* Key players: Colin Hill, CEO, president and chairman; James Watson, chief operating officer and chief financial officer; Iya Khalil, vice president of research and development and executive vice president; Jeffrey Fox, vice president of cardiovascular research; George Reigeluth, director of business development

* What does your company do? Gene Network Sciences (GNS) is a biosimulation company. Its technology is used to create computer models that help pharmaceutical companies improve the quality of the drugs they're developing.

* Why is this technology useful in the marketplace? Drug companies face staggering research-and-development costs associated with the production of new medications, says Colin Hill, Gene Network's CEO, president, and chairman. According to GNS , bringing a new drug to market costs an average of $800 million and takes about 12 years. And still, most drugs fail before they even make it to market, Hill adds. About 80 percent of drugs never make it through their clinical trials, according to GNS. Of the medications that actually enter consumer use, an average of just 60 percent provide therapeutic benefits to patients. Using computer models helps reduce the risk and uncertainty inherent in the drug-development process, Hill explains. "We're trying to make the approach to developing new drugs less haphazard," he says. "We're about making the whole process more predictive."

* How do these software models work? The company takes various genetic data, including information from the Human Genome Project, and uses it to help determine how drug candidates will interact with the body. The models can be used in a broad array of applications, but GNS currently focuses on development of cancer and heart medications, Hill says. The models can help pharmaceutical companies determine the effectiveness of their drugs, but also help them do safety screenings. In heart medications, for example, the software can be used to help determine the potential for cardiac complications.* How does this process fit with traditional laboratory testing and clinical trials? "The companies still have to do lab testing for [Food and Drug Administration] approval, but why they work with us, is we can help make those efforts more successful," Hill says. GNS software can run millions of experiments on its computers in a fraction of the time and expense it would take to test similar predictions in a laboratory setting, he says.

* What is your background? Hill graduated from Virginia Tech University with a degree in physics and earned master's degrees in physics from McGill and Cornell universities. Hill says he has been involved in academic research focused around GNS's core technology for several years. Computational advances of recent years and knowledge gained through efforts like the Human Genome Project made the use of the technology possible in a commercial setting, Hill says. GNS was launched about five years ago.

* Is the move toward computer modeling a broad trend In the drugdevelopment Industry? Pharmaceutical companies are moving rapidly toward computer simulations, Hill says. "The costs and success rates aren't getting any better," he says. "The fact is that people are dying when better drugs can't be made or matched." The investment community, academia, and regulators are also driving the move toward simulation, he adds. "We think we can help make this process cheaper, faster, and more successful," Hill says.

* What kind of growth are you predicting? The company has annual revenue of more than $1 million, but Hill declines to disclose exact figures. The firm has raised more than $4 million from investors and has received more than $7 million in grants from the National Institutes of Health, the National Institute of Standards and Technology, and the Department of Energy. The company is predicting growth of at least 50 percent annually beginning in 2006. The company also plans to boost hiring in the next year. It plans to have more than 30 employees at its 13,000-square-foot headquarters by the end of 2006, up from the current 20.

* What are some of your recent projects? The company announced in July it won a Small Business Innovation Research Grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The six-month, $137,800 grant was aimed at further cardiacmodeling efforts, according to the company. In March, GNS announced a drug-development contract with Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V. The agreement involved the use of GNS technology in development of a pre-clinical oncology compound. Financial terms of that deal were not disclosed.

Offering 32- and 64-bit support for Windows and Linux platforms as well as UNIX workstations, ALGOR v18 delivers linear static stress analysis, Mechanical Event Simulation, and fluid flow analysis capabilities. It supports display of results on isosurfaces; colored, 3-D streamlines; and particle tracking with size control. Able to export results to VRML files, software facilitates creation of fluid models and offers nonlinear material models support.

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PITTSBURGH, PA - October 17, 2005 - ALGOR, Inc., a leading provider of design, analysis and simulation software, announced that its latest software release, V18, features expanded capabilities for linear static stress analysis (optimized for 64-bit operating systems), Mechanical Event Simulation (new Arruda-Boyce and Blatz-Ko hyperelastic material models and Mooney-Rivlin, Ogden, Arruda-Boyce, Blatz-Ko and Hyperfoam finite-strain viscoelastic material models) and fluid flow analysis (automatic modeling of the fluid medium and a new segregate steady solver for faster runtimes). New presentation enhancements include the display of results on isosurfaces, colored, 3-D streamlines and particle tracking with size control and the ability to export results to VRML files.

"The 64-bit optimization is part of a significant expansion of the hardware platforms supported by all of our ALGOR solvers, which when complete in 2005, will include 32- and 64-bit support for Windows and Linux and the first platform in our support for UNIX workstations. This expanded hardware support will allow users to analyze larger, more complex models faster than ever," said ALGOR Product Manager, Bob Williams. "Additionally, the new nonlinear material models allow for the consideration of a wider range of materials - especially rubbers and foams, while the new fluid medium modeling option allows CAD users to more easily gain access to our expansive suite of CFD tools." "With the release of ALGOR V18, fluid models are now a snap to create," said Independent Contractor James A. Britch, P.E. "Model the structure in your 3-D CAD package, then select the fluid modeling option in ALGOR FEMPRO and simply define whether the fluid is internal or external. ALGOR then automatically creates the fluid model as a new part and matches the mesh to the structural elements."

