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Sample records for axonal transport implications

  1. 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.

  2. 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

  3. Cargo distributions differentiate pathological axonal transport impairments.

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    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.

  4. 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.

  5. Synaptic Democracy and Vesicular Transport in Axons

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    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".

  6. Neurogenetics of slow axonal transport: from cells to animals.

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    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.

  7. 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

  8. 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

  9. Neurotrophin Signaling via Long-Distance Axonal Transport

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    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.

  10. 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

  11. 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.

  12. Subacute ethanol consumption reverses p-xylene-induced decreases in axonal transport

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    Padilla, S.; Lyerly, D.L.; Pope, C.N.

    1992-01-01

    Organic solvants, as a class, have been implicated as neurotoxic agents in humans and laboratory animals. The study was designed to assess the interaction between subacute ingestion of moderate levels of ethanol and the p-xylene-induced decreases in protein and glycoprotein synthesis and axonal transport in the rat optic system. The results indicated that animals maintained on 10% ethanol as a drinking liquid show less p-xylene-induced neurotoxicity than animals receiving no ethanol supplement.

  13. Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma.

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    Breen, Kevin T; Anderson, Sarah R; Steele, Michael R; Calkins, David J; Bosco, Alejandra; Vetter, Monica L

    2016-01-01

    Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory

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

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    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.

  15. Internalization and Axonal Transport of the HIV Glycoprotein gp120

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    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

  16. 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)

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

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    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.

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

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    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

  19. 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

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

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    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

  1. 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

  2. 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.

  3. 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.)

  4. 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...

  5. 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

  6. 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

  7. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon.

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    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.

  8. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

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    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

  9. 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...

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  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. Effects of p-xylene inhalation on axonal transport in the rat retinal ganglion cells

    Energy Technology Data Exchange (ETDEWEB)

    Padilla, S.S.; Lyerly, D.P. (Environmental Protection Agency, Research Triangle Park, NC (USA))

    1989-12-01

    Although the solvent xylene is suspected of producing nervous system dysfunction in animals and humans, little is known regarding the neurochemical consequences of xylene inhalation. The intent of this study was to determine the effect of intermittent, acute, and subchronic p-xylene exposure on the axonal transport of proteins and glycoproteins within the rat retinofugal tract. A number of different exposure regimens were tested ranging from 50 ppm for a single 6-hr exposure to 1600 ppm 6 hr/day, 5 days/week, for a total of 8 exposure days. Immediately following removal from the inhalation chambers rats were injected intraocularly with (35S)methionine and (3H)fucose (to label retinal proteins and glycoproteins, respectively) and the axonal transport of labeled macromolecules to axons (optic nerve and optic tract) and nerve endings (lateral geniculate body and superior colliculus) was examined 20 hr after precursor injection. Only relatively severe exposure regimens (i.e., 800 or 1600 ppm 6 hr/day, 5 days/week, for 1.5 weeks) produced significant reductions in axonal transport; there was a moderate reduction in the axonal transport of 35S-labeled proteins in the 800-ppm-treated group which was more widespread in the 1600 ppm-treated group. Transport of 3H-labeled glycoproteins was less affected. Assessment of retinal metabolism immediately after isotope injection indicated that the rate of precursor uptake was not reduced in either treatment group. Furthermore, rapid transport was still substantially reduced in animals exposed to 1600 ppm p-xylene and allowed a 13-day withdrawal period. These data indicate that p-xylene inhalation decreases rapid axonal transport supplied to the projections of the rat retinal ganglion cells immediately after cessation of inhalation exposure and that this decreased transport is still apparent 13 days after the last exposure.

  19. Effects of p-xylene inhalation on axonal transport in the rat retinal ganglion cells

    International Nuclear Information System (INIS)

    Padilla, S.S.; Lyerly, D.P.

