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Tissue transglutaminase-mediated formation and cleavage of histamine-gliadin complexes: biological effects and implications for celiac disease.

Celiac disease is an HLA-DQ2-associated disorder characterized by an intestinal T cell response. The disease-relevant T cells secrete IFN-gamma upon recognition of gluten peptides that have been deamidated in vivo by the enzyme tissue transglutaminase (transglutaminase 2 (TG2)). The celiac intestinal mucosa contains elevated numbers of mast cells, and increased histamine secretion has been reported in celiac patients. This appears paradoxical because histamine typically biases T cell responses in the direction of Th2 instead of the Th1 pattern seen in the celiac lesions. We report that histamine is an excellent substrate for TG2, and it can be efficiently conjugated to gluten peptides through TG2-mediated transamidation. Histamine-peptide conjugates do not exert agonistic effects on histamine receptors, and scavenging of biologically active histamine by gluten peptide conjugation can have physiological implications and may contribute to the mucosal IFN-gamma response in active disease. Interestingly, TG2 is able to hydrolyze the peptide-histamine conjugates when the concentrations of substrates are lowered, thereby releasing deamidated gluten peptides that are stimulatory to T cells.

Amino Acid Sequence↗

Cortical oscillations and temporal interactions in a computer simulation of piriform cortex.

1. A large-scale computer model of the piriform cortex was constructed on the basis of the known anatomic and physiological organization of this region. 2. The oscillatory field potential and electroencephalographic (EEG) activity generated by the model was compared with actual physiological results. The model was able to produce patterns of activity similar to those recorded physiologically in response to both weak and strong electrical shocks to the afferent input. The model also generated activity patterns similar to EEGs recorded in behaving animals. 3. In addition to replicating known physiological responses, it has been possible to use the simulations to explore the interactions of network components that might underlie these responses. This analysis suggests that the physiological properties of the cortex are dependent on the complex interaction of both network and cellular properties. In particular, we have found that the relationship between conduction velocities in intrinsic cortical fiber systems and the time constants of excitatory and inhibitory effects are critical for replicating physiological results. 4. Analysis of the model also suggests a correspondence between the 40-Hz oscillatory patterns of activity induced by low levels of odor-like stimulation and oscillatory patterns seen in lightly anesthetized cortex in response to weak electrical shocks to the afferent fiber system. 5. The specific relationships we have found between the different components of the model also support several speculations on their functional significance. The simulations suggest that during each 40-Hz cycle of EEG activity there is a convergence in rostral cortex of afferent information from the olfactory bulb and recurrent association fiber information from caudal cortex. This convergence could underlie an iterative process central to the recognition of complex olfactory stimuli.

Animals↗

An invertebrate TNF functional analogue activates macrophages via lectin-saccharide interaction with ion channels.

The invertebrate pattern-recognition protein named coelomic cytolytic factor (CCF) and the mammalian cytokine tumor necrosis factor (TNF) share functional analogies that are based on a similar saccharide recognition specificity. In particular, CCF and TNF have been shown to interact with ion channels on the surface of vertebrate cells via N,N'-diacetylchitobiose lectin-like activity. In the present study, we show that CCF-induced membrane depolarization results in the release of TNF, IL-6 and nitric oxide (NO) by macrophages via nuclear factor-kappaB signaling. Interestingly, our data suggest that TNF contributes, through lectin-saccharide interaction, to the secretion of IL-6 and NO induced by CCF. This experimental non-physiological setting based on the interaction of an invertebrate defense lectin with vertebrate cells involved in the innate immune response may have highlighted an evolutionarily ancient mechanism of macrophage activation in vertebrates.

Animals↗

A higher concentration of an antigen within the nucleolus may prevent its proper recognition by specific antibodies.

Transient transfection of HeLa cells with a plasmid encoding the full-length human fibrillarin fused to a green fluorescent protein (GFP) resulted in two major patterns of intensity of the nucleolar labeling for the chimeric protein: weak and strong. Both patterns were maintained in fibrillarin-GFP expressing cells after fixation with formaldehyde. When the fixed fibrillarin-GFP expressing cells were used for immunolabeling with antibodies to fibrillarin, only the nucleoli with a weak GFP-signal became strongly labeled, whereas those with the heavy signals were only lightly stained, if at all. A similar pattern was observed if the cells were immunolabeled with antibodies to GFP. These observations suggest that an increase in antigen accumulation within the nucleolus, which could take place under various physiological or experimental conditions, could prevent the antigen from being recognized by specific antibodies. These results have implications regarding contradictory data on localization of various nucleolar antigens obtained by conventional immunocytochemistry.