"I have been using ALGOR V18 for a month and have been extremely pleased," said Marc A. Meadows, P.E., of Meadows Analysis & Design, LLC. "The 64-bit optimization is excellent. I look forward to the increased performance on my new 64-bit computer. The mouse customization is another great tool as I spend a lot of time switching between applications and this feature eliminates the need to change the operation of buttons and the wheel every time. I am also looking forward to the new VRML export options because my customers have requested this capability."

ALGOR V18 also includes:

CAD Support (Direct)

Ability to read surfaces and materials directly from SolidWorks

FEMPRO

Support for 3Dconnexion's advanced motion controllers (including SpacePilot, SpaceBall, SpaceMouse and SpaceTraveler)

Customizable mouse actions

Ability to match CAD mouse actions

Ability to select neighboring objects

Ability to zoom while snapping

Ability to create fillets between beams

Improved meshing capabilities

Part mesh matching

Ability to import 3-D DXF files

Mechanical Event Simulation/Nonlinear Solver

Ability to perform a draft motion-based analysis to verify linkages

Curve fitting for new hyperelastic material models

Ability to specify velocity and angular velocity throughout analysis

Smoothing contact parameters across different contact surfaces

Superview Results Environment

Contour plots for shell thickness

Factor of safety contour displays for beam elements

Ability to specify default display settings for new models

Ability to show node numbers for minimum and maximum values

To see a free learning session on the new ALGOR V18, view the "ALGOR V18" Webcast on the ALGOR web site. For more detailed information, contact an ALGOR account manager or visit the "ALGOR V18" features page.

ALGOR, Inc. provides cost-effective solutions for design, analysis and simulation and enables engineers to virtually test and predict real-world behavior of new and existing product designs, speed up time to market and make better, safer products at a lower cost. The company serves more than 20,000 customers in over 95 countries in organizations such as 3M, The Boeing Company, Delphi Corporation, DuPont, General Electric Company, General Motors Corporation, Goodrich Corporation, Hewlett-Packard Company, IBM Corporation and NASA. Partnerships with other leading software companies offer data exchange with products from Alibre, Inc.; ANSYS, Inc.; Autodesk, Inc.; IronCAD, LLC; Kubotek USA, Inc.; MSC.Software Corporation; Parametric Technology Corporation (PTC); Robert McNeel & Associates; Solid Edge from UGS; SolidWorks Corporation, a Dassault Systemes S.A. company; and others. Educational support and customer service includes the use of Internet audio/video technology for distance learning and free, live software demonstrations. For additional information, please visit our website at www.ALGOR.com.

Able to read geometry files created with most CAD packages, COMSOL Multiphysics(TM) v3.2 delivers finite-element based scientific-modeling package with moving-mesh feature and CAD or mesh file import capabilities. COMSOL Script(TM) has command-line interface, scripting capabilities, and 500 commands for numeric computations and visualization. Software allows user to perform time-domain simulation of electromagnetic waves, and GUI promotes use of consistent system of engineering units.

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BURLINGTON, MA (September 6, 2005)-COMSOL, Inc., is releasing version 3.2 of COMSOL Multiphysics(TM), a scientific-modeling package whose new features boost productivity throughout the entire modeling and simulation process. The software now reads geometry files created with all major CAD packages. It introduces COMSOL Script(TM), a standalone product featuring command-line modeling. The graphical user interface encourages the use of a consistent system of engineering units, and a moving-mesh feature allows a model to simulate moving parts and parametric geometries. Improved solvers handle models with millions of degrees of freedom and calculate the answers faster than ever before.

Perhaps most obvious to existing customers is the change of the product name to better reflect the company's offerings, which now address many areas of scientific computing. Company president Svante Littmarck remarks, "We are renaming our leading product from FEMLAB to COMSOL Multiphysics. That's already the software's name in Japan, and it's one we find better suits our growing product line. Although we started with finite-element method (FEM) software, COMSOL products today and those planned for the future cover considerably more in terms of functionality and appeal." CAD import addresses all major formats

To make it easy for users to import CAD drawings for modeling in COMSOL Multiphysics, a suite of optional CAD-import modules read a wide range of industry-standard CAD and mesh file formats starting with those for SolidWorks[R], Solid Edge[R], NX(TM), and NASTRAN[R]. Importing an existing CAD or mesh file enables users to bypass the geometry-creation step, which makes the first step in the modeling process fast and convenient.

The CAD Import Module is based on Parasolid[R] geometry kernel and includes ACIS[R] to support the SAT[R] format. In addition to the native Parasolid and SAT formats, the CAD Import Module also supports the STEP and IGES file formats. Live synchronization with the SolidWorks CAD package enables a truly productive design and modeling environment. Separate CAD-import modules accept the CATIA[R] V4, CATIA[R] V5, Autodesk Inventor[R], Pro/ENGINEER[R], and VDA-FS file formats.

COMSOL Script(TM)-a technical-computing language for modeling

The scope of modeling takes on entirely new proportions with the release of COMSOL Script, which integrates seamlessly with COMSOL Multiphysics but as also runs as a standalone package. On its own, this interpreted language handles most computation tasks through its command-line interface, scripting capabilities, and 500 commands for numeric computations and visualization. For users of COMSOL Multiphysics, COMSOL Script also offer an alternative to MATLAB[R], which up to now was a prerequisite for command-line modeling.