    1989-01-01

    Although the solvent xylene is suspected of producing nervous system dysfunction in animals and humans, little is known regarding the neurochemical consequences of xylene inhalation. The intent of this study was to determine the effect of intermittent, acute, and subchronic p-xylene exposure on the axonal transport of proteins and glycoproteins within the rat retinofugal tract. A number of different exposure regimens were tested ranging from 50 ppm for a single 6-hr exposure to 1600 ppm 6 hr/day, 5 days/week, for a total of 8 exposure days. Immediately following removal from the inhalation chambers rats were injected intraocularly with [35S]methionine and [3H]fucose (to label retinal proteins and glycoproteins, respectively) and the axonal transport of labeled macromolecules to axons (optic nerve and optic tract) and nerve endings (lateral geniculate body and superior colliculus) was examined 20 hr after precursor injection. Only relatively severe exposure regimens (i.e., 800 or 1600 ppm 6 hr/day, 5 days/week, for 1.5 weeks) produced significant reductions in axonal transport; there was a moderate reduction in the axonal transport of 35S-labeled proteins in the 800-ppm-treated group which was more widespread in the 1600 ppm-treated group. Transport of 3H-labeled glycoproteins was less affected. Assessment of retinal metabolism immediately after isotope injection indicated that the rate of precursor uptake was not reduced in either treatment group. Furthermore, rapid transport was still substantially reduced in animals exposed to 1600 ppm p-xylene and allowed a 13-day withdrawal period. These data indicate that p-xylene inhalation decreases rapid axonal transport supplied to the projections of the rat retinal ganglion cells immediately after cessation of inhalation exposure and that this decreased transport is still apparent 13 days after the last exposure

  20. Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy

    Directory of Open Access Journals (Sweden)

    De Taboada Luis

    2009-06-01

    Full Text Available Abstract Background It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD. Mitochondria supply the adenosine triphosphate (ATP needed to support axonal transport and contribute to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer controls (CNT. The absorption of low level, near-infrared laser light by components of the mitochondrial electron transport chain (mtETC enhances mitochondrial metabolism, stimulates oxidative phosphorylation and improves redox capacity. PD and CNT cybrid neuronal cells were exposed to near-infrared laser light to determine if the velocity of mitochondrial movement can be restored by low level light therapy (LLLT. Axonal transport of labeled mitochondria was documented by time lapse microscopy in dopaminergic PD and CNT cybrid neuronal cells before and after illumination with an 810 nm diode laser (50 mW/cm2 for 40 seconds. Oxygen utilization and assembly of mtETC complexes were also determined. Results The velocity of mitochondrial movement in PD cybrid neuronal cells (0.175 +/- 0.005 SEM was significantly reduced (p Conclusion The results from this study support our proposal that axonal transport is reduced in sporadic PD and that a single, brief treatment with near-infrared light can restore axonal transport to control levels. These results are the first demonstration that LLLT can increase axonal transport in model human dopaminergic neuronal cells and they suggest that LLLT could be developed as a novel treatment to improve neuronal function in patients with PD.

  1. 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

  2. Effect of MSH/ACTH peptides on fast axonal transport in intact and regenerating sciatic nerves

    International Nuclear Information System (INIS)

    Crescitelli, L.A.

    1985-01-01

    Fast axonal transport was examined in intact rats treated with ACTH 4-10 or ACTH 4-9 (ORG 2766), hypophysectomized rats, adrenalectomized rats, and in ACTH 4-10 treated rats with crushed regenerating sciatic nerves by injecting 3 H-leucine into the ventral horn region of the spinal cord. The distance traveled by the transported activity along the sciatic nerve and the rate of fast axonal transport were not significantly altered as a result of treatment with ACTH 4-10, ACTH 4-9 (ORG 2766), hypophysectomy, or adrenalectomy. Treatment with ACTH 4-9 (ORG 2766) at concentrations of 1 μg/Kg /day and 10 μg/Kg/day caused significant reductions (62% and 64% respectively) in the crest height of the fast axonal transport curve as compared to 0.9% saline treated control animals. No significant differences were found in comparing the distance, rate, slope, or crest height of ACTH 4-10 treated animals with crushed regenerating (7 or 14d) sciatic nerves to control animals. In the group of animals in days, the amount of radiolabeled activity was significantly increased in the ACTH 4-10 treated animals as compared to control animals. The results indicate that during regeneration the peptide acts to prolong the initially high levels of synthetic activity which occur in regenerating axons

  3. 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

  4. 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.

