14 research outputs found

    On the role of metaheuristic optimization in bioinformatics

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    Metaheuristic algorithms are employed to solve complex and large-scale optimization problems in many different fields, from transportation and smart cities to finance. This paper discusses how metaheuristic algorithms are being applied to solve different optimization problems in the area of bioinformatics. While the text provides references to many optimization problems in the area, it focuses on those that have attracted more interest from the optimization community. Among the problems analyzed, the paper discusses in more detail the molecular docking problem, the protein structure prediction, phylogenetic inference, and different string problems. In addition, references to other relevant optimization problems are also given, including those related to medical imaging or gene selection for classification. From the previous analysis, the paper generates insights on research opportunities for the Operations Research and Computer Science communities in the field of bioinformatics

    Population-genomic insights into emergence, crop-adaptation, and dissemination of Pseudomonas syringae pathogens

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    This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Many bacterial pathogens are well characterized but, in some cases, relatively little is known about the populations from which they emerged. This limits understanding of the molecular mechanisms underlying disease. The crop pathogen Pseudomonas syringae sensu lato has been widely isolated from the environment, including wild plants and components of the water cycle, and causes disease in several economically important crops. Here, we compared genome sequences of 45 P. syringae crop pathogen outbreak strains with 69 closely related environmental isolates. Phylogenetic reconstruction revealed that crop pathogens emerged many times independently from environmental populations. Unexpectedly, differences in gene content between environmental populations and outbreak strains were minimal with most virulence genes present in both. However, a genome-wide association study identified a small number of genes, including the type III effector genes hopQ1 and hopD1, to be associated with crop pathogens, but not with environmental populations, suggesting that this small group of genes may play an important role in crop disease emergence. Intriguingly, genome-wide analysis of homologous recombination revealed that the locus Psyr 0346, predicted to encode a protein that confers antibiotic resistance, has been frequently exchanged among lineages and thus may contribute to pathogen fitness. Finally, we found that isolates from diseased crops and from components of the water cycle, collected during the same crop disease epidemic, form a single population. This provides the strongest evidence yet that precipitation and irrigation water are an overlooked inoculum source for disease epidemics caused by P. syringae.Caroline L. Monteil received support from INRA and the European Union, in the framework of the Marie-Curie FP7 COFUND People Programme, through the award of an AgreenSkills’ fellowship (under grant agreement n° 267196). Research in Boris A. Vinatzer’s laboratory and genome sequencing was funded by the National Science Foundation of the USA (grants IOS-1354215 and DEB-1241068). Funding for work in the Vinatzer laboratory was also provided in part by the Virginia Agricultural Experiment Station and the Hatch Program of the National Institute of Food and Agriculture, U.S. Department of Agriculture. Work carried out in the Sheppard laboratory was supported by the Medical Research Council (MRC) grant MR/L015080/1, and the Wellcome Trust grant 088786/C/09/Z. GM was supported by a NISCHR Health Research Fellowship (HF-14-13)

    Blueprint: descrição da complexidade da regulação metabólica através da reconstrução de modelos metabólicos e regulatórios integrados

