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PubMed1990

Competitive and positional cues in the patterning of nerve connections.

The visual system of lower vertebrates has served as an important testing ground for the mechanisms that generate topographic neuronal connections. During both the outgrowth and the regeneration of the optic nerve, a smoothly ordered map of the retina is formed on its major target, the optic tectum (the retinotectal projection). Experiments performed on this projection have offered support for a variety of mechanisms, including the matching of positional cues in the retina and tectum, the guidance of nerve fibers by interactions between fibers, competition for synaptic space, and the refinement of connections based on neuronal activity. Unfortunately, individual experiments that support any one of these mechanisms have been taken at times as evidence against the involvement of any other mechanism; for example, experiments demonstrating the importance of positional cues have been thought mistakenly to indicate that activity-based interactions are unimportant. Computer simulations, in which multiple, somewhat opposed, mechanisms are allowed to operate in concert demonstrate that such a hybrid model is able to generate a full range of experimental results. More importantly, the elimination of any one of the mechanisms renders the model unable to fit entire classes of findings. Thus, the patterning of the retinotectal projection is best viewed as a process in which the optic nerve terminals attempt to satisfy multiple constraints in selecting their target sites.

Animals↗
PubMed2005

Disruption of ephrin-A/EphA binding alters synaptogenesis and neural connectivity in the hippocampus.

Ephrins are guidance cues that modulate axonal growth and the subsequent axonal topographic maps in many regions of the CNS. Here we studied the functional roles of ephrin-A/EphA interactions in the layer-specific pattern of axonal projections in the hippocampus by disrupting the ephrin-A signaling by over-expression of a soluble EphA receptor. Tracing experiments in EphA5-Fc over-expressing mice revealed that reduction of ephrin-A/EphA interactions did not affect the proper distribution of the main hippocampal afferents, i.e. entorhinal and commissural projections. However, further ultrastructural analyses showed a reduction in the density of synaptic terminals in the entorhinal and commissural termination layers in these mice. In addition, using anti-calbindin antibodies, we analyzed the dentate mossy fiber projections following disruption of ephrin-A/EphA interactions throughout developing hippocampus. While the main mossy fiber bundle appeared normal, the infrapyramidal bundle formed longer projections that established ectopic contacts in these transgenic mice. Later, the expected specific pruning of the infrapyramidal bundle was not observed at adult stages. Ultrastructural analyses confirmed a higher number of mossy fiber terminals in the infrapyramidal bundle in adult EphA5-Fc transgenic mice and showed that these terminals were larger and established a greater number of contacts than in controls. Our results demonstrate that ephrin-A/EphA interactions regulate the synaptogenesis of hippocampal afferents and the proper development and refinement of granule cell projections.

Age Factors↗
PubMed1983

Connections of midbrain periaqueductal gray in the monkey. I. Ascending efferent projections.

1. To obtain a comprehensive map of the ascending projection of the midbrain periaqueductal gray, small amounts of [3H]leucine were injected into discrete regions of the periaqueductal gray (PAG) of the monkey. 2. Despite the fact that different regions of the PAG were injected in separate animals, the majority of the PAG's efferent projections to the forebrain remained constant. 3. The diencephalic projection areas include the nucleus reticularis thalami, the nucleus medialis dorsalis, the midline thalamic nuclei, the intralaminar thalamic nuclei, the preoptic area, and the anterior, dorsal, periventricular, ventromedial, periarcurate, lateral, and posterior hypothalamic nuclei. 4. More caudal areas receiving a projection from the PAG include the zona incerta and the mesencephalic reticular formation. 5. The main route for PAG-diencephalic projections is through the periventricular bundle. This implies that if a stimulating electrode was placed in this region, both the diencephalic leads to PAG and PAG leads to diencephalic pathways would be stimulated. This observation may explain the wide variety of side effects often encountered in stimulation-produced analgesia in humans. 6. These results support our hypothesis that the PAG functions as a visceral, nociceptive, and cognitive integrator.

Animals↗
PubMed2004

Collaborative starts 2nd phase of connectivity push.

The Robert Wood Johnson Foundation gives financial boost to next phase of work. Incremental road map needed to prioritize actions and foster innovation. Demonstration project is planned to test products in real-world settings.

Computer Communication Networks↗
PubMed1986

Determination of the earliest site of ventricular activation in Wolff-Parkinson-White syndrome: application of digital continuous loop two-dimensional echocardiography.