  5. Glycoproteins of axonal transport: affinity chromatography on fucose-specific lectins

    Energy Technology Data Exchange (ETDEWEB)

    Gustavsson, S.; Ohlson, C.; Karlsson, J.O.

    1982-03-01

    Rapidly transported fucose-labeled glycoproteins from axons of rabbit retinal ganglion cells were solubilized with nonionic detergents. The solubilized components were subjected to affinity chromatography on three different fucose-specific lectins. A recently characterized fucose-specific lectin from Aleuria aurantia bound reversibly approximately 60% of the applied protein-bound radioactivity. The lectins from Lotus tetragonolobus and Ulex europaeus bound are very small proportions of the labeled rapidly transported glycoproteins.

  6. Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases.

    Science.gov (United States)

    Brady, Scott T; Morfini, Gerardo A

    2017-09-01

    Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.

  8. 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

  9. Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport

    Directory of Open Access Journals (Sweden)

    Martin Steuble

    2012-06-01

    Endocytosis of amyloid-β precursor protein (APP is thought to represent the major source of substrate for the production of the amyloidogenic Aβ peptide by the β-secretase BACE1. The irreversible nature of proteolytic cleavage implies the existence of an efficient replenishment route for APP from its sites of synthesis to the cell surface. We recently found that APP exits the trans-Golgi network in intimate association with calsyntenin-1, a transmembrane cargo-docking protein for Kinesin-1-mediated vesicular transport. Here we characterized the function of calsyntenin-1 in neuronal APP transport using selective immunoisolation of intracellular trafficking organelles, immunocytochemistry, live-imaging, and RNAi. We found that APP is co-transported with calsyntenin-1 along axons to early endosomes in the central region of growth cones in carriers that exclude the α-secretase ADAM10. Intriguingly, calsyntenin-1/APP organelles contained BACE1, suggesting premature cleavage of APP along its anterograde path. However, we found that APP contained in calsyntenin-1/APP organelles was stable. We further analyzed vesicular trafficking of APP in cultured hippocampal neurons, in which calsyntenin-1 was reduced by RNAi. We found a markedly increased co-localization of APP and ADAM10 in axons and growth cones, along with increased proteolytic processing of APP and Aβ secretion in these neurons. This suggested that the reduced capacity for calsyntenin-1-dependent APP transport resulted in mis-sorting of APP into additional axonal carriers and, therefore, the premature encounter of unprotected APP with its ectodomain proteases. In combination, our results characterize calsyntenin-1/APP organelles as carriers for sheltered anterograde axonal transport of APP.

  10. Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport.

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    Michelle H Le

    Full Text Available Stress exposure or increased levels of corticotropin-releasing factor (CRF induce hippocampal tau phosphorylation (tau-P in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1. Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD, the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr and chronic (2hr CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF, this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD.

  11. 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.

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

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    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.

  13. 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

  14. Cortical compression rapidly trimmed transcallosal projections and altered axonal anterograde transport machinery.

    Science.gov (United States)

