The system-biological GLOBE 3D Genome Platform.

Genomes are tremendous co-evolutionary holistic systems for molecular storage, processing and fabrication of information. Their system-biological complexity remains, however, still largely mysterious, despite immense sequencing achievements and huge advances in the understanding of the general sequential, three-dimensional and regulatory organization. Here, we present the GLOBE 3D Genome Platform a completely novel grid based virtual “paper” tool and in fact the first system-biological genome browser integrating the holistic complexity of genomes in a single easy comprehensible platform: Based on a detailed study of biophysical and IT requirements, every architectural level from sequence to morphology of one or several genomes can be approached in a real and in a symbolic representation simultaneously and navigated by continuous scale-free zooming within a unique three-dimensional OpenGL and grid driven environment. In principle an unlimited number of multi-dimensional data sets can be visualized, customized in terms of arrangement, shape, colour, and texture etc. as well as accessed and annotated individually or in groups using internal or external data bases/facilities. Any information can be searched and correlated by importing or calculating simple relations in real-time using grid resources. A general correlation and application platform for more complex correlative analysis and a front-end for system-biological simulations both using again the huge capabilities of grid infrastructures is currently under development. Hence, the GLOBE 3D Genome Platform is an example of a grid based approach towards a virtual desktop for genomic work combining the three fundamental distributed resources: i) visual data representation, ii) data access and management, and iii) data analysis and creation. Thus, the GLOBE 3D Genome Platform is the novel system-biology oriented information system urgently needed to access, present, annotate, and to simulate the holistic genome complexity in a unique gateway towards a real understanding, educative presentation and curative manipulation planning of this tremendous evolutionary information grail – genomes

Visualization, analysis, and design of COMBO-FISH probes in the grid-based GLOBE 3D genome platform

The genome architecture in cell nuclei plays an important role in modern microscopy for the monitoring of medical diagnosis and therapy since changes of function and dynamics of genes are interlinked with changing geometrical parameters. The planning of corresponding diagnostic experiments and their imaging is a complex and often interactive IT intensive challenge and thus makes high-performance grids a necessity. To detect genetic changes we recently developed a new form of fluorescence in situ hybridization (FISH) - COMBinatorial Oligonucleotide FISH (COMBO-FISH) - which labels small nucleotide sequences clustering at a desired genomic location. To achieve a unique hybridization spot other side clusters have to be excluded. Therefore, we have designed an interactive pipeline using the grid-based GLOBE 3D Genome Viewer and Platform to design and display different labelling variants of candidate probe sets. Thus, we have created a grid-based virtual "paper" tool for easy interactive calculation, analysis, management, and representation for COMBO-FISH probe design with many an advantage: Since all the calculations and analysis run in a grid, one can instantly and with great visual ease locate duplications of gene subsequences to guide the elimination of side clustering sequences during the probe design process, as well as get at least an impression of the 3D architectural embedding of the respecti

Systems Biological Determination of the Epi-Genomic Structure Function Relation:

