Molecular modelling assisted design and synthesis of cyclothialidine derivatives as DNA gyrase inhibitors

Since cyclothialidine was discovered as the most active DNA gyrase inhibitor in 1994, enormous efforts have been devoted to make it into a commercial medicine by a number of pharmaceutical companies and research groups worldwide. However, no serious breakthrough has been made up to now. An essential problem involved with cyclothialidine is that though it demonstrated the potent inhibition of DNA gyrase, it showed little activity against bacteria. This probably is attributable to its inability to penetrate bacterial cell walls and membranes. We applied the TSAR programme to generate a QSAR equation to the gram-negative organisms. In that equation, LogP is profoundly indicated as the key factor influencing the cyclothialidine activity against bacteria. However, the synthesized new analogues have failed to prove that. In the structure based drug design stage, we designed a group of open chain cyclothialidine derivatives by applying the SPROUT programme and completed the syntheses. Improved activity is found in a few analogues and a 3D pharmacophore of the DNA gyrase B is proposed to lead to synthesis of the new derivatives for development of potent antibiotics.

Measurement of ocular component contributions to residual astigmatism in adult human eyes

The aim of this study was to determine whether an ophthalmophakometric technique could offer a feasible means of investigating ocular component contributions to residual astigmatism in human eyes. Current opinion was gathered on the prevalence, magnitude and source of residual astigmatism. It emerged that a comprehensive evaluation of the astigmatic contributions of the eye's internal ocular surfaces and their respective axial separations (effectivity) had not been carried out to date. An ophthalmophakometric technique was developed to measure astigmatism arising from the internal ocular components. Procedures included the measurement of refractive error (infra-red autorefractometry), anterior corneal surface power (computerised video keratography), axial distances (A-scan ultrasonography) and the powers of the posterior corneal surface in addition to both surfaces of the crystalline lens (multi-meridional still flash ophthalmophakometry). Computing schemes were developed to yield the required biometric data. These included (1) calculation of crystalline lens surface powers in the absence of Purkinje images arising from its anterior surface, (2) application of meridional analysis to derive spherocylindrical surface powers from notional powers calculated along four pre-selected meridians, (3) application of astigmatic decomposition and vergence analysis to calculate contributions to residual astigmatism of ocular components with obliquely related cylinder axes, (4) calculation of the effect of random experimental errors on the calculated ocular component data. A complete set of biometric measurements were taken from both eyes of 66 undergraduate students. Effectivity due to corneal thickness made the smallest cylinder power contribution (up to 0.25DC) to residual astigmatism followed by contributions of the anterior chamber depth (up to 0.50DC) and crystalline lens thickness (up to 1.00DC). In each case astigmatic contributions were predominantly direct. More astigmatism arose from the posterior corneal surface (up to 1.00DC) and both crystalline lens surfaces (up to 2.50DC). The astigmatic contributions of the posterior corneal and lens surfaces were found to be predominantly inverse whilst direct astigmatism arose from the anterior lens surface. Very similar results were found for right versus left eyes and males versus females. Repeatability was assessed on 20 individuals. The ophthalmophakometric method was found to be prone to considerable accumulated experimental errors. However, these errors are random in nature so that group averaged data were found to be reasonably repeatable. A further confirmatory study was carried out on 10 individuals which demonstrated that biometric measurements made with and without cycloplegia did not differ significantly.

