WorldWideScience

Sample records for detecting progressive axonal

  1. Fiber Optic Detection of Action Potentials in Axons

    National Research Council Canada - National Science Library

    Smela, Elisabeth

    2006-01-01

    In prior exploratory research, we had designed a fiber optic sensor utilizing a long period Bragg grating for the purpose of detecting action potentials in axons optically, through a change in index...

  2. Dynamic Changes of Neuroskeletal Proteins in DRGs Underlie Impaired Axonal Maturation and Progressive Axonal Degeneration in Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Hideki Kamiya

    2009-01-01

    Full Text Available We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments and β-III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3β, and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3β correlated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.

  3. CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

    DEFF Research Database (Denmark)

    Romme Christensen, Jeppe; Börnsen, Lars; Khademi, Mohsen

    2013-01-01

    BACKGROUND: The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. OBJECTIVES: To study cerebrospinal fluid (CSF) biomarkers...... and clarify whether inflammation and axonal damage are associated in progressive MS. METHODS: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease...... (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. RESULTS: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13...

  4. Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients.

    Science.gov (United States)

    Garcia-Martin, Elena; Pueyo, Victoria; Almarcegui, Carmen; Martin, Jesus; Ara, Jose R; Sancho, Eva; Pablo, Luis E; Dolz, Isabel; Fernandez, Javier

    2011-11-01

    To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes.

  5. Detection of axonal synapses in 3D two-photon images.

    Directory of Open Access Journals (Sweden)

    Cher Bass

    Full Text Available Studies of structural plasticity in the brain often require the detection and analysis of axonal synapses (boutons. To date, bouton detection has been largely manual or semi-automated, relying on a step that traces the axons before detection the boutons. If tracing the axon fails, the accuracy of bouton detection is compromised. In this paper, we propose a new algorithm that does not require tracing the axon to detect axonal boutons in 3D two-photon images taken from the mouse cortex. To find the most appropriate techniques for this task, we compared several well-known algorithms for interest point detection and feature descriptor generation. The final algorithm proposed has the following main steps: (1 a Laplacian of Gaussian (LoG based feature enhancement module to accentuate the appearance of boutons; (2 a Speeded Up Robust Features (SURF interest point detector to find candidate locations for feature extraction; (3 non-maximum suppression to eliminate candidates that were detected more than once in the same local region; (4 generation of feature descriptors based on Gabor filters; (5 a Support Vector Machine (SVM classifier, trained on features from labelled data, and was used to distinguish between bouton and non-bouton candidates. We found that our method achieved a Recall of 95%, Precision of 76%, and F1 score of 84% within a new dataset that we make available for accessing bouton detection. On average, Recall and F1 score were significantly better than the current state-of-the-art method, while Precision was not significantly different. In conclusion, in this article we demonstrate that our approach, which is independent of axon tracing, can detect boutons to a high level of accuracy, and improves on the detection performance of existing approaches. The data and code (with an easy to use GUI used in this article are available from open source repositories.

  6. Detection of functional homotopy in traumatic axonal injury

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jian; Gao, Lei; Xie, Kai; Zhan, Jie; Luo, Xiaoping; Wang, Huifang; Zhang, Huifang; Zhao, Jing; Zhou, Fuqing; Zeng, Xianjun; He, Laichang; He, Yulin; Gong, Honghan [Nanchang University, Department of Radiology, The First Affiliated Hospital, Nanchang City, Jiangxi (China)

    2017-01-15

    This study aimed to explore the interhemispheric intrinsic connectivity in traumatic axonal injury (TAI) patients. Twenty-one patients with TAI (14 males, seven females; mean age, 38.71 ± 15.25 years) and 22 well-matched healthy controls (16 males, six females; mean age, 38.50 ± 13.82 years) were recruited, and from them we obtained resting-state fMRI data. Interhemispheric coordination was examined using voxel-mirrored homotopic connectivity (VMHC) and seed-based functional connectivity analysis was performed. We observed significantly decreased VMHC in a number of regions in TAI patients, including the prefrontal, temporal, occipital, parietal, and posterior cingulate cortices, thalami and cerebellar posterior lobes. Subsequent seed-based functional connectivity analysis revealed widely disrupted functional connectivity between the regions of local homotopic connectivity deficits and other areas of the brain, particularly the areas subserving the default, salience, integrative, and executive systems. The lower VMHC of the inferior frontal gyrus and basal ganglia, thalamus, and caudate were significant correlated with the Beck Depression Inventory score, Clinical Dementia Rating score, and Mini-Mental State Examination score, respectively. TAI is associated with regionally decreased interhemispheric interactions and extensively disrupted seed-based functional connectivity, generating further evidence of diffuse disconnection being associated with clinical symptoms in TAI patients. (orig.)

  7. Detection of functional homotopy in traumatic axonal injury

    International Nuclear Information System (INIS)

    Li, Jian; Gao, Lei; Xie, Kai; Zhan, Jie; Luo, Xiaoping; Wang, Huifang; Zhang, Huifang; Zhao, Jing; Zhou, Fuqing; Zeng, Xianjun; He, Laichang; He, Yulin; Gong, Honghan

    2017-01-01

    This study aimed to explore the interhemispheric intrinsic connectivity in traumatic axonal injury (TAI) patients. Twenty-one patients with TAI (14 males, seven females; mean age, 38.71 ± 15.25 years) and 22 well-matched healthy controls (16 males, six females; mean age, 38.50 ± 13.82 years) were recruited, and from them we obtained resting-state fMRI data. Interhemispheric coordination was examined using voxel-mirrored homotopic connectivity (VMHC) and seed-based functional connectivity analysis was performed. We observed significantly decreased VMHC in a number of regions in TAI patients, including the prefrontal, temporal, occipital, parietal, and posterior cingulate cortices, thalami and cerebellar posterior lobes. Subsequent seed-based functional connectivity analysis revealed widely disrupted functional connectivity between the regions of local homotopic connectivity deficits and other areas of the brain, particularly the areas subserving the default, salience, integrative, and executive systems. The lower VMHC of the inferior frontal gyrus and basal ganglia, thalamus, and caudate were significant correlated with the Beck Depression Inventory score, Clinical Dementia Rating score, and Mini-Mental State Examination score, respectively. TAI is associated with regionally decreased interhemispheric interactions and extensively disrupted seed-based functional connectivity, generating further evidence of diffuse disconnection being associated with clinical symptoms in TAI patients. (orig.)

  8. An automated detection for axonal boutons in vivo two-photon imaging of mouse

    Science.gov (United States)

    Li, Weifu; Zhang, Dandan; Xie, Qiwei; Chen, Xi; Han, Hua

    2017-02-01

    Activity-dependent changes in the synaptic connections of the brain are tightly related to learning and memory. Previous studies have shown that essentially all new synaptic contacts were made by adding new partners to existing synaptic elements. To further explore synaptic dynamics in specific pathways, concurrent imaging of pre and postsynaptic structures in identified connections is required. Consequently, considerable attention has been paid for the automated detection of axonal boutons. Different from most previous methods proposed in vitro data, this paper considers a more practical case in vivo neuron images which can provide real time information and direct observation of the dynamics of a disease process in mouse. Additionally, we present an automated approach for detecting axonal boutons by starting with deconvolving the original images, then thresholding the enhanced images, and reserving the regions fulfilling a series of criteria. Experimental result in vivo two-photon imaging of mouse demonstrates the effectiveness of our proposed method.

  9. CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

    Science.gov (United States)

    Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

    2018-05-01

    Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

  10. Noninvasive Detection and Differentiation of Axonal Injury/Loss, Demyelination, and Inflammation

    Science.gov (United States)

    2014-10-01

    phosphorylated neurofilament primary antibody (SMI-31; 1:1000, Covance , US) to stain non-injured axons, and in rabbit anti-myelin basic protein (MBP) primary...neurofilament antibody (SMI- 31; 1:1000, Covance , US) to stain non-injured axons or with rabbit anti-myelin basic protein (MBP) antibody (1:1000, Sigma Inc

  11. Diffuse axonal injury: detection of changes in anisotropy of water diffusion by diffusion-weighted imaging

    International Nuclear Information System (INIS)

    Chan, J.H.M.; Tsui, E.Y.K.; Yuen, M.K.; Peh, W.C.G.; Fong, D.; Fok, K.F.; Leung, K.M.; Fung, K.K.L.

    2003-01-01

    Myelinated axons of white matter demonstrate prominent directional differences in water diffusion. We performed diffusion-weighted imaging on ten patients with head injury to explore the feasibility of using water diffusion anisotropy for quantitating diffuse axonal injury. We showed significant decrease in diffusion anisotropy indices in areas with or without signal abnormality on T2 and T2*-weighted images. We conclude that the water diffusion anisotropy index a potentially useful, sensitive and quantitative way of diagnosing and assessing patients with diffuse axonal injury. (orig.)

  12. Early detection of emphysema progression

    DEFF Research Database (Denmark)

    Gorbunova, Vladlena; Jacobs, Sander S A M; Lo, Pechin

    2010-01-01

    Emphysema is one of the most widespread diseases in subjects with smoking history. The gold standard method for estimating the severity of emphysema is a lung function test, such as forced expiratory volume in first second (FEV1). However, several clinical studies showed that chest CT scans offer...... more sensitive estimates of emphysema progression. The standard CT densitometric score of emphysema is the relative area of voxels below a threshold (RA). The RA score is a global measurement and reflects the overall emphysema progression. In this work, we propose a framework for estimation of local...... emphysema progression from longitudinal chest CT scans. First, images are registered to a common system of coordinates and then local image dissimilarities are computed in corresponding anatomical locations. Finally, the obtained dissimilarity representation is converted into a single emphysema progression...

  13. Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury.

    Science.gov (United States)

    Vaquero, Jesús; Zurita, Mercedes; Bonilla, Celia; Fernández, Cecilia; Rubio, Juan J; Mucientes, Jorge; Rodriguez, Begoña; Blanco, Edelio; Donis, Luis

    2017-01-01

    Cell therapy in neurological disability after traumatic brain injury (TBI) is in its initial clinical stage. We describe our preliminary clinical experience with three patients with diffuse axonal injury (DAI) who were treated with intrathecal administration of autologous mesenchymal stromal cells (MSCs). Three patients with established neurological sequelae due to DAI received intrathecally autologous MSCs. The total number of MSCs administered was 60 × 10 6 (one patient), 100 × 10 6 (one patient) and 300 × 10 6 (one patient). All three patients showed improvement after cell therapy, and subsequent studies with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed a diffuse and progressive increase in brain glucose metabolism. Our present results suggest benefit of intrathecal administration of MSCs in patients with DAI, as well as a relationship between this type of treatment and increase in brain glucose metabolism. These preliminary findings raise the question of convenience of assessing the potential benefit of intrathecal administration of MSCs for brain diseases in which a decrease in glucose metabolism represents a crucial pathophysiological finding, such as Alzheimer's disease (AD) and other dementias. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

    Science.gov (United States)

    Vercherat, Cécile; Blanc, Martine; Lepinasse, Florian; Gadot, Nicolas; Couderc, Christophe; Poncet, Gilles; Walter, Thomas; Joly, Marie-Odile; Hervieu, Valérie; Scoazec, Jean-Yves; Roche, Colette

    2015-01-01

    Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs. SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways. This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy. PMID:26447612

  15. Brain-wide mapping of axonal connections: workflow for automated detection and spatial analysis of labeling in microscopic sections

    Directory of Open Access Journals (Sweden)

    Eszter Agnes ePapp

    2016-04-01

    Full Text Available Axonal tracing techniques are powerful tools for exploring the structural organization of neuronal connections. Tracers such as biotinylated dextran amine (BDA and Phaseolus vulgaris leucoagglutinin (Pha-L allow brain-wide mapping of connections through analysis of large series of histological section images. We present a workflow for efficient collection and analysis of tract-tracing datasets with a focus on newly developed modules for image processing and assignment of anatomical location to tracing data. New functionality includes automatic detection of neuronal labeling in large image series, alignment of images to a volumetric brain atlas, and analytical tools for measuring the position and extent of labeling. To evaluate the workflow, we used high-resolution microscopic images from axonal tracing experiments in which different parts of the rat primary somatosensory cortex had been injected with BDA or Pha-L. Parameters from a set of representative images were used to automate detection of labeling in image series covering the entire brain, resulting in binary maps of the distribution of labeling. For high to medium labeling densities, automatic detection was found to provide reliable results when compared to manual analysis, whereas weak labeling required manual curation for optimal detection. To identify brain regions corresponding to labeled areas, section images were aligned to the Waxholm Space (WHS atlas of the Sprague Dawley rat brain (v2 by custom-angle slicing of the MRI template to match individual sections. Based on the alignment, WHS coordinates were obtained for labeled elements and transformed to stereotaxic coordinates. The new workflow modules increase the efficiency and reliability of labeling detection in large series of images from histological sections, and enable anchoring to anatomical atlases for further spatial analysis and comparison with other data.

  16. Axonal loss in the multiple sclerosis spinal cord revisited.

    Science.gov (United States)

    Petrova, Natalia; Carassiti, Daniele; Altmann, Daniel R; Baker, David; Schmierer, Klaus

    2018-05-01

    Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area

  17. Completely assembled virus particles detected by transmission electron microscopy in proximal and mid-axons of neurons infected with herpes simplex virus type 1, herpes simplex virus type 2 and pseudorabies virus

    International Nuclear Information System (INIS)

    Huang Jialing; Lazear, Helen M.; Friedman, Harvey M.

    2011-01-01

    The morphology of alphaherpesviruses during anterograde axonal transport from the neuron cell body towards the axon terminus is controversial. Reports suggest that transport of herpes simplex virus type 1 (HSV-1) nucleocapsids and envelope proteins occurs in separate compartments and that complete virions form at varicosities or axon termini (subassembly transport model), while transport of a related alphaherpesvirus, pseudorabies virus (PRV) occurs as enveloped capsids in vesicles (assembled transport model). Transmission electron microscopy of proximal and mid-axons of primary superior cervical ganglion (SCG) neurons was used to compare anterograde axonal transport of HSV-1, HSV-2 and PRV. SCG cell bodies were infected with HSV-1 NS and 17, HSV-2 2.12 and PRV Becker. Fully assembled virus particles were detected intracellularly within vesicles in proximal and mid-axons adjacent to microtubules after infection with each virus, indicating that assembled virions are transported anterograde within axons for all three alphaherpesviruses.

  18. [Progress of cytogenetic detection in myelodysplastic syndromes].

    Science.gov (United States)

    Zhou, Qing-Bing; Hu, Xiao-Mei; Liu, -Feng; Ma, Rou

    2011-12-01

    In recent years, significant progresses have been got in study on pathogenesis, treatment and prognosis of myelodysplastic syndromes (MDS), especially on use of new technology, that has great importance for cytogenetics of MDS. Recently, the progress of cytogenetic detection in MDS is very remarkable. Based on the metaphase cytogenetics (MC) method, prognostic significance of cytogenetics in MDS was clarified gradually. For example, people have known the prognostic significance of 12 p-, 11 q-, +21, t(11(q23)), although these genetic abnormalities are rare in the MDS. In addition, chromosome mutation emerged in the process of MDS may indicate the poor prognosis. On the other hand, with the use of SNP-A and aCGH in the study of genetics, MDS cytogenetic abnormality detection rate has been further improved and can reach to 78%. At the same time, some of MDS patients with the "normal karyotype" detected by MC have new hidden aberrations through the SNP or CGH detection, and these patients have a poorer prognosis. In this review, the advances of study on cytogenetic detection for MDS based on MC and SNP-A or aCGH methods are summarized.

  19. A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

    Science.gov (United States)

    Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

    2015-04-29

    Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

  20. Calpain Inhibition Reduces Axolemmal Leakage in Traumatic Axonal Injury

    Directory of Open Access Journals (Sweden)

    János Sándor

    2009-12-01

    Full Text Available Calcium-induced, calpain-mediated proteolysis (CMSP has recently been implicated to the pathogenesis of diffuse (traumatic axonal injury (TAI. Some studies suggested that subaxolemmal CMSP may contribute to axolemmal permeability (AP alterations observed in TAI. Seeking direct evidence for this premise we investigated whether subaxolemmal CMSP may contribute to axolemmal permeability alterations (APA and pre-injury calpain-inhibition could reduce AP in a rat model of TAI. Horseradish peroxidase (HRP, a tracer that accumulates in axons with APA was administered one hour prior to injury into the lateral ventricle; 30 min preinjury a single tail vein bolus injection of 30 mg/kg MDL-28170 (a calpain inhibitor or its vehicle was applied in Wistar rats exposed to impact acceleration brain injury. Histological detection of traumatically injured axonal segments accumulating HRP and statistical analysis revealed that pre-injury administration of the calpain inhibitor MDL-28170 significantly reduced the average length of HRP-labeled axonal segments. The axono-protective effect of pre-injury calpain inhibition recently demonstrated with classical immunohistochemical markers of TAI was further corroborated in this experiment; significant reduction of the length of labeled axons in the drug-treated rats implicate CMSP in the progression of altered AP in TAI.

  1. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy.

    Directory of Open Access Journals (Sweden)

    Jia-Ying Sung

    Full Text Available This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr. Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05, shortened strength-duration time constant (P<0.01, increased superexcitability (P<0.01, decreased subexcitability (P<0.05, decreased accommodation to depolarizing current (P<0.01, and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1-8 and G2+3 (TNSr 9-24 groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01 in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

  2. Drug therapy for chronic idiopathic axonal polyneuropathy

    NARCIS (Netherlands)

    Vrancken, A. F. J. E.; van Schaik, I. N.; Hughes, R. A. C.; Notermans, N. C.

    2004-01-01

    BACKGROUND: Chronic idiopathic axonal polyneuropathy is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, it reduces quality of life. OBJECTIVES: To assess whether drug therapy for chronic idiopathic

  3. Recent Progress in Technology of Leak detection

    Energy Technology Data Exchange (ETDEWEB)

    Jung, H. K.; Kim, S. H.; Cho, J. W.; Joo, Y. S.; Yang, D. J

    2005-07-15

    It is very important to check for leakage points of fluids and gases on primary pressure boundary of nuclear power plants in order to maintain and manage various structures safely. Even though much investigation has been performed by a number of researchers, there are a lot of problems to detect the leakage under some areas to which people can not approach. In particular, it is certainly necessary to find the leakage point in order to repair and replace the pressure boundaries. In this report, the basic principle and application situations for the development of the leak detection system which can detect micro-leaks are introduced. As the technologies and performances of recent sensors have been improving, the application range of leak detection has been increasing steadily. Therefore the sensor technologies written in this report will be able to contribute to nuclear safety to detect the leakage rate and the leakage point with an on-line monitoring system in the near future.

  4. Flow cytogenetics: progress toward chromosomal aberration detection

    International Nuclear Information System (INIS)

    Carrano, A.V.; Gray, J.W.; Van Dilla, M.A.

    1977-01-01

    Using clonal derivatives of the Chinese hamster M3-1 cell line, we demonstrate the potential of flow systems to karyotype homogeneous aberrations (aberrations which are identical and present in every cell) and to detect heterogeneous aberrations (aberrations which occur randomly in a population and are not identical in every cell). Flow cytometry (FCM) of ethidium bromide stained isolated chromosomes from clone 650A of the M3-1 cells distinguishes nine chromosome types from the fourteen present in the actual karyotype. X-irradiation of this parent 650A clone produced two sub-clones with an altered flow karyotype, that is, their FCM distributions were characterized by the addition of new peaks and alterations in area under existing peaks. From the relative DNA content and area for each peak, as determined by computer analysis, we predicted that each clone had undergone a reciprocal translocation involving chromosomes from two peaks. This prediction was confirmed by Giemsa-banding the metaphase cells. Heterogeneous aberrations are reflected in the flow karyotype as an increase in background, that is, an increase in area underlying the chromosome peaks. This increase is dose dependent but, as yet, the sample variability has been too large for quantitative analysis. Flow sorting of the valleys between chromosome peaks produces enriched fractions of aberrant chromosomes for visual analysis. These approaches are potentially applicable to the analysis of chromsomal aberrations induced by environmental contaminants

  5. Detecting the transport of materials with axoplasm along the axon at the early stage after phrenic nerve neurotization via SPECT on a rabbit model

    International Nuclear Information System (INIS)

    Xu Wendong; Xu Jianguang; Gu Yudong; Jin Shaojin; Lin Xiangtong

    2003-01-01

    Objective: To study the feasibility of estimating the regenerative quality of transferred phrenic nerve by SPECT. Methods: Two tracers, 131 I-tyrosine and 99 Tc m -methylene diphosphonic acid (MDP) were selected. SPECT compounded with high-energy collimation implement (for 131 I) and low-energy collimation implement (for 99 Tc m ) was used. A rabbit model was set up. 131 I-tyrosine was injected into the normal sciatic nerve and transferred phrenic nerve by micro-syringe. The SPECT scanning was carried out at different intervals. The tracing image of 131 I was used for detecting the material migration along the axon and bone image of 99 Tc m -MDP was used for the bone orientation, these two images were interinfiltrated then. Results: The radioactivity of 131 I-tyrosine could be detected by SPECT, the transportation speed was about 30 mm/d in rabbit's normal sciatic nerve. For phrenic nerve transfer group, the 131 I-tyrosine was transported distally to the anastomotic site along with axoplasm in good regeneration group one month after anastomosis, the transportation speed was 40 mm/d. In scar group, the 131 I-tyrosine was accumulated approximately at the anastomotic site and could not be transported distally. Conclusions: The image of 131 I-tyrosine transported with nerve axoplasm could be displayed by SPECT in vivo. The method could be used to detect the circulation of regenerated axoplasm passing through the anastomotic site at the early stage after nerve transferring operation

  6. Progressive data transmission for anatomical landmark detection in a cloud.

    Science.gov (United States)

    Sofka, M; Ralovich, K; Zhang, J; Zhou, S K; Comaniciu, D

    2012-01-01

    In the concept of cloud-computing-based systems, various authorized users have secure access to patient records from a number of care delivery organizations from any location. This creates a growing need for remote visualization, advanced image processing, state-of-the-art image analysis, and computer aided diagnosis. This paper proposes a system of algorithms for automatic detection of anatomical landmarks in 3D volumes in the cloud computing environment. The system addresses the inherent problem of limited bandwidth between a (thin) client, data center, and data analysis server. The problem of limited bandwidth is solved by a hierarchical sequential detection algorithm that obtains data by progressively transmitting only image regions required for processing. The client sends a request to detect a set of landmarks for region visualization or further analysis. The algorithm running on the data analysis server obtains a coarse level image from the data center and generates landmark location candidates. The candidates are then used to obtain image neighborhood regions at a finer resolution level for further detection. This way, the landmark locations are hierarchically and sequentially detected and refined. Only image regions surrounding landmark location candidates need to be trans- mitted during detection. Furthermore, the image regions are lossy compressed with JPEG 2000. Together, these properties amount to at least 30 times bandwidth reduction while achieving similar accuracy when compared to an algorithm using the original data. The hierarchical sequential algorithm with progressive data transmission considerably reduces bandwidth requirements in cloud-based detection systems.

  7. Progress on a spherical TPC for low energy neutrino detection

    International Nuclear Information System (INIS)

    Aune, S; Colas, P; Deschamps, H; Dolbeau, J; Fanourakis, G; Ribas, E Ferrer; Enqvist, T; Geralis, T; Giomataris, Y; Gorodetzky, P; Gounaris, G J; Gros, M; Irastorza, I G; Kousouris, K; Lepeltier, V; Morales, J; Patzak, T; Paschos, E A; Salin, P; Savvidis, I; Vergados, J D

    2006-01-01

    The new concept of the spherical TPC aims at relatively large target masses with low threshold and background, keeping an extremely simple and robust operation. Such a device would open the way to detect the neutrino-nucleus interaction, which, although a standard process, remains undetected due to the low energy of the neutrino-induced nuclear recoils. The progress in the development of the first 1 m 3 prototype at Saclay is presented. Other physics goals of such a device could include supernova detection, low energy neutrino oscillations and study of non-standard properties of the neutrino, among others

  8. Axonal GABAA receptors.

    Science.gov (United States)

    Trigo, Federico F; Marty, Alain; Stell, Brandon M

    2008-09-01

    Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

  9. Acute nutritional axonal neuropathy.

    Science.gov (United States)

    Hamel, Johanna; Logigian, Eric L

    2018-01-01

    This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018. © 2017 Wiley Periodicals, Inc.

  10. Axons take a dive

    Science.gov (United States)

    Tong, Cheuk Ka; Cebrián-Silla, Arantxa; Paredes, Mercedes F; Huang, Eric J; García-Verdugo, Jose Manuel; Alvarez-Buylla, Arturo

    2015-01-01

    In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular–subventricular zone (V–SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells. PMID:26413556

  11. [Severe, subacute axonal polyneuropathy due to hypophosphatemia].

    NARCIS (Netherlands)

    Eijk, J.J.J. van; Abdo, W.F.; Deurwaarder, E. den; Zwarts, M.J.; Warrenburg, B.P.C. van de

    2010-01-01

    A 46-year-old man receiving tube feeding because of anorexia and weight loss developed progressive neurological symptoms initially resembling Guillain-Barre syndrome. Eventually axonal neuropathy due to severe hypophosphatemia was diagnosed. Hypophosphatemia can be caused by the so-called refeeding

  12. Drug therapy for chronic idiopathic axonal polyneuropathy

    NARCIS (Netherlands)

    Warendorf, Janna; Vrancken, Alexander F.J.E.; van Schaik, Ivo N.; Hughes, Richard A.C.; Notermans, Nicolette C.

    2017-01-01

    Background: Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for

  13. Drug therapy for chronic idiopathic axonal polyneuropathy

    NARCIS (Netherlands)

    Warendorf, Janna; Vrancken, Alexander F. J. E.; van Schaik, Ivo N.; Hughes, Richard A. C.; Notermans, Nicolette C.

    2017-01-01

    Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for evaluation of

  14. Progress on resonance ionization detection of combustion radicals

    International Nuclear Information System (INIS)

    Cool, T.A.

    1994-01-01

    Selective laser ionization techniques are used in our laboratory for the measurement of concentration profiles of radical intermediates in the combustion of chlorinated hydrocarbon flames. A new ultrasensitive detection technique, made possible with the advent of tunable VUV laser sources, enables the selective near-threshold photoionization of all radical intermediates in premixed hydrocarbon and chlorinated hydrocarbon flames. The progress made on the following three separate experiments during the past year is briefly described in this report. Flame Radical Concentration Measurements with VUV Spectroscopy; observation of hyperfine quantum beats in cyanogen; and the spectroscopy of the ClCO radical

  15. Electrophysiology of Axonal Constrictions

    Science.gov (United States)

    Johnson, Christopher; Jung, Peter; Brown, Anthony

    2013-03-01

    Axons of myelinated neurons are constricted at the nodes of Ranvier, where they are directly exposed to the extracellular space and where the vast majority of the ion channels are located. These constrictions are generated by local regulation of the kinetics of neurofilaments the most important cytoskeletal elements of the axon. In this paper we discuss how this shape affects the electrophysiological function of the neuron. Specifically, although the nodes are short (about 1 μm) in comparison to the distance between nodes (hundreds of μm) they have a substantial influence on the conduction velocity of neurons. We show through computational modeling that nodal constrictions (all other features such as numbers of ion channels left constant) reduce the required fiber diameter for a given target conduction velocity by up to 50% in comparison to an unconstricted axon. We further show that the predicted optimal fiber morphologies closely match reported fiber morphologies. Supported by The National Science Foundation (IOS 1146789)

  16. Mass Spectrometric C-14 Detection Techniques: Progress Report

    Science.gov (United States)

    Synal, H.

    2013-12-01

    Accelerator Mass Spectrometry (AMS) has been established as the best-suited radiocarbon detection technique. In the past years, significant progress with AMS instrumentation has been made resulting in a boom of new AMS facilities around the World. Today, carbon only AMS systems predominantly utilize 1+ charge state and molecule destruction in multiple ion gas collisions in stripper gas cell. This has made possible a significant simplification of the instruments, a reduction of ion energies and related to this less required space of the installations. However, state-of-the-art AMS instruments have still not reached a development stage where they can be regarded as table-top systems. In this respect, more development is needed to further advance the applicability of radiocarbon not only in the traditional fields of dating but also in biomedical research and new fields in Earth and environmental sciences. In a the proof-of-principle experiment the feasibility of radiocarbon detection over the entire range of dating applications was demonstrated using a pure mass spectrometer and ion energies below 50 keV. Now an experimental platform has been completed to test performance and to explore operation and measurement conditions of pure mass spectrometric radiocarbon detection. This contribution will overview the physical principles, which make this development possible and discuss key parameters of the instrumental design and performance of such an instrument.

  17. Progression of motor axon dysfunction and ectopic Na(v)1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

    DEFF Research Database (Denmark)

    Rosberg, Mette R.; Alvarez Herrero, Susana; Klein, Dennis

    2016-01-01

    Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months...... pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing...

  18. Schwann Cell Glycogen Selectively Supports Myelinated Axon Function

    Science.gov (United States)

    Brown, Angus M; Evans, Richard D; Black, Joel; Ransom, Bruce R

    2012-01-01

    Objectives Interruption of energy supply to peripheral axons is a cause of axon loss. We determined if glycogen was present in mammalian peripheral nerve, and if it supported axon conduction during aglycemia. Methods We used biochemical assay and electron microscopy to determine the presence of glycogen, and electrophysiology to monitor axon function. Results Glycogen was present in sciatic nerve, its concentration varying directly with ambient [glucose]. Electron microscopy detected glycogen granules primarily in myelinating Schwann cell cytoplasm and these diminished after exposure to aglycemia. During aglycemia, conduction failure in large myelinated axons (A fibers) mirrored the time-course of glycogen loss. Latency to CAP failure was directly related to nerve glycogen content at aglycemia onset. Glycogen did not benefit the function of slow-conducting, small diameter unmyelinated axons (C fibers) during aglycemia. Blocking glycogen breakdown pharmacologically accelerated CAP failure during aglycemia in A fibers, but not in C fibers. Lactate was as effective as glucose in supporting sciatic nerve function, and was continuously released into the extracellular space in the presence of glucose and fell rapidly during aglycemia. Interpretation Our findings indicated that glycogen is present in peripheral nerve, primarily in myelinating Schwann cells, and exclusively supports large diameter, myelinated axon conduction during aglycemia. Available evidence suggests that peripheral nerve glycogen breaks down during aglycemia and is passed, probably as lactate, to myelinated axons to support function. Unmyelinated axons are not protected by glycogen and are more vulnerable to dysfunction during periods of hypoglycemia. PMID:23034913

  19. Progress in Development of an Airborne Turbulence Detection System

    Science.gov (United States)

    Hamilton, David W.; Proctor, Fred H.

    2006-01-01

    Aircraft encounters with turbulence are the leading cause of in-flight injuries (Tyrvanas 2003) and have occasionally resulted in passenger and crew fatalities. Most of these injuries are caused by sudden and unexpected encounters with severe turbulence in and around convective activity (Kaplan et al 2005). To alleviate this problem, the Turbulence Prediction and Warning Systems (TPAWS) element of NASA s Aviation Safety program has investigated technologies to detect and warn of hazardous in-flight turbulence. This effort has required the numerical modeling of atmospheric convection: 1) for characterizing convectively induced turbulence (CIT) environments, 2) for defining turbulence hazard metrics, and 3) as a means of providing realistic three-dimensional data sets that can be used to test and evaluate turbulence detection sensors. The data sets are being made available to industry and the FAA for certification of future airborne turbulence-detection systems (ATDS) with warning capability. Early in the TPAWS project, a radar-based ATDS was installed and flight tested on NASA s research aircraft, a B-757. This ATDS utilized new algorithms and hazard metrics that were developed for use with existing airborne predictive windshear radars, thus avoiding the installation of new hardware. This system was designed to detect and warn of hazardous CIT even in regions with weak radar reflectivity (i.e. 5-15 dBz). Results from an initial flight test of the ATDS were discussed in Hamilton and Proctor (2002a; 2002b). In companion papers (Proctor et al 2002a; 2002b), a numerical simulation of the most significant encounter from that flight test was presented. Since the presentation of these papers a second flight test has been conducted providing additional cases for examination. In this paper, we will present results from NASA s flight test and a numerical model simulation of a turbulence environment encountered on 30 April 2002. Progress leading towards FAA certification of

  20. Glia to axon RNA transfer.

    Science.gov (United States)

    Sotelo, José Roberto; Canclini, Lucía; Kun, Alejandra; Sotelo-Silveira, José Roberto; Calliari, Aldo; Cal, Karina; Bresque, Mariana; Dipaolo, Andrés; Farias, Joaquina; Mercer, John A

    2014-03-01

    The existence of RNA in axons has been a matter of dispute for decades. Evidence for RNA and ribosomes has now accumulated to a point at which it is difficult to question, much of the disputes turned to the origin of these axonal RNAs. In this review, we focus on studies addressing the origin of axonal RNAs and ribosomes. The neuronal soma as the source of most axonal RNAs has been demonstrated and is indisputable. However, the surrounding glial cells may be a supplemental source of axonal RNAs, a matter scarcely investigated in the literature. Here, we review the few papers that have demonstrated that glial-to-axon RNA transfer is not only feasible, but likely. We describe this process in both invertebrate axons and vertebrate axons. Schwann cell to axon ribosomes transfer was conclusively demonstrated (Court et al. [2008]: J. Neurosci 28:11024-11029; Court et al. [2011]: Glia 59:1529-1539). However, mRNA transfer still remains to be demonstrated in a conclusive way. The intercellular transport of mRNA has interesting implications, particularly with respect to the integration of glial and axonal function. This evolving field is likely to impact our understanding of the cell biology of the axon in both normal and pathological conditions. Most importantly, if the synthesis of proteins in the axon can be controlled by interacting glia, the possibilities for clinical interventions in injury and neurodegeneration are greatly increased. Copyright © 2013 Wiley Periodicals, Inc.

  1. Detection of irradiated food: current progress on the MAFF programme

    International Nuclear Information System (INIS)

    Blackburn, C.M.; Holley, P.A.; Pryke, D.C.

    1994-01-01

    In their 1986 report the UK's Advisory Committee on Irradiated Food recognized that a generally applicable test was not available. In view of this the Committee advised that documentary control would have to be maintained throughout the processing chain. The Committee considered that detection tests would be an useful supplement for such a control system, and would do much to reassure consumers. In the following year MAFF initiated an R/D programme covering a wide variety of potential methods. The programme now focuses on developing and validating the most promising of these. Whilst it is unlikely that there will ever be an universal test covering all foods, this programme has now reached a point where tests are becoming available for a wide variety of foods. This paper reviews the progress on a number of last years projects of MAFF (Ministry of Agriculture, Fisheries and Food). In addition to the existing MAFF collaboratively tested non-statutory method for herbs and spices, two other methods have now been published: electron spin resonance spectroscopy for meat, and detection of irradiated poultry using the limulus lyasate test based on the presence on 2-alkyl cyclobutanones in irradiated seafood, poultry and meat. The Ministry also takes an active interest in international programmes including European Community and IAEA/FAO initiatives. (author)

  2. The Progression and Early detection of Subclinical Atherosclerosis (PESA) study

    DEFF Research Database (Denmark)

    Fernández-Ortiz, Antonio; Jiménez-Borreguero, L Jesús; Peñalvo, José L

    2013-01-01

    The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly defined.......The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly defined....

  3. Signal propagation along the axon.

    Science.gov (United States)

    Rama, Sylvain; Zbili, Mickaël; Debanne, Dominique

    2018-03-08

    Axons link distant brain regions and are usually considered as simple transmission cables in which reliable propagation occurs once an action potential has been generated. Safe propagation of action potentials relies on specific ion channel expression at strategic points of the axon such as nodes of Ranvier or axonal branch points. However, while action potentials are generally considered as the quantum of neuronal information, their signaling is not entirely digital. In fact, both their shape and their conduction speed have been shown to be modulated by activity, leading to regulations of synaptic latency and synaptic strength. We report here newly identified mechanisms of (1) safe spike propagation along the axon, (2) compartmentalization of action potential shape in the axon, (3) analog modulation of spike-evoked synaptic transmission and (4) alteration in conduction time after persistent regulation of axon morphology in central neurons. We discuss the contribution of these regulations in information processing. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Axonal diameter and density estimated with 7-Tesla hybrid diffusion imaging in transgenic Alzheimer rats

    Science.gov (United States)

    Daianu, Madelaine; Jacobs, Russell E.; Town, Terrence; Thompson, Paul M.

    2016-03-01

    Diffusion-weighted MR imaging (DWI) is a powerful tool to study brain tissue microstructure. DWI is sensitive to subtle changes in the white matter (WM), and can provide insight into abnormal brain changes in diseases such as Alzheimer's disease (AD). In this study, we used 7-Tesla hybrid diffusion imaging (HYDI) to scan 3 transgenic rats (line TgF344-AD; that model the full clinico-pathological spectrum of the human disease) ex vivo at 10, 15 and 24 months. We acquired 300 DWI volumes across 5 q-sampling shells (b=1000, 3000, 4000, 8000, 12000 s/mm2). From the top three b-value shells with highest signal-to-noise ratios, we reconstructed markers of WM disease, including indices of axon density and diameter in the corpus callosum (CC) - directly quantifying processes that occur in AD. As expected, apparent anisotropy progressively decreased with age; there were also decreases in the intra- and extra-axonal MR signal along axons. Axonal diameters were larger in segments of the CC (splenium and body, but not genu), possibly indicating neuritic dystrophy - characterized by enlarged axons and dendrites as previously observed at the ultrastructural level (see Cohen et al., J. Neurosci. 2013). This was further supported by increases in MR signals trapped in glial cells, CSF and possibly other small compartments in WM structures. Finally, tractography detected fewer fibers in the CC at 10 versus 24 months of age. These novel findings offer great potential to provide technical and scientific insight into the biology of brain disease.

  5. Oligodendrocyte Development in the Absence of Their Target Axons In Vivo.

    Directory of Open Access Journals (Sweden)

    Rafael Almeida

    Full Text Available Oligodendrocytes form myelin around axons of the central nervous system, enabling saltatory conduction. Recent work has established that axons can regulate certain aspects of oligodendrocyte development and myelination, yet remarkably oligodendrocytes in culture retain the ability to differentiate in the absence of axons and elaborate myelin sheaths around synthetic axon-like substrates. It remains unclear the extent to which the life-course of oligodendrocytes requires the presence of, or signals derived from axons in vivo. In particular, it is unclear whether the specific axons fated for myelination regulate the oligodendrocyte population in a living organism, and if so, which precise steps of oligodendrocyte-cell lineage progression are regulated by target axons. Here, we use live-imaging of zebrafish larvae carrying transgenic reporters that label oligodendrocyte-lineage cells to investigate which aspects of oligodendrocyte development, from specification to differentiation, are affected when we manipulate the target axonal environment. To drastically reduce the number of axons targeted for myelination, we use a previously identified kinesin-binding protein (kbp mutant, in which the first myelinated axons in the spinal cord, reticulospinal axons, do not fully grow in length, creating a region in the posterior spinal cord where most initial targets for myelination are absent. We find that a 73% reduction of reticulospinal axon surface in the posterior spinal cord of kbp mutants results in a 27% reduction in the number of oligodendrocytes. By time-lapse analysis of transgenic OPC reporters, we find that the reduction in oligodendrocyte number is explained by a reduction in OPC proliferation and survival. Interestingly, OPC specification and migration are unaltered in the near absence of normal axonal targets. Finally, we find that timely differentiation of OPCs into oligodendrocytes does not depend at all on the presence of target axons

  6. Neurotrophin Signaling via Long-Distance Axonal Transport

    Science.gov (United States)

    Chowdary, Praveen D.; Che, Dung L.; Cui, Bianxiao

    2012-05-01

    Neurotrophins are a family of target-derived growth factors that support survival, development, and maintenance of innervating neurons. Owing to the unique architecture of neurons, neurotrophins that act locally on the axonal terminals must convey their signals across the entire axon for subsequent regulation of gene transcription in the cell nucleus. This long-distance retrograde signaling, a motor-driven process that can take hours or days, has been a subject of intense interest. In the last decade, live-cell imaging with high sensitivity has significantly increased our capability to track the transport of neurotrophins, their receptors, and subsequent signals in real time. This review summarizes recent research progress in understanding neurotrophin-receptor interactions at the axonal terminal and their transport dynamics along the axon. We emphasize high-resolution studies at the single-molecule level and also discuss recent technical advances in the field.

  7. The genetics of axonal transport and axonal transport disorders.

    Directory of Open Access Journals (Sweden)

    Jason E Duncan

    2006-09-01

    Full Text Available Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases.

  8. Effective progression of nuclear magnetic resonance-detected fragment hits.

    Science.gov (United States)

    Eaton, Hugh L; Wyss, Daniel F

    2011-01-01

    Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade as an alternate lead generation tool to HTS approaches. Several compounds have now progressed into the clinic which originated from a fragment-based approach, demonstrating the utility of this emerging field. While fragment hit identification has become much more routine and may involve different screening approaches, the efficient progression of fragment hits into quality lead series may still present a major bottleneck for the broadly successful application of FBDD. In our laboratory, we have extensive experience in fragment-based NMR screening (SbN) and the subsequent iterative progression of fragment hits using structure-assisted chemistry. To maximize impact, we have applied this approach strategically to early- and high-priority targets, and those struggling for leads. Its application has yielded a clinical candidate for BACE1 and lead series in about one third of the SbN/FBDD projects. In this chapter, we will give an overview of our strategy and focus our discussion on NMR-based FBDD approaches. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. [Application of lysosomal detection in marine pollution monitoring: research progress].

    Science.gov (United States)

    Weng, You-Zhu; Fang, Yong-Qiang; Zhang, Yu-Sheng

    2013-11-01

    Lysosome is an important organelle existing in eukaryotic cells. With the development of the study on the structure and function of lysosome in recent years, lysosome is considered as a target of toxic substances on subcellular level, and has been widely applied abroad in marine pollution monitoring. This paper summarized the biological characteristics of lysosomal marker enzyme, lysosome-autophagy system, and lysosomal membrane, and introduced the principles and methods of applying lysosomal detection in marine pollution monitoring. Bivalve shellfish digestive gland and fish liver are the most sensitive organs for lysosomal detection. By adopting the lysosomal detection techniques such as lysosomal membrane stability (LMS) test, neutral red retention time (NRRT) assay, morphological measurement (MM) of lysosome, immunohistochemical (Ih) assay of lysosomal marker enzyme, and electron microscopy (EM), the status of marine pollution can be evaluated. It was suggested that the lysosome could be used as a biomarker for monitoring marine environmental pollution. The advantages and disadvantages of lysosomal detection and some problems worthy of attention were analyzed, and the application prospects of lysosomal detection were discussed.

  10. Enlarging the nosological spectrum of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).

    Science.gov (United States)

    Hoffmann, Sarah; Murrell, Jill; Harms, Lutz; Miller, Kelly; Meisel, Andreas; Brosch, Thomas; Scheel, Michael; Ghetti, Bernardino; Goebel, Hans-Hilmar; Stenzel, Werner

    2014-09-01

    Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system. © 2014 International Society of Neuropathology.

  11. Clinical cytometry and progress in HLA antibody detection.

    Science.gov (United States)

    Bray, Robert A; Tarsitani, Christine; Gebel, Howard M; Lee, Jar-How

    2011-01-01

    For most solid organ and selected stem cell transplants, antibodies against mismatched HLA antigens can lead to early and late graft failure. In recognition of the clinical significance of these antibodies, HLA antibody identification is one of the most critical functions of histocompatibility laboratories. Early methods employed cumbersome and insensitive complement-dependent cytotoxicity assays with a visual read-out. A little over 20 years ago flow cytometry entered the realm of antibody detection with the introduction of the flow cytometric crossmatch. Cytometry's increased sensitivity and objectivity quickly earned it popularity as a preferred crossmatch method especially for sensitized recipients. Although a sensitive method, the flow crossmatch was criticized as being "too sensitive" as false positive reactions were a know drawback. In part, the shortcomings of the flow crossmatch were due to the lack of corresponding sensitive and specific HLA antibody screening assays. However, in the mid 1990s, solid phase assays, capable of utilizing standard flow cytometers, were developed. These assays used microparticles coated with purified HLA molecules. Hence, the era of solid-phase, microparticle technology for HLA antibody detection was born permitting the sensitive and specific detection of HLA antibody. It was now possible to provide better correlation between HLA antibody detection and the flow cytometric crossmatch. This flow-based technology was soon followed by adaptation to the Luminex platform permitting a mutltiplexed approach for the identification and characterization of HLA antibodies. It is hoped that these technologies will ultimately lead to the identification of parameters that best correlate with and/or predict transplant outcomes. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Unravelling the incidence and etiology of chronic idiopathic axonal polyneuropathy

    NARCIS (Netherlands)

    Visser, N.A.

    2016-01-01

    Chronic idiopathic axonal polyneuropathy (CIAP) is a sensory or sensorimotor polyneuropathy that has a slowly progressive course without severe disability. CIAP is diagnosed in a significant proportion of patients with polyneuropathy, but precise figures on the incidence of polyneuropathy and CIAP

  13. Hazard of Sulfonamides and Detection Technology Research Progress

    Science.gov (United States)

    Jiang, Jiahui; Wang, Guangyu

    2017-12-01

    As a kind of widely used antibiotic with typical characteristics, sulfonamides have been greatly applied in clinical medicine for long time. It can’t be effectively treated by pollutant disposal system during pharmaceutical process and utilization and will be discharged into natural environment to be one of the antibiotics with great effect. This kind of substance is difficult to be biodegraded and will be easy to accumulate in the environment, generating huge eco-toxicological effect with significant mutagenicity and teratogenic effect. It is the severe threat for ecological balance, human health and drinking water safety. Its environmental behavior and detection technology attract extensive attention home and abroad.

  14. Dendrosomatic Sonic Hedgehog Signaling in Hippocampal Neurons Regulates Axon Elongation

    Science.gov (United States)

    Petralia, Ronald S.; Ott, Carolyn; Wang, Ya-Xian; Lippincott-Schwartz, Jennifer; Mattson, Mark P.

    2015-01-01

    The presence of Sonic Hedgehog (Shh) and its signaling components in the neurons of the hippocampus raises a question about what role the Shh signaling pathway may play in these neurons. We show here that activation of the Shh signaling pathway stimulates axon elongation in rat hippocampal neurons. This Shh-induced effect depends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1. The axon itself does not respond directly to Shh; instead, the Shh signal transduction originates from the somatodendritic region of the neurons and occurs in neurons with and without detectable primary cilia. Upon Shh stimulation, Smo localization to dendrites increases significantly. Shh pathway activation results in increased levels of profilin1 (Pfn1), an actin-binding protein. Mutations in Pfn1's actin-binding sites or reduction of Pfn1 eliminate the Shh-induced axon elongation. These findings indicate that Shh can regulate axon growth, which may be critical for development of hippocampal neurons. SIGNIFICANCE STATEMENT Although numerous signaling mechanisms have been identified that act directly on axons to regulate their outgrowth, it is not known whether signals transduced in dendrites may also affect axon outgrowth. We describe here a transcellular signaling pathway in embryonic hippocampal neurons in which activation of Sonic Hedgehog (Shh) receptors in dendrites stimulates axon growth. The pathway involves the dendritic-membrane-associated Shh signal transducer Smoothened (Smo) and the transcription factor Gli, which induces the expression of the gene encoding the actin-binding protein profilin 1. Our findings suggest scenarios in which stimulation of Shh in dendrites results in accelerated outgrowth of the axon, which therefore reaches its presumptive postsynaptic target cell more quickly. By this mechanism, Shh may play critical roles in the development of hippocampal neuronal circuits. PMID:26658865

  15. Exploiting Novel Radiation-Induced Electromagnetic Material Changes for Remote Detection and Monitoring: Final Progress Report

    Science.gov (United States)

    2016-04-01

    Exploiting Novel Radiation -Induced Electromagnetic Material Changes for Remote Detection and Monitoring: Final Progress Report Distribution...assess the effects of ionizing radiation on at least three classes of electromagnetic materials. The proposed approach for radiation detection was...that was desired to be monitored remotely. Microwave or low millimeter wave electromagnetic radiation would be used to interrogate the device

  16. Progress in turbulence detection via GNSS occultation data

    Directory of Open Access Journals (Sweden)

    L. B. Cornman

    2012-04-01

    Full Text Available The increased availability of radio occultation (RO data offers the ability to detect and study turbulence in the Earth's atmosphere. An analysis of how RO data can be used to determine the strength and location of turbulent regions is presented. This includes the derivation of a model for the power spectrum of the log-amplitude and phase fluctuations of the permittivity (or index of refraction field. The bulk of the paper is then concerned with the estimation of the model parameters. Parameter estimators are introduced and some of their statistical properties are studied. These estimators are then applied to simulated log-amplitude RO signals. This includes the analysis of global statistics derived from a large number of realizations, as well as case studies that illustrate various specific aspects of the problem. Improvements to the basic estimation methods are discussed, and their beneficial properties are illustrated. The estimation techniques are then applied to real occultation data. Only two cases are presented, but they illustrate some of the salient features inherent in real data.

  17. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport

    Science.gov (United States)

    Freundt, Eric C.; Maynard, Nate; Clancy, Eileen K.; Roy, Shyamali; Bousset, Luc; Sourigues, Yannick; Covert, Markus; Melki, Ronald; Kirkegaard, Karla; Brahic, Michel

    2012-01-01

    Objective The lesions of Parkinson's disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α-synuclein to misfold. Here, we characterized and quantified the axonal transport of α-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport. Methods We grew primary cortical mouse neurons in microfluidic devices to separate soma from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent α-synuclein fibrils and their transfer to second-order neurons. Results Fibrillar α-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar α-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts. Interpretation These results support the hypothesis that the progression of Parkinson's disease can be caused by neuron-to-neuron spread of α-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be transsynaptic gives hope that α-synuclein fibrils could be intercepted by drugs during the extra-cellular phase of their journey. PMID:23109146

  18. Turbo-Proton Echo Planar Spectroscopic Imaging (t-PEPSI) MR technique in the detection of diffuse axonal damage in brain injury. Comparison with Gradient-Recalled Echo (GRE) sequence.

    Science.gov (United States)

    Giugni, E; Sabatini, U; Hagberg, G E; Formisano, R; Castriota-Scanderbeg, A

    2005-01-01

    Diffuse axonal injury (DAI) is a common type of primary neuronal injury in patients with severe traumatic brain injury, and is frequently accompanied by tissue tear haemorrhage. The T2*-weighted gradient-recalled echo (GRE) sequences are more sensitive than T2-weighted spin-echo images for detection of haemorrhage. This study was undertaken to determine whether turbo-PEPSI, an extremely fast multi-echo-planar-imaging sequence, can be used as an alternative to the GRE sequence for detection of DAI. Nineteen patients (mean age 24,5 year) with severe traumatic brain injury (TBI), occurred at least 3 months earlier, underwent a brain MRI study on a 1.5-Tesla scanner. A qualitative evaluation of the turbo-PEPSI sequences was performed by identifying the optimal echo time and in-plane resolution. The number and size of DAI lesions, as well as the signal intensity contrast ratio (SI CR), were computed for each set of GRE and turbo-PEPSI images, and divided according to their anatomic location into lobar and/or deep brain. There was no significant difference between GRE and turbo-PEPSI sequences in the total number of DAI lesions detected (283 vs 225 lesions, respectively). The GRE sequence identified a greater number of hypointense lesions in the temporal lobe compared to the t-PEPSI sequence (72 vs 35, pPEPSI than for the GRE sequence (pPEPSI sequence can be used as an alternative to the GRE to assess brain DAI in severe TBI patients, especially if uncooperative and medically unstable.

  19. Axon density and axon orientation dispersion in children born preterm

    NARCIS (Netherlands)

    Kelly, Claire E.; Thompson, Deanne K.; Chen, Jian; Leemans, Alexander; Adamson, Christopher L.; Inder, Terrie E.; Cheong, Jeanie L Y; Doyle, Lex W.; Anderson, Peter J.

    2016-01-01

    Background Very preterm birth (VPT, <32 weeks' gestation) is associated with altered white matter fractional anisotropy (FA), the biological basis of which is uncertain but may relate to changes in axon density and/or dispersion, which can be measured using Neurite Orientation Dispersion and Density

  20. Optofluidic control of axonal guidance

    Science.gov (United States)

    Gu, Ling; Ordonez, Simon; Black, Bryan; Mohanty, Samarendra K.

    2013-03-01

    Significant efforts are being made for control on axonal guidance due to its importance in nerve regeneration and in the formation of functional neuronal circuitry in-vitro. These include several physical (topographic modification, optical force, and electric field), chemical (surface functionalization cues) and hybrid (electro-chemical, photochemical etc) methods. Here, we report comparison of the effect of linear flow versus microfluidic flow produced by an opticallydriven micromotor in guiding retinal ganglion axons. A circularly polarized laser tweezers was used to hold, position and spin birefringent calcite particle near growth cone, which in turn resulted in microfluidic flow. The flow rate and resulting shear-force on axons could be controlled by a varying the power of the laser tweezers beam. The calcite particles were placed separately in one chamber and single particle was transported through microfluidic channel to another chamber containing the retina explant. In presence of flow, the turning of axons was found to strongly correlate with the direction of flow. Turning angle as high as 90° was achieved. Optofluidic-manipulation can be applied to other types of mammalian neurons and also can be extended to stimulate mechano-sensing neurons.

  1. The axonal cytoskeleton : from organization to function

    NARCIS (Netherlands)

    Kevenaar, Josta T; Hoogenraad, Casper C

    The axon is the single long fiber that extends from the neuron and transmits electrical signals away from the cell body. The neuronal cytoskeleton, composed of microtubules (MTs), actin filaments and neurofilaments, is not only required for axon formation and axonal transport but also provides the

  2. ALS5/SPG11/ KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L.; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H.; Barsottini, Orlando G. P.; Kawarai, Toshitaka

    2016-01-01

    Abstract Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and

  3. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  4. Comparison of Glaucoma Progression Detection by Optical Coherence Tomography and Visual Field.

    Science.gov (United States)

    Zhang, Xinbo; Dastiridou, Anna; Francis, Brian A; Tan, Ou; Varma, Rohit; Greenfield, David S; Schuman, Joel S; Huang, David

    2017-12-01

    To compare longitudinal glaucoma progression detection using optical coherence tomography (OCT) and visual field (VF). Validity assessment. We analyzed subjects with more than 4 semi-annual follow-up visits (every 6 months) in the multicenter Advanced Imaging for Glaucoma Study. Fourier-domain optical coherence tomography (OCT) was used to map the thickness of the peripapillary retinal nerve fiber layer (NFL) and ganglion cell complex (GCC). OCT-based progression detection was defined as a significant negative trend for either NFL or GCC. VF progression was reached if either the event or trend analysis reached significance. The analysis included 356 glaucoma suspect/preperimetric glaucoma (GS/PPG) eyes and 153 perimetric glaucoma (PG) eyes. Follow-up length was 54.1 ± 16.2 months for GS/PPG eyes and 56.7 ± 16.0 for PG eyes. Progression was detected in 62.1% of PG eyes and 59.8% of GS/PPG eyes by OCT, significantly (P glaucoma. While the utility of NFL declines in advanced glaucoma, GCC remains a sensitive progression detector from early to advanced stages. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Growing axons analysis by using Granulometric Size Distribution

    International Nuclear Information System (INIS)

    Gonzalez, Mariela A; Ballarin, Virginia L; Rapacioli, Melina; CelIn, A R; Sanchez, V; Flores, V

    2011-01-01

    Neurite growth (neuritogenesis) in vitro is a common methodology in the field of developmental neurobiology. Morphological analyses of growing neurites are usually difficult because their thinness and low contrast usually prevent to observe clearly their shape, number, length and spatial orientation. This paper presents the use of the granulometric size distribution in order to automatically obtain information about the shape, size and spatial orientation of growing axons in tissue cultures. The results here presented show that the granulometric size distribution results in a very useful morphological tool since it allows the automatic detection of growing axons and the precise characterization of a relevant parameter indicative of the axonal growth spatial orientation such as the quantification of the angle of deviation of the growing direction. The developed algorithms automatically quantify this orientation by facilitating the analysis of these images, which is important given the large number of images that need to be processed for this type of study.

  6. Slowing of axonal regeneration is correlated with increased axonal viscosity during aging

    Directory of Open Access Journals (Sweden)

    Heidemann Steven R

    2010-10-01

    Full Text Available Abstract Background As we age, the speed of axonal regeneration declines. At the biophysical level, why this occurs is not well understood. Results To investigate we first measured the rate of axonal elongation of sensory neurons cultured from neonatal and adult rats. We found that neonatal axons grew 40% faster than adult axons (11.5 µm/hour vs. 8.2 µm/hour. To determine how the mechanical properties of axons change during maturation, we used force calibrated towing needles to measure the viscosity (stiffness and strength of substrate adhesion of neonatal and adult sensory axons. We found no significant difference in the strength of adhesions, but did find that adult axons were 3 times intrinsically stiffer than neonatal axons. Conclusions Taken together, our results suggest decreasing axonal stiffness may be part of an effective strategy to accelerate the regeneration of axons in the adult peripheral nervous system.

  7. Golgi bypass for local delivery of axonal proteins, fact or fiction?

    Science.gov (United States)

    González, Carolina; Cornejo, Víctor Hugo; Couve, Andrés

    2018-04-06

    Although translation of cytosolic proteins is well described in axons, much less is known about the synthesis, processing and trafficking of transmembrane and secreted proteins. A canonical rough endoplasmic reticulum or a stacked Golgi apparatus has not been detected in axons, generating doubts about the functionality of a local route. However, axons contain mRNAs for membrane and secreted proteins, translation factors, ribosomal components, smooth endoplasmic reticulum and post-endoplasmic reticulum elements that may contribute to local biosynthesis and plasma membrane delivery. Here we consider the evidence supporting a local secretory system in axons. We discuss exocytic elements and examples of autonomous axonal trafficking that impact development and maintenance. We also examine whether unconventional post-endoplasmic reticulum pathways may replace the canonical Golgi apparatus. Copyright © 2018. Published by Elsevier Ltd.

