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An efficient model for communications between CAD, CAPP, and CAM applications in distributed manufacturing planning environment has been seen as key ingredient for CIM. Integration of design model with process and scheduling information in real-time is necessary in order to increase product quality, reduce the cost, and shorten the product manufacturing cycle. This paper describes an approach to integrate key product realization activities using neutral data representation. The representation is based on established standards for product data exchange and serves as a prototype implementation of these standards. The product and process models are based on object-oriented representation of geometry, features, and resulting manufacturing processes. Relationships between objects are explicitly represented in the model (for example, feature precedence relations, process sequences, etc.). The product model is developed using XML-based representation for product data required for process planning and the process model also uses XML representation of data required for scheduling and FMS control. The procedures for writing and parsing XML representations have been developed in object-oriented approach, in such a way that each object from object-oriented model is responsible for storing its own data into XML format. Similar approach is adopted for reading and parsing of the XML model. Parsing is performed by a stack of XML handlers, each corresponding to a particular object in XML hierarchical model. This approach allows for very flexible representation, in such a way that only a portion of the model (for example, only feature data, or only the part of process plan for a single machine) may be stored and successfully parsed into another application. This is very useful approach for direct distributed applications, in which data are passed in the form of XML streams to allow real-time on-line communication. The feasibility of the proposed model is verified in a couple of scenarios for distributed manufacturing planning that involves feature mapping from CAD file, process selection for several part designs integrated with scheduling and simulation of the FMS model using alternative routings.

MicroRNAs (miRNAs) act in post-transcriptional gene silencing and are proposed to function in a wide spectrum of pathologies, including cancers and viral diseases. Currently, to our knowledge, no detailed mechanistic characterization of small molecules that interrupt miRNA pathways have been reported. In screening a small chemical library, we identified compounds that suppress RNA interference activity in cultured cells. Two compounds were characterized; one impaired Dicer activity while the other blocked small RNA-loading into an Argonaute 2 (AGO2) complex. We developed a cell-based model of miRNA-dependent tumorigenesis, and using this model, we observed that treatment of cells with either of the two compounds effectively neutralized tumor growth. These findings indicate that miRNA pathway-suppressing small molecules could potentially reverse tumorigenesis.

The 70% ethanolic extract of Peltophorum pterocarpum leaves were investigated for its hepatoprotective effect against paracetamol induced acute liver damage on albino wister rats. Paracetamol (2gm/kg, po) significantly elevated the serum levels of biochemical markers like SGPT, SGOT, ALP, bilirubin (total and direct), total cholesterol, triglycerides and depleted tissue GSH and increased the lipid peroxidation. upon administration of paracetamol (2mg/kg p.o.) to albino rats. This indicated that there The 70% ethanolic extract of leaves of Peltophorum pterocarpum at 100mg/kg and 200mg/kg doses significantly reduced the elevated levels of biochemical markers mentioned above. Test extract treatment also increased the level of tissue GSH and significantly decreased tissue lipid preoxidation. The effect of 70% ethanolic extract (ELPP) was comparable with that of the standard silymarin 100mg/kg. These results suggest that 70% ELPP may have the potential therapeutic value in the treatment of paracetamol induced hepatic damage and some liver diseases. Hepatoprotective activity of the study plant may be attributed to the anti-oxidant principles in it.

The first synthesis of a novel 5:7:5-fused heterocyclic ring system, a diimidazodiazepine, is reported. The propensity of the ring system to undergo facile, acid-catalyzed nucleophilic addition reactions by neutral carbon and nitrogen nucleophiles has been explored. The ring system has potential future applications in mechanistic studies of formation and repair of DNA interstrand cross-links.

