Monoclonal antibody screening of a phage-displayed random peptide library reveals mimotopes of chemokine receptor CCR5: Implications for the tertiary structure of the receptor and for an n-terminal binding site for HIV-1 gp120

The chemokine receptor CCR5 contains seven transmembrane-spanning domains. It binds chemokines and acts as co-receptor for macrophage (m)-tropic (or R5) strains of HIV-1. Monoclonal antibodies (mAb) to CCR5, 3A9 and 5C7, were used for biopanning a nonapeptide cysteine (C)-constrained phage-displayed random peptide library to ascertain contact residues and define tertiary structures of possible epitopes on CCR5. Reactivity of antibodies with phagotopes was established by enzyme-linked immunosorbent assay (ELISA). mAb 3A9 identified a phagotope C-HASIYDFGS-C (3A9/1), and 5C7 most frequently identified C-PHWLRDLRV-C (5C7/1). Corresponding peptides were synthesized. Phagotopes and synthetic peptides reacted in ELISA with corresponding antibodies and synthetic peptides inhibited antibody binding to the phagotopes. Reactivity by immunofluorescence of 3A9 with CCR5 was strongly inhibited by the corresponding peptide. Both mAb 3A9 and 5C7 reacted similarly with phagotopes and the corresponding peptide selected by the alternative mAb. The sequences of peptide inserts of phagotopes could be aligned as mimotopes of the sequence of CCR5. For phage 3A9/1, the motif SIYD aligned to residues at the N terminus and FG to residues on the first extracellular loop; for 5C7/1, residues at the N terminus, first extracellular loop, and possibly the third extracellular loop could be aligned and so would contribute to the mimotope. The synthetic peptides corresponding to the isolated phagotopes showed a CD4-dependent reactivity with gp120 of a primary, m-tropic HIV-1 isolate. Thus reactivity of antibodies raised to CCR5 against phage-displayed peptides defined mimotopes that reflect binding sites for these antibodies and reveal a part of the gp120 binding sites on CCR5.

Crystal structures of the potassium and rubidium salts of (3,5-dichlorophenoxy)acetic acid: Two isotypic coordination polymers

The two-dimensional coordination polymeric structures of the hydrated potassium and rubidium salts of (3,5-dichlorophenoxy)acetic acid, (3,5-D) namely, poly[mu-aqua-bis[mu3-2-(3,5-dichlorophenoxy)acetato]potassium, [K2(C8H5Cl2O3)2 (H2O)]n (I) and poly[mu-aqua-bis[mu3-2-(3,5-dichlorophenoxy)acetato]dirubidium] [Rb2(C8H5Cl2O3)2 (H2O)]n (II), respectively have been determined and are described. The two compounds are isotypic and the polymer is based on centrosymmetric dinuclear bridged complex units. The irregular six-coordination about the metal centres comprises a bridging water molecule lying on a twofold rotation axis, the phenoxy O-atom donor and and a triple bridging carboxylate O-atom of the oxoacetate side chain of the 3,5-D ligand in a bidentate chelate mode, the second carboxy O-donor, also bridging. The K-O and Rb-O bond-length ranges are 2.7238(15)--2.9459(14) and 2.832(2)--3.050(2) \%A respectively and the K...K and Rb...Rb separations in the dinuclear unit are 4.0214(7) and 4.1289(6) \%A, respectively. Within the two-dimensional layers which lie parallel to (100), the coordinated water molecule forms an O---H...O hydrogen bond to the single bridging carboxylate O atom.

Rehabilitation of individuals with bone-anchored prosthesis: State-of-the-art and challenges

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket-related discomfort leading to a significant decrease in quality of life. Bone-anchored prostheses are increasingly acknowledged as viable alternative method of attachment of artificial limb. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous fixation. To date, a few osseointegration fixations are commercially available. Several devices are at different stages of development particularly in Europe and the US.[1-15] Clearly, surgical procedures are currently blooming worldwide. Indeed, Australia and Queensland in particular have one of the fastest growing populations. Previous studies involving either screw-type implants or press-fit fixations for bone-anchorage have focused on fragmented biomechanics aspects as well as the clinical benefits and safety of the procedure. However, very few publications have synthetized this information and provided an overview of the current developments in bone-anchored prostheses worldwide, let alone in Australia. The purposes of the presentation will be: 1. To provide an overview of the state-of-art developments in bone-anchored prostheses with as strong emphasis on the design of fixations, treatment, benefits, risks as well as future opportunities and challenges, 2. To present the current international developments of procedures for bone-anchored prostheses in terms of numbers of centers, number of cases and typical case-mix, 3. To highlight the current role Australia is playing as a leader worldwide in terms of growing population, broadest range of case-mix, choices of fixations, development of reimbursement schemes, unique clinical outcome registry for evidence-based practice, cutting-edge research, consumer demand and general public interest.

