Cellular mechanisms for the formation of a soluble form derivative of T-cell receptor alpha chain by suppressor T cells.

Upon stimulation with anti-CD3, suppressor T-cell (Ts) hybridomas and homologous transfectants of T-cell receptor a (TCRalpha) cDNA in the T-cell hybridoma formed a 55-kDa TCRalpha chain derivative that bound both the monoclonal anti-TCRalpha chain and polyclonal antibodies against glycosylation inhibiting factor (GIF). The peptide is a subunit of antigen-specific suppressor T-cell factor (TsF), and is considered to be a posttranslationally-formed conjugate of TCRalpha chain with GIF peptide. The TCRalpha derivative is synthesized by the transfectant after stimulation with anti-CD3, and not derived from TCR present on the cell surface. Stimulation of the stable homologous transfectants with anti-CD3 induced translocation of the 13-kDa GIF peptide into endoplasmic reticulum (ER). When a helper Ts hybridoma or a stable transfectant of the same TCRalpha cDNA in a helper cell-derived TCRalpha- clone was stimulated with anti-CD3, translocation of GIF peptide was not detected, and these cells failed to secrete a TCRalpha derivative. However, further transfection of a chimeric cDNA encoding a procalcitonin-GIF fusion protein into the helper cell-derived stable transfectant of TCRalpha cDNA resulted in translocation of the GIF protein and formation of bioactive 55-kDa GIF. The results indicated that translocation of GIF peptide through ER is unique for Ts cells, and that this process is essential for the formation/secretion of the soluble form derivative of TCRalpha chain by T cells.

An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective.

Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for mu- and m-calpains of 0.21 microM and 0.37 microM, respectively, (ii) high specificity for calpains relative to other proteases, (iii) uncompetitive inhibition with respect to substrate, and (iv) it does not shield calpain against inactivation by the active-site inhibitor trans-(epoxysuccinyl)-L-leucyl-amido-3-methylbutane, suggesting a nonactive site action for PD150606. The recombinant calcium-binding domain from each of the large or small subunits of mu-calpain was found to interact with PD150606. In low micromolar range, PD15O6O6 inhibited calpain activity in two intact cell systems. The neuroprotective effects of this class of compound were also demonstrated by the ability of PD150606 to attenuate hypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices.

Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites.

DNA topoisomerase I (top1) is a ubiquitous nuclear enzyme. It is specifically inhibited by camptothecin, a natural product derived from the bark of the tree Camptotheca acuminata. Camptothecin and several of its derivatives are presently in clinical trial and exhibit remarkable anticancer activity. The present study is a further investigation of the molecular interactions between the drug and the enzyme-DNA complex. We utilized an alkylating camptothecin derivative, 7-chloromethyl-10,11-methylenedioxycamptothecin (7-ClMe-MDO-CPT), and compared its activity against calf thymus top1 in a DNA oligonucleotide containing a single top1 cleavage site with the activity of its nonalkylating analog, 7-ethyl-10,11-methylenedioxycamptothecin (7-Et-MDO-CPT). In the presence of top1, 7-ClMe-MDO-CPT produced a DNA fragment that migrated more slowly than the top1-cleaved DNA fragment observed with 7-Et-MDO-CPT. Top1 was unable to religate this fragment in the presence of high NaCl concentration or proteinase K at 50 degrees C. This fragment was resistant to piperidine treatment and was also formed with an oligonucleotide containing a 7-deazaguanine at the 5' terminus of the top1-cleaved DNA (base + 1). It was however cleaved by formic acid treatment followed by piperidine. These observations are consistent with alkylation of the +1 base (adenine or guanine) by 7-ClMe-MDO-CPT in the presence of top1 covalent complexes and provide direct evidence that camptothecins inhibit top1 by binding at the enzyme-DNA interface.

Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives).