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    Tese de doutoramento em Biomedical EngineeringUm modelo metabólico consegue prever o fenótipo de um organismo. No entanto, estes modelos podem obter previsões incorretas, pois alguns processos metabólicos são controlados por mecanismos reguladores. Assim, várias metodologias foram desenvolvidas para melhorar os modelos metabólicos através da integração de redes regulatórias. Todavia, a reconstrução de modelos regulatórios e metabólicos à escala genómica para diversos organismos apresenta diversos desafios. Neste trabalho, propõe-se o desenvolvimento de diversas ferramentas para a reconstrução e análise de modelos metabólicos e regulatórios à escala genómica. Em primeiro lugar, descreve-se o Biological networks constraint-based In Silico Optimization (BioISO), uma nova ferramenta para auxiliar a curação manual de modelos metabólicos. O BioISO usa um algoritmo de relação recursiva para orientar as previsões de fenótipo. Assim, esta ferramenta pode reduzir o número de artefatos em modelos metabólicos, diminuindo a possibilidade de obter erros durante a fase de curação. Na segunda parte deste trabalho, desenvolveu-se um repositório de redes regulatórias para procariontes que permite suportar a sua integração em modelos metabólicos. O Prokaryotic Transcriptional Regulatory Network Database (ProTReND) inclui diversas ferramentas para extrair e processar informação regulatória de recursos externos. Esta ferramenta contém um sistema de integração de dados que converte dados dispersos de regulação em redes regulatórias integradas. Além disso, o ProTReND dispõe de uma aplicação que permite o acesso total aos dados regulatórios. Finalmente, desenvolveu-se uma ferramenta computacional no MEWpy para simular e analisar modelos regulatórios e metabólicos. Esta ferramenta permite ler um modelo metabólico e/ou rede regulatória, em diversos formatos. Esta estrutura consegue construir um modelo regulatório e metabólico integrado usando as interações regulatórias e as ligações entre genes e proteínas codificadas no modelo metabólico e na rede regulatória. Além disso, esta estrutura suporta vários métodos de previsão de fenótipo implementados especificamente para a análise de modelos regulatórios-metabólicos.Genome-Scale Metabolic (GEM) models can predict the phenotypic behavior of organisms. However, these models can lead to incorrect predictions, as certain metabolic processes are controlled by regulatory mechanisms. Accordingly, many methodologies have been developed to extend the reconstruction and analysis of GEM models via the integration of Transcriptional Regulatory Network (TRN)s. Nevertheless, the perspective of reconstructing integrated genome-scale regulatory and metabolic models for diverse prokaryotes is still an open challenge. In this work, we propose several tools to assist the reconstruction and analysis of regulatory and metabolic models. We start by describing BioISO, a novel tool to assist the manual curation of GEM models. BioISO uses a recursive relation-like algorithm and Flux Balance Analysis (FBA) to evaluate and guide debugging of in silico phenotype predictions. Hence, this tool can reduce the number of artifacts in GEM models, decreasing the burdens of model refinement and curation. A state-of-the-art repository of TRNs for prokaryotes was implemented to support the reconstruction and integration of TRNs into GEM models. The ProTReND repository comprehends several tools to extract and process regulatory information available in several resources. More importantly, this repository contains a data integration system to unify the regulatory data into standardized TRNs at the genome scale. In addition, ProTReND contains a web application with full access to the regulatory data. Finally, we have developed a new modeling framework to define, simulate and analyze GEnome-scale Regulatory and Metabolic (GERM) models in MEWpy. The GERM model framework can read a GEM model, as well as a TRN from different file formats. This framework assembles a GERM model using the regulatory interactions and Genes-Proteins-Reactions (GPR) rules encoded into the GEM model and TRN. In addition, this modeling framework supports several methods of phenotype prediction designed for regulatory-metabolic models.I would like to thank Fundação para a Ciência e Tecnologia for the Ph.D. studentship I was awarded with (SFRH/BD/139198/2018)

    Immunity-related GTPases (IRGs) in the house mouse and the parasite Toxoplasma gondii in South America

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    "The Immunity-related GTPases (IRGs) are IFNγ-inducible genes essential for resistance against intracellular pathogens in the house mouse. In some wild-derived house mice, such as the Eurasian mice CIM strain, polymorphic IRG genes have been linked to the control of virulent strains of the intracellular parasite Toxoplasma gondii. The house mouse (Mus musculus domesticus) arrived in the Americas on the first European vessels in the 16th century, but they had never encountered infections with the highly virulent T. gondii strains present in South America.(...)"Instituto Gulbenkian de Ciência, Fundação Calouste Gulbenkia

    Biology And Phylogeny Of The Cassidinae Gyllenhal Sensu Lato (Tortoise And Leaf-Mining Beetles) (Coleoptera: Chrysomelidae)