Antibodies↗

Nuclear Fos domains in transcriptionally activated supraoptic nucleus neurons.

This study has analysed by light and electron microscopy immunolocalization the nuclear pattern of distribution of Fos-related proteins in supraotic neurons. Two experimental models of transcriptional activation have been used: sustained, global transcriptional activation, at relatively near physiological conditions, by six days of chronic intermittent salt loading; and superinduction of c-fos gene by this salt loading regime plus cycloheximide treatment for 4 h. In the first condition, the ultrastructural analysis showed a distribution of Fos-like immunoreactivity on the reticular network of dispersed chromatin that extends between the nucleolar surface and the nuclear envelope, whereas the Fos-negative adjacent interchromatin spaces appeared rich in interchromatin granules by using a cytochemical staining for ribonucleoproteins. The nucleolus associated heterochromatin, fibrillar centers of the nucleolus and coiled bodies were free of immunoreactivity. This immunoelectron pattern seems to indicate that active genes containing activator protein-1 and cyclic AMP response element recognition sites are extensively distributed in euchromatin regions and suggests that the Fos-positive nuclear domains correspond to the actively transcribing chromatin regions, at least in supraoptic neurons. It also suggests that these Fos-positive transcription domains are complementary to adjacent ribonucleoprotein-rich interchromatin spaces which are involved in the processing and splicing of pre-messenger RNA. Moreover, the absence of immunoreactivity on the fibrillar centers, the sites of pre-ribosomal RNA synthesis, suggests that the Fos protein complexes are not involved in regulating the expression of ribosomal RNA genes. Following superinduction of c-fos gene by osmotic stimulation plus cycloheximide treatment, a conspicuous Fos-like immunoreactivity was detected in dispersed chromatin regions, whereas the heterochromatin masses, nucleoli and coiled bodies showed no immunoreaction. Moreover, this treatment induced the formation of nuclear "dense bodies" of a fibrillar nature which were free of immunolabelling. Since Fos proteins are known to be short-lived, the expression of these nuclear constituents, under conditions of protein synthesis inhibition induced by the cycloheximide, suggests the stabilization of chromatin-bound Fos complexes or, alternatively, a preferential synthesis of Fos proteins.

Animals↗

Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2.

Pulmonary surfactant protein A (SP-A) plays an important role in modulation of the innate immune system of the lung. Peptidoglycan (PGN), a cell wall component of Gram-positive bacteria, is known to elicit excessive proinflammatory cytokine production from immune cells. In this study we investigated whether SP-A interacts with PGN and alters PGN-elicited cellular responses. Binding studies demonstrate that PGN is not a ligand for SP-A. However, SP-A significantly reduced PGN-elicited tumor necrosis factor alpha (TNF-alpha) secretion by U937 cells and rat alveolar macrophages. The inhibitory effect on TNF-alpha secretion was dependent upon SP-A concentrations in physiological range. Coincubation of SP-A and PGN with human embryonic kidney 293 cells that had been transiently transfected with the cDNA of Toll-like receptor 2 (TLR2), a cell signaling receptor for PGN, significantly attenuated PGN-induced nuclear factor-kappaB activity. SP-A directly bound to a soluble form of the recombinant extracellular TLR2 domain (sTLR2). Coincubation of sTLR2 with SP-A significantly reduced the binding of sTLR2 to PGN. These results indicate that the direct interaction of SP-A with TLR2 alters PGN-induced cell signaling. We propose that SP-A modulates inflammatory responses against the bacterial components by interactions with pattern-recognition receptors.

Animals↗

Time-domain signal divergence and discrimination without receptor modification in sympatric morphs of electric fishes.