Five structurally related thiophene and furane analogues of the oxathiin carboxanilide derivative NSC 615985 (UC84) (designated UC10, UC68, UC81, UC42, and UC16) were identified as potent inhibitors of HIV-1 replication in cell culture and HIV-1 reverse transcriptase activity. These compounds were markedly active against a series of mutant HIV-1 strains, containing the Leu-100-->Ile, Val-106-->Ala, Glu-138-->Lys, or Tyr-181-->Cys mutations in their reverse transcriptase. However, the thiocarboxanilide derivatives selected for mutations at amino acid positions 100 (Leu-->Ile), 101 (Lys-->Ile/Glu), 103 (Lys-->Thr/Asp) and 141 (Gly-->Glu) in the HIV-1 reverse transcriptase. The compounds completely suppressed HIV-1 replication and prevented the emergence of resistant virus strains when used at 1.3-6.6 microM--that is, 10- to 25-fold lower than the concentration required for nevirapine and bis(heteroaryl)piperazine (BHAP) U90152 to do so. If UC42 was combined with the [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)]-beta-D-pentofuranosyl (TSAO) derivative of N3-methylthymine (TSAO-m3T), virus breakthrough could be prevented for a much longer time, and at much lower concentrations, than if the compounds were used individually. Virus breakthrough could be suppressed for even longer, and at lower drug concentrations, if BHAP was added to the combination of UC42 with TSAO-m3T, which points to the feasibility of two- or three-drug combinations in preventing virus breakthrough and resistance development.

Fashions and fads in finance: contingent emulation and the political economy of sovereign wealth fund creation. IHS Political Science Series No. 131, July 2012

Sovereign wealth funds (SWFs), government-owned or managed investment vehicles, have proliferated at a remarkable rate over the past decade, even as political controversy has surrounded them. Why? The extant literature depicts the process of SWF creation as driven by functional imperatives associated with “excess” revenue and reserves accumulated from commodity booms and large current account surpluses. I argue that SWF creation also reflects in large part a process of contingent emulation in which first this policy has been constructed as appropriate for countries with given characteristics, and then when countries took on these characteristics, they followed their peers. Put simply, fashions and fads in finance matter for policy diffusion. I assess this argument using a new dataset on SWF creation that covers nearly 80 countries from 1984 to 2007. The results suggest peer-based contingent emulation has been a crucial factor shaping the decision of many countries to create a SWF, especially among fuel exporters. An earlier version of this paper was presented at the annual meeting of the American Political Science Association, Washington, DC, 2 – 5 September 2010. The author would like to thank Eric Neumayer for his many suggestions and comments on previous versions of the manuscript. The author would also like to thank Zachary Elkins for sharing data. Finally, the author would like to acknowledge the research assistance of Natali Bulamacioglu and Christopher Gandrud.

Shift, scaling and derivative properties for the discrete cosine transform

A set of DCT domain properties for shifting and scaling by real amounts, and taking linear operations such as differentiation is described. The DCT coefficients of a sampled signal are subjected to a linear transform, which returns the DCT coefficients of the shifted, scaled and/or differentiated signal. The properties are derived by considering the inverse discrete transform as a cosine series expansion of the original continuous signal, assuming sampling in accordance with the Nyquist criterion. This approach can be applied in the signal domain, to give, for example, DCT based interpolation or derivatives. The same approach can be taken in decoding from the DCT to give, for example, derivatives in the signal domain. The techniques may prove useful in compressed domain processing applications, and are interesting because they allow operations from the continuous domain such as differentiation to be implemented in the discrete domain. An image matching algorithm illustrates the use of the properties, with improvements in computation time and matching quality.

A path-dependent contingent-claims approach to capacity investments

This note presents a contingent-claims approach to strategic capacity planning. We develop models for capacity choice and expansion decisions in a single firm environment where investment is irreversible and demand is uncertain. These models illustrate specifically the relevance of path-dependent options analysis to planning capacity investments when the firm adopts demand tracking or average capacity strategies. It is argued that Asian/average type real options can explain hysteresis phenomena in addition to providing superior control of assets in place.

