Comparison of steroid substrates and inhibitors of P-glycoprotein by 3D-QSAR analysis

Steroid derivatives show a complex interaction with P-glycoprotein (Pgp). To determine the essential structural requirements of a series of structurally related and functionally diverse steroids for Pgp-mediated transport or inhibition, a three-dimensional quantitative structure activity relationship study was performed by comparative similarity index analysis modeling. Twelve models have been explored to well correlate the physiochemical features with their biological functions with Pgp on basis of substrate and inhibitor datasets, in which the best predictive model for substrate gave cross-validated q(2) = 0.720, non-cross-validated r(2) = 0.998, standard error of estimate SEE = 0.012, F = 257.955, and the best predictive model for inhibitor gave q(2) = 0.536, r(2) = 0.950, SEE = 1.761 and F = 45.800. The predictive ability of all models was validated by a set of compounds that were not included in the training set. The physiochemical similarities and differences of steroids as Pgp substrate and inhibitor, respectively, were analyzed to be helpful in developing new steroid-like compounds. (C) 2004 Elsevier B.V. All rights reserved.

Modeling the peptide-T cell receptor interaction by the comparative molecular similarity indices analysis-soft independent modeling of class analogy technique

A set of 38 epitopes and 183 non-epitopes, which bind to alleles of the HLA-A3 supertype, was subjected to a combination of comparative molecular similarity indices analysis (CoMSIA) and soft independent modeling of class analogy (SIMCA). During the process of T cell recognition, T cell receptors (TCR) interact with the central section of the bound nonamer peptide; thus only positions 4−8 were considered in the study. The derived model distinguished 82% of the epitopes and 73% of the non-epitopes after cross-validation in five groups. The overall preference from the model is for polar amino acids with high electron density and the ability to form hydrogen bonds. These so-called “aggressive” amino acids are flanked by small-sized residues, which enable such residues to protrude from the binding cleft and take an active role in TCR-mediated T cell recognition. Combinations of “aggressive” and “passive” amino acids in the middle part of epitopes constitute a putative TCR binding motif

Australian domestic violence protection order legislation : a comparative quantitative content analysis of victim safety provisions

In Australia, protection orders are a key legal response to domestic violence, and are often viewed as a way of providing for victim safety. For instance, recently the joint Australian and New South Wales Law Reform Commissions recommended that a common core purpose of all state and territory domestic violence legislation should be ‘to ensure or maximise the safety and protection of persons who fear or experience family violence’ (2010:Recommendation 7-4). Drawing and building upon prior research in Australia and the United States (‘US’), this paper uses comparative quantitative content analysis to assess the victim safety focus of domestic violence protection order legislation in each Australian state and territory. The findings of this analysis show that the Northern Territory, South Australia and Victoria ‘stand out’ from the other jurisdictions, having the highest victim safety focus in their legislation. However, there remains sizeable scope for improvement in all Australian jurisdictions, in terms of the victim safety focus of their legislative provisions and the considerations of legislative inconsistency between jurisdictions.

Comparative genomic hybridization analysis of benign and invasive male breast neoplasms

Comparative genomic hybridization (CGH) analysis was performed for the identification of chromosomal imbalances in two benign gynecomastias and one malignant breast carcinoma derived from patients with male breast disease and compared with cytogenetic analysis in two of the three cases. CGH analysis demonstrated overrepresentation of 8q in all three cases. One case of gynecomastia presented gain of 1p34.3similar topter. 11p14similar toq12. and 17p11.2similar toqter, and loss of 1q41similar toqter and 4q33similar toqter. The other gynecomastia presented del(1)(q41) as detected by both cytogenetic and CGH analysis. CGH analysis of the invasive ductal carcinoma confirmed a gain of 17p11.2similar toqter previously detected by cytogenetic analysis. These regions showed some similarity in their pattern of imbalance to the chromosomal alterations described in female and male breast cancer. (C) 2002 Elsevier B.V. All rights reserved.

Retinal image quality assessment through a visual similarity index

Retinal image quality is commonly analyzed through parameters inherited from instrumental optics. These parameters are defined for ‘good optics’ so they are hard to translate into visual quality metrics. Instead of using point or artificial functions, we propose a quality index that takes into account properties of natural images. These images usually show strong local correlations that help to interpret the image. Our aim is to derive an objective index that quantifies the quality of vision by taking into account the local structure of the scene, instead of focusing on a particular aberration. As we show, this index highly correlates with visual acuity and allows inter-comparison of natural images around the retina. The usefulness of the index is proven through the analysis of real eyes before and after undergoing corneal surgery, which usually are hard to analyze with standard metrics.

Advance Directives and the Promotion of Autonomy: a Comparative Australian Statutory Analysis

Legislation regulating advance directives exists in six Australian jurisdictions. In all of these jurisdictions, legislation was enacted to enshrine the common law right of a competent adult to refuse treatment in advance, even if that treatment was required to sustain life. It was thought that enshrining the common law would also enshrine the principle of autonomy on which the common law was based. This article explores whether this is the case by examining the legislative restrictions that are imposed on a competent adult who wishes to complete an advance directive refusing treatment. The article reviews the legislation in all Australian jurisdictions and concludes that, while many of the legislative restrictions can be justified, many cannot as they effectively erode rather than promote the right of a competent adult to refuse treatment.