When run within COMSOL Multiphysics this new language enables command-line modeling whereby users can access all functions available in that modeling package, or they can call COMSOL Script functions from within the COMSOL Multiphysics GUI to define any property of a model. They can also save work performed in the graphical user interface to a Model M-file and run that text-based file in COMSOL Script. By working with such scripts, users can conduct iterative parametric studies and optimizations as well as perform any model explorations and simulations. Further, COMSOL Script's graphing and visualization capabilities set new standards for packages in this category, and a set of GUI tools allow users to quickly construct graphical user interfaces.

Consistent units throughout

Other features make it far easier to set up a model. For instance, COMSOL Multiphysics' graphical interface presents each parameter with an appropriate unit; users select from nine common engineering unit systems so that consistent unit labels appear in all dialog boxes, next to data-entry fields, and in postprocessing plots. Examples of supported unit systems are SI, MPa, CGS, and British Imperial Units. This feature avoids the confusion that can arise especially when trying to determine the proper value to enter for a parameter that has compound units, and it eliminates many unnecessary user errors.

Moving meshes for fluid-structure interactions and parametric geometries

Extending modeling into new areas is a Moving Mesh mode that allows COMSOL Multiphysics to easily simulate geometries with moving parts such as those in MEMS (microelectromechanical systems), piezoelectrics, and biology applications as well as free-surface flow and natural wave effects. Users define the desired type of motion such as for the deflection of a flexible barrier in a strong flow of liquid or gas, or even fluid sloshing in a tank. Coupled with the moving-mesh engine is geometric parameterization, where it is possible to describe a how a geometry changes without the need to set up a loop in a script file.

M. Monto (sustainable technologies, Indian Institute of Science, Bangalore), L.S. Ganesh (management), and Koshy Varghese (civil engineering, both IIT Madras) explore the complex relationships between humans and water in an urban context, identifying fundamental issues within a framework of integrated models and simulations for sustainability assessment and forecasting. They write for students and researchers in environmental and urban studies, and for policy makers from the local to the international.

Every year, bit designers, like car designers, use newly developed technology to make drill bits run faster, drill deeper and last longer in an effort to give operators more value for their bit dollar. In some cases, the added value is real, while in other cases, it is simply perceived. In the end, it is the operators who must determine which bits actually do perform better. Here are some of the latest technologies being applied to drill bits.

TECHNOLOGY OVERVIEW

Generally, the increased use of computer modeling, for roller cone and PDC bit design and manufacturing, is producing a new generation of bits that delivers breakthroughs in rates of penetration (ROP), increased durability and longer life. These computer models utilize proprietary algorithms to model forces and bit behavior to assure maximum bit performance.

Additionally, computer modeling of the dynamics of interactions between PDC bit cutters and rock allows bits to be custom-designed for specific applications. Computer-aided design tools are being employed to model, with 3D and 4D graphics, the drag, axial and radial forces acting on the bits' cutting surfaces. One manufacturer's cutter/rock interaction model divides the cutting edge into three surfaces: cutting face, chamfer and cylinder surfaces. The computer calculates the cutter's engagement area by meshing each surface into grids, so the cutter orientation's effects on the engagement area can be considered.

Data on advanced cutter wear is one of the results of this modeling. Cutter wear depends on cutting force, relative speed, temperature, cutter material properties and rock properties. Previously, computer models estimated only the wear flat without considering its orientation, as well as the actual diamond thickness, the interface geometry of the diamond layer, and carbide and abrasive resistance. With the newer computer models, cutter wear can be considered three-dimensionally, and all factors neglected by previous models are now easily considered. Bit designers then use this information to devise a bit specifically for a particular job.

Bit balancing. Another development that is becoming more important is bit balancing, Fig. 1. This concept considers the forces acting on the bit to create designs in which no single cone or cutting system is overstressed. This increases cutting efficiency and extends bit service life. Two types of balancing methods are used--force balancing and load balancing.

[FIGURE 1 OMITTED]

Force balancing. Of the three forces acting on a bit--axial force, lateral force and bending moment--it has long been recognized that balancing the lateral force is very important for preventing whirl. In fact, previous concepts of PDC bit force balancing referred only to lateral force balance, due to the belief that once lateral force was balanced, the bit bending moment was balanced also.

However, further study revealed that bit bending moment contributes not only to bit lateral motion or whirl, but also to tilt motion, which significantly affects directional control. Even a perfectly force-balanced bit may exhibit tilt motion, if the axial forces are not balanced. Therefore, balancing the axial forces is equally as important as balancing lateral force.

A PDC bit that is balanced, both in terms of lateral force and bending moment, is a "global force-balanced" bit. Designing such a bit involves adjusting the cutting structure to reduce the imbalance numbers. For example, newer series bits are force-balanced according to a specific set of design criteria that consider the summation of cutter forces to a global, lateral and axial bit imbalance, resulting in a global force-balanced design.

Load balancing. A bit in which the drilling forces acting on each individual cutter are balanced and are evenly distributed across the entire cutting is said to be "load balanced." This technique is meant to prevent cutter wear and excessive point loading that can break or damage cutters.

Roller cone bits are load balanced in two ways--by volume and by force. Volume balancing almost equalizes rock removal among all the cones, while force balancing ensures that all cones are subjected to nearly the same loads, including weight-on-cone, bending moment and force-on-bearing.

For PDC bits, load balancing, which was employed originally on roller cone bits only, is now being used to improve the PDC bit performance. The concept of load balancing is based on the fact that the amount of formation removed by each individual cutter differs and, as a result, the force acting on each cutter also differs. Furthermore, the number of cutters differs from blade to blade. Therefore, the forces acting on each blade differ. To avoid overloading individual cutters and blades, it is necessary to control these load distributions.