Genetic determinants of bone density and fracture risk: State of the art and future directions

Context: Osteoporosis is a common, highly heritable condition that causes substantial morbidity and mortality, the etiopathogenesis of which is poorly understood. Genetic studies are making increasingly rapid progress in identifying the genes involved. Evidence Acquisition and Synthesis: In this review, we will summarize the current understanding of the genetics of osteoporosis based on publications from PubMed from the year 1987 onward. Conclusions: Most genes involved in osteoporosis identified to date encode components of known pathways involved in bone synthesis or resorption, but as the field progresses, new pathways are being identified. Only a small proportion of the total genetic variation involved in osteoporosis has been identified, and new approaches will be required to identify most of the remaining genes.

A critical analysis of the Aboriginal and Torres Strait Islander Education Action Plan

This study involves the analysis of one of the most recent Indigenous Education policies, the Aboriginal and Torres Strait Islander Education Action Plan 2010-2014 (MCEECDYA, 2011). It examines how the language used within policy positions Aboriginal and Torres Strait Islander peoples. Articulating Rigney's (1999) Indigenist Research Principles with Fairclough's (2001) Critical Discourse Analysis provides a platform for critical dialogues about policy decision-making. In doing so, this articulation enables and emphasises the need for potential policy revision to contribute to the Aboriginal and Torres Strait Islander struggle for self-determination.

(Ap)pointing the canon Rousseau's Émile, visions of the state, and education

Jean-Jacques Rousseau’s Émile, ou de I’Education (Émile, or on Education) has been described by Rousseau scholars in latter twentieth century English-language philosophy as an educational classic. In 1995 Robert Wokler argued that together with Montesquieu, Hume, Smith, and Kant among his contemporaries, Rousseau had exerted the most profound influence on modern European intellectual history, “perhaps even surpassing anyone else of his day." For Wokler Émile is “the most significant work on education after Plato’s Republic.” Earlier in 1977, Allan Bloom questioned why Émile had not been the subject of analysis in philosophy relative to the rest of Rousseau‘s work, for “Émile is truly a great book, one that lays out for the first time and with the greatest clarity and vitality the modern way of posing the problems of psychology.” Bloom also saw Émile as “one of those rare total or synoptic books... a book comparable to Plato’s Republic, which it is meant to rival or supersede” and argued that Rousseau himself was at the source of a new tradition: “Whatever else Rousseau may have accomplished, he presented alternatives available to man more comprehensively and profoundly and articulated them in the form which has dominated discussion since his time." Even Peter Gay’s earlier commentary on John Locke and education in 1964 could not escape this central positioning of the text. The significance of Locke’s Some Thoughts on Education is weighed in relation to its impact on Rousseau‘s Émile. For Gay, the latter is “probably the most influential revolutionary tract on education that we have.”

Osteopenia and rickets in the extremely low birth weight infant: A survey of the incidence and a radiological classification

A review was carried out of the radiographs of twenty-five infants with birth weights under 1000 G, who survived for more than twenty-eight days; eighteen of these had enough suitable films for a survey of the progressive bone changes which occur in these infants, including estimation of humeral cortical cross-sectional area. The incidence of the changes has been assessed and a typical progression of radiographic appearances has been shown, with a suggested system of staging. All infants showed some loss of bone mineral, with frank changes of rickets occurring in forty-four percent. Aetiological factors are mainly concerned with the difficulty of supplying and ensuring absorption of sufficient bone mineral (calcium and phosphate) and vitamin D. Liver immaturity may be another factor. Disease states additional to prematurity accentuate the problem. Rib fractures occurring around 80–90 days post-nataEy commonly draw attention to the bone disorder and are probably the major clinical factor of importance; there is a high incidence of associated lung disease of uncertain pathology. Attention is drawn to possible confusion with other bone disorders in the post-natal period.

Mathematical modelling of the impaction and spreading of spray droplets on leaves

This thesis concerns the development of mathematical models to describe the interactions that occur between spray droplets and leaves. Models are presented that not only provide a contribution to mathematical knowledge in the field of fluid dynamics, but are also of utility within the agrichemical industry. The thesis is presented in two parts. First, thin film models are implemented with efficient numerical schemes in order to simulate droplets on virtual leaf surfaces. Then the interception event is considered, whereby energy balance techniques are employed to instantaneously predict whether an impacting droplet will bounce, splash, or adhere to a leaf.

Does flexibility of the cervical and thoracic spine influence forward head posture in healthy individuals?

Background: Forward head posture (FHP) is a commonly reported deviation from a neutral neck posture, usually implying a protracted head position in the sagittal plane. Habitual FHP has been associated with a higher incidence of painful neck disorders, changes in joint mobility and muscle behaviour within the cervicothoracic regions. One factor that has received attention in the literature with regards to FHP is flexibility of the neck. A number of previous studies have previously investigated the relationship between neck flexibility and neck posture under different conditions, but at present this relationship is unclear.