  8. Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

    Directory of Open Access Journals (Sweden)

    Andreia F.R. Batista

    2017-09-01

    Full Text Available Localized protein synthesis is a mechanism for developing axons to react acutely and in a spatially restricted manner to extracellular signals. As such, it is important for many aspects of axonal development, but its role in the formation of presynapses remains poorly understood. We found that the induced assembly of presynaptic terminals required local protein synthesis. Newly synthesized proteins were detectable at nascent presynapses within 15 min of inducing synapse formation in isolated axons. The transcript for the t-SNARE protein SNAP25, which is required for the fusion of synaptic vesicles with the plasma membrane, was recruited to presynaptic sites and locally translated. Inhibition of intra-axonal SNAP25 synthesis affected the clustering of SNAP25 and other presynaptic proteins and interfered with the release of synaptic vesicles from presynaptic sites. This study reveals a critical role for the axonal synthesis of SNAP25 in the assembly of presynaptic terminals.

  9. Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats

    Science.gov (United States)

    Muradov, Johongir M.; Ewan, Eric E.; Hagg, Theo

    2013-01-01

    The mechanisms contributing to axon loss after spinal cord injury (SCI) are largely unknown but may involve microvascular loss as we have previously suggested. Here, we used a mild contusive injury (120 kdyn IH impactor) at T9 in rats focusing on ascending primary sensory dorsal column axons, anterogradely traced from the sciatic nerves. The injury caused a rapid and progressive loss of dorsal column microvasculature and oligodendrocytes at the injury site and penumbra and a ~70% loss of the sensory axons, by 24 hours. To model the microvascular loss, focal ischemia of the T9 dorsal columns was achieved via phototoxic activation of intravenously injected rose bengal. This caused an ~53% loss of sensory axons and an ~80% loss of dorsal column oligodendrocytes by 24 hours. Axon loss correlated with the extent and axial length of microvessel and oligodendrocyte loss along the dorsal column. To determine if oligodendrocyte loss contributes to axon loss, the glial toxin ethidium bromide (EB; 0.3 µg/µl) was microinjected into the T9 dorsal columns, and resulted in an ~88% loss of dorsal column oligodendrocytes and an ~56% loss of sensory axons after 72 hours. EB also caused an ~72% loss of microvessels. Lower concentrations of EB resulted in less axon, oligodendrocyte and microvessel loss, which were highly correlated (R2 = 0.81). These data suggest that focal spinal cord ischemia causes both oligodendrocyte and axon degeneration, which are perhaps linked. Importantly, they highlight the need of limiting the penumbral spread of ischemia and oligodendrocyte loss after SCI in order to protect axons. PMID:23978615

  10. Can GPS be used to detect deleterious progression in training volume among runners?

    DEFF Research Database (Denmark)

    Nielsen, Rasmus Oestergaard; Cederholm, Jens Peter; Buist, Ida

    2013-01-01

    There is a need to ascertain if an association exists between excessive progression in weekly volume and development of running-related injuries (RRI). The purpose of this study was to investigate if GPS can be used to detect deleterious progression in weekly training volume among 60 novice runners...... included in a 10-week prospective study. All participants used GPS to quantify training volume while running. In case of injury, participants attended a clinical examination. The 13 runners who sustained injuries during follow-up had a significantly higher weekly progression in total training volume...... in the week before the injury origin (86% [95% confidence interval: 12.9-159.9], p = 0.026) compared with other weeks. Although not significant, participants with injuries had an increase in weekly training volume of 31.6% compared with a 22.1% increase among the healthy participants. The error of the GPS...

  11. Characteristic detected on computed tomography angiography predict coronary artery plaque progression in non-culprit lesions

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Ya Hang; Zhou, Jia Zhou; Zhou, Ying; Yang, Xiaobo; Yang, Jun Jie; Chen, Yun Dai [Dept. of Cardiology, Chinese PLA General Hospital, Beijing (China)

    2017-06-15

    This study sought to determine whether variables detected on coronary computed tomography angiography (CCTA) would predict plaque progression in non-culprit lesions (NCL). In this single-center trial, we analyzed 103 consecutive patients who were undergoing CCTA and percutaneous coronary intervention (PCI) for culprit lesions. Follow-up CCTA was scheduled 12 months after the PCI, and all patients were followed for 3 years after their second CCTA examination. High-risk plaque features and epicardial adipose tissue (EAT) volume were assessed by CCTA. Each NCL stenosis grade was compared visually between two CCTA scans to detect plaque progression, and patients were stratified into two groups based on this. Logistic regression analysis was used to evaluate the factors that were independently associated with plaque progression in NCLs. Time-to-event curves were compared using the log-rank statistic. Overall, 34 of 103 patients exhibited NCL plaque progression (33%). Logistic regression analyses showed that the NCL progression was associated with a history of ST-elevated myocardial infarction (odds ratio [OR] = 5.855, 95% confidence interval [CI] = 1.391–24.635, p = 0.016), follow-up low-density lipoprotein cholesterol level (OR = 6.832, 95% CI = 2.103–22.200, p = 0.001), baseline low-attenuation plaque (OR = 7.311, 95% CI = 1.242–43.028, p = 0.028) and EAT (OR = 1.015, 95% CI = 1.000–1.029, p = 0.044). Following the second CCTA examination, major adverse cardiac events (MACEs) were observed in 12 patients, and NCL plaque progression was significantly associated with future MACEs (log rank p = 0.006). Noninvasive assessment of NCLs by CCTA has potential prognostic value.

  12. Research progress in machine learning methods for gene-gene interaction detection.

    Science.gov (United States)

    Peng, Zhe-Ye; Tang, Zi-Jun; Xie, Min-Zhu

    2018-03-20

    Complex diseases are results of gene-gene and gene-environment interactions. However, the detection of high-dimensional gene-gene interactions is computationally challenging. In the last two decades, machine-learning approaches have been developed to detect gene-gene interactions with some successes. In this review, we summarize the progress in research on machine learning methods, as applied to gene-gene interaction detection. It systematically examines the principles and limitations of the current machine learning methods used in genome wide association studies (GWAS) to detect gene-gene interactions, such as neural networks (NN), random forest (RF), support vector machines (SVM) and multifactor dimensionality reduction (MDR), and provides some insights on the future research directions in the field.

  13. Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice

    Directory of Open Access Journals (Sweden)

    Coralie Fassier

    2013-01-01

    Mutations in SPG4, encoding the microtubule-severing protein spastin, are responsible for the most frequent form of hereditary spastic paraplegia (HSP, a heterogeneous group of genetic diseases characterized by degeneration of the corticospinal tracts. We previously reported that mice harboring a deletion in Spg4, generating a premature stop codon, develop progressive axonal degeneration characterized by focal axonal swellings associated with impaired axonal transport. To further characterize the molecular and cellular mechanisms underlying this mutant phenotype, we have assessed microtubule dynamics and axonal transport in primary cultures of cortical neurons from spastin-mutant mice. We show an early and marked impairment of microtubule dynamics all along the axons of spastin-deficient cortical neurons, which is likely to be responsible for the occurrence of axonal swellings and cargo stalling. Our analysis also reveals that a modulation of microtubule dynamics by microtubule-targeting drugs rescues the mutant phenotype of cortical neurons. Together, these results contribute to a better understanding of the pathogenesis of SPG4-linked HSP and ascertain the influence of microtubule-targeted drugs on the early axonal phenotype in a mouse model of the disease.

  14. Elucidation of axonal transport by radioautography

    International Nuclear Information System (INIS)

    Droz, Bernard.

    1979-01-01

    Radioautography permits to distinguish various pathways within the axons: the axoplasm which includes soluble enzymes and constituents of the cytoskeleton moving with slow axoplasmic flow; the mitochondria which are conveyed as organelles; the smooth endoplasmic reticulum which ensures the fast axonal transport of membrane constituents delivered to axolemma, synaptic vesicles, presynaptic membranes or mitochondria. Furthermore radioautography makes it possible to visualize intercellular exchanges of molecules between axon and glia

  15. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.

    Directory of Open Access Journals (Sweden)

    Fabrice Ango

    2008-04-01

    Full Text Available The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1 is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.

  16. Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets.

    Science.gov (United States)

    Keeler, Austin B; Suo, Dong; Park, Juyeon; Deppmann, Christopher D

    2017-07-01

    Postganglionic sympathetic neurons detect vascular derived neurotrophin 3 (NT3) via the axonally expressed receptor tyrosine kinase, TrkA, to promote chemo-attraction along intermediate targets. Once axons arrive to their final target, a structurally related neurotrophic factor, nerve growth factor (NGF), also acts through TrkA to promote final target innervation. Does TrkA signal differently at these different locales? We previously found that Coronin-1 is upregulated in sympathetic neurons upon exposure to NGF, thereby endowing the NGF-TrkA complex with new signaling capabilities (i.e. calcium signaling), which dampens axon growth and branching. Based on the notion that axons do not express functional levels of Coronin-1 prior to final target innervation, we developed an in vitro model for axon growth and branching along intermediate targets using Coro1a -/- neurons grown in NT3. We found that, similar to NGF-TrkA, NT3-TrkA is capable of inducing MAPK and PI3K in the presence or absence of Coronin-1. However, unlike NGF, NT3 does not induce calcium release from intracellular stores. Using a combination of pharmacology, knockout neurons and in vitro functional assays, we suggest that the NT3-TrkA complex uses Ras/MAPK and/or PI3K-AKT signaling to induce axon growth and inhibit axon branching along intermediate targets. However, in the presence of Coronin-1, these signaling pathways lose their ability to impact NT3 dependent axon growth or branching. This is consistent with a role for Coronin-1 as a molecular switch for axon behavior and suggests that Coronin-1 suppresses NT3 dependent axon behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Motor axon excitability during Wallerian degeneration

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Alvarez, Susana; Krarup, Christian

    2008-01-01

    Axonal loss and degeneration are major factors in determining long-term outcome in patients with peripheral nerve disorders or injury. Following loss of axonal continuity, the isolated nerve stump distal to the lesion undergoes Wallerian degeneration in several phases. In the initial 'latent' phase......, action potential propagation and structural integrity of the distal segment are maintained. The aim of this study was to investigate in vivo the changes in membrane function of motor axons during the 'latent' phase of Wallerian degeneration. Multiple indices of axonal excitability of the tibial nerve...

  18. Axonal regeneration in zebrafish spinal cord

    Science.gov (United States)

    Hui, Subhra Prakash

    2018-01-01

    Abstract In the present review we discuss two interrelated events—axonal damage and repair—known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals. PMID:29721326

  19. Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx

    Science.gov (United States)

    Yamagishi, Yuya; Tessier-Lavigne, Marc

    2015-01-01

    Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled

  20. Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

    Science.gov (United States)

    Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

    2017-01-01

    The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

  1. The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in Drosophila

    Science.gov (United States)

    Duncan, Jason E.; Lytle, Nikki K.; Zuniga, Alfredo; Goldstein, Lawrence S. B.

    2013-01-01

    Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila . The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila , which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila , we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport. PMID:23840848

  2. Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.

    Science.gov (United States)

    Karten, Barbara; Vance, Dennis E; Campenot, Robert B; Vance, Jean E

    2003-02-07

    Niemann Pick type C (NPC) disease is a progressive neurodegenerative disorder. In cells lacking functional NPC1 protein, endocytosed cholesterol accumulates in late endosomes/lysosomes. We utilized primary neuronal cultures in which cell bodies and distal axons reside in separate compartments to investigate the requirement of NPC1 protein for transport of cholesterol from cell bodies to distal axons. We have recently observed that in NPC1-deficient neurons compared with wild-type neurons, cholesterol accumulates in cell bodies but is reduced in distal axons (Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neurochem. 83, 1154-1163). We now show that NPC1 protein is expressed in both cell bodies and distal axons. In NPC1-deficient neurons, cholesterol delivered to cell bodies from low density lipoproteins (LDLs), high density lipoproteins, or cyclodextrin complexes was transported into axons in normal amounts, whereas transport of endogenously synthesized cholesterol was impaired. Inhibition of cholesterol synthesis with pravastatin in wild-type and NPC1-deficient neurons reduced axonal growth. However, LDLs restored a normal rate of growth to wild-type but not NPC1-deficient neurons treated with pravastatin. Thus, although LDL cholesterol is transported into axons of NPC1-deficient neurons, this source of cholesterol does not sustain normal axonal growth. Over the lifespan of NPC1-deficient neurons, these defects in cholesterol transport might be responsible for the observed altered distribution of cholesterol between cell bodies and axons and, consequently, might contribute to the neurological dysfunction in NPC disease.

  3. Real-time progressive hyperspectral image processing endmember finding and anomaly detection

    CERN Document Server

    Chang, Chein-I

    2016-01-01

    The book covers the most crucial parts of real-time hyperspectral image processing: causality and real-time capability. Recently, two new concepts of real time hyperspectral image processing, Progressive Hyperspectral Imaging (PHSI) and Recursive Hyperspectral Imaging (RHSI). Both of these can be used to design algorithms and also form an integral part of real time hyperpsectral image processing. This book focuses on progressive nature in algorithms on their real-time and causal processing implementation in two major applications, endmember finding and anomaly detection, both of which are fundamental tasks in hyperspectral imaging but generally not encountered in multispectral imaging. This book is written to particularly address PHSI in real time processing, while a book, Recursive Hyperspectral Sample and Band Processing: Algorithm Architecture and Implementation (Springer 2016) can be considered as its companion book. Includes preliminary background which is essential to those who work in hyperspectral ima...

  4. Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

    NARCIS (Netherlands)

    Cambron, Melissa; Mostert, Jop; Haentjens, Patrick; D'Hooghe, Marie; Nagels, Guy; Willekens, Barbara; Heersema, Dorothea; Debruyne, Jan; Van Hecke, Wim; Algoed, Luc; De Klippel, Nina; Fosselle, Erwin; Laureys, Guy; Merckx, Henri; Van Wijmeersch, Bart; Vanopdenbosch, Ludo; Verhagen, Wim; Hupperts, Raymond; Hengstman, Gerald; Michiels, Veronique; Van Merhaegen-Wieleman, Annick; De Keyser, Jacques

    2014-01-01

    Background: Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced

  5. Differential effects of myostatin deficiency on motor and sensory axons.

    Science.gov (United States)

    Jones, Maria R; Villalón, Eric; Northcutt, Adam J; Calcutt, Nigel A; Garcia, Michael L

    2017-12-01

    Deletion of myostatin in mice (MSTN -/- ) alters structural properties of peripheral axons. However, properties like axon diameter and myelin thickness were analyzed in mixed nerves, so it is unclear whether loss of myostatin affects motor, sensory, or both types of axons. Using the MSTN -/- mouse model, we analyzed the effects of increasing the number of muscle fibers on axon diameter, myelin thickness, and internode length in motor and sensory axons. Axon diameter and myelin thickness were increased in motor axons of MSTN -/- mice without affecting internode length or axon number. The number of sensory axons was increased without affecting their structural properties. These results suggest that motor and sensory axons establish structural properties by independent mechanisms. Moreover, in motor axons, instructive cues from the neuromuscular junction may play a role in co-regulating axon diameter and myelin thickness, whereas internode length is established independently. Muscle Nerve 56: E100-E107, 2017. © 2017 Wiley Periodicals, Inc.

  6. Ascending Midbrain Dopaminergic Axons Require Descending GAD65 Axon Fascicles for Normal Pathfinding

    Directory of Open Access Journals (Sweden)

    Claudia Marcela Garcia-Peña

    2014-06-01

    Full Text Available The Nigrostriatal pathway (NSP is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold.

  7. Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function.

    Science.gov (United States)

    Cioni, Jean-Michel; Wong, Hovy Ho-Wai; Bressan, Dario; Kodama, Lay; Harris, William A; Holt, Christine E

    2018-03-07

    The axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that cytoplasmic FMR1-interacting proteins (CYFIPs) fulfill non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2's function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics, and optic tract sorting. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Dynamics of mitochondrial transport in axons

    Directory of Open Access Journals (Sweden)

    Robert Francis Niescier

    2016-05-01

    Full Text Available The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons.

  9. Detection of molecular biomarkers as a diagnostic tool in the planning and progression of orthodontic treatment

    Directory of Open Access Journals (Sweden)

    Aditi Gaur

    2017-01-01

    Full Text Available Orthodontic treatment focuses on providing patient care at the appropriate timing to utilize the growth potential for best results. It involves growth modification of the craniofacial region along with alveolar bone remodeling during tooth movement. The dynamic process of bone metabolism involves the release of biochemical mediators in the circulation. These molecules are indicative of the bone remodeling activity of osteoblastic deposition and osteoclastic resorption. Such biomarkers when detectable in the systemic circulation highlight the skeletal maturity of orthodontic patients and when detected locally as, in gingival crevicular fluid (GCF and saliva, indicate the progression of orthodontically induced alveolar bone remodeling. Assessment of molecular biomarkers of bone remodeling in the body fluids would aid the clinicians in planning orthodontic treatment at the ideal timing and evaluating the advent of the treatment.

  10. Meninges-derived cues control axon guidance.

    Science.gov (United States)

    Suter, Tracey A C S; DeLoughery, Zachary J; Jaworski, Alexander

    2017-10-01

    The axons of developing neurons travel long distances along stereotyped pathways under the direction of extracellular cues sensed by the axonal growth cone. Guidance cues are either secreted proteins that diffuse freely or bind the extracellular matrix, or membrane-anchored proteins. Different populations of axons express distinct sets of receptors for guidance cues, which results in differential responses to specific ligands. The full repertoire of axon guidance cues and receptors and the identity of the tissues producing these cues remain to be elucidated. The meninges are connective tissue layers enveloping the vertebrate brain and spinal cord that serve to protect the central nervous system (CNS). The meninges also instruct nervous system development by regulating the generation and migration of neural progenitors, but it has not been determined whether they help guide axons to their targets. Here, we investigate a possible role for the meninges in neuronal wiring. Using mouse neural tissue explants, we show that developing spinal cord meninges produce secreted attractive and repulsive cues that can guide multiple types of axons in vitro. We find that motor and sensory neurons, which project axons across the CNS-peripheral nervous system (PNS) boundary, are attracted by meninges. Conversely, axons of both ipsi- and contralaterally projecting dorsal spinal cord interneurons are repelled by meninges. The responses of these axonal populations to the meninges are consistent with their trajectories relative to meninges in vivo, suggesting that meningeal guidance factors contribute to nervous system wiring and control which axons are able to traverse the CNS-PNS boundary. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Parmenion P. Tsitsopoulos

    2017-11-01

    Full Text Available Traumatic brain injury (TBI is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key

  12. Environmental Subconcussive Injury, Axonal Injury, and Chronic Traumatic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Wendy A. Morley

    2018-03-01

    Full Text Available Brain injury occurs in two phases: the initial injury itself and a secondary cascade of precise immune-based neurochemical events. The secondary phase is typically functional in nature and characterized by delayed axonal injury with more axonal disconnections occurring than in the initial phase. Axonal injury occurs across the spectrum of disease severity, with subconcussive injury, especially when repetitive, now considered capable of producing significant neurological damage consistent with axonal injury seen in clinically evident concussion, despite no observable symptoms. This review is the first to introduce the concept of environmental subconcussive injury (ESCI and sets out how secondary brain damage from ESCI once past the juncture of microglial activation appears to follow the same neuron-damaging pathway as secondary brain damage from conventional brain injury. The immune response associated with ESCI is strikingly similar to that mounted after conventional concussion. Specifically, microglial activation is followed closely by glutamate and calcium flux, excitotoxicity, reactive oxygen species and reactive nitrogen species (RNS generation, lipid peroxidation, and mitochondrial dysfunction and energy crisis. ESCI damage also occurs in two phases, with the primary damage coming from microbiome injury (due to microbiome-altering events and secondary damage (axonal injury from progressive secondary neurochemical events. The concept of ESCI and the underlying mechanisms have profound implications for the understanding of chronic traumatic encephalopathy (CTE etiology because it has previously been suggested that repetitive axonal injury may be the primary CTE pathogenesis in susceptible individuals and it is best correlated with lifetime brain trauma load. Taken together, it appears that susceptibility to brain injury and downstream neurodegenerative diseases, such as CTE, can be conceptualized as a continuum of brain resilience. At one end

  13. Pathophysiologic insights into motor axonal function in Kennedy disease.

    Science.gov (United States)

    Vucic, Steve; Kiernan, Matthew C

    2007-11-06

    Kennedy disease (KD), or spinobulbomuscular atrophy, is a slowly progressive inherited neurodegenerative disorder, marked by prominent fasciculations that typically precede the development of other symptoms. Although the genetic basis of KD relates to triplet (CAG) repeat expansion in the androgen receptor (AR) gene on the X chromosome, the mechanisms underlying the clinical presentation in KD have yet to be established. Consequently, the present study applied axonal excitability techniques to investigate the pathophysiologic mechanisms associated with KD. Peripheral nerve excitability studies were undertaken in 7 patients with KD with compound muscle action potentials (CMAP) recorded from the right abductor pollicis brevis. Strength-duration time constant (KD 0.54 +/- 0.03 msec; controls, 0.41 +/- 0.02 msec, p TEd [90 to 100 msec], 50.75 +/- 1.98%; controls TEd [90 to 100 msec], 45.67 +/- 0.67%, p < 0.01) and hyperpolarizing (KD TEh [90 to 100 msec], 128.5 +/- 6.9%; controls TEh [90 to 100 msec], 120.5 +/- 2.4%) conditioning pulses. Measurements of refractoriness, superexcitability, and late subexcitability changed appropriately for axonal hyperpolarization, perhaps reflecting the effects of increased ectopic activity. In total, the increase in the strength-duration time constant may be the primary event, occurring early in course of the disease, contributing to the development of axonal hyperexcitability in Kennedy disease, and thereby to the generation of fasciculations, a characteristic hallmark of the disease.

  14. In vivo electrophysiological measurement of the rat ulnar nerve with axonal excitability testing

    DEFF Research Database (Denmark)

    Wild, Brandon M.; Morris, Renée; Moldovan, Mihai

    2018-01-01

    Electrophysiology enables the objective assessment of peripheral nerve function in vivo. Traditional nerve conduction measures such as amplitude and latency detect chronic axon loss and demyelination, respectively. Axonal excitability techniques "by threshold tracking" expand upon these measures...... by providing information regarding the activity of ion channels, pumps and exchangers that relate to acute function and may precede degenerative events. As such, the use of axonal excitability in animal models of neurological disorders may provide a useful in vivo measure to assess novel therapeutic...... interventions. Here we describe an experimental setup for multiple measures of motor axonal excitability techniques in the rat ulnar nerve. The animals are anesthetized with isoflurane and carefully monitored to ensure constant and adequate depth of anesthesia. Body temperature, respiration rate, heart rate...

  15. Dynamics of target recognition by interstitial axon branching along developing cortical axons.

    Science.gov (United States)

    Bastmeyer, M; O'Leary, D D

    1996-02-15

    Corticospinal axons innervate their midbrain, hindbrain, and spinal targets by extending collateral branches interstitially along their length. To establish that the axon shaft rather than the axonal growth cone is responsible for target recognition in this system, and to characterize the dynamics of interstitial branch formation, we have studied this process in an in vivo-like setting using slice cultures from neonatal mice containing the entire pathway of corticospinal axons. Corticospinal axons labeled with the dye 1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (or Dil) were imaged using time-lapse video microscopy of their pathway overlying the basilar pons, their major hindbrain target. The axon shaft millimeters behind the growth cone exhibits several dynamic behaviors, including the de novo formation of varicosities and filopodia-like extensions, and a behavior that we term "pulsation," which is characterized by a variable thickening and thining of short segments of the axon. An individual axon can have multiple sites of branching activity, with many of the branches being transient. These dynamic behaviors occur along the portion of the axon shaft overlying the basilar pons, but not just caudal to it. Once the collaterals extend into the pontine neuropil, they branch further in the neuropil, while the parent axon becomes quiescent. Thus, the branching activity is spatially restricted to specific portions of the axon, as well as temporally restricted to a relatively brief time window. These findings provide definitive evidence that collateral branches form de novo along corticospinal axons and establish that the process of target recognition in this system is a property of the axon shaft rather than the leading growth cone.

  16. Clinical evaluation of a novel population-based regression analysis for detecting glaucomatous visual field progression.

    Science.gov (United States)

    Kovalska, M P; Bürki, E; Schoetzau, A; Orguel, S F; Orguel, S; Grieshaber, M C

    2011-04-01

    The distinction of real progression from test variability in visual field (VF) series may be based on clinical judgment, on trend analysis based on follow-up of test parameters over time, or on identification of a significant change related to the mean of baseline exams (event analysis). The aim of this study was to compare a new population-based method (Octopus field analysis, OFA) with classic regression analyses and clinical judgment for detecting glaucomatous VF changes. 240 VF series of 240 patients with at least 9 consecutive examinations available were included into this study. They were independently classified by two experienced investigators. The results of such a classification served as a reference for comparison for the following statistical tests: (a) t-test global, (b) r-test global, (c) regression analysis of 10 VF clusters and (d) point-wise linear regression analysis. 32.5 % of the VF series were classified as progressive by the investigators. The sensitivity and specificity were 89.7 % and 92.0 % for r-test, and 73.1 % and 93.8 % for the t-test, respectively. In the point-wise linear regression analysis, the specificity was comparable (89.5 % versus 92 %), but the sensitivity was clearly lower than in the r-test (22.4 % versus 89.7 %) at a significance level of p = 0.01. A regression analysis for the 10 VF clusters showed a markedly higher sensitivity for the r-test (37.7 %) than the t-test (14.1 %) at a similar specificity (88.3 % versus 93.8 %) for a significant trend (p = 0.005). In regard to the cluster distribution, the paracentral clusters and the superior nasal hemifield progressed most frequently. The population-based regression analysis seems to be superior to the trend analysis in detecting VF progression in glaucoma, and may eliminate the drawbacks of the event analysis. Further, it may assist the clinician in the evaluation of VF series and may allow better visualization of the correlation between function and structure owing to VF

  17. Cargo distributions differentiate pathological axonal transport impairments.

    Science.gov (United States)

    Mitchell, Cassie S; Lee, Robert H

    2012-05-07

    Axonal transport is an essential process in neurons, analogous to shipping goods, by which energetic and cellular building supplies are carried downstream (anterogradely) and wastes are carried upstream (retrogradely) by molecular motors, which act as cargo porters. Impairments in axonal transport have been linked to devastating and often lethal neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis, Huntington's, and Alzheimer's. Axonal transport impairment types include a decrease in available motors for cargo transport (motor depletion), the presence of defective or non-functional motors (motor dilution), and the presence of increased or larger cargos (protein aggregation). An impediment to potential treatment identification has been the inability to determine what type(s) of axonal transport impairment candidates that could be present in a given disease. In this study, we utilize a computational model and common axonal transport experimental metrics to reveal the axonal transport impairment general characteristics or "signatures" that result from three general defect types of motor depletion, motor dilution, and protein aggregation. Our results not only provide a means to discern these general impairments types, they also reveal key dynamic and emergent features of axonal transport, which potentially underlie multiple impairment types. The identified characteristics, as well as the analytical method, can be used to help elucidate the axonal transport impairments observed in experimental and clinical data. For example, using the model-predicted defect signatures, we identify the defect candidates, which are most likely to be responsible for the axonal transport impairments in the G93A SOD1 mouse model of ALS. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Axonal inclusions in the crab Hemigrapsus nudus.

    Science.gov (United States)

    Smith, R S

    1978-10-01

    Light microscopic examination of living giant axons from the walking legs of Hemigrapsus nudus revealed intra-axonal inclusions which were usually several tens of micrometers long and about 5 micron wide. The inclusions were filled with small light-scattering particles. The inclusions were shown, by thin section electron microscopy, to be composed largely 68% by volume) of mitochondria. Each inclusion was surrounded by membrane bounded spaces which are presumed to represent a part of the smooth endoplasmic reticulum. Similar inclusions were not found in the leg axons of a variety of other decapod crustaceans.

  19. A joint estimation detection of Glaucoma progression in 3D spectral domain optical coherence tomography optic nerve head images

    Science.gov (United States)

    Belghith, Akram; Bowd, Christopher; Weinreb, Robert N.; Zangwill, Linda M.

    2014-03-01

    Glaucoma is an ocular disease characterized by distinctive changes in the optic nerve head (ONH) and visual field. Glaucoma can strike without symptoms and causes blindness if it remains without treatment. Therefore, early disease detection is important so that treatment can be initiated and blindness prevented. In this context, important advances in technology for non-invasive imaging of the eye have been made providing quantitative tools to measure structural changes in ONH topography, an essential element for glaucoma detection and monitoring. 3D spectral domain optical coherence tomography (SD-OCT), an optical imaging technique, has been commonly used to discriminate glaucomatous from healthy subjects. In this paper, we present a new framework for detection of glaucoma progression using 3D SD-OCT images. In contrast to previous works that the retinal nerve fiber layer (RNFL) thickness measurement provided by commercially available spectral-domain optical coherence tomograph, we consider the whole 3D volume for change detection. To integrate a priori knowledge and in particular the spatial voxel dependency in the change detection map, we propose the use of the Markov Random Field to handle a such dependency. To accommodate the presence of false positive detection, the estimated change detection map is then used to classify a 3D SDOCT image into the "non-progressing" and "progressing" glaucoma classes, based on a fuzzy logic classifier. We compared the diagnostic performance of the proposed framework to existing methods of progression detection.

  20. Emphysema progression is visually detectable in low-dose CT in continuous but not in former smokers

    DEFF Research Database (Denmark)

    Wille, Mathilde Marie Winkler; Thomsen, Laura H.; Dirksen, Asger

    2014-01-01

    prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes......: Visual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not. KEY POINTS: • Substantial interobserver consistency in determining early-stage emphysema in low-dose CT. • Longitudinal analyses show clear...... time-trends for emphysema presence and grading. • For continuous smokers, progression of emphysema was seen in all lung zones. • For former smokers, progression of emphysema was undetectable by visual assessment. • Onset and progression of interstitial abnormalities are visually detectable....

  1. Optimal filter design with progressive genetic algorithm for local damage detection in rolling bearings

    Science.gov (United States)

    Wodecki, Jacek; Michalak, Anna; Zimroz, Radoslaw

    2018-03-01

    Harsh industrial conditions present in underground mining cause a lot of difficulties for local damage detection in heavy-duty machinery. For vibration signals one of the most intuitive approaches of obtaining signal with expected properties, such as clearly visible informative features, is prefiltration with appropriately prepared filter. Design of such filter is very broad field of research on its own. In this paper authors propose a novel approach to dedicated optimal filter design using progressive genetic algorithm. Presented method is fully data-driven and requires no prior knowledge of the signal. It has been tested against a set of real and simulated data. Effectiveness of operation has been proven for both healthy and damaged case. Termination criterion for evolution process was developed, and diagnostic decision making feature has been proposed for final result determinance.

  2. Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges.

    Science.gov (United States)

    Root, Alex; Allen, Peter; Tempst, Paul; Yu, Kenneth

    2018-03-07

    Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary

  3. Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges

    Directory of Open Access Journals (Sweden)

    Alex Root

    2018-03-01

    Full Text Available Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but

  4. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins.

    Science.gov (United States)

    Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O'Sullivan, Niamh C; Kang, Zi Han; Roost, Annika; Thomas, Matthew R; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O'Kane, Cahir J

    2017-07-25

    Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

  5. Con-nectin axons and dendrites.

    Science.gov (United States)

    Beaudoin, Gerard M J

    2006-07-03

    Unlike adherens junctions, synapses are asymmetric connections, usually between axons and dendrites, that rely on various cell adhesion molecules for structural stability and function. Two cell types of adhesion molecules found at adherens junctions, cadherins and nectins, are thought to mediate homophilic interaction between neighboring cells. In this issue, Togashi et al. (see p. 141) demonstrate that the differential localization of two heterophilic interacting nectins mediates the selective attraction of axons and dendrites in cooperation with cadherins.

  6. [Research Progress of Vitreous Humor Detection Technique on Estimation of Postmortem Interval].

    Science.gov (United States)

    Duan, W C; Lan, L M; Guo, Y D; Zha, L; Yan, J; Ding, Y J; Cai, J F

    2018-02-01

    Estimation of postmortem interval (PMI) plays a crucial role in forensic study and identification work. Because of the unique anatomy location, vitreous humor is considered to be used for estima- ting PMI, which has aroused interest among scholars, and some researches have been carried out. The detection techniques of vitreous humor are constantly developed and improved which have been gradually applied in forensic science, meanwhile, the study of PMI estimation using vitreous humor is updated rapidly. This paper reviews various techniques and instruments applied to vitreous humor detection, such as ion selective electrode, capillary ion analysis, spectroscopy, chromatography, nano-sensing technology, automatic biochemical analyser, flow cytometer, etc., as well as the related research progress on PMI estimation in recent years. In order to provide a research direction for scholars and promote a more accurate and efficient application in PMI estimation by vitreous humor analysis, some inner problems are also analysed in this paper. Copyright© by the Editorial Department of Journal of Forensic Medicine.

  7. Glaucoma progression detection with frequency doubling technology (FDT) compared to standard automated perimetry (SAP) in the Groningen Longitudinal Glaucoma Study.

    Science.gov (United States)

    Wesselink, Christiaan; Jansonius, Nomdo M

    2017-09-01

    To determine the usefulness of frequency doubling perimetry (FDT) for progression detection in glaucoma, compared to standard automated perimetry (SAP). Data were used from 150 eyes of 150 glaucoma patients from the Groningen Longitudinal Glaucoma Study. After baseline, SAP was performed approximately yearly; FDT every other year. First and last visit had to contain both tests. Using linear regression, progression velocities were calculated for SAP (Humphrey Field Analyzer) mean deviation (MD) and FDT MD and the number of test locations with a total deviation probability below p glaucoma progression in patients who cannot perform SAP reliably. © 2017 The Authors Ophthalmic & Physiological Optics © 2017 The College of Optometrists.

  8. Glaucoma progression detection by retinal nerve fiber layer measurement using scanning laser polarimetry: event and trend analysis.

    Science.gov (United States)

    Moon, Byung Gil; Sung, Kyung Rim; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S

    2012-06-01

    To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression.

  9. Sensory-motor axonal polyneuropathy involving cranial nerves: An uncommon manifestation of disulfiram toxicity.

    Science.gov (United States)

    Santos, Telma; Martins Campos, António; Morais, Hugo

    2017-01-01

    Disulfiram (tetraethylthiuram disulfide) has been used for the treatment of alcohol dependence. An axonal sensory-motor polyneuropathy with involvement of cranial pairs due to disulfiram is exceedingly rare. The authors report a unique case of an extremely severe axonal polyneuropathy involving cranial nerves that developed within weeks after a regular dosage of 500mg/day disulfiram. To the authors best knowledge, such a severe and rapidly-progressive course has never been described with disulfiram dosages of only 500mg/day. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Molecular and metabolic pattern classification for detection of brain glioma progression

    Energy Technology Data Exchange (ETDEWEB)

    Imani, Farzin, E-mail: imanif@upmc.edu [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Boada, Fernando E. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Lieberman, Frank S. [Department of Neurology, University of Pittsburgh Medical Center, PA (United States); Davis, Denise K.; Mountz, James M. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States)

    2014-02-15

    %. Conclusion: This study suggests that SVM models may improve detection of glioma progression more accurately than single parametric imaging methods. Research support: National Cancer Institute, Cancer Center Support Grant Supplement Award, Imaging Response Assessment Teams.

  11. EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment

    Czech Academy of Sciences Publication Activity Database

    Eva, R.; Koseki, H.; Kanamarlapudi, V.; Fawcett, James

    2017-01-01

    Roč. 130, č. 21 (2017), s. 3663-3675 ISSN 0021-9533 Institutional support: RVO:68378041 Keywords : axon regeneration * axon transport * neuronal polarisation Subject RIV: FH - Neurology OBOR OECD: Neuroscience s (including psychophysiology Impact factor: 4.431, year: 2016

  12. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy

    NARCIS (Netherlands)

    Kole, Maarten H. P.; Letzkus, Johannes J.; Stuart, Greg J.

    2007-01-01

    Action potentials are binary signals that transmit information via their rate and temporal pattern. In this context, the axon is thought of as a transmission line, devoid of a role in neuronal computation. Here, we show a highly localized role of axonal Kv1 potassium channels in shaping the action

  13. Mitochondrial Dynamics Decrease Prior to Axon Degeneration Induced by Vincristine and are Partially Rescued by Overexpressed cytNmnat1.

    Directory of Open Access Journals (Sweden)

    Gregory Berbusse

    2016-07-01

    Full Text Available Axon degeneration is a prominent feature of various neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and is often characterized by aberrant mitochondrial dynamics. Mitochondrial fission, fusion, and motility have been shown to be particularly important in progressive neurodegeneration. Thus we investigated these imperative dynamics, as well as mitochondrial fragmentation in vincristine induced axon degradation in cultured DRG neurons. CytNmnat1 inhibits axon degeneration in various paradigms including vincristine toxicity. The mechanism of its protection is not yet fully understood; therefore, we also investigated the effect of cytNmnat1 on mitochondrial dynamics in vincristine treated neurons. We observed that vincristine treatment decreases the rate of mitochondrial fission, fusion and motility and induces mitochondrial fragmentation. These mitochondrial events precede visible axon degeneration. Overexpression of cytNmnat1 inhibits axon degeneration and preserves the normal mitochondrial dynamics and motility in vincristine treated neurons. We suggest the alterations in mitochondrial structure and dynamics are early events which lead to axon degeneration and cytNmnat1 blocks axon degeneration by halting the vincristine induced changes to mitochondrial structure and dynamics.

  14. Polygalae Radix Extract Prevents Axonal Degeneration and Memory Deficits in a Transgenic Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Kuboyama, Tomoharu; Hirotsu, Keisuke; Arai, Tetsuya; Yamasaki, Hiroo; Tohda, Chihiro

    2017-01-01

    Memory impairments in Alzheimer's disease (AD) occur due to degenerated axons and disrupted neural networks. Since only limited recovery is possible after the destruction of neural networks, preventing axonal degeneration during the early stages of disease progression is necessary to prevent AD. Polygalae Radix (roots of Polygala tenuifolia ; PR) is a traditional herbal medicine used for sedation and amnesia. In this study, we aimed to clarify and analyze the preventive effects of PR against memory deficits in a transgenic AD mouse model, 5XFAD. 5XFAD mice demonstrated memory deficits at the age of 5 months. Thus, the water extract of Polygalae Radix (PR extract) was orally administered to 4-month-old 5XFAD mice that did not show signs of memory impairment. After consecutive administrations for 56 days, the PR extract prevented cognitive deficit and axon degeneration associated with the accumulation of amyloid β (Aβ) plaques in the perirhinal cortex of the 5XFAD mice. PR extract did not influence the formation of Aβ plaques in the brain of the 5XFAD mice. In cultured neurons, the PR extract prevented axonal growth cone collapse and axonal atrophy induced by Aβ. Additionally, it prevented Aβ-induced endocytosis at the growth cone of cultured neurons. Our previous study reported that endocytosis inhibition was enough to prevent Aβ-induced growth cone collapse, axonal degeneration, and memory impairments. Therefore, the PR extract possibly prevented axonal degeneration and memory impairment by inhibiting endocytosis. PR is the first preventive drug candidate for AD that inhibits endocytosis in neurons.

  15. hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons.

    Science.gov (United States)

    Briese, Michael; Saal-Bauernschubert, Lena; Ji, Changhe; Moradi, Mehri; Ghanawi, Hanaa; Uhl, Michael; Appenzeller, Silke; Backofen, Rolf; Sendtner, Michael

    2018-03-20

    Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance. Copyright © 2018 the Author(s). Published by PNAS.

  16. Laboratory database population surveillance to improve detection of progressive chronic kidney disease.

    Science.gov (United States)

    Kennedy, David M; Chatha, Kamaljit; Rayner, Hugh C

    2013-09-01

    Some patients with chronic kidney disease are still referred late for specialist care despite the evidence that earlier detection and intervention can halt or delay progression to end-stage kidney disease (ESKD). To develop a population surveillance system using existing laboratory data to enable early detection of patients at high risk of ESKD by reviewing cumulative graphs of estimated glomerular filtration rate (eGFR). A database was developed, updated daily with data from the laboratory computer. Cumulative eGFR graphs containing up to five years of data are reviewed by clinical scientists for all primary care patients or out-patients with a low eGFR for their age. For those with a declining trend, a report containing the eGFR graph is sent to the requesting doctor. A retrospective audit was performed using historical data to assess the predictive value of the graphs. In nine months, we reported 370,000 eGFR results, reviewing 12,000 eGFR graphs. On average 60 graphs per week were flagged as 'high' or 'intermediate' risk. Patients with graphs flagged as high risk had a significantly higher mortality after 3.5 years and a significantly greater chance of requiring renal replacement therapy after 4.5 years of follow-up. Five patients (7%) with graphs flagged as high risk had a sustained >25% fall in eGFR without evidence of secondary care referral. Feedback about the service from requesting clinicians was 73% positive. We have developed a system for laboratory staff to review cumulative eGFR graphs for a large population and identify patients at highest risk of developing ESKD. Further research is needed to measure the impact of this service on patient outcomes. © 2013 European Dialysis and Transplant Nurses Association/European Renal Care Association.

  17. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

    Science.gov (United States)

    Zambonin, Jessica L.; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R.; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M.; Turnbull, Doug M.; Trapp, Bruce D.; Lassmann, Hans; Franklin, Robin J. M.

    2011-01-01

    Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in

  18. Epigenetic regulation of axon and dendrite growth

    Directory of Open Access Journals (Sweden)

    Ephraim F Trakhtenberg

    2012-03-01

    Full Text Available Neuroregenerative therapies for central nervous system (CNS injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and reinnervate their targets. However, mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases (Yiu and He, 2006. CNS’ regenerative failure may be attributable to the development of an inhibitory CNS environment by glial-associated inhibitory molecules (Yiu and He, 2006, and by various cell-autonomous factors (Sun and He, 2010. Intrinsic axon growth ability also declines developmentally (Li et al., 1995; Goldberg et al., 2002; Bouslama-Oueghlani et al., 2003; Blackmore and Letourneau, 2006 and is dependent on transcription (Moore et al., 2009. Although neurons’ intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors (Moore and Goldberg, 2011, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. Thus a potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. Here we review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study.

  19. Guidance of retinal axons in mammals.

    Science.gov (United States)

    Herrera, Eloísa; Erskine, Lynda; Morenilla-Palao, Cruz

    2017-11-26

    In order to navigate through the surrounding environment many mammals, including humans, primarily rely on vision. The eye, composed of the choroid, sclera, retinal pigmented epithelium, cornea, lens, iris and retina, is the structure that receives the light and converts it into electrical impulses. The retina contains six major types of neurons involving in receiving and modifying visual information and passing it onto higher visual processing centres in the brain. Visual information is relayed to the brain via the axons of retinal ganglion cells (RGCs), a projection known as the optic pathway. The proper formation of this pathway during development is essential for normal vision in the adult individual. Along this pathway there are several points where visual axons face 'choices' in their direction of growth. Understanding how these choices are made has advanced significantly our knowledge of axon guidance mechanisms. Thus, the development of the visual pathway has served as an extremely useful model to reveal general principles of axon pathfinding throughout the nervous system. However, due to its particularities, some cellular and molecular mechanisms are specific for the visual circuit. Here we review both general and specific mechanisms involved in the guidance of mammalian RGC axons when they are traveling from the retina to the brain to establish precise and stereotyped connections that will sustain vision. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology

    DEFF Research Database (Denmark)

    Herwerth, Marina; Kalluri, Sudhakar Reddy; Srivastava, Rajneesh

    2016-01-01

    IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics...... antibodies in mice. RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4...... antibody concentration and complement, specifically C1q. INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread...

  1. Partial Denervation of Subbasal Axons Persists Following Debridement Wounds to the Mouse Cornea

    Science.gov (United States)

    Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri; Kyne, Briana M.; Saban, Daniel R.; Stepp, Mary Ann

    2015-01-01

    Although sensory reinnervation occurs after injury in the PNS, poor reinnervation in the elderly and those with diabetes often leads to pathology. Here we quantify subbasal axon density in the central and peripheral mouse cornea over time after three different types of injury. The mouse cornea is highly innervated with a dense array of subbasal nerves that form a spiral called the vortex at the corneal center or apex; these nerves are readily detected within flat mounted corneas. After anesthesia, corneal epithelial cells were removed using either a dulled blade or a rotating burr within an area demarcated centrally with a 1.5 mm trephine. A third wound type, superficial trephination, involved demarcating the area with the 1.5 mm trephine but not removing cells. By 7d after superficial trephination, subbasal axon density returns to control levels; by 28d the vortex reforms. Although axon density is similar to control 14d after dulled blade and rotating burr wounding, defects in axon morphology at the corneal apex remain. After 14d, axons retract from the center leaving the subbasal axon density reduced by 37.2% and 36.8% at 28d after dulled blade and rotating burr wounding, respectively, compared to control. Assessment of inflammation using flow cytometry shows that persistent inflammation is not a factor in the incomplete reinnervation. Expression of mRNAs encoding 22 regeneration associated genes (RAGs) involved in axon targeting assessed by QPCR reveals that netrin-1 and ephrin signaling are altered after wounding. Subpopulations of corneal epithelial basal cells at the corneal apex stop expressing ki67 as early as 7d after injury and by 14d and 28d after wounding, many of these basal cells undergo apoptosis and die. While subbasal axons are restored to their normal density and morphology after superficial trephination, subbasal axon recovery is partial after debridement wounds. The increase in corneal epithelial basal cell apoptosis at the apex observed at 14d

  2. Partial denervation of sub-basal axons persists following debridement wounds to the mouse cornea.

    Science.gov (United States)

    Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri; Kyne, Briana M; Saban, Daniel R; Stepp, Mary Ann

    2015-11-01

    Although sensory reinnervation occurs after injury in the peripheral nervous system, poor reinnervation in the elderly and those with diabetes often leads to pathology. Here we quantify sub-basal axon density in the central and peripheral mouse cornea over time after three different types of injury. The mouse cornea is highly innervated with a dense array of sub-basal nerves that form a spiral called the vortex at the corneal center or apex; these nerves are readily detected within flat mounted corneas. After anesthesia, corneal epithelial cells were removed using either a dulled blade or a rotating burr within an area demarcated centrally with a 1.5 mm trephine. A third wound type, superficial trephination, involved demarcating the area with the 1.5 mm trephine but not removing cells. By 7 days after superficial trephination, sub-basal axon density returns to control levels; by 28 days the vortex reforms. Although axon density is similar to control 14 days after dulled blade and rotating burr wounding, defects in axon morphology at the corneal apex remain. After 14 days, axons retract from the center leaving the sub-basal axon density reduced by 37.2 and 36.8% at 28 days after dulled blade and rotating burr wounding, respectively, compared with control. Assessment of inflammation using flow cytometry shows that persistent inflammation is not a factor in the incomplete reinnervation. Expression of mRNAs encoding 22 regeneration-associated genes involved in axon targeting assessed by QPCR reveals that netrin-1 and ephrin signaling are altered after wounding. Subpopulations of corneal epithelial basal cells at the corneal apex stop expressing ki67 as early as 7 days after injury and by 14 and 28 days after wounding, many of these basal cells undergo apoptosis and die. Although sub-basal axons are restored to their normal density and morphology after superficial trephination, sub-basal axon recovery is partial after debridement wounds. The increase in corneal

  3. Detection of Progressive Retinal Nerve Fiber Layer Loss in Glaucoma Using Scanning Laser Polarimetry with Variable Corneal Compensation

    Science.gov (United States)

    Medeiros, Felipe A.; Alencar, Luciana M.; Zangwill, Linda M.; Bowd, Christopher; Vizzeri, Gianmarco; Sample, Pamela A.; Weinreb, Robert N.

    2010-01-01

    Purpose To evaluate the ability of scanning laser polarimetry with variable corneal compensation to detect progressive retinal nerve fiber layer (RNFL) loss in glaucoma patients and patients suspected of having the disease. Methods This was an observational cohort study that included 335 eyes of 195 patients. Images were obtained annually with the GDx VCC scanning laser polarimeter, along with optic disc stereophotographs and standard automated perimetry (SAP) visual fields. The median follow-up time was 3.94 years. Progression was determined using commercial software for SAP and by masked assessment of optic disc stereophotographs performed by expert graders. Random coefficient models were used to evaluate the relationship between RNFL thickness measurements over time and progression as determined by SAP and/or stereophotographs. Results From the 335 eyes, 34 (10%) showed progression over time by stereophotographs and/or SAP. Average GDx VCC measurements decreased significantly over time for both progressors as well as non-progressors. However, the rate of decline was significantly higher in the progressing group (−0.70 μm/year) compared to the non-progressing group (−0.14 μm/year; P = 0.001). Black race and male sex were significantly associated with higher rates of RNFL loss during follow-up. Conclusions The GDx VCC scanning laser polarimeter was able to identify longitudinal RNFL loss in eyes that showed progression in optic disc stereophotographs and/or visual fields. These findings suggest that this technology could be useful to detect and monitor progressive disease in patients with established diagnosis of glaucoma or suspected of having the disease. PMID:19029038

  4. Creatine pretreatment protects cortical axons from energy depletion in vitro

    Science.gov (United States)

    Shen, Hua; Goldberg, Mark P.

    2012-01-01

    Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID:22521466

  5. Nociceptive DRG neurons express muscle lim protein upon axonal injury.

    Science.gov (United States)

    Levin, Evgeny; Andreadaki, Anastasia; Gobrecht, Philipp; Bosse, Frank; Fischer, Dietmar

    2017-04-04

    Muscle lim protein (MLP) has long been regarded as a cytosolic and nuclear muscular protein. Here, we show that MLP is also expressed in a subpopulation of adult rat dorsal root ganglia (DRG) neurons in response to axonal injury, while the protein was not detectable in naïve cells. Detailed immunohistochemical analysis of L4/L5 DRG revealed ~3% of MLP-positive neurons 2 days after complete sciatic nerve crush and maximum ~10% after 4-14 days. Similarly, in mixed cultures from cervical, thoracic, lumbar and sacral DRG ~6% of neurons were MLP-positive after 2 days and maximal 17% after 3 days. In both, histological sections and cell cultures, the protein was detected in the cytosol and axons of small diameter cells, while the nucleus remained devoid. Moreover, the vast majority could not be assigned to any of the well characterized canonical DRG subpopulations at 7 days after nerve injury. However, further analysis in cell culture revealed that the largest population of MLP expressing cells originated from non-peptidergic IB4-positive nociceptive neurons, which lose their ability to bind the lectin upon axotomy. Thus, MLP is mostly expressed in a subset of axotomized nociceptive neurons and can be used as a novel marker for this population of cells.

  6. Immunohistochemical and transcriptome analyses indicate complex breakdown of axonal transport mechanisms in canine distemper leukoencephalitis.

    Science.gov (United States)

    Spitzbarth, Ingo; Lempp, Charlotte; Kegler, Kristel; Ulrich, Reiner; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Seehusen, Frauke

    2016-07-01

    CDV-DL (Canine distemper virus-induced demyelinating leukoencephalitis) represents a spontaneously occurring animal model for demyelinating disorders. Axonopathy represents a key pathomechanism in this disease; however, its underlying pathogenesis has not been addressed in detail so far. This study aimed at the characterization of axonal cytoskeletal, transport, and potential regenerative changes with a parallel focus upon Schwann cell remyelination. Immunohistochemistry of canine cerebellar tissue as well as a comparative analysis of genes from an independent microarray study were performed. Increased axonal immunoreactivity for nonphosphorylated neurofilament was followed by loss of cytoskeletal and motor proteins. Interestingly, a subset of genes encoding for neurofilament subunits and motor proteins was up-regulated in the chronic stage compared to dogs with subacute CDV-DL. However, immunohistochemically, hints for axonal regeneration were restricted to up-regulated axonal positivity of hypoxia-inducible factor 1 alpha, while growth-associated protein 43, erythropoietin and its receptor were not or even down-regulated. Periaxin-positive structures, indicative of Schwann cell remyelination, were only detected within few advanced lesions. The present findings demonstrate a complex sequence of axonal cytoskeletal breakdown mechanisms. Moreover, though sparse, this is the first report of Schwann cell remyelination in CDV-DL. Facilitation of these very limited endogenous regenerative responses represents an important topic for future research.

  7. Sodium channels in axons and glial cells of the optic nerve of Necturus maculosa.

    Science.gov (United States)

    Tang, C M; Strichartz, G R; Orkand, R K

    1979-11-01

    Experiments investigating both the binding of radioactively labelled saxitoxin (STX) and the electrophysiological response to drugs that increase the sodium permeability of excitable membranes were conducted in an effort to detect sodium channels in glial cells of the optic nerve of Necturus maculosa, the mudpuppy. Glial cells in nerves from chronically enucleated animals, which lack optic nerve axons, show no saturable uptake of STX whereas a saturable uptake is clearly present in normal optic nerves. The normal nerve is depolarized by aconitine, batrachotoxin, and veratridine (10(-6)-10(-5) M), whereas the all-glial preparation is only depolarized by veratridine and at concentrations greater than 10(-3) M. Unlike the depolarization caused by veratridine in normal nerves, the response in the all-glial tissue is not blocked by tetrodotoxin nor enhanced by scorpion venom (Leiurus quinquestriatus). In glial cells of the normal nerve, where axons are also present, the addition of 10(-5) M veratridine does lead to a transient depolarization; however, it is much briefer than the axonal response to veratridine in this same tissue. This glial response to veratridine could be caused by the efflux of K+ from the drug-depolarized axons, and is similar to the glial response to extracellular K+ accumulation resulting from action potentials in the axon.

  8. Macrophages Promote Axon Regeneration with Concurrent Neurotoxicity

    NARCIS (Netherlands)

    Gensel, J.C.; Nakamura, S.; Guan, Z.; Rooijen, van N.; Ankeny, D.P.; Popovich, P.G.

    2009-01-01

    Activated macrophages can promote regeneration of CNS axons. However, macrophages also release factors that kill neurons. These opposing functions are likely induced simultaneously but are rarely considered together in the same experimental preparation. A goal of this study was to unequivocally

  9. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

    Directory of Open Access Journals (Sweden)

    Frederickson Martyn

    2010-01-01

    Full Text Available Abstract Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal

  10. New Approaches for Early Detection of Breast Tumor Invasion or Progression

    National Research Council Canada - National Science Library

    Man, Yan-Gao

    2003-01-01

    To assess interactions between epithelial (EP) and myoepithelial (ME) cells in association with breast tumor progression and invasion, a double immunostaining technique with antibodies to smooth muscle actin (SMA...

  11. Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion

    Directory of Open Access Journals (Sweden)

    Ren Song

    2016-02-01

    Full Text Available Infection by alphaherpesviruses, including herpes simplex virus (HSV and pseudorabies virus (PRV, typically begins at epithelial surfaces and continues into the peripheral nervous system (PNS. Inflammatory responses are induced at the infected peripheral site prior to invasion of the PNS. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which includes the interferons (IFNs. The fundamental question is how do PNS cell bodies respond to these distant, potentially damaging events experienced by axons. Using compartmented cultures that physically separate neuron axons from cell bodies, we found that pretreating isolated axons with beta interferon (IFN-β or gamma interferon (IFN-γ significantly diminished the number of herpes simplex virus 1 (HSV-1 and PRV particles moving in axons toward the cell bodies in a receptor-dependent manner. Exposing axons to IFN-β induced STAT1 phosphorylation (p-STAT1 only in axons, while exposure of axons to IFN-γ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated antiviral effects induced by IFN-γ, but not those induced by IFN-β. Proteomic analysis of IFN-β- or IFN-γ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFN-γ, IFN-β induces a noncanonical, local antiviral response in axons. The activation of a local IFN response in axons represents a new paradigm for cytokine control of neuroinvasion.

  12. Axon degeneration: make the Schwann cell great again

    Directory of Open Access Journals (Sweden)

    Keit Men Wong

    2017-01-01

    Full Text Available Axonal degeneration is a pivotal feature of many neurodegenerative conditions and substantially accounts for neurological morbidity. A widely used experimental model to study the mechanisms of axonal degeneration is Wallerian degeneration (WD, which occurs after acute axonal injury. In the peripheral nervous system (PNS, WD is characterized by swift dismantling and clearance of injured axons with their myelin sheaths. This is a prerequisite for successful axonal regeneration. In the central nervous system (CNS, WD is much slower, which significantly contributes to failed axonal regeneration. Although it is well-documented that Schwann cells (SCs have a critical role in the regenerative potential of the PNS, to date we have only scarce knowledge as to how SCs 'sense' axonal injury and immediately respond to it. In this regard, it remains unknown as to whether SCs play the role of a passive bystander or an active director during the execution of the highly orchestrated disintegration program of axons. Older reports, together with more recent studies, suggest that SCs mount dynamic injury responses minutes after axonal injury, long before axonal breakdown occurs. The swift SC response to axonal injury could play either a pro-degenerative role, or alternatively a supportive role, to the integrity of distressed axons that have not yet committed to degenerate. Indeed, supporting the latter concept, recent findings in a chronic PNS neurodegeneration model indicate that deactivation of a key molecule promoting SC injury responses exacerbates axonal loss. If this holds true in a broader spectrum of conditions, it may provide the grounds for the development of new glia-centric therapeutic approaches to counteract axonal loss.

  13. Detection of COPD, lung function decline and emphysema progression in heavy smokers

    NARCIS (Netherlands)

    Mohamed Hoesein, F.A.A.

    2012-01-01

    The work presented in this thesis has improved our insights in important determinants of lung function decline and emphysema progression in heavy smokers. Secondly, it improved our insight on the question which threshold of FEV1/FVC is most appropriate in diagnosing COPD. We showed in chapter 2 that

  14. The Actin-Binding Protein α-Adducin Is Required for Maintaining Axon Diameter

    Directory of Open Access Journals (Sweden)

    Sérgio Carvalho Leite

    2016-04-01

    Full Text Available The actin-binding protein adducin was recently identified as a component of the neuronal subcortical cytoskeleton. Here, we analyzed mice lacking adducin to uncover the function of this protein in actin rings. α-adducin knockout mice presented progressive axon enlargement in the spinal cord and optic and sciatic nerves, followed by axon degeneration and loss. Using stimulated emission depletion super-resolution microscopy, we show that a periodic subcortical actin cytoskeleton is assembled in every neuron type inspected including retinal ganglion cells and dorsal root ganglia neurons. In neurons devoid of adducin, the actin ring diameter increased, although the inter-ring periodicity was maintained. In vitro, the actin ring diameter adjusted as axons grew, suggesting the lattice is dynamic. Our data support a model in which adducin activity is not essential for actin ring assembly and periodicity but is necessary to control the diameter of both actin rings and axons and actin filament growth within rings.