Polymorphism in an animal communication channel provides a framework for studying proximate rules of signal design as well as ultimate mechanisms of signal diversification. Reproductively isolated mormyrid fishes from Gabon's Brienomyrus species flock emit distinctive electric organ discharges (EODs) thought to function in species and sex recognition. Species boundaries and EODs appear congruent in these fishes, with the notable exception of three morphs designated types I, II and III. Within the species flock, these morphs compose a monophyletic group that has recently been called the magnostipes complex. Co-occurring morphs of this complex express distinctive EODs, yet they appear genetically indistinguishable at several nuclear loci. In this study, we investigated EOD discrimination by these morphs using both behavioral and physiological experiments. During the breeding season, wild-caught type I and type II males showed evidence that they can discriminate their own morph's EOD waveform from that of a sympatric and genetically distinct reference species. However, we found that type I and type II males exhibited an asymmetry in unconditioned responses to paired playback of EODs recorded from type I versus type II females. Males of the type II morph responded preferentially to EODs of type II females, whereas type I males did not appear to discriminate homotypic and heterotypic EODs in our experimental paradigm. Part of this behavioral asymmetry may have resulted from a previously undetected difference in adult size, which may have enhanced apparent discrimination by the smaller morph (type II) due to a relatively higher risk of injury from the larger morph (type I). Knollenorgan receptors, which mediate electrical communication in mormyrids, showed similar spectral tuning in type I and type II. These electroreceptors coded temporal features of any single magnostipes-complex EOD with similar patterns of time-locked spikes in both morphs. By contrast, Knollenorgans exhibited distinctive responses to different EOD waveforms. These results suggest that discrete EOD variation in this rapidly diversifying complex is functional in terms of morph-specific advertisement and recognition. Time-domain signal divergence has outpaced frequency-domain divergence between sympatric morphs, requiring little to no change in receptor response properties. We discuss our findings in light of a model for EOD time-coding by the Knollenorgan pathway, as well as evolutionary hypotheses concerning sympatric signal diversification in the magnostipes complex.

Animal Communication↗

[Compensation for disruptions of visual function in the dog after partial exclusion of the neocortex].

The recovery of visual disturbances provoked by partial neocortical deafferentation was studied in dogs with two sets of visual patterns: figures and differently oriented lines. The disturbances were more prominent, when the dogs had to solve the most complex visual tasks (6 stimuli showed to a dog simultaneously). There was a distinct recovery of figure recognition in the process of compensation, i. e. in 4--6 months after the neocortical deafferentation. On the contrary, recognition of oriented lines did not improve. Probably the differences between the two sorts of recognition mentioned above may be explained by various changes of their mechanisms' properties in the process of compensation.

Adaptation, Physiological↗

Tolerance to unfamiliar conspecifics varies with social organization in female African mole-rats.

Intolerance to familiar conspecifics characterises solitary mole-rats and distinguishes them from social ones. However, no study has compared the patterns of tolerance to unfamiliar conspecifics. Theoretically, both solitary and social species should react similarly and show intolerance to unfamiliar same-sex conspecifics, unless the evolution of grouping has favoured higher tolerance to conspecifics among the social species. Our study compares tolerance to unfamiliar conspecifics in four African mole-rat species exhibiting varying degrees of sociality. Dyadic encounters between female unfamiliar conspecifics were performed in a neutral arena, and the assessment of social tolerance was based on both behavioural observations of amicable contact behaviour as opposed to aggression and avoidance behaviour and the assessment of a stress response to the encounter measured as an increase in plasma cortisol concentrations. Our results show that the two highly social species and the solitary one presented similar high levels of agonistic behaviours during encounters with unfamiliar conspecifics. Nevertheless, all three social species displayed social tolerance and did not show a stress arousal during encounters with unfamiliar conspecifics, a pattern that contrasted significantly with that evidenced in the solitary species. The results suggest that physiological and behavioural characteristics allow a higher tolerance to unfamiliar conspecifics in the social as opposed to the solitary mole-rat, and the adaptive value of these characteristics are discussed. Finally, we discuss why constraints on social tolerance may be an important limiting factor to take into account in theories concerning the evolution of grouping.

Agonistic Behavior↗

The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects.

