Antidiabetic properties of zinc-alpha2-glycoprotein in ob/ob mice

Zinc-alpha(2)-glycoprotein (ZAG) is an adipokine associated with fat loss in cancer cachexia. The purpose of this study was to evaluate the ability of recombinant human ZAG to attenuate type 2 diabetes in the ob/ob mouse model. ZAG (50 microg daily, iv) induced a progressive loss of body weight (3.5 g in 5 d), without an effect on food or water intake but with a 0.4 C rise in body temperature, suggesting an increased energy expenditure. Despite an increased plasma glycerol, indicative of increased lipolysis, levels of glucose, triglycerides, and nonesterified fatty acids were decreased by 17, 25, and 62%, respectively, due to an increased use of both glucose and lipids by muscle and brown adipose tissue. The weight of the latter increased 2-fold, and there was increased expression of uncoupling proteins-1 and -3. Plasma insulin levels were reduced by 36%, whereas pancreatic insulin was increased 4-fold, and there was a 53% decrease in the total area under the glucose curve in the glucose tolerance test and reduced insulin requirement. There was an increase in skeletal muscle mass due to an increase in protein synthesis and a decrease in protein degradation. These results suggest that ZAG may potentially be effective in the treatment of type 2 diabetes.

Design and synthesis of potential antimicrobial agents

Tuberculosis is one of the most devastating diseases in the world primarily due to several decades of neglect and an emergence of multidrug-resitance strains (MDR) of M. tuberculosis together with the increased incidence of disseminated infections produced by other mycobacterium in AIDS patients. This has prompted the search for new antimycobacterial drugs. A series of pyridine-2-, pyridine-3-, pyridine-4-, pyrazine and quinoline-2-carboxamidrazone derivatives and new classes of carboxamidrazone were prepared in an automated fashion and by traditional synthesis. Over nine hundred synthesized compounds were screened for their anti mycobacterial activity against M. fortutium (NGTG 10394) as a surrogate for M. tuberculosis. The new classes of amidrazones were also screened against tuberculosis H37 Rv and antimicrobial activities against various bacteria. Fifteen tested compounds were found to provide 90-100% inhibition of mycobacterium growth of M. tuberculosis H37 Rv in the primary screen at 6.25 μg mL-1. The most active compound in the carboxamidrazone amide series had an MIG value of 0.1-2 μg mL-1 against M. fortutium. The enzyme dihydrofolate reductase (DHFR) has been a drug-design target for decades. Blocking of the enzymatic activity of DHFR is a key element in the treatment of many diseases, including cancer, bacterial and protozoal infection. The x-ray structure of DHFR from M. tuberculosis and human DHFR were found to have differences in substrate binding site. The presence of glycerol molecule in the Xray structure from M. tuberculosis DHFR provided opportunity to design new antifolates. The new antifolates described herein were designed to retain the pharmcophore of pyrimethamine (2,4- diamino-5(4-chlorophenyl)-6-ethylpyrimidine), but encompassing a range of polar groups that might interact with the M. tuberculosis DHFR glycerol binding pockets. Finally, the research described in this thesis contributes to the preparation of molecularly imprinted polymers for the recognition of 2,4-diaminopyrimidine for the binding the target. The formation of hydrogen bonding between the model functional monomer 5-(4-tert-butyl-benzylidene)-pyrimidine-2,4,6-trione and 2,4-diaminopyrimidine in the pre-polymerisation stage was verified by 1H-NMR studies. Having proven that 2,4-diaminopyrimidine interacts strongly with the model 5-(4-tert-butylbenzylidene)- pyrimidine-2,4,6-trione, 2,4-diaminopyrimidine-imprinted polymers were prepared using a novel cyclobarbital derived functional monomer, acrylic acid 4-(2,4,6-trioxo-tetrahydro-pyrimidin-5- ylidenemethyl)phenyl ester, capable of multiple hydrogen bond formation with the 2,4- diaminopyrimidine. The recognition property of the respective polymers toward the template and other test compounds was evaluated by fluorescence. The results demonstrate that the polymers showed dose dependent enhancement of fluorescence emissions. In addition, the results also indicate that synthesized MIPs have higher 2,4-diaminopyrimidine binding ability as compared with corresponding non-imprinting polymers.

