Parallel high-performance grid computing: Capabilities and opportunities of a novel demanding service and business class allowing highest resource efficiency

Especially in the life-science and the health-care sectors the huge IT requirements are imminent due to the large and complex systems to be analysed and simulated. Grid infrastructures play here a rapidly increasing role for research, diagnostics, and treatment, since they provide the necessary large-scale resources efficiently. Whereas grids were first used for huge number crunching of trivially parallelizable problems, increasingly parallel high-performance computing is required. Here, we show for the prime example of molecular dynamic simulations how the presence of large grid clusters including very fast network interconnects within grid infrastructures allows now parallel high-performance grid computing efficiently and thus combines the benefits of dedicated super-computing centres and grid infrastructures. The demands for this service class are the highest since the user group has very heterogeneous requirements: i) two to many thousands of CPUs, ii) different memory architectures, iii) huge storage capabilities, and iv) fast communication via network interconnects, are all needed in different combinations and must be considered in a highly dedicated manner to reach highest performance efficiency. Beyond, advanced and dedicated i) interaction with users, ii) the management of jobs, iii) accounting, and iv) billing, not only combines classic with parallel high-performance grid usage, but more importantly is also able to increase the efficiency of IT resource providers. Consequently, the mere "yes-we- can" becomes a huge opportunity like e.g. the life-science and health-care sectors as well as grid infrastructures by reaching higher level of resource efficiency

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

Are Metastases from Metastases Clinical Relevant? Computer Modelling of Cancer Spread in a Case of Hepatocellular Carcinoma

Background: Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. Methods: The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. Results: The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient’s death. Conclusion: The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e.

Modeling DNA Structure, Elasticity and Deformations at the Base-pair Level

We present a generic model for DNA at the base-pair level. We use a variant of the Gay-Berne potential to represent the stacking energy between neighboring base-pairs. The sugar-phosphate backbones are taken into account by semi-rigid harmonic springs with a non-zero spring length. The competition of these two interactions and the introduction of a simple geometrical constraint leads to a stacked right-handed B-DNA-like conformation. The mapping of the presented model to the Marko-Siggia and the Stack-of-Plates model enables us to optimize the free model parameters so as to reproduce the experimentally known observables such as persistence lengths, mean and mean squared base-pair step parameters. For the optimized model parameters we measured the critical force where the transition from B- to S-DNA occurs to be approximately $140{pN}$. We observe an overstretched S-DNA conformation with highly inclined bases that partially preserves the stacking of successive base-pairs.Comment: 15 pages, 25 figures. submitted to PR

Can visco-elastic phase separation, macromolecular crowding and colloidal physics explain nuclear organisation?

BACKGROUND: The cell nucleus is highly compartmentalized with well-defined domains, it is not well understood how this nuclear order is maintained. Many scientists are fascinated by the different set of structures observed in the nucleus to attribute functions to them. In order to distinguish functional compartments from non-functional aggregates, I believe is important to investigate the biophysical nature of nuclear organisation. RESULTS: The various nuclear compartments can be divided broadly as chromatin or protein and/or RNA based, and they have very different dynamic properties. The chromatin compartment displays a slow, constrained diffusional motion. On the other hand, the protein/RNA compartment is very dynamic. Physical systems with dynamical asymmetry go to viscoelastic phase separation. This phase separation phenomenon leads to the formation of a long-lived interaction network of slow components (chromatin) scattered within domains rich in fast components (protein/RNA). Moreover, the nucleus is packed with macromolecules in the order of 300 mg/ml. This high concentration of macromolecules produces volume exclusion effects that enhance attractive interactions between macromolecules, known as macromolecular crowding, which favours the formation of compartments. In this paper I hypothesise that nuclear compartmentalization can be explained by viscoelastic phase separation of the dynamically different nuclear components, in combination with macromolecular crowding and the properties of colloidal particles. CONCLUSION: I demonstrate that nuclear structure can satisfy the predictions of this hypothesis. I discuss the functional implications of this phenomenon

Chromatin and epigenetics: current biophysical views

Recent advances in high-throughput sequencing experiments and their theoretical descriptions have determined fast dynamics of the "chromatin and epigenetics" field, with new concepts appearing at high rate. This field includes but is not limited to the study of DNA-protein-RNA interactions, chromatin packing properties at different scales, regulation of gene expression and protein trafficking in the cell nucleus, binding site search in the crowded chromatin environment and modulation of physical interactions by covalent chemical modifications of the binding partners. The current special issue does not pretend for the full coverage of the field, but it rather aims to capture its development and provide a snapshot of the most recent concepts and approaches. Eighteen open-access articles comprising this issue provide a delicate balance between current theoretical and experimental biophysical approaches to uncover chromatin structure and understand epigenetic regulation, allowing free flow of new ideas and preliminary results

Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model

The role of each histone tail in regulating chromatin structure is elucidated by using a coarse-grained model of an oligonucleosome incorporating flexible histone tails that reproduces the conformational and dynamical properties of chromatin. Specifically, a tailored configurational-bias Monte Carlo method that efficiently samples the possible conformational states of oligonucleosomes yields positional distributions of histone tails around nucleosomes and illuminates the nature of tail/core/DNA interactions at various salt milieus. Analyses indicate that the H4 histone tails are most important in terms of mediating internucleosomal interactions, especially in highly compact chromatin with linker histones, followed by H3, H2A, and H2B tails in decreasing order of importance. In addition to mediating internucleosomal interactions, the H3 histone tails crucially screen the electrostatic repulsion between the entering/exiting DNA linkers. The H2A and H2B tails distribute themselves along the periphery of chromatin fibers and are important for mediating fiber/fiber interactions. A delicate balance between tail-mediated internucleosomal attraction and repulsion among linker DNAs allows the entering/exiting linker DNAs to align perpendicular to each other in linker-histone deficient chromatin, leading to the formation of an irregular zigzag-folded fiber with dominant pair-wise interactions between nucleosomes i and i ± 4