While behavioral research shows working memory impairments in schizophrenics and their relatives, functional neuroimaging studies of patients and healthy controls show conflicting findings of hypo- and hyperactivation, possibly indicating different relationships between physiological activity and performance. In a between-subjects regression analysis of fMRI activation and performance, low performance was associated with relatively lower activation in patients than controls, while higher performance was associated with higher activation in patients than controls in DLPFC and parietal cortex, but not occipital cortex, with unaffected twins of schizophrenics being intermediate between the groups. Accordingly, this supports the idea that both hyper and hypoactivation may be possible along a continuum of behavioral performance in a way consistent with a neural inefficiency model. Further, this study offers preliminary evidence that the relationship between behavior and physiology in schizophrenia may be heritable.

Aged↗

Correlation-based development of ocularly matched orientation and ocular dominance maps: determination of required input activities.

We extend previous models for separate development of ocular dominance and orientation selectivity in cortical layer 4 by exploring conditions permitting combined organization of both properties. These conditions are expressed in terms of functions describing the degree of correlation in the firing of two inputs from the lateral geniculate nucleus (LGN), as a function of their retinotopic separation and their "type" (ON center or OFF center and left eye or right eye). The development of ocular dominance requires that the correlations of an input with other inputs of the same eye be stronger than or equal to its correlations with inputs of the opposite eye and strictly stronger at small retinotopic separations. This must be true after summing correlations with inputs of both center types. The development of orientation-selective simple cells requires that (1) an input's correlations with other inputs of the same center type be stronger than its correlations with inputs of the opposite center type at small retinotopic separation; and (2) this relationship reverse at larger retinotopic separations within an arbor radius (the radius over which LGN cells can project to a common cortical point). This must be true after summing correlations with inputs serving both eyes. For orientations to become matched in the two eyes, correlated activity within the receptive fields must be maximized by specific between-eye alignments of ON and OFF subregions. Thus the correlations between the eyes must differ depending on center type, and this difference must vary with retinotopic separation within an arbor radius. These principles are satisfied by a wide class of correlation functions. Combined development of ocularly matched orientation maps and ocular dominance maps can be achieved either simultaneously or sequentially. In the latter case, the model can produce a correlation between the locations of orientation map singularities and local ocular dominance peaks similar to that observed physiologically. The model's main prediction is that the above correlations should exist among inputs to cortical layer 4 simple cells before vision. In addition, mature simple cells are predicted to have certain relationships between the locations of the ON and OFF subregions of the left and right eyes' receptive fields.

Animals↗

Recognition and treatment of response fluctuations in Parkinson's disease: review article.

Patients with Parkinson's disease (PD) by definition benefit from treatment with the dopamine precursor levodopa. However, after 5 years of therapy 50% of patients experience motor response complications (MRC's): the benefit from each dose becomes shorter (wearing-off fluctuations), more unpredictable (on-off fluctuations) and associated with involuntary movements (dyskinesias). In addition these patients suffer from fluctuations in motor function that are inherent to the disease itself. Recent findings have lead to the suggestion that hyperfunction of NMDA receptors on striatal efferent neurons, as a consequence of chronic non-physiologic dopaminergic stimulation, contributes to the pathogenesis of MRC's. In PD patients blockade of striatal glutamate receptors with several NMDA-antagonists improve MRC's. With progression of PD the severity and complexity of MRC's magnify, obfuscating their pattern and their relation to the medication cycle. Only through detailed history taking and patient education will the physician be able to clarify the situation and establish a rational, targeted approach to the treatment of patients with advanced PD complicated by motor fluctuations and dyskinesias.

Antiparkinson Agents↗

Computerised measures of electro-oculographic activity during sleep.

Since electro-oculographic (EOG) activity during human sleep appears to be of medical diagnostic and prognostic value, the vast amount of EOG data representative of even a single night's sleep warrants the development of automated pattern recognition and information extraction techniques. Such a technique for the analysis of sleep EOG rapid eye movement (REM) is presented in which the time of occurrence, area, height, duration and binocular symphrony for each REM are measured. This automated technique for sleep EOG analysis is currently used in the investigation of periodicities and values of REM parameters for normal subjects and in the differential diagnosis of affective disorders.

Affective Symptoms↗

Pathogen recognition and innate immunity.

Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

Adaptation, Physiological↗

Predictive microbiology: towards the interface and beyond.