  15. The Actin-Binding Protein α-Adducin Is Required for Maintaining Axon Diameter.

    Science.gov (United States)

    Leite, Sérgio Carvalho; Sampaio, Paula; Sousa, Vera Filipe; Nogueira-Rodrigues, Joana; Pinto-Costa, Rita; Peters, Luanne Laurel; Brites, Pedro; Sousa, Mónica Mendes

    2016-04-19

    The actin-binding protein adducin was recently identified as a component of the neuronal subcortical cytoskeleton. Here, we analyzed mice lacking adducin to uncover the function of this protein in actin rings. α-adducin knockout mice presented progressive axon enlargement in the spinal cord and optic and sciatic nerves, followed by axon degeneration and loss. Using stimulated emission depletion super-resolution microscopy, we show that a periodic subcortical actin cytoskeleton is assembled in every neuron type inspected including retinal ganglion cells and dorsal root ganglia neurons. In neurons devoid of adducin, the actin ring diameter increased, although the inter-ring periodicity was maintained. In vitro, the actin ring diameter adjusted as axons grew, suggesting the lattice is dynamic. Our data support a model in which adducin activity is not essential for actin ring assembly and periodicity but is necessary to control the diameter of both actin rings and axons and actin filament growth within rings. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Axonal excitability properties in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Vucic, Steve; Kiernan, Matthew C

    2006-07-01

    To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.

  17. Latest Progress of Fault Detection and Localization in Complex Electrical Engineering

    Science.gov (United States)

    Zhao, Zheng; Wang, Can; Zhang, Yagang; Sun, Yi

    2014-01-01

    In the researches of complex electrical engineering, efficient fault detection and localization schemes are essential to quickly detect and locate faults so that appropriate and timely corrective mitigating and maintenance actions can be taken. In this paper, under the current measurement precision of PMU, we will put forward a new type of fault detection and localization technology based on fault factor feature extraction. Lots of simulating experiments indicate that, although there are disturbances of white Gaussian stochastic noise, based on fault factor feature extraction principal, the fault detection and localization results are still accurate and reliable, which also identifies that the fault detection and localization technology has strong anti-interference ability and great redundancy.

  18. Research Progress of Space-Time Adaptive Detection for Airborne Radar

    Directory of Open Access Journals (Sweden)

    Wang Yong-liang

    2014-04-01

    Full Text Available Compared with Space-Time Adaptive Processing (STAP, Space-Time Adaptive Detection (STAD employs the data in the cell under test and those in the training to form reasonable detection statistics and consequently decides whether the target exists or not. The STAD has concise processing procedure and flexible design. Furthermore, the detection statistics usually possess the Constant False Alarm Rate (CFAR property, and hence it needs no additional CFAR processing. More importantly, the STAD usually exhibits improved detection performance than that of the conventional processing, which first suppresses the clutter then adopts other detection strategy. In this paper, we first summarize the key strongpoint of the STAD, then make a classification for the STAD, and finally give some future research tracks.

  19. Synaptic Democracy and Vesicular Transport in Axons

    Science.gov (United States)

    Bressloff, Paul C.; Levien, Ethan

    2015-04-01

    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  20. Retinoic acid signaling in axonal regeneration

    Directory of Open Access Journals (Sweden)

    Radhika ePuttagunta

    2012-01-01

    Full Text Available Following an acute central nervous system injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. Retinoic acid (RA signaling, essential in developmental dorsoventral patterning and specification of spinal motor neurons, has been shown through its receptor, the transcription factor RA receptor β2 (RARß2, to induce axonal regeneration following spinal cord injury (SCI. Recently, it has been shown that in dorsal root ganglia neurons, cAMP levels were greatly increased by lentiviral RARβ2 expression and contributed to neurite outgrowth. Moreover, RARβ agonists, in cerebellar granule neurons and in the brain in vivo, induced phosphoinositide 3-kinase dependent phosphorylation of AKT that was involved in RARβ-dependent neurite outgrowth. More recently, RA-RARß pathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field.

  1. En masse in vitro functional profiling of the axonal mechanosensitivity of sensory neurons.

    Science.gov (United States)

    Usoskin, Dmitry; Zilberter, Misha; Linnarsson, Sten; Hjerling-Leffler, Jens; Uhlén, Per; Harkany, Tibor; Ernfors, Patrik

    2010-09-14

    Perception of the environment relies on somatosensory neurons. Mechanosensory, proprioceptor and many nociceptor subtypes of these neurons have specific mechanosensitivity profiles to adequately differentiate stimulus patterns. Nevertheless, the cellular basis of differential mechanosensation remains largely elusive. Successful transduction of sensory information relies on the recruitment of sensory neurons and mechanosensation occurring at their peripheral axonal endings in vivo. Conspicuously, existing in vitro models aimed to decipher molecular mechanisms of mechanosensation test single sensory neuron somata at any one time. Here, we introduce a compartmental in vitro chamber design to deliver precisely controlled mechanical stimulation of sensory axons with synchronous real-time imaging of Ca(2+) transients in neuronal somata that reliably reflect action potential firing patterns. We report of three previously not characterized types of mechanosensitive neuron subpopulations with distinct intrinsic axonal properties tuned specifically to static indentation or vibration stimuli, showing that different classes of sensory neurons are tuned to specific types of mechanical stimuli. Primary receptor currents of vibration neurons display rapidly adapting conductance reliably detected for every single stimulus during vibration and are consistently converted into action potentials. This result allows for the characterization of two critical steps of mechanosensation in vivo: primary signal detection and signal conversion into specific action potential firing patterns in axons.

  2. T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases.

    Science.gov (United States)

    Newman, T A; Woolley, S T; Hughes, P M; Sibson, N R; Anthony, D C; Perry, V H

    2001-11-01

    Recent evidence has highlighted the fact that axon injury is an important component of multiple sclerosis pathology. The issue of whether a CNS antigen-specific immune response is required to produce axon injury remains unresolved. We investigated the extent and time course of axon injury in a rodent model of a delayed-type hypersensitivity (DTH) reaction directed against the mycobacterium bacille Calmette-Guérin (BCG). Using MRI, we determined whether the ongoing axon injury is restricted to the period during which the blood-brain barrier is compromised. DTH lesions were initiated in adult rats by intracerebral injection of heat-killed BCG followed by a peripheral challenge with BCG. Our findings demonstrate that a DTH reaction to a non-CNS antigen within a CNS white matter tract leads to axon injury. Ongoing axon injury persisted throughout the 3-month period studied and was not restricted to the period of blood-brain barrier breakdown, as detected by MRI enhancing lesions. We have previously demonstrated that matrix metalloproteinases (MMPs) are upregulated in multiple sclerosis plaques and DTH lesions. In this study we demonstrated that microinjection of activated MMPs into the cortical white matter results in axon injury. Our results show that axon injury, possibly mediated by MMPs, is immunologically non-specific and may continue behind an intact blood-brain barrier.

  3. Cooperative Interactions between 480 kDa Ankyrin-G and EB proteins assemble the axon initial segment

    NARCIS (Netherlands)

    Fréal, Amélie|info:eu-repo/dai/nl/412516721; Fassier, Coralie; Le Bras, Barbara; Bullier, Erika; de Gois, Stéphanie; Hazan, Jamilé; Hoogenraad, Casper C.|info:eu-repo/dai/nl/227263502; Couraud, François

    2016-01-01

    The axon initial segment (AIS) is required for generating action potentials and maintaining neuronal polarity. Significant progress has been made in deciphering the basic building blocks composing the AIS, but the underlying mechanisms required for AIS formation remains unclear. The scaffolding

  4. Action potential propagation recorded from single axonal arbors using multi-electrode arrays.

    Science.gov (United States)

    Tovar, Kenneth R; Bridges, Daniel C; Wu, Bian; Randall, Connor; Audouard, Morgane; Jang, Jiwon; Hansma, Paul K; Kosik, Kenneth S

    2018-04-11

    We report the presence of co-occurring extracellular action potentials (eAPs) from cultured mouse hippocampal neurons among groups of planar electrodes on multi-electrode arrays (MEAs). The invariant sequences of eAPs among co-active electrode groups, repeated co-occurrences and short inter-electrode latencies are consistent with action potential propagation in unmyelinated axons. Repeated eAP co-detection by multiple electrodes was widespread in all our data records. Co-detection of eAPs confirms they result from the same neuron and allows these eAPs to be isolated from all other spikes independently of spike sorting algorithms. We averaged co-occurring events and revealed additional electrodes with eAPs that would otherwise be below detection threshold. We used these eAP cohorts to explore the temperature sensitivity of action potential propagation and the relationship between voltage-gated sodium channel density and propagation velocity. The sequence of eAPs among co-active electrodes 'fingerprints' neurons giving rise to these events and identifies them within neuronal ensembles. We used this property and the non-invasive nature of extracellular recording to monitor changes in excitability at multiple points in single axonal arbors simultaneously over several hours, demonstrating independence of axonal segments. Over several weeks, we recorded changes in inter-electrode propagation latencies and ongoing changes in excitability in different regions of single axonal arbors. Our work illustrates how repeated eAP co-occurrences can be used to extract physiological data from single axons with low electrode density MEAs. However, repeated eAP co-occurrences leads to over-sampling spikes from single neurons and thus can confound traditional spike-train analysis.

  5. Dependence of regenerated sensory axons on continuous neurotrophin-3 delivery.

    Science.gov (United States)

    Hou, Shaoping; Nicholson, LaShae; van Niekerk, Erna; Motsch, Melanie; Blesch, Armin

    2012-09-19

    Previous studies have shown that injured dorsal column sensory axons extend across a spinal cord lesion site if axons are guided by a gradient of neurotrophin-3 (NT-3) rostral to the lesion. Here we examined whether continuous NT-3 delivery is necessary to sustain regenerated axons in the injured spinal cord. Using tetracycline-regulated (tet-off) lentiviral gene delivery, NT-3 expression was tightly controlled by doxycycline administration. To examine axon growth responses to regulated NT-3 expression, adult rats underwent a C3 dorsal funiculus lesion. The lesion site was filled with bone marrow stromal cells, tet-off-NT-3 virus was injected rostral to the lesion site, and the intrinsic growth capacity of sensory neurons was activated by a conditioning lesion. When NT-3 gene expression was turned on, cholera toxin β-subunit-labeled sensory axons regenerated into and beyond the lesion/graft site. Surprisingly, the number of regenerated axons significantly declined when NT-3 expression was turned off, whereas continued NT-3 expression sustained regenerated axons. Quantification of axon numbers beyond the lesion demonstrated a significant decline of axon growth in animals with transient NT-3 expression, only some axons that had regenerated over longer distance were sustained. Regenerated axons were located in white matter and did not form axodendritic synapses but expressed presynaptic markers when closely associated with NG2-labeled cells. A decline in axon density was also observed within cellular grafts after NT-3 expression was turned off possibly via reduction in L1 and laminin expression in Schwann cells. Thus, multiple mechanisms underlie the inability of transient NT-3 expression to fully sustain regenerated sensory axons.

  6. Formation of longitudinal axon pathways in Caenorhabditis elegans.

    Science.gov (United States)

    Hutter, Harald

    2017-11-18

    The small number of neurons and the simple architecture of the Caenorhabditis elegans (C. elegans) nervous system enables researchers to study axonal pathfinding at the level of individually identified axons. Axons in C. elegans extend predominantly along one of the two major body axes, the anterior-posterior axis and the dorso-ventral axis. This review will focus on axon navigation along the anterior-posterior axis, leading to the establishment of the longitudinal axon tracts, with a focus on the largest longitudinal axon tract, the ventral nerve cord (VNC). In the VNC, axons grow out in a stereotypic order, with early outgrowing axons (pioneers) playing an important role in guiding later outgrowing (follower) axons. Genetic screens have identified a number of genes specifically affecting the formation of longitudinal axon tracts. These genes include secreted proteins, putative receptors and adhesion molecules, as well as intracellular proteins regulating the cell's response to guidance cues. In contrast to dorso-ventral navigation, no major general guidance cues required for the establishment of longitudinal pathways have been identified so far. The limited penetrance of defects found in many mutants affecting longitudinal navigation suggests that guidance cues act redundantly in this process. The majority of the axon guidance genes identified in C. elegans are evolutionary conserved, i.e. have homologs in other animals, including vertebrates. For a number of these genes, a role in axon guidance has not been described outside C. elegans. Taken together, studies in C. elegans contribute to a fundamental understanding of the molecular basis of axonal navigation that can be extended to other animals, including vertebrates and probably humans as well. Copyright © 2017. Published by Elsevier Ltd.

  7. Early Magnetic Resonance Detection of Natalizumab-Related Progressive Multifocal Leukoencephalopathy in a Patient with Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Guglielmo Manenti

    2013-01-01

    Full Text Available Diagnosis of progressive multifocal leukoencephalopathy is usually based on the clinical presentation, on the demonstration of the brain lesions at the magnetic resonance imaging examination, and on the detection of the JC virus DNA in the cerebrospinal fluid with high sensitive polymerase chain reaction. The role of magnetic resonance imaging specifically in natalizumab-associated progressive multifocal leukoencephalopathy is strengthening, and it is gaining importance not only as an irreplaceable diagnostic tool but also as a surveillance and risk stratifying tool in treated patients. While other imaging techniques such as computed tomography lack sensitivity and specificity, magnetic resonance performed with morphological and functional sequences offers clinicians the possibility to early identify the stage of the disease and the emergence of an immune reconstitution inflammatory syndrome after natalizumab blood removal plasmapheresis.

  8. PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma.

    Science.gov (United States)

    Zamagni, Elena; Nanni, Cristina; Mancuso, Katia; Tacchetti, Paola; Pezzi, Annalisa; Pantani, Lucia; Zannetti, Beatrice; Rambaldi, Ilaria; Brioli, Annamaria; Rocchi, Serena; Terragna, Carolina; Martello, Marina; Marzocchi, Giulia; Borsi, Enrica; Rizzello, Ilaria; Fanti, Stefano; Cavo, Michele

    2015-10-01

    To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012. All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months. Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression. PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression. ©2015 American Association for Cancer Research.

  9. Progress in evaluation of human observer visual detection performance using the ROC curve approach

    International Nuclear Information System (INIS)

    Metz, C.E.; Starr, S.J.; Lusted, L.B.; Rossmann, K.

    1976-01-01

    The ROC approach to analysis of human observer detection performance as playing a key role in elucidation the relationships among the physical parameters of an imaging operation, the ability of a human observer to use the image to make decisions regarding the state of health or disease in a medical diagnostic situation, and the medical and social utility of those decisions, was studied. The conventional ROC curve describing observer performance in simple detection tasks can be used to predict observer performance in complex detection tasks. The conventional ROC curve thus provides a description of observer detection performance which is useful in situations more relevant clinically than those for which it is measured. Similar predictions regarding observer performance in identification and recognition tasks are currently being sought. The ROC curve can be used to relate signal detectability to various measures of the diagnostic and social benefit derived from a medical imaging procedure. These relationships provide a means for assessing the relative desirability of alternative diagnostic techniques and can be used to evaluate combinations of diagnostic studies

  10. Analysis of ovine colostrum to detect antibody against progressive pneumonia virus.

    OpenAIRE

    Taylor, T B; Banowetz, G M; Schipper, I A; Gabrielson, D A

    1982-01-01

    Immunoglobulins were isolated and purified from the colostrum and serum of progressive pneumonia virus infected sheep and also from non-infected control sheep. Four classes of immunoglobulins were isolated from sheep colostrum (IgG1, IgG2, IgA and Ig10s). Three classes of immunoglobulins were isolated from sheep serum (IgG1, IgG2 and IgM). Low levels of virus neutralizing activity were demonstrated only in the whole serum and purified serum IgG1 preparations. No complement fixing activity was...

  11. [Research Progress on the Detection Method of DNA Methylation and Its Application in Forensic Science].

    Science.gov (United States)

    Nie, Y C; Yu, L J; Guan, H; Zhao, Y; Rong, H B; Jiang, B W; Zhang, T

    2017-06-01

    As an important part of epigenetic marker, DNA methylation involves in the gene regulation and attracts a wide spread attention in biological auxology, geratology and oncology fields. In forensic science, because of the relative stable, heritable, abundant, and age-related characteristics, DNA methylation is considered to be a useful complement to the classic genetic markers for age-prediction, tissue-identification, and monozygotic twins' discrimination. Various methods for DNA methylation detection have been validated based on methylation sensitive restriction endonuclease, bisulfite modification and methylation-CpG binding protein. In recent years, it is reported that the third generation sequencing method can be used to detect DNA methylation. This paper aims to make a review on the detection method of DNA methylation and its applications in forensic science. Copyright© by the Editorial Department of Journal of Forensic Medicine.

  12. Can injured adult CNS axons regenerate by recapitulating development?

    Science.gov (United States)

    Hilton, Brett J; Bradke, Frank

    2017-10-01

    In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

  13. Detection and quantification of proteins and cells by use of elemental mass spectrometry: progress and challenges.

    Science.gov (United States)

    Yan, Xiaowen; Yang, Limin; Wang, Qiuquan

    2013-07-01

    Much progress has been made in identification of the proteins in proteomes, and quantification of these proteins has attracted much interest. In addition to popular tandem mass spectrometric methods based on soft ionization, inductively coupled plasma mass spectrometry (ICPMS), a typical example of mass spectrometry based on hard ionization, usually used for analysis of elements, has unique advantages in absolute quantification of proteins by determination of an element with a definite stoichiometry in a protein or attached to the protein. In this Trends article, we briefly describe state-of-the-art ICPMS-based methods for quantification of proteins, emphasizing protein-labeling and element-tagging strategies developed on the basis of chemically selective reactions and/or biospecific interactions. Recent progress from protein to cell quantification by use of ICPMS is also discussed, and the possibilities and challenges of ICPMS-based protein quantification for universal, selective, or targeted quantification of proteins and cells in a biological sample are also discussed critically. We believe ICPMS-based protein quantification will become ever more important in targeted quantitative proteomics and bioanalysis in the near future.

  14. Cutaneous collateral axonal sprouting re-innervates the skin component and restores sensation of denervated Swine osteomyocutaneous alloflaps.

    Directory of Open Access Journals (Sweden)

    Zuhaib Ibrahim

    Full Text Available Reconstructive transplantation such as extremity and face transplantation is a viable treatment option for select patients with devastating tissue loss. Sensorimotor recovery is a critical determinant of overall success of such transplants. Although motor function recovery has been extensively studied, mechanisms of sensory re-innervation are not well established. Recent clinical reports of face transplants confirm progressive sensory improvement even in cases where optimal repair of sensory nerves was not achieved. Two forms of sensory nerve regeneration are known. In regenerative sprouting, axonal outgrowth occurs from the transected nerve stump while in collateral sprouting, reinnervation of denervated tissue occurs through growth of uninjured axons into the denervated tissue. The latter mechanism may be more important in settings where transected sensory nerves cannot be re-apposed. In this study, denervated osteomyocutaneous alloflaps (hind- limb transplants from Major Histocompatibility Complex (MHC-defined MGH miniature swine were performed to specifically evaluate collateral axonal sprouting for cutaneous sensory re-innervation. The skin component of the flap was externalized and serial skin sections extending from native skin to the grafted flap were biopsied. In order to visualize regenerating axonal structures in the dermis and epidermis, 50 um frozen sections were immunostained against axonal and Schwann cell markers. In all alloflaps, collateral axonal sprouts from adjacent recipient skin extended into the denervated skin component along the dermal-epidermal junction from the periphery towards the center. On day 100 post-transplant, regenerating sprouts reached 0.5 cm into the flap centripetally. Eight months following transplant, epidermal fibers were visualized 1.5 cm from the margin (rate of regeneration 0.06 mm per day. All animals had pinprick sensation in the periphery of the transplanted skin within 3 months post

  15. Polygalae Radix Extract Prevents Axonal Degeneration and Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Tomoharu Kuboyama

    2017-11-01

    Full Text Available Memory impairments in Alzheimer’s disease (AD occur due to degenerated axons and disrupted neural networks. Since only limited recovery is possible after the destruction of neural networks, preventing axonal degeneration during the early stages of disease progression is necessary to prevent AD. Polygalae Radix (roots of Polygala tenuifolia; PR is a traditional herbal medicine used for sedation and amnesia. In this study, we aimed to clarify and analyze the preventive effects of PR against memory deficits in a transgenic AD mouse model, 5XFAD. 5XFAD mice demonstrated memory deficits at the age of 5 months. Thus, the water extract of Polygalae Radix (PR extract was orally administered to 4-month-old 5XFAD mice that did not show signs of memory impairment. After consecutive administrations for 56 days, the PR extract prevented cognitive deficit and axon degeneration associated with the accumulation of amyloid β (Aβ plaques in the perirhinal cortex of the 5XFAD mice. PR extract did not influence the formation of Aβ plaques in the brain of the 5XFAD mice. In cultured neurons, the PR extract prevented axonal growth cone collapse and axonal atrophy induced by Aβ. Additionally, it prevented Aβ-induced endocytosis at the growth cone of cultured neurons. Our previous study reported that endocytosis inhibition was enough to prevent Aβ-induced growth cone collapse, axonal degeneration, and memory impairments. Therefore, the PR extract possibly prevented axonal degeneration and memory impairment by inhibiting endocytosis. PR is the first preventive drug candidate for AD that inhibits endocytosis in neurons.

  16. Progress in analysis of computed tomography (CT) images of hardwood logs for defect detection

    Science.gov (United States)

    Erol Sarigul; A. Lynn Abbott; Daniel L. Schmoldt

    2003-01-01

    This paper addresses the problem of automatically detecting internal defects in logs using computed tomography (CT) images. The overall purpose is to assist in breakdown optimization. Several studies have shown that the commercial value of resulting boards can be increased substantially if defect locations are known in advance, and if this information is used to make...

  17. Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Phillips, Andrew N; Clotet, Bonaventura

    2008-01-01

    OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400...... copies/ml in the time window between 0.5 and 2 years from starting antiretroviral therapy (baseline). Patients were grouped according to evidence of virological failure and whether there was detection of the International AIDS Society resistance mutations to one, two or three drug classes in the time...... or death was 20.3% (95% CI:17.7-22.9) in patients with no evidence of virological failure and 53% (39.3-66.7) in those with virological failure and mutations to three drug classes (P = 0.0001). An almost two-fold difference in risk was confirmed in the multivariable analysis (adjusted relative hazard = 1...

  18. Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer.

    Science.gov (United States)

    Messaritakis, Ippokratis; Stogiannitsi, Maria; Koulouridi, Asimina; Sfakianaki, Maria; Voutsina, Alexandra; Sotiriou, Afroditi; Athanasakis, Elias; Xynos, Evangelos; Mavroudis, Dimitris; Tzardi, Maria; Souglakos, John

    2018-01-01

    Toll-like receptors (TLRs) play essential role in innate and acquired immunity, are expressed in various cell types, and are associated with altered susceptibility to many diseases, and cancers. The aim of this study was to investigate TLR2 (-196 to-174del), TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T1237C and T1486C) gene polymorphisms at risk of colorectal cancer (CRC) development and progression. Peripheral blood was obtained from 397 patients with adjuvant (stage II/III, n = 202) and metastatic (n = 195) CRC. Moreover, blood samples from 50 healthy volunteers and 40 patients with adenomatous polyps were also included as control groups. DNA from patients and controls was analyzed using PCR and PCR-RFLP for genotyping functional polymorphism within TLR2, TLR4 and TLR9 genotypes. TLR2-196 to-174del/del genotype was detected in 76.6% of the patients and was significantly higher that the controls groups (p<0.001). TLR4 Asp299Gly, TLR4 Thr399Ile, TLR9 T1237C and T1486C homozygous genotypes were detected in 70.5%, 70.5%, 61.5% and 61.5% of the patients respectively, and were also significantly higher than that in the control groups (p<0.001). All polymorphisms detected were also significantly associated with the metastatic disease (p<0.001) leading to shorter overall survival (p<0.001); whereas, TLR4 Asp299Gly and Thr399Ile polymorphisms were significantly associated with KRAS mutations. The detection of higher frequencies of the TLR2, TLR4 and/or TLR9 polymorphisms in CRC patients compared with the control groups highlight the role of these polymorphism in CRC development and cancer progression.

  19. The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms.

    Science.gov (United States)

    Geoffroy, Cédric G; Meves, Jessica M; Zheng, Binhai

    2017-06-23

    Age is an important consideration for recovery and repair after spinal cord injury. Spinal cord injury is increasingly affecting the middle-aged and aging populations. Despite rapid progress in research to promote axonal regeneration and repair, our understanding of how age can modulate this repair is rather limited. In this review, we discuss the literature supporting the notion of an age-dependent decline in axonal growth after central nervous system (CNS) injury. While both neuron-intrinsic and extrinsic factors are involved in the control of axon growth after injury, here we focus on possible intrinsic mechanisms for this age-dependent decline. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy

    DEFF Research Database (Denmark)

    Fenrich, Keith K; Skelton, Nicole; MacDermid, Victoria E

    2007-01-01

    Following proximal axotomy, several types of neurons sprout de novo axons from distal dendrites. These processes may represent a means of forming new circuits following spinal cord injury. However, it is not know whether mammalian spinal interneurons, axotomized as a result of a spinal cord injury......, develop de novo axons. Our goal was to determine whether spinal commissural interneurons (CINs), axotomized by 3-4-mm midsagittal transection at C3, form de novo axons from distal dendrites. All experiments were performed on adult cats. CINs in C3 were stained with extracellular injections of Neurobiotin...... at 4-5 weeks post injury. The somata of axotomized CINs were identified by the presence of immunoreactivity for the axonal growth-associated protein-43 (GAP-43). Nearly half of the CINs had de novo axons that emerged from distal dendrites. These axons lacked immunoreactivity for the dendritic protein...

  1. Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Russell, Anne-Marie; Adamali, Huzaifa; Molyneaux, Philip L; Lukey, Pauline T; Marshall, Richard P; Renzoni, Elisabetta A; Wells, Athol U; Maher, Toby M

    2016-10-15

    Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression. To determine the feasibility and reliability of measuring daily FVC in individuals with IPF. Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV 1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years. Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13-490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021-1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014-1.033; P spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.

  2. Disruption of mitochondrial DNA replication in Drosophila increases mitochondrial fast axonal transport in vivo.

    Directory of Open Access Journals (Sweden)

    Rehan M Baqri

    Full Text Available Mutations in mitochondrial DNA polymerase (pol gamma cause several progressive human diseases including Parkinson's disease, Alper's syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol gamma leads to depletion of mtDNA, disrupts the mitochondrial respiratory chain, and increases susceptibility to oxidative stress. Although recent studies have intensified focus on the role of mtDNA in neuronal diseases, the changes that take place in mitochondrial biogenesis and mitochondrial axonal transport when mtDNA replication is disrupted are unknown. Using high-speed confocal microscopy, electron microscopy and biochemical approaches, we report that mutations in pol gamma deplete mtDNA levels and lead to an increase in mitochondrial density in Drosophila proximal nerves and muscles, without a noticeable increase in mitochondrial fragmentation. Furthermore, there is a rise in flux of bidirectional mitochondrial axonal transport, albeit with slower kinesin-based anterograde transport. In contrast, flux of synaptic vesicle precursors was modestly decreased in pol gamma-alpha mutants. Our data indicate that disruption of mtDNA replication does not hinder mitochondrial biogenesis, increases mitochondrial axonal transport, and raises the question of whether high levels of circulating mtDNA-deficient mitochondria are beneficial or deleterious in mtDNA diseases.

  3. Investigating the Slow Axonal Transport of Neurofilaments: A Precursor for Optimal Neuronal Signaling

    Science.gov (United States)

    Johnson, Christopher M.

    Neurofilaments are the intermediate filaments of neurons and are the most abundant structure of the neuronal cytoskeleton. Once synthesized within the cell body they are then transported throughout the axon along microtubule tracks, driven by the molecular motors kinesin and dynein. This movement is characterized by long pauses with no movement interrupted by infrequent bouts of rapid movement, resulting in an aggregate dense cytoskeletal structure, which serves to regulate an axon's shape and size. Curiously, the modulated kinetics of these polymers produces a very regular, yet non-uniform, morphology in myelinated axons which are composed of discretely spaced myelin-ensheathed segments that are separated by short constricted regions called "nodes of Ranvier". This unique design optimizes the conduction velocity of myelinated axons at minimal fiber size. Hence, neurofilaments regulate the axon caliber to optimize neuron function. The goal of this dissertation is to investigate the motile mechanism of neurofilament transport as well as the resulting electrophysiological effects that follow. We start by examining highly time-resolved kymograph images generated from recorded neurofilament movement via epifluorescence microscopy. Using kymograph analysis, edge detection algorithms, and pixel smoothing tactics, neurofilament trajectories are extracted and used to obtain statistical distributions for the characteristics of how these filaments move within cells. The results suggest that the observed intermittent and bidirectional motions of these filaments might be explained by a model in which dynein and kinesin motors attach to a single neurofilament cargo and interact through mechanical forces only (i.e. a "tug-of-war" model). We test this hypothesis by developing two discrete-state stochastic models for the kinetic cycles of kinesin and dynein, which are then incorporated into a separate stochastic model that represents the posed tug-of-war scenario. We then

  4. Cannabinoid receptor CB2 modulates axon guidance

    DEFF Research Database (Denmark)

    Duff, Gabriel; Argaw, Anteneh; Cecyre, Bruno

    2013-01-01

    on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2 (-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted...... CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R....

  5. Progress of computer-aided detection/diagnosis (CAD in dentistryCAD in dentistry

    Directory of Open Access Journals (Sweden)

    Akitoshi Katsumata

    2014-08-01

    CAD is also useful in the detection and evaluation of dental and maxillofacial lesions. Identifying alveolar bone resorption due to periodontitis and radiolucent jaw lesions (such as radicular and dentigerous cysts are important goals for CAD. CAD can be applied not only to panoramic radiography but also to dental cone-beam computed tomography (CBCT images. Linking of CAD and teleradiology will be an important issue.

  6. Na(v)1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Alvarez Herrero, Susana; Pinchenko, Volodymyr

    2011-01-01

    Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe and prog......Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe...... and progressive dysmyelinating neuropathy from birth with compromised myelin compaction, hypomyelination and distal axonal degeneration. A previous study using immunofluorescence showed that motor nerves deficient of myelin protein zero upregulate the Na(V)1.8 voltage gated sodium channel isoform, which...... is normally present only in restricted populations of sensory axons. The aim of this study was to investigate the function of motor axons in protein zero-deficient mice with particular emphasis on ectopic Na(V)1.8 voltage gated sodium channel. We combined 'threshold tracking' excitability studies...

  7. Giant axonal neuropathy-like disease in an Alexandrine parrot (Psittacula eupatria).

    Science.gov (United States)

    Stent, Andrew; Gosbell, Matthew; Tatarczuch, Liliana; Summers, Brian A

    2015-09-01

    A chronic progressive neurological condition in an Alexandrine parrot (Psittacula eupatria) was manifest as intention tremors, incoordination, and seizure activity. Histology revealed large eosinophilic bodies throughout the central nervous system, and electron microscopy demonstrated that these bodies were greatly expanded axons distended by short filamentous structures that aggregated to form long strands. The presence of periodic acid-Schiff-positive material within the neuronal bodies of Purkinje cells and ganglionic neurons is another distinctive feature of this disease. The histological features of this case display some features consistent with giant axonal neuropathy as reported in humans and dogs. Based on investigation of the lineage in this case, an underlying inherited defect is suspected, but some additional factor appears to have altered the specific disease presentation in this bird. © 2015 The Author(s).

  8. Progress in analytical methods for the detection of geographical origin and authenticity of tea (Camellia sinensis)

    International Nuclear Information System (INIS)

    Yuan Yuwei; Hu Guixian; Shao Shengzhi; Zhang Yongzhi; Zhang Yu; Zhu Jiahong; Yang Guiling; Zhang Zhiheng

    2013-01-01

    Tea (Camellia sinensis) is one of the important agricultural products with obvious regional characteristics. Analytical methods are very important for the protection of geographical origin and authenticity of tea. The developments of analytical methods including stable isotope determination, multi-elements determination, near infrared reflectance spectroscopy, chemical fingerprint and others were reviewed. Major problems on tea origin and authenticity detection were discussed in this study, and some suggestions were also proposed which would be useful for the protection of geographical origin of tea in China. (authors)

  9. Progress in rapid detection and identification of unknown human and agricultural pathogens

    International Nuclear Information System (INIS)

    Barnes, T; Holzrichter, J F; Milanovich, F P

    1999-01-01

    The medical industry is driving pathogen detection technology from its present characteristics of$50/sample, 100 sample capability systems, with several day time responses, having several percent error rates in reported outcomes. The systems described above are capable of providing samples at and lt;$5/test, managing several million samples, and lt; 1-hour cycle times, (or just minutes in some cases) and and lt; 0.1% error rates. Because of their importance to the medical and agricultural communities, all ''important'' pathogens will have detection kits available (within air transport times, anywhere in the world) by 2020, and the most well known pathogens will have kits available within a few years. Many are available now. Because of the importance of the food supply to modern nations, these technologies will be employed everywhere in this industry. For example, the United States imports 30 B tons of food a year, but inspects and lt; 1%. Portable inspection systems will make it possible to test for dangerous pathogens in feed lots, food processing plants, markets, and points of use. Outbreaks of animal or plant disease will be immediately detectable using field instrumentation, and more complex samples can be sent to central testing laboratories where more sophisticated test systems will be available. Unusual pathogens either naturally or purposefully selected or developed, will require special attention because there is not a commercial economic driver for the development of detection systems and curative agents. Their development, and production for sufficient availability, will require significant investments by the world community. The strategy and costs for developing vaccines or curative drugs will be very expensive and will need special attention. However it is important that attention be directed to these problems because such attention has a strong deterrent effect on potential developers or users. The capacity to use the full information content

  10. Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.

    Science.gov (United States)

    Gamage, Kanchana K; Cheng, Irene; Park, Rachel E; Karim, Mardeen S; Edamura, Kazusa; Hughes, Christopher; Spano, Anthony J; Erisir, Alev; Deppmann, Christopher D

    2017-03-20

    Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury [1, 2]. Despite similar morphological characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration [3-5]. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated [5-7]. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration [8-10]. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings, DR6 -/- animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed in Wld s and Sarm1 -/- mice, preserved axons in DR6 -/- animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. PROGRESS ON DEVELOPING SONIC INFRARED IMAGING FOR DEFECT DETECTION IN COMPOSITE STRUCTURES

    International Nuclear Information System (INIS)

    Han Xiaoyan; He Qi; Li Wei; Newaz, Golam; Favro, Lawrence D.; Thomas, Robert L.

    2010-01-01

    At last year's QNDE conference, we presented our development of Sonic IR imaging technology in metal structures, with results from both experimental studies and theoretical computing. In the latest aircraft designs, such as the B787 from Boeing, composites have become the major materials in structures such as the fuselage and wings. This is in contrast to composites' use only in auxiliary components such as flaps and spoilers in the past. With today's advanced technology of fabrication, it is expected the new materials can be put in use in even more aircraft structures due to its light weight and high strength (high strength-to-weight ratio), high specific stiffness, tailorability of properties, design flexibility etc. Especially, with increases in fuel cost, reducing the aircraft's body weight becomes more and more appealing. In this presentation, we describe the progress on our development of Sonic IR imaging for aircraft composite structures. In particular, we describe the some unexpected results discovered while modeling delaminations. These results were later experimentally verified with an engineered delamination.

  12. Diffusion tensor MRI shows progressive changes in the hippocampus and dentate gyrus after status epilepticus in rat - histological validation with Fourier-based analysis.

    Science.gov (United States)

    Salo, Raimo A; Miettinen, Tuukka; Laitinen, Teemu; Gröhn, Olli; Sierra, Alejandra

    2017-05-15

    Imaging markers for monitoring disease progression, recovery, and treatment efficacy are a major unmet need for many neurological diseases, including epilepsy. Recent evidence suggests that diffusion tensor imaging (DTI) provides high microstructural contrast even outside major white matter tracts. We hypothesized that in vivo DTI could detect progressive microstructural changes in the dentate gyrus and the hippocampal CA3bc in the rat brain after status epilepticus (SE). To test this hypothesis, we induced SE with systemic kainic acid or pilocarpine in adult male Wistar rats and subsequently scanned them using in vivo DTI at five time-points: prior to SE, and 10, 20, 34, and 79 days post SE. In order to tie the DTI findings to changes in the tissue microstructure, myelin- and glial fibrillary acidic protein (GFAP)-stained sections from the same animals underwent Fourier analysis. We compared the Fourier analysis parameters, anisotropy index and angle of myelinated axons or astrocyte processes, to corresponding DTI parameters, fractional anisotropy (FA) and the orientation angle of the principal eigenvector. We found progressive detectable changes in DTI parameters in both the dentate gyrus (FA, axial diffusivity [D || ], linear anisotropy [CL] and spherical anisotropy [CS], pFourier analysis revealed that both myelinated axons and astrocyte processes played a role in the water diffusion anisotropy changes detected by DTI in individual portions of the dentate gyrus (suprapyramidal blade, mid-portion, and infrapyramidal blade). In the whole dentate gyrus, myelinated axons markedly contributed to the water diffusion changes. In CA3bc as well as in CA3b and CA3c, both myelinated axons and astrocyte processes contributed to water diffusion anisotropy and orientation. Our study revealed that DTI is a promising method for noninvasive detection of microstructural alterations in the hippocampus proper. These alterations may be potential imaging markers for epileptogenesis

  13. Progress in low light-level InAs detectors- towards Geiger-mode detection

    Science.gov (United States)

    Tan, Chee Hing; Ng, Jo Shien; Zhou, Xinxin; David, John; Zhang, Shiyong; Krysa, Andrey

    2017-05-01

    InAs avalanche photodiodes (APDs) can be designed such that only electrons are allowed to initiate impact ionization, leading to the lowest possible excess noise factor. Optimization of wet chemical etching and surface passivation produced mesa APDs with bulk dominated dark current and responsivity that are comparable and higher, respectively, than a commercial InAs detector. Our InAs electron-APDs also show high stability with fluctuation of 0.1% when operated at a gain of 11.2 over 60 s. These InAs APDs can detect very weak signal down to 35 photons per pulse. Fabrication of planar InAs by Be implantation produced planar APDs with bulk dominated dark current. Annealing at 550 °C was necessary to remove implantation damage and to activate Be dopants. Due to minimal diffusion of Be, thick depletion of 8 μm was achieved. Since the avalanche gain increases exponentially with the thickness of avalanche region, our planar APD achieved high gain > 300 at 200 K. Our work suggest that both mesa and planar InAs APDs can exhibit high gain. When combined with a suitable preamplifier, single photon detection using InAs electron-APDs could be achieved.

  14. Nondestructive Examination (NDE) Detection and Characterization of Degradation Precursors, Technical Progress Report for FY 2012

    Energy Technology Data Exchange (ETDEWEB)

    Ramuhalli, P.; Meyer, R.M.; Fricke, J.M.; Prowant, M.S.; Coble, J.B.; Griffin, J.W.; Pitman, S.G.; Dahl, M.E.; Kafentzis, T.A.; Roosendaal, T.J.

    2012-09-01

    The overall objective of this project was to investigate the effectiveness of nondestructive examination (NDE) technology in detecting material degradation precursors by initiating and growing cracks in selected materials and using NDE methods to measure crack precursors prior to the onset of cracking. Nuclear reactor components are subject to stresses over time that are not precisely known and that make the life expectancy of components difficult to determine. To prevent future issues with the operation of these plants because of unforeseen failure of components, NDE technology is needed that can be used to identify and quantify precursors to macroscopic degradation of materials. Some of the NDE methods being researched as possible solutions to the precursor detection problem are magnetic Barkhausen noise, nonlinear ultrasonics, acoustic emission, eddy current measurements, and guided wave technology. In FY12, the objective was to complete preliminary assessment of advanced NDE techniques for sensitivity to degradation precursors, using prototypical degradation mechanisms in laboratory-scale measurements. This present document reports on the deliverable that meets the following milestone: M3LW-12OR0402143 – Report detailing an initial demonstration on samples from the crack-initiation tests will be provided (demonstrating acceleration of the work).

  15. Automated detection of extended sources in radio maps: progress from the SCORPIO survey

    Science.gov (United States)

    Riggi, S.; Ingallinera, A.; Leto, P.; Cavallaro, F.; Bufano, F.; Schillirò, F.; Trigilio, C.; Umana, G.; Buemi, C. S.; Norris, R. P.

    2016-08-01

    Automated source extraction and parametrization represents a crucial challenge for the next-generation radio interferometer surveys, such as those performed with the Square Kilometre Array (SKA) and its precursors. In this paper, we present a new algorithm, called CAESAR (Compact And Extended Source Automated Recognition), to detect and parametrize extended sources in radio interferometric maps. It is based on a pre-filtering stage, allowing image denoising, compact source suppression and enhancement of diffuse emission, followed by an adaptive superpixel clustering stage for final source segmentation. A parametrization stage provides source flux information and a wide range of morphology estimators for post-processing analysis. We developed CAESAR in a modular software library, also including different methods for local background estimation and image filtering, along with alternative algorithms for both compact and diffuse source extraction. The method was applied to real radio continuum data collected at the Australian Telescope Compact Array (ATCA) within the SCORPIO project, a pathfinder of the Evolutionary Map of the Universe (EMU) survey at the Australian Square Kilometre Array Pathfinder (ASKAP). The source reconstruction capabilities were studied over different test fields in the presence of compact sources, imaging artefacts and diffuse emission from the Galactic plane and compared with existing algorithms. When compared to a human-driven analysis, the designed algorithm was found capable of detecting known target sources and regions of diffuse emission, outperforming alternative approaches over the considered fields.

  16. Axon guidance molecules in vascular patterning.

    Science.gov (United States)

    Adams, Ralf H; Eichmann, Anne

    2010-05-01

    Endothelial cells (ECs) form extensive, highly branched and hierarchically organized tubular networks in vertebrates to ensure the proper distribution of molecular and cellular cargo in the vertebrate body. The growth of this vascular system during development, tissue repair or in disease conditions involves the sprouting, migration and proliferation of endothelial cells in a process termed angiogenesis. Surprisingly, specialized ECs, so-called tip cells, which lead and guide endothelial sprouts, share many feature with another guidance structure, the axonal growth cone. Tip cells are motile, invasive and extend numerous filopodial protrusions sensing growth factors, extracellular matrix and other attractive or repulsive cues in their tissue environment. Axonal growth cones and endothelial tip cells also respond to signals belonging to the same molecular families, such as Slits and Roundabouts, Netrins and UNC5 receptors, Semaphorins, Plexins and Neuropilins, and Eph receptors and ephrin ligands. Here we summarize fundamental principles of angiogenic growth, the selection and function of tip cells and the underlying regulation by guidance cues, the Notch pathway and vascular endothelial growth factor signaling.

  17. Automatic progressive damage detection of rotor bar in induction motor using vibration analysis and multiple classifiers

    International Nuclear Information System (INIS)

    Cruz-Vega, Israel; Rangel-Magdaleno, Jose; Ramirez-Cortes, Juan; Peregrina-Barreto, Hayde

    2017-01-01

    There is an increased interest in developing reliable condition monitoring and fault diagnosis systems of machines like induction motors; such interest is not only in the final phase of the failure but also at early stages. In this paper, several levels of damage of rotor bars under different load conditions are identified by means of vibration signals. The importance of this work relies on a simple but effective automatic detection algorithm of the damage before a break occurs. The feature extraction is based on discrete wavelet analysis and auto- correlation process. Then, the automatic classification of the fault degree is carried out by a binary classification tree. In each node, com- paring the learned levels of the breaking off correctly identifies the fault degree. The best results of classification are obtained employing computational intelligence techniques like support vector machines, multilayer perceptron, and the k-NN algorithm, with a proper selection of their optimal parameters.

  18. Progress on a detection algorithm for longer lived gravitational wave bursts

    International Nuclear Information System (INIS)

    Torres, Charlie; Anderson, Warren G

    2005-01-01

    Tracksearch is an algorithm to detect unmodelled gravitational wave signals in interferometric data which was first proposed almost ten years ago by Anderson and Balasubramanian. It is one of the only methods proposed which is well suited to look for unmodelled gravitational wave signals which have hundreds of cycles or more. This paper continues the work they began. In particular, we introduce a new trigger statistic for tracksearch, the integrated power, and compare it to the track length statistic used by Anderson and Balasubramanian. Our initial findings suggest that the integrated power will perform equivalently to or better than track length in almost every case. Furthermore, the integrated power statistic appears to be far less sensitive to suboptimal parameter choices, indicating that it may be more suitable for use on real gravitational wave data

  19. Automatic progressive damage detection of rotor bar in induction motor using vibration analysis and multiple classifiers

    Energy Technology Data Exchange (ETDEWEB)

    Cruz-Vega, Israel; Rangel-Magdaleno, Jose; Ramirez-Cortes, Juan; Peregrina-Barreto, Hayde [Santa María Tonantzintla, Puebla (Mexico)

    2017-06-15

    There is an increased interest in developing reliable condition monitoring and fault diagnosis systems of machines like induction motors; such interest is not only in the final phase of the failure but also at early stages. In this paper, several levels of damage of rotor bars under different load conditions are identified by means of vibration signals. The importance of this work relies on a simple but effective automatic detection algorithm of the damage before a break occurs. The feature extraction is based on discrete wavelet analysis and auto- correlation process. Then, the automatic classification of the fault degree is carried out by a binary classification tree. In each node, com- paring the learned levels of the breaking off correctly identifies the fault degree. The best results of classification are obtained employing computational intelligence techniques like support vector machines, multilayer perceptron, and the k-NN algorithm, with a proper selection of their optimal parameters.

  20. Recent progress in the detection of bursts in the canning in French reactors

    International Nuclear Information System (INIS)

    Goupil, J.; Grenon, M.; Raffailhac, J.; Roguin, A.

    1959-01-01

    In piles cooled by pressurized carbon dioxide, type G 3 , the chief radioactivity of the gas is that of nitrogen - 16 created by 16 O (n, p) 16 N reaction of the fact neutrons on the oxygen. This activity short-lived and with a high β energy, masks the activity of fission gases escaping through a crack in the canning into the carbon dioxide, and makes it necessary to use a material method to separate the solid fission products before the detection proper. This detection is carried out by means of a special electronic system whose input is a scintillator associated with a photomultiplier. A system for measuring the evolution of a crack with compensation for power variations allows the speed of development of a crack to be followed. This instrument, baptised 'evolution-meter', is designed to make the measurement of the activity of the cooling gas in the canals by a zero method, and thus to be independent of: 1) the activity of the gas itself, left after discrimination of the fission products; 2) uranium pollution of the canning and eventual pollution of the canals after rapid splits in the canning. The 'evolution-meter' consists of a memory which stores canal activity values taken at a given moment considered as a reference. The values of canal activity during the course of prospection are compared to this memory. A difference between the values indicates the appearance or the evolution of a crack in the canning. To account for the variations of thermodynamic running conditions in the canals, the values taken from the memory are corrected by a signal from an activity detector placed in the general circuit of gas leaving the pile. In the case of the pile EL 2 , also cooled by pressurized CO 2 , a method similar to that of G 3 , has been used. Samples of cooling gas are taken successively in each of the 133 pile cells by the opening of electro-valves. The gas is filtered and the fission products extracted by an electrostatic collecting method. A scintillator and an

  1. Pαx6 expression in postmitotic neurons mediates the growth of axons in response to SFRP1.

    Directory of Open Access Journals (Sweden)

    Alvaro Sebastián-Serrano

    Full Text Available During development, the mechanisms that specify neuronal subclasses are coupled to those that determine their axonal response to guidance cues. Pax6 is a homedomain transcription factor required for the specification of a variety of neural precursors. After cell cycle exit, Pax6 expression is often shut down in the precursor progeny and most postmitotic neurons no longer express detectable levels of the protein. There are however exceptions and high Pax6 protein levels are found, for example, in postmitotic retinal ganglion cells (RGCs, dopaminergic neurons of the olfactory bulb and the limbic system in the telencephalon. The function of Pax6 in these differentiating neurons remains mostly elusive. Here, we demonstrate that Pax6 mediates the response of growing axons to SFRP1, a secreted molecule expressed in several Pax6-positive forebrain territories. Forced expression of Pax6 in cultured postmitotic cortical neurons, which do not normally express Pax6, was sufficient to increment axonal length. Growth was blocked by the addition of anti-SFRP1 antibodies, whereas exogenously added SFRP1 increased axonal growth of Pax6-transfected neurons but not that of control or untransfected cortical neurons. In the reverse scenario, shRNA-mediated knock-down of Pax6 in mouse retinal explants specifically abolished RGCs axonal growth induced by SFRP1, but had no effect on RGCs differentiation and it did not modify the effect of Shh or Netrin on axon growth. Taken together these results demonstrate that expression of Pax6 is necessary and sufficient to render postmitotic neurons competent to respond to SFRP1. These results reveal a novel and unexpected function of Pax6 in postmitotic neurons and situate Pax6 and SFRP1 as pair regulators of axonal connectivity.

  2. Parallel simulation of axon growth in the nervous system

    NARCIS (Netherlands)

    J. Wensch; B.P. Sommeijer (Ben)

    2002-01-01

    textabstractIn this paper we discuss a model from neurobiology, which describes theoutgrowth of axons from neurons in the nervous system. The model combines ordinary differential equations, defining the movement of the axons, with parabolic partial differential equations. The parabolic equations

  3. A dam for retrograde axonal degeneration in multiple sclerosis?

    NARCIS (Netherlands)

    Balk, L.J.; Twisk, J.W.R.; Steenwijk, M.D.; Daams, M.; Tewarie, P.; Killestein, J.; Uitdehaag, B.M.J.; Polman, C.H.; Petzold, A.F.S.

    2014-01-01

    Objective: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis

  4. Is action potential threshold lowest in the axon?

    NARCIS (Netherlands)

    Kole, Maarten H. P.; Stuart, Greg J.

    2008-01-01

    Action potential threshold is thought to be lowest in the axon, but when measured using conventional techniques, we found that action potential voltage threshold of rat cortical pyramidal neurons was higher in the axon than at other neuronal locations. In contrast, both current threshold and voltage

  5. MRI findings in acute diffuse axonal injured patients

    International Nuclear Information System (INIS)

    Sato, Hidetaka

    2001-01-01

    Diffuse axonal injury (DAI) in the acute stage was clinically evaluated using magnetic resonance imaging (MRI), which is considered superior to computed tomography (CT) in detecting parenchymal brain lesions. MRI was disadvantageous, however, to patients suffering from acute severe head injury because of the long time required to construct imaging and unstable patient vital signs. We conducted MRI safely under a high magnetic field (1.5 tesla) in acute DAI by close observation and with nonmagnetic respirator and electrocardiographic monitoring. MRI was conducted in 95 patients diagnosed with DAI classified into mild (14), moderate (17) and severe (64) DAI by criteria established by Gennarelli (1986). In patients with mild or moderate DAI, CT revealed no lesion in the parenchymal area although MRI detected lesions in every case, mainly in cortical white matter or basal ganglia. In patients with severe DAI, CT revealed parenchymal lesions in 14 although MRI detected further lesions in cortical white matter, basal ganglia, corpus callosum and brainstem in every case. These results correspond well to the experimental model Gennarelli's. This study concluded that MRI was useful in assessing acute DAI patients. (author)

  6. SnoN facilitates axonal regeneration after spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Jiun L Do

    Full Text Available Adult CNS neurons exhibit a reduced capacity for growth compared to developing neurons, due in part to downregulation of growth-associated genes as development is completed. We tested the hypothesis that SnoN, an embryonically regulated transcription factor that specifies growth of the axonal compartment, can enhance growth in injured adult neurons. In vitro, SnoN overexpression in dissociated adult DRG neuronal cultures significantly enhanced neurite outgrowth. Moreover, TGF-β1, a negative regulator of SnoN, inhibited neurite outgrowth, and SnoN over-expression overcame this inhibition. We then examined whether SnoN influenced axonal regeneration in vivo: indeed, expression of a mutant form of SnoN resistant to degradation significantly enhanced axonal regeneration following cervical spinal cord injury, despite peri-lesional upregulation of TGF-β1. Thus, a developmental mechanism that specifies extension of the axonal compartment also promotes axonal regeneration after adult CNS injury.

  7. Internodal function in normal and regenerated mammalian axons

    DEFF Research Database (Denmark)

    Moldovan, M; Krarup, C

    2007-01-01

    AIM: Following Wallerian degeneration, peripheral myelinated axons have the ability to regenerate and, given a proper pathway, establish functional connections with targets. In spite of this capacity, the clinical outcome of nerve regeneration remains unsatisfactory. Early studies have found...... that regenerated internodes remain persistently short though this abnormality did not seem to influence recovery in conduction. It remains unclear to which extent abnormalities in axonal function itself may contribute to the poor outcome of nerve regeneration. METHODS: We review experimental evidence indicating...... that internodes play an active role in axonal function. RESULTS: By investigating internodal contribution to axonal excitability we have found evidence that axonal function may be permanently compromised in regenerated nerves. Furthermore, we illustrate that internodal function is also abnormal in regenerated...

  8. Motor Axonal Regeneration After Partial and Complete Spinal Cord Transection

    Science.gov (United States)

    Lu, Paul; Blesch, Armin; Graham, Lori; Wang, Yaozhi; Samara, Ramsey; Banos, Karla; Haringer, Verena; Havton, Leif; Weishaupt, Nina; Bennett, David; Fouad, Karim; Tuszynski, Mark H.

    2012-01-01

    We subjected rats to either partial mid-cervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor (BDNF) gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared to several control groups. Combinatorial treatment generated motor axon regeneration beyond both C5 hemisection and complete transection sites. Yet despite formation of synapses with neurons below the lesion, motor outcomes worsened after partial cervical lesions and spasticity worsened after complete transection. These findings highlight the complexity of spinal cord repair, and the need for additional control and shaping of axonal regeneration. PMID:22699902

  9. Axon diameter mapping in crossing fibers with diffusion MRI

    DEFF Research Database (Denmark)

    Zhang, Hui; Dyrby, Tim B; Alexander, Daniel C

    2011-01-01

    This paper proposes a technique for a previously unaddressed problem, namely, mapping axon diameter in crossing fiber regions, using diffusion MRI. Direct measurement of tissue microstructure of this kind using diffusion MRI offers a new class of biomarkers that give more specific information about...... tissue than measures derived from diffusion tensor imaging. Most existing techniques for axon diameter mapping assume a single axon orientation in the tissue model, which limits their application to only the most coherently oriented brain white matter, such as the corpus callosum, where the single...... model to enable axon diameter mapping in voxels with crossing fibers. We show in simulation that the technique can provide robust axon diameter estimates in a two-fiber crossing with the crossing angle as small as 45 degrees. Using ex vivo imaging data, we further demonstrate the feasibility...

  10. Uterine cervical melanoma presenting with rapid progression detected by PET/CT

    International Nuclear Information System (INIS)

    Tsai, Ya-Ju; Shueng, Pei-Wei; Chan, Sheng-Chien; Chuang, Wen-Yu; Shiau, Yu-Chien; Hsu, Chung-Huei

    2012-01-01

    Malignant melanoma of the uterine cervix is a rare extracutaneous melanoma which develops aggressively and is associated with a bleak prognosis. To our knowledge, no prior published reports have discussed the role of 18F-FDG positron emission tomography/computed tomography (PET/CT) in managing this disease. Our case study involved a 66-year-old woman with a malignant melanoma of the uterine cervix. The patient received PET/CT that identified metastases and lesions which had not been detected from her MRI. Serial PET/CT elucidated that the disease was initially limited to the pelvis, but then metastasized to the abdominal para-aortic lymph nodes, followed by extensive metastases to the brain, lungs, breast, supraclavicular, neck, and other abdominal lymph nodes, as observed at 6-month follow-up. PET/CT was used to complement conventional anatomic imaging modalities, and provided a novel modality for whole body screening. Visualization of the metabolic activity of indeterminate lesions may help in staging, re-staging, treatment planning, and prognostic prediction for patients with this rare disease

  11. Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry.

    Science.gov (United States)

    Calès, P; Zarski, J P; Chapplain, J Marc; Bertrais, S; Sturm, N; Michelet, C; Babany, G; Chaigneau, J; Eddine Charaf, M

    2012-02-01

    We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage. © 2011 Blackwell Publishing Ltd.

  12. 4S RNA is transported axonally in normal and regenerating axons of the sciatic nerves of rats

    Energy Technology Data Exchange (ETDEWEB)

    Lindquist, T D; Ingoglia, N A; Gould, R M [Departments of Physiology and Neuroscience, New Jersey Medical School, Newark, NJ, USA

    1982-12-28

    Experiments were designed to determine if following injection of (/sup 3/H)uridine into the lumbar spinal cord of the rat, (/sup 3/H)RNA could be demonstrated within axons of the sciatic nerve, and if 4S RNA is the predominant predominant RNA species present in these axons.

  13. Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency?

    Science.gov (United States)

    Ishibashi, S; Yokota, T; Shiojiri, T; Matunaga, T; Tanaka, H; Nishina, K; Hirota, H; Inaba, A; Yamada, M; Kanda, T; Mizusawa, H

    2003-05-01

    Acute axonal polyneuropathy and Wernicke-Korsakoff encephalopathy developed simultaneously in three patients. Nerve conduction studies (NCS) detected markedly decreased compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) with minimal conduction slowing; sympathetic skin responses (SSRs) were also notably decreased. Sural nerve biopsies showed only mild axonal degeneration with scattered myelin ovoid formation. The symptoms of neuropathy lessened within two weeks after an intravenous thiamine infusion. CMAPs, SNAPs, and SSRs also increased considerably. We suggest that this is a new type of peripheral nerve impairment: physiological conduction failure with minimal conduction delay due to thiamine deficiency.

  14. Electrical resistivity for detecting subsurface non-aqueous phase liquids: A progress report

    International Nuclear Information System (INIS)

    Lee, K.H.; Shan, C.; Javandel, I.