Despite our knowledge of the sequence of the human genome, the relation of its three-dimensional dynamic architecture with its function – the storage and expression of genetic information – remains one of the central unresolved issues of our age. It became very clear meanwhile that this link is crucial for the entire holistic function of the genome on all genomic coding levels from the DNA sequence to the entire chromosomes. To fulfil the dreams for better diagnostics and treatment in the 21st century (e.g. by gene therapy by inserting a gene into a new global context), we propose here in a unique interdisciplinary project to combine experiment with theory to analyze the (epi-)genomic structure function relationships within the dynamic organization of the -Globin locus, the Immuno Globin loci, and the Tumor Necrosis Factor Alpha regulated SAMD4 region in mouse and human active and inactive cell states, and their global genomic context. The project consists of five work packages (WP1-WP5) and corresponding tasks connected in a system biological approach with iterative use of data, modelling, simulation and experiments via a unique data sharing and visualization platform: In WP1 (Längst, Rippe, Wedemann, Knoch/Grosfeld; T1-T5) to investigate nucleosomal association changes in relation to the DNA sequence and the activity of ATP-driven chromatin remodelling complexes, nucleosome positions will be determined by high-throughput sequencing. The resulting nucleosomal localization probability maps will be evaluated by a novel combination of analysis tools and innovative generic data ontologies. The relation to epigenetic modifications, to the activity of ATP-driven remodelling complexes and compaction degree of nucleosomes will be analysed to understand chromatin morphogenesis and fiber formation. In parallel, in WP2 (Grosveld/Knoch, Cook, Rippe, Längst; T1-T3) we determine by high-throughput monitoring of intra/inter chromosomal contacts and architecture absolute DNA-DNA interaction probability maps for the individual loci and their global context using a novel chromosome conformation capture approach based on deep sequencing. From these the 3D conformation of the chromatin fiber and its higher-order folding into loops and loop clusters can be derived using algorithms recently developed by us. WP3 (Cook, Grosveld/Knoch, Längst; T1-T5) focuses on the determination of transcription rates and structure by qRT-PCR, DNA and RNA fluorescence in situ hybridization using intronic probes and high-resolution laser-scanning and single molecule imaging with advanced image analysis tools. Transcription-dependent changes of active and inactive loci as well as rapid synchronous transcription alteration against the unchanged background is one main interest here. This will yield results in a detailed cartography of the structure-transcription-function dependency and its importance. To rationalize the experimental results theoretically, in WP4 (Wedemann Knoch/Grosveld, Rippe; T1-T3) simulations are made of nucleosomal structure, chromatin fiber conformation and chromosomal architecture using parallel and grid super-computers with ~10.000 CPUs. The impact of different nucleosomal positions and epigenetic modifications on the nucleosomal structure and the chromatin fiber conformation will be assessed by novel Monte Carlo approaches. To understand the higher-order architecture Brownian Dynamics simulations of entire cell nuclei with molecular re

e-Human Grid Ecology: Understanding and approaching the Inverse Tragedy of the Commons in the e-Grid Society.

With ever-new technologies emerging also the amount of information to be stored and processed is growing exponentially and is believed to be always at the limit. In contrast, however, huge resources are available in the IT sector alike e.g. the renewable energy sector, which are often even not at all used. This under-usage bares any rational especially in the IT sector where e.g. virtualisation and grid approaches could be fast implemented due to the great technical and fast turnover opportunities. Here, we describe this obvious paradox for the first time as the Inverse Tragedy of the Commons, in contrast to the Classical Tragedy of the Commons where resources are overexploited. From this perspective the grid IT sector attempting to share resources for better efficiency, reveals two challenges leading to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Thus, the challenges of grid implementation are similar to those of e.g. climate protection. This is well described by the classic Human Ecology triangle and our extension to a rectangle: environment-individual-society-environment. Extension of this classical interdisciplinary field of basic and applied research to an e-Human Grid Ecology rational, allows the Inverse Tragedy of the Commons of the grid sector to be understood and approached better and implies obvious guidelines in the day-to-day management for grid and other (networked) resources, which is of importance for many fields with similar paradoxes as in (e-)society

Large-scale resource sharing at public funded organizations. e-Human "Grid" Ecology.

With ever-new technologies emerging also the amount of information to be stored and processed is growing exponentially and is believed to be always at the limit. In contrast, however, huge resources are available in the IT sector alike e.g. the renewable energy sector, which are often even not at all used. This under-usage bares any rational especially in the IT sector where e.g. virtualisation and grid approaches could be fast implemented due to the great technical and fast turnover opportunities. Here, we describe this obvious paradox for the first time as the Inverse Tragedy of the Commons, in contrast to the Classical Tragedy of the Commons where resources are overexploited. From this perspective the grid IT sector attempting to share resources for better efficiency, reveals two challenges leading to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Thus, the challenges of grid implementation are similar to those of e.g. climate protection. This is well described by the classic Human Ecology triangle and our extension to a rectangle: environment-individual-society-environment. Extension of this classical interdisciplinary field of basic and applied research to an e-Human Grid Ecology rational, allows the Inverse Tragedy of the Commons of the grid sector to be understood and approached better and implies obvious guidelines in the day-to-day management for grid and other (networked) resources, which is of importance for many fields with similar paradoxes as in (e-)society

Large-scale resource sharing at public funded organizations. e-Human "Grid" Ecology.