    Chen, Li-Jin; Wang, Yueh-Jan; Tseng, Guo-Fang

    2017-10-24

    Trauma and tumor compressing the brain distort underlying cortical neurons. Compressed cortical neurons remodel their dendrites instantly. The effects on axons however remain unclear. Using a rat epidural bead implantation model, we studied the effects of unilateral somatosensory cortical compression on its transcallosal projection and the reversibility of the changes following decompression. Compression reduced the density, branching profuseness and boutons of the projection axons in the contralateral homotopic cortex 1week and 1month post-compression. Projection fiber density was higher 1-month than 1-week post-compression, suggesting adaptive temporal changes. Compression reduced contralateral cortical synaptophysin, vesicular glutamate transporter 1 (VGLUT1) and postsynaptic density protein-95 (PSD95) expressions in a week and the first two marker proteins further by 1month. βIII-tubulin and kinesin light chain (KLC) expressions in the corpus callosum (CC) where transcallosal axons traveled were also decreased. Kinesin heavy chain (KHC) level in CC was temporarily increased 1week after compression. Decompression increased transcallosal axon density and branching profuseness to higher than sham while bouton density returned to sham levels. This was accompanied by restoration of synaptophysin, VGLUT1 and PSD95 expressions in the contralateral cortex of the 1-week, but not the 1-month, compression rats. Decompression restored βIII-tubulin, but not KLC and KHC expressions in CC. However, KLC and KHC expressions in the cell bodies of the layer II/III pyramidal neurons partially recovered. Our results show cerebral compression compromised cortical axonal outputs and reduced transcallosal projection. Some of these changes did not recover in long-term decompression. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Fluorescence Imaging of Fast Retrograde Axonal Transport in Living Animals

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    Dawid Schellingerhout

    2009-11-01

    Full Text Available Our purpose was to enable an in vivo imaging technology that can assess the anatomy and function of peripheral nerve tissue (neurography. To do this, we designed and tested a fluorescently labeled molecular probe based on the nontoxic C fragment of tetanus toxin (TTc. TTc was purified, labeled, and subjected to immunoassays and cell uptake assays. The compound was then injected into C57BL/6 mice (N = 60 for in vivo imaging and histologic studies. Image analysis and immunohistochemistry were performed. We found that TTc could be labeled with fluorescent moieties without loss of immunoreactivity or biologic potency in cell uptake assays. In vivo fluorescent imaging experiments demonstrated uptake and retrograde transport of the compound along the course of the sciatic nerve and in the spinal cord. Ex vivo imaging and immunohistochemical studies confirmed the presence of TTc in the sciatic nerve and spinal cord, whereas control animals injected with human serum albumin did not exhibit these features. We have demonstrated neurography with a fluorescently labeled molecular imaging contrast agent based on the TTc.

  16. Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

    Science.gov (United States)

    Swanson, Eric; Breckenridge, Leigham; McMahon, Lloyd; Som, Sreemoyee; McConnell, Ian; Bloom, George S.

    2017-01-01

    Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. PMID:28482642

  17. In vivo neuronal synthesis and axonal transport of Kunitz protease inhibitor (KPI)-containing forms of the amyloid precursor protein.

    Science.gov (United States)

    Moya, K L; Confaloni, A M; Allinquant, B

    1994-11-01

    We have shown previously that the amyloid precursor protein (APP) is synthesized in retinal ganglion cells and is rapidly transported down the axons, and that different molecular weight forms of the precursor have different developmental time courses. Some APP isoforms contain a Kunitz protease inhibitor (KPI) domain, and APP that lacks the KPI domain is considered the predominant isoform in neurons. We now show that, among the various rapidly transported APPs, a 140-kDa isoform contains the KPI domain. This APP isoform is highly expressed in rapidly growing retinal axons, and it is also prominent in adult axon endings. This 140-kDa KPI-containing APP is highly sulfated compared with other axonally transported isoforms. These results show that APP with the KPI domain is a prominent isoform synthesized in neurons in vivo, and they suggest that the regulation of protease activity may be an important factor during the establishment of neuronal connections.

  18. Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons.

