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Results for “connectivity mapping”

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At least 1,117 records · Page 62Linked to original sources
PubMed2000

Unique epitopes in RNA helicase II/Gu protein recognized by serum from a watermelon stomach patient.

RNA helicase II/Gu (RH II/Gu) is a nucleolar antigen originally identified using an autoimmune serum from a patient with watermelon stomach. A later report showed that anti-RH II/Gu autoantibodies were also present at low frequency in connective tissue disease (CTD) patients who did not show any symptoms suggestive of a watermelon stomach lesion. In an attempt to understand the relationship between watermelon stomach, also called gastric antral vascular ectasia (GAVE), and autoimmune disorder, we identified the antigenic sites recognized by these autoantibodies. Serum Gu uniquely recognized epitopes at amino acids 646-748 of RH II/Gu and all four CTD patient sera recognized antigenic sites within amino acids 1-173. Anti-RH II/Gu serum produced by immunizing rabbit with recombinant human RH II/Gu protein bound to the same antigenic sites recognized by the CTD patient sera, but it did not recognize the serum Gu epitopes. Results are also presented showing the use of these anti-RH II/Gu antibodies in the analysis of the evolutionary conservation of RH II/Gu in human, monkey and mouse.

Amino Acid Sequence↗
PubMed2003

Genomic analysis of gene expression relationships in transcriptional regulatory networks.

From merging several data sources, we created an extensive map of the transcriptional regulatory network in Saccharomyces cerevisiae, comprising 7419 interactions connecting 180 transcription factors (TFs) with their target genes. We integrated this network with gene-expression data, relating the expression profiles of TFs and target genes. We found that genes targeted by the same TF tend to be co-expressed, with the degree of co-expression increasing if genes share more than one TF. Moreover, shared targets of a TF tend to have similar cellular functions. By contrast, the expression relationships between the TFs and their targets are much more complicated, often exhibiting time-shifted or inverted behavior. Further information is available at http://bioinfo.mbb.yale.edu/regulation/TIG/

Gene Expression Regulation↗
PubMed2002

Stimulating neurons with light.

Recent technological advances have enabled the use of different optical methods to activate neurons, including 'caged' glutamate, photoactivation of genetically engineered cascades, and direct two-photon excitation. The ability to use light as a stimulation tool provides, in principle, a non-invasive method for the temporally and spatially precise activation of any neuron or any part of a neuron. When combined with two-photon excitation, excellent spatial control can be achieved even in complex and highly scattering preparations, such as living nervous tissue. Different methods that have been developed in the last several decades have been used to probe neuronal sensitivity, mimic synaptic input, and elucidate patterns of neural connectivity.

Animals↗
PubMed1995

A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen.

BACKGROUND: p21WAF1 is a potent inhibitor of the cell-cycle regulatory cyclin-dependent kinases (Cdks). It acts on Cdks in the G1 and S phases of the cell cycle, and also binds to proliferating cell nuclear antigen (PCNA), blocking DNA replication in vitro. Transcription of p21WAF1 can be induced by the human tumour suppressor protein p53, suggesting that the action of p21WAF1 may be important in cancer prevention. We have investigated the interaction between p21WAF1 and PCNA using a genetic two-hybrid screen and with arrays of synthetic peptides derived from the p21WAF1 protein sequence. RESULTS: We have established that the carboxy-terminal region of p21WAF1 interacts with PCNA in a yeast two-hybrid screen. Interaction with p21WAF1 involves the central loop of PCNA, which connects the two domains of the PCNA monomer. The interaction was finely mapped using peptides derived from the entire sequence of the p21WAF1 protein, and the critical residues were found to be QTSMTDFY (amino acids 144-151 of p21WAF1). Remarkably, a 20-residue peptide containing this sequence inhibited replication of simian virus 40 (SV40) DNA in vitro and could capture PCNA from whole cell extracts, demonstrating that small molecules can retain the biological activity characteristic of the whole protein. Sequential alanine-scan mutations of the peptide demonstrated that its ability to block replication correlates with its affinity for binding PCNA. CONCLUSIONS: We have shown that PCNA and the cell-cycle regulator p21WAF1 interact in vivo, and that this interaction requires the central loop of PCNA and an eight amino-acid motif from the carboxyl terminus of p21WAF1.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

A variant of the mammalian somatotopic map in a bat.

