The spermostatic and microbicidal actions of quinones and malemides : towards a dual-purpose contraceptive agent

There is an urgent need to develop safe, effective, dual-purpose contraceptive agents that combine the prevention of pregnancy with protection against sexually transmitted diseases. Here we report the identification of a group of compounds that on contact with human spermatozoa induce a state of “spermostasis,” characterized by the extremely rapid inhibition of sperm movement without compromising cell viability. These spermostatic agents were more active and significantly less toxic than the reagent in current clinical use, nonoxynol 9, giving therapeutic indices (ratio of spermostatic to cytotoxic activity) that were orders of magnitude greater than this traditional spermicide. Although certain compounds could trigger reactive oxygen species generation by spermatozoa, this activity was not correlated with spermostasis. Rather, the latter was associated with alkylation of two major sperm tail proteins that were identified as A Kinase-Anchoring Proteins (AKAP3 and AKAP4) by mass spectrometry. As a consequence of disrupted AKAP function, the abilities of cAMP to drive protein kinase A-dependent activities in the sperm tail, such as the activation of SRC and the consequent stimulation of tyrosine phosphorylation, were suppressed. Furthermore, analysis of microbicidal activity using Chlamydia muridarum revealed powerful inhibitory effects at the same low micromolar doses that suppressed sperm movement. In this case, the microbicidal action was associated with alkylation of Major Outer Membrane Protein (MOMP), a major chlamydial membrane protein. Taken together, these results have identified for the first time a novel set of cellular targets and chemical principles capable of providing simultaneous defense against both fertility and the spread of sexually transmitted disease.

Design and experimental testing of air slab caps which convert commercial electron diodes into dual purpose, correction-free diodes for small field dosimetry

Purpose Two diodes which do not require correction factors for small field relative output measurements are designed and validated using experimental methodology. This was achieved by adding an air layer above the active volume of the diode detectors, which canceled out the increase in response of the diodes in small fields relative to standard field sizes. Methods Due to the increased density of silicon and other components within a diode, additional electrons are created. In very small fields, a very small air gap acts as an effective filter of electrons with a high angle of incidence. The aim was to design a diode that balanced these perturbations to give a response similar to a water-only geometry. Three thicknesses of air were placed at the proximal end of a PTW 60017 electron diode (PTWe) using an adjustable “air cap”. A set of output ratios (ORfclin Det ) for square field sizes of side length down to 5 mm was measured using each air thickness and compared to ORfclin Det measured using an IBA stereotactic field diode (SFD). k fclin, f msr Qclin,Qmsr was transferred from the SFD to the PTWe diode and plotted as a function of air gap thickness for each field size. This enabled the optimal air gap thickness to be obtained by observing which thickness of air was required such that k fclin, f msr Qclin,Qmsr was equal to 1.00 at all field sizes. A similar procedure was used to find the optimal air thickness required to make a modified Sun Nuclear EDGE detector (EDGEe) which s “correction-free” in small field relative dosimetry. In addition, the feasibility of experimentally transferring k fclin, f msr Qclin,Qmsr values from the SFD to unknown diodes was tested by comparing the experimentally transferred k fclin, f msr Qclin,Qmsr values for unmodified PTWe and EDGEe diodes to Monte Carlo simulated values. Results 1.0 mm of air was required to make the PTWe diode correction-free. This modified diode (PTWeair) produced output factors equivalent to those in water at all field sizes (5–50 mm). The optimal air thickness required for the EDGEe diode was found to be 0.6 mm. The modified diode (EDGEeair) produced output factors equivalent to those in water, except at field sizes of 8 and 10 mm where it measured approximately 2% greater than the relative dose to water. The experimentally calculated k fclin, f msr Qclin,Qmsr for both the PTWe and the EDGEe diodes (without air) matched Monte Carlo simulated results, thus proving that it is feasible to transfer k fclin, f msr Qclin,Qmsr from one commercially available detector to another using experimental methods and the recommended experimental setup. Conclusions It is possible to create a diode which does not require corrections for small field output factor measurements. This has been performed and verified experimentally. The ability of a detector to be “correction-free” depends strongly on its design and composition. A nonwater-equivalent detector can only be “correction-free” if competing perturbations of the beam cancel out at all field sizes. This should not be confused with true water equivalency of a detector.