Drug action on anxiety models with special reference to serotonergic mechanisms

A study has been made of drugs acting at 5-HT receptors on animal models of anxiety. An elevated X-maze was used as a model of anxiety for rats and the actions of various ligands for the 5-HT receptor, and its subtypes, were examined in this model. 5-HT agonists, with varying affinities for the 5-HT receptor subtypes, were demonstrated to have anxiogenic-like activity. The 5-HT2 receptor antagonists ritanserin and ketanserin exhibited an anxiolytic-like profile. The new putatuve anxiolytics ipsapirone and buspirone, which are believed to be selective for 5-HT1 receptors, were also examined. The former had an anxiolytic profile whilst the latter was without effect. Antagonism studies showed the anxiogenic response to 8-hydroxy-2-(Di-n-propylamino)tetralin (8-OH-DPAT) to be antagonised by ipsapirone, pindolol, alprenolol and para-chlorophenylalanine, but not by diazepam, ritanserin, metoprolol, ICI118,551 or buspirone. To confirm some of the results obtained in the elevated X-maze the Social Interaction Test of anxiety was used. Results in this test mirrored the effects seen with the 5-HT agonists, ipsapirone and pindolol, whilst the 5-HT2 receptor antagonists were without effect. Studies using operant conflict models of anxiety produced marginal and varying results which appear to be in agreement with recent criticisms of such models. Finally, lesions of the dorsal raphe nucleus (DRN) were performed in order to investigate the mechanisms involved in the production of the anxiogenic response to 8-OH-DPAT. Overall the results lend support to the involvement of 5-HT, and more precisely 5-HT1, receptors in the manifestation of anxiety in such animal models.

Body iron is associated with cognitive executive planning function in college women

Evidence of the relationship between altered cognitive function and depleted Fe status is accumulating in women of reproductive age but the degree of Fe deficiency associated with negative neuropsychological outcomes needs to be delineated. Data are limited regarding this relationship in university women in whom optimal cognitive function is critical to academic success. The aim of the present study was to examine the relationship between body Fe, in the absence of Fe-deficiency anaemia, and neuropsychological function in young college women. Healthy, non-Anaemic undergraduate women (n 42) provided a blood sample and completed a standardised cognitive test battery consisting of one manual (Tower of London (TOL), a measure of central executive function) and five computerised (Bakan vigilance task, mental rotation, simple reaction time, immediate word recall and two-finger tapping) tasks. Women's body Fe ranged from - 4·2 to 8·1 mg/kg. General linear model ANOVA revealed a significant effect of body Fe on TOL planning time (P= 0.002). Spearman's correlation coefficients showed a significant inverse relationship between body Fe and TOL planning time for move categories 4 (r - 0.39, P= 0.01) and 5 (r - 0.47, P= 0.002). Performance on the computerised cognitive tasks was not affected by body Fe level. These findings suggest that Fe status in the absence of anaemia is positively associated with central executive function in otherwise healthy college women. Copyright © The Authors 2012.

Fourth-root summation of contrast over area:no end in sight when spatially inhomogeneous sensitivity is compensated by a witch's hat

Measurements of area summation for luminance-modulated stimuli are typically confounded by variations in sensitivity across the retina. Recently we conducted a detailed analysis of sensitivity across the visual field (Baldwin et al, 2012) and found it to be well-described by a bilinear “witch’s hat” function: sensitivity declines rapidly over the first 8 cycles or so, more gently thereafter. Here we multiplied luminance-modulated stimuli (4 c/deg gratings and “Swiss cheeses”) by the inverse of the witch’s hat function to compensate for the inhomogeneity. This revealed summation functions that were straight lines (on double log axes) with a slope of -1/4 extending to ≥33 cycles, demonstrating fourth-root summation of contrast over a wider area than has previously been reported for the central retina. Fourth-root summation is typically attributed to probability summation, but recent studies have rejected that interpretation in favour of a noisy energy model that performs local square-law transduction of the signal, adds noise at each location of the target and then sums over signal area. Modelling shows our results to be consistent with a wide field application of such a contrast integrator. We reject a probability summation model, a quadratic model and a matched template model of our results under the assumptions of signal detection theory. We also reject the high threshold theory of contrast detection under the assumption of probability summation over area.