Two ordered representations of the body surface, S-I and S-II, have been described on the cortical surface of the brains of a variety of mammals; additional separate topographical maps have been found in the somatosensory cortex of the cat and monkey. Except for minor variations in the placement of the body parts, the basic somatotopy of the maps is remarkably consistent across species. As the reasons for this consistency and the minor variations are unclear, we examined the somatotopy of the bat, whose body plan has been modified extensively so that the forelimb can be used for flight. We report here that in both S-I and S-II of the grey-headed flying fox, not only is the representation of the distal forelimb displaced from its usual position on the map, but the digits are directed caudally instead of rostrally as they are in all other mammals studied. The variant somatotopy appears to reflect the postural differences between flying and walking mammals, supporting the notion that topographical maps may have functional significance apart from their point-to-point connections with the sensory periphery.

Animals↗
PubMed2004

Cycling chaotic attractors in two models for dynamics with invariant subspaces.

Nonergodic attractors can robustly appear in symmetric systems as structurally stable cycles between saddle-type invariant sets. These saddles may be chaotic giving rise to "cycling chaos." The robustness of such attractors appears by virtue of the fact that the connections are robust within some invariant subspace. We consider two previously studied examples and examine these in detail for a number of effects: (i) presence of internal symmetries within the chaotic saddles, (ii) phase-resetting, where only a limited set of connecting trajectories between saddles are possible, and (iii) multistability of periodic orbits near bifurcation to cycling attractors. The first model consists of three cyclically coupled Lorenz equations and was investigated first by Dellnitz et al. [Int. J. Bifurcation Chaos Appl. Sci. Eng. 5, 1243-1247 (1995)]. We show that one can find a "false phase-resetting" effect here due to the presence of a skew product structure for the dynamics in an invariant subspace; we verify this by considering a more general bi-directional coupling. The presence of internal symmetries of the chaotic saddles means that the set of connections can never be clean in this system, that is, there will always be transversely repelling orbits within the saddles that are transversely attracting on average. Nonetheless we argue that "anomalous connections" are rare. The second model we consider is an approximate return mapping near the stable manifold of a saddle in a cycling attractor from a magnetoconvection problem previously investigated by two of the authors. Near resonance, we show that the model genuinely is phase-resetting, and there are indeed stable periodic orbits of arbitrarily long period close to resonance, as previously conjectured. We examine the set of nearby periodic orbits in both parameter and phase space and show that their structure appears to be much more complicated than previously suspected. In particular, the basins of attraction of the periodic orbits appear to be pseudo-riddled in the terminology of Lai [Physica D 150, 1-13 (2001)].

Algorithms↗
PubMed2004

Structure-activity relationships in defensin dimers: a novel link between beta-defensin tertiary structure and antimicrobial activity.

Defensins are cationic antimicrobial peptides that have a characteristic six-cysteine motif and are important components of the innate immune system. We recently described a beta-defensin-related peptide (Defr1) that had potent antimicrobial activity despite having only five cysteines. Here we report a relationship between the structure and activity of Defr1 through a comparative study with its six cysteine-containing analogue (Defr1 Y5C). Against a panel of pathogens, we found that oxidized Defr1 had significantly higher activity than its reduced form and the oxidized and reduced forms of Defr1 Y5C. Furthermore, Defr1 displayed activity against Pseudomonas aeruginosa in the presence of 150 mm NaCl, whereas Defr1 Y5C was inactive. By using nondenaturing gel electrophoresis and Fourier transform ion cyclotron resonance mass spectrometry, we observed Defr1 and Defr1 Y5C dimers. Two complementary fragmentation techniques (collision-induced dissociation and electron capture dissociation) revealed that Defr1 Y5C dimers form by noncovalent, weak association of monomers that contain three intramolecular disulfide bonds. In contrast, Defr1 dimers are resistant to collision-induced dissociation and are only dissociated into monomers by reduction using electron capture. This is indicative of Defr1 dimerization being mediated by an intermolecular disulfide bond. Proteolysis and peptide mass mapping revealed that Defr1 Y5C monomers have beta-defensin disulfide bond connectivity, whereas oxidized Defr1 is a complex mixture of dimeric isoforms with as yet unknown inter- and intramolecular connectivities. Each isoform contains one intermolecular and four intramolecular disulfide bonds, but because we were unable to resolve the isoforms by reverse phase chromatography, we could not assign each isoform with a specific antimicrobial activity. We conclude that the enhanced activity and stability of this mixture of Defr1 dimeric isoforms are due to the presence of an intermolecular disulfide bond. This first description of a covalently cross-linked member of the defensin family provides further evidence that the antimicrobial activity of a defensin is linked to its ability to form stable higher order structures.