Surgical and transcatheter ablation of accessory atrioventricular (AV) connections (Wolff-Parkinson-White syndrome) requires accurate localization of the accessory pathway. In a canine model of endocardial pacing, a continuous loop two-dimensional echocardiographic technique was developed for determining the earliest site of ventricular activation. This technique was then used to localize accessory AV connections in patients. Echocardiographic images were acquired on videotape and converted to a digital continuous loop format, from which the earliest site of systolic motion was determined. In six dogs, using six distinct endocardial sites, two blinded observers accurately identified the earliest site of ventricular activation in 31 (86%) of 36 and 32 (89%) of 36 locations. Determination of the earliest site of ventricular activation with the continuous loop digital technique was superior to standard analog analysis in overall accuracy (p less than 0.02) and in intraobserver variability (p less than 0.004). After validation of this technique, 21 patients with 22 accessory AV connections with anterograde conduction were studied. The earliest site of mechanical activity was determined during sinus (10 patients) or atrial paced (11 patients) rhythms by two blinded observers and compared with electrophysiologic mapping and surface electrocardiograms. Digitally processed echocardiograms correctly localized the earliest site of ventricular activation in 18 of 22 connections and predicted an adjacent location in the remaining 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1999

Organization of intracortical circuits in relation to direction preference maps in ferret visual cortex.

Neurons in the primary visual cortex are selective for the direction of movement of a visual stimulus. Like other stimulus features, direction preference is mapped on the cortical surface in a systematic manner. Intracortical synaptic circuits, in particular inhibitory connections, have been implicated in the emergence of direction selectivity. Whether intracortical inhibition specifically suppresses responses to the nonpreferred direction or has a nonspecific "thresholding" effect is still controversial. To address these questions we investigated the relationship between patterns of intracortical synaptic connections and direction domains in ferret primary visual cortex (area 17) using a combined in vivo-in vitro approach. Excitatory synaptic inputs were iso-direction-tuned. The majority of local inhibitory inputs were also iso-direction-tuned. However, approximately 40% of inhibitory connections originated in regions preferring the opposite direction. These findings indicate that specific inhibitory interactions between cortical regions of opposite direction preference may contribute to the emergence and sharpening of direction selectivity.

Animals↗
PubMed1987

Topological mapping of complement component C9 by recombinant DNA techniques suggests a novel mechanism for its insertion into target membranes.

cDNA molecules coding for mouse and trout C9 have been isolated and the derived amino acid sequences compared with that of human C9. Regions of high homology between the closely related species (mouse and human) correlate with putative domains in the protein structure supporting a model of C9 having five globular domains. Comparison between the more distant species (trout and human) suggests regions of particular importance to C9 structure and function. In addition the three related sequences allow the secondary structure to be predicted with more confidence and we have tested the prediction by mapping surface features of the protein. Reported here is a recombinant DNA approach to fine mapping of antibody epitopes. Two of the putative domains of C9 are connected by a stretch of about 40 amino acid residues in which features characteristic of individual conformational forms of C9 are concentrated. We suggest that this region might act as a hinge allowing the rearrangement of globular domains necessary for membrane insertion. In the membrane inserting domain one highly conserved sequence has the potential to form an amphipathic alpha-helix once it is buried in the lipid bilayer. These features suggest a novel mechanism for the irreversible, post-translational insertion of C9 into target membranes.

Amino Acid Sequence↗
PubMed2002

Development of "normal" dermatomes and somatotopic maps by "abnormal" populations of cutaneous neurons.

During development, motor and sensory axons grow to peripheral targets with remarkable precision. Whereas much has been learned about the development of motoneuron connectivity, less is known about the regulation of cutaneous innervation. In adults, dorsal root ganglia (DRG) innervate characteristic skin regions, termed dermatomes, and their axons project somatotopically in the dorsal horn. Here, we have investigated whether cutaneous neurons are selectively matched with specific skin regions, and whether peripheral target skin influences the central connections of cutaneous neurons. To address these questions, we shifted limb buds rostrally in chick embryos prior to axon outgrowth, causing DRGs to innervate novel skin regions, and mapped the resulting dermatomes and central projections. Following limb shifts, cutaneous innervation arose from more rostral and from fewer DRGs than normal, but the overall dermatome pattern was preserved. Thus, DRGs parcel out innervation of skin in a consistent manner, with no indication of matching between skin and DRGs. Similarly, cutaneous nerves established a "normal" somatotopic map in the dorsal horn, but in more rostral segments than usual. Thus, the peripheral target skin may influence the pattern of CNS projections, but does not direct cutaneous axons to specific populations of neurons in the dorsal horn.

