Responding to health impacts of climate change in the Australian desert.

Climate change is likely to have a significant effect on the health of those living in the 70% of Australia that is desert. The direct impacts on health, such as increased temperature, are important. But so too are the secondary impacts that will occur as a result of the impact of climate change on an uncertain and highly variable natural environment and on the interlinking social and economic systems. The consequence of these secondary impacts will appear as changes in the incidence of disease and infections, and on the psychosocial determinants of health. Responding to the impacts of climate change on health in desert Australia will involve the active participation of a variety of interest groups ranging from local to state and federal governments and a range of public and private agencies, including those not traditionally defined as within the health sector. The modes of engagement required for this process need to be innovative, and will differ among regions on different trajectories. To this end, a first classification of these trajectories is proposed.

Pharmacophore fingerprinting. 2. Application to primary library design.

A methodology for pharmacophore fingerprinting (PharmPrint), previously described in the context of QSAR, has been used to address the issues involved in primary library design. A subset of the MDDR (MDDR9104) has been used to define a reference set of bioactive molecules. A statistic has been devised to measure the discriminating power of molecular descriptors using the target class assignments for this set, for which the PharmPrint fingerprint outperformed other descriptors. A principal components analysis (PCA) of the fingerprints for the MDDR9104 produces a low dimensional representation within which molecular properties and other libraries can be visualized and explored. PCA calculations on subsets of classes show that this space is robust to the addition of new classes, suggesting that pharmacophoric space is finite and rapidly converging. We demonstrate the application of the PharmPrint methodology to the analysis and design of virtual combinatorial libraries using common scaffolds and building blocks.

Pharmacophore fingerprinting. 1. Application to QSAR and focused library design.

A new method of rapid pharmacophore fingerprinting (PharmPrint method) has been developed. A basis set of 10,549 three-point pharmacophores has been constructed by enumerating several distance ranges and pharmacophoric features. Software has been developed to assign pharmacophoric types to atoms in chemical structures, generate multiple conformations, and construct the binary fingerprint according to the pharmacophores that result. The fingerprint is used as a descriptor for developing a quantitative structure-activity relationship (QSAR) model using partial least squares. An example is given using sets of ligands for the estrogen receptor (ER). The result is compared with previously published results on the same data to show the superiority of a full 3D, conformationally flexible approach. The QSAR model can be readily interpreted in structural/chemical terms. Further examples are given using binary activity data and some of our novel in-house compounds, which show the value of the model when crossing compound classes.

Examination for sexual assault: is the documentation of physical injury associated with the laying of charges? A retrospective cohort study.

BACKGROUND: Few studies have examined whether there is an association between individual medical findings and legal outcome in cases of sexual assault. This study was undertaken to determine the relation between the extent of documented physical injury and a positive legal outcome in cases of sexual assault and to determine other factors associated with the laying of charges in such cases. METHODS: In this retrospective cohort study, the authors reviewed the charts and medicolegal reports for all cases of sexual assault that were handled by the BC Women's Sexual Assault Service in 1992 for which a police report had been filed. Information on patients' characteristics, the nature of the assault and the extent of injury was extracted from these records. A system for scoring clinical injury was developed by 4 of the physicians at the Sexual Assault Service, and a clinical injury score was assigned for each case by one physician. The relation between the outcome (in terms of whether charges were laid) and the circumstances of the case was examined by logistic regression. RESULTS: A total of 95 cases with complete medical records and information about legal outcome were identified during the 1992 calendar year. After adjustment for income level and the patient's knowledge of the assailant (either as an acquaintance or as his or her partner), the odds ratio (OR) for charge-laying in a sexual assault case with documented moderate to severe injury was 3.33 (95% confidence interval [CI] 1.06-10.42). Socioeconomic status above the group median (defined as annual income greater than $21,893) (OR 3.26, 95% CI 1.09-9.71) and knowledge of the assailant (OR 4.58, 95% CI 1.52-13.79) were also associated with charge-laying. Presence of genital injury per se, age of the patient and detection of sperm by microscopy at the time of examination were not associated with the laying of charges. INTERPRETATION: The results of this study show that the extent of documented injury is associated with the laying of charges in cases of sexual assault. However, many questions remain about the effectiveness of the medical component of gathering such evidence.

Interaction between human CD2 and CD58 involves the major beta sheet surface of each of their respective adhesion domains.