Equally distributing the forces minimizes the change in work, or force, among zones of the cutting structure. Thus, designing a "torque- and drag-balanced" PDC bit involves analyzing the distribution of work and forces acting on a cutting structure, with the goal of controlling force distribution over both the blades and cutters. By controlling the force distribution, these bits are able to reduce impact damage and uneven wear while promoting improved ROP.

Enabling users to create, manage, and share design information, Autodesk Revit Systems are designed for mechanical/electrical/plumbing (MEP) engineering. Autodesk AutoCAD Revit Series is offered combined with three solutions: Revit Building 9 for architects and designers, with Revit Structure 3 for structural engineering and drafting, and Autodesk Revit Systems to facilitate user migration to and utilization of building information modeling (BIM).

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New Revit Systems for Mechanical, Electrical and Plumbing Engineering Completes Building Information Model for Building Design; New Revit Series Products Provide Easy Road to BIM Adoption

SAN RAFAEL, Calif., March 23 / -- Autodesk, Inc. (NASDAQ:ADSK) today made it faster and easier for architects, structural engineers and building systems engineers to realize their ideas and embrace the benefits of building information modeling (BIM). With the availability of Autodesk Revit Systems, a Revit-based BIM solution for mechanical/electrical/ plumbing (MEP) engineering, Autodesk has completed the building information model and now offers discipline-specific BIM solutions on the Revit platform across the entire building design enterprise. Autodesk Revit Systems will be available as part of Autodesk AutoCAD Revit Series -- Systems Plus, one of three new Revit Series products that combine AutoCAD 2007 software with the Revit family of software products to help customers move to BIM at their own pace. Revit is now the most comprehensive platform for BIM and allows customers to create, manage and share design information more effectively, contributing to increased profitability, reduced risk and fewer inefficiencies in building design, construction and management.

"Working on the Freedom Tower project with a complete building information model on the Revit platform is enhancing collaboration with the entire building design team including the architects and structural engineers," said Scott Frank, partner, Jaros, Baum & Bolles. "Adopting Revit Systems and moving to BIM is helping JB&B to improve spatial coordination and integration of the MEP systems.

Many Autodesk building industry customers are moving from CAD drafting software to building information modeling. Autodesk is releasing new Revit series products to help these customers gain the competitive advantages of BIM, preserve their current investments and provide the flexibility to move to building information modeling at their own pace. Autodesk AutoCAD Revit Series -- Building 9, for architects and designers, and Autodesk AutoCAD Revit Series -- Structure 3, for structural engineering and drafting, combine Autodesk's industry-leading AutoCAD 2007 software with Revit Building 9 and Revit Structure 3 respectively. Autodesk AutoCAD Revit Series -- Systems Plus combines Autodesk Building Systems 2007 with Autodesk Revit Systems into one comprehensive discipline-specific design solution to make it easier than ever for customers to experience the full benefits of BIM.

"Autodesk is bringing the power of BIM to new disciplines, and now that we've completed the building information model on the Revit platform, helping drive greater efficiency, productivity and collaboration in the building industry," said Jay Bhatt, Vice President, Autodesk Building Solutions Division.

Revit Systems Completes Building Information Model for Design

The Autodesk Revit platform is the best and most complete design solution for building information modeling in the industry today. BIM is the creation and use of coordinated, consistent, computable information about a building project in design that yields reliable digital representations of the building -- representations used for design decision-making, production of high-quality construction documents, performance predictions, cost-estimating and construction planning and, eventually, for managing and operating the facility. By working together on an integrated building information model, the various firms involved in the design, construction and management of buildings can greatly increase efficiency and significantly reduce coordination errors. Real-time, consistent relationships between digital design data -- with innovative parametric building modeling technology -- provide significant advantages over traditional methods of design and construction.

Enabling users to create, manage, and share design information, Autodesk Revit Systems are designed for mechanical/electrical/plumbing (MEP) engineering. Autodesk AutoCAD Revit Series is offered combined with three solutions: Revit Building 9 for architects and designers, with Revit Structure 3 for structural engineering and drafting, and Autodesk Revit Systems to facilitate user migration to and utilization of building information modeling (BIM).

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New Revit Systems for Mechanical, Electrical and Plumbing Engineering Completes Building Information Model for Building Design; New Revit Series Products Provide Easy Road to BIM Adoption

SAN RAFAEL, Calif., March 23 / -- Autodesk, Inc. (NASDAQ:ADSK) today made it faster and easier for architects, structural engineers and building systems engineers to realize their ideas and embrace the benefits of building information modeling (BIM). With the availability of Autodesk Revit Systems, a Revit-based BIM solution for mechanical/electrical/ plumbing (MEP) engineering, Autodesk has completed the building information model and now offers discipline-specific BIM solutions on the Revit platform across the entire building design enterprise. Autodesk Revit Systems will be available as part of Autodesk AutoCAD Revit Series -- Systems Plus, one of three new Revit Series products that combine AutoCAD 2007 software with the Revit family of software products to help customers move to BIM at their own pace. Revit is now the most comprehensive platform for BIM and allows customers to create, manage and share design information more effectively, contributing to increased profitability, reduced risk and fewer inefficiencies in building design, construction and management.

"Working on the Freedom Tower project with a complete building information model on the Revit platform is enhancing collaboration with the entire building design team including the architects and structural engineers," said Scott Frank, partner, Jaros, Baum & Bolles. "Adopting Revit Systems and moving to BIM is helping JB&B to improve spatial coordination and integration of the MEP systems.

