gcodeml: A Grid-enabled Tool for Detecting Positive Selection in Biological Evolution

One of the important questions in biological evolution is to know if certain changes along protein coding genes have contributed to the adaptation of species. This problem is known to be biologically complex and computationally very expensive. It, therefore, requires efficient Grid or cluster solutions to overcome the computational challenge. We have developed a Grid-enabled tool (gcodeml) that relies on the PAML (codeml) package to help analyse large phylogenetic datasets on both Grids and computational clusters. Although we report on results for gcodeml, our approach is applicable and customisable to related problems in biology or other scientific domains.

Characterization and simulation of a CdTe detector for use in PET

The Voxel Imaging PET (VIP) Path nder project got the 4 year European Research Council FP7 grant in 2010 to prove the feasibility of using CdTe detectors in a novel conceptual design of PET scanner. The work presented in this thesis is a part of the VIP project and consists of, on the one hand, the characterization of a CdTe detector in terms of energy resolution and coincidence time resolution and, on the other hand, the simulation of the setup with the single detector in order to extend the results to the full PET scanner. An energy resolution of 0.98% at 511 keV with a bias voltage of 1000 V/mm has been measured at low temperature T=-8 ºC. The coincidence time distribution of two twin detectors has been found to be as low as 6 ns FWHM for events with energies above 500 keV under the same temperature and bias conditions. The measured energy and time resolution values are compatible with similar ndings available in the literature and prove the excellent potential of CdTe for PET applications. This results have been presented in form of a poster contribution at the IEEE NSS/MIC & RTSD 2011 conference in October 2011 in Valencia and at the iWoRID 2012 conference in July 2012 in Coimbra, Portugal. They have been also submitted for publication to "Journal of Instrumentation (JINST)" in September 2012.

Calculation of Franck-Condon factors including anharmonicity: simulation of the C2 H4+ X̃2B 3u←C2 H4X̃1 Ag band in the photoelectron spectrum of ethylene

Our new simple method for calculating accurate Franck-Condon factors including nondiagonal (i.e., mode-mode) anharmonic coupling is used to simulate the C2H4+X2B 3u←C2H4X̃1 Ag band in the photoelectron spectrum. An improved vibrational basis set truncation algorithm, which permits very efficient computations, is employed. Because the torsional mode is highly anharmonic it is separated from the other modes and treated exactly. All other modes are treated through the second-order perturbation theory. The perturbation-theory corrections are significant and lead to a good agreement with experiment, although the separability assumption for torsion causes the C2 D4 results to be not as good as those for C2 H4. A variational formulation to overcome this circumstance, and deal with large anharmonicities in general, is suggested

Improved earthquake response via simulation and integrated space- and ground-based technologies: the TREMOR proposal

Earthquakes occurring around the world each year cause thousands ofdeaths, millions of dollars in damage to infrastructure, and incalculablehuman suffering. In recent years, satellite technology has been asignificant boon to response efforts following an earthquake and itsafter-effects by providing mobile communications between response teamsand remote sensing of damaged areas to disaster management organizations.In 2007, an international team of students and professionals assembledduring theInternational Space University’s Summer Session Program in Beijing, Chinato examine how satellite and ground-based technology could be betterintegrated to provide an optimised response in the event of an earthquake.The resulting Technology Resources for Earthquake MOnitoring and Response(TREMOR) proposal describes an integrative prototype response system thatwill implement mobile satellite communication hubs providing telephone anddata links between response teams, onsite telemedicine consultation foremergency first-responders, and satellite navigation systems that willlocate and track emergency vehicles and guide search-and-rescue crews. Aprototype earthquake simulation system is also proposed, integratinghistorical data, earthquake precursor data, and local geomatics andinfrastructure information to predict the damage that could occur in theevent of an earthquake. The backbone of these proposals is a comprehensiveeducation and training program to help individuals, communities andgovernments prepare in advance. The TREMOR team recommends thecoordination of these efforts through a centralised, non-governmentalorganization.

Orthotropic active strain models for the numerical simulation of cardiac biomechanics

An active strain formulation for orthotropic constitutive laws arising in cardiac mechanics modeling is introduced and studied. The passive mechanical properties of the tissue are described by the Holzapfel-Ogden relation. In the active strain formulation, the Euler-Lagrange equations for minimizing the total energy are written in terms of active and passive deformation factors, where the active part is assumed to depend, at the cell level, on the electrodynamics and on the specific orientation of the cardiac cells. The well-posedness of the linear system derived from a generic Newton iteration of the original problem is analyzed and different mechanical activation functions are considered. In addition, the active strain formulation is compared with the classical active stress formulation from both numerical and modeling perspectives. Taylor-Hood and MINI finite elements are employed to discretize the mechanical problem. The results of several numerical experiments show that the proposed formulation is mathematically consistent and is able to represent the main key features of the phenomenon, while allowing savings in computational costs.

Simulation methods with extended stability for stiff biochemical kinetics

Background: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, τ, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where τ can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called τ-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as τ grows. Results: In this paper we extend Poisson τ-leap methods to a general class of Runge-Kutta (RK) τ-leap methods. We show that with the proper selection of the coefficients, the variance of the extended τ-leap can be well-behaved, leading to significantly larger step sizes.Conclusions: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original τ-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.

