Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase

3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH-could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH-with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the R2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH-is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.

Ornstein-Uhlenbeck operator in convex domains of Banach spaces

Studiamo l'operatore di Ornstein-Uhlenbeck e il semigruppo di Ornstein-Uhlenbeck in un sottoinsieme aperto convesso $\Omega$ di uno spazio di Banach separabile $X$ dotato di una misura Gaussiana centrata non degnere $\gamma$. In particolare dimostriamo la disuguaglianza di Sobolev logaritmica e la disuguaglianza di Poincar��, e grazie a queste disuguaglianze deduciamo le propriet�� spettrali dell'operatore di Ornstein-Uhlenbeck. Inoltre studiamo l'equazione ellittica $\lambdau+L^{\Omega}u=f$ in $\Omega$, dove $L^\Omega$ �� l'operatore di Ornstein-Uhlenbeck. Dimostriamo che per $\lambda>0$ e $f\in L^2(\Omega,\gamma)$ la soluzione debole $u$ appartiene allo spazio di Sobolev $W^{2,2}(\Omega,\gamma)$. Inoltre dimostriamo che $u$ soddisfa la condizione di Neumann nel senso di tracce al bordo di $\Omega$. Questo viene fatto finita approssimazione dimensionale.

Developing a framework to evaluate business networks:the case of Ireland's industry-led network initiative

Business networks have been described as cooperative arrangements between independent business organisations that vary from contractual joint ventures to informal exchanges of information. This collaboration has become recognised as an innovative and efficient tool for organising interdependent activities, with benefits accruing to both firms and the local economy. For a number of years, resources have been devoted to supporting Irish networking policies. One recent example of such support is the Irish government's target of ���20 million per annum for five years to support the creation of enterprise-led networks. It is imperative that a clear rationale for such interventions is established, as the opportunity cost of public funds is high. This article, therefore, develops an evaluation framework for such networking interventions. This framework will facilitate effective programme planning, implementation and evaluation. It will potentially show how a chain of cause-and-effect at both micro and macro-levels for networking interventions can be established.

The analysis and case studies of successful express logistics companies

With the globalisation of world business, the border-crossing activities between organisations have substantially increased. Organisations not only need to handle supply functions, but also play a tremendous role in demand simulation through integration both inside the firm and outside with business partners and customers. Logistics has become more and more mature and sophisticated by taking on an external focus, incorporating suppliers and customers in the business processes, with all the supply chain functions integrated into a whole. By minimising the costs in the value chain or providing customised services, logistics acts as a major source of competitive advantages and profitability. To meet this goal, it would require the integration of activities to focus on customer-oriented measures. Customer service and logistics activities are a chain of interdependent activities that supplement each other to facilitate the flow of information, goods and cash within the value chain. The absence of one activity may imply some specific channels need to supplement another unit. Generally, this paper is to study the impact of corporate strategy, technology and customer satisfaction on the firm���s performance, filling the gap of good customer service effects on long-term profits. Two international delivery providers, UPS and FedEx, are studied to realise the critical success factors of express logistics.

Evaluating the impact of design decisions on the financial performance of manufacturing companies

Product design decisions can have a significant impact on the financial and operation performance of manufacturing companies. Therefore good analysis of the financial impact of design decisions is required if the profitability of the business is to be maximised. The product design process can be viewed as a chain of decisions which links decisions about the concept to decisions about the detail. The idea of decision chains can be extended to include the design and operation of the 'downstream' business processes which manufacture and support the product. These chains of decisions are not independent but are interrelated in a complex manner. To deal with the interdependencies requires a modelling approach which represents all the chains of decisions, to a level of detail not normally considered in the analysis of product design. The operational, control and financial elements of a manufacturing business constitute a dynamic system. These elements interact with each other and with external elements (i.e. customers and suppliers). Analysing the chain of decisions for such an environment requires the application of simulation techniques, not just to any one area of interest, but to the whole business i.e. an enterprise simulation. To investigate the capability and viability of enterprise simulation an experimental 'Whole Business Simulation' system has been developed. This system combines specialist simulation elements and standard operational applications software packages, to create a model that incorporates all the key elements of a manufacturing business, including its customers and suppliers. By means of a series of experiments, the performance of this system was compared with a range of existing analysis tools (i.e. DFX, capacity calculation, shop floor simulator, and business planner driven by a shop floor simulator).