With ever-new technologies emerging also the amount of information to be stored and processed is growing exponentially and is believed to be always at the limit. In contrast, however, huge resources are available in the IT sector alike e.g. the renewable energy sector, which are often even not at all used. This under-usage bares any rational especially in the IT sector where e.g. virtualisation and grid approaches could be fast implemented due to the great technical and fast turnover opportunities. Here, we describe this obvious paradox for the first time as the Inverse Tragedy of the Commons, in contrast to the Classical Tragedy of the Commons where resources are overexploited. From this perspective the grid IT sector attempting to share resources for better efficiency, reveals two challenges leading to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Thus, the challenges of grid implementation are similar to those of e.g. climate protection. This is well described by the classic Human Ecology triangle and our extension to a rectangle: environment-individual-society-environment. Extension of this classical interdisciplinary field of basic and applied research to an e-Human Grid Ecology rational, allows the Inverse Tragedy of the Commons of the grid sector to be understood and approached better and implies obvious guidelines in the day-to-day management for grid and other (networked) resources, which is of importance for many fields with similar paradoxes as in (e-)society

The Erasmus Computing Grid – Building a Super-Computer for Free

Today advances in scientific research as well as clinical diagnostics and treatment are inevitably connected with information solutions concerning computation power and information storage. The needs for information technology are enormous and are in many cases the limiting factor for new scientific results or clinical diagnostics and treatment. At the Hogeschool Rotterdam and the Erasmus MC there is a massive need for computation power on a scale of 10,000 to 15,000 computers equivalent to ~20 to ~30 Tflops (1012 floating point operations per second) for a variety of work areas ranging from e.g. MRI and CT scan and microscopic image anlysis to DNA sequence analysis, protein and other structural simulations and analysis. Both institutions have already 13,000 computers, i.e. ~18 Tflops of computer power, available! To make the needed computer power accessible, we started to build the Erasmus Computing Grid (ECG), which is connecting local computers in each institution via central management systems. The system guaranties security and any privacy rules through the used software as well as through our set-up and a NAN and ISO certification process being under way. Similar systems run already world-wide on entire institutions including secured environments like government institutions or banks. Currently, the ECG has a computational power of ~5 Tflops and is one of or already the largest desktop grid in the world. At the Hogeschool Rotterdam meanwhile all computers were included in the ECG. Currently, 10 departments with ~15 projects at the Erasmus MC depend on using the ECG and are preparing or prepared their analysis programs or are already in production state. The Erasmus Computing Grid office and an advisory and control board were set-up. To sustain the ECG now further infrastructure measures have to be taken. Central hardware and specialist personal needs to be put in place for capacity, security and usability reasons for the application at Erasmus MC. This is also necessary in respect to NAN and ISO certification towards diagnostic and commercial ECG use, for which there is great need and potential. Beyond the link to the Dutch BigGrid Initiative and the German MediGRID should be prepared for and realized due to the great interest for cooperation. There is also big political interest from the government to relieve the pressure on computational needs in The Netherlands and to strengthen the Dutch position in the field of high performance computing. In both fields the ECG should be brought into a leading position by establishing the Erasmus MC a centre of excellence for high-performance computing in the medical field in respect to Europe and world-wide. Consequently, we successfully started to build a super-computer at the Hogeschool Rotterdam and Erasmus MC with great opportunities for scientific research, clinical diagnostics and research as well as student training. This will put both institutions in the position to play a major world-wide role in high-performance computing. This will open entire new possibilities for both institutions in terms of recognition and new funding possibilities and is of major importance for The Netherlands and the EU

