Rational Design and 3D-Pharmacophore Mapping of 5 `-Thiourea-Substituted alpha-Thymidine Analogues as Mycobacterial TMPK Inhibitors

Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5`-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5`-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.

Virtual models of the HLA class I antigen processing pathway

Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class 1 binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model individual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of individual antigen processing steps, for example proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify H LA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies. (C) 2004 Elsevier Inc. All rights reserved.

Virtual plants - integrating architectural and physiological models

Recent advances in computer technology have made it possible to create virtual plants by simulating the details of structural development of individual plants. Software has been developed that processes plant models expressed in a special purpose mini-language based on the Lindenmayer system formalism. These models can be extended from their architectural basis to capture plant physiology by integrating them with crop models, which estimate biomass production as a consequence of environmental inputs. Through this process, virtual plants will gain the ability to react to broad environmental conditions, while crop models will gain a visualisation component. This integration requires the resolution of the fundamentally different time scales underlying the approaches. Architectural models are usually based on physiological time; each time step encompasses the same amount of development in the plant, without regard to the passage of real time. In contrast, physiological models are based in real time; the amount of development in a time step is dependent on environmental conditions during the period. This paper provides a background on the plant modelling language, then describes how widely-used concepts of thermal time can be implemented to resolve these time scale differences. The process is illustrated using a case study. (C) 1997 Elsevier Science Ltd.

Communicating trustworthiness and building trust in interorganizational virtual organizations

We propose a theory of trust in interorganizational virtual organizations that focuses on how trustworthiness can be communicated and trust built in this environment. The theory highlights three issues that must be dealt with if the potential obstacles to the development of trust in the virtual context are to be overcome. These are communication of trustworthiness facilitated by reliable Information and Communication Technology (ICT), establishment of a common business understanding, and strong business ethics. We propose four specific propositions relating to these issues, and suggest topics to be explored in future research. (C) 2001 Elsevier Science Inc. All rights reserved.

Simulation of insect movement with respect to plant architecture and morphogenesis

Developments in computer and three dimensional (3D) digitiser technologies have made it possible to keep track of the broad range of data required to simulate an insect moving around or over the highly heterogeneous habitat of a plant's surface. Properties of plant parts vary within a complex canopy architecture, and insect damage can induce further changes that affect an animal's movements, development and likelihood of survival. Models of plant architectural development based on Lindenmayer systems (L-systems) serve as dynamic platforms for simulation of insect movement, providing ail explicit model of the developing 3D structure of a plant as well as allowing physiological processes associated with plant growth and responses to damage to be described and Simulated. Simple examples of the use of the L-system formalism to model insect movement, operating Lit different spatial scales-from insects foraging on an individual plant to insects flying around plants in a field-are presented. Such models can be used to explore questions about the consequences of changes in environmental architecture and configuration on host finding, exploitation and its population consequences. In effect this model is a 'virtual ecosystem' laboratory to address local as well as landscape-level questions pertinent to plant-insect interactions, taking plant architecture into account. (C) 2002 Elsevier Science B.V. All rights reserved.

Database technologies for l-system simulations in virtual plant applications on bioinformatics

One of the most important advantages of database systems is that the underlying mathematics is rich enough to specify very complex operations with a small number of statements in the database language. This research covers an aspect of biological informatics that is the marriage of information technology and biology, involving the study of real-world phenomena using virtual plants derived from L-systems simulation. L-systems were introduced by Aristid Lindenmayer as a mathematical model of multicellular organisms. Not much consideration has been given to the problem of persistent storage for these simulations. Current procedures for querying data generated by L-systems for scientific experiments, simulations and measurements are also inadequate. To address these problems the research in this paper presents a generic process for data-modeling tools (L-DBM) between L-systems and database systems. This paper shows how L-system productions can be generically and automatically represented in database schemas and how a database can be populated from the L-system strings. This paper further describes the idea of pre-computing recursive structures in the data into derived attributes using compiler generation. A method to allow a correspondence between biologists' terms and compiler-generated terms in a biologist computing environment is supplied. Once the L-DBM gets any specific L-systems productions and its declarations, it can generate the specific schema for both simple correspondence terminology and also complex recursive structure data attributes and relationships.