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    Laura Restani

    2012-12-01

    Full Text Available The striking differences between the clinical symptoms of tetanus and botulism have been ascribed to the different fate of the parental neurotoxins once internalised in motor neurons. Tetanus toxin (TeNT is known to undergo transcytosis into inhibitory interneurons and block the release of inhibitory neurotransmitters in the spinal cord, causing a spastic paralysis. In contrast, botulinum neurotoxins (BoNTs block acetylcholine release at the neuromuscular junction, therefore inducing a flaccid paralysis. Whilst overt experimental evidence supports the sorting of TeNT to the axonal retrograde transport pathway, recent findings challenge the established view that BoNT trafficking is restricted to the neuromuscular junction by highlighting central effects caused by these neurotoxins. These results suggest a more complex scenario whereby BoNTs also engage long-range trafficking mechanisms. However, the intracellular pathways underlying this process remain unclear. We sought to fill this gap by using primary motor neurons either in mass culture or differentiated in microfluidic devices to directly monitor the endocytosis and axonal transport of full length BoNT/A and BoNT/E and their recombinant binding fragments. We show that BoNT/A and BoNT/E are internalised by spinal cord motor neurons and undergo fast axonal retrograde transport. BoNT/A and BoNT/E are internalised in non-acidic axonal carriers that partially overlap with those containing TeNT, following a process that is largely independent of stimulated synaptic vesicle endo-exocytosis. Following intramuscular injection in vivo, BoNT/A and TeNT displayed central effects with a similar time course. Central actions paralleled the peripheral spastic paralysis for TeNT, but lagged behind the onset of flaccid paralysis for BoNT/A. These results suggest that the fast axonal retrograde transport compartment is composed of multifunctional trafficking organelles orchestrating the simultaneous transfer

  19. Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1.

    Science.gov (United States)

    Brahic, Michel; Bousset, Luc; Bieri, Gregor; Melki, Ronald; Gitler, Aaron D

    2016-04-01

    Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention.

  20. Fast axonal transport of 3H-leucin-labelled proteins in the unhurt and isolated optical nerve of rats

    International Nuclear Information System (INIS)

    Wagner, H.E.

    1981-01-01

    The distribution of radioactivity of amino acid molecules incorporated in protein after injection of 3 H-Leucin into the right bulb was investigated and determined along optical nerve after 1, 2, and 4 h. A slightly increased radioactivity at the point of entrance of the optical nerves into the optical duct was found. A slightly reduced axon diameter was discussed as a possible cause. The radioactivity brought into the optical nerve via the vascular system was determined by measuring the contralateral optical nerve. In relation to the axonally transported activity, it was low. The speed of the fast axonal transport is 168 mm/d. If the processes ruling the amino acids in the perikaryon are taken into consideration, the transport speed is 240 mm/d. The application of the protein synthesis prohibitor, Cycloheximide, 5 minutes after the injection of Leucinin completely prevented the appearance of axonally transported labelled proteins. When cycloheximide was administered 2 h after Leucin, a significantly loner radioactivity than in the nerve could be determined after another 2 h; i.e. the incorporation of Leucin was not completed yet after 2 h. The profile of active compounds was the same as in the control group. In other experiments, the axonal transport of labelled proteins in isolated optical nerve fibres was tested. If the separation was carried out 2 h after the injection of Leucin an extreme reduction in activity could be determined after 1 or 2 h. The continued distribution of activity after cycloheximide treatment and removal of perikarya in comparison with the control indicate the continuation of the transport, also after separation of the axon from the perikaryon. This means that, during the time of the experiment, the mechanism of the fast axonal transport functions independently of the perikaryon. (orig./MG) [de

  1. A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans.

    Science.gov (United States)

    Knowlton, Wendy M; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D; Jin, Yishi

    2017-01-01

    The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo , we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1 . Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7 , and isp-1 , and the putative oxidoreductase rad-8 . In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1 . Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the

  2. Riluzole protects against glutamate-induced slowing of neurofilament axonal transport.

    LENUS (Irish Health Repository)

    Stevenson, Alison

    2009-04-24

    Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport.