Mach edges: local features predicted by 3rd derivative spatial filtering

Edges are key points of information in visual scenes. One important class of models supposes that edges correspond to the steepest parts of the luminance profile, implying that they can be found as peaks and troughs in the response of a gradient (1st derivative) filter, or as zero-crossings in the 2nd derivative (ZCs). We tested those ideas using a stimulus that has no local peaks of gradient and no ZCs, at any scale. The stimulus profile is analogous to the Mach ramp, but it is the luminance gradient (not the absolute luminance) that increases as a linear ramp between two plateaux; the luminance profile is a blurred triangle-wave. For all image-blurs tested, observers marked edges at or close to the corner points in the gradient profile, even though these were not gradient maxima. These Mach edges correspond to peaks and troughs in the 3rd derivative. Thus Mach edges are inconsistent with many standard edge-detection schemes, but are nicely predicted by a recent model that finds edge points with a 2-stage sequence of 1st then 2nd derivative operators, each followed by a half-wave rectifier.

Mach edges: a critical test of the nonlinear 3rd derivative model for edge-detection

Feature detection is a crucial stage of visual processing. In previous feature-marking experiments we found that peaks in the 3rd derivative of the luminance profile can signify edges where there are no 1st derivative peaks nor 2nd derivative zero-crossings (Wallis and George 'Mach edges' (the edges of Mach bands) were nicely predicted by a new nonlinear model based on 3rd derivative filtering. As a critical test of the model, we now use a new class of stimuli, formed by adding a linear luminance ramp to the blurred triangle waves used previously. The ramp has no effect on the second or higher derivatives, but the nonlinear model predicts a shift from seeing two edges to seeing only one edge as the added ramp gradient increases. In experiment 1, subjects judged whether one or two edges were visible on each trial. In experiment 2, subjects used a cursor to mark perceived edges and bars. The position and polarity of the marked edges were close to model predictions. Both experiments produced the predicted shift from two to one Mach edge, but the shift was less complete than predicted. We conclude that the model is a useful predictor of edge perception, but needs some modification.

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.

Mach edges: a key role for 3rd derivative filters in spatial vision

Edges are key points of information in visual scenes. One important class of models supposes that edges correspond to the steepest parts of the luminance profile, implying that they can be found as peaks and troughs in the response of a gradient (first-derivative) filter, or as zero-crossings (ZCs) in the second-derivative. A variety of multi-scale models are based on this idea. We tested this approach by devising a stimulus that has no local peaks of gradient and no ZCs, at any scale. Our stimulus profile is analogous to the classic Mach-band stimulus, but it is the local luminance gradient (not the absolute luminance) that increases as a linear ramp between two plateaux. The luminance profile is a smoothed triangle wave and is obtained by integrating the gradient profile. Subjects used a cursor to mark the position and polarity of perceived edges. For all the ramp-widths tested, observers marked edges at or close to the corner points in the gradient profile, even though these were not gradient maxima. These new Mach edges correspond to peaks and troughs in the third-derivative. They are analogous to Mach bands - light and dark bars are seen where there are no luminance peaks but there are peaks in the second derivative. Here, peaks in the third derivative were seen as light-to-dark edges, troughs as dark-to-light edges. Thus Mach edges are inconsistent with many standard edge detectors, but are nicely predicted by a new model that uses a (nonlinear) third-derivative operator to find edge points.

Perceiving edge blur: Gaussian-derivative filtering and a rectifying nonlinearity