Impact of scatterer density on the performances of double-scattering MIMO channels

We investigate a MIMO double-scattering model with both local and remote scatterers, aiming to investigate the effect of scatterer density on channel performances, such as capacity, correlation, and the condition number of the channel matrix in flat and frequency-selective fading channels. The investigations are carried out in terms of scatterer density. It is shown that in flat fading channels the scatterer density has a marginal effect on channel performances when the area of the two scatterer zones is fixed, while a significant impact is observed when the area of the scatterer zones is allowed to change. In frequency-selective fading channels, no matter the area of the scatterer zones is fixed or not, scatterer density can affect the channel capacity to a certain degree that depends on the length of the coding block of the transmitted signals. © 2010 IEEE.

Learning with noise and regularizers in multilayer neural networks

We study the effect of two types of noise, data noise and model noise, in an on-line gradient-descent learning scenario for general two-layer student network with an arbitrary number of hidden units. Training examples are randomly drawn input vectors labeled by a two-layer teacher network with an arbitrary number of hidden units. Data is then corrupted by Gaussian noise affecting either the output or the model itself. We examine the effect of both types of noise on the evolution of order parameters and the generalization error in various phases of the learning process.

Added luminance ramp alters perceived edge blur and contrast:A critical test for derivative-based models of edge coding

In many models of edge analysis in biological vision, the initial stage is a linear 2nd derivative operation. Such models predict that adding a linear luminance ramp to an edge will have no effect on the edge's appearance, since the ramp has no effect on the 2nd derivative. Our experiments did not support this prediction: adding a negative-going ramp to a positive-going edge (or vice-versa) greatly reduced the perceived blur and contrast of the edge. The effects on a fairly sharp edge were accurately predicted by a nonlinear multi-scale model of edge processing [Georgeson, M. A., May, K. A., Freeman, T. C. A., & Hesse, G. S. (in press). From filters to features: Scale-space analysis of edge and blur coding in human vision. Journal of Vision], in which a half-wave rectifier comes after the 1st derivative filter. But we also found that the ramp affected perceived blur more profoundly when the edge blur was large, and this greater effect was not predicted by the existing model. The model's fit to these data was much improved when the simple half-wave rectifier was replaced by a threshold-like transducer [May, K. A. & Georgeson, M. A. (2007). Blurred edges look faint, and faint edges look sharp: The effect of a gradient threshold in a multi-scale edge coding model. Vision Research, 47, 1705-1720.]. This modified model correctly predicted that the interaction between ramp gradient and edge scale would be much larger for blur perception than for contrast perception. In our model, the ramp narrows an internal representation of the gradient profile, leading to a reduction in perceived blur. This in turn reduces perceived contrast because estimated blur plays a role in the model's estimation of contrast. Interestingly, the model predicts that analogous effects should occur when the width of the window containing the edge is made narrower. This has already been confirmed for blur perception; here, we further support the model by showing a similar effect for contrast perception. © 2007 Elsevier Ltd. All rights reserved.

