont mis en évidence un nouveau rôle de la GTPase Rho1 et de sa cible, la protéine kinase C (Pkc1), dans la régulation de la dynamique des septines. Le but de ce travail de thèse était de déterminer les voies moléculaires par lesquelles la protéine Pkc1 intervient dans le recrutement et la stabilisation de l'anneau de septines. Pour se faire nous avons purifié le complexe de septines chez la levure bourgeonnante en présence ou en absence de la protéine Pkc1 et nous l'avons analysé par spectrométrie de masse. Cette analyse nous a permis d'observer que le niveau de phosphorylation d'un cluster (îlot) de 5 sérines était diminué sur Shs1. L'alignement de séquence nous a permis de constater que ce domaine était conservé dans la septine Cdc11. Par ailleurs ces deux protéines sont connues pour jouer un rôle dans l'assemblage des filaments et la formation de l'anneau de septines. Il a déjà été observé qu'un mutant phosphomimétique du cluster de sérine de la septine Shs1 empêche la formation des filaments in-vitro. Nous avons voulu caractériser le rôle de ce cluster dans la protéine Cdc11 en créant un mutant non-phosphorylable (CDC11-9A) et un mutant phosphomimétique (CDC11-9D). De manière très évidente, le mutant phosphomimétique provoque des problèmes de cytokinèse dans les cellules dont le gène codant la protéine Shs1 a été supprimé. A l'inverse le mutant non-phosphorylable améliore le phénotype des cellules ne comportant pas Shs1. Ces résultats sont en parfait accord avec l'observation selon laquelle les protéines Shs1 et Cdc11 pourraient avoir des fonctions très similaires, et mettent en avant le rôle important du cluster de sérines phosphorylées de Cdc11 lors de la cytokinèse. Nous avons constaté que Pkc1 ne phosphoryle pas directement les septines, mais agit par l'intermédiaire de kinases et de phosphatases impliquées dans la régulation des septines. Nous avons pu montrer que Pkc1 régule l'interaction de Gin4 avec les septines, cette kinase étant connue pour sa capacité à phosphoryler Shs1. De plus, nous avons observé que Pkc1 impacte sur le niveau de phosphorylation des deux autres kinases de la même famille, Hsl1 et Kcc4. Par ailleurs, la délétion de PKC1 diminue drastiquement la quantité de protéines Kcc4 dans la cellule.L'absence de Pkc1 augmente également l'interaction entre les septines et Bni4, une sous-unité régulatrice de la phosphatase PP1. Nous avons également observé que Bni4-PP1 peut déphosphoryler Cdc11, expliquant la diminution de son niveau de phosphorylation en cas d'absence de la protéine Pkc1.Ces travaux mettent en évidence que Pkc1 est un nouveau régulateur majeur des septines dans la levure. / Cytokinesis is the last step of mitosis and is the fundamental process leading to the physical separation of two daughter cells. Defects in cytokinesis generate polyploid cells that are prone to chromosome missegregation and cancer development. In animal cells and fungi, cytokinesis requires the formation and contraction of an actomyosin ring that drives ingression of the cleavage furrow. Additional cytoskeletal proteins called septins contribute to cytokinesis. In the budding yeast Saccharomyces cerevisiae, five different septins are expressed during the mitotic cell cycle (Cdc3, Cdc10, Cdc11, Cdc12 and Shs1). All septins, except for Shs1, are essential for cell viability. Yeast septins form filaments that in turn organize into a ring at the bud neck, which is the constriction between the mother and the future daughter cell where cytokinesis takes place. The septin ring then expands into a rigid septin collar that acts as scaffold for cytokinesis by recruiting most cytokinetic proteins to the bud neck. Cell cycle-regulated changes in septin ring dynamics are thought to be important for its cytokinetic functions and formation of the rigid septin collar is accompanied by septin phosphorylation. However, the kinases responsible for these modifications have not been fully characterized. Unpublished data from our laboratory indicate that the Rho1 GTPase, which is essential for actomyosin ring formation and contraction, and its target protein kinase C (Pkc1) contribute to deposition and stabilization of the septin ring. Here, we have addressed how Pkc1 regulates septin ring deposition and/or stability. To this end, septin complexes were purified from yeast and analyzed by mass spectrometry, comparing wild type and pkc1Δ mutant cells. This mass spectrometry analysis