Cholinesterases (ChEs) are classified as either acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) based on their substrate and inhibitor specificity. Organophosphate and carbamate compounds commonly represented by herbicides, pesticides, and nerve gases irreversibly inhibit ChEs. Therefore, exposure to organophosphates and carbamates is normally assessed by measuring ChE activity in blood. There are two approaches for measuring AChE and BChE activity present in whole blood: (1) separating blood into erythrocytes, which contain only AChE, and plasma which contains only BChE, to measure their activity individually, or (2) use a BChE-specific inhibitor to measure the activity of AChE in whole blood. A number of studies have reported the use of different inhibitors for the simultaneous measurement of AChE and BChE activities. However, the inhibitors used for completely inhibiting BChE activity also inhibited AChE activity leading to errors in reported values. The goal of this study was to find the most accurate and simple method for the simultaneous determination of AChE and BChE activity in animal whole blood. Solutions containing human AChE and BChE in various proportions were prepared and AChE and BChE activities were measured using three reported methods. Results demonstrate that ethopropazine and (−) huperzine A appear to be the most specific ChE inhibitors. Preliminary results with human and animal whole blood suggest that 20 μM ethopropazine and 500 nM (−) huperzine A can be used for measuring AChE and BChE activities across species.

Deep Impact successfully met its primary mission objective on 4 July 2005 when the smart impactor guided itself into the path of Comet 9P/Tempel 1. The mother flyby spacecraft then observed and recorded the breathtaking collision and subsequent plume development. Ground-based navigators targeted the prerelease trajectory using optical navigation image planning and data analysis, trajectory correction maneuver design and evaluation, and orbit determination using both radiometric and optical data. In-flight improvements to theTempel 1 ephemeriswere also a critical part of the overall navigation design and operations success. The achieved navigation accuracy established a new standard for comet encounters, and this difficult task taught several important lessons. This definitive work provides a mission overview, summarizes the navigation requirements, compares the achieved navigation performance with a baseline design that reflects in-flight updates, and identifies operational procedures that may benefit future comet-bound navigators.

The title compound (4) was synthesized by the reaction of ethyl 1-(2,3,5-tri-O-benzoyl-beta-d-ribofuranosyl)-5-formylimidazole-4-carboxylate with excess guanidine in ethanol at reflux. Compound 4 was evaluated in vitro against NTPases/helicases of four different viruses of the Flaviviridae family, including the West Nile virus (WNV), hepatitis C virus (HCV), dengue virus (DENV), and the Japanese encephalitis virus (JEV), employing both an RNA and a DNA substrate. The compound showed activity against NTPase/helicase of WNV and HCV with an IC(50) of 23 and 37 microM, respectively, when a DNA substrate was employed, while no activity was observed when an RNA substrate was used. There was no activity against the NTPase/helicase of either DENV or JEV irrespective of whether an RNA or a DNA substrate was employed. Considering that Flaviviridae are RNA viruses, the observed absence of activity against an RNA substrate, but the presence of activity against a DNA substrate is intriguing and somewhat surprising. The preliminary studies show that compound 4 does not form a tight complex with either an RNA or a DNA substrate, suggesting that its mechanism of action may involve direct interaction with the enzyme.

DDX3X (DDX3), a human RNA helicase, is over expressed in multiple breast cancer cell lines and its expression levels are directly correlated to cellular aggressiveness. NZ51, a ring-expanded nucleoside analogue (REN) has been reported to inhibit the ATP dependent helicase activity of DDX3. Molecular modeling of NZ51 binding to DDX3 indicated that the 5:7-fused imidazodiazepine ring of NZ51 was incorporated into the ATP binding pocket of DDX3. In this study, we investigated the anticancer properties of NZ51 in MCF-7 and MDA-MB-231 breast cancer cell lines. NZ51 treatment decreased cellular motility and cell viability of MCF-7 and MDA-MB-231 cells with IC50 values in the low micromolar range. Biological knockdown of DDX3 in MCF-7 and MDA-MB-231 cells resulted in decreased proliferation rates and reduced clonogenicity. In addition, NZ51 was effective in killing breast cancer cells under hypoxic conditions with the same potency as observed during normoxia. Mechanistic studies indicated that NZ51 did not cause DDX3 degradation, but greatly diminished its functionality. Moreover, in vivo experiments demonstrated that DDX3 knockdown by shRNA resulted in reduced tumor volume and metastasis without altering tumor vascular volume or permeability-surface area. In initial in vivo experiments, NZ51 treatment did not significantly reduce tumor volume. Further studies are needed to optimize drug formulation, dose and delivery. Continuing work will determine the in vitro-in vivo correlation of NZ51 activity and its utility in a clinical setting.