Intermediate pyrolysis and product identification by TGA and Py-GC/MS of green microalgae and their extracted protein and lipid components

The thermo-chemical conversion of green microalgae Chlamydomonas reinhardtii wild type (CCAP 11/32C), its cell wall deficient mutant C. reinhardtii CW15 (CCAP 11/32CW15) and Chlorella vulgaris (CCAP 211/11B) as well as their proteins and lipids was studied under conditions of intermediate pyrolysis. The microalgae were characterised for ultimate and gross chemical composition, lipid composition and extracted products were analysed by Thermogravimetric analysis (TG/DTG) and Pyrolysis-gaschromatography/mass-spectrometry (Py-GC/MS). Proteins accounted for almost 50% and lipids 16-22 % of dry weight of cells with little difference in the lipid compositions between the C. reinhardtii wild type and the cell wall mutant. During TGA analysis, each biomass exhibited three stages of decomposition, namely dehydration, devolatilization and decomposition of carbonaceous solids. Py-GC/MS analysis revealed significant protein derived compounds from all algae including toluene, phenol, 4-methylphenol, 1H-indole, 1H-indole-3methyl. Lipid pyrolysis products derived from C. reinhardtii wild type and C. reinhardtii CW15 were almost identical and reflected the close similarity of the fatty acid profiles of both strains. Major products identified were phytol and phytol derivatives formed from the terpenoid chain of chlorophyll, benzoic acid alkyl ester derivative, benzenedicarboxylic acid alkyl ester derivative and squalene. In addition, octadecanoic acid octyl ester, hexadecanoic acid methyl ester and hydrocarbons including heptadecane, 1-nonadecene and heneicosane were detected from C. vulgaris pyrolysed lipids. These results contrast sharply with the types of pyrolytic products obtained from terrestrial lignocellulosic feedstocks and reveal that intermediate pyrolysis of algal biomass generates a range of useful products with wide ranging applications including bio fuels.

Adoption of e-business solutions in food supply chains

The aim of this chapter is to increase understanding of e-business adoption in the food supply chain. In the first part of the paper an analysis of the concept and the context of e-business are presented along with a classification of the various e-business applications based on the dimensions of involvement and complexity. Next emphasis is given to the issue of e-business adoption. In particular an analysis of the factors that influence the adoption process is provided by exploring the specific characteristics of the food industry as well as the potential impact of the use of e-business solutions. These factors are not only related to the company but also to the supply chain of each company and the actual value of e-business applications. The chapter concludes that in many cases e-business is wrongly considered as a sole application and its adoption as mainly an intra-firm issue. Finally future trends are considered and discussed. �� 2010 Woodhead Publishing Limited All rights reserved.

Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues

The hormone glucagon-like peptide-1(7-36)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucose-dependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidylpeptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the E-amino group in the side chain of the LyS26 residue and to combine this modification with substitutions of the Ala 8 residue, namely Val or amino-butyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal) 26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys-(pal)26]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal ��-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 cells was similar, or in the case of [Val8,Lys(pal)26]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)26]GLP-1, [Abu8,Lys(pal) 26]GLP-1 and [Val8,Lys(pal) 26]GLP-1 did not demonstrate acute glucose-lowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability. Copyright �� by Walter de Gruyter.

An analysis of police interview discourse and its role(s) in the judicial process

