Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa - 1. Isolation, characterization and chemical synthesis

A novel conotoxin belonging to the 'four-loop' structural class has been isolated from the venom of the piscivorous cone snail Conus tulipa. It was identified using a chemical-directed strategy based largely on mass spectrometric techniques. The new toxin, conotoxin TVIIA, consists of 30 amino-acid residues and contains three disulfide bonds. The amino-acid sequence was determined by Edman analysis as SCSGRDSRCOOVCCMGLMCSRGKCVSIYGE where O = 4-transl-hydroxyproline. Two under-hydroxylated analogues, [Pro10]TVIIA and [Pro10,11]TVIIA, were also identified in the venom of C. tulipa. The sequences of TVIIA and [Pro10]TVIIA were further verified by chemical synthesis and coelution studies with native material. Conotoxin TVIIA has a six cysteine/four-loop structural framework common to many peptides from Conus venoms including the omega-, delta- and kappa-conotoxins. However, TVIIA displays little sequence homology with these well-characterized pharmacological classes of peptides, but displays striking sequence homology with conotoxin GS, a peptide from Conus geographus that blocks skeletal muscle sodium channels. These new toxins and GS share several biochemical features and represent a distinct subgroup of the four-loop conotoxins.

Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa - 2. Three-dimensional solution structure

The three-dimensional solution structure of conotoxin TVIIA, a 30-residue polypeptide from the venom of the piscivorous cone snail Conus tulipa, has been determined using 2D H-1 NMR spectroscopy. TVIIA contains six cysteine residues which form a 'four-loop' structural framework common to many peptides from Conus venoms including the omega-, delta-, kappa-, and mu O-conotoxins. However, TVIIA does not belong to these well-characterized pharmacological classes of conotoxins, but displays high sequence identity with conotoxin GS, a muscle sodium channel blocker from Conus geographus. Structure calculations were based on 562 interproton distance restraints inferred from NOE data, together with 18 backbone and nine side-chain torsion angle restraints derived from spin-spin coupling constants. The final family of 20 structures had mean pairwise rms differences over residues 2-27 of 0.18 +/- 0.05 Angstrom for the backbone atoms and 1.39 +/- 0.33 Angstrom for all heavy atoms. The structure consists of a triple-stranded, antiparallel beta sheet with +2x, -1 topology (residues 7-9, 16-20 and 23-27) and several beta turns. The core of the molecule is formed by three disulfide bonds which form a cystine knot motif common to many toxic and inhibitory polypeptides. The global fold, molecular shape and distribution of amino-acid sidechains in TVIIA is similar to that previously reported for conotoxin GS, and comparison with other four-loop conotoxin structures provides further indication that TVIIA and GS represent a new and distinct subgroup of this structural family. The structure of TVIIA determined in this study provides the basis for determining a structure-activity relationship for these molecules and their interaction with target receptors.

The radiation chemistry of poly(dimethylsiloxane)

The radiation chemistry of poly(dimethyl siloxane) has been investigated with respect to identification of the nature of the small molecule chain scission products. Low molecular weight linear and cyclic products have been identified through the use of Si-29 solution NMR, GPC and MALDI-TOF mass spectrometry. It has been suggested that the low molecular weight cyclic products are formed by back-biting depolymerization reactions.

Minimum-order stable recursive filter design via the genetic algorithm approach

In this paper, the minimum-order stable recursive filter design problem is proposed and investigated. This problem is playing an important role in pipeline implementation sin signal processing. Here, the existence of a high-order stable recursive filter is proved theoretically, in which the upper bound for the highest order of stable filters is given. Then the minimum-order stable linear predictor is obtained via solving an optimization problem. In this paper, the popular genetic algorithm approach is adopted since it is a heuristic probabilistic optimization technique and has been widely used in engineering designs. Finally, an illustrative example is sued to show the effectiveness of the proposed algorithm.

A qualitative study of Australian GPs' attitudes and practices in the diagnosis and management of attention-deficit/hyperactivity disorder (ADHD)

