A model system for understanding cellular signaling of the cannabinoid CB2 receptor via the inhibitory Gi protein

One key signaling pathway in the cellular signaling involving G protein coupled receptors (GPCR) is via heterotrimeric G proteins. The first step in GPCR/G protein signaling is the activation of a GPCR by the ligand binding and the next step is the activation of the G protein. Understanding the molecular mechanism behind the GPCR/G protein interactions will help in characterizing this important signaling pathway and should ultimately lead to the design of functionally selective ligands for this larger class of receptors. Earlier, the Reggio group used molecular dynamics simulations to study the activation of the cannabinoid CB2 receptor, a class A GPCR, by its endogenous ligand, 2-arachidonoylglycerol (2-AG) via the lipid bilayer. The goal of the current project was to study the next step in the G-protein mediated signal transduction, when an agonist activated CB2 receptor forms a complex with Gi protein and catalyzes the activation of Gi protein, releasing the guanosine diphosphate (GDP) bound between the ras-like (also known as GTPase domain) and helical domains of the Gá protein. To this end, we report here the CB2 / Gái1â1ã2 complex formation using our 2-AG activated CB2 receptor model. For G protein activation (dissociation of GDP), we hypothesized that GDP release from the ras-like and helical domains of Gái would be triggered by the hydration of GDP. We probed the role of the CB2 receptor interactions with the Gái protein and the resultant progression of GDP hydration. We have seen the number of waters surrounding GDP increase from 16 (t= 0 ns) to 28 waters (t=5 ìs). Two important interactions between the receptor and G-protein appear to lead to the increased hydration of GDP. (1) A hydrophobic interaction occurred between CB2 IC2 loop residue P139 and the Gái hydrophobic pocket residues: V34 (N terminus; L194 (â1 sheet); F196 (â2 sheet); and, F336, T340, I343, I344 (á5 helix) multiple times in our 5 ìs long trajectory. Each time this interaction occurred, an increase in GDP hydration was observed in our simulation. 2) We also observed an IC3 loop interaction with the Gái á4 helix between 1.4 to 1.6 ìs, in which the IC3 loop residue R229 reached to interact with E297 and E298. Taken together, our results show that the intracellular loops play a critical role in the hydration of GDP that should lead to G protein activation

Building Relationships with India's Suppliers: Exploring Perceptions of U.S. Apparel Industry Buyers

India is emerging as one of the major players in global apparel sourcing to the U.S. in the post-quota era. There has been a steady year-to-year rise of approximately 13.3% in exports of garments from India (Goel, 2007). In 2005, India ranked third in apparel exports to the U.S., increasing its total exports to 34%. Tariff and trade data from the U.S. Department of Commerce and the U.S. International Trade Commission (2007) shows that total apparel imported into the United States from India was $2.9 billion in 1997, increasing to$6.4 billion in 2006, and that the percentage change from 2005 to 2006 was an increase of 18.40%. This market growth suggests the importance of the buyer-supplier relationship throughout the supply chain. Effectively managing relationships with suppliers is an important concern for maintaining high profits as well as competitive advantage (Wuyts, 2007). Although several studies have been conducted on supply chain relationships, the particular importance of the U.S.-India relationship in the apparel sector has been overlooked. The purpose of this study is to explore U.S. apparel buyers' relationships with their Indian suppliers, including the supplier selection process, and to specifically investigate the role of buyer-supplier relationship attributes. Using a qualitative methodology, in-depth interviews were conducted with twenty three U.S. apparel industry buyers located in New York, North Carolina, and California who are engaged in buying apparel products from Indian suppliers. Interviews lasted approximately 45 to 90 minutes per participant, and were audio-taped with participant consent. Interviews were transcribed and interpreted thematically. Six themes - Expertise, Convenience, Price, Functionality, Service, and Partnership - surfaced within the interview data and were used to structure the interpretation. Based on the interpretation, four relationship types were developed: Convenience Driven, Price Sensitive, Functionality Driven, and Service Driven. The majority of participants seek to develop Service Driven relationships with their suppliers. In building this type of relationship, the most important attributes were found to be trust, communication, and commitment. Because there is a limited amount of research that explores relationships being developed between U.S. apparel companies and Indian suppliers, and no studies that explore them from the perspective of buyers, the results of this study provide an in-depth understanding of the issues and challenges involved in working together on a global platform. Strong relationships with India are critical for U.S. apparel companies, not only to increase profits, but to bring a quality product to market that will satisfy the final consumer. This study contributes to both U.S. apparel industry buyers' and Indian suppliers' knowledge of how to build strong buyer-supplier relationships in global apparel production. Future empirical research is needed to further investigate buyer-supplier relationships and thereby enrich our understanding of them

Enhancing Learning Management Systems Utility for Blind Students: A Task-oriented, User-Centered, Multi-Method Evaluation Technique