This study analyses the current role of police-suspect interview discourse in the England & Wales criminal justice system, with a focus on its use as evidence. A central premise is that the interview should be viewed not as an isolated and self-contained discursive event, but as one link in a chain of events which together constitute the criminal justice process. It examines: (1) the format changes undergone by interview data after the interview has taken place, and (2) how the other links in the chain ��� both before and after the interview ��� affect the interview-room interaction itself. It thus examines the police interview as a multi-format, multi-purpose and multi-audience mode of discourse. An interdisciplinary and multi-method discourse-analytic approach is taken, combining elements of conversation analysis, pragmatics, sociolinguistics and critical discourse analysis. Data from a new corpus of recent police-suspect interviews, collected for this study, are used to illustrate previously unaddressed problems with the current process, mainly in the form of two detailed case studies. Additional data are taken from the case of Dr. Harold Shipman. The analysis reveals several causes for concern, both in aspects of the interaction in the interview room, and in the subsequent treatment of interview material as evidence, especially in the light of s.34 of the Criminal Justice and Public Order Act 1994. The implications of the findings for criminal justice are considered, along with some practical recommendations for improvements. Overall, this study demonstrates the need for increased awareness within the criminal justice system of the many linguistic factors affecting interview evidence.

A gabonasz��ll��t��si piac sz��ne ��s vissz��ja Magyarorsz��gon (The pros and contras of the Hungarian cereals transportation market)

A tanulm��ny a szakirodalomban ��jszer�� kezdem��nyez��sk��nt k��s��rletet tesz a gabonapiac ell��t��si l��nc��nak felrajzol��s��ra, majd annak egyik, a cikk alapk��rd��se szempontj��b��l kiemelt vet��let��t, a gabonasz��ll��t��si ��s rakt��roz��si probl��m��kat elemzi. El��bbit a piac szerepl��it��l kvalitat��v m��don begy��jt��tt inform��ci��kkal, ut��bbit a szakirodalom alapj��n mutatja be. A cikk az elemz��s ut��n javaslatokkal szolg��l ahhoz, hogyan lehetne haz��nkban egy integr��lt gabonapiaci sz��ll��t��si-rakt��roz��si-��trak��si rendszert kialak��tani. __________ The aim of the article is to present the situation of the Hungarian cereals transport and storage-reloading market and by interconnection, to treat cereals market���s operations systemically. Under this process, the study trace to draw a possible supply chain of the national cereals market up, which is a new initiation in the Hungarian literature. The focus of the article is to analyse transport and storage processes in the cereals market using the framework mentioned above. Transport market is demonstrated on the grounds of a revealing qualitative research, while storage market is brought out by literature. After analysis, the article gives recommendations how to shape an integrated transport and storage-reload system in the Hungarian cereals market.

Trust and cooperation in buyer���seller relationships and networks. The co-evolution of structural balance and trust in iterated PD games

Our study has two aims: to elaborate theoretical frameworks and introduce social mechanisms of spontaneous co-operation in repeated buyer-seller relationships and to formulate hypotheses which can be empirically tested. The basis of our chain of ideas is the simple two-person Prisoner���s Dilemma game. On the one hand, its repeated variation can be applicable for the distinction of the analytical types of trust (iteration trust, strategy trust) in co-operations. On the other hand, it provides a chance to reveal those dyadic sympathy-antipathy relations, which make us understand the evolution of trust. Then we introduce the analysis of the more complicated (more than two-person) buyer-seller relationship. Firstly, we outline the possible role of the structural balancing mechanisms in forming trust in three-person buyer-seller relationships. Secondly, we put forward hypotheses to explain complex buyer-seller networks. In our research project we try to theoretically combine some of the simple concepts of game theory with certain ideas of the social-structural balance theory. Finally, it is followed by a short summary.

Innov��ci��s l��ncok falun. K��t falusi esettanulm��ny a gazdas��gi ��j��t��sok terjed��s��r��l (Rural innovation chains. Two examples for diffusion of rural innovations)

Megk��zel��t��semben az "innov��ci��s l��nc" olyan t��rsadalmi kapcsolath��l��t jelent, ahol a kapcsolat tartalma egy gazdas��gi ��j��t��s ��tad��sa. Dolgozatom f�� k��rd��se az, hogy egy telep��l��sen kialakult t��rsadalmi h��l��zat szerkezete hogyan befoly��solja az innov��ci��k ��tv��tel��nek ��tj��t ��s terjed��si sebess��g��t. __________ A chain of innovation is a social network, defined by offering or adopting an economic innovation. The main hypothesis is that the diffusion of rural innovations and the changes of life-style of the peasants (generally: the growth of market economy) do not necessarily restructure or destroy local networks, but in some cases they will be reinforceed.