  3. In vivo axonal transport deficits in a mouse model of fronto-temporal dementia.

    Science.gov (United States)

    Majid, Tabassum; Ali, Yousuf O; Venkitaramani, Deepa V; Jang, Ming-Kuei; Lu, Hui-Chen; Pautler, Robia G

    2014-01-01

    Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4-5 months of age. rTg4510 transgenic mice were used in these studies. Mice were given 2 μL of MnCl2 in each nostril 1 h prior to Magnetic Resonance Imaging (MRI). Following MnCl2 nasal lavage, mice were imaged using Manganese enhanced Magnetic Resonance Imaging (MEMRI) Protocol with TE = 8.5 ms, TR = 504 ms, FOV = 3.0 cm, matrix size = 128 × 128 × 128, number of cycles = 15 with each cycle taking approximately 2 min, 9 s, and 24 ms using Paravision software (BrukerBioSpin, Billerica, MA). During imaging, body temperature was maintained at 37.0 °C using an animal heating system (SA Instruments, Stony Brook, NY). Resulting images were analyzed using Paravision software. Regions of interest (ROI) within the olfactory neuronal layer (ONL) and the water phantom consisting of one pixel (ONL) and 9 pixels (water) were selected and copied across each of the 15 cycles. Signal intensities (SI) of ONL and water phantom ROIs were measured. SI values obtained for ONL were then normalized the water phantom SI values. The correlation between normalized signal intensity in the ONL and time were assessed using Prism (GraphPad Software, San Diego, CA). Using the MEMRI technique on 1.5, 3, 5, and 10-month old rTg4510 mice and littermate controls, we found significant axonal transport deficits present in

  4. Retrograde axonal transport of 125I-nerve growth factor in rat ileal mesenteric nerves. Effect of streptozocin diabetes

    International Nuclear Information System (INIS)

    Schmidt, R.E.; Plurad, S.B.; Saffitz, J.E.; Grabau, G.G.; Yip, H.K.

    1985-01-01

    The retrograde axonal transport of intravenously (i.v.) administered 125 I-nerve growth factor ( 125 I-NGF) was examined in mesenteric nerves innervating the small bowel of rats with streptozocin (STZ) diabetes using methods described in detail in the companion article. The accumulation of 125 I-NGF distal to a ligature on the ileal mesenteric nerves of diabetic animals was 30-40% less than in control animals. The inhibition of accumulation of 125 I-NGF in diabetic animals was greater at a ligature tied 2 h after i.v. administration than at a ligature tied after 14 h, which suggests that the diabetic animals may have a lag in initiation of NGF transport in the terminal axon or retardation of transport at some site along the axon. The 125 I-NGF transport defect was observed as early as 3 days after the induction of diabetes, a time before the development of structural axonal lesions, and did not worsen at later times when dystrophic axonopathy is present. Both the ileal mesenteric nerves, which eventually develop dystrophic axonopathy in experimental diabetes, and the jejunal mesenteric nerves, which never develop comparable structural alterations, showed similar 125 I-NGF transport deficits, suggesting that the existence of the transport abnormality does not predict the eventual development of dystrophic axonal lesions. Autoradiographic localization of 125 I-NGF in the ileal mesenteric nerves of animals that had been diabetic for 11-13 mo demonstrated decreased amounts of 125 I-NGF in transit in unligated paravascular nerve fascicles. There was, however, no evidence for focal retardation of transported 125 I-NGF at the sites of dystrophic axonal lesions

  5. The Myriad Roles of Miro in the Nervous System: Axonal Transport of Mitochondria and Beyond

    Directory of Open Access Journals (Sweden)