Mechanical Behavior of the Lamellar Structure in Semi-Crystalline Polymers

We have employed molecular dynamics simulations to study the behavior of virtual polymeric materials under an applied uniaxial tensile load. Through computer simulations, one can obtain experimentally inaccessible information about phenomena taking place at the molecular and microscopic levels. Not only can the global material response be monitored and characterized along time, but the response of macromolecular chains can be followed independently if desired. The computer-generated materials were created by emulating the step-wise polymerization, resulting in self-avoiding chains in 3D with controlled degree of orientation along a certain axis. These materials represent a simplified model of the lamellar structure of semi-crystalline polymers,being comprised of an amorphous region surrounded by two crystalline lamellar regions. For the simulations, a series of materials were created, varying i) the lamella thickness, ii) the amorphous region thickness, iii) the preferential chain orientation, and iv) the degree of packing of the amorphous region. Simulation results indicate that the lamella thickness has the strongest influence on the mechanical properties of the lamella-amorphous structure, which is in agreement with experimental data. The other morphological parameters also affect the mechanical response, but to a smaller degree. This research follows previous simulation work on the crack formation and propagation phenomena, deformation mechanisms at the nanoscale, and the influence of the loading conditions on the material response. Computer simulations can improve the fundamental understanding about the phenomena responsible for the behavior of polymeric materials, and will eventually lead to the design of knowledge-based materials with improved properties.

Estimating Local Part Thickness in Midplane Meshes for Finite Element Analysis

Within the development of motor vehicles, crash safety (e.g. occupant protection, pedestrian protection, low speed damageability), is one of the most important attributes. In order to be able to fulfill the increased requirements in the framework of shorter cycle times and rising pressure to reduce costs, car manufacturers keep intensifying the use of virtual development tools such as those in the domain of Computer Aided Engineering (CAE). For crash simulations, the explicit finite element method (FEM) is applied. The accuracy of the simulation process is highly dependent on the accuracy of the simulation model, including the midplane mesh. One of the roughest approximations typically made is the actual part thickness which, in reality, can vary locally. However, almost always a constant thickness value is defined throughout the entire part due to complexity reasons. On the other hand, for precise fracture analysis within FEM, the correct thickness consideration is one key enabler. Thus, availability of per element thickness information, which does not exist explicitly in the FEM model, can significantly contribute to an improved crash simulation quality, especially regarding fracture prediction. Even though the thickness is not explicitly available from the FEM model, it can be inferred from the original CAD geometric model through geometric calculations. This paper proposes and compares two thickness estimation algorithms based on ray tracing and nearest neighbour 3D range searches. A systematic quantitative analysis of the accuracy of both algorithms is presented, as well as a thorough identification of particular geometric arrangements under which their accuracy can be compared. These results enable the identification of each technique’s weaknesses and hint towards a new, integrated, approach to the problem that linearly combines the estimates produced by each algorithm.

A creative solution for rapid and inexpensive model-making in product design processes

Innovative Developments in Virtual and Physical Prototyping

Collecting system percutaneous access using real-time tracking sensors: first pig model in vivo experience

Purpose: Precise needle puncture of the renal collecting system is an essential but challenging step for successful percutaneous nephrolithotomy. We evaluated the efficiency of a new real-time electromagnetic tracking system for in vivo kidney puncture. Materials and Methods: Six anesthetized female pigs underwent ureterorenoscopy to place a catheter with an electromagnetic tracking sensor into the desired puncture site and ascertain puncture success. A tracked needle with a similar electromagnetic tracking sensor was subsequently navigated into the sensor in the catheter. Four punctures were performed by each of 2 surgeons in each pig, including 1 each in the kidney, middle ureter, and right and left sides. Outcome measurements were the number of attempts and the time needed to evaluate the virtual trajectory and perform percutaneous puncture. Results: A total of 24 punctures were easily performed without complication. Surgeons required more time to evaluate the trajectory during ureteral than kidney puncture (median 15 seconds, range 14 to 18 vs 13, range 11 to 16, p ¼ 0.1). Median renal and ureteral puncture time was 19 (range 14 to 45) and 51 seconds (range 45 to 67), respectively (p ¼ 0.003). Two attempts were needed to achieve a successful ureteral puncture. The technique requires the presence of a renal stone for testing. Conclusions: The proposed electromagnetic tracking solution for renal collecting system puncture proved to be highly accurate, simple and quick. This method might represent a paradigm shift in percutaneous kidney access techniques

