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Psychophysiological and subjective indicators of aversive pavlovian conditioning in generalized social phobia.

Aversive conditioning has been proposed as an important etiologic mechanism in social phobia; however, empirical evidence is scarce and has not relied on a detailed analysis of the acquisition and extinction of the conditioned emotional response. Fourteen men sustaining generalized social phobia and 19 healthy control subjects participated in differential aversive conditioning with two neutral faces as conditioned stimuli and an aversive odor as unconditioned stimulus. Subjective and peripheral physiological responses were obtained. Both groups were successfully conditioned as reflected by differential subjective (valence, arousal, subjective unconditioned stimulus expectancy) and peripheral physiological responses (skin conductance, startle response). There was no evidence for an enhanced conditionability in the social phobics; however, they showed an enhanced unconditioned stimulus expectancy, especially for the nonreinforced conditioned stimuli during acquisition, and a delayed extinction of the conditioned skin conductance response as well as a certain dissociation between subjective and physiological responses.The enhanced unconditioned stimulus expectancy during acquisition and the overall elevated subjective arousal suggest that, under threat, subjects with generalized social phobia may be more prone to associate neutral social cues and an aversive outcome. Furthermore, delayed extinction of the conditioned response seems to contribute to the etiology and maintenance of generalized social phobia.

Adult↗

Phagocytosis: elegant complexity.

Phagocytosis requires receptor-mediated recognition of particles, usually in the guise of infectious agents and apoptotic cells. Phagosomes fuse with lysosomes to generate phagolysosomes, which play a key role in enzymatic digestion of the internalized contents into component parts. Recent findings indicate that a simple paradigm of a single cognate receptor interaction that guides the phagosome to phagolysosome formation belies the complexity of combinatorial receptor recognition and diversity of phagosome function. In fact, phagosomes are comprised of hundreds of proteins that play a key role in deciphering the contents of the phagosome and in defining host response. In this review we discuss how the challenge of recognizing diverse molecular patterns is met by combinatorial interactions between phagocytic receptors. Furthermore, these combinations are dynamic and both sculpt the balance between a proinflammatory or anti-inflammatory response and direct phagosome diversity. We also indicate an important role for genetically tractable model organisms in defining key components of this evolutionarily conserved process.

Adaptation, Physiological↗

Respiratory variability and associated cardiovascular changes in adults at rest.

Breathing patterns and associated circulatory fluctuations may reflect the action of various regulatory mechanisms as well as mechanical influences of breathing on the circulation. Thus, the study of such patterns can enhance our knowledge of these mechanisms, both in normal and pathological conditions. In this review, literature is evaluated that provides insight into the breath-to-breath variation of respiration in quietly breathing adults. Also when respiration is seemingly random, deterministic patterns in the respiratory variability can often be discerned. The various methods used in the recognition of such patterns and their possible interpretation are discussed. Furthermore, the question is addressed how respiratory variability can affect the circulation and how this can be studied by analysing the time relationships of respiratory and circulatory parameters. This may add to both the understanding of normal cardiovascular regulation and to insight into cardiovascular disturbances under unstable respiratory conditions. As examples of such circumstances, some common conditions are discussed that are often, though not always, associated with pathology, viz. Cheyne-Stokes respiration, snoring and the sleep apnoea syndrome.

Adult↗

The Na-K-Cl cotransport protein of shark rectal gland. I. Development of monoclonal antibodies, immunoaffinity purification, and partial biochemical characterization.

The Na-K-Cl cotransporter mediates the coupled transport of Na, K, and Cl across the plasma membrane of many animal cell membranes. It is inhibited by loop diuretics such as furosemide, bumetanide, and benzmetanide. We have developed a panel of monoclonal antibodies directed against the 195-kDa shark rectal gland Na-K-Cl cotransport protein. Four representative antibodies (J3, J4, J7, and J25), each of which recognizes a discrete structural domain, were selected for detailed characterization. When a radiolabeled loop diuretic is bound to the cotransporter prior to solubilization, each antibody immunoprecipitates the same diuretic-protein complex. Of the four antibodies, J4 favors the native protein over the denatured one and does not bind well to proteolytic fragments; in contrast, J7 recognizes the cotransporter only after it has been solubilized. J3, J7, and J25 each recognize a unique ensemble of proteolytic fragments of the 195-kDa protein; analysis of the patterns of recognition has yielded a tentative assignment of the approximate location of the epitopes within the peptide. When the cotransport protein is treated with N-glycanase to remove N-linked oligosaccharides, its apparent mass decreases to approximately 135 kDa. The deglycosylated form is recognized by each of the antibodies except J25; this suggests that the J25 epitope is within the oligosaccharide component or in a peptide domain whose folding is disturbed by carbohydrate removal. An immunoaffinity matrix constructed with the J4 antibody permits single-step purification of the 195-kDa protein; other proteins copurify with the large glycoprotein, but none of these appear to be subunits of a stoichiometric complex. The amino acid sequence of four fragments of the 195-kDa cotransport protein is reported. Immunofluorescence and immunoelectron microscopy demonstrates, in agreement with physiological evidence, that the 195-kDa protein is distributed along the basolateral membrane and excluded from the apical membrane of the rectal gland secretory cell.