Immunization with a synthetic glycan corresponding to Plasmodium falciparum glycosylphosphatidylinositols (GPIs) has been proposed as a vaccination strategy against malaria. We investigated the structural requirements for binding of naturally elicited anti-GPI antibodies to parasite GPIs. The data show that anti-GPI antibody binding requires intact GPI structures and that the antibodies are directed predominantly against GPIs with a conserved glycan structure with three mannoses and marginally against the terminal fourth mannose. The results provide valuable insight for exploiting GPIs for the development of malaria vaccines.

The attempted synthesis of a ring-expanded guanosine (1) containing the imidazo[4,5-e][1,3]diazepine ring system by condensation of 1-(2'-deoxy-beta-D-erythropentofuranosyl)-4-ethoxycarbonylimidazole-5-carbaldehyde (2) with guanidine resulted in the formation of an unexpected product, 1-(2'-deoxy-beta-D-erythropentofuranosyl)-5-(2, 4-diamino-3, 6-dihydro-1,3, 5-triazin-6-yl)imidazole-4-carboxamide (7). The structure as well as the pathway of formation of 7 was corroborated by isolation of the intermediate, followed by its conversion to the product. Nucleoside 7 showed promising in vitro anti-helicase activity against the West Nile virus NTPase/helicase with an IC50 of 3-10 microg/mL.

An efficient and convenient method has been described for the selective conversion of an ester group into the corresponding carboxamide in vinylogous ester–aldehydes of imidazole. The method uses excess guanidine, which protects the aldehyde function as a diaminodihydro- s -triazine moiety. The carboxaldehyde group is regenerated by hydrolysis of the triazine moiety to provide vinylogous amide–aldehydes of imidazole as the final product.

Bis[2-(4-phosphonooxyphenoxy)carbonylethyl]phosphinc acid (BPPCEP) was prepared and evaluated as a site-directed affinity reagent for cross-linking human hemoglobin. It was synthesized in four steps starting from 4-benzyloxyphenol and was converted to its pentasodium salt so as to afford efficient cross-linking in an aqueous medium. The reagent was found to specifically cross-link human hemoglobin A(0) in the beta-cleft chains under oxygenated reaction conditions at neutral pH. The amino acid residues involved in the cross-linking were determined by mass spectral analyses of tryptic digest fragments of cross-linked hemoglobin, employing a MALDI-TOF mass spectrometer. The MS analyses suggested that the most likely amino acids involved in the cross-links are Val-1 or Lys-82 present on one of the beta subunits and Lys-82 or Lys-144 on the other. Molecular modeling studies performed on the reagent-HbA(0) complex corroborated the conclusions reached by MALDI-MS analyses. The oxygen equilibrium measurements of the three major BPPCEP-cross-linked Hb products, isolated and purified by preparative cation exchange chromatography, exhibited oxygen affinity (P(50)) values of 14.5, 12.1, and 15.5 Torr as compared with the P(50) of 13.1 Torr for cell-free hemoglobin. The oxygen-binding cooperativity of the modified products, as determined by the Hill coefficient generated from the Hill plots of the respective P(50) values, coupled with the absence of sigmoidal shape of the O(2) equilibrium curves, was considerably lower than that of the native hemoglobin.

Synthesis and adenosine deaminase (ADA) inhibitory activity of two analogues of coformycin, containing the imidazo[4,5-e][1,2,4]triazepine ring system, have been reported as part of the structure-activity relationship (SAR) studies to explore the factors responsible for the extremely tight-binding characteristics of coformycins to ADA.

A series of ring-expanded ("fat") nucleoside analogues (RENs) containing the 6-aminoimidazo[4,5-e][1,3]diazepine-4,8-dione ring system have been synthesized and screened for inhibition of NTPase/helicase of the West Nile Virus (WNV). To assess the selectivity of RENs against the viral enzymes, a truncated form of human enzyme Suv3((Delta)(1)(-)(159)) was also included in the study. Ring-expanded nucleosides 16, 17, and 19, which possess the long C(12), C(14), and C(18) side-chains, respectively, at position 6, as well as the ring-expanded heterocycle 39, which contains aralkyl substitution at position 1, were all found to have excellent profiles of activity and selectivity toward the viral versus human enzymes against the West Nile Virus (IC(50) ranging 1-10 muM). Compound 30, while being an equally potent inhibitor of WNV, was found to be somewhat less selective, whereas compound 36, which is an alpha-anomeric counterpart of 30, exhibited potent and selective inhibition of WNV (IC(50) 1-3 muM). The same compounds that showed potent inhibition of viral helicase activity completely failed to show any activity against the viral NTPase reaction even up to 500 muM. However, at concentrations >500 muM of RENs and the ATP concentrations >10 times the K(m) value of the enzyme, a significant activation of NTPase activity was observed. This activating effect underwent further dramatic enhancement (>1000%) by further increases in ATP concentration in the reaction mixture, suggesting that the viral helicase and NTPase reactions are not coupled. A tentative mechanistic model has been proposed to explain the observed results.

Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-β-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

A novel 5:8-fused heterocycle containing the imidazo[4,5-e][1,2,4]triazocine ring system has been synthesized in ten steps commencing from 1-benzyl-5-methyl-4-nitroimidazole. The compound is a new member of the family of ring-expanded xanthine–xanthosine analogues reported from this laboratory. The synthesis led to the unraveling of a number of novel rearrangements and ring-transformations.

Ring-expanded (ldauo;fat") nucleosides (RENs) described in this review are analogues of purine nucleosides containing a 5:7-fused imidazodiazepine or imidazotriazepine ring system. They are both of natural and synthetic origin, and are of chemical, biochemical, biophysical, as well as medicinal interest. The important natural RENs include coformycin, pentostatin, azepinomycin, adechlorin, and adecypenol. A majority of them are synergistic antitumor and/or antiviral antibiotics which potentiate the effects of other antitumor or antiviral compounds through inhibition of key enzymes such as adenosine deaminase or guanase which would otherwise metabolically degrade the active compounds into therapeutically less potent or totally inactive counterparts. However, despite the fact that some of the natural RENs such as coformycins are the strongest known enzyme inhibitors, they have not been proven as effective clinically as anticipated because of the extremely high toxicity associated with their use. Nevertheless, pentostatin (2'-deoxycoformycin) is a conspicuous exception as it is gaining wide attention in recent years as a clinically effective therapeutic agent against leukemias and lymphomas. Many of the recently reported synthetic RENs, by contrast, possess biological activities of their own, in particular against a wide spectrum of cancers and viruses with little toxicity to the host cells, and thus hold considerable promise as chemotherapeutic agents. The promising preliminary in vitro data concerning the effects of RENs on human cancers, in particular prostate and breast cancer cells, support their further pursuit in animal and clinical studies. RENs also carry promise against many viral infections belonging to the families of hepatitis, herpes, and respiratory infections, most notable being the hepatitis B (HBV), hepatitis C (HCV), and the West Nile (WNV) viruses.

RNA nucleoside triphosphatases (NTPase)/helicases represent a large family of proteins that are ubiquitously distributed over a wide range of organisms. The enzymes play essential role in cell development and differentiation, and some of them are involved in transcription and replication of viral single-stranded RNA genomes. The enzymatic activities of a NTPase/helicase were also detected in the carboxyl-terminal non-structural protein 3 (NS3) of members of the Flaviviridae family. The crucial role of the enzyme for the virus life cycle was demonstrated in knock out experiments and by using NTPase/helicase specific inhibitors. This makes the enzyme an attractive target for development of Flaviviridae-specific antiviral therapies. This review will summarize our knowledge about the function and structure of the enzyme, update the spectrum of inhibitors of the enzymatic activities of the NTPase/helicase and describe the different mechanisms by which the compounds act. Some of the compounds reviewed herein could show potential utility as antiviral agents against Flaviviridae viruses.

Novel ring-expanded nucleoside (REN) analogs (1-3) containing 5:7 fused ring systems as the heterocyclic base were found to be potent and selective inhibitors of hepatitis B virus (HBV) replication in cultured human hepatoblastoma 2.2.15 cells. The most active compound, 6-amino-4,5-dihydro-8H-1-(beta-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione (1), inhibited the synthesis of intracellular HBV replication intermediates and extracellular virion release in 2.2.15 cells with 50% effective concentration (EC50) of 0.604 and 0.131 microM, respectively. All three compounds had no effect on the synthesis of viral ribonucleic acids (RNA) in 2.2.15 cells. These compounds also exhibited low cellular toxicity in stationary and rapidly growing cell systems.