An autecological interpretation of the firm and its environment

Explaining the survival and failure of firms is an important issue for researchers and managers of firms in society. Ecological approaches to the study of firms have existed for over 100 years, and have been increasingly popular during the past 40 years, especially since the pioneering works of Hannan and Freeman on one hand, and Aldrich on the other. This paper, in keeping with recent developments elsewhere in mainstream ecology outlines and positions the theoretical and philosophical foundations of an alternative ecological approach, autecology, that has not yet been formulated for the study of firms. The autecological approach affords the individual firm more autonomy in creating its own future evolutionary trajectory. The idea of an ecological complex is developed to provide clear focus on what is central to the application of autecology to the study of firms. The paper also considers several emergent research opportunities that highlight the potential value of employing an autecological approach to the study of firms.

Meta-analyses of the determinants and outcomes of belief in climate change

Recent growth in the number of studies examining belief in climate change is a positive development, but presents an ironic challenge in that it can be difficult for academics, practitioners and policy makers to keep pace. As a response to this challenge, we report on a meta-analysis of the correlates of belief in climate change. Twenty-seven variables were examined by synthesizing 25 polls and 171 academic studies across 56 nations. Two broad conclusions emerged. First, many intuitively appealing variables (such as education, sex, subjective knowledge, and experience of extreme weather events) were overshadowed in predictive power by values, ideologies, worldviews and political orientation. Second, climate change beliefs have only a small to moderate effect on the extent to which people are willing to act in climate-friendly ways. Implications for converting sceptics to the climate change cause—and for converting believers’ intentions into action—are discussed.

Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-d-glucuronidase (heparanase)

Mammalian heparanase is an endo-β-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size. This in turn causes the release of growth factors, which accelerate tumor growth and metastasis. Heparanase has two glycosaminoglycan-binding domains; however, no three-dimensional structure information is available for human heparanase that can provide insights into how the two domains interact to degrade heparin fragments. We have constructed a new homology model of heparanase that takes into account the most recent structural and bioinformatics data available. Heparin analogs and glycosaminoglycan mimetics were computationally docked into the active site with energetically stable ring conformations and their interaction energies were compared. The resulting docked structures were used to propose a model for substrates and conformer selectivity based on the dimensions of the active site. The docking of substrates and inhibitors indicates the existence of a large binding site extending at least two saccharide units beyond the cleavage site (toward the nonreducing end) and at least three saccharides toward the reducing end (toward heparin-binding site 2). The docking of substrates suggests that heparanase recognizes the N-sulfated and O-sulfated glucosamines at subsite +1 and glucuronic acid at the cleavage site, whereas in the absence of 6-O-sulfation in glucosamine, glucuronic acid is docked at subsite +2. These findings will help us to focus on the rational design of heparanase-inhibiting molecules for anticancer drug development by targeting the two heparin/heparan sulfate recognition domains.

Computational methods for the prediction of the structure and interactions of coiled-coil peptides

The past several years have seen significant advances in the development of computational methods for the prediction of the structure and interactions of coiled-coil peptides. These methods are generally based on pairwise correlations of amino acids, helical propensity, thermal melts and the energetics of sidechain interactions, as well as statistical patterns based on Hidden Markov Model (HMM) and Support Vector Machine (SVM) techniques. These methods are complemented by a number of public databases that contain sequences, motifs, domains and other details of coiled-coil structures identified by various algorithms. Some of these computational methods have been developed to make predictions of coiled-coil structure on the basis of sequence information; however, structural predictions of the oligomerisation state of these peptides still remains largely an open question due to the dynamic behaviour of these molecules. This review focuses on existing in silico methods for the prediction of coiled-coil peptides of functional importance using sequence and/or three-dimensional structural data.

Playing the policy game: A review of the barriers and enablers of nutrition policy change

- Objective To progress nutrition policy change and develop more effective advocates, it is useful to consider real-world factors and practical experiences of past advocacy efforts to determine the key barriers and enablers to nutrition policy change. This review aimed to identify and synthesize the enablers and barriers to public policy change within the field of nutrition. - Design Electronic databases were searched systematically for studies examining policymaking in public health nutrition. An interpretive synthesis was undertaken. Setting: International, national, state and local government jurisdictions within high-income, democratic countries. - Results Sixty-three studies were selected for inclusion. Numerous themes were identified explaining the barriers and enablers to policy change, all of which fell under the overarching category, ‘political will’, underpinned by a second major category, ‘public will’. Sub-themes, including pressure from industry; neoliberal ideology; use of emotions and values, and being visible were prevalent in describing links between public will, political will and policy change. - Conclusions The frustration around lack of public policy change in nutrition frequently stems from a belief that policymaking is a rational process in which evidence is used to assess the relative costs and benefits of options. The findings from this review confirm that evidence is only one component of influencing policy change. For policy change to occur there needs to be the political will, and often the public will, for the proposed policy problem and solution. This review presents a suite of enablers which can assist health professionals to influence political and public will in future advocacy efforts.