Amino Acid Sequence↗

A physiological model for motion-stereo integration and a unified explanation of Pulfrich-like phenomena.

Many psychophysical and physiological experiments indicate that visual motion analysis and stereoscopic depth perception are processed together in the brain. However, little computational effort has been devoted to combining these two visual modalities into a common framework based on physiological mechanisms. We present such an integrated model in this paper. We have previously developed a physiologically realistic model for binocular disparity computation (Qian, 1994). Here we demonstrate that under some general and physiological assumptions, our stereo vision model can be combined naturally with motion energy models to achieve motion-stereo integration. The integrated model may be used to explain a wide range of experimental observations regarding motion-stereo interaction. As an example, we show that the model can provide a unified account of the classical Pulfrich effect (Morgan & Thompson, 1975) and the generalized Pulfrich phenomena to dynamic noise patterns (Tyler, 1974; Falk, 1980) and stroboscopic stimuli (Burr & Ross, 1979).

Depth Perception↗

Reproducibility of fMRI: effect of the use of contextual information.

We studied the effect of use of contextual information on the reproducibility of the results in analysis of fMRI data. We used data from a repeated simple motor fMRI experiment. In the first approach, statistical parametric maps were computed from a spatially unsmoothed data and thresholded using a Bonferroni corrected threshold. In the second approach, the maps were computed from a spatially unsmoothed data but were segmented into nonactive and active regions using a spatial contextual clustering method. In the third approach, the statistical parametric maps were computed from spatially smoothed data and thresholded, using, optionally, a spatial extent threshold. The variation in the classification was largest in the Bonferroni thresholded statistical parametric maps. There were no significant differences in variation between statistical parametric maps generated with all the other methods. In addition to reproducibility, the detection rates of weak simulated activations in the presence of measured scanner and physiological noise were investigated. Contextual clustering method was the most sensitive method, while the least sensitive method was the Bonferroni corrected thresholding. Using simulated data, we demonstrated that the contextual clustering method preserves the shapes of activation regions better than the method using spatial smoothing of the data.

Adult↗

Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer's disease.

Studies were performed on two groups of animals (three monkeys in each). Monkeys of group I received unilateral intracerebroventricular injections of the neurotoxin p75-saporin (the ribosomal toxin saporin bound to monoclonal antibody to the p75NTR receptor), which elicits irreversible degradation of cholinergic neurons in the basal nuclei of Meynert, along with the enzyme dopamine-beta-hydroxylase (DBH-saporin), which impairs the functioning of noradrenergic neurons in the locus ceruleus. Monkeys of group II received injections of sterile physiological saline (0.9% NaCI). Monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids, geometric figures with different colors, different spatial relationships between objects) and perform spatial selection. The characteristics of working memory were identified in delayed differentiation tasks in monkeys of both groups before and after injections. These studies provided the first evidence that the development of Alzheimer's disease in rhesus macaques is characterized by a deficiency of working memory, this being based on impairment of two components of these processes. Impairment of the first in monkeys of group I was minifest in delayed visual differentiation as a significant decrease in correct responses. The extent of decreases depended on the duration of the delay and the type of visual information. Impairment of the second component, associated with decision-taking processes, was characterized by an increase in refusals to take decisions and was independent of the duration of delays and the type of visual information. Monkeys given injections of physiological saline showed no significant differences in these characteristics. The features of impairments in these memory components resulting from the development of Alzheimer's disease demonstrate that the structural-functional organization of cholinergic and noradrenergic mechanisms responsible for sensory processing differ from those involved in decision-taking.

Alzheimer Disease↗

Regulation of lymphocyte traffic by adhesion molecules.