    1995-06-01

    Soils and groundwater have been contaminated by hazardous substances at many places in the United States and many other countries. The contaminants are commonly either petroleum products or industrial solvents with very low solubility in water. These contaminants are usually called non-aqueous phase liquids (NAPLs). The cost of cleaning up the affected sites in the United States is estimated to be of the order of 100 billion dollars. In spite of the expenditure of several billion dollars during the last 15 years, to date, very few, if any major contaminated site has been restored. The presence of NAPL pools in the subsurface is believed to be the main cause for the failure of previous cleanup activities. Due to their relatively low water solubility, and depending on their volume, it takes tens or even hundreds of years to deplete the NAPL sources if they are not removed from the subsurface. The intrinsic electrical resistivity of most NAPLs is typically in the range of 10 7 to 10 12 Ω-m, which is several orders of magnitude higher than that of groundwater containing dissolved solids (usually in the range of a few Ω-m to a few thousand Ω-m). Although a dry soil is very resistive, the electrical resistivity of a wet soil is on the order of 100 Ω-m and is dependent on the extent of water saturation. For a given soil, the electrical resistivity increases with decrease of water saturation. Therefore, if part of the pore water is replaced by a NAPL, the electrical resistivity will increase. At many NAPL sites, both the vadose and phreatic zones can be partially occupied by NAPL pools. It is the great contrast in electrical resistivity between the NAPLs and groundwater that may render the method to be effective in detecting subsurface NAPLs at contaminated sites. The following experiments were conducted to investigate the change of the electrical resistivity of porous media when diesel fuel (NAPL) replaces part of the water

  15. Axon tension regulates fasciculation/defasciculation through the control of axon shaft zippering

    Czech Academy of Sciences Publication Activity Database

    Šmít, Daniel; Fouquet, C.; Pincet, F.; Zápotocký, Martin; Trembleau, A.

    2017-01-01

    Roč. 6, Apr 19 (2017), č. článku e19907. ISSN 2050-084X R&D Projects: GA ČR(CZ) GA14-16755S; GA MŠk(CZ) 7AMB12FR002 Institutional support: RVO:67985823 Keywords : biophysics * cell adhesion * coarsening * developmental biology * mathematical model * mechanical tension * axon guidance Subject RIV: BO - Biophysics OBOR OECD: Biophysics Impact factor: 7.725, year: 2016

  16. Neuron Morphology Influences Axon Initial Segment Plasticity.

    Science.gov (United States)

    Gulledge, Allan T; Bravo, Jaime J

    2016-01-01

    In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation.

  17. Fast axonal transport of labeled proteins in motoneurons of exercise-trained rats

    International Nuclear Information System (INIS)

    Jasmin, B.J.; Lavoie, P.A.; Gardiner, P.F.

    1988-01-01

    In this study, the fast orthograde axonal transport of radiolabeled proteins was measured to determine the effects of endurance-running training on transport velocity and amounts of transported proteins in rat sciatic motoneurons. Female rats were subjected to a progressive running-training program for 10-12 wk. Twenty-four hours after the last training session, rats underwent right L4-L5 dorsal root ganglionectomy. The next day, 20 microCi of [3H]leucine was injected bilaterally in the vicinity of the motoneuronal cell bodies supplying the sciatic nerve, to study axonal transport parameters. Results showed that peak and average transport velocities of labeled proteins were significantly (P less than 0.05) increased by 22 and 29%, respectively, in the deafferented nerves of the runners as compared with controls. Moreover, the amount of total transported protein-bound radioactivity was increased in both left (40%) and right (37%) sciatic nerves of the runners. An exhaustive exercise session reduced (P less than 0.05) peak displacement (8%) and total transported protein-bound radioactivity (36%) in the sciatic nerves of control rats, whereas no changes were noticed in trained animals. The data suggest that chronic endurance running induces significant adaptations in the fast axonal transport of labeled proteins

  18. Pathology and polymerase chain reaction detection of ovine progressive pneumonia (maedi) cases in slaughtered sheep in India.

    Science.gov (United States)

    Singh, Rahul; Kumar, Pawan; Singh, Rajendra; Dhama, Kuldeep; Kumari, Swati; Yadav, Jay Prakash; Kashyap, Gayatri; Singh, Karam Pal; Singh, Vidya; Sahoo, Monalisa

    2017-11-01

    The small ruminant lentiviruses are known to cause maedi-visna (MV) and caprine arthritis - encephalitis in sheep and goats, typically affecting joints, udder, lungs, and the central nervous system. The diagnosis usually involves serology, clinical signs, immunohistochemistry, and polymerase chain reaction (PCR). In the present study, the histopathologically positive pneumonia cases of MV were confirmed by PCR in lung tissue probably for the first time in India. A total of 888 lungs of adult sheep, aged between 2 and 5 years, were screened during slaughter, of which 121 were found to have pneumonic lesions. The tissues from each pneumonic lung including associated lymph nodes were collected in 10% neutral buffered formalin for histopathology. The frozen tissues of the same were also collected and stored at -20°C for PCR confirmation. Three of 121 cases of pneumonic lungs of sheep revealed gross and histopathological lesions suggestive of maedi or ovine progressive pneumonia infection. These 3 cases were further confirmed by PCR technique that amplified 291-base pair DNA in the long terminal repeat sequence of MV provirus. This study suggests the low occurrence of MV virus (MVV) infection in India in naturally affected sheep based on pathomorphological lesions and using the molecular tool of PCR detection of the virus in tissues. Further, a combination of pathomorphology or/and PCR testing might be optimal for detecting the animals infected with MVV.

  19. Pathology and polymerase chain reaction detection of ovine progressive pneumonia (maedi cases in slaughtered sheep in India

    Directory of Open Access Journals (Sweden)

    Rahul Singh

    2017-11-01

    Full Text Available Aim: The small ruminant lentiviruses are known to cause maedi-visna (MV and caprine arthritis - encephalitis in sheep and goats, typically affecting joints, udder, lungs, and the central nervous system. The diagnosis usually involves serology, clinical signs, immunohistochemistry, and polymerase chain reaction (PCR. In the present study, the histopathologically positive pneumonia cases of MV were confirmed by PCR in lung tissue probably for the first time in India. Materials and Methods: A total of 888 lungs of adult sheep, aged between 2 and 5 years, were screened during slaughter, of which 121 were found to have pneumonic lesions. The tissues from each pneumonic lung including associated lymph nodes were collected in 10% neutral buffered formalin for histopathology. The frozen tissues of the same were also collected and stored at -20°C for PCR confirmation. Results: Three of 121 cases of pneumonic lungs of sheep revealed gross and histopathological lesions suggestive of maedi or ovine progressive pneumonia infection. These 3 cases were further confirmed by PCR technique that amplified 291-base pair DNA in the long terminal repeat sequence of MV provirus. Conclusion: This study suggests the low occurrence of MV virus (MVV infection in India in naturally affected sheep based on pathomorphological lesions and using the molecular tool of PCR detection of the virus in tissues. Further, a combination of pathomorphology or/and PCR testing might be optimal for detecting the animals infected with MVV.

  20. Pathology and polymerase chain reaction detection of ovine progressive pneumonia (maedi) cases in slaughtered sheep in India

    Science.gov (United States)

    Singh, Rahul; Kumar, Pawan; Singh, Rajendra; Dhama, Kuldeep; Kumari, Swati; Yadav, Jay Prakash; Kashyap, Gayatri; Singh, Karam Pal; Singh, Vidya; Sahoo, Monalisa

    2017-01-01

    Aim: The small ruminant lentiviruses are known to cause maedi-visna (MV) and caprine arthritis - encephalitis in sheep and goats, typically affecting joints, udder, lungs, and the central nervous system. The diagnosis usually involves serology, clinical signs, immunohistochemistry, and polymerase chain reaction (PCR). In the present study, the histopathologically positive pneumonia cases of MV were confirmed by PCR in lung tissue probably for the first time in India. Materials and Methods: A total of 888 lungs of adult sheep, aged between 2 and 5 years, were screened during slaughter, of which 121 were found to have pneumonic lesions. The tissues from each pneumonic lung including associated lymph nodes were collected in 10% neutral buffered formalin for histopathology. The frozen tissues of the same were also collected and stored at −20°C for PCR confirmation. Results: Three of 121 cases of pneumonic lungs of sheep revealed gross and histopathological lesions suggestive of maedi or ovine progressive pneumonia infection. These 3 cases were further confirmed by PCR technique that amplified 291-base pair DNA in the long terminal repeat sequence of MV provirus. Conclusion: This study suggests the low occurrence of MV virus (MVV) infection in India in naturally affected sheep based on pathomorphological lesions and using the molecular tool of PCR detection of the virus in tissues. Further, a combination of pathomorphology or/and PCR testing might be optimal for detecting the animals infected with MVV. PMID:29263606

  1. Neuronal activity in the hub of extrasynaptic Schwann cell-axon interactions

    Directory of Open Access Journals (Sweden)

    Chrysanthi eSamara

    2013-11-01

    Full Text Available The integrity and function of neurons depend on their continuous interactions with glial cells. In the peripheral nervous system glial functions are exerted by Schwann cells (SCs. SCs sense synaptic and extrasynaptic manifestations of action potential propagation and adapt their physiology to support neuronal activity. We review here existing literature data on extrasynaptic bidirectional axon-SC communication, focusing particularly on neuronal activity implications. To shed light on underlying mechanisms, we conduct a thorough analysis of microarray data from SC-rich mouse sciatic nerve at different developmental stages and in neuropathic models. We identify molecules that are potentially involved in SC detection of neuronal activity signals inducing subsequent glial responses. We further suggest that alterations in the activity-dependent axon-SC crosstalk impact on peripheral neuropathies. Together with previously reported data, these observations open new perspectives for deciphering glial mechanisms of neuronal function support.

  2. A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.

    Directory of Open Access Journals (Sweden)

    Timothy G Lesnick

    2007-06-01

    Full Text Available While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics. The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance predisposed to a complex disease (Parkinson disease [PD]. We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38, survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48, and PD age at onset (R(2 = 0.68, p = 1.68 x 10(-51. By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

  3. Release of axonally transported material from an in vitro amphibian sciatic nerve preparation

    International Nuclear Information System (INIS)

    Snyder, R.E.

    1988-01-01

    The rapid axonal transport of a pulse of [35S]methionine-labelled material was used to study the release of transported material from amphibian nerve maintained in vitro. Following creation of a moving pulse of activity in a dorsal root ganglion-sciatic nerve preparation, the ganglion was removed and the nerve placed in a three-compartment tray, the section of nerve in the middle compartment containing no truncated branches (unbranched section). All three compartments were filled with a saline solution that in some studies contained nonradioactive methionine (1.0 mmol/L). Analysis of studies in which nonradioactive methionine was absent revealed that labelled material appeared in the bathing solution of the end compartments that contained truncated branches, but not in the solution of the middle (unbranched) compartment. The quantity of label released in the branched compartments was approximately 6% of that remaining in the corresponding section of nerve following an 18-20 h incubation period. However, when nonradioactive methionine was present, all compartments showed an additional activity in the bathing solution of approximately 10% of that remaining in the nerve. In another study in which a position-sensitive detector of ionizing radiation was used to monitor progress of the pulse, it was found that activity did not enter the bathing solution of a compartment prior to the pulse of activity. It is concluded that in the absence of methionine from the bathing solution, axonally transported material is released only from regions of nerve that contain severed axons; however, the presence of methionine allows transported material to be released from nerve containing intact axons. Ultrafiltration studies and thin-layer chromatography revealed the majority of material released to be of low-molecular weight (less than 30,000 daltons) and not free [35S]methionine

  4. Persistence, spatial distribution and implications for progression detection of blind parts of the visual field in glaucoma: a clinical cohort study.

    Directory of Open Access Journals (Sweden)

    Francisco G Junoy Montolio

    Full Text Available BACKGROUND: Visual field testing is an essential part of glaucoma care. It is hampered by variability related to the disease itself, response errors and fatigue. In glaucoma, blind parts of the visual field contribute to the diagnosis but--once established--not to progression detection; they only increase testing time. The aims of this study were to describe the persistence and spatial distribution of blind test locations in standard automated perimetry in glaucoma and to explore how the omission of presumed blind test locations would affect progression detection. METHODOLOGY/PRINCIPAL FINDINGS: Data from 221 eyes of 221 patients from a cohort study with the Humphrey Field Analyzer with 30-2 grid were used. Patients were stratified according to baseline mean deviation (MD in six strata of 5 dB width each. For one, two, three and four consecutive 0.1 for all strata. Omitting test locations with three consecutive <0 dB sensitivities at baseline did not affect the performance of the MD-based Nonparametric Progression Analysis progression detection algorithm. CONCLUSIONS/SIGNIFICANCE: Test locations that have been shown to be reproducibly blind tend to display a reasonable blindness persistence and do no longer contribute to progression detection. There is no clinically useful universal MD cut-off value beyond which testing can be limited to 10 degree eccentricity.

  5. Heat Shock Cognate 70 Inhibitor, VER-155008, Reduces Memory Deficits and Axonal Degeneration in a Mouse Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Ximeng Yang

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is a progressive neurodegenerative disorder resulting in structural brain changes and memory impairment. We hypothesized that reconstructing neural networks is essential for memory recovery in AD. Heat shock cognate 70 (HSC70, a member of the heat shock protein family of molecular chaperones, is upregulated in AD patient brains, and recent studies have demonstrated that HSC70 facilitates axonal degeneration and pathological progression in AD. However, the direct effects of HSC70 inhibition on axonal development and memory function have never been investigated. In this study, we examined the effects of a small-molecule HSC70 inhibitor, VER-155008, on axonal morphology and memory function in a mouse model of AD (5XFAD mice. We found that VER-155008 significantly promoted axonal regrowth in amyloid β-treated neurons in vitro and improved object recognition, location, and episodic-like memory in 5XFAD mice. Furthermore, VER-155008 penetrated into the brain after intraperitoneal administration, suggesting that VER-155008 acts in the brain in situ. Immunohistochemistry revealed that VER-155008 reduced bulb-like axonal swelling in the amyloid plaques in the perirhinal cortex and CA1 in 5XFAD mice, indicating that VER-155008 also reverses axonal degeneration in vivo. Moreover, the two main pathological features of AD, amyloid plaques and paired helical filament tau accumulation, were reduced by VER-155008 administration in 5XFAD mice. This is the first report to show that the inhibition of HSC70 function may be critical for axonal regeneration and AD-like symptom reversal. Our study provides evidence that HSC70 can be used as a new therapeutic target for AD treatment.

  6. Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

    Directory of Open Access Journals (Sweden)

    Andrew D. Nelson

    2017-05-01

    Full Text Available Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of

  7. Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb.

    Directory of Open Access Journals (Sweden)

    Rosa-Eva Huettl

    2011-02-01

    Full Text Available The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1 in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG, we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

  8. Spontaneous axonal regeneration in rodent spinal cord after ischemic injury

    DEFF Research Database (Denmark)

    von Euler, Mia; Janson, A M; Larsen, Jytte Overgaard

    2002-01-01

    cells, while other fibers were unmyelinated. Immunohistochemistry demonstrated that some of the regenerated fibers were tyrosine hydroxylase- or serotonin-immunoreactive, indicating a central origin. These findings suggest that there is a considerable amount of spontaneous regeneration after spinal cord......Here we present evidence for spontaneous and long-lasting regeneration of CNS axons after spinal cord lesions in adult rats. The length of 200 kD neurofilament (NF)-immunolabeled axons was estimated after photochemically induced ischemic spinal cord lesions using a stereological tool. The total...... length of all NF-immunolabeled axons within the lesion cavities was increased 6- to 10-fold at 5, 10, and 15 wk post-lesion compared with 1 wk post-surgery. In ultrastructural studies we found the putatively regenerating axons within the lesion to be associated either with oligodendrocytes or Schwann...

  9. Narrow microtunnel technology for the isolation and precise identification of axonal communication among distinct hippocampal subregion networks.

    Directory of Open Access Journals (Sweden)

    Udit Narula

    Full Text Available Communication between different sub regions of the hippocampus is fundamental to learning and memory. However accurate knowledge about information transfer between sub regions from access to the activity in individual axons is lacking. MEMS devices with microtunnels connecting two sub networks have begun to approach this problem but the commonly used 10 μm wide tunnels frequently measure signals from multiple axons. To reduce this complexity, we compared polydimethylsiloxane (PDMS microtunnel devices each with a separate tunnel width of 2.5, 5 or 10 μm bridging two wells aligned over a multi electrode array (MEA. Primary rat neurons were grown in the chambers with neurons from the dentate gyrus on one side and hippocampal CA3 on the other. After 2-3 weeks of culture, spontaneous activity in the axons inside the tunnels was recorded. We report electrophysiological, exploratory data analysis for feature clustering and visual evidence to support the expectation that 2.5 μm wide tunnels have fewer axons per tunnel and therefore more clearly delineated signals than 10 or 5 μm wide tunnels. Several measures indicated that fewer axons per electrode enabled more accurate detection of spikes. A clustering analysis comparing the variations of spike height and width for different tunnel widths revealed tighter clusters representing unique spikes with less height and width variation when measured in narrow tunnels. Wider tunnels tended toward more diffuse clusters from a continuum of spike heights and widths. Standard deviations for multiple cluster measures, such as Average Dissimilarity, Silhouette Value (S and Separation Factor (average dissimilarity/S value, support a conclusion that 2.5 μm wide tunnels containing fewer axons enable more precise determination of individual action potential peaks, their propagation direction, timing, and information transfer between sub networks.

  10. Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro.

    Science.gov (United States)

    Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C; Mennerick, Steven

    2015-08-05

    action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals. Copyright © 2015 the authors 0270-6474/15/3511105-13$15.00/0.

  11. Mdivi-1 inhibits astrocyte activation and astroglial scar formation and enhances axonal regeneration after spinal cord injury in rats

    Directory of Open Access Journals (Sweden)

    gang li

    2016-10-01

    Full Text Available After spinal cord injury (SCI, astrocytes become hypertrophic and proliferative, forming a dense network of astroglial processes at the site of the lesion. This constitutes a physical and biochemical barrier to axonal regeneration. Mitochondrial fission regulates cell cycle progression; inhibiting the cell cycle of astrocytes can reduce expression levels of axon growth-inhibitory molecules as well as astroglial scar formation after SCI. We therefore investigated how an inhibitor of mitochondrial fission, Mdivi-1, would affect astrocyte proliferation, astroglial scar formation, and axonal regeneration following SCI in rats. Western blot and immunofluorescent double-labeling showed that Mdivi-1 markedly reduced the expression of the astrocyte marker glial fibrillary acidic protein (GFAP, and a cell proliferation marker, proliferating cell nuclear antigen, in astrocytes 3 days after SCI. Moreover, Mdivi-1 decreased the expression of GFAP and neurocan, a chondroitin sulfate proteoglycan. Notably, immunofluorescent labeling and Nissl staining showed that Mdivi-1 elevated the production of growth-associated protein-43 and increased neuronal survival at 4 weeks after SCI. Finally, hematoxylin-eosin staining and behavioral evaluation of motor function indicated that Mdivi-1 also reduced cavity formation and improved motor function 4 weeks after SCI. Our results confirm that Mdivi-1 promotes motor function after SCI, and indicate that inhibiting mitochondrial fission using Mdivi-1 can inhibit astrocyte activation and astroglial scar formation and contribute to axonal regeneration after SCI in rats.

  12. Detection of progression of glaucomatous visual field damage using the point-wise method with the binomial test.

    Science.gov (United States)

    Karakawa, Ayako; Murata, Hiroshi; Hirasawa, Hiroyo; Mayama, Chihiro; Asaoka, Ryo

    2013-01-01

    To compare the performance of newly proposed point-wise linear regression (PLR) with the binomial test (binomial PLR) against mean deviation (MD) trend analysis and permutation analyses of PLR (PoPLR), in detecting global visual field (VF) progression in glaucoma. 15 VFs (Humphrey Field Analyzer, SITA standard, 24-2) were collected from 96 eyes of 59 open angle glaucoma patients (6.0 ± 1.5 [mean ± standard deviation] years). Using the total deviation of each point on the 2(nd) to 16(th) VFs (VF2-16), linear regression analysis was carried out. The numbers of VF test points with a significant trend at various probability levels (pbinomial test (one-side). A VF series was defined as "significant" if the median p-value from the binomial test was binomial PLR method (0.14 to 0.86) was significantly higher than MD trend analysis (0.04 to 0.89) and PoPLR (0.09 to 0.93). The PIS of the proposed method (0.0 to 0.17) was significantly lower than the MD approach (0.0 to 0.67) and PoPLR (0.07 to 0.33). The PBNS of the three approaches were not significantly different. The binomial BLR method gives more consistent results than MD trend analysis and PoPLR, hence it will be helpful as a tool to 'flag' possible VF deterioration.

  13. Detection of polyoma virus in brain tissue of patients with progressive multifocal leukoencephalopathy by real-time PCR and pyrosequencing.

    Science.gov (United States)

    Beck, Rose C; Kohn, Debra J; Tuohy, Marion J; Prayson, Richard A; Yen-Lieberman, Belinda; Procop, Gary W

    2004-03-01

    We evaluated 2 methods, a LightCycler PCR assay and pyrosequencing for the detection of the JC polyoma virus (JCV) in fixed brain tissue of 10 patients with and 3 control patients without progressive multifocal leukoencephalopathy (PML). Nucleic acid extraction was performed after deparaffinization and proteinase K digestion. The LightCycler assay differentiates the BK virus (BKV), JCV, and SV40 using melt curve analysis. Conventional PCR was used with the same primers to generate products for pyrosequencing. Two sequencing primers were used that differentiate the polyoma viruses. Seven of 11 biopsies (1 patient had 2 biopsies) with PML were positive for JCV by real-time PCR and/or PCR/pyrosequencing. Three of 4 remaining biopsies were positive by real-time PCR but had melting points between JCV and SV40. The 4 specimens that were negative or atypical by LightCycler PCR were positive by traditional PCR, but 1 had an amplicon of lower molecular weight by gel electrophoresis. These were shown to represent JCV by at least 1 of the 2 pyrosequencing primers. The biopsies from patients without PML were PCR negative. Both the LightCycler and pyrosequencing assays are useful for confirming JCV in brain biopsies from patients with PML, but variant JCVs may require supplementary methods to confirm JCV infection.

  14. Functional characterization and axonal transport of quantum dot labeled BDNF

    OpenAIRE

    Xie, Wenjun; Zhang, Kai; Cui, Bianxiao

    2012-01-01

    Brain derived neurotrophic factor (BDNF) plays a key role in the growth, development and maintenance of the central and peripheral nervous systems. Exogenous BDNF activates its membrane receptors at the axon terminal, and subsequently sends regulation signals to the cell body. To understand how BDNF signal propagates in neurons, it is important to follow the trafficking of BDNF after it is internalized at the axon terminal. Here we labeled BDNF with bright, photostable quantum dot (QD-BDNF) a...

  15. Modality-Specific Axonal Regeneration: Towards selective regenerative neural interfaces

    Directory of Open Access Journals (Sweden)

    Parisa eLotfi

    2011-10-01

    Full Text Available Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control of robotic prosthetic devices. However, sensory and motor axons at the neural interface are of mixed submodality types, which difficult the specific recording from motor axons and the eliciting of precise sensory modalities through selective stimulation. Here we evaluated the possibility of using type-specific neurotrophins to preferentially entice the regeneration of defined axonal populations from transected peripheral nerves into separate compartments. Segregation of mixed sensory fibers from dorsal root ganglion neurons was evaluated in vitro by compartmentalized diffusion delivery of nerve growth factor (NGF and neurotrophin-3 (NT-3, to preferentially entice the growth of TrkA+ nociceptive and TrkC+ proprioceptive subsets of sensory neurons, respectively. The average axon length in the NGF channel increased 2.5 fold compared to that in saline or NT-3, whereas the number of branches increased 3 fold in the NT-3 channels. These results were confirmed using a 3-D Y-shaped in vitro assay showing that the arm containing NGF was able to entice a 5-fold increase in axonal length of unbranched fibers. To address if such segregation can be enticed in vivo, a Y-shaped tubing was used to allow regeneration of the transected adult rat sciatic nerve into separate compartments filled with either NFG or NT-3. A significant increase in the number of CGRP+ pain fibers were attracted towards the sural nerve, while N-52+ large diameter axons were observed in the tibial and NT-3 compartments. This study demonstrates the guided enrichment of sensory axons in specific regenerative chambers, and supports the notion that neurotrophic factors can be used to segregate sensory and perhaps motor axons in separate peripheral interfaces.

  16. Self-amplifying autocrine actions of BDNF in axon development

    OpenAIRE

    Cheng, Pei-Lin; Song, Ai-Hong; Wong, Yu-Hui; Wang, Sheng; Zhang, Xiang; Poo, Mu-Ming

    2011-01-01

    A critical step in neuronal development is the formation of axon/dendrite polarity, a process involving symmetry breaking in the newborn neuron. Local self-amplifying processes could enhance and stabilize the initial asymmetry in the distribution of axon/dendrite determinants, but the identity of these processes remains elusive. We here report that BDNF, a secreted neurotrophin essential for the survival and differentiation of many neuronal populations, serves as a self-amplifying autocrine f...

  17. Fcγ receptor-mediated inflammation inhibits axon regeneration.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

  18. Kinematics of turnaround and retrograde axonal transport

    International Nuclear Information System (INIS)

    Snyder, R.E.

    1986-01-01

    Rapid axonal transport of a pulse of 35 S-methionine-labelled material was studied in vitro in the sensory neurons of amphibian sciatic nerve using a position-sensitive detector. For 10 nerves studied at 23.0 +/- 0.2 degrees C it was found that a pulse moved in the anterograde direction characterized by front edge, peak, and trailing edge transport rates of (mm/d) 180.8 +/- 2.2 (+/- SEM), 176.6 +/- 2.3, and 153.7 +/- 3.0, respectively. Following its arrival at a distal ligature, a smaller pulse was observed to move in the retrograde direction characterized by front edge and peak transport rates of 158.0 +/- 7.3 and 110.3 +/- 3.5, respectively, indicating that retrograde transport proceeds at a rate of 0.88 +/- 0.04 that of anterograde. The retrograde pulse was observed to disperse at a rate greater than the anterograde. Reversal of radiolabel at the distal ligature began 1.49 +/- 0.15 h following arrival of the first radiolabel. Considerable variation was seen between preparations in the way radiolabel accumulated in the end (ligature) regions of the nerve. Although a retrograde pulse was seen in all preparations, in 7 of 10 preparations there was no evidence of this pulse accumulating within less than 2-3 mm of a proximal ligature; however, accumulation was observed within less than 5 mm in all preparations

  19. Morphology and distribution of chandelier cell axon terminals in the mouse cerebral cortex and claustroamygdaloid complex.

    Science.gov (United States)

    Inda, M C; DeFelipe, J; Muñoz, A

    2009-01-01

    Chandelier cells represent a unique type of cortical gamma-aminobutityric acidergic interneuron whose axon terminals (Ch-terminals) only form synapses with the axon initial segments of some pyramidal cells. Here, we have used immunocytochemistry for the high-affinity plasma membrane transporter GAT-1 and the calcium-binding protein parvalbumin to analyze the morphology and distribution of Ch-terminals in the mouse cerebral cortex and claustroamygdaloid complex. In general, 2 types of Ch-terminals were distinguished on the basis of their size and the density of the axonal boutons that made up the terminal. Simple Ch-terminals were made up of 1 or 2 rows of labeled boutons, each row consisting of only 3-5 boutons. In contrast, complex Ch-terminals were tight cylinder-like structures made up of multiple rows of boutons. Simple Ch-terminals were detected throughout the cerebral cortex and claustroamygdaloid complex, the complex type was only occasionally found in certain regions, whereas in others they were very abundant. These results indicate that there are substantial differences in the morphology and distribution of Ch-terminals between different areas and layers of the mouse cerebral cortex. Furthermore, we suggest that the distribution of complex Ch-terminals may be related to the developmental origin of the different brain regions analyzed.

  20. Quantitative Analysis of Axonal Branch Dynamics in the Developing Nervous System.

    Directory of Open Access Journals (Sweden)

    Kelsey Chalmers

    2016-03-01

    Full Text Available Branching is an important mechanism by which axons navigate to their targets during neural development. For instance, in the developing zebrafish retinotectal system, selective branching plays a critical role during both initial pathfinding and subsequent arborisation once the target zone has been reached. Here we show how quantitative methods can help extract new information from time-lapse imaging about the nature of the underlying branch dynamics. First, we introduce Dynamic Time Warping to this domain as a method for automatically matching branches between frames, replacing the effort required for manual matching. Second, we model branch dynamics as a birth-death process, i.e. a special case of a continuous-time Markov process. This reveals that the birth rate for branches from zebrafish retinotectal axons, as they navigate across the tectum, increased over time. We observed no significant change in the death rate for branches over this time period. However, blocking neuronal activity with TTX slightly increased the death rate, without a detectable change in the birth rate. Third, we show how the extraction of these rates allows computational simulations of branch dynamics whose statistics closely match the data. Together these results reveal new aspects of the biology of retinotectal pathfinding, and introduce computational techniques which are applicable to the study of axon branching more generally.

  1. A fast and robust method for automated analysis of axonal transport.

    Science.gov (United States)

    Welzel, Oliver; Knörr, Jutta; Stroebel, Armin M; Kornhuber, Johannes; Groemer, Teja W

    2011-09-01

    Cargo movement along axons and dendrites is indispensable for the survival and maintenance of neuronal networks. Key parameters of this transport such as particle velocities and pausing times are often studied using kymograph construction, which converts the transport along a line of interest from a time-lapse movie into a position versus time image. Here we present a method for the automatic analysis of such kymographs based on the Hough transform, which is a robust and fast technique to extract lines from images. The applicability of the method was tested on simulated kymograph images and real data from axonal transport of synaptophysin and tetanus toxin as well as the velocity analysis of synaptic vesicle sharing between adjacent synapses in hippocampal neurons. Efficiency analysis revealed that the algorithm is able to detect a wide range of velocities and can be used at low signal-to-noise ratios. The present work enables the quantification of axonal transport parameters with high throughput with no a priori assumptions and minimal human intervention.

  2. Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo

    Science.gov (United States)

    Tukker, John J; Klausberger, Thomas; Somogyi, Peter

    2015-01-01

    Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation. PMID:24141313

  3. Developmental time windows for axon growth influence neuronal network topology.

    Science.gov (United States)

    Lim, Sol; Kaiser, Marcus

    2015-04-01

    Early brain connectivity development consists of multiple stages: birth of neurons, their migration and the subsequent growth of axons and dendrites. Each stage occurs within a certain period of time depending on types of neurons and cortical layers. Forming synapses between neurons either by growing axons starting at similar times for all neurons (much-overlapped time windows) or at different time points (less-overlapped) may affect the topological and spatial properties of neuronal networks. Here, we explore the extreme cases of axon formation during early development, either starting at the same time for all neurons (parallel, i.e., maximally overlapped time windows) or occurring for each neuron separately one neuron after another (serial, i.e., no overlaps in time windows). For both cases, the number of potential and established synapses remained comparable. Topological and spatial properties, however, differed: Neurons that started axon growth early on in serial growth achieved higher out-degrees, higher local efficiency and longer axon lengths while neurons demonstrated more homogeneous connectivity patterns for parallel growth. Second, connection probability decreased more rapidly with distance between neurons for parallel growth than for serial growth. Third, bidirectional connections were more numerous for parallel growth. Finally, we tested our predictions with C. elegans data. Together, this indicates that time windows for axon growth influence the topological and spatial properties of neuronal networks opening up the possibility to a posteriori estimate developmental mechanisms based on network properties of a developed network.

  4. Parametric Probability Distribution Functions for Axon Diameters of Corpus Callosum

    Directory of Open Access Journals (Sweden)

    Farshid eSepehrband

    2016-05-01

    Full Text Available Axon diameter is an important neuroanatomical characteristic of the nervous system that alters in the course of neurological disorders such as multiple sclerosis. Axon diameters vary, even within a fiber bundle, and are not normally distributed. An accurate distribution function is therefore beneficial, either to describe axon diameters that are obtained from a direct measurement technique (e.g., microscopy, or to infer them indirectly (e.g., using diffusion-weighted MRI. The gamma distribution is a common choice for this purpose (particularly for the inferential approach because it resembles the distribution profile of measured axon diameters which has been consistently shown to be non-negative and right-skewed. In this study we compared a wide range of parametric probability distribution functions against empirical data obtained from electron microscopy images. We observed that the gamma distribution fails to accurately describe the main characteristics of the axon diameter distribution, such as location and scale of the mode and the profile of distribution tails. We also found that the generalized extreme value distribution consistently fitted the measured distribution better than other distribution functions. This suggests that there may be distinct subpopulations of axons in the corpus callosum, each with their own distribution profiles. In addition, we observed that several other distributions outperformed the gamma distribution, yet had the same number of unknown parameters; these were the inverse Gaussian, log normal, log logistic and Birnbaum-Saunders distributions.

  5. Axon-glia interaction and membrane traffic in myelin formation

    Directory of Open Access Journals (Sweden)

    Robin eWhite

    2014-01-01

    Full Text Available In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialised glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarisation followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasising the central role of the Src-family kinase Fyn during CNS myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of PLP (proteolipid protein transport by SNARE proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.

  6. Persistence, Spatial Distribution and Implications for Progression Detection of Blind Parts of the Visual Field in Glaucoma : A Clinical Cohort Study

    NARCIS (Netherlands)

    Montolio, Francisco G. Junoy; Wesselink, Christiaan; Jansonius, Nomdo M.

    2012-01-01

    Background: Visual field testing is an essential part of glaucoma care. It is hampered by variability related to the disease itself, response errors and fatigue. In glaucoma, blind parts of the visual field contribute to the diagnosis but - once established - not to progression detection; they only

  7. Progressive supranuclear palsy dopamine D2 receptor tomoscintigraphy to detect L-dopamine efficiency. Paralysies supra-nucleaires progressives. Quantification des recepteurs dopaminergiques D2 par tomoscintigraphie

    Energy Technology Data Exchange (ETDEWEB)

    Tranquart, F; Henry Le Bras, F; Toffol, B de; Autret, A; Guilloteau, D; Baulieu, J L [Hopital Bretonneau, 37 - Tours (France)

    1994-09-01

    Progressive supranuclear palsy (PSP) may sometimes be misdiagnosed as Parkinson's disease in its early stages, hence an early positive diagnosis of PSP based on dopamine D2 receptor density could be extremely valuable. In the present case report, the absence of dopamine D2 receptors was clearly demonstrated in the striatum using [sup 123]I-iodobenzamide (IBZM) tomoscintigraphy. This illustrates the potential use of IBZM tomoscintigraphy to identify Parkinson-like's disease presenting with decreased dopamine D2 receptor density; and hence to predict L-Dopa effectiveness. Further studies are needed to evaluate the value of IBZM tomoscintigraphy in the different Parkinson's like diseases. (authors). 11 refs., 2 figs.

  8. Axonal Conduction Delays, Brain State, and Corticogeniculate Communication.

    Science.gov (United States)

    Stoelzel, Carl R; Bereshpolova, Yulia; Alonso, Jose-Manuel; Swadlow, Harvey A

    2017-06-28

    Thalamocortical conduction times are short, but layer 6 corticothalamic axons display an enormous range of conduction times, some exceeding 40-50 ms. Here, we investigate (1) how axonal conduction times of corticogeniculate (CG) neurons are related to the visual information conveyed to the thalamus, and (2) how alert versus nonalert awake brain states affect visual processing across the spectrum of CG conduction times. In awake female Dutch-Belted rabbits, we found 58% of CG neurons to be visually responsive, and 42% to be unresponsive. All responsive CG neurons had simple, orientation-selective receptive fields, and generated sustained responses to stationary stimuli. CG axonal conduction times were strongly related to modulated firing rates (F1 values) generated by drifting grating stimuli, and their associated interspike interval distributions, suggesting a continuum of visual responsiveness spanning the spectrum of axonal conduction times. CG conduction times were also significantly related to visual response latency, contrast sensitivity (C-50 values), directional selectivity, and optimal stimulus velocity. Increasing alertness did not cause visually unresponsive CG neurons to become responsive and did not change the response linearity (F1/F0 ratios) of visually responsive CG neurons. However, for visually responsive CG neurons, increased alertness nearly doubled the modulated response amplitude to optimal visual stimulation (F1 values), significantly shortened response latency, and dramatically increased response reliability. These effects of alertness were uniform across the broad spectrum of CG axonal conduction times. SIGNIFICANCE STATEMENT Corticothalamic neurons of layer 6 send a dense feedback projection to thalamic nuclei that provide input to sensory neocortex. While sensory information reaches the cortex after brief thalamocortical axonal delays, corticothalamic axons can exhibit conduction delays of <2 ms to 40-50 ms. Here, in the corticogeniculate

  9. Cooperative Interactions between 480 kDa Ankyrin-G and EB Proteins Assemble the Axon Initial Segment.

    Science.gov (United States)

    Fréal, Amélie; Fassier, Coralie; Le Bras, Barbara; Bullier, Erika; De Gois, Stéphanie; Hazan, Jamilé; Hoogenraad, Casper C; Couraud, François

    2016-04-20

    The axon initial segment (AIS) is required for generating action potentials and maintaining neuronal polarity. Significant progress has been made in deciphering the basic building blocks composing the AIS, but the underlying mechanisms required for AIS formation remains unclear. The scaffolding protein ankyrin-G is the master-organizer of the AIS. Microtubules and their interactors, particularly end-binding proteins (EBs), have emerged as potential key players in AIS formation. Here, we show that the longest isoform of ankyrin-G (480AnkG) selectively associates with EBs via its specific tail domain and that this interaction is crucial for AIS formation and neuronal polarity in cultured rodent hippocampal neurons. EBs are essential for 480AnkG localization and stabilization at the AIS, whereas 480AnkG is required for the specific accumulation of EBs in the proximal axon. Our findings thus provide a conceptual framework for understanding how the cooperative relationship between 480AnkG and EBs induces the assembly of microtubule-AIS structures in the proximal axon. Neuronal polarity is crucial for the proper function of neurons. The assembly of the axon initial segment (AIS), which is the hallmark of early neuronal polarization, relies on the longest 480 kDa ankyrin-G isoform. The microtubule cytoskeleton and its interacting proteins were suggested to be early key players in the process of AIS formation. In this study, we show that the crosstalk between 480 kDa ankyrin-G and the microtubule plus-end tracking proteins, EBs, at the proximal axon is decisive for AIS assembly and neuronal polarity. Our work thus provides insight into the functional mechanisms used by 480 kDa ankyrin-G to drive the AIS formation and thereby to establish neuronal polarity. Copyright © 2016 the authors 0270-6474/16/364421-13$15.00/0.

  10. Wnt5a regulates midbrain dopaminergic axon growth and guidance.

    Directory of Open Access Journals (Sweden)

    Brette D Blakely

    2011-03-01

    Full Text Available During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM the cues that guide dopaminergic (DA axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway. Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a-/- mice, where fasciculation of the medial forebrain bundle (MFB as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.

  11. Modelling in vivo action potential propagation along a giant axon.

    Science.gov (United States)

    George, Stuart; Foster, Jamie M; Richardson, Giles

    2015-01-01

    A partial differential equation model for the three-dimensional current flow in an excitable, unmyelinated axon is considered. Where the axon radius is significantly below a critical value R(crit) (that depends upon intra- and extra-cellular conductivity and ion channel conductance) the resistance of the intracellular space is significantly higher than that of the extracellular space, such that the potential outside the axon is uniformly small whilst the intracellular potential is approximated by the transmembrane potential. In turn, since the current flow is predominantly axial, it can be shown that the transmembrane potential is approximated by a solution to the one-dimensional cable equation. It is noted that the radius of the squid giant axon, investigated by (Hodgkin and Huxley 1952e), lies close to R(crit). This motivates us to apply the three-dimensional model to the squid giant axon and compare the results thus found to those obtained using the cable equation. In the context of the in vitro experiments conducted in (Hodgkin and Huxley 1952e) we find only a small difference between the wave profiles determined using these two different approaches and little difference between the speeds of action potential propagation predicted. This suggests that the cable equation approximation is accurate in this scenario. However when applied to the it in vivo setting, in which the conductivity of the surrounding tissue is considerably lower than that of the axoplasm, there are marked differences in both wave profile and speed of action potential propagation calculated using the two approaches. In particular, the cable equation significantly over predicts the increase in the velocity of propagation as axon radius increases. The consequences of these results are discussed in terms of the evolutionary costs associated with increasing the speed of action potential propagation by increasing axon radius.

  12. miR126-5p down-regulation facilitates axon degeneration and NMJ disruption via a non-cell-autonomous mechanism in ALS.

    Science.gov (United States)

    Maimon, Roy; Ionescu, Ariel; Bonnie, Avichai; Sweetat, Sahar; Wald-Altman, Shane; Inbar, Shani; Gradus, Tal; Trotti, Davide; Weil, Miguel; Behar, Oded; Perlson, Eran

    2018-05-17

    Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in Amyotrophic Lateral Sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR-126-5p in pre-symptomatic ALS male mice models, and an increase in its targets: axon destabilizing type-3 Semaphorins and their co-receptor Neuropilins. Utilizing compartmentalized in vitro co-cultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 (NRP1) blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non-cell-autonomous mechanism of motor neuron degeneration in ALS. SIGNIFICANCE STATEMENT In spite of some progress, currently no effective treatment is available for ALS. We suggest a novel regulatory role for miR126-5p in ALS and demonstrate for the first time a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo. Copyright © 2018 Maimon et al.

  13. An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease.

    Science.gov (United States)

    Uchihara, Toshiki

    2017-04-01

    Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected

  14. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties.

    Science.gov (United States)

    Casale, Amanda E; Foust, Amanda J; Bal, Thierry; McCormick, David A

    2015-11-25

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main

  15. Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein.

    Science.gov (United States)

    Garrity, P A; Rao, Y; Salecker, I; McGlade, J; Pawson, T; Zipursky, S L

    1996-05-31

    Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type-specific expression of dock transgenes demonstrate dock is required in R cells for proper innervation. Dock protein contains one SH2 and three SH3 domains, implicating it in tyrosine kinase signaling, and is highly related to the human proto-oncogene Nck. Dock expression is detected in R cell growth cones in the target region. We propose Dock transmits signals in the growth cone in response to guidance and targeting cues. These findings provide an important step for dissection of signaling pathways regulating growth cone motility.

  16. Mechanistic logic underlying the axonal transport of cytosolic proteins

    Science.gov (United States)

    Scott, David A.; Das, Utpal; Tang, Yong; Roy, Subhojit

    2011-01-01

    Proteins vital to presynaptic function are synthesized in the neuronal perikarya and delivered into synapses via two modes of axonal transport. While membrane-anchoring proteins are conveyed in fast axonal transport via motor-driven vesicles, cytosolic proteins travel in slow axonal transport; via mechanisms that are poorly understood. We found that in cultured axons, populations of cytosolic proteins tagged to photoactivable-GFP (PA-GFP) move with a slow motor-dependent anterograde bias; distinct from vesicular-trafficking or diffusion of untagged PA-GFP. The overall bias is likely generated by an intricate particle-kinetics involving transient assembly and short-range vectorial spurts. In-vivo biochemical studies reveal that cytosolic proteins are organized into higher-order structures within axon-enriched fractions that are largely segregated from vesicles. Data-driven biophysical modeling best predicts a scenario where soluble molecules dynamically assemble into mobile supra-molecular structures. We propose a model where cytosolic proteins are transported by dynamically assembling into multi-protein complexes that are directly/indirectly conveyed by motors. PMID:21555071

  17. Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

    Directory of Open Access Journals (Sweden)

    Hai Li

    2016-07-01

    Full Text Available Suboptimal axonal regeneration contributes to the consequences of nervous system trauma and neurodegenerative disease, but the intrinsic mechanisms that regulate axon growth remain unclear. We screened 50,400 small molecules for their ability to promote axon outgrowth on inhibitory substrata. The most potent hits were the statins, which stimulated growth of all mouse- and human-patient-derived neurons tested, both in vitro and in vivo, as did combined inhibition of the protein prenylation enzymes farnesyltransferase (PFT and geranylgeranyl transferase I (PGGT-1. Compensatory sprouting of motor axons may delay clinical onset of amyotrophic lateral sclerosis (ALS. Accordingly, elevated levels of PGGT1B, which would be predicted to reduce sprouting, were found in motor neurons of early- versus late-onset ALS patients postmortem. The mevalonate-prenylation pathway therefore constitutes an endogenous brake on axonal growth, and its inhibition provides a potential therapeutic approach to accelerate neuronal regeneration in humans.

  18. Mechanisms of Distal Axonal Degeneration in Peripheral Neuropathies

    Science.gov (United States)

    Cashman, Christopher R.; Höke, Ahmet

    2015-01-01

    Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wlds) and Sarmknockout animal models. These studies have shown axonal degeneration to occur througha programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration. PMID:25617478

  19. Subtypes of GABAergic neurons project axons in the neocortex

    Directory of Open Access Journals (Sweden)

    Shigeyoshi Higo

    2009-11-01

    Full Text Available γ-aminobutyric acid (GABAergic neurons in the neocortex have been regarded as interneurons and speculated to modulate the activity of neurons locally. Recently, however, several experiments revealed that neuronal nitric oxide synthase (nNOS-positive GABAergic neurons project cortico-cortically with long axons. In this study, we illustrate Golgi-like images of the nNOS-positive GABAergic neurons using a nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d reaction and follow the emanating axon branches in cat brain sections. These axon branches projected cortico-cortically with other non-labeled arcuate fibers, contra-laterally via the corpus callosum and anterior commissure. The labeled fibers were not limited to the neocortex but found also in the fimbria of the hippocampus. In order to have additional information on these GABAergic neuron projections, we investigated green fluorescent protein (GFP-labeled GABAergic neurons in GAD67-Cre knock-in / GFP Cre-reporter mice. GFP-labeled axons emanate densely, especially in the fimbria, a small number in the anterior commissure, and very sparsely in the corpus callosum. These two different approaches confirm that not only nNOS-positive GABAergic neurons but also other subtypes of GABAergic neurons project long axons in the cerebral cortex and are in a position to be involved in information processing.

  20. Characterization of patients with head trauma and traumatic axonal injury

    International Nuclear Information System (INIS)

    Mosquera Betancourt, Dra.C. Gretel; Van Duc, Dr. Hanh; Casares Delgado, Dr. Jorge Alejandro; Hernández González, Dr. Erick Héctor

    2016-01-01

    Background: traumatic axonal injury is characterized by multifocal lesions, consequences of primary, secondary and tertiary damage which is able to cause varying degrees of disability. Objective: to characterize patients with traumatic axonal injury. Methods: a cross-sectional analytical study was conducted from January 2014 to December 2015. The target population was composed of 35 patients over age 18 whose diagnosis was traumatic axonal injury type I and IV of the Marshall computed tomographic (CT) classification. With the data collected from medical records revisions and direct observation, a database was created in SPSS for its processing through univariate and multivariate techniques. Results: male patients between 18 and 30 years old without bad habits prevailed. Most of the patients survived and death was associated with the presence of severe traumatic axonal injury, Marshall computed tomographic (CT) classification degree III, complications and presence of trauma in thorax, abdomen and cervical spine. Conclusions: diagnosis of traumatic axonal injury is based on the clinical radiological correlation based on images from tomography and it is confirmed by Magnetic resonance imaging (MRI). Histological study shows injuries that are not demonstrated in the most advanced radiological studies. Its prevention is the most fundamental base in medical assistance, followed by neurocritical attention oriented by neuromonitoring. (author)

  1. Highly effective photonic cue for repulsive axonal guidance.

    Directory of Open Access Journals (Sweden)

    Bryan J Black

    Full Text Available In vivo nerve repair requires not only the ability to regenerate damaged axons, but most importantly, the ability to guide developing or regenerating axons along paths that will result in functional connections. Furthermore, basic studies in neuroscience and neuro-electronic interface design require the ability to construct in vitro neural circuitry. Both these applications require the development of a noninvasive, highly effective tool for axonal growth-cone guidance. To date, a myriad of technologies have been introduced based on chemical, electrical, mechanical, and hybrid approaches (such as electro-chemical, optofluidic flow and photo-chemical methods. These methods are either lacking in desired spatial and temporal selectivity or require the introduction of invasive external factors. Within the last fifteen years however, several attractive guidance cues have been developed using purely light based cues to achieve axonal guidance. Here, we report a novel, purely optical repulsive guidance technique that uses low power, near infrared light, and demonstrates the guidance of primary goldfish retinal ganglion cell axons through turns of up to 120 degrees and over distances of ∼90 µm.

  2. Functional complexity of the axonal growth cone: a proteomic analysis.

    Directory of Open Access Journals (Sweden)

    Adriana Estrada-Bernal

    Full Text Available The growth cone, the tip of the emerging neurite, plays a crucial role in establishing the wiring of the developing nervous system. We performed an extensive proteomic analysis of axonal growth cones isolated from the brains of fetal Sprague-Dawley rats. Approximately 2000 proteins were identified at ≥ 99% confidence level. Using informatics, including functional annotation cluster and KEGG pathway analysis, we found great diversity of proteins involved in axonal pathfinding, cytoskeletal remodeling, vesicular traffic and carbohydrate metabolism, as expected. We also found a large and complex array of proteins involved in translation, protein folding, posttranslational processing, and proteasome/ubiquitination-dependent degradation. Immunofluorescence studies performed on hippocampal neurons in culture confirmed the presence in the axonal growth cone of proteins representative of these processes. These analyses also provide evidence for rough endoplasmic reticulum and reveal a reticular structure equipped with Golgi-like functions in the axonal growth cone. Furthermore, Western blot revealed the growth cone enrichment, relative to fetal brain homogenate, of some of the proteins involved in protein synthesis, folding and catabolism. Our study provides a resource for further research and amplifies the relatively recently developed concept that the axonal growth cone is equipped with proteins capable of performing a highly diverse range of functions.

  3. Axonal transport and axon sprouting in the adult rat dentate gyrus: an autoradiographic study

    International Nuclear Information System (INIS)

    Goldowitz, D.; Cotman, C.W.

    1980-01-01

    In response to an entorhinal lesion, the commissural and associational afferents to the dentate gyrus have been shown to expand beyond their normal terminal zone into the area denervated by the entorhinal lesion. The present study has investigated the axonal transport of [ 3 H]-labeled proteins in the commissural and associational projections following an entorhinal lesion. Injections of [ 3 H]proline, [ 3 H]leucine or [ 3 H)fucose were given in the vicinity of the commissural and associational cells of origin before, immediately subsequent to, or at 5 to 15 days after the entorhinal lesion. The disposition of previously- or newly-synthesized proteins was examined in the commissural and associational terminal field at different times after an entorhinal lesion by light-microscopic autoradiography. (author)

  4. Axonal transport and axon sprouting in the adult rat dentate gyrus: an autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Goldowitz, D; Cotman, C W [California Univ., Irvine (USA)

    1980-12-01

    In response to an entorhinal lesion, the commissural and associational afferents to the dentate gyrus have been shown to expand beyond their normal terminal zone into the area denervated by the entorhinal lesion. The present study has investigated the axonal transport of (/sup 3/H)-labeled proteins in the commissural and associational projections following an entorhinal lesion. Injections of (/sup 3/H)proline, (/sup 3/H)leucine or (/sup 3/H)fucose were given in the vicinity of the commissural and associational cells of origin before, immediately subsequent to, or at 5 to 15 days after the entorhinal lesion. The disposition of previously- or newly-synthesized proteins was examined in the commissural and associational terminal field at different times after an entorhinal lesion by light-microscopic autoradiography.

  5. Investigating the usefulness of a cluster-based trend analysis to detect visual field progression in patients with open-angle glaucoma.

    Science.gov (United States)

    Aoki, Shuichiro; Murata, Hiroshi; Fujino, Yuri; Matsuura, Masato; Miki, Atsuya; Tanito, Masaki; Mizoue, Shiro; Mori, Kazuhiko; Suzuki, Katsuyoshi; Yamashita, Takehiro; Kashiwagi, Kenji; Hirasawa, Kazunori; Shoji, Nobuyuki; Asaoka, Ryo

    2017-12-01

    To investigate the usefulness of the Octopus (Haag-Streit) EyeSuite's cluster trend analysis in glaucoma. Ten visual fields (VFs) with the Humphrey Field Analyzer (Carl Zeiss Meditec), spanning 7.7 years on average were obtained from 728 eyes of 475 primary open angle glaucoma patients. Mean total deviation (mTD) trend analysis and EyeSuite's cluster trend analysis were performed on various series of VFs (from 1st to 10th: VF1-10 to 6th to 10th: VF6-10). The results of the cluster-based trend analysis, based on different lengths of VF series, were compared against mTD trend analysis. Cluster-based trend analysis and mTD trend analysis results were significantly associated in all clusters and with all lengths of VF series. Between 21.2% and 45.9% (depending on VF series length and location) of clusters were deemed to progress when the mTD trend analysis suggested no progression. On the other hand, 4.8% of eyes were observed to progress using the mTD trend analysis when cluster trend analysis suggested no progression in any two (or more) clusters. Whole field trend analysis can miss local VF progression. Cluster trend analysis appears as robust as mTD trend analysis and useful to assess both sectorial and whole field progression. Cluster-based trend analyses, in particular the definition of two or more progressing cluster, may help clinicians to detect glaucomatous progression in a timelier manner than using a whole field trend analysis, without significantly compromising specificity. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Localization of mRNA in vertebrate axonal compartments by in situ hybridization.

    Science.gov (United States)

    Sotelo-Silveira, José Roberto; Calliari, Aldo; Kun, Alejandra; Elizondo, Victoria; Canclini, Lucía; Sotelo, José Roberto

    2011-01-01

    The conclusive demonstration of RNA in vertebrate axons by in situ hybridization (ISH) has been elusive. We review the most important reasons for difficulties, including low concentration of axonal RNAs, localization in specific cortical domains, and the need to isolate axons. We demonstrate the importance of axon micro-dissection to obtain a whole mount perspective of mRNA distribution in the axonal territory. We describe a protocol to perform fluorescent ISH in isolated axons and guidelines for the preservation of structural and molecular integrity of cortical RNA-containing domains (e.g., Periaxoplasmic Ribosomal Plaques, or PARPs) in isolated axoplasm.

  7. Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene

    DEFF Research Database (Denmark)

    Rosberg, Mette Romer; Alvarez, Susana; Krarup, Christian

    2013-01-01

    Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate...... whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using...... threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated...

  8. Comparing the detection and agreement of parapapillary atrophy progression using digital optic disk photographs and alternation flicker.

    Science.gov (United States)

    VanderBeek, Brian L; Smith, Scott D; Radcliffe, Nathan M

    2010-09-01

    Parapapillary atrophy (PPA) progression has been associated with progressive glaucoma, but has proven to be difficult to assess clinically. We compared inter- and intra-observer agreement using a novel automated alternation flicker technology and side-by-side digital photography inspection for the evaluation of PPA progression. Consecutive patients with serial digital optic nerve photographs at least 1 year apart were included. Two graders (NR, BV) masked to image chronology assessed a set of photographs for progressive PPA using predefined criteria based on reference photographs containing mild, moderate, extensive or no PPA progression. At a separate session, the graders evaluated photographs using alternation flicker (EyeIC, Narberth, PA, USA) applying the same criteria. The order of patients and technique was randomized. Graders then assessed the same set of flickers and photographs a second time with the order of presentation reversed. The main outcome measure was the assessment of progressive PPA as identified by alternation flicker and digital photography inspection. Inter- and intra-observer agreement using each technique was assessed using the kappa statistic. A bootstrap method for comparing correlated kappa coefficients was used to assess statistical significance. Serial photographs from 131 eyes of 68 patients were evaluated. Both graders identified significantly more cases of PPA progression using flicker compared to photography (27-34% vs 8-13%; both pphotographs (kappa=0.52 vs 0.18, p=0.02). Intra-observer agreement was similar for both graders (photos: kappa=0.58 vs 0.57, p=0.97; flicker: kappa=0.61 vs 0.70, p=0.37). When progression was assessed by the number of progressive quadrants identified by each grader using a weighted kappa statistic, flicker inter-observer agreement was still moderate (kappa=0.45) and significantly better (p=0.01) than photography, which showed poor agreement (kappa=0.15). Intra-observer agreement with a weighted kappa for

  9. Perilesional edema in radiation necrosis reflects axonal degeneration

    International Nuclear Information System (INIS)

    Perez-Torres, Carlos J; Yuan, Liya; Schmidt, Robert E; Rich, Keith M; Ackerman, Joseph JH; Garbow, Joel R

    2015-01-01

    Recently, we characterized a Gamma Knife® radiation necrosis mouse model with various magnetic resonance imaging (MRI) protocols to identify biomarkers useful in differentiation from tumors. Though the irradiation was focal to one hemisphere, a contralateral injury was observed that appeared to be localized in the white matter only. Interestingly, this injury was identifiable in T2-weighted images, apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) maps, but not on post-contrast T1-weighted images. This observation of edema independent of vascular changes is akin to the perilesional edema seen in clinical radiation necrosis. The pathology underlying the observed white-matter MRI changes was explored by performing immunohistochemistry for healthy axons and myelin. The presence of both healthy axons and myelin was reduced in the contralateral white-matter lesion. Based on our immunohistochemical findings, the contralateral white-matter injury is most likely due to axonal degeneration

  10. The nano-architecture of the axonal cytoskeleton.

    Science.gov (United States)

    Leterrier, Christophe; Dubey, Pankaj; Roy, Subhojit

    2017-12-01

    The corporeal beauty of the neuronal cytoskeleton has captured the imagination of generations of scientists. One of the easiest cellular structures to visualize by light microscopy, its existence has been known for well over 100 years, yet we have only recently begun to fully appreciate its intricacy and diversity. Recent studies combining new probes with super-resolution microscopy and live imaging have revealed surprising details about the axonal cytoskeleton and, in particular, have discovered previously unknown actin-based structures. Along with traditional electron microscopy, these newer techniques offer a nanoscale view of the axonal cytoskeleton, which is important for our understanding of neuronal form and function, and lay the foundation for future studies. In this Review, we summarize existing concepts in the field and highlight contemporary discoveries that have fundamentally altered our perception of the axonal cytoskeleton.

  11. Chondroitin-4-sulfation negatively regulates axonal guidance and growth

    Science.gov (United States)

    Wang, Hang; Katagiri, Yasuhiro; McCann, Thomas E.; Unsworth, Edward; Goldsmith, Paul; Yu, Zu-Xi; Tan, Fei; Santiago, Lizzie; Mills, Edward M.; Wang, Yu; Symes, Aviva J.; Geller, Herbert M.