This paper presents a novel task-oriented, user-centered, multi-method evaluation (TUME) tech-nique and shows how it is useful in providing a more complete, practical and solution-oriented assessment of the accessibility and usability of Learning Management Systems (LMS) for blind and visually impaired (BVI) students. Novel components of TUME include a purposeful integra-tion of a multi-theoretic foundation and multiple methods to accurately identify users’ accessibil-ity and usability problems in Web interaction and identify design problems and solutions to en-sure technical feasibility of recommendations. The problems identified by TUME remain hidden from extant evaluation methods - therefore, these problems remain in Web-based applications. As a result, evaluation of Web-based applications remains confounded by users’ Web interaction challenges; their utility for specific user types remains unclear. Without appropriate evaluation of users’ problems and challenges in using Web-based applications, we cannot begin to solve these problems and challenges. This paper demonstrates how TUME can be used to identify the unique problems and challenges of specific user types in using Web-based applications and suggests po-tential solutions. The outcome is an accurate understanding of specific design elements that pre-sent roadblocks and challenges for the user in interacting with the Web-based application and feasible design modifications to potentially improve the utility of these applications for specific user types

A semantic approach to monitoring business process performance

The productivity and profitability of organizations depend on the efficacy of their business processes. Monitoring the performance of these processes in delivering organizational value propositions provides a basis for critical managerial decision-making activities including work scheduling, capacity planning, and process design or refinement [8] . Business processes are automated in whole or in part using workflow management systems (WFMS), where documents, information, and activities flow between participants according to existing process models and rules [9]. Workflows are abstractions of business processes that are typically modeled as deterministic, action-event sequences in WFMS [8] . Organizations employ tactical WFMS with sampling-based schemes or data-driven operational WFMS using firsthand observations for process evaluation. Managing the performance and quality of business processes based on accurate performance measures has direct impact on the success of an organization [8, 10]

A real-time information system for multivariate statistical process control

Statistical process control (SPC) is widely used in process industries to monitor variations in process attributes. Typically, automatic devices capture a multitude of measurements on process and product characteristics every few seconds. Operators and engineers commonly monitor only a small subset of these. Multivariate SPC has been proposed to fully utilize the available data, however, interpretation of multivariate information is often too complex for most line operators. This paper describes the design and implementation of a real-time multivariate process control system that features a graphical user interface (GUI) and provides useful information for both line operators and engineers. The information system described in this paper should provide large-scale manufacturers with better access to information for identifying opportunities in continuing to improve processes performance and business competitiveness

Thermal management and electromechanical noise suppression in a portable josephson junction voltage standard

A self-contained, fully portable, Josephson junction voltage reference standard system has been designed, developed and tested. The system relies on an active, closed-cycle refrigerator (CCR) cryocooler system and completely eliminates the reliance on liquid helium for cooling the Josephson Junction Array (JJA) chip to the required superconducting temperature of approximately to 4.2 K. The CCR based system has performance capabilities comparable to the liquid helium Dewar-based system and is packaged to operate as a portable system in environments like the US Army's calibration vans or calibration labs that do not have access to liquid helium. The use of a CCR based cryocooling system brings forth many challenges not found in the classic Dewar-based system. This work identifies the principal challenges for achieving an operating system, and provides unique solutions to overcoming two areas of significant concern, thermal management and electromagnetic noise. Dewar based systems provide three-dimensional convective cooling. While very effective in cooling, they are inappropriate for portable labs and are subject to evaporation. The challenge for an active system is in providing adequate thermal management to ensure sufficient cooling despite having only one-dimensional conductive cooling. An extensive study was conducted into various methodologies for mounting the chip in the new system and ensuring that superconducting temperatures were obtained. The surface roughness of a conventional machined surface is in the range of several micrometers. The random peaks and valleys of the surface offer insufficient contact area between the cryocooler cold-head and the Josephson junction array chip, resulting in higher than superconducting temperatures at the JJA chip surface. Several approaches researched to increase the thermal contact conductance included thermal grease, adhesives and other high conductivity interstitial materials. The solution provided in this research is an elegantly simple technique, which eliminated the introduction of viscous materials or adhesives, thereby improving the maintainability of the chip. An innovative chip-mount was designed and machined using a state-of-the-art diamond turning technique to achieve a surface roughness of lower than 5 nm and completely eliminate the use of any foreign material. The diamond turned surface attained an operational temperature of 4.2 ± 0.2 K indicating a 30% improvement in the ability to cool the JJA chip. The second area of interest is understanding the presence of magnetic fields and electromagnetic noise in the vicinity of the JJA chip and eliminating or greatly reducing them. High permeability MuMetal® magnetic shields were designed and installed to reduce the presence of magnetic field by up to 90%, and the nature of magnetic field noises were experimentally quantified. Performance deterioration due to the presence of electromagnetic noise induced by the cryocooler, motor and pump was expected, but for the first time detailed experiments were conducted to measure the magnetic fields in the system, understand their effects, and systematically eliminate or reduce them

Evaluating the Performance and Quality of Web Services in Electronic Marketplaces