Many Autodesk building industry customers are moving from CAD drafting software to building information modeling. Autodesk is releasing new Revit series products to help these customers gain the competitive advantages of BIM, preserve their current investments and provide the flexibility to move to building information modeling at their own pace. Autodesk AutoCAD Revit Series -- Building 9, for architects and designers, and Autodesk AutoCAD Revit Series -- Structure 3, for structural engineering and drafting, combine Autodesk's industry-leading AutoCAD 2007 software with Revit Building 9 and Revit Structure 3 respectively. Autodesk AutoCAD Revit Series -- Systems Plus combines Autodesk Building Systems 2007 with Autodesk Revit Systems into one comprehensive discipline-specific design solution to make it easier than ever for customers to experience the full benefits of BIM.

"Autodesk is bringing the power of BIM to new disciplines, and now that we've completed the building information model on the Revit platform, helping drive greater efficiency, productivity and collaboration in the building industry," said Jay Bhatt, Vice President, Autodesk Building Solutions Division.

Revit Systems Completes Building Information Model for Design

The Autodesk Revit platform is the best and most complete design solution for building information modeling in the industry today. BIM is the creation and use of coordinated, consistent, computable information about a building project in design that yields reliable digital representations of the building -- representations used for design decision-making, production of high-quality construction documents, performance predictions, cost-estimating and construction planning and, eventually, for managing and operating the facility. By working together on an integrated building information model, the various firms involved in the design, construction and management of buildings can greatly increase efficiency and significantly reduce coordination errors. Real-time, consistent relationships between digital design data -- with innovative parametric building modeling technology -- provide significant advantages over traditional methods of design and construction.

The Echinococcus granulosus actin filament-fragmenting protein (EgAFFP) is a three domain member of the gelsolin family of proteins, which is antigenic to human hosts. These proteins, formed by three or six conserved domains, are involved in the dynamic rearrangements of the cytoskeleton, being responsible for severing and capping actin filaments and promoting nucleation of actin monomers. Various structures of six domain gelsolin-related proteins have been investigated, but little information on the structure of three domain members is available. In this work, the solution structure of the three domain EgAFFP has been investigated through small-angle x-ray scattering (SAXS) studies. EgAFFP exhibits an elongated molecular shape. The radius of gyration and the maximum dimension obtained by SAXS were, respectively, 2.52 ± 0.01 nm and 8.00 ± 1.00 nm, both in the absence and presence of Ca^sup 2+^. Two different molecular homology models were built for EgAFFP, but only one was validated through SAXS studies. The predicted structure for EgAFFP consists of three repeats of a central β-sheet sandwiched between one short and one long α-helix. Possible implications of the structure of EgAFFP upon actin binding are discussed.

The larval stage of the cestode tapeworm Echinococcus granulosus is the causative agent of cystic hydatid disease or hydatidosis, recognized as one of the world's major zoonoses (1). This parasite requires two mammalian hosts for completion of its life cycle. Adult tapeworms develop in the small intestine of definitive hosts (domestic dogs and wild canids), whereas the metacestode or hydatid cyst usually develops in the liver or lungs of intermediate hosts (mainly in ungulates, and accidentally in humans). The pathological effect of the disease is caused by the pressure exerted by the hydatid cyst on the intermediate host's viscera. Within the cyst, protoscoleces are produced by asexual reproduction and develop into the adult worm when ingested by the definitive host.

The E. granulosus complex life cycle involves important changes in cell morphology and physiology (2). The molecular and cellular mechanisms involved in E. granulosus development are still largely unknown but are likely to require extensive cytoskeleton reorganization (3,4).

The actin cytoskeleton is a vital component of several key cellular and developmental processes in eukaryotes, such as motility, cytokinesis, cytoplasmic organization, and endocytosis (5). In cells, the assembly and disassembly of actin filaments, in addition to their organization into functional three-dimensional (3D) networks, are regulated by a variety of actin-binding proteins (6-10). Among these proteins, those from the gelsolin superfamily control actin organization by severing filaments, capping filament ends, and nucleating actin assembly (11).

The best-studied members of this protein family are severin (12-14) and fragmin (15,16) from Dictyostelium discoideum and Physarum polycephalum, respectively, and gelsolin (17,18) and villin (19,20) from higher organisms. A common feature of this family is the segmentai organization into three (severin, fragmin) or six (gelsolin, villin) homologous domains that might have evolved from an ancestral one domain protein through a stepwise process, involving a gene triplication followed by an additional duplication event (21,17). The activities of these proteins are often modulated by signaling molecules, such as Ca^sup 2+^ or phosphorylated phosphoinositides (22). Based on gelsolin (23,24), the most extensively studied member of the family, it is generally accepted that the second domain binds F-actin, whereas the first domain (and the fourth one, for six domain proteins) binds G-actin.

So far, only a few proteins of the gelsolin superfamily have solved 3D structures. A search in the database of protein structures indicates that of all known members of this family to date, gelsolin is the only protein that has its fulllength (six domains) structure solved (25). Structures of other proteins, like villin (26) and severin (27,28), have been determined only for the first or second domains, usually bound to ligands (Ca^sup 2+^ and/or actin). Domain comparisons between the known structures show that they all share a common fold built around a central five-stranded mixed β-sheet, which is flanked by a long α-helix running parallel to the sheet and a short perpendicular running α-helix (25-29).