Another angle on contact lens surface analysis

Purpose: Dynamic contact angle (DCA) methods have advantages over other contact angle methodologies, not least that they can provide more than single contact angle values. Here we illustrate the use of DCA analysis to provide “fingerprint” characterisation of contact lens surfaces, and the way that different materials change in the early stages of wear. Method: The DCA method involves attaching to a microbalance weighted strips cut from a lens. The strips are then cyclically inserted into and removed from an aqueous solution. Conventionally, readings of force taken from linear portions of the resultant dipping curves are translated into advancing (CAa) and receding contact (CAr) angles. Additionally, analysis of the force versus immersion profile provides a “fingerprint” characterisation of the state of the lens surface. Results: CAa and CAr values from DCA traces provide a useful means of differentiating gross differences in hydrophilicity and molecular mobility of surfaces under particular immersion and emersion conditions, such as dipping rate and dwell times. Typical values for etafilcon A (CAa:63.1; CAr:37) and balafilcon B (CAa:118.4; CAr:36.4) illustrate this. Surface modifications induced in lens manufacture are observed to produce not only changes in these value, which may be small, but also changes in the DCA “fingerprint” (slope, undulations, length of plateau). Interestingly, similar changes are induced in the first few hours of lens wear with some lens-patient combinations. Conclusions: Although single parameter contact angles are useful for material characterisation, information of potential clinical interest can be obtained from more detailed analysis of DCA traces.

Metabolic and morphological alterations induced by proteolysis-inducing factor from Walker tumour-bearing rats in C2C12 myotubes

BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model. © 2008 Yano et al; licensee BioMed Central Ltd.

Clinical monitoring of ocular physiology using digital image analysis

Aim: To examine the use of image analysis to quantify changes in ocular physiology. Method: A purpose designed computer program was written to objectively quantify bulbar hyperaemia, tarsal redness, corneal staining and tarsal staining. Thresholding, colour extraction and edge detection paradigms were investigated. The repeatability (stability) of each technique to changes in image luminance was assessed. A clinical pictorial grading scale was analysed to examine the repeatability and validity of the chosen image analysis technique. Results: Edge detection using a 3 × 3 kernel was found to be the most stable to changes in image luminance (2.6% over a +60 to -90% luminance range) and correlated well with the CCLRU scale images of bulbar hyperaemia (r = 0.96), corneal staining (r = 0.85) and the staining of palpebral roughness (r = 0.96). Extraction of the red colour plane demonstrated the best correlation-sensitivity combination for palpebral hyperaemia (r = 0.96). Repeatability variability was <0.5%. Conclusions: Digital imaging, in conjunction with computerised image analysis, allows objective, clinically valid and repeatable quantification of ocular features. It offers the possibility of improved diagnosis and monitoring of changes in ocular physiology in clinical practice. © 2003 British Contact Lens Association. Published by Elsevier Science Ltd. All rights reserved.

Analysis of the Distributions of Color Characteristics in Art Painting Images

In this paper we study some of the characteristics of the art painting image color semantics. We analyze the color features of differ- ent artists and art movements. The analysis includes exploration of hue, saturation and luminance. We also use quartile’s analysis to obtain the dis- tribution of the dispersion of defined groups of paintings and measure the degree of purity for these groups. A special software system “Art Paint- ing Image Color Semantics” (APICSS) for image analysis and retrieval was created. The obtained result can be used for automatic classification of art paintings in image retrieval systems, where the indexing is based on color characteristics.

A Partition Metric for Clustering Features Analysis

A new distance function to compare arbitrary partitions is proposed. Clustering of image collections and image segmentation give objects to be matched. Offered metric intends for combination of visual features and metadata analysis to solve a semantic gap between low-level visual features and high-level human concept.

Receptor for activated C Kinase 1 protein binds to and activates the human estrogen receptor α

The classical concept of estrogen receptor (ER) activation is that steroid passes the cell membrane, binds to its specific protein receptor in the cell's cytoplasm and the steroid-receptor complex travels to the nucleus where it activates responsive genes. This basic idea has been challenged by results of experiments demonstrating insulin-like growth factor 1 (IGF-1) activation of the ER in the complete absence of estrogen suggesting at least one other mechanism of ER activation not involving steroid. One explanation is that activation of the cell surface IGF-1 receptor leads to synthesis of an intracellular protein(s) able to bind to and stimulate the ER. Based on results using the two-hybrid system, coimmunoprecipitation and transfection-luciferase assays, we herein show that one of these proteins could well be receptor for activated C kinase 1 (RACK-1). Using the human ER type α (ER-α) as bait, a cloned complementary deoxyribonucleic acid (cDNA) library from IGF-1 treated human breast cancer MCF-7 cells was screened for ER-α - protein interactions. Many positive clones were obtained which contained the RACK-1 cDNA sequence. Coimmunoprecipitation of in-vitro translation products of the ER-α and RACK-1 confirmed the interaction between the two proteins. Transfection studies using the estrogen response element spliced to a luciferase reporter gene revealed that constitutive RACK-1 expression was able to powerfully stimulate ER-α activity under estrogen-free conditions. This effect could be enhanced by 17β-estradiol (E2) and blocked by tamoxifen, an E2 antagonist. These results show that RACK-1 is able to activate the ER-α in the absence of E2, although together with the latter, enhanced effects occur. Since RACK-1 gene expression is stimulated by IGF-1, it is distinctly possible that RACK-1 is the mediator of the stimulatory effects of IGF-1 on ER-α. © 2014 JMS.