A Web service is a software interface that describes a collection of operations that can be accessed over the network through standardized messaging. Effective performance and quality measures of Web services on Web service electronic marketplaces should include both technical and business aspects and consider Web services as business services delivered through multiple channels. In this research, we integrate technical measures of e-service performance with established measures for evaluating service quality in a business. This integrated view of Web service performance is lacking in extant knowledge and is critically needed to evaluate the overall quality and performance of business environment where information services are delivered through Web services

A multi-criteria approach to local tax planning

A city tax model based on the analytic hierarchy process is developed. This model allows city officials to explicitly take into account the existence of multiple decision criteria in selecting new tax options. Opinions from tax experts are used to relate tax plans to decision criteria. The paper explores the feasibility of applying commonly available decision tools to facilitate and improve decision making in local government

FLUID-STRUCTURE INTERACTION DURING SEISMICALLY EXCITED SLOSHING WITHIN SHALLOW SKIRT SUPPORTED PRESSURE VESSELS

This dissertation describes the finite element considerations employed in a seismic response spectrum analysis of a skirt supported, liquid containing pressure vessel. Like many axisymmetric cylindrical vessels, the gross seismic response to an input response spectrum can be categorized by a simplified lump mass model that includes both the mass of the vessel proper in combination with the associated mass of multiple fluid levels. This simplified response may be utilized to determine the initial sizing of the supporting configuration, such as a skirt, but lacks the ability to properly address the fluid-structure interaction that creates sloshing loads on the vessel walls. The most obvious method to address the fluid-structure interaction when considering the finite element method is to build a three-dimensional model of the vessel proper, including, but not limited to the shell courses, the top and bottom heads (for a vertical vessel), and the support skirt. The inclusion of the fluid effects may now be incorporated with a “contained fluid” finite element, however, for vessels of any significant volume, the number of finite elements can easily exceed 100,0000 and the number of degrees of freedom can sore from as few as 300,0000 to as many as 500,0000 or more. While these types of finite element analysis problems can be solved with today’s computer hardware and software, it is not desirable in any analysis to have that volume of information that has to be reviewed and approved in a highly regulated nuclear QA environment (if at all possible).With these items in mind, the methodology described in this dissertation seeks to minimize the number of degrees of freedom associated with a response spectrum analysis of a liquid filled, skirt supported vertical pressure vessel. The input response spectra are almost always provided in Cartesian coordinates, while many, if not most liquid containing pressure vessels are almost always axisymmetric in geometry without having benefit of being subjected to an axisymmetric load (acceleration in this case) due to the specified seismic event. The use of harmonic finite elements for both the vessel structure and the contained fluid medium permit the efficiencies associated with an axisymmetric geometry to be leveraged when the seismic response spectrum is formulated in terms of a Fourier series and combined to regain the effects of the two orthogonal, horizontally applied accelerations as a function of frequency. The end result as discussed and shown in this dissertation is a finite element model that permits a dense mesh of both the fluid and the structure, while economizing on the number of simultaneous equations required to be solved by the chosen finite element analysis. The method to obtain results at any chosen circumferential location is first developed for a simpler geometry utilizing a ground supported tank with flat heads. The results of the method developed herein are verified by comparison to published analytical results. The subject methodology is then applied to the skirt supported pressure vessel

BUCKLING LOAD PREDICTIONS IN PRESSURE VESSELS UTILIZING MONTE CARLO METHOD

In practice, large diameter, thin wall shells of revolution are never fabricated with constant diameters and thicknesses over the entire length of the assembly. These initial geometric imperfections have significant effect on the load carrying capacity of cylindrical shells. The cylindrical shell in the study is flue gas desulphurization (FGD) "vessel" which is a large hybrid tank-vessel-stack assembly in a major Canadian refinery. The function of the FGD vessel is to contain and support a proprietary process that utilizes an ammonium sulphate scrubbing system to produce environmentally friendly air emissions. FGD vessel stack has internal diameter of 6.1m, height of 45.34m and wall thickness of 9.525mm. Initial imperfections in FGD vessel is in the form of wall thickness variations. FGD wall thickness at 144 points along the circumference and elevation are measured. Monte Carlo method is employed to generate the measured data again. Test of significance is carried out to see the accuracy of the data generated. This Monte Carlo algorithm can be used to create data for any type of shell without spending time in actual measurements. Next, load carrying capacity of shell is determined considering imperfections to be axisymmetric and then asymmetric. Fourier decomposition is used to interpret imperfections as structural features can be easily related to the different components of imperfections. Further, double Fourier series is used to represent asymmetric initial geometric imperfections. The ultimate objective of these representations is to achieve a quantitative assessment of the critical buckling load considering the small axisymmetric and asymmetric deviations from the nominal cylindrical shell wall thickness. Analysis of cylindrical shells when used as pressure vessels and are under external pressure is also carried out. Comparison of reliability techniques that employ Fourier series representations of random axisymmetric and asymmetric imperfections in axially compressed cylindrical shells and shells under external pressure with evaluations prescribed by ASME Boiler and Pressure Vessel Code, Section VIII, Division 1 and 2 is also carried out