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    A parsimony analysis was undertaken to test subfamily and tribal group concepts of Cassidinae (ca. 2000 genera, ca. 6000 species). An integrated account of their biology was synthesized from the primary literature. A detailed morphological study of adults, using Hemisphaerota palmarum Boheman as a model, formed the basis for evaluating characters previously utilized and for defining novel characters. The data matrix comprised 210 characters (from adults and immature stages, ecology and behavior), 6 outgroups, and 98 ingroup exemplar species (representing 94 genera and 39 of the 43 recognized cassidine tribes). Results support the monophyly of Cassidinae and place it as sister to Galerucinae. The classical Hispinae s.str. is paraphyletic whereas the classical Cassidinae s.str. is monophyletic if some Imatidiine genera are included. Four tribes—Aproidini, Delocraniini, Hemisphaerotini, and Notosacanthini—are well supported by many autapomorphies. Multiple genera were sampled to test the monophyly of 14 cassidine tribes. Seven were recovered as monophyletic: Anisoderini, Cassidini, Dorynotini, Eugenysini, Hispini, Omocerini, and Spilophorini. Relationships and character support of all cassidine tribes are discussed and compared with phylogenies proposed by Borowiec (1995) and Hsiao and Windsor (1999). The biological account and these phylogenetic results provide an opportunity for identifying some general trends and major innovations in the evolutionary history of Cassidinae. The alteration of the adult head from prognathy to hypognathy and the compaction of the body, legs, and various elytral-locking mechanisms are recurrent themes in adult morphology. Maternal care may have arisen once or twice. Seven trophic guilds are defined here for Cassidine larvae. They arise from two large radiations of leaf-mining and exophagous-feeding, a minor radiation in cryptic rolled-leaf feeding, and small generic and sub-generic specializations in stem mining, leaf scraping, petalophagy, and leaf-shelter chewers. Fecal shield construction and retention appear to be correlated with innovations in life history and in larval and pupal morphology, and they may have played an important role in cassidine diversification