A world full of surprises:Bayesian theory of surprise to quantify degrees of uncertainty

In the specific area of software engineering (SE) for self-adaptive systems (SASs) there is a growing research awareness about the synergy between SE and artificial intelligence (AI). However, just few significant results have been published so far. In this paper, we propose a novel and formal Bayesian definition of surprise as the basis for quantitative analysis to measure degrees of uncertainty and deviations of self-adaptive systems from normal behavior. A surprise measures how observed data affects the models or assumptions of the world during runtime. The key idea is that a "surprising" event can be defined as one that causes a large divergence between the belief distributions prior to and posterior to the event occurring. In such a case the system may decide either to adapt accordingly or to flag that an abnormal situation is happening. In this paper, we discuss possible applications of Bayesian theory of surprise for the case of self-adaptive systems using Bayesian dynamic decision networks. Copyright © 2014 ACM.

Social and financial efficiency of Islamic microfinance institutions:a Data Envelopment Analysis application

Microfinance has been developed as alternative solution for global poverty alleviation effort in the last 30 years. Microfinance institution (MFI) has unique characteristic wherein they face double bottom line objectives of outreach to the poor and financial sustainability. This study proposes a two-stage analysis to measure Islamic Microfinance institutions (IMFIs) performance by comparing them to conventional MFIs. First, we develop a Data Envelopment Analysis (DEA) framework to measure MFIs' efficiency in its double bottom line objectives, i.e. in terms of social and financial efficiency. In the second stage non-parametric tests are used to compare the performance and identify factors that contribute to the efficiency of IMFIs and MFIs.

Can psychometric testing be used to explain, predict and measure behavioural competences and the funding resource orchestration of the entrepreneur?

Financing is a critical entrepreneurial activity (Shane et al. 2003) and within the study of entrepreneurship, behaviour has been identified as an area requiring further exploration (Bird et al. 2012). Since 2008 supply side conditions for SMEs have been severe and increasingly entrepreneurs have to bundle or ‘orchestrate’ funding from a variety of sources in order to successfully finance the firm (Wright and Stigliani 2013: p.15). This longitudinal study uses psychometric testing to measure the behavioural competences of a panel of sixty entrepreneurs in the Creative Industries sector. Interviews were conducted over a 3 year period to identify finance finding behaviour. The research takes a pragmatic realism perspective to examine process and the different behavioural competences of entrepreneurs. The predictive qualities of this behaviour are explored in a funding context. The research confirmed a strong behavioural characteristic as validated through interviews and psychometric testing, was an orientation towards engagement and working with other organisations. In a funding context, this manifested itself in entrepreneurs using networks, seeking advice and sharing equity to fund growth. These co-operative, collaborative characteristics are different to the classic image of the entrepreneur as a risk-taker or extrovert. Leadership and achievement orientation were amongst the lowest scores. Three distinctive groups were identified and also shown by subsequent analysis to be a positive contribution to how entrepreneurial behavioural competences can be considered. Belonging to one of these three clusters is a strong predictive indicator of entrepreneurial behaviour – in this context, how entrepreneurs access finance. These Clusters were also proven to have different characteristics in relation to funding outcomes. The study seeks to make a contribution through the development of a methodology for entrepreneurs, policy makers and financial institutions to identify competencies in finding finance and overcome problems in information asymmetry.