Phonophoresis and topical drug delivery

In this study, investigations into phonophoresis were conducted by employing 3 distinct in vitro models. The aim of the first model was to evaluate the effect of ultrasound on the migration rate of different classes of molecules through agar gel. The derived data suggested that small, relatively hydrophobic molecules are more susceptible to ultrasound-enhanced diffusion through the water-filled channels of the agar gel. The application of heat alone increased drug migration by a similar magnitude as the ultrasound, indicating that ultrasonic heating directly increases the thermodynamic potential for diffusion. In the second experimental system, whole rat skin was pre-sonicated and then examined for changes in its barrier properties. At high intensities (1 to 2W cm-2), ultrasonic waves irreversibly compromised the barrier properties of the skin, following the general patterns described in the literature reports. At low intensities (< 1W cm-2), ultrasound discharged sebum from the sebaceous glands so as to fill much of the hair follicle shafts. This entirely novel phenomenon is probably produced by the mechanical effects of the beam. The deposition of sebaceous lipids within the hair follicle shafts can mean that this absorption pathway is blocked for hydrophilic molecules that penetrate via this route. Consequently, this phenomenon can be utilised as a probe to measure the relative follicular contribution to total penetration for these molecules. In the final phonophoresis model, modified Franz cells were employed in order to assess the ultrasound effect on the concurrent transdermal permeation of various molecules through whole rat skin. For the most lipophilic agent tested, the rate-limiting step of absorption was partitioning from the stratum corneum into the viable epidermis. Sonication did not accelerate this step.

A micro-compression study of shape-memory deformation in U-13 at.% Nb

Microcompression specimens, 10–15 µm in diameter by 20–30 µm in height, were produced from individual parent grains in a polycrystalline U–13 at.%Nb shape-memory alloy using the focused ion beam technique. The specimens were tested in a nanoindentation instrument with a flat diamond tip to investigate stress–strain behavior as a function of crystallographic orientation. The results are in qualitative agreement with a single-crystal accommodation strain (Bain strain) model of the shape-memory effect for this alloy.

Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure

A key factor in the use of assisted reproductive technologies (ART) for diverse species is the safety of procedures for long-term health. By using a mouse model, we have investigated the effect of in vitro culture and embryo transfer (ET) of superovulated embryos on postnatal growth and physiological activity compared with that of embryos developing in vivo. Embryo culture from two-cell to blastocyst stages in T6 medium either with or without a protein source reduced blastocyst trophectoderm and inner cell mass cell number compared with that of embryos developing in vivo. Embryo culture and ET had minimal effects on postnatal growth when compared with in vivo development with an equivalent litter size. However, embryo culture, and to a lesser extent ET, led to an enhanced systolic blood pressure at 21 weeks compared with in vivo development independent of litter size, maternal origin, or body weight. Moreover, activity of enzymatic regulators of cardiovascular and metabolic physiology, namely, serum angiotensin-converting enzyme and the gluconeogenesis controller, hepatic phosphoeno/pyruvate carboxykinase, were significantly elevated in response to embryo culture and/or ET in female offspring at 27 weeks, independent of maternal factors and postnatal growth. These animal data indicate that postnatal physiological criteria important in cardiovascular and metabolic health may be more sensitive to routine ART procedures than growth. © 2007 by The National Academy of Sciences of the USA.

DVMS 1.5: A user manual (the data visualization and modeling system)

The data available during the drug discovery process is vast in amount and diverse in nature. To gain useful information from such data, an effective visualisation tool is required. To provide better visualisation facilities to the domain experts (screening scientist, biologist, chemist, etc.),we developed a software which is based on recently developed principled visualisation algorithms such as Generative Topographic Mapping (GTM) and Hierarchical Generative Topographic Mapping (HGTM). The software also supports conventional visualisation techniques such as Principal Component Analysis, NeuroScale, PhiVis, and Locally Linear Embedding (LLE). The software also provides global and local regression facilities . It supports regression algorithms such as Multilayer Perceptron (MLP), Radial Basis Functions network (RBF), Generalised Linear Models (GLM), Mixture of Experts (MoE), and newly developed Guided Mixture of Experts (GME). This user manual gives an overview of the purpose of the software tool, highlights some of the issues to be taken care while creating a new model, and provides information about how to install & use the tool. The user manual does not require the readers to have familiarity with the algorithms it implements. Basic computing skills are enough to operate the software.

Binocular interaction:Contrast matching and contrast discrimination are predicted by the same model

How do signals from the 2 eyes combine and interact? Our recent work has challenged earlier schemes in which monocular contrast signals are subject to square-law transduction followed by summation across eyes and binocular gain control. Much more successful was a new 'two-stage' model in which the initial transducer was almost linear and contrast gain control occurred both pre- and post-binocular summation. Here we extend that work by: (i) exploring the two-dimensional stimulus space (defined by left- and right-eye contrasts) more thoroughly, and (ii) performing contrast discrimination and contrast matching tasks for the same stimuli. Twenty-five base-stimuli made from 1 c/deg patches of horizontal grating, were defined by the factorial combination of 5 contrasts for the left eye (0.3-32%) with five contrasts for the right eye (0.3-32%). Other than in contrast, the gratings in the two eyes were identical. In a 2IFC discrimination task, the base-stimuli were masks (pedestals), where the contrast increment was presented to one eye only. In a matching task, the base-stimuli were standards to which observers matched the contrast of either a monocular or binocular test grating. In the model, discrimination depends on the local gradient of the observer's internal contrast-response function, while matching equates the magnitude (rather than gradient) of response to the test and standard. With all model parameters fixed by previous work, the two-stage model successfully predicted both the discrimination and the matching data and was much more successful than linear or quadratic binocular summation models. These results show that performance measures and perception (contrast discrimination and contrast matching) can be understood in the same theoretical framework for binocular contrast vision. © 2007 VSP.

Creation of relational assets through the 'library of equipment' model:an industrial modernization approach of Japan's local technology centres

SMEs with a weak internal R&D capacity show the tendency to shy away from using external sources of technical expertise. The tendency deters providers of industrial modernization services from supporting such structurally weak SMEs. This paper examines how Japan's local technology centres - kosetsushi - remove the bottleneck and reach out to a significant proportion of SMEs with a weak R&D capacity in their localities. Kosetsushi centres sustain habitual interactions with client firms through 'low information gap' services solving immediate needs and lead the clients to a riskier and longer path toward innovation capacity building. This gives kosetsushi centres a position distinct from universities and consultancies in the regional innovation system. While long-term relationships between kosetsushi centres and their client firms can increase switching costs and produce lock-in effects, a case study of two kosetsushi centres illustrates the importance of 'low-information gap' services and relational assets created thereby to the modernization of SMEs with a weak internal R&D capacity. The paper calls for long-term commitment by the public sector if it addresses the issue through modernization services.

Electronic information sharing in local government authorities:factors influencing the decision-making process

Local Government Authorities (LGAs) are mainly characterised as information-intensive organisations. To satisfy their information requirements, effective information sharing within and among LGAs is necessary. Nevertheless, the dilemma of Inter-Organisational Information Sharing (IOIS) has been regarded as an inevitable issue for the public sector. Despite a decade of active research and practice, the field lacks a comprehensive framework to examine the factors influencing Electronic Information Sharing (EIS) among LGAs. The research presented in this paper contributes towards resolving this problem by developing a conceptual framework of factors influencing EIS in Government-to-Government (G2G) collaboration. By presenting this model, we attempt to clarify that EIS in LGAs is affected by a combination of environmental, organisational, business process, and technological factors and that it should not be scrutinised merely from a technical perspective. To validate the conceptual rationale, multiple case study based research strategy was selected. From an analysis of the empirical data from two case organisations, this paper exemplifies the importance (i.e. prioritisation) of these factors in influencing EIS by utilising the Analytical Hierarchy Process (AHP) technique. The intent herein is to offer LGA decision-makers with a systematic decision-making process in realising the importance (i.e. from most important to least important) of EIS influential factors. This systematic process will also assist LGA decision-makers in better interpreting EIS and its underlying problems. The research reported herein should be of interest to both academics and practitioners who are involved in IOIS, in general, and collaborative e-Government, in particular. © 2013 Elsevier Ltd. All rights reserved.