Developments of the total entropy utility function for the dual purpose of model discrimination and parameter estimation in Bayesian design

The total entropy utility function is considered for the dual purpose of Bayesian design for model discrimination and parameter estimation. A sequential design setting is proposed where it is shown how to efficiently estimate the total entropy utility for a wide variety of data types. Utility estimation relies on forming particle approximations to a number of intractable integrals which is afforded by the use of the sequential Monte Carlo algorithm for Bayesian inference. A number of motivating examples are considered for demonstrating the performance of total entropy in comparison to utilities for model discrimination and parameter estimation. The results suggest that the total entropy utility selects designs which are efficient under both experimental goals with little compromise in achieving either goal. As such, the total entropy utility is advocated as a general utility for Bayesian design in the presence of model uncertainty.

A socially responsible model of micro-credit delivery to support sustainable community development in emerging economies

Micro-finance, which includes micro-credit as one of its core services, has become an important component of a range of business models – from those that operate on a strictly economic basis to those that come from a philanthropic base, through Non Government Organisations (NGOs). Its success is often measured by the number of loans issued, their size, and the repayment rates. This paper has a dual purpose: to identify whether the models currently used to deliver micro-credit services to the poor are socially responsible and to suggest a new model of delivery that addresses some of the social responsibility issues, while supporting community development. The proposed model is currently being implemented in Beira, the second largest city in Mozambique. Mozambique exhibits many of the characteristics found in other African countries so the model, if successful, may have implications for other poor African nations as well as other developing economies.

Model-predictive control and closed-loop stability considerations for nonlinear plants described by local ARX-type models

In this paper, a model-predictive control (MPC) method is detailed for the control of nonlinear systems with stability considerations. It will be assumed that the plant is described by a local input/output ARX-type model, with the control potentially included in the premise variables, which enables the control of systems that are nonlinear in both the state and control input. Additionally, for the case of set point regulation, a suboptimal controller is derived which has the dual purpose of ensuring stability and enabling finite-iteration termination of the iterative procedure used to solve the nonlinear optimization problem that is used to determine the control signal.

A diode for correction-less small field output factor measurements

Introduction Due to their high spatial resolution diodes are often used for small field relative output factor measurements. However, a field size specific correction factor [1] is required and corrects for diode detector over-response at small field sizes. A recent Monte Carlo based study has shown that it is possible to design a diode detector that produces measured relative output factors that are equivalent to those in water. This is accomplished by introducing an air gap at the upstream end of the diode [2]. The aim of this study was to physically construct this diode by placing an ‘air cap’ on the end of a commercially available diode (the PTW 60016 electron diode). The output factors subsequently measured with the new diode design were compared to current benchmark small field output factor measurements. Methods A water-tight ‘cap’ was constructed so that it could be placed over the upstream end of the diode. The cap was able to be offset from the end of the diode, thus creating an air gap. The air gap width was the same as the diode width (7 mm) and the thickness of the air gap could be varied. Output factor measurements were made using square field sizes of side length from 5 to 50 mm, using a 6 MV photon beam. The set of output factor measurements were repeated with the air gap thickness set to 0, 0.5, 1.0 and 1.5 mm. The optimal air gap thickness was found in a similar manner to that proposed by Charles et al. [2]. An IBA stereotactic field diode, corrected using Monte Carlo calculated kq,clin,kq,msr values [3] was used as the gold standard. Results The optimal air thickness required for the PTW 60016 electron diode was 1.0 mm. This was close to the Monte Carlo predicted value of 1.15 mm2. The sensitivity of the new diode design was independent of field size (kq,clin,kq,msr = 1.000 at all field sizes) to within 1 %. Discussion and conclusions The work of Charles et al. [2] has been proven experimentally. An existing commercial diode has been converted into a correction-less small field diode by the simple addition of an ‘air cap’. The method of applying a cap to create the new diode leads to the diode being dual purpose, as without the cap it is still an unmodified electron diode.

