Using lambda networks to enhance performance of interactive large simulations

The ability to use a visualisation tool to steer large simulations provides innovative and novel usage scenarios, e.g. the ability to use new algorithms for the computation of free energy profiles along a nanopore [1]. However, we find that the performance of interactive simulations is sensitive to the quality of service of the network with variable latency and packet loss in particular having a detrimental effect The use of dedicated networks (provisioned in this case as a circuit-switched point-to-point optical lightpath or lambda) can lead to significant (50% or more) performance enhancement, When funning on say 128 or 256 processors of a high-end supercomputer this saving has a significant value. We perform experiments to understand the impact of network characteristics on the performance of a large parallel classical molecular dynamics simulation when coupled interactively to a remote visualisation tool. This paper discusses the experiments performed and presents the results from the systematic studies. © 2006 IEEE.Published versio

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate

Large-scale simulations of layered double hydroxide nanocomposite materials

Layered double hydroxides (LDHs) have generated a large amount of interest in recent years due to their ability to intercalate a multitude of anionic species. Atomistic simulation techniques such as molecular dynamics have provided considerable insight into the behaviour of these materials. The advent of supercomputing grids allows us to explore larger scale models with considerable ease. In this thesis we present our findings from large scale molecular dynamics simulations of Mg_2AI-LDHs intercalated with either chloride ions or a mixture of DNA and chloride ions. The system exhibits emergent properties, which are suppressed in smaller scale simulations. Undulatory modes are caused by the collective thermal motion of atoms in the LDH layers. Thermal undulations provide information about the materials properties of the system. In this way, we obtain values for elastic properties of the system including the bending modulus, Young's moduli and Poisson's ratios. The intercalation of DNA into LDHs has various applications, including drug delivery for gene therapy and origins of life studies. The nanoscale dimensions of the interlayer region make the exact conformation of the intercalated DNA difficult to elucidate experimentally. We use molecular dynamics techniques to perform simulations of double stranded, linear and plasmid DNA up to 480 base pairs in length intercalated within LDHs. Currently only limited experimental data has been reported for these systems. Our models are found to be in agreement with experimental observations, according to which hydration is a crucial factor in determining the structural stability of DNA. Phosphate backbone groups are found to align with aluminium lattice positions. At elevated temperatures and pressures, relevant to origins of life studies which maintain that the earliest life forms originated around deep ocean hydrothermal vents, the structural stability of LDH-intercalated DNA is substantially enhanced as compared to DNA in bulk water. We also discuss how the materials properties of the LDH are modified due to DNA intercalation. Recent experimental studies of LDHs have shown that these minerals can form staged intermediate structures during intercalation. However, the mechanism which produces staged structures remains undetermined. Our studies show that LDHs are flexible enough to deform around bulky intercalants such as DNA. The flexibility of layered materials has been shown to affect the pathway by which staging occurs. Even though the structures under study are all energetically very similar, overall there is greater diffusion of DNA strands in a Daumas-Hérold configuration compared to a Rüdorff model and a stage-1 structure

Structure and dynamics of multiple cationic vectors-siRNA complexation by all-atomic molecular dynamics simulations

Understanding the molecular mechanism of gene condensation is a key component to rationalizing gene delivery phenomena, including functional properties such as the stability of the gene-vector complex and the intracellular release of the gene. In this work, we adopt an atomistic molecular dynamics simulation approach to study the complexation of short strand duplex RNA with four cationic carrier systems of varying charge and surface topology at different charge ratios. At lower charge ratios, polymers bind quite effectively to siRNA, while at high charge ratios, the complexes are saturated and there are free polymers that are unable to associate with RNA. We also observed reduced fluctuations in RNA structures when complexed with multiple polymers in solution as compared to both free siRNA in water and the single polymer complexes. These novel simulations provide a much better understanding of key mechanistic aspects of gene-polycation complexation and thereby advance progress toward rational design of nonviral gene delivery systems

