Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.

Influence of the perception of biological or non-biological motion on movement execution.

The perception of a human actor performing movements may involve processes related to action execution. This resonance of the motor system may support observational learning and imitation, and could also explain the fact that observers'/actors' movements are disturbed by the observation of a human model making different movements (Kilner et al., 2003). In this study, we tried to specify what information available in the model's behaviour triggers this influence on an observer's behaviour. In two experiments, we had participants make horizontal or vertical arm movements while observing similar movements. In the first experiment, the observers' pattern of behaviour was affected by the observation of a human model making incongruent movements. In the second experiment, similar results were obtained with participants observing a moving dot depicting either biological or non-biological motion. Movement execution was affected differentially by biological and non-biological motion observation. These results show that an observer's behaviour is sensitive to information available in biological motion.

Surface integration influences depth discrimination.

Image fragments arising from partial occlusion may be perceptually unified by a surface integration process on the basis of similar color or texture. In a new objective measure pitting surface feature similarity against binocular disparity, observers discriminated whether a colored circle had either crossed or uncrossed disparity relative to a surrounding gray rectangle. Sensitivity to disparity was impaired only when (1) the configuration of the other surface fragments in the display supported the integration of a surface behind the rectangle and circle, and (2) matched the color of the central circle. Results were consistent with the hypothesis that a surface integration process integrated similarly-colored surface fragments into a smooth surface, even when those fragments were at different depths. Surface integration caused small and reliable effects on depth perception despite unambiguous disparity information. Perceived depth does not depend solely upon disparity, and may be determined after three-dimensional figural unity is established.

Induction of AIDS virus-specific CTL activity in fresh, unstimulated peripheral blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified vaccinia virus Ankara boost regimen.

The observed role of CTL in the containment of AIDS virus replication suggests that an effective HIV vaccine will be required to generate strong CTL responses. Because epitope-based vaccines offer several potential advantages for inducing strong, multispecific CTL responses, we tested the ability of an epitope-based DNA prime/modified vaccinia virus Ankara (MVA) boost vaccine to induce CTL responses against a single SIVgag CTL epitope. As assessed using both 51Cr release assays and tetramer staining of in vitro stimulated PBMC, DNA vaccinations administered to the skin with the gene gun induced and progressively increased p11C, C-->M (CTPYDINQM)-specific CD8+ T lymphocyte responses in six of six Mamu-A*01+ rhesus macaques. Tetramer staining of fresh, unstimulated PBMC from two of the DNA-vaccinated animals indicated that as much as 0.4% of all CD3+/CD8alpha+ T lymphocytes were specific for the SIVgag CTL epitope. Administration of MVA expressing the SIVgag CTL epitope further boosted these responses, such that 0.8-20.0% of CD3+/CD8alpha+ T lymphocytes in fresh, unstimulated PBMC were now Ag specific. Enzyme-linked immunospot assays confirmed this high frequency of Ag-specific cells, and intracellular IFN-gamma staining demonstrated that the majority of these cells produced IFN-gamma after peptide stimulation. Moreover, direct ex vivo SIV-specific cytotoxic activity could be detected in PBMC from five of the six DNA/MVA-vaccinated animals, indicating that this epitope-based DNA prime/MVA boost regimen represents a potent method for inducing high levels of functionally active, Ag-specific CD8+ T lymphocytes in non-human primates.

Prism adaptation to dynamic events.

In the present study, we explored adaptation to prism-displaced dynamic and static events under conditions of minimal information. Many of our interactions with the world are dynamic and involve reaching for or intercepting moving objects. The consequences (or feedback) of those interactions entail the presence or absence of physical contact with the moving objects. In this study, humans learned, with only heptic feedback, to intercept optically displaced falling balls. To eliminate visual feedback, the falling balls disappeared behind an occluder (which systematically varied in size across groups) prior to either striking or missing a subject's hand. As occluder size decreased, adaptation increased. With minimum occluder sizes, the greatest adaptation occurred around the training position, and adaptation decreased as distance between training and testing positions increased. The results can best be described in terms of a generalization gradient centered around the training position. This generalization gradient was not present when subjects were trained with ecologically similar static arrays. Implications for models of adaptation are discussed.

