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.

Effect of supplementation with a by-product of molasses fermentation or a non-protein nitrogen/mineral mix on feed intake and microbial protein supply in sheep consuming chopped oat (Avena sativa) hay

Crossbred ewes, weighing 30-40 kg, were assigned to three groups of six animals. One group of sheep was fed chopped oat hay (control), the second group was fed the control diet plus 30 g per head per day spray dried residue from the fermentation of molasses and the third group was fed the control diet plus 30 g per head per day of a non-protein nitrogen/mineral mix. Voluntary feed intake, digestibility of DM, OM and nitrogen, nitrogen balance and microbial nitrogen flow to the intestines were significantly increased by supplementation but efficiency of microbial protein production was not affected. (C) 2001 Elsevier Science BN. All rights reserved,

Loss as a universal concept: Review of the literature to identify common aspects of loss in diverse situations

It has long been recognized that loss and its associated grief are important elements of many adverse life events that affect the entire global population: death, disability, traumatic events, abuse., terminal and chronic illness, aging, addiction, unemployment, relationship breakdown, war, migration, and educational failure. While there is significant empirical evidence of the potential deleterious effects of specific situations of loss across the global community, systematic discussion concerning the common elements of loss that are associated with adverse life situations in general has been limited. This review of the theoretical and empirical literature concerning various losses and the recommendations for care of those affected by such losses identifies common aspects of situations of loss and common recommendations in the care of those confronted by such losses. These common themes of loss are described by simple summary statements that can be communicated to a broad audience, hence enhancing community education and, potentially, community-wide mental health promotion.

Lexicographic decomposition of chains and the concept of a planar chain

In an earlier paper [Journal of Mathematical Economics, 37 (2002) 17-38], we proved that if a preference relation on a commodity space is non-representable by a real-valued function then that chain is necessarily a long chain, a planar chain, an Aronszajn-like chain or a Souslin chain. In this paper, we study the class of planar chains, the simplest example of which is the Debreu chain (R-2, <(l)). (C) 2002 Elsevier Science B.V. All rights reserved.

History of the events leading to the formulation of the apoptosis concept

Histological studies of ischaemic liver injury performed between 1962 and 1964 distinguished two types of cell death: classical necrosis, and a process involving conversion of scattered cells into small round masses of cytoplasm that often contained specks of condensed nuclear chromatin. Enzyme histochemistry demonstrated rupture of lysosomes in the former, but preservation of lysosomes in the latter. Similar small round masses were also observed sparsely in normal liver. Electron microscopy showed that the small round bodies resulted from cellular condensation and budding, that they were bounded by membranes and contained intact organelles, and that they were phagocytosed and digested by resident tissue cells, including epithelial cells. In work done in association with Jeffrey Searle, the process was found to occur spontaneously in a variety of malignant tumours and to be enhanced in squamous cell carcinomas of skin responding to radiotherapy. During 1971-1972, I collaborated with Andrew Wyllie and Alastair Currie while on sabbatical leave in Scotland. The newly defined type of cell death was shown to be regulated by hormones in the adrenal cortex and in breast carcinomas. Further, review of published electron micrographs of the cell death known to play an essential role in normal development revealed the same morphological pattern. We proposed that this distinctive phenomenon subserves a general homoeostatic function and suggested it be called apoptosis. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

R-matrices and the tensor product graph method

A systematic method for constructing trigonometric R-matrices corresponding to the (multiplicity-free) tensor product of any two affinizable representations of a quantum algebra or superalgebra has been developed by the Brisbane group and its collaborators. This method has been referred to as the Tensor Product Graph Method. Here we describe applications of this method to untwisted and twisted quantum affine superalgebras.

New product warranty: A literature review

Warranty is an important element of marketing new products as better warranty signals higher product quality and provides greater assurance to customers. Servicing warranty involves additional costs to the manufacturer and this cost depends on product reliability and warranty terms. Product reliability is influenced by the decisions made during the design and manufacturing of the product. As such warranty is very important in the context of new products. Product warranty has received the attention of researchers from many different disciplines and the literature on warranties is vast. This paper carries out a review of the literature that has appeared in the last ten years. It highlights issues of interest to manufacturers in the context of managing new products from an overall business perspective. (C) 2002 Elsevier Science B.V. All rights reserved.

Calculation of resonances and product state distributions for the unimolecular dissociation of H2S

Resonance phenomena associated with the unimolecular dissociation of H2S --> SH + H have been investigated quantum mechanically by the Lanczos homogeneous filter diagonalization method using a newly developed potential energy surface (J. Chem. Phys. 2001, 114, 320). Resonance energies, widths (rates), and product state distributions have been obtained. Both dissociation rates and product state distributions of SH show, strong fluctuations, indicating that the dissociation of H2S is essentially irregular. Statistical analysis of neighboring level spacing and width distributions also confirms this behavior. The dissociation rates and product state distributions are compared to the predictions of quantum phase space theory.

Prediction of absolute rate coefficients and product branching ratios for the C(P-3) plus allene reaction system

Complex chemical reactions in the gas phase can be decomposed into a network of elementary (e.g., unimolecular and bimolecular) steps which may involve multiple reactant channels, multiple intermediates, and multiple products. The modeling of such reactions involves describing the molecular species and their transformation by reaction at a detailed level. Here we focus on a detailed modeling of the C(P-3)+allene (C3H4) reaction, for which molecular beam experiments and theoretical calculations have previously been performed. In our previous calculations, product branching ratios for a nonrotating isomerizing unimolecular system were predicted. We extend the previous calculations to predict absolute unimolecular rate coefficients and branching ratios using microcanonical variational transition state theory (mu-VTST) with full energy and angular momentum resolution. Our calculation of the initial capture rate is facilitated by systematic ab initio potential energy surface calculations that describe the interaction potential between carbon and allene as a function of the angle of attack. Furthermore, the chemical kinetic scheme is enhanced to explicitly treat the entrance channels in terms of a predicted overall input flux and also to allow for the possibility of redissociation via the entrance channels. Thus, the computation of total bimolecular reaction rates and partial capture rates is now possible. (C) 2002 American Institute of Physics.