Structure, dynamics, and energetics of siRNA-cationic vector complexation: A molecular dynamics study

The design and synthesis of safe and efficient nonviral vectors for gene delivery has attracted significant attention in recent years. Previous experiments have revealed that the charge density of a polycation (the carrier) plays a crucial role in complexation and the release of the gene from the complex in the cytosol. In this work, we adopt an atomistic molecular dynamics simulation approach to study the complexation of short strand duplex RNA with six cationic carrier systems of varying charge and surface topology. The simulations reveal detailed molecular-level pictures of the structures and dynamics of the RNA-polycation complexes. Estimates for the binding free energy indicate that electrostatic contributions are dominant followed by van der Waals interactions. The binding free energy between the 8(+)polymers and the RNA is found to be larger than that of the 4(+)polymers, in general agreement with previously published data. Because reliable binding free energies provide an effective index of the ability of the polycationic carrier to bind the nucleic acid and also carry implications for the process of gene release within the cytosol, these novel simulations have the potential to provide us with a much better understanding of key mechanistic aspects of gene-polycation complexation and thereby advance the rational design of nonviral gene delivery systems

Computer modeling study for intercalation of drug heparin into layered double hydroxide

We have performed computational modeling studies to explore the properties of functionalized Mg-Al layered double hydroxides (LDHs) for drug (heparin) delivery applications. Using molecular dynamics (MD) simulations, we investigated the intercalation of heparin into a Mg:Al 2:1 LDH system, for which some limited experimental data have been reported (Gu, Z. Chem. Mater. 2008, 20, 3715). Counterions and explicit water molecules have been included in order to simulate the experimental conditions performed for the related hybrid LDH systems. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: COMPASS) was used for the MD simulations of the hybrid organic-inorganic systems. The interlayer structure, arrangement, and orientation of the intercalated species were examined and contrasted with the geometry of the isolated systems. The close contacts and hydrogen bonds between drug heparin and its surroundings in the hybrid system were analyzed, and the self-diffusion coefficients of both heparin and water molecules were estimated to be 5.6 x 10(-9) cm(2)/s and 8.5 x 10(-8) cm(2)/s at 300 K on the basis of 2 ns MD simulations. Implications for the stability of the hybrid LDH-drug systems were also discussed. Computed powder X-ray diffraction patterns were compared with those of related LDH-drug experiments

Bending of Layered Silicates on the Nanometer Scale: Mechanism, Stored Energy, and Curvature Limits

Bending and failure of aluminosilicate layers are common in polymer matrices although mechanical properties of curved layers and curvature limits are hardly known. We examined the mechanism of bending, the stored energy, and failure of several clay minerals. We employed molecular dynamics simulation, AFM data, and transmission electron microscopy (TEM) of montmorillonite embedded in epoxy and silk elastin polymer matrices with different weight percentage and different processing conditions. The bending energy per layer area as a function of bending radius can be converted into force constants for a given layer geometry and is similar for minerals of different cation exchange capacity (pyrophyllite, montmorillonite, mica). The bending energy increases from zero for a flat single layer to 10 mJ/m2 at a bending radius of 20 nm and exceeds 100 mJ/m2 at a bending radius of 6 nm. The smallest observed curvature of a bent layer is 3 nm. Failure proceeds through kink and split into two straight layers of shorter length. The mechanically stored energy per unit mass in highly bent aluminosilicate layers is close to the electrical energy stored in batteries. Molecular contributions to the bending energy include bond stretching and bending of bond angles in the mineral as well as rearrangements of alkali ions on the surface of the layers. When embedded in polymers, average radii of curvature of aluminosilicates exceed hundreds of nanometers. The small fraction of highly bent layers (radius) can be increased by extrusion, especially in stacked layers, and by an increase in weight percentage of layered silicates above 5%. Extrusion also promotes failure and shortening of isolated layers