Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: Synthesis, biological evaluation, and molecular modeling in the homology model

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compoundsthe bisulfate salt of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (−)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(−)-3-(4-chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.

Molecular modeling of Bt Cry1Ac (DI–DII)–ASAL (Allium sativum lectin)–fusion protein and its interaction with aminopeptidase N (APN) receptor of Manduca sexta

Genetic engineering of Bacillus thuringiensis (Bt) Cry proteins has resulted in the synthesis of various novel toxin proteins with enhanced insecticidal activity and specificity towards different insect pests. In this study, a fusion protein consisting of the DI–DII domains of Cry1Ac and garlic lectin (ASAL) has been designed in silico by replacing the DIII domain of Cry1Ac with ASAL. The binding interface between the DI–DII domains of Cry1Ac and lectin has been identified using protein–protein docking studies. Free energy of binding calculations and interaction profiles between the Cry1Ac and lectin domains confirmed the stability of fusion protein. A total of 18 hydrogen bonds was observed in the DI–DII–lectin fusion protein compared to 11 hydrogen bonds in the Cry1Ac (DI–DII–DIII) protein. Molecular mechanics/Poisson–Boltzmann (generalized-Born) surface area [MM/PB (GB) SA] methods were used for predicting free energy of interactions of the fusion proteins. Protein–protein docking studies based on the number of hydrogen bonds, hydrophobic interactions, aromatic–aromatic, aromatic–sulphur, cation–pi interactions and binding energy of Cry1Ac/fusion proteins with the aminopeptidase N (APN) of Manduca sexta rationalised the higher binding affinity of the fusion protein with the APN receptor compared to that of the Cry1Ac–APN complex, as predicted by ZDOCK, Rosetta and ClusPro analysis. The molecular binding interface between the fusion protein and the APN receptor is well packed, analogously to that of the Cry1Ac–APN complex. These findings offer scope for the design and development of customized fusion molecules for improved pest management in crop plants.

An open source service oriented Mobile Business Intelligence Tool (MBIT)

Corporate executives require relevant and intelligent business information in real-time to take strategic decisions. They require the freedom to access this information anywhere and anytime. There is a need to extend this functionality beyond the office and on the fingertips of the decision makers. Mobile Business Intelligence Tool (MBIT) aims to provide these features in a flexible and cost-efficient manner. This paper describes the detailed architecture of MBIT to overcome the limitations of existing mobile business intelligence tools. Further, a detailed implementation framework is presented to realize the design. This research highlights the benefits of using service oriented architecture to design flexible and platform independent mobile business applications. © 2009 IEEE.

An efficient and light-weight multi-tasking model to achieve Intra-Agent concurrency for SAGE

Multi-agent systems implicate a high degree of concurrency at both the Inter- and Intra-Agent levels. Scalable, fault tolerant, Agent Grooming Environment (SAGE), the second generation, FIPA compliant MAS requires a built in mechanism to achieve both the Inter- and Intra-Agent concurrency. This paper dilates upon an attempt to provide a reliable, efficient and light-weight solution to provide intra-agent concurrency with-in the internal agent architecture of SAGE. It addresses the issues related to using the JAVA threading model to provide this level of concurrency to the agent and provides an alternative approach that is based on an eventdriven, concurrent and user-scalable multi-tasking model for the agent's internal model. The findings of this paper show that our proposed approach is suitable for providing an efficient and lightweight concurrent task model for SA GE and considerably outweighs the performance of multithreaded tasking model based on JAVA in terms of throughput and efficiency. This has been illustrated using the practical implementation and evaluation of both models. © 2004 IEEE.

A collaborative multi-agent based conference planner application using web and grid services

Distributed Collaborative Computing services have taken over centralized computing platforms allowing the development of distributed collaborative user applications. These applications enable people and computers to work together more productively. Multi-Agent System (MAS) has emerged as a distributed collaborative environment which allows a number of agents to cooperate and interact with each other in a complex environment. We want to place our agents in problems whose solutions require the collation and fusion of information, knowledge or data from distributed and autonomous information sources. In this paper we present the design and implementation of an agent based conference planner application that uses collaborative effort of agents which function continuously and autonomously in a particular environment. The application also enables the collaborative use of services deployed geographically wide in different technologies i.e. Software Agents, Grid computing and Web service. The premise of the application is that it allows autonomous agents interacting with web and grid services to plan a conference as a proxy to their owners (humans). © 2005 IEEE.