    2008-01-01

    Summary Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition, and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate (CS) mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated CS GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings provide the evidence showing that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function. PMID:18768934

  12. The axon-protective WLD(S) protein partially rescues mitochondrial respiration and glycolysis after axonal injury.

    Science.gov (United States)

    Godzik, Katharina; Coleman, Michael P

    2015-04-01

    The axon-protective Wallerian degeneration slow (WLD(S)) protein can ameliorate the decline in axonal ATP levels after neurite transection. Here, we tested the hypothesis that this effect is associated with maintenance of mitochondrial respiration and/or glycolysis. We used isolated neurites of superior cervical ganglion (SCG) cultures in the Seahorse XF-24 Metabolic Flux Analyser to determine mitochondrial respiration and glycolysis under different conditions. We observed that both mitochondrial respiration and glycolysis declined significantly during the latent phase of Wallerian degeneration. WLD(S) partially reduced the decline both in glycolysis and in mitochondrial respiration. In addition, we found that depleting NAD levels in uncut cultures led to changes in mitochondrial respiration and glycolysis similar to those rescued by WLD(S) after cut, suggesting that the maintenance of NAD levels in Wld(S) neurites after axonal injury at least partially underlies the maintenance of ATP levels. However, by using another axon-protective mutation (Sarm1(-/-)), we could demonstrate that rescue of basal ECAR (and hence probably glycolysis) rather than basal OCR (mitochondrial respiration) may be part of the protective phenotype to delay Wallerian degeneration. These findings open new routes to study glycolysis and the connection between NAD and ATP levels in axon degeneration, which may help to eventually develop therapeutic strategies to treat neurodegenerative diseases.

  13. Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia.

    Science.gov (United States)

    Rocco, Brad R; DeDionisio, Adam M; Lewis, David A; Fish, Kenneth N

    2017-07-01

    The axons of chandelier cells (ChCs) target the axon initial segment of pyramidal neurons, forming an array of boutons termed a cartridge. In schizophrenia, the density of cartridges detectable by gamma-aminobutyric acid (GABA) membrane transporter 1 immunoreactivity is lower, whereas the density of axon initial segments detectable by immunoreactivity for the α2 subunit of the GABA A receptor is higher in layers 2/superficial 3 of the prefrontal cortex. These findings were interpreted as compensatory responses to lower GABA levels in ChCs. However, we recently found that in schizophrenia, ChC cartridge boutons contain normal levels of the 67 kDa isoform of glutamic acid decarboxylase (GAD67) protein, the enzyme responsible for GABA synthesis in these boutons. To understand these findings we quantified the densities of ChC cartridges immunoreactive for vesicular GABA transporter (vGAT+), which is present in all cartridge boutons, and the subset of cartridges that contain calbindin (CB+). Prefrontal cortex tissue sections from 20 matched pairs of schizophrenia and unaffected comparison subjects were immunolabeled for vGAT, GAD67, and CB. The mean density of vGAT+/CB+ cartridges was 2.7-fold higher, exclusively in layer 2 of schizophrenia subjects, whereas the density of vGAT+/CB- cartridges did not differ between subject groups. Neither vGAT, CB, or GAD67 protein levels per ChC bouton nor the number of boutons per cartridge differed between subject groups. Our findings of a greater density of CB+ ChC cartridges in prefrontal cortex layer 2 from schizophrenia subjects suggests that the normal developmental pruning of these cartridges is blunted in the illness. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Pannexin 1 Modulates Axonal Growth in Mouse Peripheral Nerves

    Directory of Open Access Journals (Sweden)

    Steven M. Horton

    2017-11-01

    Full Text Available The pannexin family of channels consists of three members—pannexin-1 (Panx1, pannexin-2 (Panx2, and pannexin-3 (Panx3 that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Pannexin-mediated release of intracellular ATP into the extracellular space has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors. Previous work indicates that the opening of Panx1 channels and activation of purinergic receptors by extracellular ATP may cause inflammation and apoptosis. In the CNS (central nervous system and PNS (peripheral nervous system, coupled pannexin, and P2 functions have been linked to peripheral sensitization (pain pathways. Purinergic pathways are also essential for other critical processes in the PNS, including myelination and neurite outgrowth. However, whether such pathways are pannexin-dependent remains to be determined. In this study, we use a Panx1 knockout mouse model and pharmacological inhibitors of the Panx1 and the ATP-mediated signaling pathway to fill gaps in our understanding of Panx1 localization in peripheral nerves, roles for Panx1 in axonal outgrowth and myelination, and neurite extension. Our data show that Panx1 is localized to axonal, myelin, and vascular compartments of the peripheral nerves. Knockout of Panx1 gene significantly increased axonal caliber in vivo and axonal growth rate in cultured dorsal root ganglia (DRG neurons. Furthermore, genetic knockout of Panx1 or inhibition of components of purinergic signaling, by treatment with probenecid and apyrase, resulted in denser axonal outgrowth from cultured DRG explants compared to untreated wild-types. Our findings suggest that Panx1 regulates axonal growth in the peripheral nervous system.

  15. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    International Nuclear Information System (INIS)

    Menelaou, Evdokia; Paul, Latoya T.; Perera, Surangi N.; Svoboda, Kurt R.

    2015-01-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. - Highlights: • Embryonic nicotine exposure can specifically affect secondary motoneuron axons in a dose-dependent manner.

  16. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    Energy Technology Data Exchange (ETDEWEB)

    Menelaou, Evdokia; Paul, Latoya T. [Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803 (United States); Perera, Surangi N. [Joseph J. Zilber School of Public Health, University of Wisconsin — Milwaukee, Milwaukee, WI 53205 (United States); Svoboda, Kurt R., E-mail: svobodak@uwm.edu [Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803 (United States); Joseph J. Zilber School of Public Health, University of Wisconsin — Milwaukee, Milwaukee, WI 53205 (United States)

    2015-04-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. - Highlights: • Embryonic nicotine exposure can specifically affect secondary motoneuron axons in a dose-dependent manner.

  17. Progressive cerebral atrophy in neuromyelitis optica.

    Science.gov (United States)

    Warabi, Yoko; Takahashi, Toshiyuki; Isozaki, Eiji

    2015-12-01

    We report two cases of neuromyelitis optica patients with progressive cerebral atrophy. The patients exhibited characteristic clinical features, including elderly onset, secondary progressive tetraparesis and cognitive impairment, abnormally elevated CSF protein and myelin basic protein levels, and extremely highly elevated serum anti-AQP-4 antibody titer. Because neuromyelitis optica pathology cannot switch from an inflammatory phase to the degenerative phase until the terminal phase, neuromyelitis optica rarely appears as a secondary progressive clinical course caused by axonal degeneration. However, severe intrathecal inflammation and massive destruction of neuroglia could cause a secondary progressive clinical course associated with cerebral atrophy in neuromyelitis optica patients. © The Author(s), 2015.

  18. Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury.

    Science.gov (United States)

    Gordon, Tessa; Chan, K Ming; Sulaiman, Olawale A R; Udina, Esther; Amirjani, Nasim; Brushart, Thomas M

    2009-10-01

    Injured peripheral nerves regenerate at very slow rates. Therefore, proximal injury sites such as the brachial plexus still present major challenges, and the outcomes of conventional treatments remain poor. This is in part attributable to a progressive decline in the Schwann cells' ability to provide a supportive milieu for the growth cone to extend and to find the appropriate target. These challenges are compounded by the often considerable delay of regeneration across the site of nerve laceration. Recently, low-frequency electrical stimulation (as brief as an hour) has shown promise, as it significantly accelerated regeneration in animal models through speeding of axon growth across the injury site. To test whether this might be a useful clinical tool, we carried out a randomized controlled trial in patients who had experienced substantial axonal loss in the median nerve owing to severe compression in the carpal tunnel. To further elucidate the potential mechanisms, we applied rolipram, a cyclic adenosine monophosphate agonist, to rats after axotomy of the femoral nerve. We demonstrated that effects similar to those observed in animal studies could also be attained in humans. The mechanisms of action of electrical stimulation likely operate through up-regulation of neurotrophic factors and cyclic adenosine monophosphate. Indeed, the application of rolipram significantly accelerated nerve regeneration. With new mechanistic insights into the influencing factors of peripheral nerve regeneration, the novel treatments described above could form part of an armament of synergistic therapies that could make a meaningful difference to patients with peripheral nerve injuries.

  19. Plasminogen deficiency causes reduced corticospinal axonal plasticity and functional recovery after stroke in mice.

    Directory of Open Access Journals (Sweden)

    Zhongwu Liu

    Full Text Available Tissue plasminogen activator (tPA has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg into plasmin. In this study, using plasminogen knockout (Plg-/- mice and their Plg-native littermates (Plg+/+, we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo. A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA was injected into the left motor cortex to anterogradely label the corticospinal tract (CST. Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p0.82, p<0.01. Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord.

  20. Studies of axon-glial cell interactions and periaxonal K+ homeostasis--II. The effect of axonal stimulation, cholinergic agents and transport inhibitors on the resistance in series with the axon membrane.

    Science.gov (United States)

    Hassan, S; Lieberman, E M

    1988-06-01

    The small electrical resistance in series with the axon membrane is generally modeled as the intercellular pathway for current flow through the periaxonal glial (Schwann cell) sheath. The series resistance of the medial giant axon of the crayfish, Procambarus clarkii, was found to vary with conditions known to affect the electrical properties of the periaxonal glia. Series resistance was estimated from computer analysed voltage waveforms generated by axial wire-constant current and space clamp techniques. The average series resistance for all axons was 6.2 +/- 0.5 omega cm2 (n = 128). Values ranged between 1 and 30 omega cm2. The series resistance of axons with low resting membrane resistance (less than 1500 omega cm2) increased an average of 30% when stimulated for 45 s to 7 min (50 Hz) whereas the series resistance of high membrane resistance (greater than 1500 omega cm2) axons decreased an average of 10%. Carbachol (10(-7) M) caused the series resistance of low membrane resistance axons to decrease during stimulation but had no effect on high membrane resistance axons. d-Tubocurare (10(-8) M) caused the series resistance of high membrane resistance axons to increase during stimulation but had no effect on low membrane resistance axons. Bumetanide, a Na-K-Cl cotransport inhibitor and low [K+]o, prevented the stimulation-induced increase in series resistance of low membrane resistance axons but had no effect on the high membrane resistance axons. The results suggest that the series resistance of axons varies in response to the activity of the glial K+ uptake mechanisms stimulated by the appearance of K+ in the periaxonal space during action potential generation.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance

    Directory of Open Access Journals (Sweden)

    Jeffery Glen

    2008-05-01

    Full Text Available Abstract Background The transcription factor Pax6 is expressed by many cell types in the developing eye. Eyes do not form in homozygous loss-of-function mouse mutants (Pax6Sey/Sey and are abnormally small in Pax6Sey/+ mutants. Eyes are also abnormally small in PAX77 mice expressing multiple copies of human PAX6 in addition to endogenous Pax6; protein sequences are identical in the two species. The developmental events that lead to microphthalmia in PAX77 mice are not well-characterised, so it is not clear whether over- and under-expression of Pax6/PAX6 cause microphthalmia through similar mechanisms. Here, we examined the consequences of over-expression for the eye and its axonal connections. Results Eyes form in PAX77+/+ embryos but subsequently degenerate. At E12.5, we found no abnormalities in ocular morphology, retinal cell cycle parameters and the incidence of retinal cell death. From E14.5 on, we observed malformations of the optic disc. From E16.5 into postnatal life there is progressively more severe retinal dysplasia and microphthalmia. Analyses of patterns of gene expression indicated that PAX77+/+ retinae produce a normal range of cell types, including retinal ganglion cells (RGCs. At E14.5 and E16.5, quantitative RT-PCR with probes for a range of molecules associated with retinal development showed only one significant change: a slight reduction in levels of mRNA encoding the secreted morphogen Shh at E16.5. At E16.5, tract-tracing with carbocyanine dyes in PAX77+/+ embryos revealed errors in intraretinal navigation by RGC axons, a decrease in the number of RGC axons reaching the thalamus and an increase in the proportion of ipsilateral projections among those RGC axons that do reach the thalamus. A survey of embryos with different Pax6/PAX6 gene dosage (Pax6Sey/+, Pax6+/+, PAX77+ and PAX77+/+ showed that (1 the total number of RGC axons projected by the retina and (2 the proportions that are sorted into the ipsilateral and

  2. Sodium boiling detection in LMFBRs (Phase I). 5th quarterly technical progress report, July 1, 1975--October 31, 1975

    International Nuclear Information System (INIS)

    Albrecht, R.W.; McCormick, N.J.

    1975-01-01

    Progress summarized includes the design of a gamma heated subassembly for sodium boiling experiments and an experiment showing that neutronic noise and acoustic noise caused by sodium boiling are highly correlated in a wide frequency band about the bubble repetition frequency

  3. Quantifying mechanical force in axonal growth and guidance

    Directory of Open Access Journals (Sweden)

    Ahmad Ibrahim Mahmoud Athamneh

    2015-09-01

    Full Text Available Mechanical force plays a fundamental role in neuronal development, physiology, and regeneration. In particular, research has shown that force is involved in growth cone-mediated axonal growth and guidance as well as stretch-induced elongation when an organism increases in size after forming initial synaptic connections. However, much of the details about the exact role of force in these fundamental processes remain unknown. In this review, we highlight (1 standing questions concerning the role of mechanical force in axonal growth and guidance and (2 different experimental techniques used to quantify forces in axons and growth cones. We believe that satisfying answers to these questions will require quantitative information about the relationship between elongation, forces, cytoskeletal dynamics, axonal transport, signaling, substrate adhesion, and stiffness contributing to directional growth advance. Furthermore, we address why a wide range of force values have been reported in the literature, and what these values mean in the context of neuronal mechanics. We hope that this review will provide a guide for those interested in studying the role of force in development and regeneration of neuronal networks.

  4. Investigation on the mechanism of peripheral axonal injury in glaucoma

    Directory of Open Access Journals (Sweden)

    Jun- Hong Zhao

    2013-05-01

    Full Text Available AIM: To compare the angles of longitudinal section of sclera around optic nerve heads and the never fiber layer changes in healthy adults and patients with glaucoma, and to investigate the mechanism of peripheral retinal axonal injury, with the combined knowledge of biomechanics. METHODS: The optical nerves and their peripheral tissue specimen in the 12 eyes from health adult donators and 12 eyes from glaucoma patient donators were dyed by Glees' method to compare the angles of longitudinal section of sclera around optic nerve heads(through optic nerve center, and to observe the anatomical features of the peripheral retinal axons. RESULTS: The mean angle of longitudinal section of sclera around optic nerve in healthy adults was 73.3°, while that in patients with absolute glaucoma was 75.6°. The difference showed no significance(t=1.44, P>0.05. There was a sharp bend in the course of peripheral optical fiber in healthy adults. However, the optic nerve fiber disappeared completely in patients with glaucoma end stage. CONCLUSION: The angle between the medial edge and leading edge of sclera(around optic nerve headsis an acute angle. The optical fiber in glaucoma end stage disappeared completely. The phenomenon may be related to high intraocular pressure, the sclera shape, the shear modulus of sclera and axons, and “axonal bending-injury” mechanism.

  5. RGM is a repulsive guidance molecule for retinal axons

    DEFF Research Database (Denmark)

    Monnier, Philippe P; Sierra, Ana; Macchi, Paolo

    2002-01-01

    with known guidance cues, and its messenger RNA is distributed in a gradient with increasing concentration from the anterior to posterior pole of the embryonic tectum. Recombinant RGM at low nanomolar concentration induces collapse of temporal but not of nasal growth cones and guides temporal retinal axons...

  6. IFNgamma enhances microglial reactions to hippocampal axonal degeneration

    DEFF Research Database (Denmark)

    Jensen, M B; Hegelund, I V; Lomholt, N D

    2000-01-01

    periods. Message for the immune cytokine interferon-gamma (IFNgamma) was undetectable, and glial reactivity to axonal lesions occurred as normal in IFNgamma-deficient mice. Microglial responses to lesion-induced neuronal injury were markedly enhanced in myelin basic protein promoter-driven transgenic mice...

  7. Multiple sclerosis and anterograde axonal degeneration study by magnetic resonance

    International Nuclear Information System (INIS)

    Martinez Pardo, P.; Capdevila Cirera, A.; Sanz Marin, P.M.; Gili Planas, J.

    1993-01-01

    Multiple sclerosis (MS) is a disease of the central nervous system that affects specifically the myelin. Its diagnosis by imaging techniques is, since the development of magnetic resonance (MR), relatively simple, and its occasional association with anterograde axonal degeneration (WD) has been reported. In both disorders, there is a lengthening of the T1 and T2 relaxation times. In the present report, 76 patients with MS with less than 4 plaques in the typical periventricular position were studied retrospectively, resulting in a rate of association with anterograde axonal degeneration of 8%. We consider that in spite of their same behavior in MR,MS and WD, with moreover represent completely different pathologies, are perfectly differential by MR. The S-E images with longer repetition and echo times in the axial and coronal planes have proved to be those most sensitive for this differentiation. Given that MS is specific pathology of then myelin, the axonal damages in delayed until several plaques adjacent to an axon affect it. We consider that this, added to the restriction of our study group (less than 4 plaques), is the cause of the pow percentage of the MS-WD association in our study. (Author)

  8. Chronic severe axonal polyneuropathy associated with hyperthyroidism and multivitamin deficiency.

    Science.gov (United States)

    Sugie, Kazuma; Umehara, Fujio; Kataoka, Hiroshi; Kumazawa, Aya; Ueno, Satoshi

    2012-01-01

    Hyperthyroidism is often associated with various neuromuscular disorders, most commonly proximal myopathy. Peripheral nerve involvement in hyperthyroidism is very uncommon and has rarely been reported. We describe a 29-year-old woman with untreated hyperthyroidism who presented with chronic severe axonal sensory-motor polyneuropathy. Peripheral nerve involvement developed together with other symptoms of hyperthyroidism 2 years before presentation. She also had anorexia nervosa for the past 6 months, resulting in multivitamin deficiency. Electrophysiological and pathological findings as well as clinical manifestations confirmed the diagnosis of severe axonal polyneuropathy. Anorexia nervosa has been considered a manifestation of untreated hyperthyroidism. We considered hyperthyroidism to be an important causal factor in the polyneuropathy in our patient, although peripheral nerve involvement in hyperthyroidism is rare. To our knowledge, this is the first documented case of chronic severe axonal polyneuropathy ascribed to both hyperthyroidism and multivitamin deficiency. Our findings strongly suggest that not only multivitamin deficiency, but also hyperthyroidism can cause axonal polyneuropathy, thus expanding the clinical spectrum of hyperthyroidism.

  9. Impaired Mitochondrial Dynamics Underlie Axonal Defects in Hereditary Spastic Paraplegias.

    Science.gov (United States)

    Denton, Kyle; Mou, Yongchao; Xu, Chong-Chong; Shah, Dhruvi; Chang, Jaerak; Blackstone, Craig; Li, Xue-Jun

    2018-05-02

    Mechanisms by which long corticospinal axons degenerate in hereditary spastic paraplegia (HSP) are largely unknown. Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of HSP, SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. In patient iPSC-derived telencephalic glutamatergic and midbrain dopaminergic neurons, neurite number, length and branching are significantly reduced, recapitulating disease-specific phenotypes. We analyzed mitochondrial morphology and noted a significant reduction in both mitochondrial length and their densities within axons of these HSP neurons. Mitochondrial membrane potential was also decreased, confirming functional mitochondrial defects. Notably, mdivi-1, an inhibitor of the mitochondrial fission GTPase DRP1, rescues mitochondrial morphology defects and suppresses the impairment in neurite outgrowth and late-onset apoptosis in HSP neurons. Furthermore, knockdown of these HSP genes causes similar axonal defects, also mitigated by treatment with mdivi-1. Finally, neurite outgrowth defects in SPG15 and SPG48 cortical neurons can be rescued by knocking down DRP1 directly. Thus, abnormal mitochondrial morphology caused by an imbalance of mitochondrial fission and fusion underlies specific axonal defects and serves as a potential therapeutic target for SPG15 and SPG48.

  10. Botulinum toxin's axonal transport from periphery to the spinal cord.

    Science.gov (United States)

    Matak, Ivica; Riederer, Peter; Lacković, Zdravko

    2012-07-01

    Axonal transport of enzymatically active botulinum toxin A (BTX-A) from periphery to the CNS has been described in facial and trigeminal nerve, leading to cleavage of synaptosomal-associated protein 25 (SNAP-25) in central nuclei. Aim of present study was to examine the existence of axonal transport of peripherally applied BTX-A to spinal cord via sciatic nerve. We employed BTX-A-cleaved SNAP-25 immunohistochemistry of lumbar spinal cord after intramuscular and subcutaneous hind limb injections, and intraneural BTX-A sciatic nerve injections. Truncated SNAP-25 in ipsilateral spinal cord ventral horns and dorsal horns appeared after single peripheral BTX-A administrations, even at low intramuscular dose applied (5 U/kg). Cleaved SNAP-25 appearance in the spinal cord after BTX-A injection into the sciatic nerve was prevented by proximal intrasciatic injection of colchicine (5 mM, 2 μl). Cleaved SNAP-25 in ventral horn, using choline-acetyltransferase (ChAT) double labeling, was localized within cholinergic neurons. These results extend the recent findings on BTX-A retrograde axonal transport in facial and trigeminal nerve. Appearance of truncated SNAP-25 in spinal cord following low-dose peripheral BTX-A suggest that the axonal transport of BTX-A occurs commonly following peripheral application. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Computed tomography in diagnosis of diffuse axonal injury

    International Nuclear Information System (INIS)

    Iwadate, Yasuo; Ono, Juniti; Okimura, Yoshitaka; Suda, Sumio; Isobe, Katsumi; Yamaura, Akira.

    1990-01-01

    Diffuse axonal injury (DAI) has been described in instances of prolonged traumatic coma on the basis of the neuropathological findings, but the same findings are also found in patients with cerebral concussion. Experimental studies confirm that the quality of survivors following trauma is directly proportional to the amount of primarily injured-axon. When the injured axon lies in a widespread area of the brain, outcome for the patient is always poor. In a series of 260 severely head-injured patients, based on their poor outcome, 69 (27%) were diagnosed as DAI. Because of their relatively good outcome, eighty-two patients (32%) were classified into non-DAI group. The predominant CT finding of DAI patients was intraparenchymal deep-seated hemorrhagic lesion. This was observed in 28 patients (41%). Normal CT was also observed in 11 patients (16%). On the other hand, 8 of the non-DAI group (10%) manifested deep-seated lesions. Diffuse cerebral swelling (DCS) appeared in both groups in the same incidence. Subarachnoid hematoma in the perimesencephalic cistern (SAH (PMC)) and intraventricular hematoma (IVH) were observed in 64% of the DAI group, and in 23% of the non-DAI group. The available evidence indicates that various types of hematoma seen in the deep-seated structures of the brain do not have an absolute diagnostic value, but the frequency of hematoma is thought to increase in proportion to the amount of injured-axon. (author)

  12. Differential Axonal Projection of Mitral and Tufted Cells in the Mouse Main Olfactory System

    Directory of Open Access Journals (Sweden)

    Shin Nagayama

    2010-09-01

    Full Text Available In the past decade, much has been elucidated regarding the functional organization of the axonal connection of olfactory sensory neurons to olfactory bulb (OB glomeruli. However, the manner in which projection neurons of the OB process odorant input and send this information to higher brain centers remains unclear. Here, we report long-range, large-scale tracing of the axonal projection patterns of OB neurons using two-photon microscopy. Tracer injection into a single glomerulus demonstrated widely distributed mitral/tufted cell axonal projections on the lateroventral surface of the mouse brain, including the anterior/posterior piriform cortex (PC and olfactory tubercle (OT. We noted two distinct groups of labeled axons: PC-orienting axons and OT-orienting axons. Each group occupied distinct parts of the lateral olfactory tract. PC-orienting axons projected axon collaterals to a wide area of the PC but only a few collaterals to the OT. OT-orienting axons densely projected axon collaterals primarily to the anterolateral OT (alOT. Different colored dye injections into the superficial and deep portions of the OB external plexiform layer revealed that the PC-orienting axon populations originated in presumed mitral cells and the OT-orienting axons in presumed tufted cells. These data suggest that although mitral and tufted cells receive similar odor signals from a shared glomerulus, they process the odor information in different ways and send their output to different higher brain centers via the PC and alOT.

  13. Optical Coherence Tomography-A New Diagnostic Tool to Evaluate Axonal Degeneration in Multiple Sclerosis: A Review

    Directory of Open Access Journals (Sweden)

    Nilüfer Kale

    2010-09-01

    Full Text Available Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system with a wide spectrum of clinical signs and symptoms. Multiple sclerosis lesions have a predilection for the optic nerves, periventricular white matter, brainstem, spinal cord, and cerebellum. The mechanisms responsible for multiple sclerosis are complex and heterogeneous across patients and disease stages. No specific markers exist for the definite diagnosis and prognosis of multiple sclerosis. The afferent visual pathway, which extends from the retina to the primary visual cortex including the optic nerve, is one of the most commonly affected sites in multiple sclerosis (94-99%. Pathology of affected optic nerves exhibits inflammation, demyelination, gliosis, axonal injury, and thinning of the retinal nerve fiber layer (RNFL. The RNFL is composed of unmyelinated axons, and measuring RNFL thickness is a viable method to monitor axonal loss reflecting disease progression. Optical coherence tomography is a noninvasive and reproducible tool in assessing the impact of multiple sclerosis on the thickness of the RNFL. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods provides insights into the pathophysiology of multiple sclerosis and may also serve a prognostic role in multiple sclerosis

  14. Detection of long-term progression of myocardial fibrosis in Duchenne muscular dystrophy in an affected family: A cardiovascular magnetic resonance study

    International Nuclear Information System (INIS)

    Walcher, Thomas; Steinbach, Peter; Spiess, Jochen; Kunze, Markus; Gradinger, Robert; Walcher, Daniel; Bernhardt, Peter

    2011-01-01

    Background: Detection of myocardial fibrosis and left ventricular dysfunction in Duchenne muscular dystrophy (DMD) is the corner stone for further therapeutic studies. Little is known about the ability of cardiac magnetic resonance imaging (CMR) to evaluate progression of myocardial fibrosis. Aim of our study was to provide CMR data in a previously genotyped DMD family and to evaluate whether progression of myocardial fibrosis could be visualized. Methods and results: DMD genotypes were available in 14 family members. CMR was performed in 4/5 carrier females, in 2/2 affected males and in one healthy family member with normal genotype. Functional images and late gadolinium enhanced (LGE) images in contiguous short-axis orientation were acquired at baseline and follow-up of 1231 days CMR examination could be repeated in three carrier females, in one affected male and in the healthy subject previously scanned. Mean decrease of left ventricular ejection fraction during the follow-up period was 10.5 ± 11.0%, mean progression of LGE volume 11.7 ± 9.5%. Conclusions: Myocardial fibrosis seems to occur prior to global left ventricular dysfunction in DMD diseased males and carrier females. CMR could be used to evaluate progression of myocardial fibrosis and left ventricular function and may thus serve as an important diagnostic tool in the evaluation of therapeutical options in DMD.

  15. Detection of long-term progression of myocardial fibrosis in Duchenne muscular dystrophy in an affected family: A cardiovascular magnetic resonance study

    Energy Technology Data Exchange (ETDEWEB)

    Walcher, Thomas [Department of Internal Medicine II, University of Ulm, Ulm (Germany); Steinbach, Peter [Institute of Human Genetics, University of Ulm, Ulm (Germany); Spiess, Jochen; Kunze, Markus; Gradinger, Robert; Walcher, Daniel [Department of Internal Medicine II, University of Ulm, Ulm (Germany); Bernhardt, Peter, E-mail: peter.bernhardt@uniklinik-ulm.de [Department of Internal Medicine II, University of Ulm, Ulm (Germany)

    2011-10-15

    Background: Detection of myocardial fibrosis and left ventricular dysfunction in Duchenne muscular dystrophy (DMD) is the corner stone for further therapeutic studies. Little is known about the ability of cardiac magnetic resonance imaging (CMR) to evaluate progression of myocardial fibrosis. Aim of our study was to provide CMR data in a previously genotyped DMD family and to evaluate whether progression of myocardial fibrosis could be visualized. Methods and results: DMD genotypes were available in 14 family members. CMR was performed in 4/5 carrier females, in 2/2 affected males and in one healthy family member with normal genotype. Functional images and late gadolinium enhanced (LGE) images in contiguous short-axis orientation were acquired at baseline and follow-up of 1231 days CMR examination could be repeated in three carrier females, in one affected male and in the healthy subject previously scanned. Mean decrease of left ventricular ejection fraction during the follow-up period was 10.5 {+-} 11.0%, mean progression of LGE volume 11.7 {+-} 9.5%. Conclusions: Myocardial fibrosis seems to occur prior to global left ventricular dysfunction in DMD diseased males and carrier females. CMR could be used to evaluate progression of myocardial fibrosis and left ventricular function and may thus serve as an important diagnostic tool in the evaluation of therapeutical options in DMD.

  16. Progress in proton-detected solid-state NMR (SSNMR): Super-fast 2D SSNMR collection for nano-mole-scale proteins

    Science.gov (United States)

    Ishii, Yoshitaka; Wickramasinghe, Ayesha; Matsuda, Isamu; Endo, Yuki; Ishii, Yuji; Nishiyama, Yusuke; Nemoto, Takahiro; Kamihara, Takayuki

    2018-01-01

    Proton-detected solid-state NMR (SSNMR) spectroscopy has attracted much attention due to its excellent sensitivity and effectiveness in the analysis of trace amounts of amyloid proteins and other important biological systems. In this perspective article, we present the recent sensitivity limit of 1H-detected SSNMR using "ultra-fast" magic-angle spinning (MAS) at a spinning rate (νR) of 80-100 kHz. It was demonstrated that the high sensitivity of 1H-detected SSNMR at νR of 100 kHz and fast recycling using the paramagnetic-assisted condensed data collection (PACC) approach permitted "super-fast" collection of 1H-detected 2D protein SSNMR. A 1H-detected 2D 1H-15N correlation SSNMR spectrum for ∼27 nmol of a uniformly 13C- and 15N-labeled GB1 protein sample in microcrystalline form was acquired in only 9 s with 50% non-uniform sampling and short recycle delays of 100 ms. Additional data suggests that it is now feasible to detect as little as 1 nmol of the protein in 5.9 h by 1H-detected 2D 1H-15N SSNMR at a nominal signal-to-noise ratio of five. The demonstrated sensitivity is comparable to that of modern solution protein NMR. Moreover, this article summarizes the influence of ultra-fast MAS and 1H-detection on the spectral resolution and sensitivity of protein SSNMR. Recent progress in signal assignment and structural elucidation by 1H-detected protein SSNMR is outlined with both theoretical and experimental aspects.

  17. Detecting the progression of ocean acidification from the saturation state of CaCO3 in the subtropical South Pacific

    Science.gov (United States)

    Murata, Akihiko; Hayashi, Kazuhiko; Kumamoto, Yuichiro; Sasaki, Ken-ichi

    2015-04-01

    Progression of ocean acidification in the subtropical South Pacific was investigated by using high-quality data from trans-Pacific zonal section at 17°S (World Ocean Circulation Experiment section P21) collected in 1994 and 2009. During this 15 year period, the CaCO3 saturation state of seawater with respect to calcite (Ωcal) and aragonite (Ωarg) in the upper water column (Pacific Ocean.

  18. Time course of ongoing activity during neuritis and following axonal transport disruption.

    Science.gov (United States)

    Satkeviciute, Ieva; Goodwin, George; Bove, Geoffrey M; Dilley, Andrew

    2018-05-01

    Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.

  19. Emphysema progression is visually detectable in low-dose CT in continuous but not in former smokers

    Energy Technology Data Exchange (ETDEWEB)

    Winkler Wille, Mathilde Marie; Thomsen, Laura H.; Dirksen, Asger; Shaker, Saher B. [Gentofte Hospital, Department of Respiratory Medicine, Hellerup (Denmark); Petersen, Jens [Copenhagen University, Department of Computer Science, Copenhagen (Denmark); Pedersen, Jesper Holst [Copenhagen University Hospital, Department of Thoracic Surgery, Rigshospitalet, Copenhagen (Denmark)

    2014-11-15

    To evaluate interobserver agreement and time-trend in chest CT assessment of emphysema, airways, and interstitial abnormalities in a lung cancer screening cohort. Visual assessment of baseline and fifth-year examination of 1990 participants was performed independently by two observers. Results were standardised by means of an electronic score sheet; kappa and time-trend analyses were performed. Interobserver agreement was substantial in early emphysema diagnosis; highly significant (p < 0.001) time-trends in both emphysema presence and grading were found (higher prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes was only fair. Agreement was fair regarding airway analysis. Interstitial abnormalities were infrequent in the cohort, and agreement on these was fair to moderate. A highly significant time-trend was found regarding interstitial abnormalities, which were more frequent in late examinations. Visual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not. (orig.)

  20. Emphysema progression is visually detectable in low-dose CT in continuous but not in former smokers

    International Nuclear Information System (INIS)

    Winkler Wille, Mathilde Marie; Thomsen, Laura H.; Dirksen, Asger; Shaker, Saher B.; Petersen, Jens; Pedersen, Jesper Holst

    2014-01-01

    To evaluate interobserver agreement and time-trend in chest CT assessment of emphysema, airways, and interstitial abnormalities in a lung cancer screening cohort. Visual assessment of baseline and fifth-year examination of 1990 participants was performed independently by two observers. Results were standardised by means of an electronic score sheet; kappa and time-trend analyses were performed. Interobserver agreement was substantial in early emphysema diagnosis; highly significant (p < 0.001) time-trends in both emphysema presence and grading were found (higher prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes was only fair. Agreement was fair regarding airway analysis. Interstitial abnormalities were infrequent in the cohort, and agreement on these was fair to moderate. A highly significant time-trend was found regarding interstitial abnormalities, which were more frequent in late examinations. Visual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not. (orig.)

  1. Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.

    Directory of Open Access Journals (Sweden)

    Qingyu Qin

    Full Text Available Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK and murine double minute (Mdm2 E3 ligase. Growth cone collapse induced by genetic (npc1-/- or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.

  2. Clinical and genetic characteristics of autosomal recessive axonal neuropathy with neuromyotonia in Russian patients

    Directory of Open Access Journals (Sweden)

    E. L. Dadali

    2017-01-01

    Full Text Available Introduction. Hereditary motor and sensory neuropathies are genetically heterogeneous group of disorders characterized by a progressive muscle weakness, atrophy of hand and leg muscles often associated with deformations, and mild to moderate sensory loss. Axonal neuropathy with neuromyotonia (AR-ANM is one of the rarest autosomal recessive hereditary neuropathies. Materials and methods. Six (6 patients (4 men, 2 women aged 14–40 years from unrelated families with suspicion of HMSN were examined clinically, neurophysiologically and using DNA analysis. Results. Neurophysiological examination revealed motor and sensory neuropathy with neuromyotonia signs in all patients. In all cases homozygous variant of recessive mutations с.110G/C (р.Arg37Pro in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1 has been revealed. Conclusion. There is the first description of the clinical and neurophysiological features of six patients with AR-ANM in Russia. 

  3. Proteomic analysis in giant axonal neuropathy: new insights into disease mechanisms.

    Science.gov (United States)

    Mussche, Silke; De Paepe, Boel; Smet, Joél; Devreese, Katrien; Lissens, Willy; Rasic, Vedrana Milic; Murnane, Matthew; Devreese, Bart; Van Coster, Rudy

    2012-08-01

    Giant axonal neuropathy (GAN) is a progressive hereditary disease that affects the peripheral and central nervous systems. It is characterized morphologically by aggregates of intermediate filaments in different tissues. Mutations have been reported in the gene that codes for gigaxonin. Nevertheless, the underlying molecular mechanism remains obscure. Cell lines from 4 GAN patients and 4 controls were analyzed by iTRAQ. Among the dysregulated proteins were ribosomal protein L29, ribosomal protein L37, galectin-1, glia-derived nexin, and aminopeptidase N. Also, nuclear proteins linked to formin-binding proteins were found to be dysregulated. Although the major role of gigaxonin is reported to be degradation of cytoskeleton-associated proteins, the amount of 76 structural cytoskeletal proteins was unaltered. Several of the dysregulated proteins play a role in cytoskeletal reorganization. Based on these findings, we speculate that disturbed cytoskeletal regulation is responsible for formation of aggregates of intermediate filaments. Copyright © 2012 Wiley Periodicals, Inc.

  4. An αII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration.

    Science.gov (United States)

    Huang, Claire Yu-Mei; Zhang, Chuansheng; Zollinger, Daniel R; Leterrier, Christophe; Rasband, Matthew N

    2017-11-22

    Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. Avil-cre;Sptan1 f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K + channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1 f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier. SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in

  5. A Review of Traumatic Axonal Injury following Whiplash Injury As Demonstrated by Diffusion Tensor Tractography

    Directory of Open Access Journals (Sweden)

    Sung Ho Jang

    2018-02-01

    Full Text Available Whiplash is a bony or soft tissue injury resulting from an acceleration–deceleration energy transfer in the neck. Although patients with whiplash injury often complain of cerebral symptoms, and previous studies have reported evidence indicating brain injury, such an association has not been clearly elucidated. Traumatic axonal injury (TAI is tearing of axons due to indirect shearing forces during acceleration, deceleration, and rotation of the brain or to direct head trauma. Diffusion tensor imaging (DTI has a unique advantage to detect TAI in patients whose conventional brain CT or magnetic resonance imaging (MRI results were negative following head trauma. Since the introduction of DTI, six studies using diffusion tensor tractography (DTT based on DTI data have reported TAI in patients with whiplash injury, even though conventional brain CT or MRI results were negative. A precise TAI diagnosis in whiplash patients is clinically important for proper management and prognosis. Among the methods employed to diagnose TAI in the six previous studies, the common diagnostic approach for neural tract TAI in individual patients with whiplash injury were (1 whiplash injury history due to car accident; (2 development of new clinical symptoms and signs after whiplash injury; (3 evidence of neural tract TAI in DTT results, mainly via configurational analysis; and (4 coincidence of newly developed clinical manifestations and the function of injured neural tracts. All six studies were individual patient case studies; therefore, further prospective studies involving larger number of subjects should be encouraged.

  6. Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

    Science.gov (United States)

    Filippi, M; Campi, A; Martinelli, V; Colombo, B; Yousry, T; Canal, N; Scotti, G; Comi, G

    1995-01-01

    This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients. Images PMID:8530944

  7. Recent progress in the development of CsI(Tl) crystal-Si-photodiode spectrometric detection assemblies

    International Nuclear Information System (INIS)

    Semynozhenko, V.P.; Grinyov, B.V.; Nekrasov, V.V.; Borodenko, Yu.A.

    2005-01-01

    Highly sensitive spectrometric γ-detection assemblies are developed using a comprehensive approach (optimization of crystal growth conditions as well as of treatment and packing of scintillators, creation of low-noise charge-sensitive preamplifiers and shapers). The detection assemblies with CsI(Tl)≤100 cm 3 have a sensitivity of about 20 pulse/s(mcR/h), their energy resolution with respect to 137 Cs γ-line being ≤8.5%. The assemblies with lesser scintillator volumes (1-5 cm 3 ) provide a resolution lower than 6% with respect to 137 Cs and ≤40% with respect to 241 Am

  8. A growing field: The regulation of axonal regeneration by Wnt signaling.

    Science.gov (United States)

    Garcia, Armando L; Udeh, Adanna; Kalahasty, Karthik; Hackam, Abigail S

    2018-01-01

    The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system (CNS). Recently, studies in mammalian and fish model systems have demonstrated that Wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that Wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for Wnt signaling in the injured CNS, and discuss possible mechanisms by which Wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of Wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for Wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that Wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical Wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone

  9. Use of self-complementary adeno-associated virus serotype 2 as a tracer for labeling axons: implications for axon regeneration.

    Directory of Open Access Journals (Sweden)

    Yingpeng Liu

    Full Text Available Various types of tracers are available for use in axon regeneration, but they require an extra operational tracer injection, time-consuming immunohistochemical analysis and cause non-specific labeling. Considerable efforts over the past years have explored other methodologies, especially the use of viral vectors, to investigate axon regeneration after injury. Recent studies have demonstrated that self-complementary Adeno-Associated Virus (scAAV induced a high transduction efficiency and faster expression of transgenes. Here, we describe for the first time the use of scAAV2-GFP to label long-projection axons in the corticospinal tract (CST, rubrospinal tract (RST and the central axons of dorsal root ganglion (DRG in the normal and lesioned animal models. We found that scAAV2-GFP could efficiently transduce neurons in the sensorimotor cortex, red nucleus and DRG. Strong GFP expression could be transported anterogradely along the axon to label the numerous axon fibers from CST, RST and central axons of DRG separately. Comparison of the scAAV2 vector with single-stranded (ss AAV2 vector in co-labeled sections showed that the scAAV2 vector induced a faster and stronger transgene expression than the ssAAV2 vector in DRG neurons and their axons. In both spinal cord lesion and dorsal root crush injury models, scAAV-GFP could efficiently label the lesioned and regenerated axons around the lesion cavity and the dorsal root entry zone (DREZ respectively. Further, scAAV2-GFP vector could be combined with traditional tracer to specifically label sensory and motor axons after spinal cord lesion. Thus, we show that using scAAV2-GFP as a tracer is a more effective and efficient way to study axon regeneration following injury.

  10. Non-invasive aneuploidy detection using free fetal DNA and RNA in maternal plasma: recent progress and future possibilities.

    NARCIS (Netherlands)

    Go, A.T.; Vugt, J.M.G. van; Oudejans, C.B.

    2011-01-01

    BACKGROUND: Cell-free fetal DNA (cff DNA) and RNA can be detected in maternal plasma and used for non-invasive prenatal diagnostics. Recent technical advances have led to a drastic change in the clinical applicability and potential uses of free fetal DNA and RNA. This review summarizes the latest

  11. First year progress report on the co-ordinated research programme on signal processing techniques for sodium boiling noise detection

    International Nuclear Information System (INIS)

    Singh, O.P.; Prabhakar, R.; John, T.M.; Vyjayanthi, R.K.; Reddy, C.P.; Parikh, M.V.; Ponpandi, S.

    1989-01-01

    The present paper deals with investigations of acoustic signals from a boiling experiment performed on the KNS I loop at KfK Karlsruhe. Signals have been analysed in frequency as well as in time domain. Signal characteristics successfully used to detect the boiling process have been found in time domain. (author). 3 refs, 5 figs, 5 tabs

  12. The protection of acetylcholinesterase inhibitor on β-amyloid-induced injury of neurite outgrowth via regulating axon guidance related genes expression in neuronal cells

    OpenAIRE

    Shen, Jiao-Ning; Wang, Deng-Shun; Wang, Rui

    2012-01-01

    Cognitive deficits in AD correlate with progressive synaptic dysfunction and loss. The Rho family of small GTPases, including Rho, Rac, and Cdc42, has a central role in cellular motility and cytokinesis. Acetylcholinesterase inhibitor has been found to protect cells against a broad range of reagents-induced injuries. Present studies examined if the effect of HupA on neurite outgrowth in Aβ-treated neuronal cells executed via regulating Rho-GTPase mediated axon guidance relative gene expressio...

  13. Antiretroviral Therapy-Associated Acute Motor and Sensory Axonal Neuropathy

    Directory of Open Access Journals (Sweden)

    Kimberly N. Capers

    2011-01-01

    Full Text Available Guillain-Barré syndrome (GBS has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome.

  14. Craniocerebral trauma. Magnetic resonance imaging of diffuse axonal injury

    International Nuclear Information System (INIS)

    Mallouhi, A.

    2014-01-01

    Acceleration-deceleration rotational brain trauma is a common cause of disability or death in young adults and often leads to a focal destruction of axons. The resulting pathology, axonal shear injury is referred to as diffuse axonal injury (DAI). The DAI-associated lesions occur bilaterally, are widely dispersed and have been observed in the surface and deep white matter. They are found near to and far from the impact site. When DAI is clinically suspected, magnetic resonance imaging (MRI) is the method of choice for further clarification, especially in patients where cranial computed tomography (CT) is inconspicuous. To investigate the presence of DAI after traumatic brain injury (TBI), a multimodal MRI approach is applied including the common structural and also functional imaging sequences. For structural MRI, fluid-attenuated inversion recovery (FLAIR) weighted and susceptibility contrast imaging (SWI) are the sequences mainly used. The SWI technique is extremely sensitive to blood breakdown products, which appear as small signal voids at three locations, at the gray-white interface, in the corpus callosum and in the brain stem. Functional MRI comprises a group of constantly developing techniques that have great potential in optimal evaluation of the white matter in patients after craniocerebral trauma. These imaging techniques allow the visualization of changes associated with shear injuries, such as functional impairment of axons and decreased blood flow and abnormal metabolic activity of the brain parts affected. The multimodal MRI approach in patients with DAI results in a more detailed and differentiated representation of the underlying pathophysiological changes of the injured nerve tracts and helps to improve the diagnostic and prognostic accuracy of MRI. When DAI is suspected multimodal MRI should be performed as soon as possible after craniocerebral injury. (orig.) [de

  15. Polyethylene glycol restores axonal conduction after corpus callosum transection

    Directory of Open Access Journals (Sweden)

    Ravinder Bamba

    2017-01-01

    Full Text Available Polyethylene glycol (PEG has been shown to restore axonal continuity after peripheral nerve transection in animal models. We hypothesized that PEG can also restore axonal continuity in the central nervous system. In this current experiment, coronal sectioning of the brains of Sprague-Dawley rats was performed after animal sacrifice. 3Brain high-resolution microelectrode arrays (MEA were used to measure mean firing rate (MFR and peak amplitude across the corpus callosum of the ex-vivo brain slices. The corpus callosum was subsequently transected and repeated measurements were performed. The cut ends of the corpus callosum were still apposite at this time. A PEG solution was applied to the injury site and repeated measurements were performed. MEA measurements showed that PEG was capable of restoring electrophysiology signaling after transection of central nerves. Before injury, the average MFRs at the ipsilateral, midline, and contralateral corpus callosum were 0.76, 0.66, and 0.65 spikes/second, respectively, and the average peak amplitudes were 69.79, 58.68, and 49.60 μV, respectively. After injury, the average MFRs were 0.71, 0.14, and 0.25 spikes/second, respectively and peak amplitudes were 52.11, 8.98, and 16.09 μV, respectively. After application of PEG, there were spikes in MFR and peak amplitude at the injury site and contralaterally. The average MFRs were 0.75, 0.55, and 0.47 spikes/second at the ipsilateral, midline, and contralateral corpus callosum, respectively and peak amplitudes were 59.44, 45.33, 40.02 μV, respectively. There were statistically differences in the average MFRs and peak amplitudes between the midline and non-midline corpus callosum groups (P < 0.01, P < 0.05. These findings suggest that PEG restores axonal conduction between severed central nerves, potentially representing axonal fusion.

  16. Polyethylene glycol restores axonal conduction after corpus callosum transection.

    Science.gov (United States)

    Bamba, Ravinder; Riley, D Colton; Boyer, Richard B; Pollins, Alonda C; Shack, R Bruce; Thayer, Wesley P

    2017-05-01

    Polyethylene glycol (PEG) has been shown to restore axonal continuity after peripheral nerve transection in animal models. We hypothesized that PEG can also restore axonal continuity in the central nervous system. In this current experiment, coronal sectioning of the brains of Sprague-Dawley rats was performed after animal sacrifice. 3Brain high-resolution microelectrode arrays (MEA) were used to measure mean firing rate (MFR) and peak amplitude across the corpus callosum of the ex-vivo brain slices. The corpus callosum was subsequently transected and repeated measurements were performed. The cut ends of the corpus callosum were still apposite at this time. A PEG solution was applied to the injury site and repeated measurements were performed. MEA measurements showed that PEG was capable of restoring electrophysiology signaling after transection of central nerves. Before injury, the average MFRs at the ipsilateral, midline, and contralateral corpus callosum were 0.76, 0.66, and 0.65 spikes/second, respectively, and the average peak amplitudes were 69.79, 58.68, and 49.60 μV, respectively. After injury, the average MFRs were 0.71, 0.14, and 0.25 spikes/second, respectively and peak amplitudes were 52.11, 8.98, and 16.09 μV, respectively. After application of PEG, there were spikes in MFR and peak amplitude at the injury site and contralaterally. The average MFRs were 0.75, 0.55, and 0.47 spikes/second at the ipsilateral, midline, and contralateral corpus callosum, respectively and peak amplitudes were 59.44, 45.33, 40.02 μV, respectively. There were statistically differences in the average MFRs and peak amplitudes between the midline and non-midline corpus callosum groups ( P < 0.01, P < 0.05). These findings suggest that PEG restores axonal conduction between severed central nerves, potentially representing axonal fusion.

  17. Effects of kainic acid lesions in lateral geniculate nucleus: activity dependence of retrograde axonal transport of fluorescent dyes.

    Science.gov (United States)

    Woodward, W R; Coull, B M

    1988-06-28

    Kainic acid lesions in the dorsal lateral geniculate nucleus of rats block the retrograde axonal transport of fluorescent dyes in corticogeniculate neurons without affecting the retrograde transport of D-aspartate or the orthograde transport of radiolabelled proteins in these neurons. This blocking of dye transport does not appear to be a consequence of kainic acid-induced damage to axon terminals in the geniculate since retinal ganglion cells are still able to transport dyes retrograde. A more likely explanation for these results is that fluorescent dye transport requires electrical activity in neurons, and elimination of the geniculate afferents to visual cortex reduces impulse traffic in cortical output fibers to a level below that required to support detectable dye transport. This interpretation is supported by the observation that kainic acid lesions also reduce retrograde transport of dyes in cortical neurons which project to the superior colliculus. Electrical stimulation in the subcortical white matter restores the transport of dye compounds in corticogeniculate neurons: evidence consistent with an activity-dependent mechanism of retrograde transport for these substances. These results provide evidence that axon terminals of retinal ganglion cells and corticogeniculate neurons survive in kainate-lesioned geniculates and are capable of normal neuronal function.

  18. Prediction of Functional Outcome in Axonal Guillain-Barre Syndrome.

    Science.gov (United States)

    Sung, Eun Jung; Kim, Dae Yul; Chang, Min Cheol; Ko, Eun Jae

    2016-06-01

    To identify the factors that could predict the functional outcome in patients with the axonal type of Guillain-Barre syndrome (GBS). Two hundred and two GBS patients admitted to our university hospital between 2003 and 2014 were reviewed retrospectively. We defined a good outcome as being "able to walk independently at 1 month after onset" and a poor outcome as being "unable to walk independently at 1 month after onset". We evaluated the factors that differed between the good and poor outcome groups. Twenty-four patients were classified into the acute motor axonal neuropathy type. There was a statistically significant difference between the good and poor outcome groups in terms of the GBS disability score at admission, and GBS disability score and Medical Research Council sum score at 1 month after admission. In an electrophysiologic analysis, the good outcome group showed greater amplitude of median, ulnar, deep peroneal, and posterior tibial nerve compound muscle action potentials (CMAP) and greater amplitude of median, ulnar, and superficial peroneal sensory nerve action potentials (SNAP) than the poor outcome group. A lower GBS disability score at admission, high amplitude of median, ulnar, deep peroneal, and posterior tibial CMAPs, and high amplitude of median, ulnar, and superficial peroneal SNAPs were associated with being able to walk at 1 month in patients with axonal GBS.

  19. Axonal Control of the Adult Neural Stem Cell Niche

    Science.gov (United States)

    Tong, Cheuk Ka; Chen, Jiadong; Cebrián-Silla, Arantxa; Mirzadeh, Zaman; Obernier, Kirsten; Guinto, Cristina D.; Tecott, Laurence H.; García-Verdugo, Jose Manuel; Kriegstein, Arnold; Alvarez-Buylla, Arturo

    2014-01-01

    SUMMARY The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSC) in the walls of the lateral ventricles of the adult brain. How the adult brain’s neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C. PMID:24561083

  20. Vesicular glutamate release from central axons contributes to myelin damage.

    Science.gov (United States)

    Doyle, Sean; Hansen, Daniel Bloch; Vella, Jasmine; Bond, Peter; Harper, Glenn; Zammit, Christian; Valentino, Mario; Fern, Robert

    2018-03-12

    The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.

  1. Retinal glia promote dorsal root ganglion axon regeneration.

    Directory of Open Access Journals (Sweden)

    Barbara Lorber

    Full Text Available Axon regeneration in the adult central nervous system (CNS is limited by several factors including a lack of neurotrophic support. Recent studies have shown that glia from the adult rat CNS, specifically retinal astrocytes and Müller glia, can promote regeneration of retinal ganglion cell axons. In the present study we investigated whether retinal glia also exert a growth promoting effect outside the visual system. We found that retinal glial conditioned medium significantly enhanced neurite growth and branching of adult rat dorsal root ganglion neurons (DRG in culture. Furthermore, transplantation of retinal glia significantly enhanced regeneration of DRG axons past the dorsal root entry zone after root crush in adult rats. To identify the factors that mediate the growth promoting effects of retinal glia, mass spectrometric analysis of retinal glial conditioned medium was performed. Apolipoprotein E and secreted protein acidic and rich in cysteine (SPARC were found to be present in high abundance, a finding further confirmed by western blotting. Inhibition of Apolipoprotein E and SPARC significantly reduced the neuritogenic effects of retinal glial conditioned medium on DRG in culture, suggesting that Apolipoprotein E and SPARC are the major mediators of this regenerative response.

  2. Internalization and Axonal Transport of the HIV Glycoprotein gp120

    Science.gov (United States)

    Berth, Sarah; Caicedo, Hector Hugo; Sarma, Tulika; Morfini, Gerardo

    2015-01-01

    The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity. PMID:25636314

  3. Fourth year progress report on the co-ordinated research programme on signal processing techniques for sodium boiling noise detection

    International Nuclear Information System (INIS)

    Singh, O.P.; Prabhakar, R.; Reddy, C.P.; Vyjayanthi, R.K.; Srinivasan, G.S.

    1989-01-01

    The present paper deals with investigations of acoustic signals from a boiling experiment performed on the BOR 60 reactor in the USSR. Signals have been analysed in frequency as well as in time domain. Signal characteristics successfully used to detect the boiling process have been found in time domain. A proposal for in-service boiling monitoring by acoustic means is described. (author). 4 refs, 11 figs, 5 tabs

  4. Third year progress report on the co-ordinated research programme on signal processing techniques for sodium boiling noise detection

    International Nuclear Information System (INIS)

    Singh, O.P.; Prabhakar, R.; Reddy, C.P.; Vyjayanthi, R.K.; Srinivasan, G.S.

    1989-01-01

    The present paper deals with investigations of acoustic signals from a boiling experiment performed on the BOR 60 reactor in the USSR. Signals have been analysed in frequency as well as in time domain. Signal characteristics successfully used to detect the boiling process have been found in time domain. A proposal for in-service boiling monitoring by acoustic means is described. (author). 1 ref., 13 figs, 4 tabs

  5. Depolarization and electrical stimulation enhance in vitro and in vivo sensory axon growth after spinal cord injury.

    Science.gov (United States)

    Goganau, Ioana; Sandner, Beatrice; Weidner, Norbert; Fouad, Karim; Blesch, Armin

    2018-02-01

    Activity dependent plasticity is a key mechanism for the central nervous system (CNS) to adapt to its environment. Whether neuronal activity also influences axonal regeneration in the injured CNS, and whether electrical stimulation (ES) can activate regenerative programs in the injured CNS remains incompletely understood. Using KCl-induced depolarization, in vivo ES followed by ex-vivo neurite growth assays and ES after spinal cord lesions and cell grafting, we aimed to identify parameters important for ES-enhanced neurite growth and axonal regeneration. Using cultures of sensory neurons, neurite growth was analyzed after KCl-induced depolarization for 1-72h. Increased neurite growth was detected after short-term stimulation and after longer stimulation if a sufficient delay between stimulation and growth measurements was provided. After in vivo ES (20Hz, 2× motor threshold, 0.2ms, 1h) of the intact sciatic nerve in adult Fischer344 rats, sensory neurons showed a 2-fold increase in in vitro neurite length one week later compared to sham animals, an effect not observed one day after ES. Longer ES (7h) and repeated ES (7days, 1h each) also increased growth by 56-67% one week later, but provided no additional benefit. In vivo growth of dorsal column sensory axons into a graft of bone marrow stromal cells 4weeks after a cervical spinal cord lesion was also enhanced with a single post-injury 1h ES of the intact sciatic nerve and was also observed after repeated ES without inducing pain-like behavior. While ES did not result in sensory functional recovery, our data indicate that ES has time-dependent influences on the regenerative capacity of sensory neurons and might further enhance axonal regeneration in combinatorial approaches after SCI. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Limited utility of tissue micro-arrays in detecting intra-tumoral heterogeneity in stem cell characteristics and tumor progression markers in breast cancer.

    Science.gov (United States)

    Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna

    2018-05-08

    Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the

  7. In vivo imaging reveals mitophagy independence in the maintenance of axonal mitochondria during normal aging.

    Science.gov (United States)

    Cao, Xu; Wang, Haiqiong; Wang, Zhao; Wang, Qingyao; Zhang, Shuang; Deng, Yuanping; Fang, Yanshan

    2017-10-01

    Mitophagy is thought to be a critical mitochondrial quality control mechanism in neurons and has been extensively studied in neurological disorders such as Parkinson's disease. However, little is known about how mitochondria are maintained in the lengthy neuronal axons in the context of physiological aging. Here, we utilized the unique Drosophila wing nerve model and in vivo imaging to rigorously profile changes in axonal mitochondria during aging. We revealed that mitochondria became fragmented and accumulated in aged axons. However, lack of Pink1 or Parkin did not lead to the accumulation of axonal mitochondria or axonal degeneration. Further, unlike in in vitro cultured neurons, we found that mitophagy rarely occurred in intact axons in vivo, even in aged animals. Furthermore, blocking overall mitophagy by knockdown of the core autophagy genes Atg12 or Atg17 had little effect on the turnover of axonal mitochondria or axonal integrity, suggesting that mitophagy is not required for axonal maintenance; this is regardless of whether the mitophagy is PINK1-Parkin dependent or independent. In contrast, downregulation of mitochondrial fission-fusion genes caused age-dependent axonal degeneration. Moreover, Opa1 expression in the fly head was significantly decreased with age, which may underlie the accumulation of fragmented mitochondria in aged axons. Finally, we showed that adult-onset, neuronal downregulation of the fission-fusion, but not mitophagy genes, dramatically accelerated features of aging. We propose that axonal mitochondria are maintained independently of mitophagy and that mitophagy-independent mechanisms such as fission-fusion may be central to the maintenance of axonal mitochondria and neural integrity during normal aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  8. Sodium Channel β2 Subunits Prevent Action Potential Propagation Failures at Axonal Branch Points.