The dynamic specification of surfaces and boundaries.

Sequential changes in small separated texture elements can produce perception of a moving form with continuous boundaries. This process of spatiotemporal boundary formation may exist to provide a robust means of detecting moving objects that occlude more distant textured surfaces. Whereas most research on spatiotemporal boundary formation has been focused on boundary and shape perception, two experiments are reported here on the perception of surface qualities in spatiotemporal boundary formation. In experiment 1 a free-report procedure was used to investigate whether surface perception can be determined by dynamic information alone, apart from static spatial differences. Results showed that dynamic information was sufficient to determine the appearance of a surface. This dynamic information may play an important role in other aspects of perception. In experiment 2, it was shown that dynamically specifying an extended, opaque surface facilitated edge perception. Implications for the relation of boundary and surface perception and for theories of perceptual transparency are discussed.

Interactions between spatial and spatiotemporal information in spatiotemporal boundary formation.

The surface and boundaries of an object generally move in unison, so the motion of a surface could provide information about the motion of its boundaries. Here we report the results of three experiments on spatiotemporal boundary formation that indicate that information about the motion of a surface does influence the formation of its boundaries. In Experiment 1, shape identification at low texture densities was poorer for moving forms in which stationary texture was visible inside than for forms in which the stationary texture was visible only outside. In Experiment 2, the disruption found in Experiment 1 was removed by adding a second external boundary. We hypothesized that the disruption was caused by boundary assignment that perceptually grouped the moving boundary with the static texture. Experiment 3 revealed that accurate information about the motion of the surface facilitated boundary formation only when the motion was seen as coming from the surface of the moving form. Potential mechanisms for surface motion effects in dynamic boundary formation are discussed.

A common mechanism for illusory and occluded object completion.

New phenomena and results are reported that implicate a common contour interpolation mechanism in illusory and occluded (modal and amodal) object completion. In 3 experiments, a speeded classification task was used to study novel quasimodal displays in which occluded and illusory contours join. Results showed the same advantages in speed and accuracy over control displays for quasimodal, illusory, and occluded displays. The implications of quasimodal displays, along with another new display type in which contour linkages must precede determination of modal or amodal appearance, are considered. These logical considerations and empirical results suggest that amodal and modal completion depend on a common underlying mechanism that connects edges across gaps.

Spatio-temporal boundary formation: the role of local motion signals in boundary perception.

Spatio-temporal boundary formation (SBF) refers to a perceptual process responsible for perception of moving, bounded surfaces from sequential changes in spatially separated local elements. Previous research has indicated that this process produces perception of global form, continuous boundaries and global motion from spatially and temporally sparse element changes. In the present paper, we sought to distinguish between two classes of models for SBF: form-precedes-motion and motion-precedes-form models. Experiment 1 tested the effects of the addition of spurious motion signals, a manipulation that should affect a motion-precedes-form computation but not a form-precedes-motion computation. Shape identification in a 10-alternative forced-choice procedure was disrupted by this manipulation, supporting the former class of models. A particular computational scheme, edge orientation from motion (EOFM) instantiating a motion-precedes-form model is described and tested in Experiment 2. The EOFM model should be disrupted when initiating element changes occur in a certain type of sequential order, relative to randomly arranged changes. Sequential changes markedly disrupted performance, supporting this EOFM approach. The results favor motion-precedes-form models of SBF and are consistent with the particular computational scheme proposed.

Surface completion complements boundary interpolation in the visual integration of partly occluded objects.

Previous research on perceptual completion has emphasized how the spatial relationships of edges influence the visual integration of the image fragments that result from partial occlusion. We report studies testing the hypothesis that the similarity of surface features also influences visual integration, complementing edge interpolation processes. Using displays that separated edge interpolation processes from surface-feature interpolation processes, we tested the hypotheses that a surface completion process integrates image fragments with similar surface features, and that surface completion is constrained by amodally interpolated and amodally extended boundaries. Both edge relatability and surface-feature similarity were manipulated in a series of paired-comparison and classification tasks. The results of these studies supported the hypotheses and were extended to surface features of colors, textures, and color gradients. Results also suggest that, under certain conditions, surface completion may interact with and influence edge interpolation.