Lymphocytes are antigen specific cells whose effector function is acquired through complex differentiation pathways. This implies, firstly, antigen encounter and recognition at specific sites, and, subsequently, the transition from a naive to a memory/effector phenotype. Clonotypically expanded cells must then be capable of recirculating to the tissue where their effector function is needed. To this aim, defined receptor-counter receptor pairs are expressed on lymphocytes versus endothelial cells. Extravasation is therefore a key-process in this scenario. Indeed, different lymphocyte subsets display distinct recirculation patterns and capability to migrate into lymphoid and non-lymphoid tissues. As a general rule, naive lymphocytes preferentially migrate into secondary lymphoid organs, where all the requirements for effective antigen presentation and differentiation are available; in contrast, memory/effector lymphocytes preferentially migrate to peripheral tissues, such as skin and mucosa. We review here the molecular events that regulate leukocyte extravasation and the specific migration properties acquired by both naive and memory/effector lymphocytes under physiological and pathological conditions.

Animals↗

Stereopsis and binocularity in the squirrel monkey.

The squirrel monkey lacks anatomically demonstrable ocular dominance columns, and physiologically it has an ocular dominance distribution in V1 that is very different from that of macaques, with far fewer cells that strongly favor one eye over the other. We tested an alert squirrel monkey for physiological responses to stereoscopic stimuli by measuring evoked potentials in response to cytclopean patterns generated in dynamic random-dot stereograms. The monkey showed evoked responses both to changes in disparity and to shifts between correlation and uncorrelation between the two eyes. This result strongly suggests that the squirrel monkey can detect stereoscopic depth, which in turn casts some doubt on the assumption that ocular dominance columns bear an important relation to stereopsis.

Animals↗

Purification, characterization, and substrate and inhibitor structure-activity studies of rat liver FAD-AMP lyase (cyclizing): preference for FAD and specificity for splitting ribonucleoside diphosphate-X into ribonucleotide and a five-atom cyclic phosphodiester of X, either a monocyclic compound or a cis-bicyclic phosphodiester-pyranose fusion.

An enzyme with FAD-AMP lyase (cyclizing) activity, splitting FAD to AMP and riboflavin 4',5'-phosphate (cFMN), was recently identified [Fraiz, F., et al. (1998) Biochem. J. 330, 881-888]. Now, it has been purified to apparent homogeneity from a rat liver supernatant, by a procedure that includes affinity for ADP-agarose (adsorption required the activating cation Mn2+ and desorption required its removal), to a final activity of 2.2 units/mg after a 240-fold purification with a 15% yield. By SDS-PAGE, only one protein band was observed (Mr = 59 000). The correspondence between protein and enzyme activity was demonstrated by renaturation after SDS-PAGE, by gradient ultracentrifugation followed by analytical SDS-PAGE, and by native PAGE with visualization of enzyme activity by fluorescence. A native Mr of 100 000 (ultracentrifugation) or 140 000 (gel filtration) indicated that FAD-AMP lyase could be a dimer. The enzyme required millimolar concentrations of Mn2+ or Co2+, exhibited different optimum pH values with these cations (pH 8.5 or 7.3, respectively), and was strongly inhibited by ADP or ATP, but not by dADP, dATP, or the reaction products AMP and cFMN. A specificity study was conducted with 35 compounds related to FAD, mostly nucleoside diphosphate-X (NDP-X) derivatives. Besides FAD, the enzyme split 11 of these compounds with the pattern NDP-X --> NMP + P=X. Structure-activity correlations of substrates, nonsubstrates, and inhibitors, and the comparison of the enzymic reactivities of NDP-X compounds with their susceptibilities to metal-dependent chemical degradation, pinpointed the following specificity pattern. FAD-AMP lyase splits ribonucleoside diphosphate-X compounds in which X is an acyclic or cyclic monosaccharide or derivative bearing an X-OH group that is able to attack internally the proximal phosphorus with the geometry necessary to form a P=X product, either a five-atom monocyclic phosphodiester or a cis-bicyclic phosphodiester-pyranose fusion. For instance, NDP-glucose and GDP-alpha-L-fucose were substrates, but dTDP-glucose, NDP-mannose, and GDP-beta-L-fucose were not. Judging from kcat/Km ratios, we found the best substrate to be FAD, followed closely by ADP-glucose (kcat/Km only 2-fold lower, but not a physiological compound in mammals), whereas other substrates exhibited 50-500-fold lower kcat/Km values. However, there was no evidence for specific flavin recognition. Instead, what seems to be recognized is the NDP moiety of NDP-X, with a strong preference for ADP-X. Splitting would then depend on the presence of an adequate X-OH group. The possibility that, besides FAD, there could be in mammals other ADP-X substrates of FAD-AMP lyase is discussed, with emphasis placed on some ADP-ribose derivatives.