Absolute configuration and biosynthesis of pahayokolide A from Lyngbya sp. Strain 15-2 of the Florida Everglades

Pahayokolides A-D are cytotoxic cyclic polypeptides produced by the freshwater cyanobacterium Lyngbya sp. strain 15-2 that possess an unusual ��-amino acid, 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid (Athmu). The absolute configuration of pahayokolides A-D was determined using advanced Marfey���s method. It was also confirmed that a pendant N-acetyl- N-methyl leucine moiety in pahayokolide A was absent in pahayokolides B and pahayokolides C-D were conformers of pahayokolide A. Feeding experiments indicated that the biosynthesis of the Athmu sidechain arises from leucine or ��-ketoisovalerate, however could not be further extended by three rounds of condensation with malonate units. Putative four peptide and one unique polyketide synthetases in Lyngbya sp. strain 15-2 were identified by using a PCR method and degenerate primers derived from conserved core sequences of known NRPSs and PKSs. Identification of one unique KS domain conflicted with the logic rule that the long side chain of Athmu was assembled by three rounds of ketide extensions if PKSs were involved. A gene cluster (pah) encoding a peptide synthetase putatively producing pahayokolide was cloned, partially sequenced and characterized. Seven modules of the non-ribosomal peptide synthetase (NRPS) were identified. Ten additional opening reading frames (ORFs) were found, responsible for peptide resistance, transport and degradation. Although the predicted substrate specificities of NRPS agreed with the structure of pahayokolide A partially, the disagreement could be explained. However, no PKS gene was found in the pah gene cluster.

Implicit metaphysis of the Visuddhimagga : ass��sa-pass��sa as a vital animating force

This research examines how assasa-passisa and its surrounding concepts are discussed in Buddhaghossa's 5th century Theravada work, the Visuddhimagga (The Path of Purification) to determine if there is metaphysical use of the term in the text and to determine if the concept of assasa-passasa is similar to the better-known Indian concept of prana (metaphysical vital animating force), indicating whether Theravada Buddhism more closely resembles other Indian religions in terms of metaphysical content. Text analysis reveals how assasa-passasa is described in the Visuddhimagga as an animating vital force, suggesting that Theravada Buddhism has an implicit ontology similar to other Indian schools of philosophy. Secondarily, this paper argues that because assisa-passasa plays a similar role to prana in the Visuddhimagga, it is also operationally similar and could be functioning as the implicit intermediary between links in the chain of dependent co-arising-as the vehicle of paticcasamuppada.

Absolute Configuration and Biosynthesis of Pahayokolide A from Lyngbya sp. Strain 15-2 of the Florida Everglades

Pahayokolides A-D are cytotoxic cyclic polypeptides produced by the freshwater cyanobacterium Lyngbya sp. strain 15-2 that possess an unusual ��-amino acid, 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid (Athmu). The absolute configuration of pahayokolides A-D was determined using advanced Marfey���s method. It was also confirmed that a pendant N-acetyl-N-methyl leucine moiety in pahayokolide A was absent in pahayokolides B and pahayokolides C-D were conformers of pahayokolide A. Feeding experiments indicated that the biosynthesis of the Athmu sidechain arises from leucine or ��-ketoisovalerate, however could not be further extended by three rounds of condensation with malonate units. Putative four peptide and one unique polyketide synthetases in Lyngbya sp. strain 15-2 were identified by using a PCR method and degenerate primers derived from conserved core sequences of known NRPSs and PKSs. Identification of one unique KS domain conflicted with the logic rule that the long side chain of Athmu was assembled by three rounds of ketide extensions if PKSs were involved. A gene cluster (pah) encoding a peptide synthetase putatively producing pahayokolide was cloned, partially sequenced and characterized. Seven modules of the non-ribosomal peptide synthetase (NRPS) were identified. Ten additional opening reading frames (ORFs) were found, responsible for peptide resistance, transport and degradation. Although the predicted substrate specificities of NRPS agreed with the structure of pahayokolide A partially, the disagreement could be explained. However, no PKS gene was found in the pah gene cluster.