Our laboratory has previously cloned and functionally characterized a 42 kDa actin filament-fragmenting protein from E. granulosus (EgAFFP) (30). The recombinant EgAFFP protein is recognized by sera of ~69% of human hydatid disease patients (31) and, in vitro, was able to induce actin polymerization and sever actin filaments, confirming that it belongs to the gelsolin superfamily (30). According to sequence analysis, EgAFFP presents three repeated domains and is similar (36% identity) to the gelsolin NH^sub 2^-terminal half (G1-G3). The lack of structural data for full-length three domain members of the gelsolin superfamily, such as EgAFFP, represents an obstacle to the understanding of structure-function relationships of these smaller proteins, which are functionally equivalent to their six domain counterparts. Structural characterization of EgAFFP might help to understand how three domain members function and how they are regulated

We describe a finite-element model of mast cell calcium dynamics that incorporates the endoplasmic reticulum's complex geometry. The model is built upon a three-dimensional reconstruction of the endoplasmic reticulum (ER) from an electron tomographic tilt series. Tetrahedral meshes provide volumetric representations of the ER lumen, ER membrane, cytoplasm, and plasma membrane. The reaction-diffusion model simultaneously tracks changes in cytoplasmic and ER intraluminal calcium concentrations and includes luminal and cytoplasmic protein buffers. Transport fluxes via PMCA, SERCA, ER leakage, and Type II IP^sub 3^ receptors are also represented. Unique features of the model include stochastic behavior of IP^sub 3^ receptor calcium channels and comparisons of channel open times when diffusely distributed or aggregated in clusters on the ER surface. Simulations show that IP^sub 3^R channels in close proximity modulate activity of their neighbors through local Ca^sup 2+^ feedback effects. Cytoplasmic calcium levels rise higher, and ER luminal calcium concentrations drop lower, after IP^sub 3^-mediated release from receptors in the diffuse configuration. Simulation results also suggest that the buffering capacity of the ER, and not restricted diffusion, is the predominant factor influencing average luminal calcium concentrations.

The mobilization of calcium is a vital step in mast cell activation. Cross linking of high affinity IgE receptors initiates a tyrosine kinase cascade that activates phospholipase Cγ isoforms and leads to elevated levels of inositol 1.4.5-trisphosphate (IP^sub 3^) (I). Phosphatidylinositol 3-kinase lipid products enhance PLCy activity and are required for maximal IP^sub 3^ synthesis (1-4). Under optimal cross-linking conditions, intracellular Ca^sup 2+^ stores are rapidly depleted and do not refill tor minutes (5). Concomitant Ca^sup 2+^ influx supports a persistent elevation in cytoplasmic Ca^sup 2+^. The sustained phase of Ca^sup 2+^ influx occurs primarily via the capadtutive Ca^sup 2+^ pathway (6) and, paradoxically, is the phase of the response that is most dramatically affected by PI 3-kinase inhibition (1.4). Sustained elevations in cytoplasmic Ca^sup 2+^ are absolutely required for secretion of histamine, serotonin, and other preformed mediators of the allergic response (7).

Intracellular calcium stores in nonmuscle cells are principally released by IP^sub 3^ receptors, of which there are three closely related types (8). In 1998 we reported that Type II IP^sub 3^ receptors of RBL-2H3 cells, a mast tumor cell line, redistribute into large clusters in the endoplasmic reticulum (ER) after short periods of elevated intracellular calcium (9). Similar results were observed for Type 1 receptors in rat pancreatoma cells and for Type II receptors in hamster lung fibroblasts, suggesting that the induction of IP^sub 3^ receptor clustering is a common feature of this family of channels. We hypothesized that redistribution of receptors modulates Ca^sup 2+^ release from the ER. To address this issue, we have created a three-dimensional modeling environment that incorporates a realistic ER geometry and tracks free and hound calcium based upon reaction-diffusion rates and spatial constraints.

The modeling of an entire cell has been proposed as a grand challenge for this century (10). Modeling platforms such as Virtual Cell (11) and Mcell (12,13) represent important advances in this direction. Here we describe the development of a model cell that houses a geometric reconstruction of the ER and is populated with basic components of the calcium response pathway in most nonexcitable cells, including IP^sub 3^ receptors, SERCA and PMCA ATP-driven pumps, and calcium buffering proteins in the cytosol and ER lumen. A simpler ER disk model was also developed for comparison to the complex ER geometry model and for less costly pilot simulations. In both models, individual domains representing membranes, cytosol, and ER lumen are composed of tetrahedrons, providing a framework for solving multispecies diffusion/reaction equations at millisecond timescales. We report computational support for the concept that clustering influences channel behavior. Mobilization of clustered IP^sub 3^ receptors can result in modest gradients of calcium within the ER lumen during the initial phase of stores release though IP^sub 3^ receptors. However, its most important effect is to dramatically reduce the open channel probability and the release of stored calcium. Luminal buffers effectively minimize gradients, despite the potential for restricted diffusion in tight spaces within the ER. Hence, the principal consequence of stimulus-coupled receptor clustering may he to reduce IP^sub 3^R channel activity, protecting luminal calcium levels when cells are repeatedly stimulated.