We studied the visual mechanisms that encode edge blur in images. Our previous work suggested that the visual system spatially differentiates the luminance profile twice to create the `signature' of the edge, and then evaluates the spatial scale of this signature profile by applying Gaussian derivative templates of different sizes. The scale of the best-fitting template indicates the blur of the edge. In blur-matching experiments, a staircase procedure was used to adjust the blur of a comparison edge (40% contrast, 0.3 s duration) until it appeared to match the blur of test edges at different contrasts (5% - 40%) and blurs (6 - 32 min of arc). Results showed that lower-contrast edges looked progressively sharper. We also added a linear luminance gradient to blurred test edges. When the added gradient was of opposite polarity to the edge gradient, it made the edge look progressively sharper. Both effects can be explained quantitatively by the action of a half-wave rectifying nonlinearity that sits between the first and second (linear) differentiating stages. This rectifier was introduced to account for a range of other effects on perceived blur (Barbieri-Hesse and Georgeson, 2002 Perception 31 Supplement, 54), but it readily predicts the influence of the negative ramp. The effect of contrast arises because the rectifier has a threshold: it not only suppresses negative values but also small positive values. At low contrasts, more of the gradient profile falls below threshold and its effective spatial scale shrinks in size, leading to perceived sharpening.

The primal sketch revisited: locating and representing edges in human vision via Gaussian-derivative filtering

Marr's work offered guidelines on how to investigate vision (the theory - algorithm - implementation distinction), as well as specific proposals on how vision is done. Many of the latter have inevitably been superseded, but the approach was inspirational and remains so. Marr saw the computational study of vision as tightly linked to psychophysics and neurophysiology, but the last twenty years have seen some weakening of that integration. Because feature detection is a key stage in early human vision, we have returned to basic questions about representation of edges at coarse and fine scales. We describe an explicit model in the spirit of the primal sketch, but tightly constrained by psychophysical data. Results from two tasks (location-marking and blur-matching) point strongly to the central role played by second-derivative operators, as proposed by Marr and Hildreth. Edge location and blur are evaluated by finding the location and scale of the Gaussian-derivative `template' that best matches the second-derivative profile (`signature') of the edge. The system is scale-invariant, and accurately predicts blur-matching data for a wide variety of 1-D and 2-D images. By finding the best-fitting scale, it implements a form of local scale selection and circumvents the knotty problem of integrating filter outputs across scales. [Supported by BBSRC and the Wellcome Trust]

Mach bands and multiscale models of spatial vision:the role of first, second, and third derivative operators in encoding bars and edges

Ernst Mach observed that light or dark bands could be seen at abrupt changes of luminance gradient in the absence of peaks or troughs in luminance. Many models of feature detection share the idea that bars, lines, and Mach bands are found at peaks and troughs in the output of even-symmetric spatial filters. Our experiments assessed the appearance of Mach bands (position and width) and the probability of seeing them on a novel set of generalized Gaussian edges. Mach band probability was mainly determined by the shape of the luminance profile and increased with the sharpness of its corners, controlled by a single parameter (n). Doubling or halving the size of the images had no significant effect. Variations in contrast (20%-80%) and duration (50-300 ms) had relatively minor effects. These results rule out the idea that Mach bands depend simply on the amplitude of the second derivative, but a multiscale model, based on Gaussian-smoothed first- and second-derivative filtering, can account accurately for the probability and perceived spatial layout of the bands. A key idea is that Mach band visibility depends on the ratio of second- to first-derivative responses at peaks in the second-derivative scale-space map. This ratio is approximately scale-invariant and increases with the sharpness of the corners of the luminance ramp, as observed. The edges of Mach bands pose a surprisingly difficult challenge for models of edge detection, but a nonlinear third-derivative operation is shown to predict the locations of Mach band edges strikingly well. Mach bands thus shed new light on the role of multiscale filtering systems in feature coding. © 2012 ARVO.

Universalistic or contingency model? Contribution of HRM towards firms’ performance in Greece

This paper investigates the impact of HRM systems on organisational performance in a sample of 178 Greek manufacturing organisations. The results show strong support for the ‘universalistic’ model, highlighting that both resource-development and reward-relations systems are positively related with organisational performance. The results also show weak and partial support for the ‘contingency model’, i.e., resourcedevelopment and reward-relations systems are contingent on the business strategies of quality, innovation, and cost in determining organisational efficiency. The study concludes that the universalistic and contingency perspectives are not necessarily mutually exclusive but on the contrary are in some cases complementary.