    Genome evolution and systems biology in bacterial endosymbionts of insects

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    Gene loss is the most important event in the process of genome reduction that appears associated with bacterial endosymbionts of insects. These small genomes were derived features evolved from ancestral prokaryotes with larger genome sizes, consequence of a massive process of genome reduction due to drastic changes in the ecological conditions and evolutionary pressures acting on these prokaryotic lineages during their ecological transition to host-dependent lifestyle. In the present thesis, the process of genome reduction is studied from different perspectives. In the first chapter, genome rearrangements have been studied in a set of 31 complete γ-proteobacterial genomes that includes five genomes of bacterial endosymbionts of insects. This is carried out by comparing the order of a subset of 244 single-copy orthologous genes presents in all the genomes and calculating the number of inversions and breakpoints between each genome pair. This reveals that inversions were the main rearrangement event in γ-proteobacteria evolution, with a progressive increase in the number of rearrangements with increased evolutionary distance. However, significant heterogeneity in different γ-proteobacterial lineages was also detected, with a significant acceleration in the rates of genome rearrangements in bacterial endosymbionts of insects at initial stages of the association. In the second chapter, the structure and functional capabilities of Sodalis glossinidius has been studied. S. glossinidius is the secondary endosymbiont of tsetse flies, and it´s at very initial stages of genome reduction process. It´s genome is experiencing a massive process of gene inactivation, with 972 pseudogenes (inactivated genes) that were described but not annotated in the original annotation of the genome. In this chapter, a complete functional re-annotation of this genome was carried out, that includes the characterization of 1501 pseudogenes though analysis of S. glossinidius intergenic regions. A massive presence of CDSs related with mobile genetic elements and surface proteins were detected, being also the functional classes most affected by pseudogenization. The reconstruction of the metabolic map of S. glossinidius revealed a functional profile very similar to that of free-living enterics, with inactivation of L-arginine biosynthesis pathway, whereas the comparison with Wigglesworthia glossinidia (tsetse primary endosymbiont) reveals possible cases of metabolic complementation between both tsetse endosymbionts at thiamine, coenzyme A and tetrahydrofolate biosynthesis level. Finally, in the third chapter of the thesis, the complete reductive evolution process associated with S. glossinidius was studied from a systems biology perspective through the reconstruction of their genome-scale metabolic networks at different stages of this process and the prediction of their internal reaction fluxes under different external conditions through Flux Balance Analysis. This revealed the decisive role of the pseudogenization of genes involved in L-arginine and glycogen biosynthesis and specially the pseudogenization of the key anaplerotic enzyme phosphoenolpyruvate carboxylase in the ecological transition to a host-dependent lifestyle experienced by S. glossinidius. A progressive decrease in network robustness to gene deletion events and to changes in particular reaction fluxes were detected. Finally, reductive evolution simulations over the functional network of S. glossinidius under different external conditions revealed a higher plasticity in minimal networks evolved in a nutrient-rich environment, and allow defining different sets of essential and disposable genes based on their presence or absence in minimal metabolic networks. These essential genes had more optimized patterns of codon usage and more restricted patterns of sequence evolution than disposable genes that could be lost without affecting the functionality of the network. However, lineage-specific estimates of dN and dS in S. glossinidius and Escherichia coli revealed that common features of ancient bacterial endosymbionts like acceleration in the rates of sequence evolution and the loss of adaptative codon usage were starting to affect S. glossinidius evolution.En esta tesis doctoral, el proceso de reducción genómica característico de bacterias endosimbiontes de insectos ha sido estudiado utilizando diferentes aproximaciones computacionales basadas en la genómica comparada y la biología de sistemas. Por un lado, las dinámicas de reordenaciones genómicas han sido estudiadas en un subconjunto de 31 genomas completos de γ-proteobacterias que incluyen 5 genomas completos de endosimbiontes bacterianos de insectos, revelando una aceleración significativa de las tasas de reordenaciones en estos genomas en etapas iniciales del proceso de reducción. Posteriormente, el genoma de Sodalis glossinidius, el endosimbionte secundario de la mosca tsétsé, fue re-anotado con el objetivo de evaluar el impacto de los procesos de inactivación génica y proliferación de elementos genéticos móviles en etapas tempranas del proceso de reducción, asi como su impacto sobre las capacidades funcionales de la bacteria en el contexto ecológico de su coexistencia con el endosimbionte primario ancestral Wigglesworthia glossinidia. Finalmente, el proceso completo de reducción genómica en S. glossinidius ha sido estudiado a través de la reconstrucción de su red metabólica a diferentes etapas de este proceso y su análisis funcional mediante Análisis de Balance de Flujos, evaluando la robustez de las redes frente a sucesos de deleción asi como las dinámicas evolutivas de genes esenciales y no esenciales en base a su presencia en redes mínimas evolucionadas a partir de la red funcional. Este análisis permitió identificar sucesos de inactivación génica con efectos drásticos sobre las capacidades funcionales del sistema como los genes implicados en la biosíntesis de arginina y glicógeno, y especialmente la inactivación de la enzima fosfoenolpiruvato carboxilasa, asi como una disminución progresiva de la robustez de las redes frente a diferentes sucesos mutacionales asociada al proceso de pérdida génica. Finalmente, simulaciones de evolución reductiva sobre la red funcional bajo diferentes condiciones de entorno ha permitido definir conjuntos de genes esenciales y delecionables en base a su presencia o ausencia en las redes mínimas producto de las simulaciones, revelando una mayor conservación a nivel de secuencia y un uso de codones más optimizado en genes esenciales frente a genes cuya pérdida no afecta a la funcionalidad del sistema

    Dairy farm Campylobacteraceae

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    Infection with Campylobacter is considered to be the most common bacterial cause of human gastroenteritis worldwide. In light of the dramatic increase of antibiotic resistant bacteria, alternative solutions including biological controls such as bacteriophage therapy and bacteriophage biosanitization are being considered. One way in which campylobacters enter the human food chain is through consumption of contaminated raw milk. An updated study of the ability of campylobacters to survive in milk, including species other than C. jejuni, was carried out. Isolation of bacteriophages from bovine slurry, with potential for biocontrol and therapeutic purposes was attempted using conventional methods. Campylobacter and Arcobacter hosts were isolated and characterised, including genome sequencing, from the same environment. The method used for this purpose was proven efficacious for porcine slurry; however, no lytic phage were isolated from bovine samples. During the isolation experiments unusual plaques were formed on the lawn of the C. hyointestinalis S12 host strain. The causative agent of this lytic activity was found to be due to a new predatory bacterium, which was characterised with respect host range and genome sequence. Phylogenetic analysis placed the new bacterium in the family Oceanospirillaceae and the name Venatorbacter cucullus gen. nov. sp. nov proposed