clearly showed that phosphorylation of a cluster of residues in Shs1 decreased in the absence of Pkc1. Interestingly, we found that this cluster is conserved in the septin Cdc11, which together with Shs1 is known to play an important role in the assembly of high-order structures like filaments and rings. Phosphomimetic mutations of the phosphorylatable cluster in Shs1 have been previously shown to disrupt filament formation in-vitro. We therefore proceeded to mutagenise the same cluster in Cdc11, generating a phosphomimetic (CDC11-9D) and in a non-phosphorylatable mutant (CDC11-9A). Strikingly, the phosphomimetic CDC11-9D caused cytokinesis defects in cells lacking Shs1, whereas the non-phosphorylatable CDC11-9A allele partially rescued the sickness of shs1∆ mutant cells. These observations are in agreement with the notion that Cdc11 and Shs1 share overlapping functions and highlight an important role of the phosphorylatable cluster of Cdc11 for cytokinesis. We also found that Pkc1 does not phosphorylate septins directly, but rather regulates the activity of septin kinases and phosphatases. Consistently, we show that Pkc1 affects the interaction between septins and the bud neck kinase Gin4, which is known to interact with septins and to phosphorylate them. In addition, Pkc1 impacts on the phosphorylation of two additional bud neck kinases, Hsl1 and Kcc4, which are part of the same family of Nim1-related kinases as Gin4. In addition, PKC1 deletion leads to a dramatic decrease in the levels of Kcc4 , so that it is barely detected at the bud neck.Deletion of PKC1 affects also the interaction between septins and the Bni4 protein, which is a regulatory subunit for the PP1 phosphatase at the bud neck. In turn, we found that Bni4-PP1 modulates Cdc11 phosphorylation, thereby explaining how the latter is decreased in the absence of Pkc1. Altogether, our data strongly suggest that Pkc1 is a novel major regulator of septins in yeast.

Produtores de pêssegos e nectarinas utilizam mudas cujos porta-enxertos são provenientes de sementes, gerando desuniformidade entre as plantas e nenhum aproveitamento das vantagens trazidas por porta-enxertos clonais, de aspectos genéticos conhecidos. O presente estudo objetivou avaliar o desempenho inicial de nectarineiras Sunraycer de 1-2 anos de idade autoenraizadas e sobre treze porta-enxertos clonais nas condições edafoclimáticas de Piracicaba, SP, durante os anos de 2015 e 2016. No primeiro capítulo dessa dissertação, apresentaram-se os resultados relacionados à ocorrência das fases de florescimento, brotação e colheita, volume de copa, massa de ramos retirada nas podas, massa de fruto, número de frutos e produção por planta, eficiência produtiva, produtividade e diâmetro transversal dos frutos. O intervalo entre o final do florescimento e o fim da colheita foi de 78 dias para a copa de \'Sunraycer\' sobre os porta-enxertos \'G x N.9\' e \'Santa Rosa\' e de 64 dias sobre \'Ishtara\', períodos menores que os relacionados aos demais materiais genéticos. \'Flordaguard\' e \'Ishtara\' induziram maior e menor vigor à copa de \'Sunraycer\', respectivamente, enquanto a maior produção ocorreu sobre o porta-enxerto \'Flordaguard\'. A copa de \'Sunraycer\' é influenciada negativamente pelo porta-enxerto \'Cadaman\' quanto a variáveis de produção. Frutos de maior massa são obtidos em plantas de \'Sunraycer\' autoenraizadas. O tradicional \'Okinawa\' não se destaca como porta-enxerto para \'Sunraycer\'. É possível colher nectarinas \'Sunraycer\' entre 03/10 e 18/10 em Piracicaba, SP, período este de pouca oferta. No segundo capítulo, objetivou-se determinar os teores de macro e micronutrientes (N, P, K, Ca, Mg, S, Fe, Mn, Cu, Zn e B) presentes em folhas de nectarineiras Sunraycer, treze semanas após o florescimento, visando a avaliar, interpretar e determinar o estado nutricional das mesmas, identificando possíveis materiais genéticos mais eficientes em absorver/translocar tais elementos. Observa-se distinta composição nutricional das folhas de \'Sunraycer\' em plantas autoenraizadas e sobre porta-enxertos clonais. \'Ishtara\', \'Tsukuba-3\', \'Barrier\' e \'Flordaguard\' são porta-enxertos eficientes na absorção da maioria dos nutrientes sob nectarineiras Sunraycer. Mais casos de deficiência nutricional são observados em plantas de \'Sunraycer\' sobre o porta-enxerto \'Santa Rosa\', para nitrogênio, potássio, cálcio, enxofre, ferro e zinco. / Peach and nectarine