The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides

Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.

Biostatistics in Australia: Directions in the new millennium

The Biostatistics Collaboration of Australia (BCA) was formed in response to a shortage of statisticians seeking careers in the medical and health professions. The Collaboration has been successful in developing postgraduate courses (Graduate Certificate, Graduate Diploma and Masters) offered by a consortium of seven Australian Universities. These courses are available through a distance learning medium. The BCA was successful in securing funding from the Federal government to launch these courses, which commenced in March 2001. Two traineeships by the NSW Department of Health have also been awarded and a third is currently advertised. There has been close collaboration with governments, the pharmaceutical industry and research organisations to ensure that course content reflects practical problems and addresses industry needs. A second objective of the BCA is to provide ongoing workshops for practising biostatisticians to enhance professional development. These workshops serve to ring together biostatisticians from both within Australia and the Asia-Pacific region, providing a forum for discussion of current statistical thinking. (author abstract)

Growth regime map for liquid-bound granules: further development and experimental validation

An attempt was made to quantify the boundaries and validate the granule growth regime map for liquid-bound granules recently proposed by Iveson and Litster (AlChE J. 44 (1998) 1510). This regime map postulates that the type of granule growth behaviour is a function of only two dimensionless groups: the amount of granule deformation during collision (characterised by a Stokes deformation number, St(def)) and the maximum granule pore saturation, s(max). The results of experiments performed with a range of materials (glass ballotini, iron ore fines, copper chalcopyrite powder and a sodium sulphate and cellulose mixture) using both drum and high shear mixer granulators were examined. The drum granulation results gave good agreement with the proposed regime map. The boundary between crumb and steady growth occurs at St(def) of order 0.1 and the boundary between steady and induction growth occurs at St(def) of order 0.001. The nucleation only boundary occurs at pore saturations that increase from 70% to 80% with decreasing St(def). However, the high shear mixer results all had St(def) numbers which were too large. This is most likely to be because the chopper tip-speed is an over-estimate of the average impact velocity granules experience and possibly also due to the dynamic yield strength of the materials being significantly greater than the yield strengths measured at low strain rates. Hence, the map is only a useful tool for comparing the granulation behaviour of different materials in the same device. Until we have a better understanding of the flow patterns and impact velocities in granulators, it cannot be used to compare different types of equipment. Theoretical considerations also revealed that several of the regime boundaries are also functions of additional parameters not explicitly contained on the map, such as binder viscosity. (C) 2001 Elsevier Science B.V. All rights reserved.

Ecology, shell morphology, anatomy and sperm ultrastructure of the caenogastropod Pyrgula annulata, with a discussion of the relationship between the 'Pyrgulidae' and Caspian and Baikalian rissooideans

The composition of the Pyrgulidae and its relationships to other member families of the caenogastropod superfamily Rissooidea are examined after a consideration of new anatomical (including gross anatomy, sperm ultrastructure), conchological (including protoconch features), ecological, biogeographical and palaeontological data and a re-evaluation of existing literature. Pyrgulidae can be distinguished from hydrobiids unequivocally only with the aid of the radula. Sperm ultrastructural features suggest a very close relationship between the Pyrgulidae, the Hydrobiidae and the Bithyniidae (in fact no family-diagnostic sperm characters can be found to separate these three taxa). Based upon neontological and fossil evidence it is likely that pyrgulids represent a Miocene offshoot from a paratethyal hydrobiid lineage. Pyrgulids may also represent the stock from which the baicaliids arose, in which case the Pyrgulidae must be considered a paraphyletic group. The huge biogeographic gap between the Caspian Sea and Lake Baikal is to some extent bridged by the finding of a Neogene pyrgulid from the Altai Mountains. An alternative scenario for the origin of baicaliids is presented.

Effects of phosphonate and salicylic acid treatments on anthracnose disease development and ripening of 'Kensington Pride' mango fruit

This study investigated treatment of mango (Mangifera indica L.) fruit with 2 host defence-promoting compounds for suppression of anthracnose disease (Colletotrichum gloeosporioides). Cultivar 'Kensington Pride' fruit were treated at concentrations of up to 1000 mg/L with either potassium phosphonate or salicylic acid. Applications were by various combinations of pre- and postharvest dips and vacuum infiltration. Postharvest treatments at up to 2000 mg/L salicylic acid were evaluated in a second fruiting season. Fruit were either uninoculated or inoculated with the fungal pathogen. Colour, firmness and disease-severity were assessed during shelf life at 23 degreesC. There were no significant (P>0.05) effects of potassium phosphonate or salicylic acid on anthracnose disease severity in the first season. Moreover, phosphonate or salicylic acid treatment did not significantly affect fruit colour or firmness changes. There were significant (P

Rate and timing of vegetative growth, flowering and fruit development of Persoonia virgata (Proteaceae)