    One-carbon metabolism in acetogenic and sulfate-reducing bacteria

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    ABSTRACT One-carbon metabolism in acetogenic and sulfate-reducing bacteria Life on earth is sustained by the constant cycling of six essential elements: oxygen, hydrogen, nitrogen, sulfur, phosphorous, and carbon. The continuous cycling of these elements is due to geo-chemical processes and the combined metabolism of all life on earth. Microorganisms like bacteria and archaea play a major role in this. This is also true for the carbon cycle. In this cycle carbon dioxide and methane are two important C-1 compounds present in the atmosphere. Carbon dioxide is the highest oxidative state of carbon while methane is the highest reduced form of carbon. The art to use light to produce organic compounds and conserve energy from the highest oxidative state of carbon is called photosynthesis and is performed by plants, algae and cyanobacteria. Photosynthesis is not the only system to fix carbon from carbon dioxide. Chemolithotrophs can fix carbon from carbon dioxide using inorganic electron donors, like hydrogen. Subsequently, fixed carbon can be used by other organisms, which also makes life possible for them. Microorganisms play a major role in the degradation of complex organic matter, producing smaller compounds including C-1 compounds. C-1 compounds other than carbon dioxide are e.g. carbon monoxide (CO), methanol and formate. Bacteria and archaea can utilize these relative simple compounds in the presence and absence of oxygen, alone and in cooperation with others (syntrophy). The complex and simple carbon compounds are finally oxidized to carbon dioxide, which closes the carbon cycle. In addition to their importance to the carbon cycle, one carbon compounds like CO, methanol and formate are important for several applications. They are used as a building block for the production of chemicals. They are also used for bioremediation purposes and for wastewater treatment. Therefore, it is important to gain insight in the one carbon metabolism of microorganisms. The research described in this thesis focuses on the proteins and encoding genes involved in anaerobic degradation of C1 compounds by using genome and proteome analysis. In Chapter 2 the genomes of two closely related sulfate-reducing bacteria, Desulfotomaculum nigrificans and D. nigrificans strain CO-1-SRB, are compared including their CO metabolism. Both the D. nigrificans type strain and strain CO-1-SRB can grow with CO. However, there are differences. The type strain can grow with 20% CO coupled to sulfate reduction in the presence of yeast extract, while strain CO-1-SRB can grow with 100% CO in the presence of yeast extract. Moreover, strain CO-1-SRB can grow with CO in the presence and absence of sulfate. It couples the oxidation of CO to carbon dioxide to hydrogen production. This conversion, the protein complex involved, and the genes coding for these proteins have been described before in other microorganisms. The genome of strain CO-1-SRB contains the genes coding for this protein complex while the genome of the D. nigrificans type strain does not. However, the genome of the type strain contains genes encoding two other CO dehydrogenases. This indicates that one or both are necessary for the type strain to grow with 20% CO. Additional research on the different CO dehydrogenases and their regulation is essential to assess if all different CO dehydrogenases can facilitate growth and how they are linked to for example creating a proton motive force for ATP production. The methanol metabolism of anaerobic bacteria seems to differ more from that of methanogens than initially described. Methanogens use a methanol methyltransferase system that consists of two methyltranferases, methyltransferase 1 (subunits MtaB and MtaC) and methyltransferase 2 (MtaA). The methyl group from methanol is transferred to the MtaC subunit by MtaB. Subsequently, MtaA transports the methyl group from MtaC to coenzyme M. A genome and proteome analysis of the acetogenic bacterium Sporomusa strain An4 suggests that instead of MtaA a methyl-tetrahydrofolate methyltransferase is involved in the transport of the methyl bound to MtaC to tetrahydrofolate (Chapter 3). Research done on the methanol metabolism of the sulfate-reducing bacterium Desulfotomaculum kuznetsovii also shows differences with that of methanogens (Chapter 5). The methanol methyltransferase system is vitamin B12 and cobalt dependent. D. kuznetsovii grows with methanol and sulfate, but can do this in presence and