    Science.gov (United States)

    Cho, In Ha; Panzera, Lauren C; Chin, Morven; Hoppa, Michael B

    2017-09-27

    Neurotransmitter release depends on voltage-gated Na + channels (Na v s) to propagate an action potential (AP) successfully from the axon hillock to a synaptic terminal. Unmyelinated sections of axon are very diverse structures encompassing branch points and numerous presynaptic terminals with undefined molecular partners of Na + channels. Using optical recordings of Ca 2+ and membrane voltage, we demonstrate here that Na + channel β2 subunits (Na v β2s) are required to prevent AP propagation failures across the axonal arborization of cultured rat hippocampal neurons (mixed male and female). When Na v β2 expression was reduced, we identified two specific phenotypes: (1) membrane excitability and AP-evoked Ca 2+ entry were impaired at synapses and (2) AP propagation was severely compromised with >40% of axonal branches no longer responding to AP-stimulation. We went on to show that a great deal of electrical signaling heterogeneity exists in AP waveforms across the axonal arborization independent of axon morphology. Therefore, Na v β2 is a critical regulator of axonal excitability and synaptic function in unmyelinated axons. SIGNIFICANCE STATEMENT Voltage-gated Ca 2+ channels are fulcrums of neurotransmission that convert electrical inputs into chemical outputs in the form of vesicle fusion at synaptic terminals. However, the role of the electrical signal, the presynaptic action potential (AP), in modulating synaptic transmission is less clear. What is the fidelity of a propagating AP waveform in the axon and what molecules shape it throughout the axonal arborization? Our work identifies several new features of AP propagation in unmyelinated axons: (1) branches of a single axonal arborization have variable AP waveforms independent of morphology, (2) Na + channel β2 subunits modulate AP-evoked Ca 2+ -influx, and (3) β2 subunits maintain successful AP propagation across the axonal arbor. These findings are relevant to understanding the flow of excitation in the

  9. Second year progress report on the co-ordinated research programme on signal processing techniques for sodium boiling noise detection

    International Nuclear Information System (INIS)

    Singh, O.P.; Harish, R.; Prabhakar, R.; Reddy, C.P.; Srinivasan, G.S.; Vyjayanthi, R.K.

    1989-01-01

    The present paper deals with the second stage of investigations of acoustic signals from a boiling experiment performed on the KNS I loop at KfK Karlsruhe and first results of analysis of data from a series of boiling experiments carried out in the BOR 60 reactor in the USSR. Signals have been analysed in frequency as well as in time domain. Signal characteristics successfully used to detect the boiling process have been found in time domain. A proposal for in-service boiling monitoring by acoustic means is briefly described. (author). 9 refs, 22 figs, 19 tabs

  10. Progress of a Cross-Correlation Based Optical Strain Measurement Technique for Detecting Radial Growth on a Rotating Disk

    Science.gov (United States)

    Clem, Michelle M.; Woike, Mark R.; Abdul-Aziz, Ali

    2014-01-01

    The Aeronautical Sciences Project under NASA's Fundamental Aeronautics Program is interested in the development of novel measurement technologies, such as optical surface measurements for the in situ health monitoring of critical constituents of the internal flow path. In situ health monitoring has the potential to detect flaws, i.e. cracks in key components, such as engine turbine disks, before the flaws lead to catastrophic failure. The present study, aims to further validate and develop an optical strain measurement technique to measure the radial growth and strain field of an already cracked disk, mimicking the geometry of a sub-scale turbine engine disk, under loaded conditions in the NASA Glenn Research Center's High Precision Rotordynamics Laboratory. The technique offers potential fault detection by imaging an applied high-contrast random speckle pattern under unloaded and loaded conditions with a CCD camera. Spinning the cracked disk at high speeds (loaded conditions) induces an external load, resulting in a radial growth of the disk of approximately 50.0-µm in the flawed region and hence, a localized strain field. When imaging the cracked disk under static conditions, the disk will be undistorted; however, during rotation the cracked region will grow radially, thus causing the applied particle pattern to be 'shifted'. The resulting particle displacements between the two images is measured using the two-dimensional cross-correlation algorithms implemented in standard Particle Image Velocimetry (PIV) software to track the disk growth, which facilitates calculation of the localized strain field. A random particle distribution is adhered onto the surface of the cracked disk and two bench top experiments are carried out to evaluate the technique's ability to measure the induced particle displacements. The disk is shifted manually using a translation stage equipped with a fine micrometer and a hotplate is used to induce thermal growth of the disk, causing the

  11. A new unified framework for the early detection of the progression to diabetic retinopathy from fundus images.

    Science.gov (United States)

    Leontidis, Georgios

    2017-11-01

    Human retina is a diverse and important tissue, vastly studied for various retinal and other diseases. Diabetic retinopathy (DR), a leading cause of blindness, is one of them. This work proposes a novel and complete framework for the accurate and robust extraction and analysis of a series of retinal vascular geometric features. It focuses on studying the registered bifurcations in successive years of progression from diabetes (no DR) to DR, in order to identify the vascular alterations. Retinal fundus images are utilised, and multiple experimental designs are employed. The framework includes various steps, such as image registration and segmentation, extraction of features, statistical analysis and classification models. Linear mixed models are utilised for making the statistical inferences, alongside the elastic-net logistic regression, boruta algorithm, and regularised random forests for the feature selection and classification phases, in order to evaluate the discriminative potential of the investigated features and also build classification models. A number of geometric features, such as the central retinal artery and vein equivalents, are found to differ significantly across the experiments and also have good discriminative potential. The classification systems yield promising results with the area under the curve values ranging from 0.821 to 0.968, across the four different investigated combinations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Induction of neuronal axon outgrowth by Shati/Nat8l by energy metabolism in mice cultured neurons.

    Science.gov (United States)

    Sumi, Kazuyuki; Uno, Kyosuke; Matsumura, Shohei; Miyamoto, Yoshiaki; Furukawa-Hibi, Yoko; Muramatsu, Shin-Ichi; Nabeshima, Toshitaka; Nitta, Atsumi

    2015-09-09

    A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens of mice repeatedly treated with methamphetamine (METH). Shati/Nat8l has been reported to inhibit the pharmacological action induced by METH. Shati/Nat8l produces N-acetylaspartate from aspartate and acetyl-CoA. Previously, we reported that overexpression of Shati/Nat8l in nucleus accumbens attenuates the response to METH by N-acetylaspartylglutamate (which is derived from N-acetylaspartate)-mGluR3 signaling in the mice brain. In the present study, to clarify the type of cells that produce Shati/Nat8l, we carried out in-situ hybridization for the detection of Shati/Nat8l mRNA along with immunohistochemical studies using serial sections of mice brain. Shati/Nat8l mRNA was detected in neuronal cells, but not in astrocytes or microglia cells. Next, we investigated the function of Shati/Nat8l in the neuronal cells in mice brain; then, we used an adeno-associated virus vector containing Shati/Nat8l for transfection and overexpression of Shati/Nat8l protein into the primary cultured neurons to investigate the contribution toward the neuronal activity of Shati/Nat8l. Overexpression of Shati/Nat8l in the mice primary cultured neurons induced axonal growth, but not dendrite elongation at day 1.5 (DIV). This finding indicated that Shati/Nat8l contributes toward neuronal development. LY341495, a selective group II mGluRs antagonist, did not abolish this axonal growth, and N-acetylaspartylglutamate itself did not abolish axon outgrowth in the same cultured system. The cultured neurons overexpressing Shati/Nat8l contained high ATP, suggesting that axon outgrowth is dependent on energy metabolism. This study shows that Shati/Nat8l in the neuron may induce axon outgrowth by ATP synthesis and not through mGluR3 signaling.

  13. Quantitative measurements and modeling of cargo–motor interactions during fast transport in the living axon

    International Nuclear Information System (INIS)

    Seamster, Pamela E; Loewenberg, Michael; Pascal, Jennifer; Chauviere, Arnaud; Gonzales, Aaron; Cristini, Vittorio; Bearer, Elaine L

    2012-01-01

    The kinesins have long been known to drive microtubule-based transport of sub-cellular components, yet the mechanisms of their attachment to cargo remain a mystery. Several different cargo-receptors have been proposed based on their in vitro binding affinities to kinesin-1. Only two of these—phosphatidyl inositol, a negatively charged lipid, and the carboxyl terminus of the amyloid precursor protein (APP-C), a trans-membrane protein—have been reported to mediate motility in living systems. A major question is how these many different cargo, receptors and motors interact to produce the complex choreography of vesicular transport within living cells. Here we describe an experimental assay that identifies cargo–motor receptors by their ability to recruit active motors and drive transport of exogenous cargo towards the synapse in living axons. Cargo is engineered by derivatizing the surface of polystyrene fluorescent nanospheres (100 nm diameter) with charged residues or with synthetic peptides derived from candidate motor receptor proteins, all designed to display a terminal COOH group. After injection into the squid giant axon, particle movements are imaged by laser-scanning confocal time-lapse microscopy. In this report we compare the motility of negatively charged beads with APP-C beads in the presence of glycine-conjugated non-motile beads using new strategies to measure bead movements. The ensuing quantitative analysis of time-lapse digital sequences reveals detailed information about bead movements: instantaneous and maximum velocities, run lengths, pause frequencies and pause durations. These measurements provide parameters for a mathematical model that predicts the spatiotemporal evolution of distribution of the two different types of bead cargo in the axon. The results reveal that negatively charged beads differ from APP-C beads in velocity and dispersion, and predict that at long time points APP-C will achieve greater progress towards the presynaptic

  14. Modality-Based Organization of Ascending Somatosensory Axons in the Direct Dorsal Column Pathway

    Science.gov (United States)

    Niu, Jingwen; Ding, Long; Li, Jian J.; Kim, Hyukmin; Liu, Jiakun; Li, Haipeng; Moberly, Andrew; Badea, Tudor C.; Duncan, Ian D.; Son, Young-Jin; Scherer, Steven S.

    2013-01-01

    The long-standing doctrine regarding the functional organization of the direct dorsal column (DDC) pathway is the “somatotopic map” model, which suggests that somatosensory afferents are primarily organized by receptive field instead of modality. Using modality-specific genetic tracing, here we show that ascending mechanosensory and proprioceptive axons, two main types of the DDC afferents, are largely segregated into a medial–lateral pattern in the mouse dorsal column and medulla. In addition, we found that this modality-based organization is likely to be conserved in other mammalian species, including human. Furthermore, we identified key morphological differences between these two types of afferents, which explains how modality segregation is formed and why a rough “somatotopic map” was previously detected. Collectively, our results establish a new functional organization model for the mammalian direct dorsal column pathway and provide insight into how somatotopic and modality-based organization coexist in the central somatosensory pathway. PMID:24198362

  15. Immuno-Spin Trapping-Based Detection of Oxidative Modifications in Cardiomyocytes and Coronary Endothelium in the Progression of Heart Failure in Tgαq*44 Mice

    Directory of Open Access Journals (Sweden)

    Bartosz Proniewski

    2018-05-01

    Full Text Available Recent studies suggest both beneficial and detrimental role of increased reactive oxygen species and oxidative stress in heart failure (HF. However, it is not clear at which stage oxidative stress and oxidative modifications occur in the endothelium in relation to cardiomyocytes in non-ischemic HF. Furthermore, most methods used to date to study oxidative stress are either non-specific or require tissue homogenization. In this study, we used immuno-spin trapping (IST technique with fluorescent microscopy-based detection of DMPO nitrone adducts to localize and quantify oxidative modifications of the hearts from Tgαq*44 mice; a murine model of HF driven by cardiomyocyte-specific overexpression of Gαq* protein. Tgαq*44 mice and age-matched FVB controls at early, transition, and late stages of HF progression were injected with DMPO in vivo and analyzed ex vivo for DMPO nitrone adducts signals. Progressive oxidative modifications in cardiomyocytes, as evidenced by the elevation of DMPO nitrone adducts, were detected in hearts from 10- to 16-month-old, but not in 8-month-old Tgαq*44 mice, as compared with age-matched FVB mice. The DMPO nitrone adducts were detected in left and right ventricle, septum, and papillary muscle. Surprisingly, significant elevation of DMPO nitrone adducts was also present in the coronary endothelium both in large arteries and in microcirculation simultaneously, as in cardiomyocytes, starting from 10-month-old Tgαq*44 mice. On the other hand, superoxide production in heart homogenates was elevated already in 6-month-old Tgαq*44 mice and progressively increased to high levels in 14-month-old Tgαq*44 mice, while the enzymatic activity of catalase, glutathione reductase, and glutathione peroxidase was all elevated as early as in 4-month-old Tgαq*44 mice and stayed at a similar level in 14-month-old Tgαq*44. In summary, this study demonstrates that IST represents a unique method that allows to quantify oxidative

  16. Axonal Spheroid Accumulation In the Brainstem and Spinal Cord of A Young Angus Cow with Ataxia.

    Science.gov (United States)

    Hanshaw, D M; Finnie, J W; Manavis, J; Kessell, A E

    2015-08-01

    An 18-month-old Angus cow presented with rapidly developing ataxia and subsequently died. The finding of large numbers of axonal spheroids in brainstem nuclei and spinal cord grey matter, bilaterally symmetrical in distribution, was consistent with a histopathological diagnosis of neuroaxonal dystrophy (NAD). Most of the axonal swellings were immunopositive to amyloid precursor protein, suggesting that interruption to axonal flow was important in their genesis. The topographical distribution of axonal spheroids in the brain and spinal cord in this bovine case closely resembled that found in the ovine neurodegenerative disorder termed NAD, in which axonal swellings are the major pathological feature. This appears to be the first reported case of this type of NAD in cattle. The aetiology of the spheroidal aggregations in this case was not determined. There was no evidence from the case history or neuropathology to indicate whether the axonal spheroids in this case involved an acquired or heritable aetiology. © 2015 Australian Veterinary Association.

  17. Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon.

    Science.gov (United States)

    Ma, Marek

    2013-12-01

    Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed. © 2013.

  18. A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord

    DEFF Research Database (Denmark)

    Hoeber, Jan; Konig, Niclas; Trolle, Carl

    2017-01-01

    Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly......MIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along “bridges” formed by migrating stem cells. Coimplantation of Meso...... their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular “bridges” in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient...

  19. Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study.

    Science.gov (United States)

    Skinner, S Rachel; Wheeler, Cosette M; Romanowski, Barbara; Castellsagué, Xavier; Lazcano-Ponce, Eduardo; Del Rosario-Raymundo, M Rowena; Vallejos, Carlos; Minkina, Galina; Pereira Da Silva, Daniel; McNeil, Shelly; Prilepskaya, Vera; Gogotadze, Irina; Money, Deborah; Garland, Suzanne M; Romanenko, Viktor; Harper, Diane M; Levin, Myron J; Chatterjee, Archana; Geeraerts, Brecht; Struyf, Frank; Dubin, Gary; Bozonnat, Marie-Cécile; Rosillon, Dominique; Baril, Laurence

    2016-05-15

    The control arm of the phase III VIVIANE (Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; NCT00294047) study in women >25 years was studied to assess risk of progression from cervical HPV infection to detectable cervical intraepithelial neoplasia (CIN). The risk of detecting CIN associated with the same HPV type as the reference infection was analysed using Kaplan-Meier and multivariable Cox models. Infections were categorised depending upon persistence as 6-month persistent infection (6MPI) or infection of any duration. The 4-year interim analysis included 2,838 women, of whom 1,073 (37.8%) experienced 2,615 infections of any duration and 708 (24.9%) experienced 1,130 6MPIs. Infection with oncogenic HPV types significantly increased the risk of detecting CIN grade 2 or greater (CIN2+) versus non-oncogenic types. For 6MPI, the highest risk was associated with HPV-33 (hazard ratio [HR]: 31.9 [8.3-122.2, p 25 years in this study was similar to that in women 15-25 years in PATRICIA. © 2015 The Authors and GlaxoSmithKline. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

  20. Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Esther Nkuipou-Kenfack

    conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data.

  1. REGENERATIVE GROWTH OF CORTICOSPINAL TRACT AXONS VIA THE VENTRAL COLUMN AFTER SPINAL CORD INJURY IN MICE

    OpenAIRE

    Steward, Oswald; Zheng, Binhai; Tessier-Lavigne, Marc; Hofstadter, Maura; Sharp, Kelli; Yee, Kelly Matsudaira

    2008-01-01

    Studies that have assessed regeneration of corticospinal tract (CST) axons in mice following genetic modifications or other treatments have tacitly assumed that there is little if any regeneration of CST axons in normal mice in the absence of some intervention. Here, we document a previously unrecognized capability for regenerative growth of CST axons in normal mice that involves growth past the lesion via the ventral column. Mice received dorsal hemisection injuries at thoracic level 6–7, wh...

  2. Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy

    OpenAIRE

    Jablonka, Sibylle; Beck, Marcus; Lechner, Barbara Dorothea; Mayer, Christine; Sendtner, Michael

    2007-01-01

    Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced β-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)–deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced f...

  3. Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0524 TITLE:Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis PRINCIPAL INVESTIGATOR: Jeffrey D...29 Sep 2015 4. TITLE AND SUBTITLE Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis 5a. CONTRACT NUMBER W81XWH-14-1-0524...MCT1 in injured oligodendroglia of multiple sclerosis patients contributes to axon neurodegeneration and that increasing MCT1 will be protective in the

  4. Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination.

    Science.gov (United States)

    Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas

    2017-08-01

    Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

  5. Annual Progress Report on the Development of Waste Tank Leak Monitoring and Detection and Mitigation Activities in Support of M-45-08

    International Nuclear Information System (INIS)

    DEFIGH PRICE, C.

    2000-01-01

    Milestone M-45-09E of the Hanford Federal Facility Agreement and Consent Order (Tri-Party Agreement or TPA) [TPA 1996] requires submittal of an annual progress report on the development of waste tank leak detection, monitoring, and mitigation (LDMM) activities associated with the retrieval of waste from single-shell tanks (SSTs). This report details progress for fiscal year 2000, building on the current LDMM strategy and including discussion of technologies, applications, cost, schedule, and technical data. The report also includes discussion of demonstrations conducted and recommendations for additional testing. Tri-Party Agreement Milestones M-45-08A and M-45-08B required design and demonstration of LDMM systems for initial retrieval of SST waste. These specific milestones have recently been deleted as part of the M-45-00A change package. Future LDMM development work has been incorporated into specific technology demonstration milestones and SST waste retrieval milestones in the M-45-03 and M-45-05 milestone series

  6. N-Propionylmannosamine stimulates axonal elongation in a murine model of sciatic nerve injury

    Directory of Open Access Journals (Sweden)

    Christian Witzel

    2015-01-01

    Full Text Available Increasing evidence indicates that sialic acid plays an important role during nerve regeneration. Sialic acids can be modified in vitro as well as in vivo using metabolic oligosaccharide engineering of the N-acyl side chain. N-Propionylmannosamine (ManNProp increases neurite outgrowth and accelerates the reestablishment of functional synapses in vitro. We investigated the influence of systemic ManNProp application using a specific in vivo mouse model. Using mice expressing axonal fluorescent proteins, we quantified the extension of regenerating axons, the number of regenerating axons, the number of arborising axons and the number of branches per axon 5 days after injury. Sciatic nerves from non-expressing mice were grafted into those expressing yellow fluorescent protein. We began a twice-daily intraperitoneal application of either peracetylated ManNProp (200 mg/kg or saline solution 5 days before injury, and continued it until nerve harvest (5 days after transection. ManNProp significantly increased the mean distance of axonal regeneration (2.49 mm vs. 1.53 mm; P < 0.005 and the number of arborizing axons (21% vs. 16% P = 0.008 5 days after sciatic nerve grafting. ManNProp did not affect the number of regenerating axons or the number of branches per arborizing axon. The biochemical glycoengineering of the N-acyl side chain of sialic acid might be a promising approach for improving peripheral nerve regeneration.

  7. The Molecular and Cellular Mechanisms of Axon Guidance in Mossy Fiber Sprouting

    Directory of Open Access Journals (Sweden)

    Ryuta Koyama

    2018-05-01

    Full Text Available The question of whether mossy fiber sprouting is epileptogenic has not been resolved; both sprouting-induced recurrent excitatory and inhibitory circuit hypotheses have been experimentally (but not fully supported. Therefore, whether mossy fiber sprouting is a potential therapeutic target for epilepsy remains under debate. Moreover, the axon guidance mechanisms of mossy fiber sprouting have attracted the interest of neuroscientists. Sprouting of mossy fibers exhibits several uncommon axonal growth features in the basically non-plastic adult brain. For example, robust branching of axonal collaterals arises from pre-existing primary mossy fiber axons. Understanding the branching mechanisms in adulthood may contribute to axonal regeneration therapies in neuroregenerative medicine in which robust axonal re-growth is essential. Additionally, because granule cells are produced throughout life in the neurogenic dentate gyrus, it is interesting to examine whether the mossy fibers of newly generated granule cells follow the pre-existing trajectories of sprouted mossy fibers in the epileptic brain. Understanding these axon guidance mechanisms may contribute to neuron transplantation therapies, for which the incorporation of transplanted neurons into pre-existing neural circuits is essential. Thus, clarifying the axon guidance mechanisms of mossy fiber sprouting could lead to an understanding of central nervous system (CNS network reorganization and plasticity. Here, we review the molecular and cellular mechanisms of axon guidance in mossy fiber sprouting by discussing mainly in vitro studies.

  8. NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion

    Science.gov (United States)

    Sasaki, Yo; Nakagawa, Takashi; Mao, Xianrong; DiAntonio, Aaron; Milbrandt, Jeffrey

    2016-01-01

    Overexpression of the NAD+ biosynthetic enzyme NMNAT1 leads to preservation of injured axons. While increased NAD+ or decreased NMN levels are thought to be critical to this process, the mechanism(s) of this axon protection remain obscure. Using steady-state and flux analysis of NAD+ metabolites in healthy and injured mouse dorsal root ganglion axons, we find that rather than altering NAD+ synthesis, NMNAT1 instead blocks the injury-induced, SARM1-dependent NAD+ consumption that is central to axon degeneration. DOI: http://dx.doi.org/10.7554/eLife.19749.001 PMID:27735788

  9. GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules

    Science.gov (United States)

    Hur, Eun-Mi; Saijilafu; Lee, Byoung Dae; Kim, Seong-Jin; Xu, Wen-Lin; Zhou, Feng-Quan

    2011-01-01

    Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs. PMID:21937714

  10. Regulation of Axonal Midline Guidance by Prolyl 4-Hydroxylation in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Torpe, Nanna; Pocock, Roger David John

    2014-01-01

    , little is known of its importance in the control of axon guidance. In a screen of prolyl 4-hydroxylase (P4H) mutants, we found that genetic removal of a specific P4H subunit, DPY-18, causes dramatic defects in C. elegans neuroanatomy. In dpy-18 mutant animals, the axons of specific ventral nerve cord......Neuronal wiring during development requires that the growth cones of axons and dendrites are correctly guided to their appropriate targets. As in other animals, axon growth cones in Caenorhabditis elegans integrate information in their extracellular environment via interactions among transiently...

  11. The neuropathic oesophagus. A radiographic and manometric study on the evolution of megaoesophagus in dogs with developing axonal neuropathy

    International Nuclear Information System (INIS)

    Satchell, P.M.

    1990-01-01

    Dogs given the neurotoxin acrylamide develop peripheral neuropathy and megaoesophagus. Sequential radiographic and manometric studies on the oesophagus demonstrated that the initial abnormalities consisted of a progressive decrease in the proportion of swallows that initiated peristalsis and a gradual increase in oesophageal calibre. Regurgitation, peristaltic failure and oesophageal dilatation all appeared within three days. The eating behaviour and gait abnormalities quickly resolved on stopping the neurotoxin, but the oesophagus remained dilated for longer. Previous studies have suggested that the abnormalities present in dogs which are developing a distal axonal neuropathy or in some dogs with idiopathic megaoesophagus may be limited to the proprioceptive elements of the oesophageal innervation. The present study suggests that the progressive inefficiency in the transmission of swallows and changes in oesophageal calibre in dogs with evolving megaoesophagus may be a consequence of damage to these proprioceptive elements

  12. Speciation and detection of arsenic in aqueous samples: A review of recent progress in non-atomic spectrometric methods

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Jian [State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, Xiamen 361102 (China); Department of Chemistry and Biochemistry, University of Texas, 700 Planetarium Place, Arlington, TX 76019 (United States); Sengupta, Mrinal K. [Department of Chemistry and Biochemistry, University of Texas, 700 Planetarium Place, Arlington, TX 76019 (United States); Thermo Fisher Scientific, Dionex Products, 445 Lakeside Drive, Sunnyvale, CA, 94085 (United States); Yuan, Dongxing [State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, Xiamen 361102 (China); Dasgupta, Purnendu K., E-mail: Dasgupta@uta.edu [Department of Chemistry and Biochemistry, University of Texas, 700 Planetarium Place, Arlington, TX 76019 (United States)

    2014-06-01

    Highlights: • Compilation of principal official documents and major review articles, including the toxicology and chemistry of As. • Review of non-atomic spectrometric methods for speciation and detection of arsenic in aqueous samples (2005–2013) of the performance of field-usable methods. - Abstract: Inorganic arsenic (As) displays extreme toxicity and is a class A human carcinogen. It is of interest to both analytical chemists and environmental scientists. Facile and sensitive determination of As and knowledge of the speciation of forms of As in aqueous samples are vitally important. Nearly every nation has relevant official regulations on permissible limits of drinking water As content. The size of the literature on As is therefore formidable. The heart of this review consists of two tables: one is a compilation of principal official documents and major review articles, including the toxicology and chemistry of As. This includes comprehensive official compendia on As speciation, sample treatment, recommended procedures for the determination of As in specific sample matrices with specific analytical instrument(s), procedures for multi-element (including As) speciation and analysis, and prior comprehensive reviews on arsenic analysis. The second table focuses on the recent literature (2005–2013, the coverage for 2013 is incomplete) on As measurement in aqueous matrices. Recent As speciation and analysis methods based on spectrometric and electrochemical methods, inductively coupled plasma-mass spectrometry, neutron activation analysis and biosensors are summarized. We have deliberately excluded atomic optical spectrometric techniques (atomic absorption, atomic fluorescence, inductively coupled plasma-optical emission spectrometry) not because they are not important (in fact the majority of arsenic determinations are possibly carried out by one of these techniques) but because these methods are sufficiently mature and little meaningful innovation has been

  13. Speciation and detection of arsenic in aqueous samples: A review of recent progress in non-atomic spectrometric methods

    International Nuclear Information System (INIS)

    Ma, Jian; Sengupta, Mrinal K.; Yuan, Dongxing; Dasgupta, Purnendu K.

    2014-01-01

    Highlights: • Compilation of principal official documents and major review articles, including the toxicology and chemistry of As. • Review of non-atomic spectrometric methods for speciation and detection of arsenic in aqueous samples (2005–2013) of the performance of field-usable methods. - Abstract: Inorganic arsenic (As) displays extreme toxicity and is a class A human carcinogen. It is of interest to both analytical chemists and environmental scientists. Facile and sensitive determination of As and knowledge of the speciation of forms of As in aqueous samples are vitally important. Nearly every nation has relevant official regulations on permissible limits of drinking water As content. The size of the literature on As is therefore formidable. The heart of this review consists of two tables: one is a compilation of principal official documents and major review articles, including the toxicology and chemistry of As. This includes comprehensive official compendia on As speciation, sample treatment, recommended procedures for the determination of As in specific sample matrices with specific analytical instrument(s), procedures for multi-element (including As) speciation and analysis, and prior comprehensive reviews on arsenic analysis. The second table focuses on the recent literature (2005–2013, the coverage for 2013 is incomplete) on As measurement in aqueous matrices. Recent As speciation and analysis methods based on spectrometric and electrochemical methods, inductively coupled plasma-mass spectrometry, neutron activation analysis and biosensors are summarized. We have deliberately excluded atomic optical spectrometric techniques (atomic absorption, atomic fluorescence, inductively coupled plasma-optical emission spectrometry) not because they are not important (in fact the majority of arsenic determinations are possibly carried out by one of these techniques) but because these methods are sufficiently mature and little meaningful innovation has been

  14. Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients.

    Directory of Open Access Journals (Sweden)

    Jan Jessen Krut

    Full Text Available Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL in CSF with a novel, sensitive method.With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL (marker of neuronal injury, neopterin (intrathecal immunoactivation and CSF/Plasma albumin ratio (blood-brain barrier integrity were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200, HIV-associated dementia (HAD (n = 14 and on combinations antiretroviral treatment (cART (n = 85, and healthy controls (n = 204. 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation.While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups.Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further

  15. Axon-Schwann cell interaction in the squid nerve fibre.

    Science.gov (United States)

    Villegas, J

    1972-09-01

    The electrical properties of Schwann cells and the effects of neuronal impulses on their membrane potential have been studied in the giant nerve fibre of the squid.1. The behaviour of the Schwann cell membrane to current injection into the cell was ohmic. No impulse-like responses were observed with displacements of 35 mV in the membrane potential. The resistance of the Schwann cell membrane was found to be approximately 10(3) Omega cm(2).2. A long-lasting hyperpolarization is observed in the Schwann cells following the conduction of impulse trains by the axon. Whereas the propagation of a single impulse had little effect, prolonged stimulation of the fibre at 250 impulses/sec was followed by a hyperpolarization of the Schwann cell that gradually declined over a period of several minutes.3. The prolonged effects of nerve impulse trains on the Schwann cell were similar to those produced by depolarizing current pulses applied to the axon by the voltage-clamp technique. Thus, a series of depolarizing pulses in the axon was followed by a long-lasting hyperpolarization of the Schwann cells. In contrast, the application of a series of hyperpolarizing 100 mV pulses at a frequency of 1/sec had no apparent effects.4. Changes in the external potassium concentration did not reproduce the long-lasting effects of nerve excitation.5. The hyperpolarizing effects of impulse trains were abolished by the incubation of the nerve fibre in a sea-water solution containing trypsin.6. These findings are discussed in relation to the possible mechanisms that might be responsible for the long-lasting hyperpolarizations of the Schwann cells.

  16. Excitability properties of motor axons in adults with cerebral palsy

    Directory of Open Access Journals (Sweden)

    Cliff S. Klein

    2015-06-01

    Full Text Available Cerebral Palsy (CP is a permanent disorder caused by a lesion to the developing brain that significantly impairs motor function. The neurophysiological mechanisms underlying motor impairment are not well understood. Specifically, few have addressed whether motoneuron or peripheral axon properties are altered in CP, even though disruption of descending inputs to the spinal cord may cause them to change. In the present study, we have compared nerve excitability properties in seven adults with CP and fourteen healthy controls using threshold tracking techniques by stimulating the median nerve at the wrist and recording the compound muscle action potential (CMAP over the abductor pollicis brevis. The excitability properties in the CP subjects were found to be abnormal. Early and late depolarizing and hyperpolarizing threshold electrotonus was significantly larger (i.e., fanning out, and resting current-threshold (I/V slope was smaller, in CP compared to control. In addition resting threshold and rheobase tended to be larger in CP. According to a modeling analysis of the data, an increase in leakage current under or through the myelin sheath, i.e., the Barrett-Barrett conductance (GBB, combined with a slight hyperpolarization of the resting membrane potential, best explained the group differences in excitability properties. There was a trend for those with greater impairment in gross motor function to have more abnormal axon properties. The findings indicate plasticity of motor axon properties far removed from the site of the lesion. We suspect that this plasticity is caused by disruption of descending inputs to the motoneurons at an early age around the time of their injury.

  17. Mechanisms of hyperpolarization in regenerated mature motor axons in cat

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Krarup, Christian

    2004-01-01

    We found persistent abnormalities in the recovery of membrane excitability in long-term regenerated motor nerve fibres in the cat as indicated in the companion paper. These abnormalities could partly be explained by membrane hyperpolarization. To further investigate this possibility, we compared...... the changes in excitability in control nerves and long-term regenerated cat nerves (3-5 years after tibial nerve crush) during manoeuvres known to alter axonal membrane Na(+)-K(+) pump function: polarization, cooling to 20 degrees C, reperfusion after 10 min ischaemia, and up to 60 s of repetitive stimulation...

  18. Emotion detection deficits and changes in personality traits linked to loss of white matter integrity in primary progressive aphasia

    Directory of Open Access Journals (Sweden)

    Namita Multani

    2017-01-01

    Full Text Available Non-cognitive features including personality changes are increasingly recognized in the three PPA variants (semantic-svPPA, non fluent-nfvPPA, and logopenic-lvPPA. However, differences in emotion processing among the PPA variants and its association with white matter tracts are unknown. We compared emotion detection across the three PPA variants and healthy controls (HC, and related them to white matter tract integrity and cortical degeneration. Personality traits in the PPA group were also examined in relation to white matter tracts. Thirty-three patients with svPPA, nfvPPA, lvPPA, and 32 HC underwent neuropsychological assessment, emotion evaluation task (EET, and MRI scan. Patients' study partners were interviewed on the Clinical Dementia Rating Scale (CDR and completed an interpersonal traits assessment, the Interpersonal Adjective Scale (IAS. Diffusion tensor imaging of uncinate fasciculus (UF, superior longitudinal fasciculus (SLF and inferior longitudinal fasciculus (ILF, and voxel-based morphometry to derive gray matter volumes for orbitofrontal cortex (OFC, anterior temporal lobe (ATL regions were performed. In addition, gray matter volumes of white matter tract-associated regions were also calculated: inferior frontal gyrus (IFG, posterior temporal lobe (PTL, inferior parietal lobe (IPL and occipital lobe (OL. ANCOVA was used to compare EET performance. Partial correlation and multivariate linear regression were conducted to examine association between EET and neuroanatomical regions affected in PPA. All three variants of PPA performed significantly worse than HC on EET, and the svPPA group was least accurate at recognizing emotions. Performance on EET was related to the right UF, SLF, and ILF integrity. Regression analysis revealed EET performance primarily relates to the right UF integrity. The IAS subdomain, cold-hearted, was also associated with right UF integrity. Disease-specific emotion recognition and personality changes occur

  19. Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection.

    Science.gov (United States)

    Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali

    2017-04-15

    Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression. Copyright © 2016. Published by Elsevier B.V.

  20. The Fourier-Kelvin Stellar Interferometer (FKSI): Infrared Detection and Characterization of Exozodiacal Dust to Super-Earths, A Progress Report

    Science.gov (United States)

    Danchi, W.

    2010-01-01

    The Fourier-Kelvin Stellar Interferometer (FKSI) is a structurally connected infrared space interferometer with 0.5 m diameter telescopes on a 12.5 m baseline, and is passively cooled to approx.60K. The FKSI operates in the thermal infrared from 3-8 microns in a nulling (or starlight suppressing) mode for the detection and characterization of exoplanets, debris disks, extrasolar zodiacal dust levels. The FKSI will have the highest angular resolution of any infrared space instrument ever made with its nominal resolution of 40 mas at a 5 micron center wavelength. This resolution exceeds that of Spitzer by a factor of 38 and JWST by a factor of 5. The FKSI mission is conceived as a "probe class" or "mid-sized" strategic mission that utilizes technology advances from flagship projects like JWST, SIM, Spitzer, and the technology programs of TPF-I/Darwin. During the past year we began investigating an enhanced version of FKSI with 1-2 m diameter telescopes, passively cooled to 40K, on a 20-m baseline, with a sunshade giving a +/- 45 degree Field-of-Regard. This enhanced design is capable of detecting and characterizing the atmospheres of many 2 Earth-radius super-Earths and a few Earth-twins. We will report progress on the design of the enhanced mission concept and current status of the technologies needed for this mission.

  1. Plexin A3 and turnout regulate motor axonal branch morphogenesis in zebrafish.

    Directory of Open Access Journals (Sweden)

    Rajiv Sainath

    Full Text Available During embryogenesis motor axons navigate to their target muscles, where individual motor axons develop complex branch morphologies. The mechanisms that control axonal branching morphogenesis have been studied intensively, yet it still remains unclear when branches begin to form or how branch locations are determined. Live cell imaging of individual zebrafish motor axons reveals that the first axonal branches are generated at the ventral extent of the myotome via bifurcation of the growth cone. Subsequent branches are generated by collateral branching restricted to their synaptic target field along the distal portion of the axon. This precisely timed and spatially restricted branching process is disrupted in turnout mutants we identified in a forward genetic screen. Molecular genetic mapping positioned the turnout mutation within a 300 kb region encompassing eight annotated genes, however sequence analysis of all eight open reading frames failed to unambiguously identify the turnout mutation. Chimeric analysis and single cell labeling reveal that turnout function is required cell non-autonomously for intraspinal motor axon guidance and peripheral branch formation. turnout mutant motor axons form the first branch on time via growth cone bifurcation, but unlike wild-type they form collateral branches precociously, when the growth cone is still navigating towards the ventral myotome. These precocious collateral branches emerge along the proximal region of the axon shaft typically devoid of branches, and they develop into stable, permanent branches. Furthermore, we find that null mutants of the guidance receptor plexin A3 display identical motor axon branching defects, and time lapse analysis reveals that precocious branch formation in turnout and plexin A3 mutants is due to increased stability of otherwise short-lived axonal protrusions. Thus, plexin A3 dependent intrinsic and turnout dependent extrinsic mechanisms suppress collateral branch

  2. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    Science.gov (United States)

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  3. Profiling biomarkers of traumatic axonal injury: From mouse to man.

    Science.gov (United States)

    Manivannan, Susruta; Makwana, Milan; Ahmed, Aminul Islam; Zaben, Malik

    2018-05-18

    Traumatic brain injury (TBI) poses a major public health problem on a global scale. Its burden results from high mortality and significant morbidity in survivors. This stems, in part, from an ongoing inadequacy in diagnostic and prognostic indicators despite significant technological advances. Traumatic axonal injury (TAI) is a key driver of the ongoing pathological process following TBI, causing chronic neurological deficits and disability. The science underpinning biomarkers of TAI has been a subject of many reviews in recent literature. However, in this review we provide a comprehensive account of biomarkers from animal models to clinical studies, bridging the gap between experimental science and clinical medicine. We have discussed pathogenesis, temporal kinetics, relationships to neuro-imaging, and, most importantly, clinical applicability in order to provide a holistic perspective of how this could improve TBI diagnosis and predict clinical outcome in a real-life setting. We conclude that early and reliable identification of axonal injury post-TBI with the help of body fluid biomarkers could enhance current care of TBI patients by (i) increasing speed and accuracy of diagnosis, (ii) providing invaluable prognostic information, (iii) allow efficient allocation of rehabilitation services, and (iv) provide potential therapeutic targets. The optimal model for assessing TAI is likely to involve multiple components, including several blood biomarkers and neuro-imaging modalities, at different time points. Copyright © 2018. Published by Elsevier B.V.

  4. Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.

    Science.gov (United States)

    Torres, Manuel; Jimenez, Sebastian; Sanchez-Varo, Raquel; Navarro, Victoria; Trujillo-Estrada, Laura; Sanchez-Mejias, Elisabeth; Carmona, Irene; Davila, Jose Carlos; Vizuete, Marisa; Gutierrez, Antonia; Vitorica, Javier

    2012-11-22

    Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer's patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be

  5. Bridging the gap: axonal fusion drives rapid functional recovery of the nervous system

    Directory of Open Access Journals (Sweden)

    Jean-Sébastien Teoh

    2018-01-01

    Full Text Available Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair. This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients. Compared to humans, a number of species possess far greater regenerative capabilities, and can therefore provide important insights into how our own nervous systems can be repaired. In particular, several invertebrate species have been shown to rapidly initiate regeneration post-injury, allowing separated axon segments to re-join. This process, known as axonal fusion, represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure. Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons. Moreover, we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion, and discovered that the level of axonal fusion can be enhanced by promoting a neuron's intrinsic growth potential. A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

  6. MuSC is involved in regulating axonal fasciculation of mouse primary vestibular afferents.

    Science.gov (United States)

    Kawauchi, Daisuke; Kobayashi, Hiroaki; Sekine-Aizawa, Yoko; Fujita, Shinobu C; Murakami, Fujio

    2003-10-01

    Regulation of axonal fasciculation plays an important role in the precise patterning of neural circuits. Selective fasciculation contributes to the sorting of different types of axons and prevents the misrouting of axons. However, axons must defasciculate once they reach the target area. To study the regulation of fasciculation, we focused on the primary vestibulo-cerebellar afferents (PVAs), which show a dramatic change from fasciculated axon bundles to defasciculated individual axons at their target region, the cerebellar primordium. To understand how fasciculation and defasciculation are regulated in this system, we investigated the roles of murine SC1-related protein (MuSC), a molecule belonging to the immunoglobulin superfamily. We show: (i) by comparing 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) labelling and anti-MuSC immunohistochemistry, that downregulation of MuSC in PVAs during development is concomitant with the defasciculation of PVA axons; (ii) in a binding assay with cells expressing MuSC, that MuSC has cell-adhesive activity via a homophilic binding mechanism, and this activity is increased by multimerization; and (iii) that MuSC also displays neurite outgrowth-promoting activity in vestibular ganglion cultures. These findings suggest that MuSC is involved in axonal fasciculation and its downregulation may help to initiate the defasciculation of PVAs.

  7. Interaction between the soma and the axon terminal of horizontal cells in carp retina

    NARCIS (Netherlands)

    Kamermans, M.; van Dijk, B. W.; Spekreijse, H.

    1990-01-01

    In teleost retina, the receptive fields of horizontal cell axon terminals have a larger space constant than the receptive fields of the horizontal cell somata. Generally this difference in receptive field size is attributed to the cell coupling which is assumed to be stronger in the horizontal axon

  8. Axon-somatic back-propagation in detailed models of spinal alpha motoneurons

    Directory of Open Access Journals (Sweden)

    Pietro eBalbi

    2015-02-01

    Full Text Available Antidromic action potentials following distal stimulation of motor axons occasionally fail to invade the soma of alpha motoneurons in spinal cord, due to their passing through regions of high non-uniformity.Morphologically detailed conductance-based models of cat spinal alpha motoneurons have been developed, with the aim to reproduce and clarify some aspects of the electrophysiological behavior of the antidromic axon-somatic spike propagation. Fourteen 3D morphologically detailed somata and dendrites of cat spinal alpha motoneurons have been imported from an open-access web-based database of neuronal morphologies, NeuroMorpho.org, and instantiated in neurocomputational models. An axon hillock, an axonal initial segment and a myelinated axon are added to each model.By sweeping the diameter of the axonal initial segment (AIS and the axon hillock, as well as the maximal conductances of sodium channels at the AIS and at the soma, the developed models are able to show the relationships between different geometric and electrophysiological configurations and the voltage attenuation of the antidromically travelling wave.In particular, a greater than usually admitted sodium conductance at AIS is necessary and sufficient to overcome the dramatic voltage attenuation occurring during antidromic spike propagation both at the myelinated axon-AIS and at the AIS-soma transitions.

  9. Structure and Function of an Actin-Based Filter in the Proximal Axon

    Directory of Open Access Journals (Sweden)

    Varuzhan Balasanyan

    2017-12-01

    Full Text Available Summary: The essential organization of microtubules within neurons has been described; however, less is known about how neuronal actin is arranged and the functional implications of its arrangement. Here, we describe, in live cells, an actin-based structure in the proximal axon that selectively prevents some proteins from entering the axon while allowing the passage of others. Concentrated patches of actin in proximal axons are present shortly after axonal specification in rat and zebrafish neurons imaged live, and they mark positions where anterogradely traveling vesicles carrying dendritic proteins halt and reverse. Patches colocalize with the ARP2/3 complex, and when ARP2/3-mediated nucleation is blocked, a dendritic protein mislocalizes to the axon. Patches are highly dynamic, with few persisting longer than 30 min. In neurons in culture and in vivo, actin appears to form a contiguous, semipermeable barrier, despite its apparently sparse distribution, preventing axonal localization of constitutively active myosin Va but not myosin VI. : Balasanyan et al. find dynamic patches of actin in proximal axons of live neurons, mature and newly differentiated, in culture and in vivo. Patches contribute to a filter that sequesters some proteins within the somatodendritic domain while allowing others to pass into the axon, leading to polarized localization of proteins.

  10. N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons

    Directory of Open Access Journals (Sweden)

    Giorgi Kharebava

    2015-12-01

    Full Text Available Axonogenesis, a process for the establishment of neuron connectivity, is central to brain function. The role of metabolites derived from docosahexaenoic acid (DHA, 22:6n-3 that is specifically enriched in the brain, has not been addressed in axon development. In this study, we tested if synaptamide (N-docosahexaenoylethanolamine, an endogenous metabolite of DHA, affects axon growth in cultured cortical neurons. We found that synaptamide increased the average axon length, inhibited GLI family zinc finger 1 (GLI1 transcription and sonic hedgehog (Shh target gene expression while inducing cAMP elevation. Similar effects were produced by cyclopamine, a regulator of the Shh pathway. Conversely, Shh antagonized elevation of cAMP and blocked synaptamide-mediated increase in axon length. Activation of Shh pathway by a smoothened (SMO agonist (SAG or overexpression of SMO did not inhibit axon growth mediated by synaptamide or cyclopamine. Instead, adenylate cyclase inhibitor SQ22536 abolished synaptamide-mediated axon growth indicating requirement of cAMP elevation for this process. Our findings establish that synaptamide promotes axon growth while Shh antagonizes synaptamide-mediated cAMP elevation and axon growth by a SMO-independent, non-canonical pathway.

  11. A high mitochondrial transport rate characterizes CNS neurons with high axonal regeneration capacity.

    Directory of Open Access Journals (Sweden)

    Romain Cartoni

    Full Text Available Improving axonal transport in the injured and diseased central nervous system has been proposed as a promising strategy to improve neuronal repair. However, the contribution of each cargo to the repair mechanism is unknown. DRG neurons globally increase axonal transport during regeneration. Because the transport of specific cargos after axonal insult has not been examined systematically in a model of enhanced regenerative capacity, it is unknown whether the transport of all cargos would be modulated equally in injured central nervous system neurons. Here, using a microfluidic culture system we compared neurons co-deleted for PTEN and SOCS3, an established model of high axonal regeneration capacity, to control neurons. We measured the axonal transport of three cargos (mitochondria, synaptic vesicles and late endosomes in regenerating axons and found that the transport of mitochondria, but not the other cargos, was increased in PTEN/SOCS3 co-deleted axons relative to controls. The results reported here suggest a pivotal role for this organelle during axonal regeneration.

  12. In silico modeling of axonal reconnection within a discrete fiber tract after spinal cord injury.

    Science.gov (United States)

    Woolfe, Franco; Waxman, Stephen G; Hains, Bryan C

    2007-02-01

    Following spinal cord injury (SCI), descending axons that carry motor commands from the brain to the spinal cord are injured or transected, producing chronic motor dysfunction and paralysis. Reconnection of these axons is a major prerequisite for restoration of function after SCI. Thus far, only modest gains in motor function have been achieved experimentally or in the clinic after SCI, identifying the practical limitations of current treatment approaches. In this paper, we use an ordinary differential equation (ODE) to simulate the relative and synergistic contributions of several experimentally-established biological factors related to inhibition or promotion of axonal repair and restoration of function after SCI. The factors were mathematically modeled by the ODE. The results of our simulation show that in a model system, many factors influenced the achievability of axonal reconnection. Certain factors more strongly affected axonal reconnection in isolation, and some factors interacted in a synergistic fashion to produce further improvements in axonal reconnection. Our data suggest that mathematical modeling may be useful in evaluating the complex interactions of discrete therapeutic factors not possible in experimental preparations, and highlight the benefit of a combinatorial therapeutic approach focused on promoting axonal sprouting, attraction of cut ends, and removal of growth inhibition for achieving axonal reconnection. Predictions of this simulation may be of utility in guiding future experiments aimed at restoring function after SCI.

  13. A developmental timing switch promotes axon outgrowth independent of known guidance receptors.

    Directory of Open Access Journals (Sweden)

    Katherine Olsson-Carter

    2010-08-01

    Full Text Available To form functional neuronal connections, axon outgrowth and guidance must be tightly regulated across space as well as time. While a number of genes and pathways have been shown to control spatial features of axon development, very little is known about the in vivo mechanisms that direct the timing of axon initiation and elongation. The Caenorhabditis elegans hermaphrodite specific motor neurons (HSNs extend a single axon ventrally and then anteriorly during the L4 larval stage. Here we show the lin-4 microRNA promotes HSN axon initiation after cell cycle withdrawal. Axons fail to form in lin-4 mutants, while they grow prematurely in lin-4-overexpressing animals. lin-4 is required to down-regulate two inhibitors of HSN differentiation--the transcriptional regulator LIN-14 and the "stemness" factor LIN-28--and it likely does so through a cell-autonomous mechanism. This developmental switch depends neither on the UNC-40/DCC and SAX-3/Robo receptors nor on the direction of axon growth, demonstrating that it acts independently of ventral guidance signals to control the timing of HSN axon elongation.

  14. Modeling of the axon membrane skeleton structure and implications for its mechanical properties.

    Directory of Open Access Journals (Sweden)

    Yihao Zhang

    2017-02-01

    Full Text Available Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy. Our proposed computational model accurately simulates the median value of the Young's modulus of the axon plasma membrane determined by atomic force microscopy. It also predicts that because the spectrin filaments are under entropic tension, the thermal random motion of the voltage-gated sodium channels (Nav, which are bound to ankyrin particles, a critical axonal protein, is reduced compared to the thermal motion when spectrin filaments are held at equilibrium. Lastly, our model predicts that because spectrin filaments are under tension, any axonal injuries that lacerate spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration.

  15. Modeling of the axon membrane skeleton structure and implications for its mechanical properties.

    Science.gov (United States)

    Zhang, Yihao; Abiraman, Krithika; Li, He; Pierce, David M; Tzingounis, Anastasios V; Lykotrafitis, George

    2017-02-01

    Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM) to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy. Our proposed computational model accurately simulates the median value of the Young's modulus of the axon plasma membrane determined by atomic force microscopy. It also predicts that because the spectrin filaments are under entropic tension, the thermal random motion of the voltage-gated sodium channels (Nav), which are bound to ankyrin particles, a critical axonal protein, is reduced compared to the thermal motion when spectrin filaments are held at equilibrium. Lastly, our model predicts that because spectrin filaments are under tension, any axonal injuries that lacerate spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration.

  16. Blast overpressure induced axonal injury changes in rat brainstem and spinal cord

    Directory of Open Access Journals (Sweden)

    Srinivasu Kallakuri

    2015-01-01

    Full Text Available Introduction: Blast induced neurotrauma has been the signature wound in returning soldiers from the ongoing wars in Iraq and Afghanistan. Of importance is understanding the pathomechansim(s of blast overpressure (OP induced axonal injury. Although several recent animal models of blast injury indicate the neuronal and axonal injury in various brain regions, animal studies related to axonal injury in the white matter (WM tracts of cervical spinal cord are limited. Objective: The purpose of this study was to assess the extent of axonal injury in WM tracts of cervical spinal cord in male Sprague Dawley rats subjected to a single insult of blast OP. Materials and Methods: Sagittal brainstem sections and horizontal cervical spinal cord sections from blast and sham animals were stained by neurofilament light (NF-L chain and beta amyloid precursor protein immunocytochemistry and observed for axonal injury changes. Results: Observations from this preliminary study demonstrate axonal injury changes in the form of prominent swellings, retraction bulbs, and putative signs of membrane disruptions in the brainstem and cervical spinal cord WM tracts of rats subjected to blast OP. Conclusions: Prominent axonal injury changes following the blast OP exposure in brainstem and cervical spinal WM tracts underscores the need for careful evaluation of blast induced injury changes and associated symptoms. NF-L immunocytochemistry can be considered as an additional tool to assess the blast OP induced axonal injury.

  17. The Kinesin Adaptor Calsyntenin-1 Organizes Microtubule Polarity and Regulates Dynamics during Sensory Axon Arbor Development

    Directory of Open Access Journals (Sweden)

    Mary C. Halloran

    2017-04-01

    Full Text Available Axon growth and branching, and development of neuronal polarity are critically dependent on proper organization and dynamics of the microtubule (MT cytoskeleton. MTs must organize with correct polarity for delivery of diverse cargos to appropriate subcellular locations, yet the molecular mechanisms regulating MT polarity remain poorly understood. Moreover, how an actively branching axon reorganizes MTs to direct their plus ends distally at branch points is unknown. We used high-speed, in vivo imaging of polymerizing MT plus ends to characterize MT dynamics in developing sensory axon arbors in zebrafish embryos. We find that axonal MTs are highly dynamic throughout development, and that the peripheral and central axons of sensory neurons show differences in MT behaviors. Furthermore, we show that Calsyntenin-1 (Clstn-1, a kinesin adaptor required for sensory axon branching, also regulates MT polarity in developing axon arbors. In wild type neurons the vast majority of MTs are directed in the correct plus-end-distal orientation from early stages of development. Loss of Clstn-1 causes an increase in MTs polymerizing in the retrograde direction. These misoriented MTs most often are found near growth cones and branch points, suggesting Clstn-1 is particularly important for organizing MT polarity at these locations. Together, our results suggest that Clstn-1, in addition to regulating kinesin-mediated cargo transport, also organizes the underlying MT highway during axon arbor development.

  18. Integration of shallow gradients of Shh and Netrin-1 guides commissural axons.

    Science.gov (United States)

    Sloan, Tyler F W; Qasaimeh, Mohammad A; Juncker, David; Yam, Patricia T; Charron, Frédéric

    2015-03-01

    During nervous system development, gradients of Sonic Hedgehog (Shh) and Netrin-1 attract growth cones of commissural axons toward the floor plate of the embryonic spinal cord. Mice defective for either Shh or Netrin-1 signaling have commissural axon guidance defects, suggesting that both Shh and Netrin-1 are required for correct axon guidance. However, how Shh and Netrin-1 collaborate to guide axons is not known. We first quantified the steepness of the Shh gradient in the spinal cord and found that it is mostly very shallow. We then developed an in vitro microfluidic guidance assay to simulate these shallow gradients. We found that axons of dissociated commissural neurons respond to steep but not shallow gradients of Shh or Netrin-1. However, when we presented axons with combined Shh and Netrin-1 gradients, they had heightened sensitivity to the guidance cues, turning in response to shallower gradients that were unable to guide axons when only one cue was present. Furthermore, these shallow gradients polarized growth cone Src-family kinase (SFK) activity only when Shh and Netrin-1 were combined, indicating that SFKs can integrate the two guidance cues. Together, our results indicate that Shh and Netrin-1 synergize to enable growth cones to sense shallow gradients in regions of the spinal cord where the steepness of a single guidance cue is insufficient to guide axons, and we identify a novel type of synergy that occurs when the steepness (and not the concentration) of a guidance cue is limiting.

  19. Brief electrical stimulation accelerates axon regeneration in the peripheral nervous system and promotes sensory axon regeneration in the central nervous system.

    Science.gov (United States)

    Gordon, Tessa; Udina, Esther; Verge, Valerie M K; de Chaves, Elena I Posse

    2009-10-01

    Injured peripheral but not central nerves regenerate their axons but functional recovery is often poor. We demonstrate that prolonged periods of axon separation from targets and Schwann cell denervation eliminate regenerative capacity in the peripheral nervous system (PNS). A substantial delay of 4 weeks for all regenerating axons to cross a site of repair of sectioned nerve contributes to the long period of separation. Findings that 1h 20Hz bipolar electrical stimulation accelerates axon outgrowth across the repair site and the downstream reinnervation of denervated muscles in rats and human patients, provides a new and exciting method to improve functional recovery after nerve injuries. Drugs that elevate neuronal cAMP and activate PKA promote axon outgrowth in vivo and in vitro, mimicking the electrical stimulation effect. Rapid expression of neurotrophic factors and their receptors and then of growth associated proteins thereafter via cAMP, is the likely mechanism by which electrical stimulation accelerates axon outgrowth from the site of injury in both peripheral and central nervous systems.

  20. Low-dose CT detects more progression of bone formation in comparison to conventional radiography in patients with ankylosing spondylitis: results from the SIAS cohort.

    Science.gov (United States)

    de Koning, Anoek; de Bruin, Freek; van den Berg, Rosaline; Ramiro, Sofia; Baraliakos, Xenofon; Braun, Juergen; van Gaalen, Floris A; Reijnierse, Monique; van der Heijde, Désirée

    2018-02-01

    To compare the CT Syndesmophyte Score (CTSS) for low-dose CT (ldCT) with the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) for conventional radiographs (CR) in patients with ankylosing spondylitis (AS). Patients with AS in the Sensitive Imaging in Ankylosing Spondylitis cohort had lateral cervical and lumbar spine CR and whole spine ldCT at baseline and 2 years. CR and ldCT images were scored by two readers, paired by patient, blinded to time order, per imaging modality. For the total score analysis, we used average scores of readers per corner on CR or quadrant on ldCT. For the syndesmophyte analysis we used individual reader and consensus scores, regarding new or growing syndesmophyte at the same corner/quadrant. 50 patients were included in the syndesmophyte analysis and 37 in the total score analysis. Mean (SD) status scores for mSASSS (range 0-72) and CTSS (range 0-552) at baseline were 17.9 (13.8) and 161.6 (126.6), and mean progression was 2.4 (3.8) and 17.9 (22.1). Three times as many patients showed new or growing syndesmophytes at ≥3 quadrants on ldCT compared with ≥3 corners on CR for individual readers; for consensus this increased to five times. In 50 patients, 36 new or growing syndesmophytes are seen on CR compared with 151 on ldCT, most being found in the thoracic spine. ldCT, covering the whole spine, detects more progression in the form of new and growing syndesmophytes in patients with AS compared with CR, which is limited to the cervical and lumbar spine. Most progression occurred in the thoracic spine. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. Transfer of vesicles from Schwann cell to axon: a novel mechanism of communication in the peripheral nervous system

    Directory of Open Access Journals (Sweden)

    María Alejandra eLopez-Verrilli

    2012-06-01

    Full Text Available Schwann cells (SCs are the glial component of the peripheral nervous system, with essential roles during development and maintenance of axons, as well as during regenerative processes after nerve injury. SCs increase conduction velocities by myelinating axons, regulate synaptic activity at presynaptic nerve terminals and are a source of trophic factors to neurons. Thus, development and maintenance of peripheral nerves are crucially dependent on local signalling between SCs and axons. In addition to the classic mechanisms of intercellular signalling, the possibility of communication through secreted vesicles has been poorly explored to date. Interesting recent findings suggest the occurrence of lateral transfer mediated by vesicles from glial cells to axons that could have important roles in axonal growth and axonal regeneration. Here, we review the role of vesicular transfer from SCs to axons and propose the benefits of this means in supporting neuronal and axonal maintenance and regeneration after nerve damage.