Oral thin films of 6-mercaptopurine were fabricated from mucoadhesive polymer, chitosan and polyvinylpyrrolidone for the purpose of prolonging drug release and improving its bioavailability. All fabricated film formulations prepared were smooth and translucent, with good flexibility. The weight and thickness of all the formulations were found to be uniform. These films were also evaluated for surface pH, folding endurance, swelling percentage (% S) and in vitro disintegration time. Scanning Electron Microscopy (SEM) and Fourier Transform Infrared (FTIR) were used to evaluate the physico-chemical nature of the films. In-vitro drug release have shown enhanced release profiles for thin films compared to pure drug and the release patterns have been found to be pH dependant. The results of the study reveals that fabrication of 6-MP oral thin film by using solvent cast technology is a simple and an efficient method for drug delivery to achieve desired therapeutic compliance.Keywords: 6-mercaptopurine; In Vitro Drug Release; SEM; FTIR

A modern gas turbine engine functions with a full authority digital engine control (FADEC) unit. This, in addition to providing superior controls, makes pilot free from the anxiety of monitoring engine performance and health. This confidence is a result of reliable machine (gas turbine) along with complementing control system. Many a times short comings of the individual aerodynamic modules ,structural issues, subsystem related concerns , matching of components, scaling of performance degradation over time, health management and performance management must be complimented by a smart control system. Hence it is imperative that control system has to be built with high reliability and redundancy to improve the reliability parameters. This very philosophy increases complexity of the system as well as increased part count and weight during development. Interplay among many design parameters warrants Systems Engineering (SE) approach as an essential approach for effective management of complexity and change. SE process has to be used for concept exploration and design path formulation to reap the benefit at the later part of life cycle costs. Development of a complex system is recursive and conflicting during various life cycle stages. Projects undertaken in the previous century used to be more than 10- 15 years duration and today similar projects are to deliver with reduced time frame. The main thrust is on automating and optimizing the processes, with continual improvement of quality and reducing waste. Management of change along with empowering the resources and manpower makes it indispensable use the lean principles to build these complex systems. Lean Architecture encompasses the above requirements. An existing control system having cleared by IV&V team and has matured to Technology Readiness Level (TRL) of 6-7 is considered in this study for upgradation for future application. A modern control system is being upgraded and lean architecture principle are followed to optimize the system along with reduction of weight by understanding the physical system design and data study from Integrated vehicle health monitoring (IVHM) system. The upgradation or redesigning approach can be inferred through various decision making process of systems engineering. This paper brings out the risk assessment concept of reducing the complexity through Analytic Hierarchy Process (AHP) approach where various alternatives, criterions and sub-criterions are evaluated and thereby assessing the risk in attempting to reduce the complexity and weight.

The synthesis and enzyme inhibition studies of a novel ring-expanded acyclic nucleoside analogue are reported. Compound has been found to be a competitive inhibitor of both adenosine deaminase (ADA) and guanine deaminase (GDA; guanase) with K(i)'s equal to 1.52+/-0.34 x 10(-4) M and 2.97+/-0.25 x 10(-5) M, respectively. Inhibition of two enzymes of purine metabolism may bear beneficial implications in antiviral therapy.

Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4, 5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicyano-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC50 of2.5 microg/mL and an SI value of176.

The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by protein tyrosine kinase (PTK)- and protein kinase C (PKC)-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-alpha by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways, since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-alpha production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-alpha secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responses.

An improved synthesis of 9-benzyladenine (I), a model for a variety of biologically and therapeutically significant adenine nucleosides, has been reported. The target compound was synthesized by condensation of 1-benzyl-4-cyano-5-methoxymethyleneimino-imidazole (14) with guanidine. Compound 14 was prepared from 5-amino-1-benzyl-4-cyanoimidazole (5), which in turn was prepared by reaction of benzylamine with ethyl (Z)-N-(2-amino-1,2-dicyanovinyl) formimidate (13). The latter was synthesized by reaction of diaminomaleonitrile (6) with triethyl orthoformate.