    Bingwei eLu

    2014-10-01

    Full Text Available Mitochondrial rho GTPase (Miro is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca2+-binding domains called EF hands. Pioneering genetic studies in Drosophila first revealed a key function of Miro in regulating the axonal transport of mitochondria, during which Miro forms a multi-protein transport complex with Milton and Kinesin heavy chain (KHC to link trafficking mitochondria with the microtubule cytoskeleton. Recent studies showed that through binding to the EF hands of Miro and causing conformational changes of Miro and alteration of protein-protein interactions within the transport complex, Ca2+ can alter the engagement of mitochondria with the microtubule (MT/kinesin network, offering one mechanism to match mitochondrial distribution with neuronal activity. Despite the importance of the Miro/Milton/Kinesin complex in regulating mitochondrial transport in metazoans, not all components of the transport complex are conserved in lower organisms, and transport-independent functions of Miro are emerging. Here we review the diverse functions of the evolutionarily conserved Miro proteins that are relevant to the development, maintenance, and functioning of the nervous system and discuss the potential contribution of Miro dysfunction to the pathogenesis of diseases of the nervous system.

  6. 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.

  7. Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain.

    Directory of Open Access Journals (Sweden)

    Hiroaki Mochizuki

    2011-05-01

    Full Text Available Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II, an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM and No distributive disjunction (Nod, remains unaltered. Genetic analyses of kinesin light chain (Klc and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of

  8. A study of signalling events regulating the retrograde axonal transport of neurotrophic factors in vivo

    International Nuclear Information System (INIS)

    Reynolds, A.J.; Bartlett, S.E.; Hendry, I.A.

    1998-01-01

    Full text: Soluble neurotrophic factors such as NGF promote the survival of sympathetic and sensory neuronal populations by binding to receptors present on the nerve terminal and transported to the cell body. This study aimed to establish the molecular mechanisms regulating this process by identifying potential signalling molecules that may be involved using specific pharmacological inhibitors. Adult Balb/c or CBA mice were anaesthetized using 88 μg/g ketamine and 16 μg/g rompun (i.p.) and 1 μl containing 4 μCi of 125 I-labelled NT-3 (37 ng) or pNGF (22 ng) was co-injected with inhibitors into the anterior eye chamber. After 20 hours the accumulated radioactivity was measured in the superior cervical and trigeminal ganglia. The PI3-kinase inhibitor Wortmannin inhibited 125 I-NT-3 transport in the range of 0.1-1 nmol/eye as previously shown with 125 I-βOeGF. The cPLA 2 inhibitor AACOCF3 did not significantly affect the retrograde transport of either 125 I-NT-3 or 125 I-βNGF suggesting that Wortmannin is not influencing the transport of these neurotrophins by inhibiting cPLA 2 activity. The dynein ATPase inhibitor erythro-9-[3-(2-hydroxynonyl)]adenine (1 mM) also selectively reduced 125 I-βNGF transport. Non-specific tyrosine kinase inhibitors did not have a significant effect. These results further suggest that PI3-kinase might regulate the intracellular transport of neurotrophic factors, and that retrograde axonal transport of these proteins relies on the dynein motor protein in vivo. Copyright (1998) Australian Neuroscience Society

  9. Axonal collateral-collateral transport of tract tracers in brain neurons: false anterograde labelling and useful tool.

    Science.gov (United States)

    Chen, S; Aston-Jones, G

    1998-02-01

    It is well established that some neuroanatomical tracers may be taken up by local axonal terminals and transported to distant axonal collaterals (e.g., transganglionic transport in dorsal root ganglion cells). However, such collateral-collateral transport of tracers has not been systematically examined in the central nervous system. We addressed this issue with four neuronal tracers--biocytin, biotinylated dextran amine, cholera toxin B subunit, and Phaseolus vulgaris-leucoagglutinin--in the cerebellar cortex. Labelling of distant axonal collaterals in the cerebellar cortex (indication of collateral-collateral transport) was seen after focal iontophoretic microinjections of each of the four tracers. However, collateral-collateral transport properties differed among these tracers. Injection of biocytin or Phaseolus vulgaris-leucoagglutinin in the cerebellar cortex yielded distant collateral labelling only in parallel fibres. In contrast, injection of biotinylated dextran amine or cholera toxin B subunit produced distant collateral labelling of climbing fibres and mossy fibres, as well as parallel fibres. The present study is the first systematic examination of collateral-collateral transport following injection of anterograde tracers in brain. Such collateral-collateral transport may produce false-positive conclusions regarding neural connections when using these tracers for anterograde transport. However, this property may also be used as a tool to determine areas that are innervated by common distant afferents. In addition, these results may indicate a novel mode of chemical communication in the nervous system.