Negotiation schemes for multi-agent cooperative search

Because of limited sensor and communication ranges, designing efficient mechanisms for cooperative tasks is difficult. In this article, several negotiation schemes for multiple agents performing a cooperative task are presented. The negotiation schemes provide suboptimal solutions, but have attractive features of fast decision-making, and scalability to large number of agents without increasing the complexity of the algorithm. A software agent architecture of the decision-making process is also presented. The effect of the magnitude of information flow during the negotiation process is studied by using different models of the negotiation scheme. The performance of the various negotiation schemes, using different information structures, is studied based on the uncertainty reduction achieved for a specified number of search steps. The negotiation schemes perform comparable to that of optimal strategy in terms of uncertainty reduction and also require very low computational time, similar to 7 per cent to that of optimal strategy. Finally, analysis on computational and communication requirement for the negotiation schemes is carried out.

A potent nonporphyrin class of photodynamic therapeutic agent: Cellular localisation, cytotoxic potential and influence of hypoxia

We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics. © 2005 Cancer Research UK.

Modeling of Freezing Phenomena Induced by Chemical Reactions

Spatial variations in the concentration of a reactive solute in solution are often encountered in a catalyst particle, and this leads to variation in the freezing point of the solution. Depending on the operating temperature, this can result in freezing of the solvent oil a portion of catalyst, rendering that part of the active area ineffective Freezing call occur by formation of a sharp front or it mush that separates the solid and fluid phases. In this paper, we model the extent of reduction in the active area due to freezing. Assuming that the freezing point decreases linearly with solute concentration, conditions for freezing to occur have been derived. At steady state, the ineffective fraction of catalyst pellet is found to be the same irrespective of the mode of freezing. Progress of freezing is determined by both the heat of reaction and the latent heat of fusion Unlike in freezing of alloys where the latter plays a dominant role, the exothermicity of the reaction has a significant effect on freezing in the presence of chemical reactions. A dimensionless group analogous to the Stefan number could be defined to capture the combined effect of both of these.

Modeling finite buffer effects on TCP traffic over an IEEE 802.11 infrastructure WLAN

The network scenario is that of an infrastructure IEEE 802.11 WLAN with a single AP with which several stations (STAs) are associated. The AP has a finite size buffer for storing packets. In this scenario, we consider TCP-controlled upload and download file transfers between the STAs and a server on the wireline LAN (e.g., 100 Mbps Ethernet) to which the AP is connected. In such a situation, it is well known that because of packet losses due to finite buffers at the AP, upload file transfers obtain larger throughputs than download transfers. We provide an analytical model for estimating the upload and download throughputs as a function of the buffer size at the AP. We provide models for the undelayed and delayed ACK cases for a TCP that performs loss recovery only by timeout, and also for TCP Reno. The models are validated incomparison with NS2 simulations.

Ferrous iron oxidation by foam immobilized Acidithiobacillus ferrooxidans: Experiments and modeling

Ferrous iron bio-oxidation by Acidithiobacillus ferrooxidans immobilized on polyurethane foam was investigated. Cells were immobilized on foams by placing them in a growth environment and fully bacterially activated polyurethane foams (BAPUFs) were prepared by serial subculturing in batches with partially bacterially activated foam (pBAPUFs). The dependence of foam density on cell immobilization process, the effect of pH and BAPUF loading on ferrous oxidation were studied to choose operating parameters for continuous operations. With an objective to have high cell densities both in foam and the liquid phase, pretreated foams of density 50 kg/m3 as cell support and ferrous oxidation at pH 1.5 to moderate the ferric precipitation were preferred. A novel basket-type bioreactor for continuous ferrous iron oxidation, which features a multiple effect of stirred tank in combination with recirculation, was designed and operated. The results were compared with that of a free cell and a sheet-type foam immobilized reactors. A fivefold increase in ferric iron productivity at 33.02 g/h/L of free volume in foam was achieved using basket-type bioreactor when compared to a free cell continuous system. A mathematical model for ferrous iron oxidation by Acidithiobacillus ferrooxidans cells immobilized on polyurethane foam was developed with cell growth in foam accounted by an effectiveness factor. The basic parameters of simulation were estimated using the experimental data on free cell growth as well as from cell attachment to foam under nongrowing conditions. The model predicted the phase of both oxidation of ferrous in shake flasks by pBAPUFs as well as by fully activated BAPUFs for different cell loadings in foam. Model for stirred tank basket bioreactor predicted within 5% both transient and steady state of the experiments closely for the simulated dilution rates. Bio-oxidation at high Fe2+ concentrations were simulated with experiments when substrate and product inhibition coefficients were factored into cell growth kinetics.