Induction of proinflammatory cytokine responses by glycosylphosphatidylinositols (GPIs) of intraerythrocytic Plasmodium falciparum is believed to contribute to malaria pathogenesis. In this study, we purified the GPIs of P. falciparum to homogeneity and determined their structures by biochemical degradations and mass spectrometry. The parasite GPIs differ from those of the host in that they contain palmitic (major) and myristic (minor) acids at C-2 of inositol, predominantly C18:0 and C18:1 at sn-1 and sn-2, respectively, and do not contain additional phosphoethanolamine substitution in their core glycan structures. The purified parasite GPIs can induce tumor necrosis factor α release from macrophages. We also report a new finding that adults who have resistance to clinical malaria contain high levels of persistent anti-GPI antibodies, whereas susceptible children lack or have low levels of short-lived antibody response. Individuals who were not exposed to the malaria parasite completely lack anti-GPI antibodies. Absence of a persistent anti-GPI antibody response correlated with malaria-specific anemia and fever, suggesting that anti-GPI antibodies provide protection against clinical malaria. The antibodies are mainly directed against the acylated phosphoinositol portion of GPIs. These results are likely to be valuable in studies aimed at the evaluation of chemically defined structures for toxicity versus immunogenicity with implications for the development of GPI-based therapies or vaccines.

Glycosylphosphatidylinositols (GPIs) are the major glycoconjugates in intraerythrocytic stage Plasmodium falciparum. Several functional proteins including merozoite surface protein 1 are anchored to the cell surface by GPI modification, and GPIs are vital to the parasite. Here, we studied the developmental stage-specific biosynthesis of GPIs by intraerythrocytic P. falciparum. The parasite synthesizes GPIs exclusively during the maturation of early trophozoites to late trophozoites but not during the development of rings to early trophozoites or late trophozoites to schizonts and merozoites. Mannosamine, an inhibitor of GPI biosynthesis, inhibits the growth of the parasite specifically at the trophozoite stage, preventing further development to schizonts and causing death. Mannosamine has no effect on the development of either rings to early trophozoites or late trophozoites to schizonts and merozoites. The analysis of GPIs and proteins synthesized by the parasite in the presence of mannosamine demonstrates that the effect is because of the inhibition of GPI biosynthesis. The data also show that mannosamine inhibits GPI biosynthesis by interfering with the addition of mannose to an inositol-acylated GlcN-phosphatidylinositol (PI) intermediate, which is distinctively different from the pattern seen in other organisms. In other systems, mannosamine inhibits GPI biosynthesis by interfering with either the transfer of a mannose residue to the Manalpha1-6Manalpha1-4GlcN-PI intermediate or the formation of ManN-Man-GlcN-PI, an aberrant GPI intermediate, which cannot be a substrate for further addition of mannose. Thus, the parasite GPI biosynthetic pathway could be a specific target for antimalarial drug development.

An efficient, short synthesis of a ring-expanded nucleoside analogue containing a novel 5:7-fused, planar, and potentially aromatic imidazo[4,5-e][1,3]diazepine heterocyclic ring system is reported. The target compound, 6-amino-8-hydroxy-4H-1-beta-D- ribofuranosylimidazo[4,5-e][1,3]diazepin-4-one (2) was synthesized in a single step inor = 90% yield by condensation of guanidine with either methyl 1-beta-D-ribofuranosylimidazole-4,5- dicarboxylate(1a) or its 2',3',5'-tri-O-benzoyl derivative (1b). Compound 2 showed potent anti-hepatitis B virus (anti-HBV) activity with an EC50 value of 0.17 microM in the transfected hepatoma cell line 2.2.15, and a low cellular toxicity with a CC50 value of 2.4 mM (TI14,000).

The increasing demand for processing power in database applications can be satisfied by having a number of processors serving database requests concurrently. In this paper, an attempt is made to develop a database management system on Flosover Mk3, a distributed memory, shared disk, parallel computer. The aim of this paper is to utilise the number of processors available on Flosolver Mk3 to serve user requests for data manipulation activity. The independence of records in data file provides parallelism to process data partially on different processors. An interpreter has been developed with commands to define data and group data, and to manipulate data through which user can communicate with the database management system.