Background. The importance of general practice involvement in the care of attention-deficit/hyperactivity disorder (ADHD) is increasing due to the rising numbers of patients who present with the disorder. It has been suggested by consensus bodies that GPs should be identifying and referring patients at the severe end of the ADHD spectrum and managing those with less severe symptoms. However, GPs' views of their role in ADHD care are unknown. Objective. Our aim was to explore the attitudes and practices of Australian GPs towards the diagnosis and management of ADHD. Methods. We conducted a series of focus groups to explore GPs' beliefs regarding the causes of ADHD, their perceived role in ADHD diagnosis and management and their views on the role of behaviour therapies and pharmacotherapies in ADHD management. The subjects were 28 GPs in six focus groups. Results. GPs in this study did not want to be the primary providers of care for patients with ADHD. Participants indicated a preference to refer the patient to medical specialists for diagnosis and treatment of ADHD, and expressed low levels of interest in becoming highly involved in ADHD care. Concerns about overdiagnosis and misdiagnosis of the disorder, diagnostic complexity, time constraints, insufficient education and training about the disorder, and concerns regarding misuse and diversion of stimulant medications were the reasons cited for their lack of willingness. Conclusions. The Australian GPs in this study identify a role for themselves in ADHD care which is largely supportive in nature, and involves close liaison with specialist services.

NMR characterization of blends of poly(hydroxybutyrate-co-hydroxyvalerate) with poly(vinyl acetate)

The extent of mixing in blends of poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) (27% HV) and poly(vinyl acetate) (PVAc) has been measured using a number of different techniques, principally solid-state NMR. Differential scanning calorimetry DSC measurements indicated effective mixing of the polymer chains on a scale of several nanometres. The results of H-1 T-1 and H-1 T-1rho. measurements confirm intimate mixing of the chains. A change on blending in the H-1 T-1rho, and the H-1 NMR line width of the signal from the protons of PVAc was consistent with an increase in the amplitude and frequency of motion of this component. The PVAc chains reside within the inter-lamellar space, as confirmed by spin diffusion measurements after H-1 T-1rho preparation. (C) 2003 Society of Chemical Industry.

Cytokine expanded myeloid precursors function as regulatory antigen presenting cells and induce tolerance through IL-10 producing regulatory T cells

The initiation of graft vs. host disease (GVHD) after stem cell transplantation is dependent on direct antigen presentation by host antigen presenting cells (APC) while the effect of indirect antigen presentation by donor APC is unknown. We have studied the role of indirect antigen presentation in allogenic responses by adding populations of cytokine-expanded donor APC to haematopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 L molecule) and G-CSF expanded myeloid DC, plasmacytoid DC and a novel granulocyte-monocyte precursor population (GM) that differentiate into class IIpos, CD80/CD86pos, CD40neg APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells induced transplant tolerance via MHC class II restricted generation of IL-10-secreting regulatory T cells. Thus a population of cytokine expanded granulocyte-monocyte precursors function as regulatory antigen presenting cells, suggesting that G-CSF derivatives may have application in disorders characterised by a loss of self-tolerance.