Teaching Statistics to Engineers: Learning from Experiential Data

The purpose of the work is to claim that engineers can be motivated to study statistical concepts by using the applications in their experience connected with Statistical ideas. The main idea is to choose a data from the manufacturing factility (for example, output from CMM machine) and explain that even if the parts used do not meet exact specifications they are used in production. By graphing the data one can show that the error is random but follows a distribution, that is, there is regularily in the data in statistical sense. As the error distribution is continuous, we advocate that the concept of randomness be introducted starting with continuous random variables with probabilities connected with areas under the density. The discrete random variables are then introduced in terms of decision connected with size of the errors before generalizing to abstract concept of probability. Using software, they can then be motivated to study statistical analysis of the data they encounter and the use of this analysis to make engineering and management decisions.

Reviewing the evidence base for the Children and Young People Safety Thermometer (CYPST):a mixed studies review

The objective was to identify evidence to support use of specific harms for the development of a children and young people's safety thermometer (CYPST). We searched PubMed, Web of Knowledge, and Cochrane Library post-1999 for studies in pediatric settings about pain, skin integrity, extravasation injury, and use of pediatric early warning scores (PEWS). Following screening, nine relevant articles were included. Convergent synthesis methods were used drawing on thematic analysis to combine findings from studies using a range of methods (qualitative, quantitative, and mixed methods). A review of PEWS was identified so other studies on this issue were excluded. No relevant studies about extravasation injury were identified. The synthesized results therefore focused on pain and skin integrity. Measurement and perception of pain were complex and not always carried out according to best practice. Skin abrasions were common and mostly associated with device related injuries. The findings demonstrate a need for further work on perceptions of pain and effective communication of concerns about pain between parents and nursing staff. Strategies for reducing device-related injuries warrant further research focusing on prevention. Together with the review of PEWS, these synthesized findings support the inclusion of pain, skin integrity, and PEWS in the CYPST.

Integration of Satellite and Financial Data to Model Future Economic Impact of Citrus Crops (Final Project Report)

This study analyzed the health and overall landcover of citrus crops in Florida. The analysis was completed using Landsat satellite imagery available free of charge from the University of Maryland Global Landcover Change Facility. The project hypothesized that combining citrus production (economic) data with citrus area per county derived from spectral signatures would yield correlations between observable spectral reflectance throughout the year, and the fiscal impact of citrus on local economies. A positive correlation between these two data types would allow us to predict the economic impact of citrus using spectral data analysis to determine final crop harvests.

Temporal analysis of land use and transportation investments with geographic information system

Land use and transportation interaction has been a research topic for several decades. There have been efforts to identify impacts of transportation on land use from several different perspectives. One focus has been the role of transportation improvements in encouraging new land developments or relocation of activities due to improved accessibility. The impacts studied have included property values and increased development. Another focus has been on the changes in travel behavior due to better mobility and accessibility. Most studies to date have been conducted in metropolitan level, thus unable to account for interactions spatially and temporally at smaller geographic scales. ^ In this study, a framework for studying the temporal interactions between transportation and land use was proposed and applied to three selected corridor areas in Miami-Dade County, Florida. The framework consists of two parts: one is developing of temporal data and the other is applying time series analysis to this temporal data to identify their dynamic interactions. Temporal GIS databases were constructed and used to compile building permit data and transportation improvement projects. Two types of time series analysis approaches were utilized: univariate models and multivariate models. Time series analysis is designed to describe the dynamic consequences of time series by developing models and forecasting the future of the system based on historical trends. Model estimation results from the selected corridors were then compared. ^ It was found that the time series models predicted residential development better than commercial development. It was also found that results from three study corridors varied in terms of the magnitude of impacts, length of lags, significance of the variables, and the model structure. Long-run effect or cumulated impact of transportation improvement on land developments was also measured with time series techniques. The study offered evidence that congestion negatively impacted development and transportation investments encouraged land development. ^