Alleles↗
PubMed2006

Autoantibodies to intracellular autoantigens and their B-cell epitopes: molecular probes to study the autoimmune response.

A common laboratory finding in systemic autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Although their pathogenesis is not fully understood, autoantibodies are important tools for establishing diagnosis, classification, and prognosis of autoimmune diseases. Autoantibodies mainly target multicomponent complexes containing both protein antigens and (ribo)-nucleic acid(s), such as the spliceosome or Ro/La RNPs. In this review, we address the main characteristics and the clinical value of the main autoantibody types with respect to their disease association, and we describe the corresponding autoantigens, their biologic function, and their B-cell antigenic determinants (epitopes). The structural characteristics and clinical associations of these epitopes, and their utility as tools to investigate the autoimmune response, are discussed in detail. New insights into the pathogenetic role of epitopes in systemic autoimmunity are also examined. In this regard, using the defined structures of the B-cell antigenic epitopes, complementary epitopes can be designed according to the "molecular recognition" theory. These complementary epitopes can be used as probes to study pathogenetic and immunoregulatory aspects of the anti-idiotypic response. The origin of humoral autoimmunity and the spreading of the epitopes in systemic lupus erythematosus are also discussed. Finally, the ability of post-translational modifications to induce autoreactive immune attack via the generation of neo-epitopes is summarized.

Autoantibodies↗
PubMed2005

Spatio-temporal modeling of localized brain activity.

Functional neuroimaging, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), plays an important role in identifying specific brain regions associated with experimental stimuli or psychiatric disorders such as schizophrenia. PET and fMRI produce massive data sets that contain both temporal correlations from repeated scans and complex spatial correlations. Several methods exist for handling temporal correlations, some of which rely on transforming the response data to induce either a known or an independence covariance structure. Despite the presence of spatial correlations between the volume elements (voxels) comprising a brain scan, conventional methods perform voxel-by-voxel analyses of measured brain activity. We propose a two-stage spatio-temporal model for the estimation and testing of localized activity. Our second-stage model specifies a spatial auto-regression, capturing correlations within neural processing clusters defined by a data-driven cluster analysis. We use maximum likelihood methods to estimate parameters from our spatial autoregressive model. Our model protects against type-I errors, enables the detection of both localized and regional activations (including volume of interest effects), provides information on functional connectivity in the brain, and establishes a framework to produce spatially smoothed maps of distributed brain activity for each individual. We illustrate the application of our model using PET data from a study of working memory in individuals with schizophrenia.

Brain↗
PubMed2000

Global relationship between anatomical connectivity and activity propagation in the cerebral cortex.

Anatomical connectivity is a prerequisite for cooperative interactions between cortical areas, but it has yet to be demonstrated that association fibre networks determine the macroscopical flow of activity in the cerebral cortex. To test this notion, we constructed a large-scale model of cortical areas whose interconnections were based on published anatomical data from tracing studies. Using this model we simulated the propagation of activity in response to activation of individual cortical areas and compared the resulting topographic activation patterns to electrophysiological observations on the global spread of epileptic activity following intracortical stimulation. Here we show that a neural network with connectivity derived from experimental data reproduces cortical propagation of activity significantly better than networks with different types of neighbourhood-based connectivity or random connections. Our results indicate that association fibres and their relative connection strengths are useful predictors of global topographic activation patterns in the cerebral cortex. This global structure-function relationship may open a door to explicit interpretation of cortical activation data in terms of underlying anatomical connectivity.

Animals↗
PubMed1999

Predicting allosteric switches in myosins.