absence of vitamin B12 and cobalt. In the absence of vitamin B12 and cobalt D. kuznetsovii grows slower and reaches a lower optical density compared to growth in the presence of vitamin B12 and cobalt. This suggests that D. kuznetsovii can use both a methyltransferase system and a vitamin B12 and cobalt independent system for the degradation of methanol. Proteome results confirm this and suggest that the vitamin B12 and cobalt independent system consists of an alcohol dehydrogenase and an aldehyde ferredoxin oxidoreductase. Moreover, the alcohol dehydrogenase seems to be involved in the oxidation of both methanol and ethanol (Chapter 5). The presence of two methanol degradation pathways give an ecological advantage to D. kuznetsovii in environments containing methanol and sulfate but limiting cobalt and vitamin B12 concentrations. Future research should elucidate if more sulfate-reducing bacteria, or perhaps even acetogenic bacteria, have two methanol degrading pathways. Additional to the genome analysis of D. kuznetsovii to assess the genes coding for the proteins involved in the two methanol degradation pathways, the genome was also analyzed to assess genes encoding other degradation pathways (Chapter 4). This analysis shows many genes present in D. kuznetsovii are also present in Pelotomaculum thermopropionicum. P. thermopropionicum is known to degrade propionate in syntrophic interaction with a methanogen. D. kuznetsovii can also degrade propionate, but only coupled to sulfate reduction and not in syntrophy with methanogens. Moreover, P. thermopropionicum is not able to reduce sulfate. D. kuznetsovii is the only close related, non-syntrophic, propionate degrader of which the genome is available. Therefore, a genome comparison was performed between D. kuznetsovii and P. thermopropionicum to define the differences between a non-syntrophic and a syntrophic lifestyle. D. kuznetsovii misses membrane bound protein complexes like hydrogenases and an extra-cytoplasmic formate dehydrogenase. In order to expand the analysis between non-syntrophs and syntrophs, more genomes of propionate- and butyrate-degrading bacteria were included (Chapter 6). This extended analysis shows that the genomes of non-syntrophs do not contain genes coding for an extra-cytoplasmic formate dehydrogenase, in contrast to all syntrophs included in the analysis. This indicates the importance of this protein complex and the importance of formate as an interspecies electron carrier in syntrophic degradation of propionate and butyrate. Thanks to the extra cytoplasmic formate dehydrogenase the syntrophic bacteria can couple the degradation of propionate and butyrate to formate production. Subsequently, the formate is utilized by methanogens to produce methane. This keeps the formate concentration low, which is necessary for the entire process to be energetically favorable. </p

    Dairy farm Campylobacteraceae

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    Infection with Campylobacter is considered to be the most common bacterial cause of human gastroenteritis worldwide. In light of the dramatic increase of antibiotic resistant bacteria, alternative solutions including biological controls such as bacteriophage therapy and bacteriophage biosanitization are being considered. One way in which campylobacters enter the human food chain is through consumption of contaminated raw milk. An updated study of the ability of campylobacters to survive in milk, including species other than C. jejuni, was carried out. Isolation of bacteriophages from bovine slurry, with potential for biocontrol and therapeutic purposes was attempted using conventional methods. Campylobacter and Arcobacter hosts were isolated and characterised, including genome sequencing, from the same environment. The method used for this purpose was proven efficacious for porcine slurry; however, no lytic phage were isolated from bovine samples. During the isolation experiments unusual plaques were formed on the lawn of the C. hyointestinalis S12 host strain. The causative agent of this lytic activity was found to be due to a new predatory bacterium, which was characterised with respect host range and genome sequence. Phylogenetic analysis placed the new bacterium in the family Oceanospirillaceae and the name Venatorbacter cucullus gen. nov. sp. nov proposed

    Using MapReduce Streaming for Distributed Life Simulation on the Cloud

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    Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp
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