  2. The disruption of mitochondrial axonal transport is an early event in neuroinflammation

    DEFF Research Database (Denmark)

    Errea, Oihana; Moreno, Beatriz; Gonzalez-Franquesa, Alba

    2015-01-01

    in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production. RESULTS: Both conditions promoted an increase in the size and complexity of axonal mitochondria evident in electron microscopy images, suggesting a compensatory...... acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target...... response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired...

  3. Nuclear-Encoded Mitochondrial mRNAs: A Powerful Force in Axonal Growth and Development.

    Science.gov (United States)

    Gale, Jenna R; Aschrafi, Armaz; Gioio, Anthony E; Kaplan, Barry B

    2018-04-01

    Axons, their growth cones, and synaptic nerve terminals are neuronal subcompartments that have high energetic needs. As such, they are enriched in mitochondria, which supply the ATP necessary to meet these demands. To date, a heterogeneous population of nuclear-encoded mitochondrial mRNAs has been identified in distal axons and growth cones. Accumulating evidence suggests that the local translation of these mRNAs is required for mitochondrial maintenance and axonal viability. Here, we review evidence that suggests a critical role for axonal translation of nuclear-encoded mitochondrial mRNAs in axonal growth and development. Additionally, we explore the role that site-specific translation at the mitochondria itself may play in this process. Finally, we briefly review the clinical implications of dysregulation of local translation of mitochondrial-related mRNAs in neurodevelopmental disorders.

  4. BmRobo2/3 is required for axon guidance in the silkworm Bombyx mori.

    Science.gov (United States)

    Li, Xiao-Tong; Yu, Qi; Zhou, Qi-Sheng; Zhao, Xiao; Liu, Zhao-Yang; Cui, Wei-Zheng; Liu, Qing-Xin

    2016-02-15

    Axon guidance is critical for proper wiring of the nervous system. During the neural development, the axon guidance molecules play a key role and direct axons to choose the correct way to reach the target. Robo, as the receptor of axon guidance molecule Slit, is evolutionarily conserved from planarians to humans. However, the function of Robo in the silkworm, Bombyx mori, remained unknown. In this study, we cloned robo2/3 from B. mori (Bmrobo2/3), a homologue of robo2/3 in Tribolium castaneum. Moreover, BmRobo2/3 was localized in the neuropil, and RNAi-mediated knockdown of Bmrobo2/3 resulted in the longitudinal connectives forming closer to the midline. These data demonstrate that BmRobo2/3 is required for axon guidance in the silkworm. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Axonal sprouting regulates myelin basic protein gene expression in denervated mouse hippocampus

    DEFF Research Database (Denmark)

    Jensen, M B; Poulsen, F R; Finsen, B

    2000-01-01

    to 35 days after transection of the entorhino-hippocampal perforant path axonal projection. In situ hybridization analysis showed that anterograde axonal and terminal degeneration lead to upregulated oligodendrocyte MBP mRNA expression starting between day 2 and day 4, in (1) the deep part of stratum...... axonal and terminal degeneration, myelin degenerative changes, microglial activation and axotomi-induced axonal sprouting. Oligodendrocyte MBP mRNA expression reached maximum in both these areas at day 7. MBP gene transcription remained constant in stratum radiatum, stratum pyramidale and stratum oriens...... of CA1, areas that were unaffected by perforant path transection. These results provide strong evidence that oligodendrocyte MBP gene expression can be regulated by axonal sprouting independently of microglial activation in the injured adult CNS....

  6. Severe pulmonary hypertension associated with the acute motor sensory axonal neuropathy subtype of Guillain-Barré syndrome.

    Science.gov (United States)

    Rooney, Kris A; Thomas, Neal J

    2010-01-01

    To evaluate pulmonary hypertension associated with acute motor sensory axonal neuropathy subtype of Guillain-Barré syndrome. Guillain-Barré syndrome consists of a group of autoimmune disorders that generally manifest as symmetric, progressive, ascending paralysis. There are five subtypes of Guillain-Barré syndrome, and autonomic involvement has been described in all subtypes, including cardiovascular, vasomotor, or pseudomotor dysfunction of both the sympathetic and parasympathetic systems. Case report. Tertiary care pediatric intensive care unit. Three-yr-old female patient. None. Serial measurements of pulmonary artery pressure. We report the case of a young girl with acute motor sensory axonal neuropathy who presented with severe cardiovascular collapse secondary to severe pulmonary hypertension. In this patient, multiple factors may have played a role in the development of pulmonary hypertension including autonomic dysfunction, hypoventilation, and immobility as a risk for thrombosis and pulmonary emboli. It is possible that many other individuals suffering from severe forms of Guillain-Barré syndrome, especially those with significant autonomic dysfunction, may actually have undiagnosed and therefore untreated pulmonary hypertension. Therefore, it is recommended that clinicians caring for critically ill children with Guillain-Barré syndrome have a high index of suspicion for pulmonary hypertension and consider echocardiography if there are clinical signs of this potentially fatal process.

  7. Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

    Directory of Open Access Journals (Sweden)

    Young-Eun Yoo

    Full Text Available Amyotrophic lateral sclerosis (ALS is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT, which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

  8. Early detection of emphysema progression

    DEFF Research Database (Denmark)

    Gorbunova, Vladlena; Jacobs, Sander S. A. M.; Lo, Pechin Chien Pau

    2010-01-01

    Emphysema is one of the most widespread diseases in subjects with smoking history. The gold standard method for estimating the severity of emphysema is a lung function test, such as forced expiratory volume in first second (FEV1). However, several clinical studies showed that chest CT scans offer...

  9. Construction of the Orsay ACO storage ring, 1: progress report. 2: detecting systems; La construction de l'anneau de stockage ACO d'Orsay, 1: etat des travaux. 2: systemes de detection

    Energy Technology Data Exchange (ETDEWEB)

    Blanc-Lapierre, A; Arzelier, G; Beck, R A; Belbeoch, R; Boutouyrie, B; Bruck, H; Burnod, L; Gendreau, G; Gratreau, P; Haissinski, J; Jolivot, R; Laborde, J; Le Duff, J; Leleux, G; Marin, P C; Milman, B; Sommer, E; Zyngier, H [Laboratoire de l' Accelerateur Lineaire, 91 - Orsay (France); [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires; Augustin, J E; Rumpf, F; Silva, E

    1966-07-01

    1. - A brief progress report is given, with mention of the difficulties solved since the 1963 Dubna Conference and the extra facilities which will be available on the ring (beam observation and measurements); 2. - Typical large solid angle detecting systems and equipment for accurate monitoring under construction at Orsay are also presented. Emphasis is put on some peculiar features at ACO as a tool for physics: long experimental straight section and short length of the bunches. (authors) [French] 1. - Un bref rapport est presente sur l'etat d'avancement du projet ACO en precisant les difficultes resolues depuis la Conference de Dubna en 1963, et les moyens nouveaux mis en place sur l'anneau pour les observations et mesures sur les faisceaux; 2. - Des systemes de detection a grand angle solide et de monitorage precis, en construction a Orsay, sont egalement presentes. On insiste sur quelques traits particuliers d'ACO en tant qu'outil de travail de physique: section droite experimentale longue et paquets courts. (auteurs)

  10. Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice

    Directory of Open Access Journals (Sweden)

    Belén Mollá

    2017-08-01

    Full Text Available Friedreich’s ataxia (FRDA is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

  11. Extrinsic and intrinsic regulation of axon regeneration at a crossroads.

    Science.gov (United States)

    Kaplan, Andrew; Ong Tone, Stephan; Fournier, Alyson E

    2015-01-01

    Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

  12. The cholinergic ligand binding material of axonal membranes

    International Nuclear Information System (INIS)

    Mautner, H.G.; Coronado, R.; Jumblatt, J.E.

    1986-01-01

    Choline acetyltransferase and acetylcholinesterase, the enzymes responsible for the synthesis and hydrolysis of ACh, are present in nerve fibers. In crustacean peripheral nerves, release of ACh from cut nerve fibers has been demonstrated. Previously closed membrane vesicles have been prepared from lobster walking leg nerve plasma membrane and saturable binding of cholinergic agonsist and antagonists to such membranes have been demonstrated. This paper studies this axonal cholinergic binding material, and elucidates its functions. The binding of tritium-nicotine to lobster nerve plasma membranes was antagonized by a series of cholinergic ligands as well as by a series of local anesthetics. This preparation was capable of binding I 125-alpha-bungarotoxin, a ligand widely believed to be a specific label for nicotinic ACh receptor. The labelling of 50 K petide band with tritium-MBTA following disulfide reduction is illustrated

  13. The axonal guidance receptor neogenin promotes acute inflammation.

    Directory of Open Access Journals (Sweden)

    Klemens König

    Full Text Available Neuronal guidance proteins (NGP were originally described in the context of axonal growth and migration. Yet recent work has demonstrated that NGPs also serve as guidance cues for immune competent cells. A crucial target receptor for NGPs during embryonic development is the neogenin receptor, however its role during acute inflammation is unknown. We report here that neogenin is abundantly expressed outside the nervous system and that animals with endogenous repression of neogenin (Neo1(-/- demonstrate attenuated changes of acute inflammation. Studies using functional inhibition of neogenin resulted in a significant attenuation of inflammatory peritonitis. In studies employing bone marrow chimeric animals we found the hematopoietic presence of Neo1(-/- to be responsible for the attenuated inflammatory response. Taken together our studies suggest that the guidance receptor neogenin holds crucial importance for the propagation of an acute inflammatory response and further define mechanisms shared between the nervous and the immune system.

  14. Neurogenetics of slow axonal transport: from cells to animals.

    Science.gov (United States)

    Sadananda, Aparna; Ray, Krishanu

    2012-09-01

    Slow axonal transport is a multivariate phenomenon implicated in several neurodegenerative disorders. Recent reports have unraveled the molecular basis of the transport of certain slow component proteins, such as the neurofilament subunits, tubulin, and certain soluble enzymes such as Ca(2+)/calmodulin-dependent protein kinase IIa (CaM kinase IIa), etc., in tissue cultured neurons. In addition, genetic analyses also implicate microtubule-dependent motors and other housekeeping proteins in this process. However, the biological relevance of this phenomenon is not so well understood. Here, the authors have discussed the possibility of adopting neurogenetic analyses in multiple model organisms to correlate molecular level measurements of the slow transport phenomenon to animal behavior, thus facilitating the investigation of its biological efficacy.

  15. Competition from newborn granule cells does not drive axonal retraction of silenced old granule cells in the adult hippocampus

    Directory of Open Access Journals (Sweden)

    Carla M Lopez

    2012-11-01

    Full Text Available In the developing nervous system synaptic refinement, typified by the neuromuscular junction where supernumerary connections are eliminated by axon retraction leaving the postsynaptic target innervated by a single dominant input, critically regulates neuronal circuit formation. Whether such competition based pruning continues in established circuits of mature animals remains unknown. This question is particularly relevant in the context of adult neurogenesis where newborn cells must integrate into preexisting circuits, and thus, potentially compete with functionally mature synapses to gain access to their postsynaptic targets. The hippocampus plays an important role in memory formation/retrieval and the dentate gyrus subfield (DG exhibits continued neurogenesis into adulthood. Therefore, this region contains both mature granule cells (old GCs and immature recently born GCs that are generated throughout adult life (young GCs, providing a neurogenic niche model to examine the role of competition in synaptic refinement. Recent work from an independent group in developing animals indicated that embryonically/early postnatal generated GCs placed at a competitive disadvantage by selective expression of tetanus toxin (TeTX to prevent synaptic release rapidly retracted their axons, and that this retraction was driven by competition from newborn GCs lacking TeTX. In contrast, following 3-6 months of selective TeTX expression in old GCs of adult mice we did not observe any evidence of axon retraction. Indeed ultrastructural analyses indicated that the terminals of silenced GCs even maintained synaptic contact with their postsynaptic targets. Furthermore, we did not detect any significant differences in the electrophysiological properties between old GCs in control and TeTX conditions. Thus, our data demonstrate a remarkable stability in the face of a relatively prolonged period of altered synaptic competition between two populations of neurons within the

  16. Central connectivity of transient receptor potential melastatin 8-expressing axons in the brain stem and spinal dorsal horn.

    Directory of Open Access Journals (Sweden)

    Yun Sook Kim

    Full Text Available Transient receptor potential melastatin 8 (TRPM8 ion channels mediate the detection of noxious and innocuous cold and are expressed by primary sensory neurons, but little is known about the processing of the TRPM8-mediated cold information within the trigeminal sensory nuclei (TSN and the spinal dorsal horn (DH. To address this issue, we characterized TRPM8-positive (+ neurons in the trigeminal ganglion and investigated the distribution of TRPM8+ axons and terminals, and their synaptic organization in the TSN and in the DH using light and electron microscopic immunohistochemistry in transgenic mice expressing a genetically encoded axonal tracer in TRPM8+ neurons. TRPM8 was expressed in a fraction of small myelinated primary afferent fibers (23.7% and unmyelinated fibers (76.3%, suggesting that TRPM8-mediated cold is conveyed via C and Aδ afferents. TRPM8+ axons were observed in all TSN, but at different densities in the dorsal and ventral areas of the rostral TSN, which dominantly receive sensory afferents from intra- and peri-oral structures and from the face, respectively. While synaptic boutons arising from Aδ and non-peptidergic C afferents usually receive many axoaxonic contacts and form complex synaptic arrangements, TRPM8+ boutons arising from afferents of the same classes of fibers showed a unique synaptic connectivity; simple synapses with one or two dendrites and sparse axoaxonic contacts. These findings suggest that TRPM8-mediated cold is conveyed via a specific subset of C and Aδ afferent neurons and is processed in a unique manner and differently in the TSN and DH.

  17. Neuron Morphology Influences Axon Initial Segment Plasticity123

    Science.gov (United States)

    2016-01-01

    In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation. PMID:27022619

  18. Dynein is the motor for retrograde axonal transport of organelles

    International Nuclear Information System (INIS)

    Schnapp, B.J.; Reese, T.S.

    1989-01-01

    Vesicular organelles in axons of nerve cells are transported along microtubules either toward their plus ends (fast anterograde transport) or toward their minus ends (retrograde transport). Two microtubule-based motors were previously identified by examining plastic beads induced to move along microtubules by cytosol fractions from the squid giant axon: (i) an anterograde motor, kinesin, and (ii) a retrograde motor, which is characterized here. The retrograde motor, a cytosolic protein previously termed HMW1, was purified from optic lobes and extruded axoplasm by nucleotide-dependent microtubule affinity and release; microtubule gliding was used as the assay of motor activity. The following properties of the retrograde motor suggest that it is cytoplasmic dynein: (i) sedimentation at 20-22 S with a heavy chain of Mr greater than 200,000 that coelectrophoreses with the alpha and beta subunits of axonemal dynein, (ii) cleavage by UV irradiation in the presence of ATP and vanadate, and (iii) a molecular structure resembling two-headed dynein from axonemes. Furthermore, bead movement toward the minus end of microtubules was blocked when axoplasmic supernatants were treated with UV/vanadate. Treatment of axoplasmic supernatant with UV/vanadate also blocks the retrograde movement of purified organelles in vitro without changing the number of anterograde moving organelles, indicating that dynein interacts specifically with a subgroup of organelles programmed to move toward the cell body. However, purified optic lobe dynein, like purified kinesin, does not by itself promote the movement of purified organelles along microtubules, suggesting that additional axoplasmic factors are necessary for retrograde as well as anterograde transport

  19. Diffuse axonal injury at ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Christoph Moenninghoff

    Full Text Available Diffuse axonal injury (DAI is a specific type of traumatic brain injury caused by shearing forces leading to widespread tearing of axons and small vessels. Traumatic microbleeds (TMBs are regarded as a radiological marker for DAI. This study aims to compare DAI-associated TMBs at 3 Tesla (T and 7 T susceptibility weighted imaging (SWI to evaluate possible diagnostic benefits of ultra-high field (UHF MRI.10 study participants (4 male, 6 female, age range 20-74 years with known DAI were included. All MR exams were performed with a 3 T MR system (Magnetom Skyra and a 7 T MR research system (Magnetom 7 T, Siemens AG, Healthcare Sector, Erlangen, Germany each in combination with a 32-channel-receive coil. The average time interval between trauma and imaging was 22 months. Location and count of TMBs were independently evaluated by two neuroradiologists on 3 T and 7 T SWI images with similar and additionally increased spatial resolution at 7 T. Inter- and intraobserver reliability was assessed using the interclass correlation coefficient (ICC. Count and diameter of TMB were evaluated with Wilcoxon signed rank test.Susceptibility weighted imaging revealed a total of 485 TMBs (range 1-190, median 25 at 3 T, 584 TMBs (plus 20%, range 1-262, median 30.5 at 7 T with similar spatial resolution, and 684 TMBs (plus 41%, range 1-288, median 39.5 at 7 T with 10-times higher spatial resolution. Hemorrhagic DAI appeared significantly larger at 7 T compared to 3 T (p = 0.005. Inter- and intraobserver correlation regarding the counted TMB was high and almost equal 3 T and 7 T.7 T SWI improves the depiction of small hemorrhagic DAI compared to 3 T and may be supplementary to lower field strengths for diagnostic in inconclusive or medicolegal cases.

  20. Axonal transport of proteoglycans to the goldfish optic tectum

    International Nuclear Information System (INIS)

    Ripellino, J.A.; Elam, J.S.

    1988-01-01

    The study addressed the question of whether 35 SO 4 labeled molecules that have been delivered to the goldfish optic nerve terminals by rapid axonal transport include soluble proteoglycans. For analysis, tectal homogenates were subfractionated into a soluble fraction (soluble after centrifugation at 105,000 g), a lysis fraction (soluble after treatment with hypotonic buffer followed by centrifugation at 105,000 g) and a final 105,000 g pellet fraction. The soluble fraction contained 25.7% of incorporated radioactivity and upon DEAE chromatography was resolved into a fraction of sulfated glycoproteins eluting at 0-0.32 M NaCl and containing 39.5% of total soluble label and a fraction eluting at 0.32-0.60 M NaCl containing 53.9% of soluble label. This latter fraction was included on columns of Sepharose CL-6B with or without 4 M guanidine and after pronase digestion was found to have 51% of its radioactivity contained in the glycosaminoglycans (GAGs) heparan sulfate and chondroitin (4 or 6) sulfate in the ratio of 70% to 30%. Mobility of both intact proteoglycans and constituent GAGs on Sepharose CL-6B indicated a size distribution that is smaller than has been observed for proteoglycans and GAGs from cultured neuronal cell lines. Similar analysis of lysis fraction, containing 11.5% of incorporated 35 SO 4 , showed a mixture of heparan sulfate and chondroitin sulfate containing proteoglycans, apparent free heparan sulfate and few, if any, sulfated glycoproteins. Overall, the results support the hypothesis that soluble proteoglycans are among the molecules axonally transported in the visual system

  1. Acute motor and sensory axonal neuropathy-associated syndrome of inappropriate antidiuretic hormone secretion

    Directory of Open Access Journals (Sweden)

    Weeraporn Srisung

    2015-10-01

    Full Text Available A 36-year-old man presented with a six week history of progressive ascending weakness. Physical examination showed generalized motor weakness, more severe in the lower extremities (LE, muscle wasting, absent LE reflexes, dysesthesia, and no cranial nerve involvement. Neurologic workup was consistent with acute motor and sensory axonal neuropathy (AMSAN, a variant of Guillain-Barre syndrome. Concomitantly on admission, serum chemistry panel showed a sodium (Na 115 mmol/L with normal kidney function. Urine showed Na <20 mmol/L, and specific gravity 1.045. Urine osmolality was not available initially. He received IV fluid for volume expansion. The Na did not significantly improve after he became euvolemic. Fluid restriction was then tried with mild improvement. Endocrine work-up ruled out hypothyroidism and adrenal insufficiency. Repeat labs showed serum Na 124 mmol/L, urine Na 191 mmol/L and urine Osm 531 mOsm, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH was diagnosed. Our case report suggests that SIADH should be high on the differential diagnosis for hyponatremia in patients with AMSAN, especially in the setting of euvolemia.

  2. Long live the axon. Parallels between ageing and pathology from a presynaptic point of view.

    Science.gov (United States)

    Grillo, Federico W

    2016-10-01

    All animals have to find the right balance between investing resources into their reproductive cycle and protecting their tissues from age-related damage. In higher order organisms the brain is particularly vulnerable to ageing, as the great majority of post-mitotic neurons are there to stay for an entire life. While ageing is unavoidable, it may progress at different rates in different individuals of the same species depending on a variety of genetic and environmental factors. Inevitably though, ageing results in a cognitive and sensory-motor decline caused by changes in neuronal structure and function. Besides normal ageing, age-related pathological conditions can develop in a sizeable proportion of the population. While this wide array of diseases are considerably different compared to physiological ageing, the two processes share many similarities and are likely to interact. At the subcellular level, two key structures are involved in brain ageing: axons and their synapses. Here I highlight how the ageing process affects these structures in normal and neurodegenerative states in different brain areas. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

    Science.gov (United States)

    Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

    2017-03-01

    Smn +/- transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn +/- transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn +/- transgenic mouse increases their susceptibility to cell death demonstrated

  4. Mitosis in neurons: Roughex and APC/C maintain cell cycle exit to prevent cytokinetic and axonal defects in Drosophila photoreceptor neurons.

    Directory of Open Access Journals (Sweden)

    Robert Ruggiero

    Full Text Available The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.

  5. Hindsight regulates photoreceptor axon targeting through transcriptional control of jitterbug/Filamin and multiple genes involved in axon guidance in Drosophila.

    Science.gov (United States)

    Oliva, Carlos; Molina-Fernandez, Claudia; Maureira, Miguel; Candia, Noemi; López, Estefanía; Hassan, Bassem; Aerts, Stein; Cánovas, José; Olguín, Patricio; Sierralta, Jimena

    2015-09-01

    During axon targeting, a stereotyped pattern of connectivity is achieved by the integration of intrinsic genetic programs and the response to extrinsic long and short-range directional cues. How this coordination occurs is the subject of intense study. Transcription factors play a central role due to their ability to regulate the expression of multiple genes required to sense and respond to these cues during development. Here we show that the transcription factor HNT regulates layer-specific photoreceptor axon targeting in Drosophila through transcriptional control of jbug/Filamin and multiple genes involved in axon guidance and cytoskeleton organization.Using a microarray analysis we identified 235 genes whose expression levels were changed by HNT overexpression in the eye primordia. We analyzed nine candidate genes involved in cytoskeleton regulation and axon guidance, six of which displayed significantly altered gene expression levels in hnt mutant retinas. Functional analysis confirmed the role of OTK/PTK7 in photoreceptor axon targeting and uncovered Tiggrin, an integrin ligand, and Jbug/Filamin, a conserved actin- binding protein, as new factors that participate of photoreceptor axon targeting. Moreover, we provided in silico and molecular evidence that supports jbug/Filamin as a direct transcriptional target of HNT and that HNT acts partially through Jbug/Filamin in vivo to regulate axon guidance. Our work broadens the understanding of how HNT regulates the coordinated expression of a group of genes to achieve the correct connectivity pattern in the Drosophila visual system. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1018-1032, 2015. © 2015 Wiley Periodicals, Inc.

  6. Conspicuity of diffuse axonal injury lesions on diffusion-weighted MR imaging

    International Nuclear Information System (INIS)

    Kinoshita, Toshibumi; Moritani, Toshio; Hiwatashi, Akio; Wang, Henry Z.; Shrier, David A.; Numaguchi, Yuji; Westesson, Per-Lennart A.

    2005-01-01

    Objective: (1) To detect diffuse axonal injury (DAI) lesions by diffusion-weighted imaging (DWI), as compared with fluid-attenuated inversion recovery (FLAIR) imaging and (2) to evaluate hemorrhagic DAI lesions by b 0 images obtained from DWI, as compared with gradient-echo (GRE) imaging. Methods: We reviewed MR images of 36 patients with a diagnosis of DAI. MR imaging was performed 20 h to 14 days (mean, 3.7 days) after traumatic brain injury. We evaluated: (1) conspicuity of lesions on DWI and FLAIR and (2) conspicuity of hemorrhage in DAI lesions on b 0 images and GRE imaging. Results: DWI clearly depicted high-signal DAI lesions. The sensitivity of DWI to lesional conspicuity in DAI lesions was almost equal to that of FLAIR. The sensitivity of b 0 images to identification of hemorrhagic DAI lesions was inferior to that of GRE. Conclusion: DWI is as useful as FLAIR in detecting DAI lesions. GRE imaging is still the superior tool for the evaluation of hemorrhagic DAI

  7. Conspicuity of diffuse axonal injury lesions on diffusion-weighted MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Toshibumi [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States)]. E-mail: kino@grape.med.tottori-u.ac.jp; Moritani, Toshio [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States); Hiwatashi, Akio [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States); Wang, Henry Z. [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States); Shrier, David A. [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States); Numaguchi, Yuji [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States); Westesson, Per-Lennart A. [Department of Radiology, Division of Neuroradiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 (United States)

    2005-10-01

    Objective: (1) To detect diffuse axonal injury (DAI) lesions by diffusion-weighted imaging (DWI), as compared with fluid-attenuated inversion recovery (FLAIR) imaging and (2) to evaluate hemorrhagic DAI lesions by b{sub 0} images obtained from DWI, as compared with gradient-echo (GRE) imaging. Methods: We reviewed MR images of 36 patients with a diagnosis of DAI. MR imaging was performed 20 h to 14 days (mean, 3.7 days) after traumatic brain injury. We evaluated: (1) conspicuity of lesions on DWI and FLAIR and (2) conspicuity of hemorrhage in DAI lesions on b{sub 0} images and GRE imaging. Results: DWI clearly depicted high-signal DAI lesions. The sensitivity of DWI to lesional conspicuity in DAI lesions was almost equal to that of FLAIR. The sensitivity of b{sub 0} images to identification of hemorrhagic DAI lesions was inferior to that of GRE. Conclusion: DWI is as useful as FLAIR in detecting DAI lesions. GRE imaging is still the superior tool for the evaluation of hemorrhagic DAI.

  8. Glia-axon interactions and the regulation of the extracellular K+ in the peripheral nerve.

    Science.gov (United States)

    Jirounek, P; Robert, A; Kindler, E; Blazek, T

    1998-01-01

    Changes in membrane potential of both axons and Schwann cells were measured simultaneously during electrical activity and during the period of recovery in the rabbit vagus nerve by the use of the sucrose-gap apparatus. During low-frequency stimulation (0.5-1 Hz) the preparation developed a ouabain-sensitive hyperpolarization. This hyperpolarization increased when the inwardly rectifying K+ channels in Schwann cells were blocked with Ba2+, indicating that the hyperpolarization was generated by the electrogenic glial Na(+)-K+ pump. During trains at higher frequencies (15 Hz), the preparation depolarized, but after cessation of the stimulation it developed a posttetanic hyperpolarization (PTH). The PTH was also ouabain-sensitive and was strongly enhanced by Cs+ which is known to block the hyperpolarization-activated inward current (Ih) in axons but not in glial cells. These results show that the PTH reflects mainly the axonal electrogenic pump. Our results indicate that during activity the K+ released from the firing axons is removed from the extracellular space by Schwann cells and that after cessation of the stimulation the K+ surplus returns from Schwann cells back to axons. Both the glial and axonal K+ uptake is mediated by successive activation of the glial and axonal Na(+)-K+ pump. The nature of the signalling mechanisms that control the pumping rates of the respective pumps remain unknown.

  9. Characterization of axon formation in the embryonic stem cell-derived motoneuron.

    Science.gov (United States)

    Pan, Hung-Chuan; Wu, Ya-Ting; Shen, Shih-Cheng; Wang, Chi-Chung; Tsai, Ming-Shiun; Cheng, Fu-Chou; Lin, Shinn-Zong; Chen, Ching-Wen; Liu, Ching-San; Su, Hong-Lin

    2011-01-01

    The developing neural cell must form a highly organized architecture to properly receive and transmit nerve signals. Neural formation from embryonic stem (ES) cells provides a novel system for studying axonogenesis, which are orchestrated by polarity-regulating molecules. Here the ES-derived motoneurons, identified by HB9 promoter-driven green fluorescent protein (GFP) expression, showed characteristics of motoneuron-specific gene expression. In the majority of motoneurons, one of the bilateral neurites developed into an axon that featured with axonal markers, including Tau1, vesicle acetylcholine transporter, and synaptophysin. Interestingly, one third of the motoneurons developed bi-axonal processes but no multiple axonal GFP cell was found. The neuronal polarity-regulating proteins, including the phosphorylated AKT and ERK, were compartmentalized into both of the bilateral axonal tips. Importantly, this aberrant axon morphology was still present after the engraftment of GFP(+) neurons into the spinal cord, suggesting that even a mature neural environment fails to provide a proper niche to guide normal axon formation. These findings underscore the necessity for evaluating the morphogenesis and functionality of neurons before the clinical trials using ES or somatic stem cells.

  10. Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration

    Science.gov (United States)

    Cosker, Katharina E.; Pazyra-Murphy, Maria F.; Fenstermacher, Sara J.

    2013-01-01

    Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target-derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation can be integrated over time, so that axonal survival is restricted to neurons connected within a stable circuit. PMID:23516285

  11. A Communication Theoretical Modeling of Axonal Propagation in Hippocampal Pyramidal Neurons.

    Science.gov (United States)

    Ramezani, Hamideh; Akan, Ozgur B

    2017-06-01

    Understanding the fundamentals of communication among neurons, known as neuro-spike communication, leads to reach bio-inspired nanoscale communication paradigms. In this paper, we focus on a part of neuro-spike communication, known as axonal transmission, and propose a realistic model for it. The shape of the spike during axonal transmission varies according to previously applied stimulations to the neuron, and these variations affect the amount of information communicated between neurons. Hence, to reach an accurate model for neuro-spike communication, the memory of axon and its effect on the axonal transmission should be considered, which are not studied in the existing literature. In this paper, we extract the important factors on the memory of axon and define memory states based on these factors. We also describe the transition among these states and the properties of axonal transmission in each of them. Finally, we demonstrate that the proposed model can follow changes in the axonal functionality properly by simulating the proposed model and reporting the root mean square error between simulation results and experimental data.

  12. Optogenetically enhanced axon regeneration: motor versus sensory neuron-specific stimulation.

    Science.gov (United States)

    Ward, Patricia J; Clanton, Scott L; English, Arthur W

    2018-02-01

    Brief neuronal activation in injured peripheral nerves is both necessary and sufficient to enhance motor axon regeneration, and this effect is specific to the activated motoneurons. It is less clear whether sensory neurons respond in a similar manner to neuronal activation following peripheral axotomy. Further, it is unknown to what extent enhancement of axon regeneration with increased neuronal activity relies on a reflexive interaction within the spinal circuitry. We used mouse genetics and optical tools to evaluate the precision and selectivity of system-specific neuronal activation to enhance axon regeneration in a mixed nerve. We evaluated sensory and motor axon regeneration in two different mouse models expressing the light-sensitive cation channel, channelrhodopsin (ChR2). We selectively activated either sensory or motor axons using light stimulation combined with transection and repair of the sciatic nerve. Regardless of genotype, the number of ChR2-positive neurons whose axons had regenerated successfully was greater following system-specific optical treatment, with no effect on the number of ChR2-negative neurons (whether motor or sensory neurons). We conclude that acute system-specific neuronal activation is sufficient to enhance both motor and sensory axon regeneration. This regeneration-enhancing effect is likely cell autonomous. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  13. The Drosophila HEM-2/NAP1 homolog KETTE controls axonal pathfinding and cytoskeletal organization.

    Science.gov (United States)

    Hummel, T; Leifker, K; Klämbt, C

    2000-04-01

    In Drosophila, the correct formation of the segmental commissures depends on neuron-glial interactions at the midline. The VUM midline neurons extend axons along which glial cells migrate in between anterior and posterior commissures. Here, we show that the gene kette is required for the normal projection of the VUM axons and subsequently disrupts glial migration. Axonal projection defects are also found for many other moto- and interneurons. In addition, kette affects the cell morphology of mesodermal and epidermal derivatives, which show an abnormal actin cytoskeleton. The KETTE protein is homologous to the transmembrane protein HEM-2/NAP1 evolutionary conserved from worms to vertebrates. In vitro analysis has shown a specific interaction of the vertebrate HEM-2/NAP1 with the SH2-SH3 adapter protein NCK and the small GTPase RAC1, which both have been implicated in regulating cytoskeleton organization and axonal growth. Hypomorphic kette mutations lead to axonal defects similar to mutations in the Drosophila NCK homolog dreadlocks. Furthermore, we show that kette and dock mutants genetically interact. NCK is thought to interact with the small G proteins RAC1 and CDC42, which play a role in axonal growth. In line with these observations, a kette phenocopy can be obtained following directed expression of mutant DCDC42 or DRAC1 in the CNS midline. In addition, the kette mutant phenotype can be partially rescued by expression of an activated DRAC1 transgene. Our data suggest an important role of the HEM-2 protein in cytoskeletal organization during axonal pathfinding.

  14. The Influence of Glutamate on Axonal Compound Action Potential In Vitro.

    Science.gov (United States)

    Abouelela, Ahmed; Wieraszko, Andrzej

    2016-01-01

    Background  Our previous experiments demonstrated modulation of the amplitude of the axonal compound action potential (CAP) by electrical stimulation. To verify assumption that glutamate released from axons could be involved in this phenomenon, the modification of the axonal CAP induced by glutamate was investigated. Objectives  The major objective of this research is to verify the hypothesis that axonal activity would trigger the release of glutamate, which in turn would interact with specific axonal receptors modifying the amplitude of the action potential. Methods  Segments of the sciatic nerve were exposed to exogenous glutamate in vitro, and CAP was recorded before and after glutamate application. In some experiments, the release of radioactive glutamate analog from the sciatic nerve exposed to exogenous glutamate was also evaluated. Results  The glutamate-induced increase in CAP was blocked by different glutamate receptor antagonists. The effect of glutamate was not observed in Ca-free medium, and was blocked by antagonists of calcium channels. Exogenous glutamate, applied to the segments of sciatic nerve, induced the release of radioactive glutamate analog, demonstrating glutamate-induced glutamate release. Immunohistochemical examination revealed that axolemma contains components necessary for glutamatergic neurotransmission. Conclusion  The proteins of the axonal membrane can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance, leading to a change in the amplitude of CAP. We suggest that increased axonal activity leads to the release of glutamate that results in changes in the amplitude of CAPs.

  15. Progress report on nuclear science and technology in China (Vol.3). Proceedings of academic annual meeting of China Nuclear Society in 2013, No.7--Nuclear electronics and nuclear detection technology sub-volume

    International Nuclear Information System (INIS)

    2014-05-01

    Progress report on nuclear science and technology in China (Vol. 3) includes 57 articles which are communicated on the third national academic annual meeting of China Nuclear Society. There are 10 books totally. This is the seventh one, the content is about Nuclear electronics and nuclear detection technology sub-volume

  16. Progress report on nuclear science and technology in China (Vol.2). Proceedings of academic annual meeting of China Nuclear Society in 2011, No.7--Nuclear electronics and nuclear detection technology sub-volume

    International Nuclear Information System (INIS)

    2012-10-01

    Progress report on nuclear science and technology in China (Vol. 2) includes 698 articles which are communicated on the second national academic annual meeting of China Nuclear Society. There are 10 books totally. This is the seventh one, the content is about Nuclear electronics and nuclear detection technology

  17. [{sup 11}C]Choline PET/CT detection of bone metastases in patients with PSA progression after primary treatment for prostate cancer: comparison with bone scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Picchio, Maria [San Raffaele Scientific Institute, Nuclear Medicine Department, Milan (Italy); National Research Council (IBFM-CNR), Institute for Bioimaging and Molecular Physiology, Milan (Italy); Spinapolice, Elena Giulia; Crivellaro, Cinzia [University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); Fallanca, Federico; Gianolli, Luigi [San Raffaele Scientific Institute, Nuclear Medicine Department, Milan (Italy); Giovacchini, Giampiero [University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Messa, Cristina [National Research Council (IBFM-CNR), Institute for Bioimaging and Molecular Physiology, Milan (Italy); University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); San Gerardo Hospital, Department of Nuclear Medicine, Monza (Italy)

    2012-01-15

    The aim of this study was to evaluate the clinical usefulness of [{sup 11}C]choline positron emission tomography (PET)/CT in comparison with bone scintigraphy (BS) in detecting bone metastases (BM) of patients with biochemical progression after radical treatment for prostate cancer (PCa). Seventy-eight consecutive patients with biochemical progression of PCa (mean prostate-specific antigen 21.1 ng/ml, range 0.2-500.0 ng/ml) referred for both [{sup 11}C]choline PET/CT and BS for restaging purposes were retrospectively analysed. The diagnostic accuracy of [{sup 11}C]choline PET/CT and BS was assessed by using morphological imaging and/or follow-up as standards of reference. As equivocal findings were found, the accuracy analysis was performed twice, once including them as positive and once as negative. A separate analysis was also performed in hormone-resistant patients and data compared with those of patients who did not receive anti-androgenic treatment. Equivocal findings occurred in 1 of 78 (1%) cases in [{sup 11}C]choline PET/CT and in 21 of 78 (27%) cases in BS. Depending on their attribution as either positive or negative, the ranges of sensitivity, specificity, positive predictive value, negative predictive value and accuracy for [{sup 11}C]choline PET/CT were 89-89%, 98-100%, 96-100%, 94-96% and 95-96%, respectively. For BS they were 100-70%, 75-100%, 68-100%, 100-86% and 83-90%, respectively. Concordant findings between [{sup 11}C]choline PET/CT and BS occurred in 55 of 78 (71%) cases. The accuracy of [{sup 11}C]choline PET/CT did not significantly (p = 0.30) differ between hormone-resistant patients (97%) and those who did not receive anti-androgenic treatment (95%). In clinical practice, [{sup 11}C]choline PET/CT may not replace BS because of its lower sensitivity. However, for its high specificity, [{sup 11}C]choline PET/CT positive findings may accurately predict the presence of BM. Equivocal findings are more frequent in BS than [{sup 11}C]choline PET

  18. Schwann cell transplantation improves reticulospinal axon growth and forelimb strength after severe cervical spinal cord contusion.

    Science.gov (United States)

    Schaal, S M; Kitay, B M; Cho, K S; Lo, T P; Barakat, D J; Marcillo, A E; Sanchez, A R; Andrade, C M; Pearse, D D

    2007-01-01

    Schwann cell (SC) implantation alone has been shown to promote the growth of propriospinal and sensory axons, but not long-tract descending axons, after thoracic spinal cord injury (SCI). In the current study, we examined if an axotomy close to the cell body of origin (so as to enhance the intrinsic growth response) could permit supraspinal axons to grow onto SC grafts. Adult female Fischer rats received a severe (C5) cervical contusion (1.1 mm displacement, 3 KDyn). At 1 week postinjury, 2 million SCs ex vivo transduced with lentiviral vector encoding enhanced green fluorescent protein (EGFP) were implanted within media into the injury epicenter; injury-only animals served as controls. Animals were tested weekly using the BBB score for 7 weeks postimplantation and received at end point tests for upper body strength: self-supported forelimb hanging, forearm grip force, and the incline plane. Following behavioral assessment, animals were anterogradely traced bilaterally from the reticular formation using BDA-Texas Red. Stereological quantification revealed a twofold increase in the numbers of preserved NeuN+ neurons rostral and caudal to the injury/graft site in SC implanted animals, corroborating previous reports of their neuroprotective efficacy. Examination of labeled reticulospinal axon growth revealed that while rarely an axon was present within the lesion site of injury-only controls, numerous reticulospinal axons had penetrated the SC implant/lesion milieu. This has not been observed following implantation of SCs alone into the injured thoracic spinal cord. Significant behavioral improvements over injury-only controls in upper limb strength, including an enhanced grip strength (a 296% increase) and an increased self-supported forelimb hanging, accompanied SC-mediated neuroprotection and reticulospinal axon growth. The current study further supports the neuroprotective efficacy of SC implants after SCI and demonstrates that SCs alone are capable of supporting

  19. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Alexandre Dumoulin

    2018-04-01

    Full Text Available Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP, the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα. In the absence of any one of these components, neurons in dorsal root ganglia (DRG and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  20. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade.

    Science.gov (United States)

    Dumoulin, Alexandre; Ter-Avetisyan, Gohar; Schmidt, Hannes; Rathjen, Fritz G

    2018-04-24

    Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  1. Axonal degeneration stimulates the formation of NG2+ cells and oligodendrocytes in the mouse

    DEFF Research Database (Denmark)

    Nielsen, Helle Hvilsted; Ladeby, Rune; Drøjdahl, Nina

    2006-01-01

    the response of the NG2+ cells to the different components of demyelinating pathology, we investigated the response of adult NG2+ cells to axonal degeneration in the absence of primary myelin or oligodendrocyte pathology. Axonal degeneration was induced in the hippocampal dentate gyrus of adult mice...... by transection of the entorhino-dentate perforant path projection. The acutely induced degeneration of axons and terminals resulted in a prompt response of NG2+ cells, consisting of morphological transformation, cellular proliferation, and upregulation of NG2 expression days 2-3 after surgery. This was followed...

  2. Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves.

    Science.gov (United States)

    Klein, Amanda H; Vyshnevska, Alina; Hartke, Timothy V; De Col, Roberto; Mankowski, Joseph L; Turnquist, Brian; Bosmans, Frank; Reeh, Peter W; Schmelz, Martin; Carr, Richard W; Ringkamp, Matthias

    2017-05-17

    Voltage-gated sodium (Na V ) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine Na V channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (Na V 1.1-Na V 1.4, Na V 1.6-Na V 1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (Na V 1.8 and Na V 1.9) inhibited by millimolar concentrations, with Na V 1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different Na V channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys ( Macaca nemestrina ). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and Na V 1.9 -/- mice. In nerves from Na V 1.8 -/- mice, TTX-r C-CAPs could not be detected. These data indicate that Na V 1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of Na V 1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of Na V 1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin. SIGNIFICANCE STATEMENT It is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve

  3. Early Glucose Derangement Detected by Continuous Glucose Monitoring and Progression of Liver Fibrosis in Nonalcoholic Fatty Liver Disease: An Independent Predictive Factor?

    Science.gov (United States)

    Schiaffini, Riccardo; Liccardo, Daniela; Alisi, Anna; Benevento, Danila; Cappa, Marco; Cianfarani, Stefano; Nobili, Valerio

    2016-01-01

    Glucose derangement has been reported to increase oxidative stress, one of the most important factors underlying the progression of hepatic fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). To date, careful evaluation of the glucose profile in pediatric NAFLD has not been performed. A total of 30 severely obese children (15 males; mean age 12.87 ± 2.19 years) with biopsy-proven NAFLD were enrolled in this study from September to December 2013. All patients underwent anthropometric and laboratory evaluation, including the oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM). Our study reveals some differences between OGTT and CGM in detecting NAFLD children with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). OGTT showed 2 (6.67%) patients with IFG and 1 (3.34%) with IGT, while CGM showed 5 (16.67%) patients with IFG and 6 (20%) with IGT. The daily blood glucose profile positively correlated with the baseline blood glucose (r = 0.39, p = 0.04) and the homeostatic model assessment (r = 0.56, p = 0.05). A positive correlation between hyperglycemia and liver fibrosis was found (r = 0.65, p < 0.05). Mean glucose values (F3-F4 group: 163.2 ± 35.92 mg/dl vs. F1 group: 136.58 ± 46.83 mg/dl and F2 group: 154.12 ± 22.51 mg/dl) and the difference between the minimum and maximum blood glucose levels (F3-F4 group: 110.21 ± 25.26 mg/dl vs. F1 group: 91.67 ± 15.97 mg/dl and F2 group: 92 ± 15.48 mg/dl) were significantly (p < 0.05) higher in the F3-F4 group compared to the F1 and F2 groups. Glucose profile derangement as detected by CGM is associated with the severity of hepatic fibrosis in children with NAFLD. © 2015 S. Karger AG, Basel.

  4. Clinical pathological and genetic analysis of 2 cases of mitochondrial myopathy presented as acute motor axonal neuropathy

    Directory of Open Access Journals (Sweden)

    Hou-min YIN

    2014-06-01

    Full Text Available Background The main clinical manifestations of mitochondrial myopathy are chronic limb weakness and muscular soreness. Subclinical peripheral nerve injury is also reported, but acute axonal neuropathy.like syndrome concurrent with lactic acidosis is rare. In this paper the clinical features of 2 patients presenting as acute lactic acidosis and sudden muscle weakness were analyzed. Pathological changes and genetic mutations were detected.  Methods Electromyography (EMG and muscle biopsy were performed. Modified Gomori trichrome (MGT and succinodehydrogenase (SDH staining were used to identify pathological changes. Changes of ultra microstructure of muscular tissue were observed under electron microscope. Mitochondrial DNA (mtDNA full length sequencing was performed using 24 pairs of partially overlapping primers.  Results EMG showed a coexistence of neurogenic and myogenic changes. Dramatic decrease of motor nerve amplitude and moderately reduced sensory nerve amplitude were observed but nerve conduction velocity was normal in both patients. Impressive ragged red fibers were seen on MGT staining. Electron microscope showed dramatic mitochondrial abnormalities in Case 1 and paracrystaline inclusions in Case 2. mtDNA sequencing showed 3243A > G mutation in Case 1 and 8344A > G mutation in Case 2. Conclusions Mitochondrial myopathy can present as metabolic crisis like acute lactic acidosis, dyspnea and acute motor axonal neuropathy.like syndrome. It is a life.threatening phenotype that needs more attention. doi: 10.3969/j.issn.1672-6731.2014.06.007

  5. Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling

    DEFF Research Database (Denmark)

    Cheng, Jin; Sahani, Sadhna; Hausrat, Torben Johann

    2016-01-01

    Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both...

  6. Axonal plasticity elicits long-term changes in oligodendroglia and myelinated fibers

    DEFF Research Database (Denmark)

    Drøjdahl, Nina; Nielsen, Helle Hvilsted; Gardi, Jonathan E

    2010-01-01

    Axons are linked to induction of myelination during development and to the maintenance of myelin and myelinated tracts in the adult CNS. Currently, it is unknown whether and how axonal plasticity in adult CNS impacts the myelinating cells and their precursors. In this article, we report that newly...... formed axonal sprouts are able to induce a protracted myelination response in adult CNS. We show that newly formed axonal sprouts, induced by lesion of the entorhino-hippocampal perforant pathway, have the ability to induce a myelination response in stratum radiatum and lucidum CA3. The lesion resulted...... in significant recruitment of newly formed myelinating cells, documented by incorporation of the proliferation marker bromodeoxyuridine into chondroitin sulphate NG2 expressing cells in stratum radiatum and lucidum CA3 early after lesion, and the occurrence of a 28% increase in the number of oligodendrocytes...

  7. Organophosphate-Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

    Science.gov (United States)

    2014-10-01

    stress, impairments of mitochondrial function, neuroinflammation, altered neurotrophin responses, etc. (reviewed, Soltaninejad and Abdollahi, 2009...Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

  8. Organophosphate Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

    Science.gov (United States)

    2015-10-01

    function, neuroinflammation, al- tered neurotrophin responses, etc. (reviewed, Soltaninejad and Abdollahi, 2009; Banks and Lein, 2012; Terry, 2012). Conflict...JN, Middlemore ML, Williamson LN, et al. Chronic, intermittent exposure to chlorpyrifos in rats: protracted effects on axonal transport, neurotrophin

  9. Effects of X-irradiation on axonal sprouting induced by botulinum toxin

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, S; Duchen, L W [National Hospital, London (UK); Hornsey, S [Hammersmith Hospital, London (UK). M.R.C. Cyclotron Unit

    1982-01-01

    The effect of X-irradiation on axonal sprouting of motor nerves induced by botulinum toxin was examined. Muscles of one leg in the mouse were X-irradiated (15Gy) prior to the injection of a locally paralysing dose of botulinum toxin. It was found that axonal sprouting occurred as expected, but the sprouts remained unmyelinated and many degenerated. Fewer new end-plates were formed, muscles remained more severely atrophied and supersensitive to acetylcholine and recovery of neuromuscular transmission was greatly delayed when compared with the effects of botulinum toxin alone. X-irradiation did not prevent sprouting but, probably by impairing Schwann cell proliferation, altered axon-Schwann cell relationships and prevented the maturation of newly-formed axons and the differentiation of new end-plates.

  10. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon.

    Science.gov (United States)

    Farías, Ginny G; Guardia, Carlos M; De Pace, Raffaella; Britt, Dylan J; Bonifacino, Juan S

    2017-04-04

    The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

  11. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

    Science.gov (United States)

    Farías, Ginny G.; Guardia, Carlos M.; De Pace, Raffaella; Britt, Dylan J.; Bonifacino, Juan S.

    2017-01-01

    The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes. PMID:28320970

  12. Rearrangement of potassium ions and Kv1.1/Kv1.2 potassium channels in regenerating axons following end-to-end neurorrhaphy: ionic images from TOF-SIMS.

    Science.gov (United States)

    Liu, Chiung-Hui; Chang, Hung-Ming; Wu, Tsung-Huan; Chen, Li-You; Yang, Yin-Shuo; Tseng, To-Jung; Liao, Wen-Chieh

    2017-10-01

    The voltage-gated potassium channels Kv1.1 and Kv1.2 that cluster at juxtaparanodal (JXP) regions are essential in the regulation of nerve excitability and play a critical role in axonal conduction. When demyelination occurs, Kv1.1/Kv1.2 activity increases, suppressing the membrane potential nearly to the equilibrium potential of K + , which results in an axonal conduction blockade. The recovery of K + -dependent communication signals and proper clustering of Kv1.1/Kv1.2 channels at JXP regions may directly reflect nerve regeneration following peripheral nerve injury. However, little is known about potassium channel expression and its relationship with the dynamic potassium ion distribution at the node of Ranvier during the regenerative process of peripheral nerve injury (PNI). In the present study, end-to-end neurorrhaphy (EEN) was performed using an in vivo model of PNI. The distribution of K + at regenerating axons following EEN was detected by time-of-flight secondary-ion mass spectrometry. The specific localization and expression of Kv1.1/Kv1.2 channels were examined by confocal microscopy and western blotting. Our data showed that the re-establishment of K + distribution and intensity was correlated with the functional recovery of compound muscle action potential morphology in EEN rats. Furthermore, the re-clustering of Kv1.1/1.2 channels 1 and 3 months after EEN at the nodal region of the regenerating nerve corresponded to changes in the K + distribution. This study provided direct evidence of K + distribution in regenerating axons for the first time. We proposed that the Kv1.1/Kv1.2 channels re-clustered at the JXP regions of regenerating axons are essential for modulating the proper patterns of K + distribution in axons for maintaining membrane potential stability after EEN.

  13. Sensory axon-derived neuregulin-1 is required for axoglial signaling and normal sensory function but not for long-term axon maintenance

    DEFF Research Database (Denmark)

    Fricker, F.R.; Zhu, N.; Tsantoulas, C.

    2009-01-01

    " pockets. The total number of axons in the sural nerve was unchanged, but a greater proportion was unmyelinated. In addition, we observed large-diameter axons that were in a 1:1 relationship with Schwann cells, surrounded by a basal lamina but not myelinated. There was no evidence of DRG or Schwann cell...... death; the markers of different DRG cell populations and cutaneous innervation were unchanged. These anatomical changes were reflected in a slowing of conduction velocity at the lower end of the A-fiber conduction velocity range and a new population of more rapidly conducting C-fibers that are likely...

  14. Developmental plasticity of ascending spinal axons studies using the North American opossum, Didelphis virginiana.

    Science.gov (United States)

    Terman, J R; Wang, X M; Martin, G F

    1999-01-11

    The objectives of the present study were to determine if axons of all ascending tracts grow through the lesion after transection of the thoracic spinal cord during development in the North American opossum, and if so, whether they reach regions of the brain they normally innervate. Opossum pups were subjected to transection of the mid-thoracic cord at PD5, PD8, PD12, PD20, or PD26 and injections of Fast Blue (FB) into the lower thoracic or upper lumbar cord 30-40 days or 6 months later. In the PD5 transected cases, labeled axons were present in all of the supraspinal areas labeled by comparable injections in unlesioned, age-matched controls. In the experimental cases, however, labeled axons appeared to be fewer in number and in some areas more restricted in location than in the controls. When lesions were made at PD8, labeled axons were present in the brain of animals allowed to survive 30-40 days prior to FB injections but they were not observed in those allowed to survive 6 months. When lesions were made at PD12 or later, labeled axons were never found rostral to the lesion. It appears, therefore, that axons of all ascending spinal pathways grow though the lesion after transection of the thoracic cord in developing opossums and that they innervate appropriate areas of the brain. Interestingly, the critical period for such growth is shorter than that for most descending axons, suggesting that factors which influence loss of developmental plasticity are not the same for all axons.

  15. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

    OpenAIRE

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R. Douglas

    2004-01-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility...

  16. Selective axonal growth of embryonic hippocampal neurons according to topographic features of various sizes and shapes

    Directory of Open Access Journals (Sweden)

    Christine E Schmidt

    2010-12-01

    Full Text Available David Y Fozdar1*, Jae Y Lee2*, Christine E Schmidt2–6, Shaochen Chen1,3–5,7,1Departments of Mechanical Engineering, 2Chemical Engineering, 3Biomedical Engineering; 4Center for Nano Molecular Science and Technology; 5Texas Materials Institute; 6Institute of Neuroscience; 7Microelectronics Research Center, The University of Texas at Austin, Austin, TX, USA *Contributed equally to this workPurpose: Understanding how surface features influence the establishment and outgrowth of the axon of developing neurons at the single cell level may aid in designing implantable scaffolds for the regeneration of damaged nerves. Past studies have shown that micropatterned ridge-groove structures not only instigate axon polarization, alignment, and extension, but are also preferred over smooth surfaces and even neurotrophic ligands.Methods: Here, we performed axonal-outgrowth competition assays using a proprietary four-quadrant topography grid to determine the capacity of various micropatterned topographies to act as stimuli sequestering axon extension. Each topography in the grid consisted of an array of microscale (approximately 2 µm or submicroscale (approximately 300 nm holes or lines with variable dimensions. Individual rat embryonic hippocampal cells were positioned either between two juxtaposing topographies or at the borders of individual topographies juxtaposing unpatterned smooth surface, cultured for 24 hours, and analyzed with respect to axonal selection using conventional imaging techniques.Results: Topography was found to influence axon formation and extension relative to smooth surface, and the distance of neurons relative to topography was found to impact whether the topography could serve as an effective cue. Neurons were also found to prefer submicroscale over microscale features and holes over lines for a given feature size.Conclusion: The results suggest that implementing physical cues of various shapes and sizes on nerve guidance conduits

  17. Regional Retinal Ganglion Cell Axon Loss in a Murine Glaucoma Model.

    Science.gov (United States)

    Schaub, Julie A; Kimball, Elizabeth C; Steinhart, Matthew R; Nguyen, Cathy; Pease, Mary E; Oglesby, Ericka N; Jefferys, Joan L; Quigley, Harry A

    2017-05-01

    To determine if retinal ganglion cell (RGC) axon loss in experimental mouse glaucoma is uniform in the optic nerve. Experimental glaucoma was induced for 6 weeks with a microbead injection model in CD1 (n = 78) and C57BL/6 (B6, n = 68) mice. From epoxy-embedded sections of optic nerve 1 to 2 mm posterior to the globe, total nerve area and regional axon density (axons/1600 μm2) were measured in superior, inferior, nasal, and temporal zones. Control eyes of CD1 mice have higher axon density and more total RGCs than control B6 mice eyes. There were no significant differences in control regional axon density in all mice or by strain (all P > 0.2, mixed model). Exposure to elevated IOP caused loss of RGC in both strains. In CD1 mice, axon density declined without significant loss of nerve area, while B6 mice had less density loss, but greater decrease in nerve area. Axon density loss in glaucoma eyes was not significantly greater in any region in either mouse strain (both P > 0.2, mixed model). In moderately damaged CD1 glaucoma eyes, and CD1 eyes with the greatest IOP elevation exposure, density loss differed by region (P = 0.05, P = 0.03, mixed model) with the greatest loss in the temporal and superior regions, while in severely injured B6 nerves superior loss was greater than inferior loss (P = 0.01, mixed model, Bonferroni corrected). There was selectively greater loss of superior and temporal optic nerve axons of RGCs in mouse glaucoma at certain stages of damage. Differences in nerve area change suggest non-RGC responses differ between mouse strains.

  18. Normal axonal ion channel function in large peripheral nerve fibers following chronic ciguatera sensitization.

    Science.gov (United States)

    Vucic, Steve; Kiernan, Matthew C

    2008-03-01

    Although the acute clinical effects of ciguatera poisoning, due to ingestion of ciguatoxin, are mediated by activation of transient Na+ channels, the mechanisms underlying ciguatera sensitization remain undefined. Axonal excitability studies were performed by stimulating the median motor and sensory nerves in two patients with ciguatera sensitization. Excitability parameters were all within normal limits, thereby arguing against dysfunction of axonal membrane ion channels in large-diameter fibers in ciguatera sensitization.