Adenosine Diphosphate↗

State-space analysis of joint angle kinematics in normal treadmill walking.

By restricting analysis to single averaged strides considered to be characteristic for the individual under investigation, current methods in gait analysis do not exploit the full dynamics of continuous locomotion. Therefore, a novel approach is presented that is based on long-term measurements of kinematic data during treadmill walking. The method consists of reconstructing the system attractor in the embedding space and then analyzing its geometric structure. Estimating the dimension of movement trajectories correlates well with the notion of controlling multiple degrees of freedom during performance of complex movement tasks such as walking. The influence of walking speed on the complexity of physiologic walking was investigated in 10 healthy subjects walking on a treadmill at seven fixed speeds. The results suggest that human walking becomes more complex at slower speeds. This may be associated with results from EMG studies demonstrating more irregular EMG patterns at very slow walking speeds. This study emphasizes that tools from non-linear dynamics are well suited for providing more insight into motor control in humans.

Algorithms↗

Dynamic optical imaging.

The main direction in modern imaging is increasing the spatial resolution and selectivity for pathology pattern recognition at the microscale. Dynamic optical imaging (DOl) has enormous potential in the selectivity of description of living tissue state at cellular and subcellular levels. However, multiple light scattering creates considerable difficulties in revealing the tissue microstructure in its depth. On the other hand, along with changes in the microstructure, pathology should also manifest itself in the integral macroscopic pattern of the tissue. Actually, living tissue, as a distributed active media with well-developed reception and self-regulation, is characterized by a high spatial synergy. In such a media, even morphologically small pathology could disturb tissue functioning in a rather extended area. As a result, after some definite time, a diffuse "field" of the pathological phenomena appears even in the morphological image. Since optical contrast is determined by tissue components (such as blood), which actively participate in physiological functioning, the distributed functional pattern of the tissue is reflected in optical images in the form of spatiotemporal modulation of the optical density. This observation opens up the possibility of investigating the diffuse pattern of the pathology at the functional stage of its development, even before the actual appearance of noticeable morphological changes .

Journal Article↗

The role in cell binding of a beta-bend within the triple helical region in collagen alpha 1 (I) chain: structural and biological evidence for conformational tautomerism on fiber surface.

In its physiological solid state, type I collagen serves as a host for many types of cells. Only the molecules on fiber surface are available for interaction. In this interfacial environment, the conformation of a cell binding domain can be expected to fluctuate between the collagen fold and a distinctive non-collagen molecular marker for recognition and allosteric binding. If the cell binding domain can be localized in contiguous residues within the exposed half of a turn of the triple helix (approximately 15 residues), the need for extensive structural modification and unraveling of the triple helix is avoided. We examined the conformational preferences and biological activity of a synthetic 15-residue peptide (P-15), analogous to the sequence 766GTPGPQGIAGQRGVV780 in the alpha 1 (I) chain. Theoretical studies showed a high potential for a stable beta-bend for the central GIAG sequence. The flanking sequences showed facile transition to extended conformations. Circular dichroism of the synthetic peptide in anisotropic solvents confirmed the presence of beta-strand and beta-bend structures. P-15 inhibited fibroblast binding to collagen in a concentration dependent manner, with near maximal inhibition occurring at a concentration of 7.2 x 10(-6) M. The temporal pattern of cell attachment was altered markedly in the presence of P-15. No inhibition was seen with a peptide P-15(AI), an analogue of P-15 with the central IA residues reversed to AI or with collagen-related peptides (Pro-Pro-Gly)10, (Pro-Hyp-Gly)10, and polyproline, and with several unrelated peptides. Our studies suggest a molecular mechanism for cell binding to collagen fibers based on a conformational transition in collagen molecules on the fiber surface. Since the energy barrier between the collagen fold and beta-strand conformation is low, a local conformational change may be possible in molecules on the fiber surface because of their location in an anisotropic environment. Our observations also suggest that the sequence incorporated in P-15 may be a specific ligand for cells. Unlike other reported cell binding peptides, the residues involved in this interaction are non-polar.