Collecting system percutaneous access using real-time tracking sensors: first pig model in vivo experience

Purpose: Precise needle puncture of the renal collecting system is an essential but challenging step for successful percutaneous nephrolithotomy. We evaluated the efficiency of a new real-time electromagnetic tracking system for in vivo kidney puncture. Materials and Methods: Six anesthetized female pigs underwent ureterorenoscopy to place a catheter with an electromagnetic tracking sensor into the desired puncture site and ascertain puncture success. A tracked needle with a similar electromagnetic tracking sensor was subsequently navigated into the sensor in the catheter. Four punctures were performed by each of 2 surgeons in each pig, including 1 each in the kidney, middle ureter, and right and left sides. Outcome measurements were the number of attempts and the time needed to evaluate the virtual trajectory and perform percutaneous puncture. Results: A total of 24 punctures were easily performed without complication. Surgeons required more time to evaluate the trajectory during ureteral than kidney puncture (median 15 seconds, range 14 to 18 vs 13, range 11 to 16, p ¼ 0.1). Median renal and ureteral puncture time was 19 (range 14 to 45) and 51 seconds (range 45 to 67), respectively (p ¼ 0.003). Two attempts were needed to achieve a successful ureteral puncture. The technique requires the presence of a renal stone for testing. Conclusions: The proposed electromagnetic tracking solution for renal collecting system puncture proved to be highly accurate, simple and quick. This method might represent a paradigm shift in percutaneous kidney access techniques.

Remuneration and tariffs in the context of virtual power players

Power systems have been through deep changes in recent years, namely with the operation of competitive electricity markets in the scope and the increasingly intensive use of renewable energy sources and distributed generation. This requires new business models able to cope with the new opportunities that have emerged. Virtual Power Players (VPPs) are a new player type which allows aggregating a diversity of players (Distributed Generation (DG), Storage Agents (SA), Electrical Vehicles, (V2G) and consumers), to facilitate their participation in the electricity markets and to provide a set of new services promoting generation and consumption efficiency, while improving players` benefits. A major task of VPPs is the remuneration of generation and services (maintenance, market operation costs and energy reserves), as well as charging energy consumption. This paper proposes a model to implement fair and strategic remuneration and tariff methodologies, able to allow efficient VPP operation and VPP goals accomplishment in the scope of electricity markets.

Optimization model for medium term natural gas commitment

In this paper we study the optimal natural gas commitment for a known demand scenario. This study implies the best location of GSUs to supply all demands and the optimal allocation from sources to gas loads, through an appropriate transportation mode, in order to minimize total system costs. Our emphasis is on the formulation and use of a suitable optimization model, reflecting real-world operations and the constraints of natural gas systems. The mathematical model is based on a Lagrangean heuristic, using the Lagrangean relaxation, an efficient approach to solve the problem. Computational results are presented for Iberian and American natural gas systems, geographically organized in 65 and 88 load nodes, respectively. The location model results, supported by the computational application GasView, show the optimal location and allocation solution, system total costs and suggest a suitable gas transportation mode, presented in both numerical and graphic supports.

Virtual power producers market strategies

This paper presents MASCEM - a multi-agent based electricity market simulator. MASCEM uses game theory, machine learning techniques, scenario analysis and optimisation techniques to model market agents and to provide them with decision-support. This paper mainly focus on the MASCEM ability to provide the means to model and simulate Virtual Power Producers (VPP). VPPs are represented as a coalition of agents, with specific characteristics and goals. The paper detail some of the most important aspects considered in VPP formation and in the aggregation of new producers and includes a case study.

MASCEM - an electricity market simulator providing coalition support for virtual power players

This paper presents MASCEM - a multi-agent based electricity market simulator. MASCEM uses game theory, machine learning techniques, scenario analysis and optimization techniques to model market agents and to provide them with decision-support. This paper mainly focus on the MASCEM ability to provide the means to model and simulate Virtual Power Players (VPP). VPPs are represented as a coalition of agents, with specific characteristics and goals. The paper details some of the most important aspects considered in VPP formation and in the aggregation of new producers and includes a case study based on real data.