Afferent Pathways↗
PubMed2000

Molecular cloning of a novel NF2/ERM/4.1 superfamily gene, ehm2, that is expressed in high-metastatic K1735 murine melanoma cells.

We have cloned a novel gene, Ehm2, that is expressed in high-metastatic but not in low-metastatic K-1735 murine melanoma cells. The Ehm2 gene encodes a protein of 527 amino acid residues, showing up to 41% amino acid identity with the FERM domain of NF2/ERM/4.1 superfamily proteins, which have the function of connecting cell surface transmembrane proteins to cytoskeletal molecules. The Ehm2 gene was mapped to chromosome 4 and was expressed in the liver, lung, kidney, and testis and in 7- to 17-day embryos. The highest level of homology was observed with NBL4, which is a new subfamily protein of the NF2/ERM/4.1 superfamily. A human homologue of the mouse Ehm2 gene, showing significant homology (83% identity), was identified in the genomic DNA and EST databases. Furthermore, seven rat EST clones and one pig EST clone in the GenBank EST database were identified as having 83-92% sequence homology with the cDNA sequence of the mouse Ehm2 gene. Thus, Ehm2 is a highly conserved gene that encodes a novel member of the NF2/ERM/4.1 superfamily proteins.

Animals↗
PubMed2001

Sensory modification of leech swimming: interactions between ventral stretch receptors and swim-related neurons.

The neuronal circuits that generate the leech swimming rhythm comprise oscillatory interneurons that provide appropriately phased output to drive swim-related motoneurons. Within ganglia, these interneurons express three phases; between ganglia there exists a phase delay between homologs. Our earlier experiments revealed that stretch receptors embedded in the body wall participate in intersegmental coordination and setting intersegmental phases. To identify the basis for these sensory effects, we mapped interactions between a ventral stretch receptor and swim-related neurons. Connections between this receptor and motoneurons are weak and variable in quiescent preparations, but during fictive swimming stretch receptor activation modulates motoneuron oscillations, hence, these effects are polysynaptic, mediated by interneurons. We identified a strong, nonrectifying, and apparently direct electrical connection between the stretch receptor and oscillator neuron 33. The ventral stretch receptor also interacts with most of the other oscillatory interneurons, including inhibitory inputs to cells 28 and 208, excitatory input to the contralateral cell 115, and mixed input to the ipsilateral cell 115. These direct and indirect interactions can account for previously described effects of body-wall stretch on motoneuron activity. They also could mediate the previously described modification of intersegmental phase relationships by appropriately phased stretch receptor activation.

Animals↗
PubMed1979

Columnar cortico-cortical interconnections within the visual system of the squirrel and macaque monkeys.

Cortico-cortical interconnections within the visual cortex of squirrel monkeys (Saimiri sciureus) were studied by means of single or multiple injections of [3H]leucine or combined [3H]leucine and horseradish peroxidase into the dorsolateral striate and prestriate cortices. Injections of [3H]leucine were also made into the dorsolateral striate cortex of a Macaca speciosa for comparison. The results indicated that in Saimiri the dorsolateral prestriate cortex is precisely and reciprocally connected with the striate and peristriate cortex, and with the posterior bank of the superior temporal sulcus, including the middle temporal area (MT). The dorsolateral striate area is precisely and reciprocally connected with the prestriate and MT area, but does not project to the perstriate cortex as in the case of the macaque. At each target site, the radioactively labelled terminal fields are distributed in a distinctly columnar fashion, with labelled columns (120-480 microm in diameter, commonly 240 microm) interdigitating with sparsely labelled or unlabelled columns of lesser widths. The HRP-labelled neurons invariably exist within the radioactively labelled columns. For all of the cortical areas examined except area 17, lamina IV is the principal 'receptive' layer for associational fibers, while layers III and II, as well as V and VI within the same column, receive progressively less input. As for area 17, associational fibers from the prestriate cortex terminate mainly within lamina I, with laminae II, III, V and VI receiving decreasing amounts of input. The present results indicate that the major visual cortical areas are interconnected in precise, topographical and reciprocal fashion. The columnar arrangement is found to be the basis of both extra- and intercortical connections.

Animals↗
PubMed1994

Efficient product clearance through exit channels in substrate hydrolysis by acetylcholinesterase.