Production-Grid: Task-Farming in D-Grid

Die D-Grid Initiative stellt Bundesweit derzeit >30.000 Rechencores insgesamt 36 Community-Projekten zur Verfügung. Insgesamt wurden bisher in 3 „Calls“ und mehreren Infrastruktursonderinvestitionen ca. 134 Millionen Euro investiert. Auf den Resourcen laufen mehrere sogenannte Middlewares. Die Auslastung der Ressourcen die mithilfe der Middleware Globus benutzt werden (~70% der total installierten Leistung) beträgt praktisch mittlerweile 100%. Im wesentlichen nutzen zwei Usecases diese Resourcen zu ca. 98%: Im astrophysikalischen Bereich sind dies Gravitationswellenanalysen mittels der einstein@home-Jobs vom Max-Planck-Institut für Gravitationsphysik Albert-Einstein-Institut (AEI) und sowie Genomanalysen der Biophysikalischen Genomik, BioQuant/DKFZ. Beide nehmen derzeit mehr als 150.000 CPU-Stunden auf den Globus-Ressourcen im D-Grid auf. Vom wissenschaftlichen Standpunkt sind diese Rechnungen und Analysen von großer Bedeutung wie sich an der ansteigenden Zahl an Publikationen zeigt. Hinter den zwei hierbei verwendeten Nutzerkennungen verbergen sich dabei mehrere Nutzer die durch A. Beck-Ratzka und T. A. Knoch in Kooperationsprojekten gebündelt sind, die entweder einzelne Applikationen und/oder ganze Pipelinesysteme benutzen. Dazu gehören auch Nutzer die u.a. in nationalen, europäischen bzw. internationalen Konsortien für den Informatikpart zuständig sind. Im astrophysikalischen Fall handelt es sich dabei um 10 Nutzer/Projekte, im biomedizinischen Fall sind dies international mittlerweile ca. 200 Nutzer/Projekte (180 hierbei durch die Nutzung einer sog. Assoziation Pipeline, die von äußerst wichtiger diagnostischer Relevanz ist). Die Stärkung des Standorts Deutschland durch die erfolgreiche Nutzung im Produktionsbetrieb hat einerseits die Machbarkeit einer funktionierenden Grid-Infrastruktur für die Globus Ressourcen-Betreiber gezeigt und andererseits durch die Schaffung wissenschaftlich hoch-relevanter Ergebnisse zu einer damit verbundenen forschungspolitischen Stärkung geführt. Beides kann nicht hoch genug eingeschätzt werden, da beide Usecases vor allem auch im internationalen Vergleich eine herausragende Stellung einehmen – faktisch gehören sie mittlerweile zu den größten Nutzern von Rechenzeit weltweit. Der große Erfolg der zwei Usecases Gravitationswellenanalyse und Genomanalyse hat die Ressourcen bezüglich der Globus basierten Infrastruktur zu nahezu 100% ausgeschöpft Er basiert auf unabhängig voneinander entwickelten Komponenten, welche die Middleware in eine produktive Umgebung integrieren, und damit ein Produktionsgrid erst ermöglichen. Dies ist einzigartig im D-Grid-Umfeld. Die Personalkapatzität von A. Beck-Ratzka und T. A. Knoch sind aufgrund der Unterstützungsanforderungen von weiteren/neuen Nutzern zu 100% ausgereizt. Folglich stoßen wir in Bezug auf i) Rechenzeit für unsere eigenen Projekte sowie die neuer Nutzer, ii) die Unterstützung und Anwerbung neuer Nutzer, sowie iii) entsprechenden Unterstützung beim Management in Hinblick auf Daten Sicherheits/Vertraulichkeit, SLAs und Coaching, an die Grenze unserer bisher existierenden Möglichkeiten. Die entsprechende Projektanforderungen bezüglich Rechenleistung sind klar durch die entsprechenden Projekterfolge gegeben, d.h. dass über die Laufzeit der D-Grid Infrastruktur bis 2014 massive Anforderungen über den bisher für uns zugänglichen Rahmen hinaus bestehen. Anfragen von neuen Nutzer gibt es von 10 weiteren im astrophysikalischen (Berliner Raum) und 50-60 weiteren im biomedizinischen Bereich (Raum Heidelberg), die uns als verläßliche bzw. erfahrene Garanten für erfolgreiche Hoch-Durchsatz Gridnutzung ansehen, aber entsprechende Unterstützung brauchen. Zusätzlich gibt es auch Anfragen von mehreren nationalen und internationalen Verbünden, die genau solche Komponenten wie die unsrigen sofort benutzen würden. Darüberhinaus besteht in diesem Zusammenhang der Bedarf an weiteren Lösungen im Datensicherheits- und Vertraulichkeits-Bereich, die durch diese Bereiche konkret angefordert werden, was mit entsprechendem Coaching und Management einhergehen muss und immer wieder von uns eingefordert wird. Wir sind fest davon überzeugt, dass mit dem im folgenden beschriebenen Vorschlag nicht nur diese Flaschenhälse beseitigt werden können, sondern auch die Nachhaltigeit und damit der Erfolg des gesamten D-Grid Projektes massiv gestärkt werden kann! Ein weiterer Aspekt der produktiven Usecases ist, dass erst mit diesen die Grid-Ressourcen richtig für den Produktionsbetrieb getestet werden können. Die Problematik im DGUS-Ticket 853 beispielsweise ist ein Problem, dass erst durch produktive Usecases aufgedeckt wird Die Globus basierten Grid-Ressourcen im D-Grid sind durch die beiden produktiven Usecases Gravitationswellenanalyse und Genomanalyse stabiler geworden. Durch die in im Rahmen dieses Projektes geplante Erweiterung der Usecases auf gLite- und Unicore-Ressourcen würden auch die Betreiber dieser Ressourcen enorm profitieren, weil es damit auf diesen Ressourcen zu einem Produktionsbetrieb kommen würde