Transport-Regional Equity Issue Revisited

Almeida E. S. de, Haddad E. A. and Hewings G. J. D. Transport-regional equity issue revisited, Regional Studies. The objective of this paper is to analyse the relationship between transport and regional equity in Minas Gerais, Brazil. Furthermore, the existence of a trade-off between economic performance and regional equity is investigated as well. To do so, the paper develops a spatial computable general equilibrium model based on Brocker and Schneider`s approach of 2002 to implement comparative static analysis, explicitly incorporating iceberg transportation costs. Four activities are modelled, namely production, final demand, transportation and exports. Two production factors are assumed: labour and other factors. The model has 12 domestic regions and three external regions. Four counterfactual experiments are developed based on decreases in transportation costs due to a `distance shortening`. The main findings indicate that if the transport infrastructure improvement is focused only among poor regions, the promotion of regional equity is insignificant. If the transport infrastructure improvement links are concentrated among rich regions, there is an increase in regional income inequalities. However, if the improvements are targeted to the roads linking poor regions and rich ones, there is greater promotion of regional equity. The same result will occur when improvements are made to all road links of the state. [image omitted] Almeida E. S. de, Haddad E. A. et Hewings G. J. D. La question du rapport entre le transport et l`equilibre regional vue sous un jour nouveau, Regional Studies. Cet article cherche a analyser le rapport entre le transport et l`equilibre regional en Minas Gerais au Bresil. En outre, on examine la presence d`un echange entre la performance economoique et l`equilibre regional. Pour le faire, on construit un modele geographique de l`equilibre general a utiliser sur ordinateur fonde sur l`approche de Brockner et Schneider en 2002 afin de mettre en oeuvre une analyse statique comparative qui comprend explicitement les frais de transport iceberg. On modelise quatre activites, a savoir, la production, la demande finale, le transport et l`exportation. On fait deux suppositions quant aux facteurs de production: la main-d`oevre et d`autres facteurs. Le modele embrasse douze regions internes et trois regions externes. On fait quatre experiences paradoxales fondees sur la baisse des frais de transport due a une `reduction des distances`. Les principaux resultats indiquent que si l`amelioration de l`equipement de transport ne porte que sur les regions defavorisees, la promotion de l`equilibre regional s`avere negligeable. Si l`amelioration de l`equipement de transport focalise les regions riches, il s`avere un creusement des ecarts des revenus regionaux. Cependant, si les ameliorations ciblent les routes qui relient les regions defavorisees aux regions riches, il s`avere une plus grande promotion de l`equilibre regional. Il en va de meme pour la situation ou on a apporte des amenagements a toutes les liaisons routieres de l`etat. Modele geographique de l`equilibre general a utiliser sur ordinateur Equilibre regional Peformance economique Frais de transport Almeida E. S. de, Haddad E. A. und Hewings G. J. D. Die Wiederaufnahme der Frage von Verkehrswesen im Verhaltnis zu regionaler Fairness, Regional Studies. Dieser Aufsatz beabsichtigt, die Beziehung zwischen Verkehrswesen und regionaler Fairness in Minas Gerais (Brasilien) zu analysieren und zugleich auch das Vorkommen von Einbussen entweder bei wirtschaftlicher Leistung der regionaler Fairness zu untersuchen. Zu diesem Zwecke wird ein auf dem Ansatz von Brocker und Schneider (2002) aufbauendes raumliches komputables allgemeines Gleichgewichtsmodell entwickelt, um vergleichende statistische Analysen durchzufuhren, wobei verborgene `Eisberg`-Transportkosten ausdrucklich berucksichtigt werden. Es werden vier Unternehmenstatigk eiten aufgefuhrt: Herstellung, Nachfrage, Transportwesen und Exporte, und zwei Produktionsfaktoren vorausgesetzt: Arbeitskrafte und andere Faktoren. Das Modell umfasst zwolf Inlandsregionen und drei externe Regionen. Es werden vier gegensatzliche Experimente entwickelt, die auf einer Abnahme der Transportkosten infolge einer `Verkurzung der Entfernungen` beruhen. Die Hauptbefunde weisen darauf hin, dass die Forderung regionaler Fairness unbedeutend bleibt, wenn die Verbesserungen der Transportinfrastruktur sich nur auf minderbemittelte Regionen konzentrieren; werden die Verbesserungen der Verbindungen der Transportinfrastruktur in wohlhabenden Regionen durchgefuhrt, so nehmen regionale Einkommensunterschiede zu. Wenn die Verbesserungen jedoch auf Strassen abzielen, die wohlhabende Regionen mit weniger bemittelten verbinden, wird regionale Fairness starker gefordert. Das gleiche Ergebnis wird sich einstellen, wenn Verbesserungen an allen Strassenverbindungen des Staates vorgenommen werden. Raumliches, komputables, allgemeines Gleichgewichtsmodell Regionale Fairness Wirtschaftsleistung Transportkosten Almeida E. S. de, Haddad E. A. y Hewings G. J. D. Revisando el tema de la igualdad del transporte en las regiones, Regional Studies. El objetivo de este documento es analizar la relacion entre el transporte y la igualdad regional en Minas Gerais, Brasil. Asimismo investigamos la existencia de una compensacion entre el rendimiento economico y la igualdad regional. Para ello desarrollamos un modelo de equilibrio general computable y espacial basado en el enfoque de Brocker y Schneider en 2002 para hacer un analisis estatico y comparativo, explicitamente incorporando los costes ocultos de transporte. Se modelan cuatro actividades: la produccion, la demanda final, el transporte y las exportaciones. Suponemos que existen dos factores de produccion: mano de obra y otros factores. En este modelo, existen doce regiones internas y tres regiones externas. Desarrollamos cuatro experimentos contrafactuales basados en la disminucion de los costes de transporte debido a una `acortamiento de las distancias`. Los principales resultados indican que si la mejora de la infraestructura del transporte se centra solo entre las regiones mas pobres, el fomento de la igualdad regional es insignificante. Si los enlaces de la mejora de la infraestructura del transporte se concentran en las regiones ricas, aumentan las desigualdades de ingresos regionales. Sin embargo, si se mejoran los enlaces de carreteras entre las regiones pobres y ricas, se fomenta mejor la igualdad regional. El mismo resultado ocurre cuando se mejoran los enlaces de todas las carreteras del estado. Modelo de equilibrio general computable y espacial Igualdad regional Rendimiento economico Costes de transporte.