The sequences of several members of the myosin family of molecular motors are evaluated using ASP (Ambivalent Structure Predictor), a new computational method. ASP predicts structurally ambivalent sequence elements by analyzing the output from a secondary structure prediction algorithm. These ambivalent sequence elements form secondary structures that are hypothesized to function as switches by undergoing conformational rearrangement. For chicken skeletal muscle myosin, 13 discrete structurally ambivalent sequence elements are identified. All 13 are located in the heavy chain motor domain. When these sequence elements are mapped into the myosin tertiary structure, they form two compact regions that connect the actin binding site to the adenosine 5'-triphosphate (ATP) site, and the ATP site to the fulcrum site for the force-producing bending of the motor domain. These regions, predicted by the new algorithm to undergo conformational rearrangements, include the published known and putative switches of the myosin motor domain, and they form plausible allosteric connections between the three main functional sites of myosin. The sequences of several other members of the myosin I and II families are also analyzed.

Allosteric Regulation↗
PubMed1994

Morphology of callosal axons interconnecting areas 17 and 18 of the cat.

Seventeen callosally projecting axons originating near the border between areas 17 and 18 in adult cats were anterogradely labelled with biocytin and reconstructed in 3-D from serial sections. All axons terminated near the contralateral 17/18 border. However, they differed in their diameter, tangential and radial distributions, and overall geometry of terminal arbors. Diameters of reconstructed axons ranged between 0.45 and 2.25 microns. Most of the axons terminated in multiple terminal columns scattered over several square millimetres of cortex. Thus in general callosal connections are not organized according to simple, point-to-point spatial mapping rules. Usually terminal boutons were more numerous in supragranular layers; some were also found in infragranular layers, none in layer IV. However, a few axons were distributed only or mainly in layer IV, others included this layer in their termination. Thus, different callosal axons may selectively activate distinct cell populations. The geometry of terminal arbors defined two types of architecture, which were sometimes represented in the same axon: parallel architecture was characterized by branches of considerable length which supplied different columns or converged onto the same column; serial architecture was characterized by a tangentially running trunk or main branch with radial collaterals to the cortex. These architectures may relate to temporal aspects of inter-hemispheric interactions. In conclusion, communication between corresponding areas of the two hemispheres appears to use channels with different morphological and probably functional properties.

Animals↗
PubMed1996

Organization of the visual reticular thalamic nucleus of the rat.

The visual sector of the reticular thalamic nucleus has come under some intense scrutiny over recent years, principally because of the key role that the nucleus plays in the processing of visual information. Despite this scrutiny, we know very little of how the connections between the reticular nucleus and the different areas of visual cortex and the different visual dorsal thalamic nuclei are organized. This study examines the patterns of reticular connections with the visual cortex and the dorsal thalamus in the rat, a species where the visual pathways have been well documented. Biotinylated dextran, an anterograde and retrograde tracer, was injected into different visual cortical areas [17; rostral 18a: presumed area AL: (anterolateral); caudal 18a: presumed area LM (lateromedial); rostral 18b: presumed area AM (anteromedial); caudal 18b: presumed area PM (posteromedial)] and into different visual dorsal thalamic nuclei (posterior thalamic, lateral geniculate nuclei), and the patterns of anterograde and retrograde labelling in the reticular nucleus were examined. From the cortical injections, we find that the visual sector of the reticular nucleus is divided into subsectors that each receive an input from a distinct visual cortical area, with little or no overlap. Further, the resulting pattern of cortical terminations in the reticular nucleus reflects largely the patterns of termination in the dorsal thalamus. That is, each cortical area projects to a largely distinct subsector of the reticular nucleus, as it does to a largely distinct dorsal thalamic nucleus. As with each of the visual cortical areas, each of the visual dorsal thalamic (lateral geniculate, lateral posterior, posterior thalamic) nuclei relate to a separate territory of the reticular nucleus, with little or no overlap. Each of these dorsal thalamic territories within the reticular nucleus receives inputs from one or more of the visual cortical areas. For instance, the region to the reticular nucleus that is labelled after an injection into the lateral geniculate nucleus encompasses the reticular regions which receive afferents from cortical areas 17, rostral 18b and caudal 18b. These results suggest that individual cortical areas may influence the activity of different dorsal thalamic nuclei through their reticular connections.

Animals↗
PubMed1992

Interaction between permanent cardiac pacing and electrocautery: the significance of electrode position.