The synthesis and biochemical screening of four novel spironucleosides 1-4 against rabbit liver glycogen phosphorylase b (Gpb), along with molecular modeling studies on compound 2 and its 4-hydroxy analogue VII, have been presented. Gpb is a key enzyme of glycogen metabolism, and is known to be involved in the control of diabetes mellitus. The general strategy for synthesis involved base-catalyzed condensation of diethyl 2,4-dioxoimidazolidine-5-phosphonate (5) with either 2-deoxy-D-ribose or D-ribose, followed by sequential reactions involving ring-closure with phenylselenenyl chloride and reduction with tri-n-butyltin hydride catalyzed by azobisisobutyronitrile. Compounds 2 and 4 were found to be weak competitive inhibitors of Gpb, whereas 1 and 3 were inactive.

Synthesis and biochemical screening against guanase of analogues of the naturally occurring guanase inhibitor azepinomycin (2) are reported. Compound e-amino-5,6,7,8,-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (3) was synthesized in six steps commencing with 1-benzyl-5-nitroimidazole-4-carboxylic acid (5). Compound 3 and its synthetic precursor 3-benzyl-6-(N-benzyloxycarbonyl)amino-5,6,7,8-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (12) were screened against rabbit liver guanase. Both were found to be moderate inhibitors of the enzyme with K1′s in the range of 10−4 M.

The design, synthesis, and hemoglobin cross-linking studies of a novel organic reagent, bis[2-(4 carboxyphenoxy)carbonylethyl]phosphinic acid (BCCEP, 1 ) have been reported. The reagent was designed with the aid of molecular modeling, employing crystal coordinates of human hemoglobin A 0 . It was synthesized in three steps commencing from 4- t -butoxycarbonylphenol. The tri-sodium salt of 1 was employed to cross-link human oxyHb. While SDS–PAGE analyses of the modified hemoglobin product pointed to the molecular mass range of 32 kDa, the HPLC analyse suggested that the cross-link had formed between the β 1 -β 2 subunits. The oxygen equilibrium measurements of the modified hemoglobin at 37 °C showed significantly reduced oxygen affinity (P 50 =31.3 Torr) as compared with that of cell-free hemoglobin (P 50 =6.6 Torr). The sigmoidal shape of O 2 curves of the modified Hb pointed to reasonable retainment of oxygen-binding cooperativity after the cross-link formation. Molecular dynamics simulation studies on the reagent-HbA 0 complex suggested that the most likely amino acid residues involved in the cross-linking are N-terminus Val-1 or Lys-82 on one of the-chains, and Lys-144 on the other. These predictions were consistent with the results of MALDI-MS analyses of the peptide fragments obtained from tryptic digestion of the cross-linked product.

The use of pentafluorophenol as a superior reagent for heterocyclic condensations, where other traditional condensing agents such as DCC and CDI failed, has been demonstrated.

Petroleum fuel resources are now depleting at a faster rate. Due to this reason many researchers are now attracted towards the biodiesel. India is having a large potential of Jatropha and Karanja seeds. These seeds are the source of biodiesel. More over these are not the human food grains. Refereeing to the availability at the fields these two kinds of seed fuels can be blended together as fuel instead of diesel with no any major modification in an engine. Hence main aim of this research was to blend Jatropha and Karanja biodiesel and testing these fuels for a diesel engine. Two kinds of biodiesel Jatropha and Karanja are blended in different proportions. Basically percentage of Karanja in Jatropha fuel was varied. These blends are then tested on single cylinder DI diesel engine. Results show that the Energy performance of diesel engine was deteriorated with the addition of Karanja biodiesel in Jatropha biodiesel. However emission performance was improved.

Coformycin analogues 1–6 were synthesized and biochemically screened against adenosine deaminase in order to assess the relative contributions of N-4, N-6, and the N-3 sugar moiety to the mode of enzyme inhibition. Our results indicate that N-4 plays a relatively greater role than N-6 in enzyme tight-binding, and that a benzyl group can substitute for the sugar moiety at N-3. The absence of a sugar or benzyl group at N-3, however, leads to loss of activity. The hydroxyl group at C-8, while crucial for activity, does not alone confer the tight-binding characteristics to coformycins.

Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O(5) oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O(5) results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O(5) considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a Ki value of 8.0±1.5μM against rabbit liver guanase.

Synthesis, properties, and reactions of the title reagent, bis(phenoxycarbonylethyl)phosphinic acid, are reported. The reagent's utility for biomacromolecular modification has been demonstrated by successfully cross-linking human hemoglobin.