A normative study of distortion product otoacoustic emissions in six-year-old school children

Evoked otoacoustic emissions have demonstrated potential for application in the community-based hearing screening of paediatric populations. Distortion-product otoacoustic emissions (DPOAEs), as opposed to transient evoked otoacoustic emissions (TEOAEs), have not been extensively researched in this regard. The current study aimed to describe the range of DPOAE values obtained in a large cohort (1576 ears) of 6-year-old children in school settings and to examine possible ear asymmetry, gender and history of ear infection effects on the data. Results indicated a variety of significant effects, particularly in the high frequencies, for DPOAE signal-to-noise ratio. The measurement parameter, DPOAE amplitude (DP-amp), was found to display potentially less clinical applicability due to large standard deviation values. Use of descriptive normative data, as derived in the present investigation, may contribute toward future improvements in the hearing screening of 6-year-old schoolchildren

Polymer product engineering utilising oscillatory baffled reactors

The Oscillatory baffled reactor (OBR) can be used to produce particles with controlled size and morphology, in batch or continuous flow. This is due to the effect of the superimposed oscillations that radially mixes fluid but still allows plug-flow (or close to plug flow) behaviour in a continuous system. This mixing, combined with a close to a constant level of turbulence intensity in the reactor, leads to tight droplet and subsequent product particle size distributions. By applying population balance equations together with experimental droplet size distributions, breakage rates of droplets can be determined and this is a useful tool for understanding the product engineering in OBRs. (C) 2002 Elsevier Science B.V All rights reserved.

Supply chain management as beyond operational efficiency

The orthodoxy of supply chain management (SCM) emphasises competitive advantage through increased operational efficiency and market responsiveness from production and distribution processes into the hands of consumers. It anticipates that future competition will be between chains rather than between firms. While well established in other industry sectors, the SCM concept is newly developed in the Australian agri-food sector. Critical review of the concept has identified key issues of power among channel members, processes of chain initiation and innovation, and the inability of SCM to offer a viable business strategy for some firms. Building on those insights, this paper examines the supply chain concept for horticulture. Horticultural products are characterised by perishability, heterogeneity and lags in production response to market signals. Producers’ profits are vulnerable to quantity, timing of supply and product specification. Many supply chains in smaller industries are loose, fragmented, interwoven, unstable and unique! Firms operating within these environments need an astute understanding of the chains, the hierarchy of channel members and their relative position. Effective business strategies – for individual firms and supply chains - need to be developed and redeveloped to accommodate the dynamic nature of horticulture. Two case studies are discussed as contributions to this early stage of the theoretical development of supply chain management. The SCM concept also has implications for horticultural researchers, involving a wider range of industry stakeholders, technical problems and research skills. As for business management, the usefulness of the concept will depend on its capacity to increase responsiveness to customers’ preferences and customer value.

Managing new product development in the Chinese steel industry: An empirical investigation

This study explores several important aspects of the management of new product development (NPD) in the Chinese steel industry. Specifically it explores NPD success factors, the importance of management functions to new product success and measures of new product success from the perspective of the industry's practitioners. Based on a sample of 190 industrial practitioners from 18 Chinese steel companies, the study provides a mixed picture as China makes the transition from a centrally-controlled to market-based economy. On one hand, respondents ranked understanding users' needs as the most important factor influencing the performance of the new products. Further, formulating new product strategy and strengthening market research are perceived as the most important managerial functions in NPD. However, technical performance measures are regarded as more important and are more widely used in industry than market-based or financial measures of success.

The JK three-product cyclone - performance and potential applications

In spite of their wide application in comminution circuits, hydrocyclones have at least one significant disadvantage in that their operation inherently tends to return the fine denser liberated minerals to the grinding mill. This results in unnecessary overgrinding which adds to the milling cost and can adversely affect the efficiency of downstream processes. In an attempt to solve this problem, a three-product cyclone has been developed at the Julius Kruttschnitt Mineral Research Centre (JKMRC) to generate a second overflow in which the fine dense liberated minerals can be selectively concentrated for further treatment. In this paper, the design and operation of the three-product cyclone are described. The influence of the length of the second vortex finder on the performance of a 150-mm unit treating a mixture of magnetite and silica is investigated. Conventional cyclone tests were also conducted under similar conditions. Using the operational performance data of the three-product and conventional cyclones, it is shown that by optimising the length of the second vortex finder, the amount of fine dense mineral particles that reports to the three-product cyclone underflow can be reduced. In addition, the three-product cyclone can be used to generate middlings stream that may be more suitable for flash flotation than the conventional cyclone underflow, or alternatively, could be classified with a microscreen to separate the valuables from the gangue. At the same time, a fines stream having similar properties to those of the conventional overflow can be obtained. Hence, if the middlings stream was used as feed for flash flotation or microscreening, the fines stream could be used in lieu of the conventional overflow without compromising the feed requirements for the conventional flotation circuit. Some of the other potential applications of the new cyclone are described. (C) 2003 Elsevier Science B.V. All rights reserved.