The channels connecting the active site of acetylcholinesterase (AChE) to the protein exterior were mapped by computational techniques in order to find potential exit routes for charged reaction products. 3.9% of the total volume of the AChE monomer is hollow space and over 50% of the void is located in the center; it is partitioned into three chambers, a deep entry channel, below it a wide channel located in a slightly positive region of AChE and ideally suitable for the exit of negatively charged fragments and a small chamber above Trp84 and Met83. The latter serve as gates for the departure of the positively charged choline product of the hydrolysis of acetylcholine into the small cavity. An efficient product clearance is a prerequisite to a very low energy pathway for the irreversible hydrolysis of acetylcholine.

Acetates↗
PubMed2005

Anti-p80 coilin autoantibodies react with a conserved epitope and are associated with anti-DFS70/LEDGF autoantibodies.

p80 coilin is a nuclear autoantigen that strongly accumulates in Cajal bodies (CB) and is considered a marker for CBs. No clear clinical features have been associated with anti-p80 autoantibodies, and the epitopes recognized by these antibodies are entirely unknown. We determined the epitope specificity for 34 anti-p80 coilin-positive sera from Japanese patients to better understand its clinical significance. Western blotting and immunoprecipitation analysis revealed that the autoepitope of p80 coilin was restricted to a single region encompassing amino acid residues 421-576 from the C-terminus of p80 coilin. Additionally, sera from 30 of 34 (88%) patients with anti-p80 coilin antibody titers were also positive for anti-DFS70/LEDGF antibody. This autoantibody is sometimes found in patients with some allergic diseases but rarely in patients with connective tissue disease (CTD). Other similar characteristics between these two autoantibodies were also noted. In contrast, few anti-p80 coilin positive patients were positive for CTD-marker antibodies, such as anti-Sm, anti-dsDNA, and anti-SS-A. We conclude that the presence of anti-p80 coilin autoantibodies is not associated with any particular clinical syndromes nor is it diagnostic of any conditions.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Comparative estimations of 137Cs distribution in a boreal forest in northern Sweden using a traditional sampling approach and a portable NaI detector.

Field-portable detectors have been frequently used in routine monitoring and hazard assessment studies. However, there have been few thorough attempts to evaluate their potential as an alternative to the traditional procedure of collecting samples and analysing them in the laboratory. Thus, in this study the two approaches were compared in terms of their utility for monitoring (137)Cs activity in the Nyänget catchment in northern Sweden. The objectives were: (i) to determine the (137)Cs activity in soils associated with three types of vegetation, (ii) to map the geographical distribution of (137)Cs using the portable NaI detector connected to a GPS system (GDM-40), (iii) to identify (137)Cs anomalies in the catchment, and (iv) to compare the measurements obtained with the NaI detector and traditional sampling followed by laboratory analysis. Our results demonstrate that the GDM-40 has very good potential for making (137)Cs inventories and for detecting (137)Cs anomalies within large areas. The GDM-40 measurements identified differences between different hydrological areas that were not determined with the soil sampling method. The GDM-40 method is much faster than a traditional soil sampling method. However, soil sampling cannot be totally excluded because it is needed to calibrate the GDM-40. The agreement between the (137)Cs activity values obtained by the two approaches was 20% which is good in the field where so many factors vary.

Cesium Radioisotopes↗
PubMed2006

Comparative evaluation of positive tests to Mycobacterium avium subsp. paratuberculosis in clinically healthy sheep and goats in south-west Greece using molecular techniques, serology, and culture.

Mycobacterium avium subsp. paratuberculosis (MAP) is the cause of paratuberculosis, which affects mainly ruminants although there is a growing concern about its possible implication in Crohn's disease in humans especially in connection with environmental spread and risks to the food chain. Retail cheese may represent a significant source of human exposure to MAP and the aim of this study was to assess MAP status in clinically healthy sheep and goats in Greece, comparing techniques routinely used in the positive diagnosis of the disease. From a total of 30 flocks, 632 sheep and goats had faecal, serum, and whole-blood samples examined by culture, complement fixation test (CFT), and polymerase chain reaction (PCR) targeted at IS900, IS1245, and IS6110. PCR produced positive results in 21% of the animals tested, with 5.6%, 3.9%, and 11.5% being identified as MAP, Mycobacterium avium subsp. avium, and Mycobacterium tuberculosis complex, respectively. CFT produced positive and suspicious results in 4.4% and 14.4% of the cases. Faecal cultures were negative in all but a single case that was identified as restriction fragment length polymorphism (RFLP)-type BC1. Agreement between results obtained by PCR and CFT was poor with isolated cases although an assessment of the MAP positive tests produced similar results for both methods. The findings indicate the need for additional measures of control, although the costs may be substantial if public health protection justifies elimination of MAP from livestock.

Animals↗