A comparative social network analysis of wasp colonies and classrooms: Linking network structure to functioning

A major question in current network science is how to understand the relationship between structure and functioning of real networks. Here we present a comparative network analysis of 48 wasp and 36 human social networks. We have compared the centralisation and small world character of these interaction networks and have studied how these properties change over time. We compared the interaction networks of (1) two congeneric wasp species (Ropalidia marginata and Ropalidia cyathiformis), (2) the queen-right (with the queen) and queen-less (without the queen) networks of wasps, (3) the four network types obtained by combining (1) and (2) above, and (4) wasp networks with the social networks of children in 36 classrooms. We have found perfect (100%) centralisation in a queen-less wasp colony and nearly perfect centralisation in several other queen-less wasp colonies. Note that the perfectly centralised interaction network is quite unique in the literature of real-world networks. Differences between the interaction networks of the two wasp species are smaller than differences between the networks describing their different colony conditions. Also, the differences between different colony conditions are larger than the differences between wasp and children networks. For example, the structure of queen-right R. marginata colonies is more similar to children social networks than to that of their queen-less colonies. We conclude that network architecture depends more on the functioning of the particular community than on taxonomic differences (either between two wasp species or between wasps and humans).

A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information

The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activation of their tyrosine kinase domain is still not well understood. We have carried out an amino acid residue conservation analysis in order to reconstruct the phylogeny of the IR Family. We have confirmed the location of ligand binding site 1 of the IGF1R and IR. Importantly, we have also predicted the likely location of the insulin binding site 2 on the surface of the fibronectin type III domains of the IR. An evolutionary conserved surface on the second leucine-rich domain that may interact with the ligand could not be detected. We suggest a possible mechanical trigger of the activation of the IR that involves a slight ‘twist’ rotation of the last two fibronectin type III domains in order to face the likely location of insulin. Finally, a strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals.

A FUNCTIONAL, COMPARATIVE AND CLINICAL ANALYSIS OF SPERM-BORNE OOCYTE ACTIVATING FACTOR, PAWP

Successful fertilization depends upon the activation of metaphase II arrested oocytes by sperm-borne oocyte activating factor (SOAF). Failure of oocyte activation is considered as the cause of treatment failure in a proportion of infertile couples. SOAF induces the release of intracellular calcium in oocyte which leads to meiotic resumption and pronuclear formation. Calcium release is either in the form of single calcium transient in echinoderm and amphibian oocytes or several calcium oscillations in ascidian and mammalian oocytes. Although the SOAF attributes are established, it is not clear which sperm protein(s) play such role. Sperm postacrosomal WW binding protein (PAWP) satisfies a developmental criteria set for a candidate SOAF. This study shows that recombinant human PAWP protein or its transcript acts upstream of calcium release and fully activates the amphibian and mammalian oocytes. Interference trials provided evidence for the first time that PAWP mediates sperm-induced intracellular calcium release through a PPXY/WWI domain module in Xenopus, mouse and human oocytes. Clinical applications of PAWP were further investigated by prospective study on the sperm samples from patients undergoing intracytoplasmic sperm injection (ICSI). PAWP expression level, analyzed by flow cytometry, was correlated to ICSI success rate and embryonic development. This study also explored the developmental expression of the other SOAF candidate, PLCζ in male reproductive system and its function during fertilization. Our findings showed for the first time that PLCζ most likely binds to the sperm head surface during epididymal passage and is expressed in epididymis. We demonstrated that PLCζ is also compartmentalized early in spermiogenesis and thus could play an important role during spermiogenesis. Detailed analysis of in vitro fertilization revealed that PLCζ disappears from sperm head during acrosome reaction and is not detectable during sperm incorporation into the oocyte cytoplasm. In conclusion, this dissertation provides evidence for the essential non-redundant role of sperm PAWP in amphibian and mammalian fertilization; recommends PAWP as a biomarker for prediction of ICSI outcomes in infertile couples; and proposes that sperm PLCζ may have functions other than inducing oocyte activation during fertilization.

3D-QSAR studies on 4-Hydroxyphenylpyruvate Dioxygenase inhibitors by comparative molecular field analysis (CoMFA)

A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4-hydroxyphenylpyruvate dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrate's conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

Selectivity fields: comparative molecular field analysis (CoMFA) of the glycine/NMDA and AMPA receptors

An approach for evaluation of binding selectivity was suggested and exemplified using glycine/NMDA and AMPA receptors. For analyzing the pairwise selectivity, we propose to use the difference between biological activities (expressed as -log Ki) of ligands with respect to different receptor subtypes as a dependent variable for building comparative molecular field analysis (CoMFA) models. The resulting fields (which will be referred to as the "selectivity fields") indicate the ways of increasing selectivity of binding, inhibition, etc. As an example, CoMFA of a set of pyrazolo[1,5-c]quinazolines and triazolo[1,5-c]quinazolines was used for considering the binding selectivity with respect to glycine/NMDA and AMPA receptors. In addition, the mapping of these fields onto the molecular models of the corresponding receptors makes it possible to reveal the reasons for experimentally observed selectivity as well as to suggest additional ways of increasing selectivity.

Why do national court judges refer to human rights treaties?: A comparative international law analysis of CEDAW

An analysis was conducted of 325 national judicial decisions across 55 jurisdictions, in which CEDAW was referred to in the reported decision. Despite predictions to the contrary based on previous scholarship, significant variations between courts in their interpretation of CEDAW occurred relatively infrequently, courts referred relatively seldom to interpretations of CEDAW by other national courts, and there was little evidence of transnational dialogic approaches to judging. An analysis of these results suggests that domestic judges invoking CEDAW act primarily as domestic actors who use international law in order to advance domestic goals, rather than acting primarily as agents of the international community in applying CEDAW domestically, or contributing to the transnational shaping of international law to suit national interests. The Article suggests an understanding of the domestic implementation of a human rights treaty as not only law, but a unique kind of law that performs a particular function, in light of its quality as something akin to hard and soft law simultaneously.