Discordance between physician and patient perceptions in the treatment of diabetes mellitus: a pilot study of the relationship to adherence and glycemic control.

Glycolsylated hemoglobin (G Hb) levels and data on adherence and patient-provider discordance in beliefs about diabetes were collected from 42 insulin-requiring patients with diabetes. Discordance was calculated for both degree of discordance (absolute amount of disagreement) and direction of discordance (degree to which physician > patient or patient < physician). Patients generally agreed with physicians in perceptions of severity, costs of adherence, and immediate and long-term benefits of adherence. Significant differences were found between these dimensions. Only discordance on long-term benefits of adherence correlated with adherence, with greater discordance related to greater adherence. Discordance on the cost dimension correlated negatively with G Hb, suggesting better glycemic control with greater disagreement. Those who underestimate the cost of adherence show greater adherence. Adherence did not correlate significantly with glycemic control.

Evaluating alternative treatments for homeless substance-abusing men: outcomes and predictors of success.

The present study was designed to explore the relative efficacy of three types of service delivery intervention models for homeless men with alcohol and/or drug problems: integrated comprehensive residential services provided at one site (Group 1); on-site shelter-based intensive case management with referrals to a community network of services (Group 2); and usual care shelter services with case management (Group 3). In addition to assessing the relative efficacy of these approaches in terms of drug and alcohol use, residential stability, economic and employment status, the project also sought to examine what personal factors best predicted successful outcomes for clients. Clients were assessed at baseline and approximately six months following discharge. All three treatment groups improved significantly over time in terms of reduced alcohol and cocaine use, increased employment, and increased stable housing, but no differential improvement was found among groups. Successful outcomes were predicted by lower recent and lifetime substance use, fewer prior treatment episodes, more stable housing at baseline, fewer incarcerations, and less social isolation.

"Inside-out" signal transduction inhibited by isolated integrin cytoplasmic domains.

The affinities of integrin alpha beta heterodimers for extracellular ligands are important regulators of cell adhesion. Intracellular signals provoke changes in the integrin extracellular domain resulting in "activation," as manifested by an increase in affinity. Interactions of integrin cytoplasmic domains with intracellular elements may mediate this "inside-out signaling." Here we report that overexpression of chimeras of the cytoplasmic domain of integrin beta 3 or beta 1 subunits, joined to the extracellular and transmembrane domains of the Tac subunit of the interleukin-2 receptor, reduced integrin affinity. In contrast, chimeras containing the cytoplasmic domain of alpha 5 or alpha IIb or of beta 3 bearing a mutation that disrupts inside-out signaling lacked inhibitory activity. These data suggest that limiting quantities of intracellular factors bind to integrin beta 3 and beta 1 cytoplasmic domains to modulate ligand binding affinity. Structural mimics of these domains may provide a novel means to alter cell adhesion.

Spatiotemporal boundary formation: boundary, form, and motion perception from transformations of surface elements.

Continuous surface boundaries, object shape, and global motion can be perceived from information that is fragmentary in both space and time. The authors report investigations indicating that accretion and deletion of texture is only 1 member of a broader class of element transformations that produce boundaries, shape, and motion, through spatiotemporal boundary formation (SBF). The authors report 4 experiments exploring SBF. The first 3 examine the class of transformations producing SBF, indicating that local element changes in color, orientation, or location are all effective. A 4th experiment examines temporal constraints on SBF. Integration of local element changes to produce boundaries, form, and global motion appears to be confined to a 165-ms window. Two classes of spatiotemporal integration models are considered; the relation between SBF and other cases of boundary interpolation are discussed.

Optical tearing in spatiotemporal boundary formation: when do local element motions produce boundaries, form, and global motion?