Towards reusability and tailorability in collaborative learning systems using IMS-LD and grid services

CSCL applications are complex distributed systems that posespecial requirements towards achieving success in educationalsettings. Flexible and efficient design of collaborative activitiesby educators is a key precondition in order to provide CSCL tailorable systems, capable of adapting to the needs of eachparticular learning environment. Furthermore, some parts ofthose CSCL systems should be reused as often as possible inorder to reduce development costs. In addition, it may be necessary to employ special hardware devices, computational resources that reside in other organizations, or even exceed thepossibilities of one specific organization. Therefore, theproposal of this paper is twofold: collecting collaborativelearning designs (scripting) provided by educators, based onwell-known best practices (collaborative learning flow patterns) in a standard way (IMS-LD) in order to guide the tailoring of CSCL systems by selecting and integrating reusable CSCL software units; and, implementing those units in the form of grid services offered by third party providers. More specifically, this paper outlines a grid-based CSCL system having these features and illustrates its potential scope and applicability by means of a sample collaborative learning scenario.

@neurIST infrastructure for advanced disease management through integration of heterogeneous data, computing, and complex processing services

The increasing volume of data describing humandisease processes and the growing complexity of understanding, managing, and sharing such data presents a huge challenge for clinicians and medical researchers. This paper presents the@neurIST system, which provides an infrastructure for biomedical research while aiding clinical care, by bringing together heterogeneous data and complex processing and computing services. Although @neurIST targets the investigation and treatment of cerebral aneurysms, the system’s architecture is generic enough that it could be adapted to the treatment of other diseases.Innovations in @neurIST include confining the patient data pertaining to aneurysms inside a single environment that offers cliniciansthe tools to analyze and interpret patient data and make use of knowledge-based guidance in planning their treatment. Medicalresearchers gain access to a critical mass of aneurysm related data due to the system’s ability to federate distributed informationsources. A semantically mediated grid infrastructure ensures that both clinicians and researchers are able to seamlessly access andwork on data that is distributed across multiple sites in a secure way in addition to providing computing resources on demand forperforming computationally intensive simulations for treatment planning and research.

Population PK-guided simulation study in children exposed to drugs in human milk

Risks of significant infant drug exposure through human milk arepoorly defined due to lack of large-scale PK data. We propose to useBayesian approach based on population PK (popPK)-guided modelingand simulation for risk prediction. As a proof-of-principle study, weexploited fluoxetine milk concentration data from 25 women. popPKparameters including milk-to-plasma ratio (MP ratio) were estimatedfrom the best model. The dose of fluoxetine the breastfed infant wouldreceive through mother's milk, and infant plasma concentrations wereestimated from 1000 simulated mother-infant pairs, using randomassignment of feeding times and milk volume. A conservative estimateof CYP2D6 activity of 20% of the allometrically-adjusted adult valuewas assumed. Derived model parameters, including MP ratio were consistentwith those reported in the literature. Visual predictive check andother model diagnostics showed no signs of model misspecifications.The model simulation predicted that infant exposure levels to fluoxetinevia mother's milk were below 10% of weight-adjusted maternal therapeuticdoses in >99% of simulated infants. Predicted median ratio ofinfant-mother serum levels at steady state was 0.093 (range 0.033-0.31),consistent with literature reported values (mean=0.07; range 0-0.59).Predicted incidence of relatively high infant-mother ratio (>0.2) ofsteady-state serum fluoxetine concentrations was <1.3%. Overall, ourpredictions are consistent with clinical observations. Our approach maybe valid for other drugs, allowing in silico prediction of infant drugexposure risks through human milk. We will discuss application of thisapproach to another drug used in lactating women.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Technical note: Preliminary estimation of rockfall runout zones

Rockfall propagation areas can be determined using a simple geometric rule known as shadow angle or energy line method based on a simple Coulomb frictional model implemented in the CONEFALL computer program. Runout zones are estimated from a digital terrain model (DTM) and a grid file containing the cells representing rockfall potential source areas. The cells of the DTM that are lowest in altitude and located within a cone centered on a rockfall source cell belong to the potential propagation area associated with that grid cell. In addition, the CONEFALL method allows estimation of mean and maximum velocities and energies of blocks in the rockfall propagation areas. Previous studies indicate that the slope angle cone ranges from 27° to 37° depending on the assumptions made, i.e. slope morphology, probability of reaching a point, maximum run-out, field observations. Different solutions based on previous work and an example of an actual rockfall event are presented here.

Stoneley wave modeling in heterogeneous porous media with viscous pore fluids

We implemented Biot-type porous wave equations in a pseudo-spectral numerical modeling algorithm for the simulation of Stoneley waves in porous media. Fourier and Chebyshev methods are used to compute the spatial derivatives along the horizontal and vertical directions, respectively. To prevent from overly short time steps due to the small grid spacing at the top and bottom of the model as a consequence of the Chebyshev operator, the mesh is stretched in the vertical direction. As a large benefit, the Chebyshev operator allows for an explicit treatment of interfaces. Boundary conditions can be implemented with a characteristics approach. The characteristic variables are evaluated at zero viscosity. We use this approach to model seismic wave propagation at the interface between a fluid and a porous medium. Each medium is represented by a different mesh and the two meshes are connected through the above described characteristics domain-decomposition method. We show an experiment for sealed pore boundary conditions, where we first compare the numerical solution to an analytical solution. We then show the influence of heterogeneity and viscosity of the pore fluid on the propagation of the Stoneley wave and surface waves in general.