In this study, we investigate the extent to which techniques for homology modeling that were developed for water-soluble proteins are appropriate for membrane proteins as well. To this end we present an assessment of current strategies for homology modeling of membrane proteins and introduce a benchmark data set of homologous membrane protein structures, called HOMEP. First, we use HOMEP to reveal the relationship between sequence identity and structural similarity in membrane proteins. This analysis indicates that homology modeling is at least as applicable to membrane proteins as it is to water-soluble proteins and that acceptable models (with Cα-RMSD values to the native of 2 [Angstrom] or less in the transmembrane regions) may be obtained for template sequence identities of 30% or higher if an accurate alignment of the sequences is used. Second, we show that secondary-structure prediction algorithms that were developed for water-soluble proteins perform approximately as well for membrane proteins. Third, we provide a comparison of a set of commonly used sequence alignment algorithms as applied to membrane proteins. We find that high-accuracy alignments of membrane protein sequences can be obtained using state-of-the-art profile-to-profile methods that were developed for water-soluble proteins. Improvements are observed when weights derived from the secondary structure of the query and the template are used in the scoring of the alignment, a result which relies on the accuracy of the secondary-structure prediction of the query sequence. The most accurate alignments were obtained using template profiles constructed with the aid of structural alignments. In contrast, a simple sequence-to-sequence alignment algorithm, using a membrane protein-specific substitution matrix, shows no improvement in alignment accuracy. We suggest that profile-to-profile alignment methods should be adopted to maximize the accuracy of homology models of membrane proteins.Membrane proteins are believed to comprise 20-30% of the proteins in a genome (1-3) and represent a significant proportion of therapeutic drug targets (4). However, as a result of difficulties in experimental structure determination, they constitute only ~1% of the structures available in the protein data bank (PDB) (5). The absence of structural information severely limits our ability to understand membrane protein function. Based on previous experience with water-soluble proteins, it is likely that computational structure prediction will provide a useful approach to generating models for these proteins. Typically, the most accurate models of protein structures are achieved through homology modeling, where a known structure is used as a template for the construction of a model of a related protein (6). However, it remains unclear whether the methods and assumptions used in homology modeling of water-soluble proteins can be applied directly to membrane proteins without modification.

The transport of reactive contaminants in the subsurface is generally affected by a large number of nonlinear and often interactive physical, chemical, and biological processes. Simulating these processes requires a comprehensive reactive transport code that couples the physical processes of water flow and advective-dispersive transport with a range of biogeochemical processes. Two recently developed coupled geochemical models that are both based on the HYDRUS-1D software package for variably saturated flow and transport are summarized in this paper. One model resulted from coupling HYDRUS-1D with the UNSATCHEM module. While restricted to major ion chemistry, this program enables quantitative predictions of such problems as analyzing the effects of salinity on plant growth and the amount of water and amendments required to reclaim salt-affected soil profiles. The second model, HP1, resulted from coupling HYDRUS-1D with the PHREEQC biogeochemical code. The latter program accounts for a wide range of instantaneous or kinetic chemical and biological reactions, including complexation, cation exchange, surface complexation, precipitation dissolution and/or redox reactions. The versatility of HP1 is illustrated in this paper by means of two examples: the leaching of toxic trace elements and the transport of the explosive TNT and its degradation products.

InfoSewer v4, for power ArcGIS (ESRI, Redlands, CA) users, includes Automated Intelligent Design Technology that automates challenging wastewater collection systems design, expansion, and rehabilitation activities. To improve system management, operation, and regulatory compliance, software helps create detailed, accurate models of sewer infrastructure systems. It provides users with various tools for calculation as well as design analysis, evaluation, and viewing.

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Revolutionary New Release Offers Unsurpassed Capabilities, Raising the Bar for Design,

Expansion and Rehabilitation of Wastewater Collection Systems

Broomfield, Colorado USA, June 28, 2006 - In its ongoing effort to provide the global wastewater industry with the world's most comprehensive and innovative GIS-centric modeling and design solutions, MWH Soft, a leading global provider of environmental and water resources applications software, today announced the worldwide availability of the V4 Generation of InfoSewer for power ArcGIS (ESRI, Redlands, CA) users.

In response to customer feedback, this latest version introduces valuable user-driven enhancements and functionalities, along with architectural and database improvements that make sophisticated sewer systems analysis and design applications fast and easy to use. V4 also debuts Automated Intelligent Design Technology, which for the first time puts expert-level, high performance techniques in the hands of every user that enable automation of the most challenging wastewater collection systems design, expansion and rehabilitation activities. These enhancements equip wastewater utilities with unprecedented power to improve system management, operation and regulatory compliance.

InfoSewer is used worldwide by municipal engineers and planners to create detailed, accurate models of sewer infrastructure systems. These models enable users to evaluate the effect of new developments, zoning changes, and other additional loads on system flows; pinpoint current and future problem areas; predict overflows and backups; and determine how to best restore needed capacity lost to infiltration and inflow with the least rehabilitation. In addition, users rely on these models to compute hydrogen sulfide generation and corrosion potential; analyze the rate of Biochemical Oxygen Demand (BOD) exertion; track sediment movement and deposition; calculate the amount of pollutant transported to the wastewater treatment plant; and assess pollutants' impacts on receiving waters. The application also provides vital tools for meeting and exceeding environmental regulations and improving community relations.

Toppling the notion that powerful software is necessarily complex, InfoSewer V4 delivers advanced design functionality and exponential increases in efficiency while simplifying its use. Users can now quickly and reliably design new sewer collection systems that consider standard design criteria such as flow depth-to-pipe diameter ratios, velocity, slope, soil cover depth, and pipe crown drop. Using user-input manhole locations, InfoSewer V4 calculates the optimal pipe size and slope, invert elevation of conduits and manholes, soil cover depths at both ends of each pipe section, and cost of excavation and reinstatement to meet target design criteria. Results can be reviewed using profile plots, color coding of sewer maps, or comprehensive tabular reports. They can then be automatically updated in the model database, simplifying the model building process.