The CD58 binding site on human CD2 was recently shown by nuclear magnetic resonance structural data in conjunction with site-directed mutagenesis to be a highly charged surface area covering approximately 770A2 on the major AGFCC'C" face of the CD2 immunoglobulin-like (Ig-like) NH2-terminal domain. Here we have identified the other binding surface of the CD2-CD58 adhesion pair by mutating charged residues shared among CD2 ligands (human CD58, sheep CD58, and human CD48) that are predicted to be solvent exposed on a molecular model of the Ig-like adhesion domain of human CD58. This site includes beta strand residues along the C strand (E25, K29, and K30), in the middle of the C' strand (E37) and in the G strand (K87). In addition, several residues on the CC' loop (K32, D33, and K34) form this site. Thus, the interaction between CD2 and CD58 involves the major beta sheet surface of each adhesion domain. Possible docking orientations for the CD2-CD58 molecular complex are offered. Strict conservation of human and sheep CD58 residues within the involved C and C' strands and CC' loop suggests that this region is particularly important for stable formation of the CD2-CD58 complex. The analysis of this complex offers molecular insight into the nature of a receptor-ligand pair involving two Ig family members.

Conformation of CD4-derived cyclic hexapeptides by NMR and molecular dynamics.

Two cyclic hexapeptides, cyclo[Ala1-D-Ala2-Ser3-Phe4-Gly5-Ser6] and cyclo[Ala1-Gly2-Ser3-Phe4-Gly5-Ser6], derived from the loop portion of the C'C" ridge of CD4, were characterized by high-resolution nmr spectroscopy and simulated annealing studies. In DMSO-d6 both of these peptides display a single conformer on the nmr time scale with two intramolecular H-bond (1<--4) stabilized beta-turns at positions 2-3 and 5-6. The nmr derived distance constraints were used in simulated annealing calculations to generate the solution structures. These structures adopt energetically comparable conformational substates that are not resolvable on the nmr time scale. In aqueous solution, the H-bond stabilized beta-turn conformation for cyclo[Ala-D-Ala-Ser-Phe-Gly-Ser] is no longer the predominant structural form. Structures generated using molecular dynamics simulations with no experimental constraints were compared with those from nmr analysis. The correlation between these two sets of structures allows the use of molecular simulations as a predictive tool for the conformational analysis of small peptides.

A predicted three-dimensional structure for the human immunodeficiency virus binding domains of CD4 antigen.

A predicted three-dimensional structure of the two N-terminal extracellular domains of human CD4 antigen, a cell surface glycoprotein, is reported. This region of CD4, particularly the first domain, has been identified as containing the binding region for the envelope gp120 protein of the human immunodeficiency virus. The model was predicted based on the sequence homology of each domain with the variable light chain of immunoglobulins. The framework beta-sheet regions were taken from the crystal coordinates of REI. For one region in the first domain of CD4 there was an ambiguity in the alignment with REI and two alternate models are presented. Loops connecting the framework were modelled from fragments selected from a database of main chain coordinates from all known protein structures. Residues identified as involved in binding gp120 have been located in several other studies within the first domain of CD4. Epitopes from eight monoclonal antibodies have been mapped onto residues in both domains. Competition of these antibodies with each other and with gp120 can be interpreted from the structural model.

Prediction of beta-turns in proteins using neural networks.

The use of neural networks to improve empirical secondary structure prediction is explored with regard to the identification of the position and conformational class of beta-turns, a four-residue chain reversal. Recently an algorithm was developed for beta-turn predictions based on the empirical approach of Chou and Fasman using different parameters for three classes (I, II and non-specific) of beta-turns. In this paper, using the same data, an alternative approach to derive an empirical prediction method is used based on neural networks which is a general learning algorithm extensively used in artificial intelligence. Thus the results of the two approaches can be compared. The most severe test of prediction accuracy is the percentage of turn predictions that are correct and the neural network gives an overall improvement from 20.6% to 26.0%. The proportion of correctly predicted residues is 71%, compared to a chance level of about 58%. Thus neural networks provide a method of obtaining more accurate predictions from empirical data than a simpler method of deriving propensities.

Analysis of the relationship between side-chain conformation and secondary structure in globular proteins.

The relationship between the preferred side-chain dihedral angles and the secondary structure of a residue was examined. The structures of 61 proteins solved to a resolution of 2.0 A (1 A = 0.1 nm) or better were analysed using a relational database to store the information. The strongest feature observed was that the chi 1 distribution for most side-chains in an alpha-helix showed an absence of the g- conformation and a shift towards the t conformation when compared to the non-alpha/beta structures. The exceptions to this tendency were for short polar side-chains that form hydrogen bonds with the main-chain which prefer g+. Shifts in the chi 1 preferences for residues in the beta-sheet were observed. Other side-chain dihedral angles (chi 2, chi 3, chi 4) were found to be influenced by the main-chain. This paper presents more accurate distributions for the side-chain dihedral angles which were obtained from the increased number of proteins determined to high resolution. The means and standard deviations for chi 1 and chi 2 angles are presented for all residues according to the secondary structure of the main-chain. The means and standard deviations are given for the most popular conformations for side-chains in which chi 3 and chi 4 rotations affect the position of C atoms.