The danger in utilizing electrocautery during a surgical procedure on a pacemaker patient depends, to a great extent, on the position of the electrodes. We have studied this influence in an experimental model consisting of a plexiglass tank filled with a saline solution. Seven pacemakers were successively attached to an immersed and fixed frame and connected to a lead whose tip remains in the same location throughout the experiments. An ERBOTOM T 400 C generator (450 kHz) was used in an unmodulated unipolar mode at a maximum output (400 W). The high frequency current was delivered between a patch located successively at six preset positions in the tank and another electrode applied to 176 surface locations. For each position, we measured the currents in the lead with a separate measurement circuit connected in parallel on the same lead. Results were displayed on a map. Regardless of the patch position, currents were: (1) at a maximum when high frequency was delivered close to the pacemakers and around the tip of the lead; (2) negligible when applied to the path followed by the lead; and (3) a function of the distance between electrodes. These results may help to formulate recommendations to prevent accidents when using electrocautery in pacemaker patients.

Animals↗
PubMed1979

Siamese cat: altered connections of visual cortex.

In siamese cats, each side of the brain receives a retinal input serving part of the ipsilateral visual field as well as the normal contralateral field representation. Both corticothalamic and cortico-cortical projections are systematically rearranged, but while one is retinotopically appropriate, the other fails to make a distinction between ipsilateral and contralateral fields. Different rules appear to govern the development of these two sets of connections.

Animals↗
PubMed1978

Conducting tissues in congenitally corrected transposition with situs inversus.

Three cases of congenitally corrected transposition in situs inversus individuals were characterised by visceroatrial situs inversus, atrioventricular discordance, and ventiruloarterial discordance: one case was studied clinically, and the other 2 were necropsy specimens. The disposition of the atrioventricular conducting tissues was established in each case, in the living patient by intraoperative mapping, and in the necropsy specimens by histopathological investigation. In all, the connecting atrioventricular bundle arose from a normally situated posterior atrioventricular node, normally related to the landmarks of the atrial septum. Though anterior nodes were identified in the necropsy specimens, as reported in congenitally corrected transposition in situs individuals, they differed from those in the latter situation in that they made no atrioventricular connection. These findings have obvious surgical importance. It is suggested that the posterior connection is related to the good septal alignment in these cases which lacked significant septal defects. Posterior connections are not necessarily present in all situs inversus individuals with corrected transposition, particularly when there are malalignment ventricular septal defects: further studies are required in such cases.

Aorta, Thoracic↗
PubMed2006

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro.

Tetraspanin protein CD151 is abundant on endothelial cells. To determine whether CD151 affects angiogenesis, Cd151-null mice were prepared. Cd151-null mice showed no vascular defects during normal development or during neonatal oxygen-induced retinopathy. However, Cd151-null mice showed impaired pathologic angiogenesis in other in vivo assays (Matrigel plug, corneal micropocket, tumor implantation) and in the ex vivo aortic ring assay. Cd151-null mouse lung endothelial cells (MLECs) showed normal adhesion and proliferation, but marked alterations in vitro, in assays relevant to angiogenesis (migration, spreading, invasion, Matrigel contraction, tube and cable formation, spheroid sprouting). Consistent with these functional impairments, and with the close, preferential association of CD151 with laminin-binding integrins, Cd151-null MLECs also showed selective signaling defects, particularly on laminin substrate. Adhesion-dependent activation of PKB/c-Akt, e-NOS, Rac, and Cdc42 was diminished, but Raf, ERK, p38 MAP kinase, FAK, and Src were unaltered. In Cd151-null MLECs, connections were disrupted between laminin-binding integrins and at least 5 other proteins. In conclusion, CD151 modulates molecular organization of laminin-binding integrins, thereby supporting secondary (ie, after cell adhesion) functions of endothelial cells, which are needed for some types of pathologic angiogenesis in vivo. Selective effects of CD151 on pathologic angiogenesis make it a potentially useful target for anticancer therapy.

Animals↗
PubMedDate not supplied

[Structure of alpha-spiral hairpins with short connections in globular proteins].

The analysis of conformations of more than 100 alpha-alpha-hairpins with closely packed helical segments and connections up to four amino acid residues in length was carried out. Five types of the connections were revealed and their phi and psi values on the Ramachandran map were found. Each type of alpha-alpha-hairpins was shown to have a unique sequence pattern for hydrophobic and hydrophilic residues.

Models, Molecular↗