  19. Hydrogels as scaffolds and delivery systems to enhance axonal regeneration after injuries

    Directory of Open Access Journals (Sweden)

    Oscar A. Carballo-Molina

    2015-02-01

    Full Text Available Damage caused to neural tissue by disease or injury frequently produces a discontinuity in the nervous system. Such damage generates diverse alterations that are commonly permanent, due to the limited regeneration capacity of the adult nervous system, particularly the Central Nervous System (CNS. The cellular reaction to noxious stimulus leads to several events such as the formation of glial and fibrous scars, which inhibit axonal regeneration in both the CNS and the Peripheral Nervous System (PNS. Although in the PNS there is some degree of nerve regeneration, it is common that the growing axons reinnervate incorrect areas, causing mismatches. Providing a permissive substrate for axonal regeneration in combination with delivery systems for the release of molecules, which enhances axonal growth, could increase regeneration and the recovery of functions in the CNS or the PNS. Currently, there are no effective vehicles to supply growth factors or cells to the damaged/diseased nervous system. Hydrogels are polymers that are biodegradable, biocompatible and have the capacity to deliver a large range of molecules in situ. The inclusion of cultured neural cells into hydrogels forming three-dimensional structures allows the formation of synapses and neuronal survival. There is also evidence showing that hydrogels constitute an amenable substrate for axonal growth of endogenous or grafted cells, overcoming the presence of axonal regeneration inhibitory molecules, in both the central and peripheral nervous systems. Recent experiments suggest that hydrogels can carry and deliver several proteins relevant for improving neuronal survival and axonal growth. Although the use of hydrogels is appealing, its effectiveness is still a matter of discussion, and more results are needed to achieve consistent recovery using different parameters. This review also discusses areas of opportunity where hydrogels can be applied, in order to promote axonal regeneration of

  20. Axonal Elongation into Peripheral Nervous System ``Bridges'' after Central Nervous System Injury in Adult Rats

    Science.gov (United States)

    David, Samuel; Aguayo, Albert J.

    1981-11-01

    The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as ``bridges'' between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.

  1. Axon-Sorting Multifunctional Nerve Guides: Accelerating Restoration of Nerve Function

    Science.gov (United States)

    2014-10-01

    factor (singly & in selected combinations) in the organotypic model system for preferential sensory or motor axon extension. Use confocal microscopy to...track axon extension of labeled sensory or motor neurons from spinal cord slices (motor) or dorsal root ganglia ( DRG ) (sensory). 20 Thy1-YFP mice...RESEARCH ACCOMPLISHMENTS: • Established a system of color-coded mixed nerve tracking using GFP and RFP expressing motor and sensory neurons (Figure 1

  2. Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8.

    Directory of Open Access Journals (Sweden)

    Eleanna Stamatakou

    Full Text Available Upon arrival at their synaptic targets, axons slow down their growth and extensively remodel before the assembly of presynaptic boutons. Wnt proteins are target-derived secreted factors that promote axonal remodelling and synaptic assembly. In the developing spinal cord, Wnts secreted by motor neurons promote axonal remodelling of NT-3 responsive dorsal root ganglia neurons. Axon remodelling induced by Wnts is characterised by growth cone pausing and enlargement, processes that depend on the re-organisation of microtubules. However, the contribution of the actin cytoskeleton has remained unexplored. Here, we demonstrate that Wnt3a regulates the actin cytoskeleton by rapidly inducing F-actin accumulation in growth cones from rodent DRG neurons through the scaffold protein Dishevelled-1 (Dvl1 and the serine-threonine kinase Gsk3β. Importantly, these changes in actin cytoskeleton occurs before enlargement of the growth cones is evident. Time-lapse imaging shows that Wnt3a increases lamellar protrusion and filopodia velocity. In addition, pharmacological inhibition of actin assembly demonstrates that Wnt3a increases actin dynamics. Through a yeast-two hybrid screen, we identified the actin-binding protein Eps8 as a direct interactor of Dvl1, a scaffold protein crucial for the Wnt signalling pathway. Gain of function of Eps8 mimics Wnt-mediated axon remodelling, whereas Eps8 silencing blocks the axon remodelling activity of Wnt3a. Importantly, blockade of the Dvl1-Eps8 interaction completely abolishes Wnt3a-mediated axonal remodelling. These findings demonstrate a novel role for Wnt-Dvl1 signalling through Eps8 in the regulation of axonal remodeling.

  3. Independent signaling by Drosophila insulin receptor for axon guidance and growth

    Directory of Open Access Journals (Sweden)

    Caroline Rita Li

    2014-01-01

    Full Text Available The Drosophila insulin receptor (DInR regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin-receptor-substrate proteins IRS1-4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock. In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail, important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock-binding sites were in separate portions of the C-tail from the previously identified Chico-binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth, and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all 5 NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. Mutation of these 5 NPXY motifs did not affect photoreceptor axon guidance, showing that different sites within DInR control growth and axon guidance.

  4. Inter-Subject Variability of Axonal Injury in Diffuse Traumatic Brain Injury.

    Science.gov (United States)

    Ware, Jeffrey B; Hart, Tessa; Whyte, John; Rabinowitz, Amanda; Detre, John A; Kim, Junghoon

    2017-07-15

    Traumatic brain injury (TBI) is a leading cause of cognitive morbidity worldwide for which reliable biomarkers are needed. Diffusion tensor imaging (DTI) is a promising biomarker of traumatic axonal injury (TAI); however, existing studies have been limited by a primary reliance on group-level analytic methods not well suited to account for inter-subject variability. In this study, 42 adults with TBI of at least moderate severity were examined 3 months following injury and compared with 35 healthy controls. DTI data were used for both traditional group-level comparison and subject-specific analysis using the distribution-corrected Z-score (DisCo-Z) approach. Inter-subject variation in TAI was assessed in a threshold-invariant manner using a threshold-weighted overlap map derived from subject-specific analysis. Receiver operator curve analysis was used to examine the ability of subject-specific DTI analysis to identify TBI subjects with significantly impaired processing speed in comparison with region of interest-based fractional anisotropy (FA) measurements and clinical characteristics. Traditional group-wise analysis demonstrated widespread reductions of white matter FA within the TBI group (voxel-wise p traumatic deficits in processing speed. Significant group-level effects do not necessarily represent consistent effects at the individual level. Better accounting for inter-subject variability in neurobiological manifestations of TBI may substantially improve the ability to detect and classify patterns of injury.

  5. Structural study of Purkinje cell axonal torpedoes in essential tremor.

    Science.gov (United States)

    Louis, Elan D; Yi, Hong; Erickson-Davis, Cordelia; Vonsattel, Jean-Paul G; Faust, Phyllis L

    2009-02-06

    Essential tremor (ET) is one of the most common neurological diseases. A basic understanding of its neuropathology is now emerging. Aside from Purkinje cell loss, a prominent finding is an abundance of torpedoes (rounded swellings of Purkinje cell axons). Such swellings often result from the mis-accumulation of cell constituents. Identifying the basic nature of these accumulations is an important step in understanding the underlying disease process. Torpedoes, only recently identified in ET, have not yet been characterized ultrastructurally. Light and electron microscopy were used to characterize the structural constituents of torpedoes in ET. Formalin-fixed cerebellar cortical tissue from four prospectively collected ET brains was sectioned and immunostained with a monoclonal phosphorylated neurofilament antibody (SMI-31, Covance, Emeryville, CA). Using additional sections from three ET brains, torpedoes were assessed using electron microscopy. Immunoreactivity for phosphorylated neurofilament protein revealed clear labeling of torpedoes in each case. Torpedoes were strongly immunoreactive; in many instances, two or more torpedoes were noted in close proximity to one another. On electron microscopy, torpedoes were packed with randomly arranged 10-12nm neurofilaments. Mitochondria and smooth endoplasmic reticulum were abundant as well, particularly at the periphery of the torpedo. We demonstrated that the torpedoes in ET represent the mis-accumulation of disorganized neurofilaments and other organelles. It is not known where in the pathogenic cascade these accumulations occur (i.e., whether these accumulations are the primary event or a secondary/downstream event) and this deserves further study.

  6. Myelin-associated proteins labelled by slow axonal transport

    International Nuclear Information System (INIS)

    Giorgi, P.P.; DuBois, H.

    1981-01-01

    This paper deals with the problem of protein metabolism and provides evidence that the neuronal contribution to myelin metabolism may be restricted to lipids only. On the other hand this line of research led to the partial characterization of a group of neuronal proteins probably involved in axo-glial interactions subserving the onset of myelination and the structural maintenance of the mature myelin sheath. Intraocular injection of radioactive amino acids allows the study of the anterograde transport of labelled proteins along retinofugal fibres which are well myelinated. Myelin extracted from the optic nerve and tract under these conditions also contains labelled proteins. Three hypotheses are available to explain this phenomenon. To offer an explanation for this phenomenon the work was planned as follows. a) Characterization of the spatio-temporal pattern of labelling of myelin, in order to define the experimental conditions (survival time and region of the optic pathway to be studied) necessary to obtain maximal labelling. b) Characterization (by gel electrophoresis) of the myelin-associated proteins which become labelled by axonal transport, in order to work on a consistent pattern of labelling. c) Investigation of the possible mechanism responsible for the labelling of myelin-associated proteins. (Auth.)

  7. Bridging Physics and Biology Using Resistance and Axons

    Science.gov (United States)

    Dyer, Joshua M.

    2014-11-01

    When teaching physics, it is often difficult to get biology-oriented students to see the relevance of physics.1 A complaint often heard is that biology students are required to take physics for the Medical College Admission Test (MCAT) as part of a "weeding out" process, but that they don't feel like they need physics for biology. Despite this impression held by students, there have been calls for better physics education for future physicians and life scientists.2,3 Research is being performed to improve physics classes and labs by linking topics in biology and physics.4,5 Described here is a laboratory experiment covering the topics of resistance of materials and circuits/Kirchhoff's laws in a biology context with their direct application to neurons, axons, and electrical impulse transmission within animals. This experiment will also demonstrate the mechanism believed to cause multiple sclerosis. The apparatus was designed with low-cost and readily available materials in mind.

  8. EFFECT OF DETERGENT ON ELECTRICAL PROPERTIES OF SQUID AXON MEMBRANE.

    Science.gov (United States)

    KISHIMOTO, U; ADELMAN, W J

    1964-05-01

    The effects of detergents on squid giant axon action and resting potentials as well as membrane conductances in the voltage clamp have been studied. Anionic detergents (sodium lauryl sulfate, 0.1 to 1.0 mM; dimethyl benzene sulfonate, 1 to 20 mM, pH 7.6) cause a temporary increase and a later decrease of action potential height and the value of the resting potential. Cationic detergent (cetyl trimethyl ammonium chloride, 6 x 10(-5)M or more, pH 7.6) generally brings about immediate and irreversible decreases in the action and resting potentials. Non-ionic detergent (tween 80, 0.1 M, pH 7.6) causes a slight reversible reduction of action potential height without affecting the value of the resting potential. Both anionic and cationic detergents generally decrease the sodium and potassium conductances irreversibly. The effect of non-ionic detergent is to decrease the sodium conductance reversibly, leaving the potassium conductance almost unchanged.

  9. Early development of the circumferential axonal pathway in mouse and chick spinal cord.

    Science.gov (United States)

    Holley, J A

    1982-03-10

    The early development of the circumferential axonal pathway in the brachial and lumbar spinal cord of mouse and chick embryos was studied by scanning and transmission electron microscopy. The cellular processes which comprise this pathway grow in the transverse plane and along the lateral margin of the marginal zone (i.e., circumferentially oriented), as typified by the early embryonic commissural axons. The first formative event observed was in the ventrolateral margin of the primitive spinal cord ventricular zone. Cellular processes were found near the external limiting membrane that appeared to grow a variable distance either dorsally or ventrally. Later in development, presumptive motor column neurons migrated into the ventrolateral region, distal to these early circumferentially oriented processes. Concurrently, other circumferentially oriented perikarya and processes appeared along the dorsolateral margin. Due to their aligned sites of origin and parallel growth, the circumferential processes formed a more or less continuous line or pathway, which in about 10% of the scanned specimens could be followed along the entire lateral margin of the embryonic spinal cord. Several specimens later in development had two sets of aligned circumferential processes in the ventral region. Large numbers of circumferential axons were then found to follow the preformed pathway by fasciculation, after the primitive motor column had become established. Since the earliest circumferential processes appeared to differentiate into axons and were found nearly 24 hours prior to growth of most circumferential axons, their role in guidance as pioneering axons was suggested.

  10. PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure.

    Science.gov (United States)

    LaSarge, Candi L; Santos, Victor R; Danzer, Steve C

    2015-03-01

    Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offsets the reduction in boutons per axon length. These morphological changes predict a net increase in granule cell innervation of CA3. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell communication with CA3. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Fractional cable equation for general geometry: A model of axons with swellings and anomalous diffusion

    Science.gov (United States)

    López-Sánchez, Erick J.; Romero, Juan M.; Yépez-Martínez, Huitzilin

    2017-09-01

    Different experimental studies have reported anomalous diffusion in brain tissues and notably this anomalous diffusion is expressed through fractional derivatives. Axons are important to understand neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. Indeed, abnormal accumulation of proteins and organelles in axons is a hallmark of these diseases. The diffusion in the axons can become anomalous as a result of this abnormality. In this case the voltage propagation in axons is affected. Another hallmark of different neurodegenerative diseases is given by discrete swellings along the axon. In order to model the voltage propagation in axons with anomalous diffusion and swellings, in this paper we propose a fractional cable equation for a general geometry. This generalized equation depends on fractional parameters and geometric quantities such as the curvature and torsion of the cable. For a cable with a constant radius we show that the voltage decreases when the fractional effect increases. In cables with swellings we find that when the fractional effect or the swelling radius increases, the voltage decreases. Similar behavior is obtained when the number of swellings and the fractional effect increase. Moreover, we find that when the radius swelling (or the number of swellings) and the fractional effect increase at the same time, the voltage dramatically decreases.

  12. Vesicular Axonal Transport is Modified In Vivo by Tau Deletion or Overexpression in Drosophila

    Directory of Open Access Journals (Sweden)

    Yasmina Talmat-Amar

    2018-03-01

    Full Text Available Structural microtubule associated protein Tau is found in high amount in axons and is involved in several neurodegenerative diseases. Although many studies have highlighted the toxicity of an excess of Tau in neurons, the in vivo understanding of the endogenous role of Tau in axon morphology and physiology is poor. Indeed, knock-out mice display no strong cytoskeleton or axonal transport phenotype, probably because of some important functional redundancy with other microtubule-associated proteins (MAPs. Here, we took advantage of the model organism Drosophila, which genome contains only one homologue of the Tau/MAP2/MAP4 family to decipher (endogenous Tau functions. We found that Tau depletion leads to a decrease in microtubule number and microtubule density within axons, while Tau excess leads to the opposite phenotypes. Analysis of vesicular transport in tau mutants showed altered mobility of vesicles, but no change in the total amount of putatively mobile vesicles, whereas both aspects were affected when Tau was overexpressed. In conclusion, we show that loss of Tau in tau mutants not only leads to a decrease in axonal microtubule density, but also impairs axonal vesicular transport, albeit to a lesser extent compared to the effects of an excess of Tau.

  13. Drosophila growth cones: a genetically tractable platform for the analysis of axonal growth dynamics.

    Science.gov (United States)

    Sánchez-Soriano, Natalia; Gonçalves-Pimentel, Catarina; Beaven, Robin; Haessler, Ulrike; Ofner-Ziegenfuss, Lisa; Ballestrem, Christoph; Prokop, Andreas

    2010-01-01

    The formation of neuronal networks, during development and regeneration, requires outgrowth of axons along reproducible paths toward their appropriate postsynaptic target cells. Axonal extension occurs at growth cones (GCs) at the tips of axons. GC advance and navigation requires the activity of their cytoskeletal networks, comprising filamentous actin (F-actin) in lamellipodia and filopodia as well as dynamic microtubules (MTs) emanating from bundles of the axonal core. The molecular mechanisms governing these two cytoskeletal networks, their cross-talk, and their response to extracellular signaling cues are only partially understood, hindering our conceptual understanding of how regulated changes in GC behavior are controlled. Here, we introduce Drosophila GCs as a suitable model to address these mechanisms. Morphological and cytoskeletal readouts of Drosophila GCs are similar to those of other models, including mammals, as demonstrated here for MT and F-actin dynamics, axonal growth rates, filopodial structure and motility, organizational principles of MT networks, and subcellular marker localization. Therefore, we expect fundamental insights gained in Drosophila to be translatable into vertebrate biology. The advantage of the Drosophila model over others is its enormous amenability to combinatorial genetics as a powerful strategy to address the complexity of regulatory networks governing axonal growth. Thus, using pharmacological and genetic manipulations, we demonstrate a role of the actin cytoskeleton in a specific form of MT organization (loop formation), known to regulate GC pausing behavior. We demonstrate these events to be mediated by the actin-MT linking factor Short stop, thus identifying an essential molecular player in this context.

  14. DISCO Interacting Protein 2 regulates axonal bifurcation and guidance of Drosophila mushroom body neurons.

    Science.gov (United States)

    Nitta, Yohei; Yamazaki, Daisuke; Sugie, Atsushi; Hiroi, Makoto; Tabata, Tetsuya

    2017-01-15

    Axonal branching is one of the key processes within the enormous complexity of the nervous system to enable a single neuron to send information to multiple targets. However, the molecular mechanisms that control branch formation are poorly understood. In particular, previous studies have rarely addressed the mechanisms underlying axonal bifurcation, in which axons form new branches via splitting of the growth cone. We demonstrate that DISCO Interacting Protein 2 (DIP2) is required for precise axonal bifurcation in Drosophila mushroom body (MB) neurons by suppressing ectopic bifurcation and regulating the guidance of sister axons. We also found that DIP2 localize to the plasma membrane. Domain function analysis revealed that the AMP-synthetase domains of DIP2 are essential for its function, which may involve exerting a catalytic activity that modifies fatty acids. Genetic analysis and subsequent biochemical analysis suggested that DIP2 is involved in the fatty acid metabolization of acyl-CoA. Taken together, our results reveal a function of DIP2 in the developing nervous system and provide a potential functional relationship between fatty acid metabolism and axon morphogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Wnt3 and Gata4 regulate axon regeneration in adult mouse DRG neurons.

    Science.gov (United States)

    Duan, Run-Shan; Liu, Pei-Pei; Xi, Feng; Wang, Wei-Hua; Tang, Gang-Bin; Wang, Rui-Ying; Saijilafu; Liu, Chang-Mei

    2018-05-05

    Neurons in the adult central nervous system (CNS) have a poor intrinsic axon growth potential after injury, but the underlying mechanisms are largely unknown. Wingless-related mouse mammary tumor virus integration site (WNT) family members regulate neural stem cell proliferation, axon tract and forebrain development in the nervous system. Here we report that Wnt3 is an important modulator of axon regeneration. Downregulation or overexpression of Wnt3 in adult dorsal root ganglion (DRG) neurons enhances or inhibits their axon regeneration ability respectively in vitro and in vivo. Especially, we show that Wnt3 modulates axon regeneration by repressing mRNA translation of the important transcription factor Gata4 via binding to the three prime untranslated region (3'UTR). Downregulation of Gata4 could restore the phenotype exhibited by Wnt3 downregulation in DRG neurons. Taken together, these data indicate that Wnt3 is a key intrinsic regulator of axon growth ability of the nervous system. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges.

    Science.gov (United States)

    De Col, Roberto; Messlinger, Karl; Carr, Richard W

    2008-02-15

    Axonal conduction velocity varies according to the level of preceding impulse activity. In unmyelinated axons this typically results in a slowing of conduction velocity and a parallel increase in threshold. It is currently held that Na(+)-K(+)-ATPase-dependent axonal hyperpolarization is responsible for this slowing but this has long been equivocal. We therefore examined conduction velocity changes during repetitive activation of single unmyelinated axons innervating the rat cranial meninges. In direct contradiction to the currently accepted postulate, Na(+)-K(+)-ATPase blockade actually enhanced activity-induced conduction velocity slowing, while the degree of velocity slowing was curtailed in the presence of lidocaine (10-300 microm) and carbamazepine (30-500 microm) but not tetrodotoxin (TTX, 10-80 nm). This suggests that a change in the number of available sodium channels is the most prominent factor responsible for activity-induced changes in conduction velocity in unmyelinated axons. At moderate stimulus frequencies, axonal conduction velocity is determined by an interaction between residual sodium channel inactivation following each impulse and the retrieval of channels from inactivation by a concomitant Na(+)-K(+)-ATPase-mediated hyperpolarization. Since the process is primarily dependent upon sodium channel availability, tracking conduction velocity provides a means of accessing relative changes in the excitability of nociceptive neurons.

  17. p27Kip1 Modulates Axonal Transport by Regulating α-Tubulin Acetyltransferase 1 Stability

    Directory of Open Access Journals (Sweden)

    Giovanni Morelli

    2018-05-01

    Full Text Available Summary: The protein p27Kip1 plays roles that extend beyond cell-cycle regulation during cerebral cortex development, such as the regulation of neuronal migration and neurite branching via signaling pathways that converge on the actin and microtubule cytoskeletons. Microtubule-dependent transport is essential for the maturation of neurons and the establishment of neuronal connectivity though synapse formation and maintenance. Here, we show that p27Kip1 controls the transport of vesicles and organelles along the axon of mice cortical projection neurons in vitro. Moreover, suppression of the p27Kip1 ortholog, dacapo, in Drosophila melanogaster disrupts axonal transport in vivo, leading to the reduction of locomotor activity in third instar larvae and adult flies. At the molecular level, p27Kip1 stabilizes the α-tubulin acetyltransferase 1, thereby promoting the acetylation of microtubules, a post-translational modification required for proper axonal transport. : Morelli et al. report that p27Kip1/Dacapo modulates the acetylation of microtubules in axons via stabilization of ATAT1, the main α-tubulin acetyltransferase. Its conditional loss leads to the reduction of bidirectional axonal transport of vesicles and mitochondria in vitro in mice and in vivo in Drosophila. Keywords: p27Kip1, dacapo, acetylation, axonal transport, ATAT1, alpha-tubulin, HDAC6, Drosophila, mouse, cerebral cortex

  18. Robotic gait assistive technology as means to aggressive mobilization strategy in acute rehabilitation following severe diffuse axonal injury: a case study.

    Science.gov (United States)

    Stam, Daniel; Fernandez, Jennifer

    2017-07-01

    Diffuse axonal injury is a prominent cause of disablement post-traumatic brain injury. Utilization of the rapid expansion of our current scientific knowledge base combined with greater access to neurological and assistive technology as adjuncts to providing sensorimotor experience may yield innovative new approaches to rehabilitation based upon a dynamic model of brain response following injury. A 24-year-old female who sustained a traumatic brain injury, bilateral subdural hemorrhage, subarachnoid hemorrhage and severe diffuse axonal injury secondary to a motor vehicle collision. Evidence-based appraisal of present literature suggests a link between graded intensity of aerobic activity to facilitation of neuro-plastic change and up-regulation of neurotrophins essential to functional recovery post-diffuse axonal injury. Following resolution of paroxysmal autonomic instability with dystonia, aggressive early mobilization techniques were progressed utilizing robotic assistive gait technology in combination with conventional therapy. This approach allowed for arguably greater repetition and cardiovascular demands across a six-month inpatient rehabilitation stay. Outcomes in this case suggest that the use of assistive technology to adjunct higher level and intensity rehabilitation strategies may be a safe and effective means towards reduction of disablement following severe traumatic brain and neurological injury. Implications for Rehabilitation Functional recovery and neuroplasticity following diffuse neurological injury involves a complex process determined by the sensorimotor experience provided by rehabilitation clinicians. This process is in part modulated by intrinsic brain biochemical processes correlated to cardiovascular intensity of the activity provided. It is important that rehabilitation professionals monitor physiological response to higher intensity activities to provide an adaptive versus maladaptive response of central nervous system plasticity with

  19. Polarized axonal surface expression of neuronal KCNQ potassium channels is regulated by calmodulin interaction with KCNQ2 subunit.

    Directory of Open Access Journals (Sweden)

    John P Cavaretta

    Full Text Available KCNQ potassium channels composed of KCNQ2 and KCNQ3 subunits give rise to the M-current, a slow-activating and non-inactivating voltage-dependent potassium current that limits repetitive firing of action potentials. KCNQ channels are enriched at the surface of axons and axonal initial segments, the sites for action potential generation and modulation. Their enrichment at the axonal surface is impaired by mutations in KCNQ2 carboxy-terminal tail that cause benign familial neonatal convulsion and myokymia, suggesting that their correct surface distribution and density at the axon is crucial for control of neuronal excitability. However, the molecular mechanisms responsible for regulating enrichment of KCNQ channels at the neuronal axon remain elusive. Here, we show that enrichment of KCNQ channels at the axonal surface of dissociated rat hippocampal cultured neurons is regulated by ubiquitous calcium sensor calmodulin. Using immunocytochemistry and the cluster of differentiation 4 (CD4 membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum. Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2/KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon. Consistently, hippocampal neuronal excitability is dampened by transient expression of wild-type KCNQ2 but not mutant KCNQ2 deficient in calmodulin binding. Furthermore, coexpression of mutant calmodulin, which can interact with KCNQ2/KCNQ3 channels but not calcium, reduces but does not abolish their enrichment at the axonal surface, suggesting that apo calmodulin but not calcium-bound calmodulin is necessary for their preferential targeting to the axonal

  20. Sustained maximal voluntary contraction produces independent changes in human motor axons and the muscle they innervate.

    Directory of Open Access Journals (Sweden)

    David A Milder

    Full Text Available The repetitive discharges required to produce a sustained muscle contraction results in activity-dependent hyperpolarization of the motor axons and a reduction in the force-generating capacity of the muscle. We investigated the relationship between these changes in the adductor pollicis muscle and the motor axons of its ulnar nerve supply, and the reproducibility of these changes. Ten subjects performed a 1-min maximal voluntary contraction. Activity-dependent changes in axonal excitability were measured using threshold tracking with electrical stimulation at the wrist; changes in the muscle were assessed as evoked and voluntary electromyography (EMG and isometric force. Separate components of axonal excitability and muscle properties were tested at 5 min intervals after the sustained contraction in 5 separate sessions. The current threshold required to produce the target muscle action potential increased immediately after the contraction by 14.8% (p<0.05, reflecting decreased axonal excitability secondary to hyperpolarization. This was not correlated with the decline in amplitude of muscle force or evoked EMG. A late reversal in threshold current after the initial recovery from hyperpolarization peaked at -5.9% at ∼35 min (p<0.05. This pattern was mirrored by other indices of axonal excitability revealing a previously unreported depolarization of motor axons in the late recovery period. Measures of axonal excitability were relatively stable at rest but less so after sustained activity. The coefficient of variation (CoV for threshold current increase was higher after activity (CoV 0.54, p<0.05 whereas changes in voluntary (CoV 0.12 and evoked twitch (CoV 0.15 force were relatively stable. These results demonstrate that activity-dependent changes in motor axon excitability are unlikely to contribute to concomitant changes in the muscle after sustained activity in healthy people. The variability in axonal excitability after sustained activity

  1. Transient developmental Purkinje cell axonal torpedoes in healthy and ataxic mouse cerebellum

    Directory of Open Access Journals (Sweden)

    Lovisa Ljungberg

    2016-11-01

    Full Text Available Information is carried out of the cerebellar cortical microcircuit via action potentials propagated along Purkinje cell axons. In several human neurodegenerative diseases, focal axonal swellings on Purkinje cells – known as torpedoes – have been associated with Purkinje cell loss. Interestingly, torpedoes are also reported to appear transiently during development in rat cerebellum. The function of Purkinje cell axonal torpedoes in health as well as in disease is poorly understood. We investigated the properties of developmental torpedoes in the postnatal mouse cerebellum of wildtype and transgenic mice. We found that Purkinje cell axonal torpedoes transiently appeared on axons of Purkinje neurons, with the largest number of torpedoes observed at postnatal day 11 (P11. This was after peak developmental apoptosis had occurred, when Purkinje cell counts in a lobule were static, suggesting that most developmental torpedoes appear on axons of neurons that persist into adulthood. We found that developmental torpedoes were not associated with a presynaptic GABAergic marker, indicating that they are not synapses. They were seldom found at axonal collateral branch points, and lacked microglia enrichment, suggesting that they are unlikely to be involved in axonal refinement. Interestingly, we found several differences between developmental torpedoes and disease-related torpedoes: developmental torpedoes occured largely on myelinated axons, and were not associated with changes in basket cell innervation on their parent soma. Disease-related torpedoes are typically reported to contain neurofilament; while the majority of developmental torpedoes did as well, a fraction of smaller developmental torpedoes did not. These differences indicate that developmental torpedoes may not be functionally identical to disease-related torpedoes. To study this further, we used a mouse model of spinocerebellar ataxia type 6 (SCA6, and found elevated disease

  2. The Pseudopod System for Axon-Glia Interactions: Stimulation and Isolation of Schwann Cell Protrusions that Form in Response to Axonal Membranes.

    Science.gov (United States)

    Poitelon, Yannick; Feltri, M Laura

    2018-01-01

    In the peripheral nervous system, axons dictate the differentiation state of Schwann cells. Most of this axonal influence on Schwann cells is due to juxtacrine interactions between axonal transmembrane molecules (e.g., the neuregulin growth factor) and receptors on the Schwann cell (e.g., the ErbB2/ErbB3 receptor). The fleeting nature of this interaction together with the lack of synchronicity in the development of the Schwann cell population limits our capability to study this phenomenon in vivo. Here we present a simple Boyden Chamber-based method to study this important cell-cell interaction event. We isolate the early protrusions of Schwann cells that are generated in response to juxtacrine stimulation by sensory neuronal membranes. This method is compatible with a large array of current biochemical analyses and provides an effective approach to study biomolecules that are differentially localized in Schwann cell protrusions and cell bodies in response to axonal signals. A similar approach can be extended to different kinds of cell-cell interactions.

  3. Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A

    NARCIS (Netherlands)

    Pasterkamp, R Jeroen; Anderson, Patrick N; Verhaagen, J

    We have investigated the hypothesis that the chemorepellent Semaphorin3A may be involved in the failure of axonal regeneration after injury to the ascending dorsal columns of adult rats. Following transection of the thoracic dorsal columns, fibroblasts in the dorsolateral parts of the lesion site

  4. beta(2)-ADRENERGIC RECEPTORS PROTECT AXONS DURING ENERGETIC STRESS BUT DO NOT INFLUENCE BASAL GLIO-AXONAL LACTATE SHUTTLING IN MOUSE WHITE MATTER

    NARCIS (Netherlands)

    Laureys, G.; Valentino, M.; Demol, F.; Zammit, C.; Muscat, R.; Cambron, M.; Kooijman, R.; De Keyser, J.

    2014-01-01

    In vitro studies have demonstrated that beta 2-adrenergic receptor activation stimulates glycogen degradation in astrocytes, generating lactate as a potential energy source for neurons. Using in vivo microdialysis in mouse cerebellar white matter we demonstrate continuous axonal lactate uptake and

  5. Noncanonical Adult Human Neurogenesis and Axonal Growth as Possible Structural Basis of Recovery From Traumatic Vegetative State

    Directory of Open Access Journals (Sweden)

    Yulia Vainshenker

    2017-09-01

    Full Text Available Patient recovering from traumatic vegetative state has suddenly died from cardiac arrest. In-life improvement of consciousness appeared after reduction of generalized spasticity due to botulinum toxin administration. Neuropathologic examination revealed Musashi1+, Nestin+, PCNA+, and Ki67+ cells in the hippocampus, frontal, parietal and occipital cortex, caudate, thalamus, mammillary bodies, brainstem, cerebellum, and near the posterior horn of the lateral ventricle. New neurons with neurite growth (TUC4+ appeared in corpus callosum. At the same time, axonal growth was detected in all areas of interest. New cells whose functional state was continuously improving, as revealed by in-life neurologic and positron emission tomography monitoring, have mainly been found in brain areas without neuropathologic signs of damage. We suggest that the possible role of neurogenesis consists in improvement of the microenvironment and interneuron interactions, whereas the activation of neurogenesis and the induction of neurite growth may be associated with reduction of spasticity.

  6. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

    Science.gov (United States)

    Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

    2016-11-01

    Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Channelrhodopsin-2 localised to the axon initial segment.

    Directory of Open Access Journals (Sweden)

    Matthew S Grubb

    2010-10-01

    Full Text Available The light-gated cation channel Channelrhodopsin-2 (ChR2 is a powerful and versatile tool for controlling neuronal activity. Currently available versions of ChR2 either distribute uniformly throughout the plasma membrane or are localised specifically to somatodendritic or synaptic domains. Localising ChR2 instead to the axon initial segment (AIS could prove an extremely useful addition to the optogenetic repertoire, targeting the channel directly to the site of action potential initiation, and limiting depolarisation and associated calcium entry elsewhere in the neuron. Here, we describe a ChR2 construct that we localised specifically to the AIS by adding the ankyrinG-binding loop of voltage-gated sodium channels (Na(vII-III to its intracellular terminus. Expression of ChR2-YFP-Na(vII-III did not significantly affect the passive or active electrical properties of cultured rat hippocampal neurons. However, the tiny ChR2 currents and small membrane depolarisations resulting from AIS targeting meant that optogenetic control of action potential firing with ChR2-YFP-Na(vII-III was unsuccessful in baseline conditions. We did succeed in stimulating action potentials with light in some ChR2-YFP-Na(vII-III-expressing neurons, but only when blocking KCNQ voltage-gated potassium channels. We discuss possible alternative approaches to obtaining precise control of neuronal spiking with AIS-targeted optogenetic constructs and propose potential uses for our ChR2-YFP-Na(vII-III probe where subthreshold modulation of action potential initiation is desirable.

  8. In vivo intracellular recordings from spinal lumbar motoneurones in P0-deficient mice indicate an activity-dependent axonal conduction failure in otherwise functional motoneurones

    DEFF Research Database (Denmark)

    Lehnhoff, Janna; Moldovan, Mihai; Hedegaard, Anne

    2014-01-01

    Mice deficient for the peripheral myelin binding protein zero (P0-/-) show a progressive dysmyelinating neuropathy phenotypically resembling severe forms of Charcot-Marie-Tooth (CMT) disease. Traditionally, the progression of the disease was attributed to axonal loss, but the effect of chronic...... dysmyelination remains poorly understood. In this study, in vivo electrophysiological recordings were used to assess the function of both central and axonal components of spinal lumbar motoneurones in adult P0-/- mice.Three month old P0-/- mice (n=7) and wild type (WT) littermate controls (n=5) were...... anaesthetized with Hypnorm (0.315 mg/mL fentanyl-citrate + 10 mg/mL fluanisone), Midazolam (5 mg/mL), and sterile water, mixed in the ratio 1:1:2 (induction: 0.15mL/25g, maintenance: 0.05 mL/20 minutes, S.C.). Anaesthesia during surgery was assessed by the lack of reflexes to a short noxious pinch on the hind...

  9. Mapping axonal density and average diameter using non-monotonic time-dependent gradient-echo MRI

    DEFF Research Database (Denmark)

    Nunes, Daniel; Cruz, Tomás L; Jespersen, Sune N

    2017-01-01

    available in the clinic, or extremely long acquisition schemes to extract information from parameter-intensive models. In this study, we suggest that simple and time-efficient multi-gradient-echo (MGE) MRI can be used to extract the axon density from susceptibility-driven non-monotonic decay in the time...... the quantitative results are compared against ground-truth histology, they seem to reflect the axonal fraction (though with a bias, as evident from Bland-Altman analysis). As well, the extra-axonal fraction can be estimated. The results suggest that our model is oversimplified, yet at the same time evidencing......-dependent signal. We show, both theoretically and with simulations, that a non-monotonic signal decay will occur for multi-compartmental microstructures – such as axons and extra-axonal spaces, which we here used in a simple model for the microstructure – and that, for axons parallel to the main magnetic field...

  10. The distribution of chandelier cell axon terminals that express the GABA plasma membrane transporter GAT-1 in the human neocortex.

    Science.gov (United States)

    Inda, M C; Defelipe, J; Muñoz, A

    2007-09-01

    Chandelier cells represent a unique type of cortical GABAergic interneuron whose axon terminals (Ch-terminals) form synapses exclusively with the axon initial segments of pyramidal cells. In this study, we have used immunocytochemistry for the high-affinity plasma membrane transporter-1 (GAT-1) to analyze the distribution and density of Ch-terminals in various cytoarchitectonic and functional areas of the human neocortex. The lowest density of GAT-1-immuoreactive (-ir) Ch-terminals was detected in the primary and secondary visual (areas 17 and 18) and in the somatosensory areas (areas 3b and 1). In contrast, an intermediate density was observed in the motor area 4 and the associative frontolateral areas 45 and 46, whereas the associative frontolateral areas 9 and 10, frontal orbitary areas 11, 12, 13, 14, and 47, associative temporal areas 20, 21, 22, and 38, and cingulate areas 24 and 32 displayed the highest density of GAT-1-ir Ch-terminals. Despite these differences, the laminar distribution of GAT-1-ir Ch-terminals was similar in most cortical areas. Hence, the highest density of this transporter was observed in layer II, followed by layers III, V, VI, and IV. In most cortical areas, the density of GAT-1-ir Ch-terminals was positively correlated with the neuronal density, although a negative correlation was detected in layer III across all cortical areas. These results indicate that there are substantial differences in the distribution and density of GAT-1-ir Ch-terminals between areas and layers of the human neocortex. These differences might be related to the different functional attributes of the cortical regions examined.

  11. Progress Report

    DEFF Research Database (Denmark)

    Duer, Karsten

    1999-01-01

    Progress report describing the work carried out by the Danish participant in the ALTSET project in the period January 1999 to July 1999.......Progress report describing the work carried out by the Danish participant in the ALTSET project in the period January 1999 to July 1999....

  12. Progress Report

    Science.gov (United States)

    2018-05-16

    This report summarizes the annual progress of EPA’s Clean Air Markets Programs such as the Acid Rain Program (ARP) and the Cross-State Air Pollution Rule (CSAPR). EPA systematically collects data on emissions, compliance, and environmental effects, these data are highlighted in our Progress Reports.

  13. ON Cone Bipolar Cell Axonal Synapses in the OFF Inner Plexiform Layer of the Rabbit Retina

    Science.gov (United States)

    Lauritzen, J. Scott; Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Mohammed, Shoeb; Hoang, John V.; Marc, Robert E.

    2012-01-01

    Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make non-canonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscope (ATEM) imaging, molecular tagging, tracing, and rendering of ≈ 400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include GABA-positive amacrine cells (γACs), glycine-positive amacrine cells (GACs) and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON-OFF amacrine cells. Many of these ON-OFF GACs target ON cone bipolar cell axons, ON γACs and/or ON-OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF γACs presynaptic to OFF bipolar cells, forming γAC-mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON-OFF ganglion cells in the OFF layer and provide ON drive to polarity-appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. PMID:23042441

  14. Chlorpyrifos and chlorpyrifos-oxon inhibit axonal growth by interfering with the morphogenic activity of acetylcholinesterase

    International Nuclear Information System (INIS)

    Yang Dongren; Howard, Angela; Bruun, Donald; Ajua-Alemanj, Mispa; Pickart, Cecile; Lein, Pamela J.

    2008-01-01

    A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE -/- ) versus wild type (AChE +/+ ) mice indicated that while these OPs inhibited axonal growth in AChE +/+ DRG neurons, they had no effect on axonal growth in AChE -/- DRG neurons. However, transfection of AChE -/- DRG neurons with cDNA encoding full-length AChE restored the wild type response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs

  15. Phospholipid synthesis in the squid giant axon: incorporation of lipid precursors

    Energy Technology Data Exchange (ETDEWEB)

    Gould, R.M.; Pant, H.; Gainer, H.; Tytell, M.

    1983-05-01

    The squid giant axon and extruded axoplasm from the giant axon were used to study the capacity of axoplasm for phospholipid synthesis. Extruded axoplasm, suspended in chemically defined media, catalyzed the synthesis of phospholipids from all of the precursors tested. /sup 32/P-Labeled inorganic phosphate and gamma-labeled ATP were actively incorporated into phosphatidylinositol phosphate, while (2-/sup 3/H)myo-inositol and L-(/sup 3/H(G))serine were actively incorporated into phosphatidylinositol and phosphatidylserine, respectively. Though less well utilized. (2-/sup 3/H)glycerol was incorporated into phosphatidic acid, phosphatidylinositol, and triglyceride, and methyl-3H)choline and (1-/sup 3/H)ethanolamine were incorporated into phosphatidylcholine and phosphatidylethanolamine, respectively. Isolated squid giant axons were incubated in artificial seawater containing the above precursors. The axoplasm was extruded following the incubations. Although most of the product lipids were recovered in the sheath (composed of cortical axoplasm, axolemma, and surrounding satellite cells), significant amounts (4-20%) were present in the extruded axoplasm. With tritiated choline and myo-inositol, the major labeled phospholipids found in both the extruded axoplasm and the sheath were phosphatidylcholine and phosphatidylinositol, respectively. With both glycerol and phosphate, phosphatidylethanolamine was a major labeled lipid in both axoplasm and sheath. These findings demonstrate that all classes of phospholipids are formed by endogenous synthetic enzymes in axoplasm. In addition, we feel that the different patterns of incorporation by intact axons and extruded axoplasm indicate that surrounding sheath cells contribute lipids to axoplasm. A comprehensive picture of axonal lipid metabolism should include axoplasmic synthesis and glial-axon transfer as pathways complementing the axonal transport of perikaryally formed lipids.

  16. Development of the Early Axon Scaffold in the Rostral Brain of the Small Spotted Cat Shark (Scyliorhinus canicula) Embryo

    OpenAIRE

    Ware, Michelle; Waring, Colin P.; Schubert, Frank R.

    2014-01-01

    International audience; The cat shark is increasingly used as a model for Chondrichthyes, an evolutionarily important sister group of the bony vertebrates that include teleosts and tetrapods. In the bony vertebrates, the first axon tracts form a highly conserved early axon scaffold. The corresponding structure has not been well characterised in cat shark and will prove a useful model for comparative studies. Using pan-neural markers, the early axon scaffold of the cat shark, Scyliorhinus cani...

  17. Axonal transport and incorporation of radioactivity after injection of N-[3H]acetyl-D-mannosamine into rat mesencephalon

    International Nuclear Information System (INIS)

    Loopuijt, L.D.

    1980-01-01

    A study has been performed to demonstrate the possibility of incorporation of sialic acid into nerve endings of the rubrospinal tract after antegrade axonal transport. Young adult rats received injections of N-[ 3 H]acetyl-D-mannosamine into the red nucleus and axonal transport of the tritiated compounds along the axons of afferent and efferent connections of the red nucleus was studied and the transported material was analysed. Light microscopic autoradiography and biochemical methods were used. (Auth./C.F.)

  18. Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury.

    Science.gov (United States)

    Liu, Shengwen; Sandner, Beatrice; Schackel, Thomas; Nicholson, LaShae; Chtarto, Abdelwahed; Tenenbaum, Liliane; Puttagunta, Radhika; Müller, Rainer; Weidner, Norbert; Blesch, Armin

    2017-09-15

    Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord. Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within

  19. Co-immobilization of semaphorin3A and nerve growth factor to guide and pattern axons.

    Science.gov (United States)

    McCormick, Aleesha M; Jarmusik, Natalie A; Leipzig, Nic D

    2015-12-01

    Immobilization of axon guidance cues offers a powerful tissue regenerative strategy to control the presentation and spatial location of these biomolecules. We use our previously developed immobilization strategy to specifically tether recombinant biotinylated nerve growth factor (bNGF) and biotinylated semaphorin3A (bSema3A) to chitosan films as an outgrowth and guidance platform. DRG neurite length and number for a range of single cues of immobilized bNGF or bSema3A were examined to determine a concentration response. Next single and dual cues of bNGF and bSema3A were immobilized and DRG guidance was assessed in response to a step concentration change from zero. Overall, immobilized groups caused axon extension, retraction and turning depending on the ratio of bNGF and bSema3A immobilized in the encountered region. This response indicated the exquisite sensitivity of DRG axons to both attractive and repulsive tethered cues. bSema3A concentrations of 0.10 and 0.49 ng/mm(2), when co-immobilized with bNGF (at 0.86 and 0.43 ng/mm(2) respectively), caused axons to turn away from the co-immobilized region. Immunocytochemical analysis showed that at these bSema3A concentrations, axons inside the co-immobilized region display microtubule degradation and breakdown of actin filaments. At the lowest bSema3A concentration (0.01 ng/mm(2)) co-immobilized with a higher bNGF concentration (2.16 ng/mm(2)), neurite lengths are shorter in the immobilized area, but bNGF dominates the guidance mechanism as neurites are directed toward the immobilized region. Future applications can pattern these cues in various geometries and gradients in order to better modulate axon guidance in terms of polarity, extension and branching. Nervous system formation and regeneration requires key molecules for guiding the growth cone and nervous system patterning. In vivo these molecules work in conjunction with one another to modulate axon guidance, and often they are tethered to limit spatial

  20. Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation.

    Science.gov (United States)

    Guillon, Emilie; Bretaud, Sandrine; Ruggiero, Florence

    2016-03-02

    The extracellular matrix (ECM) provides local positional information to guide motoneuron axons toward their muscle target. Collagen XV is a basement membrane component mainly expressed in skeletal muscle. We have identified two zebrafish paralogs of the human COL15A1 gene, col15a1a and col15a1b, which display distinct expression patterns. Here we show that col15a1b is expressed and deposited in the motor path ECM by slow muscle precursors also called adaxial cells. We further demonstrate that collagen XV-B deposition is both temporally and spatially regulated before motor axon extension from the spinal cord in such a way that it remains in this region after the adaxial cells have migrated toward the periphery of the myotome. Loss- and gain-of-function experiments in zebrafish embryos demonstrate that col15a1b expression and subsequent collagen XV-B deposition and organization in the motor path ECM depend on a previously undescribed two-step mechanism involving Hedgehog/Gli and unplugged/MuSK signaling pathways. In silico analysis predicts a putative Gli binding site in the col15a1b proximal promoter. Using col15a1b promoter-reporter constructs, we demonstrate that col15a1b participates in the slow muscle genetic program as a direct target of Hedgehog/Gli signaling. Loss and gain of col15a1b function provoke pathfinding errors in primary and secondary motoneuron axons both at and beyond the choice point where axon pathway selection takes place. These defects result in muscle atrophy and compromised swimming behavior, a phenotype partially rescued by injection of a smyhc1:col15a1b construct. These reveal an unexpected and novel role for collagen XV in motor axon pathfinding and neuromuscular development. In addition to the archetypal axon guidance cues, the extracellular matrix provides local information that guides motor axons from the spinal cord to their muscle targets. Many of the proteins involved are unknown. Using the zebrafish model, we identified an

  1. Persistence, spatial distribution and implications for progression detection of blind parts of the visual field in glaucoma: A clinical cohort study

    NARCIS (Netherlands)

    F.G. Junoy Montolio (Francisco); C. Wesselink (Christiaan); N.M. Jansonius (Nomdo)

    2012-01-01

    textabstractBackground: Visual field testing is an essential part of glaucoma care. It is hampered by variability related to the disease itself, response errors and fatigue. In glaucoma, blind parts of the visual field contribute to the diagnosis but - once established - not to progression

  2. Dendrites of cerebellar granule cells correctly recognize their target axons for synaptogenesis in vitro.

    Science.gov (United States)

    Ito, Shoko; Takeichi, Masatoshi

    2009-08-04

    Neural circuits are generated by precisely ordered synaptic connections among neurons, and this process is thought to rely on the ability of neurons to recognize specific partners. However, it is also known that neurons promiscuously form synapses with nonspecific partners, in particular when cultured in vitro, causing controversies about neural recognition mechanisms. Here we reexamined whether neurons can or cannot select particular partners in vitro. In the cerebellum, granule cell (GC) dendrites form synaptic connections specifically with mossy fibers, but not with climbing fibers. We cocultured GC neurons with pontine or inferior olivary axons, the major sources for mossy and climbing fibers, respectively, as well as with hippocampal axons as a control. The GC neurons formed synapses with pontine axons predominantly at the distal ends of their dendrites, reproducing the characteristic morphology of their synapses observed in vivo, whereas they failed to do so when combined with other axons. In the latter case, synaptic proteins could accumulate between axons and dendrites, but these synapses were randomly distributed throughout the contact sites, and also their synaptic vesicle recycling was anomalous. These observations suggest that GC dendrites can select their authentic partners for synaptogenesis even in vitro, forming the synapses with a GC-specific nature only with them.

  3. The transmembrane collagen COL-99 guides longitudinally extending axons in C. elegans.

    Science.gov (United States)

    Taylor, Jesse; Unsoeld, Thomas; Hutter, Harald

    2018-06-01

    We have identified the transmembrane collagen, COL-99, in a genetic screen for novel genes involved in axon guidance in the nematode C. elegans. COL-99 is similar to transmembrane collagens type XIII, XXIII and XXV in vertebrates. col-99 mutants exhibit guidance defects in axons extending along the major longitudinal axon tracts, most prominently the left ventral nerve cord (VNC). COL-99 is expressed in the hypodermis during the time of axon outgrowth. We provide evidence that a furin cleavage site in COL-99 is essential for function, suggesting that COL-99 is released from the cells producing it. Vertebrate homologs of COL-99 have been shown to be expressed in mammalian nervous systems and linked to various neurological disease but have not been associated with guidance of extending neurons. col-99 acts genetically with the discoidin domain receptors ddr-1 and ddr-2, which are expressed by neurons affected in col-99 mutants. Discoidin domain receptors are activated by collagens in vertebrates. DDR-1 and DDR-2 may function as receptors for COL-99. Our results establish a novel role for a transmembrane collagen in axonal guidance and asymmetry establishment of the VNC. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron.

    Science.gov (United States)

    Locatelli, Denise; d'Errico, Paolo; Capra, Silvia; Finardi, Adele; Colciaghi, Francesca; Setola, Veronica; Terao, Mineko; Garattini, Enrico; Battaglia, Giorgio

    2012-05-01

    The axonal survival of motor neuron (a-SMN) protein is a truncated isoform of SMN1, the spinal muscular atrophy (SMA) disease gene. a-SMN is selectively localized in axons and endowed with remarkable axonogenic properties. At present, the role of a-SMN in SMA is unknown. As a first step to verify a link between a-SMN and SMA, we investigated by means of over-expression experiments in neuroblastoma-spinal cord hybrid cell line (NSC34) whether SMA pathogenic mutations located in the N-terminal part of the protein affected a-SMN function. We demonstrated here that either SMN1 missense mutations or small intragenic re-arrangements located in the Tudor domain consistently altered the a-SMN capability of inducing axonal elongation in vitro. Mutated human a-SMN proteins determined in almost all NSC34 motor neurons the growth of short axons with prominent morphologic abnormalities. Our data indicate that the Tudor domain is critical in dictating a-SMN function possibly because it is an association domain for proteins involved in axon growth. They also indicate that Tudor domain mutations are functionally relevant not only for FL-SMN but also for a-SMN, raising the possibility that also a-SMN loss of function may contribute to the pathogenic steps leading to SMA. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  5. Assessing the direct effects of deep brain stimulation using embedded axon models

    Science.gov (United States)

    Sotiropoulos, Stamatios N.; Steinmetz, Peter N.

    2007-06-01

    To better understand the spatial extent of the direct effects of deep brain stimulation (DBS) on neurons, we implemented a geometrically realistic finite element electrical model incorporating anisotropic and inhomogenous conductivities. The model included the subthalamic nucleus (STN), substantia nigra (SN), zona incerta (ZI), fields of Forel H2 (FF), internal capsule (IC) and Medtronic 3387/3389 electrode. To quantify the effects of stimulation, we extended previous studies by using multi-compartment axon models with geometry and orientation consistent with anatomical features of the brain regions of interest. Simulation of axonal firing produced a map of relative changes in axonal activation. Voltage-controlled stimulation, with clinically typical parameters at the dorso-lateral STN, caused axon activation up to 4 mm from the target. This activation occurred within the FF, IC, SN and ZI with current intensities close to the average injected during DBS (3 mA). A sensitivity analysis of model parameters (fiber size, fiber orientation, degree of inhomogeneity, degree of anisotropy, electrode configuration) revealed that the FF and IC were consistently activated. Direct activation of axons outside the STN suggests that other brain regions may be involved in the beneficial effects of DBS when treating Parkinsonian symptoms.

  6. Formation of compact myelin is required for maturation of the axonal cytoskeleton

    Science.gov (United States)

    Brady, S. T.; Witt, A. S.; Kirkpatrick, L. L.; de Waegh, S. M.; Readhead, C.; Tu, P. H.; Lee, V. M.

    1999-01-01

    Although traditional roles ascribed to myelinating glial cells are structural and supportive, the importance of compact myelin for proper functioning of the nervous system can be inferred from mutations in myelin proteins and neuropathologies associated with loss of myelin. Myelinating Schwann cells are known to affect local properties of peripheral axons (de Waegh et al., 1992), but little is known about effects of oligodendrocytes on CNS axons. The shiverer mutant mouse has a deletion in the myelin basic protein gene that eliminates compact myelin in the CNS. In shiverer mice, both local axonal features like phosphorylation of cytoskeletal proteins and neuronal perikaryon functions like cytoskeletal gene expression are altered. This leads to changes in the organization and composition of the axonal cytoskeleton in shiverer unmyelinated axons relative to age-matched wild-type myelinated fibers, although connectivity and patterns of neuronal activity are comparable. Remarkably, transgenic shiverer mice with thin myelin sheaths display an intermediate phenotype indicating that CNS neurons are sensitive to myelin sheath thickness. These results indicate that formation of a normal compact myelin sheath is required for normal maturation of the neuronal cytoskeleton in large CNS neurons.

  7. Progressive Business

    DEFF Research Database (Denmark)

    Christiansen, Christian O.

    2016-01-01

    Guest Post to the Society for U.S. Intellectual History Blog. Brief introduction to the book Progressive Business: An Intellectual History of the Role of Business in American Society, Oxford U.P., 2015.......Guest Post to the Society for U.S. Intellectual History Blog. Brief introduction to the book Progressive Business: An Intellectual History of the Role of Business in American Society, Oxford U.P., 2015....

  8. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X; Villoslada, Pablo

    2013-01-01

    Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines

  9. Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

    2013-01-01

    Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of

  10. Neurofilament subunit (NFL) head domain phosphorylation regulates axonal transport of neurofilaments.

    LENUS (Irish Health Repository)

    Yates, Darran M

    2009-04-01

    Neurofilaments are the intermediate filaments of neurons and are synthesised in neuronal cell bodies and then transported through axons. Neurofilament light chain (NFL) is a principal component of neurofilaments, and phosphorylation of NFL head domain is believed to regulate the assembly of neurofilaments. However, the role that NFL phosphorylation has on transport of neurofilaments is poorly understood. To address this issue, we monitored axonal transport of phosphorylation mutants of NFL. We mutated four known phosphorylation sites in NFL head domain to either preclude phosphorylation, or mimic permanent phosphorylation. Mutation to preclude phosphorylation had no effect on transport but mutation of three sites to mimic permanent phosphorylation inhibited transport. Mutation of all four sites together to mimic permanent phosphorylation proved especially potent at inhibiting transport and also disrupted neurofilament assembly. Our results suggest that NFL head domain phosphorylation is a regulator of neurofilament axonal transport.

  11. Myosin-Va-dependent cell-to-cell transfer of RNA from Schwann cells to axons.

    Directory of Open Access Journals (Sweden)

    José R Sotelo

    Full Text Available To better understand the role of protein synthesis in axons, we have identified the source of a portion of axonal RNA. We show that proximal segments of transected sciatic nerves accumulate newly-synthesized RNA in axons. This RNA is synthesized in Schwann cells because the RNA was labeled in the complete absence of neuronal cell bodies both in vitro and in vivo. We also demonstrate that the transfer is prevented by disruption of actin and that it fails to occur in the absence of myosin-Va. Our results demonstrate cell-to-cell transfer of RNA and identify part of the mechanism required for transfer. The induction of cell-to-cell RNA transfer by injury suggests that interventions following injury or degeneration, particularly gene therapy, may be accomplished by applying them to nearby glial cells (or implanted stem cells at the site of injury to promote regeneration.

  12. Myosin-Va-dependent cell-to-cell transfer of RNA from Schwann cells to axons.

    Science.gov (United States)

    Sotelo, José R; Canclini, Lucía; Kun, Alejandra; Sotelo-Silveira, José R; Xu, Lei; Wallrabe, Horst; Calliari, Aldo; Rosso, Gonzalo; Cal, Karina; Mercer, John A

    2013-01-01

    To better understand the role of protein synthesis in axons, we have identified the source of a portion of axonal RNA. We show that proximal segments of transected sciatic nerves accumulate newly-synthesized RNA in axons. This RNA is synthesized in Schwann cells because the RNA was labeled in the complete absence of neuronal cell bodies both in vitro and in vivo. We also demonstrate that the transfer is prevented by disruption of actin and that it fails to occur in the absence of myosin-Va. Our results demonstrate cell-to-cell transfer of RNA and identify part of the mechanism required for transfer. The induction of cell-to-cell RNA transfer by injury suggests that interventions following injury or degeneration, particularly gene therapy, may be accomplished by applying them to nearby glial cells (or implanted stem cells) at the site of injury to promote regeneration.

  13. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Pitceathly, Robert D S

    2012-09-11

    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).

  14. Action of a diffusible target-derived chemoattractant on cortical axon branch induction and directed growth.

    Science.gov (United States)

    Sato, M; Lopez-Mascaraque, L; Heffner, C D; O'Leary, D D

    1994-10-01

    Cortical axons innervate their brainstem target, the basilar pons, by the initiation and extension of collateral branches interstitially along their length. To address whether a diffusible pons-derived chemoattractant controls these events, we used cocultures in collagen matrices and time-lapse microscopy. Pontine explants enhanced by 5-fold the de novo initiation of transient branches along cortical axons; most branches were directed toward pons. Of the branches extended toward pons, 2%-3% were stabilized; those extended away were not. Pontine explants also enhanced the stable bifurcation of growth cones and prompted directional changes by growth cone turning and collateral extension. These effects were distance dependent and mimicked by pons-conditioned medium. This evidence indicates that the pons activity promotes branch initiation interstitially along cortical axons, a novel property for a chemoattractant, and provides a directional cue for their growth. These findings suggest that the pons chemoattractant serves as a diffusible target-recognition molecule.

  15. Cross-talk between KLF4 and STAT3 regulates axon regeneration

    Science.gov (United States)

    Qin, Song; Zou, Yuhua; Zhang, Chun-Li

    2013-10-01

    Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment