Pharmacological discrimination of calcitonin receptor:receptor activity-modifying protein complexes

Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT (a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of αCGRP, being a weak agonist at CT(a), AMY 2(a), and AMY3(a) receptors but considerably more potent at AMY1(a) receptors. Likewise, the linear calcitonin gene-related peptide (CGRP) analogs (Cys(ACM)2,7)hαCGRP and (Cys(Et) 2,7)haCGRP were only effective at AMY1(a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY2(a) receptor phenotype; thus, AMY 2(a) was not examined further in this study. The antagonist peptide salmon calcitonin8-32 (sCT8-32) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY1(a) over AMY3(a) receptors. CGRP8-37 also demonstrated receptor-dependent effects. CGRP 8-37 more effectively antagonized AMY at AMY1(a) than AMY3(a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT(a) receptor. Low CGRP 8-37 affinity and agonism by linear CGRP analogs at AMY 1(a) are the classic signature of a CGRP2 receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT(a), AMY1(a), and AMY3(a) receptors, providing a means to delineate the physiological significance of these receptors. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.

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.

Improving discrimination in data envelopment analysis:some practical suggestions

In some contexts data envelopment analysis (DEA) gives poor discrimination on the performance of units. While this may reflect genuine uniformity of performance between units, it may also reflect lack of sufficient observations or other factors limiting discrimination on performance between units. In this paper, we present an overview of the main approaches that can be used to improve the discrimination of DEA. This includes simple methods such as the aggregation of inputs or outputs, the use of longitudinal data, more advanced methods such as the use of weight restrictions, production trade-offs and unobserved units, and a relatively new method based on the use of selective proportionality between the inputs and outputs. © 2007 Springer Science+Business Media, LLC.

Workplace gender discrimination and the implicit association test

Women are under-represented at senior levels within organisations. They also fareless well than their male counterparts in reward and career opportunities. Attitudestoward women in the workplace are thought to underpin these disparities and moreand more organisations are introducing attitude measures into diversity and inclusioninitiatives to: 1) raise awareness amongst employees of implicit attitudes, 2) educateemployees on how these attitudes can influence behaviour and 3) re-measure theattitude after an intervention to assess whether the attitude has changed. TheImplicit Association Test (IAT: Greenwald, et al., 1998) is the most popular tool usedto assess attitudes. However, questions over the predictive validity of the measurehave been raised and the evidence for the real world impact of the implicit attitudes islimited (Blanton et al., 2009; Landy, 2008; Tetlock & Mitchell, 2009; Wax, 2010).Whilst there is growing research in the area of race, little research has explored theability of the IAT to predict gender discrimination. This thesis addresses thisimportant gap in the literature. Three empirical studies were conducted. The firststudy explored whether gender IATs were predictive of personnel decisions thatfavour men and whether affect- and cognition-based gender IATs were equallypredictive of behaviour. The second two studies explored the predictive validity ofthe IAT in comparison to an explicit measure of one type of gender attitude,benevolent sexism. The results revealed implicit gender attitudes were stronglyheld. However, they did not consistently predict behaviour across the studies.Overall, the results suggest that the IAT may only predict workplace genderdiscrimination in a very select set of circumstances. The attitude component that anIAT assesses, the personnel decision and participant demographics all impact thepredictive validity of the tool. The interplay between the IAT and behaviour thereforeappears to be more complex than is assumed.

Contrast discrimination with simultaneous monocular and dichoptic masks

In experiments reported elsewhere at this conference, we have revealed two striking results concerning binocular interactions in a masking paradigm. First, at low mask contrasts, a dichoptic masking grating produces a small facilitatory effect on the detection of a similar test grating. Second, the psychometric slope for dichoptic masking starts high (Weibull ß~4) at detection threshold, becomes low (ß~1.2) in the facilitatory region, and then unusually steep at high mask contrasts (ß~5.5). Neither of these results is consistent with Legge's (1984 Vision Research 24 385 - 394) model of binocular summation, but they are predicted by a two-stage gain control model in which interocular suppression precedes binocular summation. Here, we pose a further challenge for this model by using a 'twin-mask' paradigm (cf Foley, 1994 Journal of the Optical Society of America A 11 1710 - 1719). In 2AFC experiments, observers detected a patch of grating (1 cycle deg-1, 200 ms) presented to one eye in the presence of a pedestal in the same eye and a spatially identical mask in the other eye. The pedestal and mask contrasts varied independently, producing a two-dimensional masking space in which the orthogonal axes (10X10 contrasts) represent conventional dichoptic and monocular masking. The resulting surface (100 thresholds) confirmed and extended the observations above, and fixed the six parameters in the model, which fitted the data well. With no adjustment of parameters, the model described performance in a further experiment where mask and test were presented to both eyes. Moreover, in both model and data, binocular summation was greater than a factor of v2 at detection threshold. We conclude that this two-stage nonlinear model, with interocular suppression, gives a good account of early binocular processes in the perception of contrast. [Supported by EPSRC Grant Reference: GR/S74515/01]

Fixed or variable noise in contrast discrimination? The jury's still out

The ability to distinguish one visual stimulus from another slightly different one depends on the variability of their internal representations. In a recent paper on human visual-contrast discrimination, Kontsevich et al (2002 Vision Research 42 1771 - 1784) re-considered the long-standing question whether the internal noise that limits discrimination is fixed (contrast-invariant) or variable (contrast-dependent). They tested discrimination performance for 3 cycles deg-1 gratings over a wide range of incremental contrast levels at three masking contrasts, and showed that a simple model with an expansive response function and response-dependent noise could fit the data very well. Their conclusion - that noise in visual-discrimination tasks increases markedly with contrast - has profound implications for our understanding and modelling of vision. Here, however, we re-analyse their data, and report that a standard gain-control model with a compressive response function and fixed additive noise can also fit the data remarkably well. Thus these experimental data do not allow us to decide between the two models. The question remains open. [Supported by EPSRC grant GR/S74515/01]

Contrast discrimination and pattern masking: contrast gain control with fixed additive noise

We studied the visual mechanisms that serve to encode spatial contrast at threshold and supra-threshold levels. In a 2AFC contrast-discrimination task, observers had to detect the presence of a vertical 1 cycle deg-1 test grating (of contrast dc) that was superimposed on a similar vertical 1 cycle deg-1 pedestal grating, whereas in pattern masking the test grating was accompanied by a very different masking grating (horizontal 1 cycle deg-1, or oblique 3 cycles deg-1). When expressed as threshold contrast (dc at 75% correct) versus mask contrast (c) our results confirm previous ones in showing a characteristic 'dipper function' for contrast discrimination but a smoothly increasing threshold for pattern masking. However, fresh insight is gained by analysing and modelling performance (p; percent correct) as a joint function of (c, dc) - the performance surface. In contrast discrimination, psychometric functions (p versus logdc) are markedly less steep when c is above threshold, but in pattern masking this reduction of slope did not occur. We explored a standard gain-control model with six free parameters. Three parameters control the contrast response of the detection mechanism and one parameter weights the mask contrast in the cross-channel suppression effect. We assume that signal-detection performance (d') is limited by additive noise of constant variance. Noise level and lapse rate are also fitted parameters of the model. We show that this model accounts very accurately for the whole performance surface in both types of masking, and thus explains the threshold functions and the pattern of variation in psychometric slopes. The cross-channel weight is about 0.20. The model shows that the mechanism response to contrast increment (dc) is linearised by the presence of pedestal contrasts but remains nonlinear in pattern masking.