STRUCTURAL INTERDEPENDENCE AMONG COLOMBIAN DEPARTMENTS

This paper analyzes structural interdependence among Colombian departments. The results show that Bogota has a large influence on the other regional economies through the power of its purchases. Additionally, a center-periphery pattern emerges in the spatial concentration of the effects of the hypothetical extraction of any territory. From a policy point of view, the main findings reaffirm the role played by Bogota in the recent polarization process observed in the regional economies in Colombia. Any policy action oriented to reduce these regional disparities should take into account that, given the structural interdependence among Colombian departments, the effects of new investment in the lagged regions would flow through Bogota and the major regional economies.

Regional Effects of Port Infrastructure: A Spatial CGE Application to Brazil

This article attempts to elucidate one of the mechanisms that link trade barriers, in the form of port costs, and subsequent growth and regional inequality. Prior attention has focused on inland or link costs, but port costs can be considered as a further barrier to enhancing trade liberalization and growth. In contrast to a highway link, congestion at a port may have severe impacts that are spread over space and time whereas highway link congestion may be resolved within several hours. Since a port is part of the transportation network, any congestion/disruption is likely to ripple throughout the hinterland. In this sense, it is important to model properly the role nodal components play in the context of spatial models and international trade. In this article, a spatial computable general equilibrium (CGE) model that is integrated to a transport network system is presented to simulate the impacts of increases in port efficiency in Brazil. The role of ports of entry and ports of exit are explicitly considered to grasp the holistic picture in an integrated interregional system. Measures of efficiency for different port locations are incorporated in the calibration of the model and used as the benchmark in our simulations. Three scenarios are evaluated: (1) an overall increase in port efficiency in Brazil to achieve international standards; (2) efficiency gains associated with decentralization in port management in Brazil; and (3) regionally differentiated increases in port efficiency to reach the boundary of the national efficiency frontier.

History of vegetation and habitat change in the Austral-Asian region

Over 1000 marine and terrestrial pollen diagrams and Some hundreds of vertebrate faunal sequences have been studied in the Austral-Asian region bisected by the PEPII transect, from the Russian arctic extending south through east Asia, Indochina, southern Asia, insular Southeast Asia (Sunda), Melanesia, Australasia (Sahul) and the western south Pacific. The majority of these records are Holocene but sufficient data exist to allow the reconstruction of the changing biomes over at least the past 200,000 years. The PEPII transect is free of the effects of large northern ice caps yet exhibits vegetational change in glacial cycles of a similar scale to North America. Major processes that can be discerned are the response of tropical forests in both lowlands and uplands to glacial cycles, the expansion of humid vegetation at the Pleistocene-Holocene transition and the change in faunal and vegetational controls as humans occupy the region. There is evidence for major changes in the intensity of monsoon and El Nino-Southern oscillation variability both on glacial-interglacial and longer time scales with much of the region experiencing a long-term trend towards more variable and/or drier climatic conditions. Temperature variation is most marked in high latitudes and high altitudes with precipitation providing the major climate control in lower latitude, lowland areas. At least some boundary shifts may be the response of vegetation to changing CO2 levels in the atmosphere. Numerous questions of detail remain, however, and current resolution is too coarse to examine the degree of synchroneity of millennial scale change along the transect. (C) 2003 Elsevier Ltd and INQUA. All rights reserved.

Modulation of cytochrome P450 monooxygenase by cadmium chloride in the mouse liver: Involvement of transcription factor Nrf2.

Modulation of the cytochrome P450 (CYP) monooxygenase system and haem oxygenase by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 Amol/kg body weight, i.p.) of cadmium chloride (CdCl2), at various time points. Total CYP content of liver microsomes decreased significantly (P < 0.05) at 12, 18, and 24 hours (22%, 47%, and 56%, respectively) after treatment. In contrast, progressive increases of hepatic coumarin 7-hydroxylase (COH) activity (indicative of CYP2A5 activity) were observed at 8 hrs (2-fold), 12 hrs (3-fold), and 7-fold at 18 and 24 hrs. Simultaneously, haem oxygenase activity increased significantly at 4 hours and continued to increase progressively to more than 50-fold compared to control. Liver CYP2A5 mRNA levels increased maximally 12 hours after treatment and decreased to almost half 6 hours later, while western blot analysis showed 2- and 3- fold increase in CYP2A5 apoprotein at 12 and 24 hours. The CYP2A5 mRNA levels in the liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 / mouse. This study demonstrates that hepatic haem oxygenase and CYP2A5 are upregulated by cadmium. The upregulation of haem oxygenase precedes that of CYP2A5. The strong upregulation of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous decrease in the total CYP concentration suggest an unusual mode of regulation of CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed increase in the mRNA but not in protein levels after maximal induction may suggest involvement of post-transcriptional mechanisms in the regulation. Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2 / mice indicates a role for this transcription factor in the regulation.