Crowdsourcing in developing countries : a possible model to co-create with the poor

The interest in poverty and the moral sense of'helping the poor' are a constant topic in Western culture (Mayo 2009).ln recent years, multinational corporations (MNCs) have evolved in their understanding of how social issues, such as poverty alleviation, relate to their fundamental purposes. From a business strategy point of view, 'socially responsible' initiatives are generally born with lhe dual purpose of attaining social visibility (i.e. marketing) and increasing economic returns. Besides addressing social challenges as part of their corporate social responsibility strategies, MNCs have also begun 'selling to the poor' in emerging markets (Prahalad 2004). A few forward -looking companies consider tltis base of the pyramid (BOP) market also as a source of innovation and have started to co-create with consumers (Simanis and Hart 2008).

A general-purpose simulator for train operations

Computer simulation has been widely accepted as an essential tool for the analysis of many engineering systems. It is nowadays perceived to be the most readily available and feasible means of evaluating operations in real railway systems. Based on practical experience and theoretical models developed in various applications, this paper describes the design of a general-purpose simulation system for train operations. Its prime objective is to provide a single comprehensive computer-aided engineering tool for most studies on railway operations so that various aspects of the railway systems with different operation characteristics can be investigated and analysed in depth. This system consists of three levels of simulation. The first is a single-train simulator calculating the running time of a train between specific points under different track geometry and traction conditions. The second is a dual-train simulator which is to find the minimum headway between two trains under different movement constraints, such as signalling systems. The third is a whole-system multi-train simulator which carries out process simulation of the real operation of a railway system according to a practical or planned train schedule or headway; and produces an overall evaluation of system performance.

Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hreceptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

A biomechanical investigation of dual growing rods used for fusionless scoliosis correction

Background The use of dual growing rods is a fusionless surgical approach to the treatment of early onset scoliosis (EOS), which aims of harness potential growth in order to correct spinal deformity. The purpose of this study was to compare the in-vitro biomechanical response of two different dual rod designs under axial rotation loading. Methods Six porcine spines were dissected into seven level thoracolumbar multi-segmental units. Each specimen was mounted and tested in a biaxial Instron machine, undergoing nondestructive left/right axial rotation to peak moments of 4Nm at a constant rotation rate of 8deg.s-1. A motion tracking system (Optotrak) measured 3D displacements of individual vertebrae. Each spine was tested in an un-instrumented state first and then with appropriately sized semi-constrained growing rods and ‘rigid’ rods in alternating sequence. Range of motion, neutral zone size and stiffness were calculated from the moment-rotation curves and intervertebral ranges of motion were calculated from Optotrak data. Findings Irrespective of test sequence, rigid rods showed significantly reduction of total rotation across all instrumented levels (with increased stiffness) whilst semi-constrained rods exhibited similar rotation behavior to the un-instrumented (P<0.05). An 11% and 8% increase in stiffness for left and right axial rotation respectively and 15% reduction in total range of motion was recorded with dual rigid rods compared with semi-constrained rods. Interpretation Based on these findings, the semi-constrained growing rods do not increase axial rotation stiffness compared with un-instrumented spines. This is thought to provide a more physiological environment for the growing spine compared to dual rigid rod constructs.

Path+Ways. Towards best practice bridging and Indigenous participation through regional dual-sector universities

Regional and remote Indigenous students are underrepresented in both higher education and vocational education and training. Enabling education courses are important in lifting participation rates and potentially in encouraging mobility between the sectors, yet there is a clear lack of evidence underpinning their development. This report provides an overview of the data collection and analysis activities undertaken via a research project funded by the National Centre for Student Equity in Higher Education. The project purpose was to explore current practices dealing with Indigenous enabling courses, particularly in the context of regional, dual-sector universities. In particular, the project examined how these programs vary by institution (and region) in terms of structure, mode and ethos of offering; and direct and indirect impacts of these initiatives on Indigenous student participation and attainment; with a view to designing a best practice framework and implementation statement. Through its focus on students accessing Indigenous and mainstream enabling education, the project focussed on range of equity groups including those of low socio-economic status (both school leaver and mature-age categories), regional and/or remote students, Indigenous students and students with disability.