Allosteric Regulation↗

Pattern generator system as a versatile visual stimulator.

We have designed and implemented a Motorola 68000 microprocessor-based pattern generator system (PGS) that uses a color video display terminal (VDT) to provide light stimuli to the intact vertebrate retina. This communication is intended for those who are considering acquisition of a commercial retinal stimulator or those who are custom designing their own pattern generator system. The discussion surveys the features to be included as well as design factors which must be considered in such a device. The memory organization of the PGS allows as stimuli multiple, complex patterns consisting of one or more disks, annuli, bars or gratings to flash or modulate in intensity according to a pre-defined function. In addition, patterns can move smoothly in any direction at selectable, uniform speeds without the re-drawing of video memory. The presence of a 12-bit A/D converter internal to the PGS allows a dynamic change in stimulus position, speed or pattern based upon physiological feedback. A physically realistic image size (0.9 cm2) and resolution (20 mu/pixel) in the retinal plane are achieved with simple intervening optics. The video field rate of 60 Hz is above the flicker fusion frequency for most vertebrate animals and does not induce artifacts in cellular responses. The PGS operating in a PC-based environment meets the requirements of a versatile optical stimulator for investigations in retinal electrophysiology.

Ambystoma↗

Mechanisms for spatial integration in visual detection: a model based on lateral interactions.

Recent studies of visual detection show a configuration dependent weak improvement of thresholds with the number of targets, which corresponds to a fourth-root power law. We find this result to be inconsistent with probability summation models, and account for it by a model of 'physiological' integration that is based on excitatory lateral interactions in the visual cortex. The model explains several phenomena which are confirmed by the experimental data, such as the absence of spatial and temporal uncertainty effects, temporal summation curves, and facilitation by a pedestal in 2AFC tasks. The summation exponents are dependent on the strength of the lateral interactions, and on the distance and orientation relationship between the elements.

Computer Simulation↗

Circulatory effects of whole blood, packed red cells, albumin, starch, and crystalloids in resuscitation of shock and acute critical illness.

Circulatory deficiencies and the effectiveness of transfusion and fluid therapy may be evaluated by invasive and noninvasive monitoring after high risk surgery, hemorrhage, trauma, and sepsis in the ED, OR, and ICU. Earlier recognition and therapy of circulatory problems in emergency and critically ill patients to achieve optimal goals empirically defined by the survivors' patterns is recommended to improve outcome. WB, Prbc, and colloids markedly and statistically significantly improved pressure, flow, and tissue perfusion and best achieved these goals. Noninvasive monitoring may be used in the ED and OR shortly after admission to identify circulatory deficiencies and to titrate therapy, or they may be used initially as the front-end of subsequent invasive monitoring.

Blood Transfusion↗

Validation of automatically measured monophasic action potential recordings.

This study devised an automatic monophasic action potential (MAP) measurement program, and compared the computer-measured MAP durations with those measured manually by two independent observers in order to facilitate the analysis of MAP data obtained during a clinical electrophysiology study. The results were compared at various cycle lengths and during pharmacologic or physiologic interventions. This program identified the onset, plateau, and baseline accurately using the MAP data. The automatically measured MAP durations at the 90% repolarization level (MAPd) strongly correlated with those measured manually (r = 0.99). The MAPd shortened in parallel as the pacing cycle length was progressively shortened from 800 to 600, 400 and 300 ms.

Action Potentials↗

Dynamic causal modelling of evoked responses in EEG/MEG with lead field parameterization.

Dynamical causal modeling (DCM) of evoked responses is a new approach to making inferences about connectivity changes in hierarchical networks measured with electro- and magnetoencephalography (EEG and MEG). In a previous paper, we illustrated this concept using a lead field that was specified with infinite prior precision. With this prior, the spatial expression of each source area, in the sensors, is fixed. In this paper, we show that using lead field parameters with finite precision enables the data to inform the network's spatial configuration and its expression at the sensors. This means that lead field and coupling parameters can be estimated simultaneously. Alternatively, one can also view DCM for evoked responses as a source reconstruction approach with temporal, physiologically informed constraints. We will illustrate this idea using, for each area, a 4-shell equivalent current dipole (ECD) model with three location and three orientation parameters. Using synthetic and real data, we show that this approach furnishes accurate and robust conditional estimates of coupling among sources and their orientations.

Auditory Perception↗