This review considers the concept and history of predictive microbiology and explores aspects of the modelling process including kinetic and probability modelling approaches. The "journey" traces the route from reproducible responses observed under close to optimal conditions for growth, through recognition and description of the increased variability in responses as conditions become progressively less favourable for growth, to defining combinations of factors at which growth ceases (the growth/no growth interface). Death kinetics patterns are presented which form a basis on which to begin the development of nonthermal death models. This will require incorporation of phenotypic, adaptive responses and may be influenced by factors such as the sequence in which environmental constraints are applied. A recurrent theme is that probability (stochastic) approaches are required to complement or replace kinetic models as the growth/no growth interface is approached and microorganisms adopt a survival rather than growth mode. Attention is also drawn to the interfaces of predictive microbiology with microbial physiology, information technology and food safety initiatives such as HACCP and risk assessment.

Bacteria↗

Activation peaking in intoxicated and detoxified alcoholics during visuospatial learning.

Physiologic activation response patterning, termed activation peaking, and visuospatial learning performance were examined to understand the effects of chronic alcohol use on complex information processing. A total of 18 alcoholic male inpatients in an alcoholism treatment unit served as participants. Nine persons were seen while intoxicated (mean blood alcohol level [BAL] = 18.0mg/dl) at time of admission to the unit. The second group of nine persons were seen detoxified after 4 weeks in the treatment unit (BAL = 0 mg/dl). Skin conductance and heart rate were measured before and during learning. Learning consisted of a paired-associate paradigm requiring participants to learn the distinct spatial positions of six randomly presented "nonsense" shapes. The visuospatial learning of the intoxicated alcoholics was superior to that of the detoxified alcoholics. The physiological patterning of intoxicated alcoholics clearly and correctly tracked their learning performance, while the detoxified alcoholics displayed no clear pattern. The results indicated that the detoxified alcoholic may suffer a disruption in attentional mechanisms related to visuospatial information processing, providing support for theory that alcohol ingestion may serve to balance information processing in the alcoholic.

Adult↗

The contributions of ON- and OFF-pathways to contrast sensitivity and spatial resolution in goldfish.

DL-2-amino-4-phosphonobutyric acid (APB) reduces the sensitivity of ON- and OFF-responses in goldfish retina, although the ON-responses are reduced significantly more than the OFF-responses. This paper describes the effects of APB on behavioral sensitivity of goldfish to spatial sinusoidal gratings. Fish were classically conditioned to suppress respiration upon presentation of gratings drifting at 1 Hz; contrast thresholds were measured by an observer-based two-alternative forced-choice procedure. Thresholds were repeated following intraocular injections of APB or physiological saline. Saline had no effect, but APB dramatically reduced contrast sensitivity and shifted contrast sensitivity functions to lower spatial frequencies. The results suggest that both ON- and OFF-pathways are necessary for normal spatial vision and that the effects of APB are consistent with the disruption of both ON- and OFF-pathways.

Aminobutyrates↗

Additive genetic variation of transcriptional regulation: metallothionein expression in the soil insect Orchesella cincta.

Field-selected metal tolerance in Orchesella cincta is correlated with overexpression of the single copy cadmium (Cd) inducible metallothionein (mt). Previously, we have demonstrated large phenotypic variation in mt gene expression, and a higher frequency of high-expression phenotypes in a tolerant population. Here, we describe midparent-offspring regression analysis of mt gene expression in a laboratory culture originating from a noncontaminated natural population. Families were either not exposed (n=47) or exposed to 0.5 micromol Cd per gram dry food (n=46). Mean mt gene expressions normalized to 28S rRNA and beta-actin RNA were generated using real-time RT-PCR applied to parents and offspring RNA and subjected to regression analysis. A significant heritability (h2) for mt gene expression was estimated between 0.36 (beta-actin normalized) and 0.46 (28S normalized) in Cd exposed families. Nontreated families did not yield a significant h2 value. Restriction Fragment Length Polymorphism analysis of the metallothionein promoter sequence revealed eight promoter alleles that show structural variation. Three alleles show increased frequencies in families with high mt expression. Another gene, croquemort (isolated from a differential screening for 1 micromole Cd treatment) showed no h2 of gene expression in response to 0.5 micromol Cd. This gene codes for a receptor-protein involved in recognition of apoptotic cells and may participate in the general stress response. The present data suggest that evolution of metal tolerance in O. cincta can occur in the field by selection for high mt expression due to structural changes in mt cis-regulation.

Adaptation, Physiological↗