DNA Sequence Patterns – A Successful Example of Grid Computing in Genome Research and Building Virtual Super-Computers for the Research Commons of e-Societies

The amount of information is growing exponentially with ever-new technologies emerging and is believed to be always at the limit. In contrast, huge resources are obviously available, which are underused in the IT sector, similar as e.g. in the renewable energy sector. Genome research is one of the boosting areas, which needs an extreme amount of IT resources to analyse the sequential organization of genomes, i.e. the relations between distant base pairs and regions within sequences, and its connection to the three-dimensional organization of genomes, which is still a largely unresolved problem. The underusage of resources as those accessible by grid with its fast turnover rates is very astonishing considering the barriers for further development put forward by the inability to satisfy the need for such resources. The phenomenon is a typical example of the Inverse Tragedy of the Commons, i.e. resources are underexploited in contrast to the unsustainable and destructing overexploitation in the Classic Tragedy of the Commons. An analysis of IT and the grid sector which attempts to share resources for better usage efficiency, reveals two challenges, which lead to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Consequently, the challenges of grid implementation are similar to those of other pressing global issues as e.g. climate protection. This is well described by extending the Human Ecology triangle to a rectangle: invironment-individual-society-environment. By applying this extension of this classical field of interdisciplinary basic and applied research to the grid sector, i.e. by further extension to an e-Human Grid Ecology rational, the Grid Inverse Tragedy of the Commons can be understood and approached regarding the internalization challenge into e-Society and e-Life, from which then guidelines for the day-to-day management can be derived. This is of general importance for many complex fields and thus with similar paradoxes and challenges. By using grid Long-range power-law correlations were found using correlation analysis on almost the entire observable scale of 132 completely sequenced chromosomes of 0.5x106 to 3.0x107 bp from Archaea, Bacteria, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. The local correlation coeffi