Scalable fault tolerant agent grooming environment-SAGE

Multi-agent systems (MAS) advocate an agent-based approach to software engineering based on decomposing problems in terms of decentralized, autonomous agents that can engage in flexible, high-level interactions. This chapter introduces scalable fault tolerant agent grooming environment (SAGE), a second-generation Foundation for Intelligent Physical Agents (FIPA)-compliant multi-agent system developed at NIIT-Comtec, which provides an environment for creating distributed, intelligent, and autonomous entities that are encapsulated as agents. The chapter focuses on the highlight of SAGE, which is its decentralized fault-tolerant architecture that can be used to develop applications in a number of areas such as e-health, e-government, and e-science. In addition, SAGE architecture provides tools for runtime agent management, directory facilitation, monitoring, and editing messages exchange between agents. SAGE also provides a built-in mechanism to program agent behavior and their capabilities with the help of its autonomous agent architecture, which is the other major highlight of this chapter. The authors believe that the market for agent-based applications is growing rapidly, and SAGE can play a crucial role for future intelligent applications development. © 2007, IGI Global.

Modeling of heat and mass transfer for solid state fermentation process in tray bioreactor

A mathematical model is developed to simulate oxygen consumption, heat generation and cell growth in solid state fermentation (SSF). The fungal growth on the solid substrate particles results in the increase of the cell film thickness around the particles. The model incorporates this increase in the biofilm size which leads to decrease in the porosity of the substrate bed and diffusivity of oxygen in the bed. The model also takes into account the effect of steric hindrance limitations in SSF. The growth of cells around single particle and resulting expansion of biofilm around the particle is analyzed for simplified zero and first order oxygen consumption kinetics. Under conditions of zero order kinetics, the model predicts upper limit on cell density. The model simulations for packed bed of solid particles in tray bioreactor show distinct limitations on growth due to simultaneous heat and mass transport phenomena accompanying solid state fermentation process. The extent of limitation due to heat and/or mass transport phenomena is analyzed during different stages of fermentation. It is expected that the model will lead to better understanding of the transport processes in SSF, and therefore, will assist in optimal design of bioreactors for SSF.

The role of glycodelin as an immune-modulating agent at the feto-maternal interface

Glycodelin A is a progesterone-induced endometrial glycoprotein which has been amply documented to play a role in down-modulation of the maternal immune response to fetal allo-antigens and to be indispensable for the maintenance and progression of pregnancy. Earlier studies from our laboratory have focused on the effect of glycodelin on T cells, key regulators of both the antibody and cell-mediated arms of the acquired immune system. Glycodelin-induced apoptosis inactivated T cells occurs through a caspase-dependant intrinsic mitochondrial pathway. Interestingly, glycodelin inhibited the proliferation of B cells but did not induce apoptosis. More recently, we have studied the effect of glycodelin on the cells of the innate immune system, namely monocytes and NK cells. We have found that glycodelin induced apoptosis in monocytic cells before their differentiation to macrophages, via the mitochondrial pathway, but did not affect their phagocytic capacity after differentiation. Glycodelin induced apoptosis in NK cells but this activity was independent of caspases. In conclusion, glycodelin is observed to affect many cells of the immune system, although the nature of the effect and signaling mechanisms involved in each cell type may be distinct.

Continually adjustable oriented 1D TiO2 nanostructure arrays with controlled growth of morphology and their application in dye-sensitized solar cells

Oriented, single-crystalline, one-dimensional (1D) TiO2 nanostructures would be most desirable for providing fascinating properties and features, such as high electron mobility or quantum confinement effects, high specific surface area, and even high mechanical strength, but achieving these structures has been limited by the availability of synthetic techniques. In this study, a concept for precisely controlling the morphology of 1D TiO2 nanostructures by tuning the hydrolysis rate of titanium precursors is proposed. Based on this innovation, oriented 1D rutile TiO2 nanostructure arrays with continually adjustable morphologies, from nanorods (NRODs) to nanoribbons (NRIBs), and then nanowires (NWs), as well as the transient state morphologies, were successfully synthesized. The proposed method is a significant finding in terms of controlling the morphology of the 1D TiO2 nano-architectures, which leads to significant changes in their band structures. It is worth noting that the synthesized rutile NRIBs and NWs have a comparable bandgap and conduction band edge height to those of the anatase phase, which in turn enhances their photochemical activity. In photovoltaic performance tests, the photoanode constructed from the oriented NRIB arrays possesses not only a high surface area for sufficient dye loading and better light scattering in the visible light range than for the other morphologies, but also a wider bandgap and higher conduction band edge, with more than 200% improvement in power conversion efficiency in dye-sensitized solar cells (DSCs) compared with NROD morphology.