producers employ scions grafted in seedling rootstocks, resulting in unevenness between plants and disregarding advantages brought by clonal rootstocks, with known genetic aspects. The present study aimed to evaluate the initial performance of 1-2-year-old Sunraycer nectarine trees on their own roots and grafted on thirteen clonal rootstocks in the edaphoclimatic conditions of Piracicaba city, São Paulo State, Brazil, in the years of 2015 and 2016. Results related to the occurrence of flowering, budding and harvest phases, the canopy volume, pruning fresh weight, fruit mass, number of fruits and production per plant, productive efficiency, yield and fruit transverse diameter are presented in the first chapter of this dissertation. The interval between the end of flowering and the end of the harvest period was 78 days to \'Sunraycer\' grafted onto \'G x N.9\' and \'Santa Rosa\' rootstocks and 64 days to this scion onto \'Ishtara\', shorter periods than those related to other rootstocks. \'Flordaguard\' and \'Ishtara\' induced higher and lower vigor to \'Sunraycer\', respectively, whereas \'Flordaguard\' enabled greater production to \'Sunraycer\'. The \'Sunraycer\' scion is negatively influenced by \'Cadaman\' rootstock in terms of production variables. Heavier fruits are provided by self-rooted plants. The traditional \'Okinawa\' does not stand out as a rootstock for \'Sunraycer\'. It is possible to harvest \'Sunraycer\' nectarines between 03/10 and 18/10 in Piracicaba, SP, which is a period of low supply. In the second chapter, the objective was to determine the foliar levels of macro and micronutrients (N, P, K, Ca, Mg, S, Fe, Mn, Cu, Zn and B) in Sunraycer nectarine trees, thirteen weeks after flowering to evaluate, interpret and determine their nutritional status, identifying some possible more efficient genetic materials in absorbing / translocating such elements. It was verified that clonal rootstocks and self-rooted plants provide a distinct nutritional composition to \'Sunraycer\' leaves. \'Ishtara\', \'Tsukuba-3\', \'Barrier\' and \'Flordaguard\' are efficient rootstocks to the absorption of most of the nutrients under Sunraycer nectarine trees. \'Santa Rosa\' allows more nutritional deficiencies to \'Sunraycer\' plants, as of nitrogen, potassium, calcium, sulfur, iron and zinc.

Investigating the arrangement of the packed DNA inside the nucleus has revealed the essential role of genome organisation in controlling genome function. Furthermore, genome architecture is highly dynamic and significant chromatin re-organisation occurs in response to environmental changes. However, the mechanisms that drive the 3D organisation of the genome remain largely unknown. To understand the effect of biophysical properties of chromatin on the dynamics and structure of chromosomes, I developed a 3D computational model of the nucleus of the yeast S. cerevisiae during interphase. In the model, each chromosome was a hetero-polymer informed by our bioinformatics analysis for heterogeneous occupancy of chromatin-associated proteins across the genome. Two different conditions were modelled, normal growth (25°C) and heat shock (37°C), where a concerted redistribution of proteins was observed upon transition from one temperature to the other. Movement of chromatin segments was based on Langevin dynamics and each segment had a mobility according to their protein occupancy and the expression level of their corresponding genes. The model provides a significantly improved match with quantitative microscopy measurements of telomere positions, the distributions of 3D distances between pairs of different loci, and the mean squared displacement of a labelled locus. The quantified contacts between chromosomal segments were similar to the observed Hi-C data. At both 25°C and 37°C conditions, the segments that were highly occupied by proteins had high number of interactions with each other, and the highly transcribed genes had lower contacts with other segments. In addition, similar to the experimental observations, heat-shock genes were found to be located closer to the nuclear periphery upon activation in the simulations. It was also shown that the determined distribution of proteins along the genome is crucial to achieve the correct genome organisation. Hence, the heterogeneous binding of proteins, which results in differential mobility of chromatin segments, leads to 3D self-organisation.