Persoonia virgata R. Br. is harvested from the wild in both its vegetative and flowering stages. There has been no systematic study published on the annual growth cycle and anecdotal reports are conflicting. The growth pattern, flowering and fruit development of P. virgata in its natural habitat was recorded monthly for two consecutive years. The main growth period occurred in late spring-mid-autumn (November-May) when the shrubs were producing little or no fruit. Very few open flowers were observed at the site over the 2 years, with only 6.7 and 12.7% of stems bearing open flowers in January and February 1996, respectively. A second study of flowering on container-grown shrubs showed that individual flowers were open for only 2-5 days, with individual stems taking 3-8.5 weeks to complete flowering. The main fruit growth period occurred from May to September, and in June and July 1996 the total fruit set per stem was 41.6 and 36.1%, respectively. The fruit took at least 6 months to develop during which vegetative growth was minimal. The harvesting of plants in the flowering or fruiting stages removes the annual seed crop, which may reduce regeneration of this obligate seed regenerator and threaten its survival after fire.

State Banks and Economic Development in China

State-owned banks remain dominant in China's financial sector despite over two decades of gradual financial liberalization. Their performance is typically evaluated using commercial banking criteria. The standard view is that because state banks have experienced declining profitability and capital adequacy, they have been a drain on past economic development and endanger future growth prospects. However, we argue that state banks have strong development bank characteristics and hence warrant different performance criteria. The analysis in this paper suggests that while thier commercial performance may have been poor, the overall impact of state banks on China's economic development appears to have been both positive and sustainable. Copyright © 2001 John Wiley & Sons, Ltd.

A methodology for discipline-specific curriculum development

A methodology and framework for discipline-specific curriculum development in a local context is described. These activities, as part of the Thailand-Australia Science and Engineering Assistance Project, were in response to a needs analysis for curriculum assistance to a number of publicly-funded Thai universities in the engineering priority area of Materials Processing and Manufacturing. The paper outlines a strategy for the delivery of a centralised curriculum development workshop for academic staff follow-up visits and local curriculum activities with participating universities, and the presentation of technical short courses as guidance for such activity in other settings and/or discipline areas. This paper is part of a process of documentation so that others can apply the developed methodology and framework for curriculum development. While the paper is a report on curriculum activities in a particular setting, it is written in a manner that allows application of the methodology to other settings. The reader is advised that each curriculum activity needs to adopt a methodology and strategy to fit the particular circumstances being considered To assist in applying this approach elsewhere, a description of the various steps in the curriculum process, and typical responses to some of the more global issues, have been presented. Full details are available in the various TASEAP reports prepared by the authors. Specific detail has been omitted where this detail does not provide any information for generalized consumption.

Genetic organization of Pasteurella multocida cap Loci and development of a multiplex capsular PCR typing system

Current serotyping methods classify Pasteurella multocida into five capsular serogroups (serogroups A, B, D, E, and F) and 16 somatic serotypes (serotypes 1 to 16). In the present study, we have developed a multiplex PCR assay as a rapid alternative to the conventional capsular serotyping system. The serogroup-specific primers used in this assay were designed following identification, sequence determination, and analysis of the capsular biosynthetic loci of each capsular serogroup. The entire capsular biosynthetic loci of P. multocida A:1 (X-73) and B:2 (M1404) have been cloned and sequenced previously (J. Y. Chung, Y. M. Zhang, and B. Adler, FEMS Microbiol. Lett. 166:289-296, 1998; J. D. Boyce, J. Y. Chung, and B. Adler, Vet. Microbiol. 72:121-134, 2000). Nucleotide sequence analysis of the biosynthetic region (region 2) from each of the remaining three serogroups, serogroups D, E, and F, identified serogroup-specific regions and gave an indication of the capsular polysaccharide composition. The multiplex capsular PCR assay was highly specific, and its results, with the exception of those for some serogroup F strains, correlated well with conventional serotyping results. Sequence analysis of the strains that gave conflicting results confirmed the validity of the multiplex PCR and indicated that these strains were in fact capsular serogroup A. The multiplex PCR will clarify the distinction between closely related serogroups A and F and constitutes a rapid assay for the definitive classification of P. multocida capsular types

The Winnipeg principles, WTO and sustainable development: Proposed policies for reconciling trade and the environment

There is, a widespread belief that the WTO has made virtually no concessions to environmentalists about their concerns arising from free trade and the process of globalization. There are concerns that these processes may undermine prospects for sustainable development. Following, the United Nations Conference on Environment and Development held in Rio de Janeiro in 1992, the International Institute for Sustainable Development was established to advocate policies to support sustainable development within Canada and globally. In 1994, it proposed the Winnipeg Principles as. a means for reconciling international trade and development so as to: achieve sustainable development (ISD, 1994a,b). These seven principles are outlined in this article and assessed:. Although the International Institute for Sustainable Development had hoped: through these principles to influence the work programme of the Environment and Trade Committee of WTO, it seems to have little effect. Probably if these principles had been seriously considered by WTO, the serious social conflicts which emerged globally at the beginning of this century would have been avoided, and we would be in a better position to understand the complex links between trade, environment and sustainable development and adopt relevant policies. Copyright (C) 2001 John Wiley & Sons, Ltd and ERP Environment.