Together, these important capabilities will help wastewater utilities worldwide dramatically raise productivity and efficiency by rapidly developing practical and optimal capital improvement strategies that minimize costs while improving system reliability, integrity and performance. By making engineering professionals more productive and their organizations more competitive, V4 delivers benefits utilities can pass on to their customers through better designs and higher quality standards, achieved in a shorter turnaround time.

"InfoSewer is the ideal choice for organizations that need a single reliable, affordable and easily implemented solution for advanced geocentric modeling and design of sewer collection systems," said Paul F. Boulos, Ph.D, President and Chief Operating Officer of MWH Soft. "The program is built on the experience our company has gained from our large user community. Their input continuously drives us to add new functionalities and set new standards through pioneering technology. Our latest version gives users the trusted tool they need to identify the most cost-effective ways to keep their systems operating efficiently into the future. We are confident that it will influence wastewater design engineering for years to come."

ARTiSAN Studio v6.1 supports SysML standard as well as range of safety-related process standards. Included SysML Requirements Profile brings textual requirements to UML by making use of Ergonomic Profiling capabilities to provide menus, diagrams, and browser for exploring systems requirements and traceability relationships. Software also supports OMG's Model Driven Architecture with single-step process for transforming state machines into code.

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ARTiSAN Studio 6.1 Includes Support for New SysML Standard

CHELTENHAM, England, July 20 -- ARTiSAN Software Tools, a global leader for UML 2.0 and SysML-based real-time systems and software modeling tools, has announced that it has started shipping ARTiSAN Studio 6.1 which includes features and functionality in support of the new SysML standard. The shipping of ARTiSAN Studio 6.1 follows the announcement by The Object Management Group (OMG) that the SysML specification was formally adopted on July 6th, 2006.

SysML represents a subset of UML 2.0 with extensions to satisfy the needs of systems engineers. ARTiSAN Studio 6.1 provides support for requirements modeling, one of the principal extensions introduced by SysML, in an easy-to-use, out-of-the-box solution that supports a range of safety-related process standards such as DO178B for avionics software, IEC/DIN/EN 61508 for automotive and other safety-critical applications, CENELEC DIN/EN 50126, 50128, 50129 for railway transportation and DO254 for hardware. The new SysML Requirements Profile (RP) brings textual requirements to the UML world by making use of ARTiSAN Studio's advanced Ergonomic Profiling capabilities to provide new menus, diagrams and a browser for exploring systems requirements and traceability relationships. It also supports a wide external tool chain allowing textual requirements to be displayed and traced inside the UML/SysML model and synchronization with requirements held in external tools such as DOORS, RequisitePro, Word, Excel and Access.

ARTiSAN Studio 6.1 also supports the OMG's concept of Model Driven Architecture (MDA) with a practical and usable solution that provides a fast, single-step process for transforming state machines into code. ARTiSAN's Template Development Kit (TDK) provides ground breaking technology for configuring the model-to-code transformations to support in-house standards, key hardware/software constraints, target-ready code and reusable design patterns.

As further support for model simulation and animation, ARTiSAN Studio 6.1 also sees the roll-out of the integration of iSYSTEM's emulation and debug technology to provide a contiguous solution for the on-target simulation of embedded applications modeled in UML.

Additionally, ARTiSAN Studio 6.1 introduces a new repository-based configuration management capability in support of model-driven, team-based software development. Aligned with the built-in change tracking facility, the internal versioning provides a significantly enhanced ability to efficiently baseline large models to support key review and audit processes. Also included is the ability to create private views of the repository.

As part of ARTiSAN's UML 2 compliance strategy, ARTiSAN Studio 6.1 also delivers leading support for XML Metadata Interchange (XMI) 2.1 functionality. XMI enables the exchange of data between UML modeling tools and metadata repositories and is especially important for supporting third party add-ins built in Eclipse.

ARTiSAN Studio 6.1 incorporates a range of user-requested usability improvements to increase developer productivity. These include a powerful web-style navigation toolbar for navigating through the user interface and additional support for fine tuning diagrams to improve presentation and display. Also included are infrastructure enhancements to support tool roll-out on large-scale, mission-critical systems development including further support for Active Directory, Chinese Windows and emulation under Linux. Support for ARTiSAN Studio's Rational Rose migration tool has also been improved, reinforcing its position as the tool of choice for Rose migration.

MF: All of our readers are dying to know: How'd you earn the name "the Pleasure Machine"?

GR: [Laughs] It actually has nothing to do with what most people would think. I did a commercial for Virgin Airways where I played a stripper, in a real strip club, wearing black boots and a black bikini. In the commercial, there was a famous poet doing a voice-over, and he read the words, "Step aboard the pleasure machine," just as they showed me dancing and spinning around the pole. In Australia, everyone has a nickname, so when people saw the commercial, it just stuck. I love it; I think it's great!

What would a guy need to do to earn the label "Pleasure Machine" in your eyes?

He'd have to have a great body! [Laughs] Especially nice, muscled arms or a nice butt. When I'm in the gym and American football is on, I can't resist stating at the players' tight, shiny pants, because most of the guys have such great buns, legs, and thighs.