Perception of continuous boundaries, shape, and global motion can be produced by transformations in local elements separated in both space and time, a process here called spatiotemporal boundary formation (SBF). Prior research has shown that a broad class of element transformations gives rise to SBF. The present work used the transformation of local element displacement to explore the initiating conditions for SBF. Three experiments assessed SBF using a 10-alternative, forced-choice, shape identification task. Experiment 1a showed that large element displacements, but not small ones, produced high accuracy in shape identification. Experiment 1b tested the detectability of the small and large element displacements in an unrelated task, indicating that the results of Experiment 1a were not due to poor detectability for small displacements. Experiment 2 found no variation in SBF performance with changes in viewing distance. Experiment 3 provided evidence that initiating SBF depends on a ratio of element displacement to element separation. These results support an interpretation of SBF as a process geared to detection of object boundaries from spatiotemporal change. Initiating SBF requires transformations in local elements that are classified as spatiotemporal discontinuities (STDs). Small element displacements in a display of a given density do not register as STDs because they are classified as local deformations in an intact, implicit surface connecting visible elements. Complementarity is suggested between element changes which preserve continuity with their neighbors (optic flow) and those comprising spatiotemporal discontinuities (optic tearing). Classification of element transformations as optic flow or tearing may determine whether they provide information about surface form (e.g., through structure-from-motion) or about object boundaries, through SBF.

Strength of visual interpolation depends on the ratio of physically specified to total edge length.

We report four experiments in which the strength of edge interpolation in illusory figure displays was tested. In Experiment 1, we investigated the relative contributions of the lengths of luminance-specified edges and the gaps between them to perceived boundary clarity as measured by using a magnitude estimation procedure. The contributions of these variables were found to be best characterized by a ratio of the length of luminance-specified contour to the length of the entire edge (specified plus interpolated edge). Experiment 2 showed that this ratio predicts boundary clarity for a wide range of ratio values and display sizes. There was no evidence that illusory figure boundaries are clearer in displays with small gaps than they are in displays with larger gaps and equivalent ratios. In Experiment 3, using a more sensitive pairwise comparison paradigm, we again found no such effect. Implications for boundary interpolation in general, including perception of partially occluded objects, are discussed. The dependence of interpolation on the ratio of physically specified edges to total edge length has the desirable ecological consequence that unit formation will not change with variations in viewing distance.

A theory of visual interpolation in object perception.

We describe a new theory explaining the perception of partly occluded objects and illusory figures, from both static and kinematic information, in a unified framework. Three ideas guide our approach. First, perception of partly occluded objects, perception of illusory figures, and some other object perception phenomena derive from a single boundary interpolation process. These phenomena differ only in respects that are not part of the unit formation process, such as the depth placement of units formed. Second, unit formation from static and kinematic information can be treated in the same general framework. Third, spatial and spatiotemporal discontinuities in the boundaries of optically projected areas are fundamental to the unit formation process. Consistent with these ideas, we develop a detailed theory of unit formation that accounts for most cases of boundary perception in the absence of local physical specification. According to this theory, discontinuities in the first derivative of projected edges are initiating conditions for unit formation. A formal notion of relatability is defined, specifying which physically given edges leading into discontinuities can be connected to others by interpolated edges. Intuitively, relatability requires that two edges be connectable by a smooth, monotonic curve. The roots of the discontinuity and relatability notions in ecological constraints on object perception are discussed. Finally, we elaborate our approach by discussing related issues, some new phenomena, connections to other approaches, and issues for future research.

Neurological implications of aniseikonic tilts and stereoscopic completions through homogeneous visual space.

In 1965, it was first reported that BROKEN visual contours complete themselves in textured stereovision across empty or homogeneous space and that they do so strongly following directly the optics of crossed versus uncrossed disparities. The importance was then also noted of this completion effect for any neurophysiological model of stereovision. We now extend these measurements with several additional targets and to an analogous aniseikonic target, and confirm that the completion range has a maximum of about 5 degrees. There is much dependence upon target eccentricity and disparity sign, and some on size. That aniseikonic tilts may also be generated over this same range confirms the fact that global neurointegrative processes are of critical importance in all facets of stereovision, and in texture vision in general.