Being able to respond to extracellular cues such as nutrients and growth factors is of vital importance to all living cells. Pathways have therefore evolved which can sense the extracellular status, transmit a signal through the cell and affect gene expression, which ultimately enables adaptation. Intriguingly, research has revealed that such signaling pathways responding to nutrient status are intrinsically linked to the lifespan of organisms, a phenomenon known as caloric restriction. This thesis utilizes budding yeast, Saccharomyces cerevisiae, as a model system to investigate how transcription factors affect gene expression in response to nutrient signaling pathways. Paper I investigates the role of the three homologous transcription factors Mig1, Mig2 and Mig3 in regulating gene expression in response to glucose. This is done by transcriptional profiling with microarrays of wild type yeast, as well as mutant strains where the MIG1, MIG2 and MIG3 genes have been deleted in all possible combinations. The results reveal that Mig1 and Mig2 act together, with Mig1 having a larger effect in general while Mig2 has a role specialized for high-glucose conditions. Using a strategy similar to that in paper I, paper II examines the roles of the two homologous transcription factors Gis1 and Rph1 in gene regulation. This study shows that Gis1 and Rph1 are both involved in nutrient signaling, acting in parallel with a large degree of redundancy. Furthermore, we find that these two transcription factors change both target genes as well as the effects on transcription when the yeast cell transitions through different growth phases. Rph1 is a functional JmjC histone demethylase, and paper III investigates the connection between this activity and the transcriptional regulation studied in paper II. We find that rendering Rph1 catalytically inactive has little effect on its role in nutrient signaling and gene regulation, but subtly affects certain groups of genes. Paper IV reveals that Rph1 does not affect the chronological lifespan of yeast as does its homolog Gis1. However, deleting or overexpressing RPH1 has effects on the response to rapamycin and caffeine, inhibitors of the evolutionary conserved TORC1 complex affecting lifespan in both yeast and mammals.

Aberrant DNA synthesis and maintenance have been implicated in numerous human diseases. I describe here a novel strategy for systematically identifying budding yeast mutants with elevated levels of DNA damage foci, which represent hubs of DNA damage and repair. A previous study manually scored foci in single mutants but was limited in its ability to survey many conditions in large populations. I developed an automated and statistically robust method for identifying aberrant foci phenotypes by combining synthetic genetic array (SGA) and high-content screening (HCS) methodology. Using this approach, I scored thousands of essential and non-essential gene mutants subjected to environmental and genetic perturbations, including the DNA damaging agent, phleomycin, and deletions of DNA repair genes, SGS1 and YKU80. Collectively, I identified a functionally enriched set of 367 mutants that had increased frequencies of DNA damage foci and established SGA-HCS as a powerful tool for investigating the yeast DNA damage response.

Aberrant DNA synthesis and maintenance have been implicated in numerous human diseases. I describe here a novel strategy for systematically identifying budding yeast mutants with elevated levels of DNA damage foci, which represent hubs of DNA damage and repair. A previous study manually scored foci in single mutants but was limited in its ability to survey many conditions in large populations. I developed an automated and statistically robust method for identifying aberrant foci phenotypes by combining synthetic genetic array (SGA) and high-content screening (HCS) methodology. Using this approach, I scored thousands of essential and non-essential gene mutants subjected to environmental and genetic perturbations, including the DNA damaging agent, phleomycin, and deletions of DNA repair genes, SGS1 and YKU80. Collectively, I identified a functionally enriched set of 367 mutants that had increased frequencies of DNA damage foci and established SGA-HCS as a powerful tool for investigating the yeast DNA damage response.

Structural changes in society have often been related to social problems such as crime, alcoholism and social elimination. In this analysis of the development of social elimination in Sweden during the period 1860-1975, which is mainly based on official data, it is demonstrated that there is not always a causal relationship between structural change and such social problems. If structural changes lead to social problems or not depend on whether the structural changes occur according to a "Budding" or an "Ex­pansion" model. The historical period in which a rapid structural change followed the "Budding" model closely was the time right before and after the turn of the century in which the final leap into the industrial society occured. This was a period characterized by an increasing number of industries, communities and organizations. During this period the structural changes increased the legal economic opportunities, strengthened the social and cultural integration as well as the informal social control within the working class. This period was also a period with decreasing human malad­justment symptoms and social elimination. After World War II a new period of rapid structural changes occured. But now the development followed closely to the "Expansion" model. This was a period when different subsystems in society became larger, more centra­lized specialized and difficult to survey. The consequences were not only more individual freedom and higher standards of living but also many individuals experienced a great deal of social stress together with a decreasing social and cultural integration. Increasing opportunities for crime and drugs to­gether with a decreasing social control increased the risks for social mal­adjustment for many people. This latter period can also be described as a period of rapidly increasing human maladjustment symptoms and increasing social elimination of the socially maladjusted. / digitalisering@umu