  10. 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.

  11. 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.

  12. Increased slow transport in axons of regenerating newt limbs after a nerve conditioning lesion made prior to amputation

    International Nuclear Information System (INIS)

    Maier, C.E.

    1989-01-01

    The first part of this study shows that axonal density is constant in the limb stump of the next proximal to the area of traumatic nerve degeneration caused by limb amputation. The results of the second part of this work reveal that a nerve conditioning lesion made two weeks prior to amputation is associated with accelerated limb regeneration and that this accelerated limb regeneration is accompanied by an earlier arrival of axons. This is the first demonstration of naturally occurring limb regeneration being enhanced. In this study SCb cytoskeletal proteins were identified and measured using SDS-PAGE and liquid scintillation counting. Proteins were measured at 7, 14, 21, and 28 days after 35 S-methionine injection and the normal rate of SCb transport determined to be 0.19 mm/day. A single axotomy does not enhance the rate of SCb transport but does increase the amount of labeled SCb proteins that are transported. When a conditioning lesion is employed prior to limb amputation and SCb proteins are measured at 7, 14, and 21 days after injection, there is a twofold acceleration in the rate of SCb transport and an increase in the amount of SCb proteins transported in conditioned axons

  13. 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)

  14. Impaired axonal Na+ current by hindlimb unloading: implication for disuse neuromuscular atrophy

    Directory of Open Access Journals (Sweden)

    Chimeglkham eBanzrai

    2016-02-01

    Full Text Available This study aimed to characterize the excitability changes in peripheral motor axons caused by hindlimb unloading, which is a model of disuse neuromuscular atrophy. Hindlimb unloading was performed in normal 6-week-old male mice by fixing the proximal tail by a clip connected to the top of the animal’s cage for 3 weeks. Axonal excitability studies were performed by stimulating the sciatic nerve at the ankle and recording the compound muscle action potential from the foot. The amplitudes of the motor responses of the unloading group were 51% of the control amplitudes (2.2 ± 1.3 mV [HLU] vs. 4.3 ± 1.2 mV [Control], P = 0.03. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC and late subexcitability (recovery cycle than the controls (0.075 ± 0.01 [HLU] vs. 0.12 ± 0.01 [Control], P < 0.01; 5.4 ± 1.0 [HLU] vs. 10.0 ± 1.3 % [Control], P = 0.01, respectively. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent Na+ currents along with parameters related to current leakage. Quantification of RNA of a SCA1A gene coding a voltage-gated Na+ channel tended to be decreased in the sciatic nerve in HLU. The present study suggested that axonal ion currents are altered in vivo by hindlimb unloading. It is still undetermined whether the dysfunctional axonal ion currents have any pathogenicity on neuromuscular atrophy or are the results of neural plasticity by atrophy.

  15. Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons

    Directory of Open Access Journals (Sweden)

    Philip R Lee

    2009-06-01

    Full Text Available Myelination is a highly dynamic process that continues well into adulthood in humans. Several recent gene expression studies have found abnormal expression of genes involved in myelination in the prefrontal cortex of brains from patients with schizophrenia and other psychiatric illnesses. Defects in myelination could contribute to the pathophysiology of psychiatric illness by impairing information processing as a consequence of altered impulse conduction velocity and synchrony between cortical regions carrying out higher level cognitive functions. Myelination can be altered by impulse activity in axons and by environmental experience. Psychiatric illness is treated by psychotherapy, behavioral modification, and drugs affecting neurotransmission, raising the possibility that myelinating glia may not only contribute to such disorders, but that activity-dependent effects on myelinating glia could provide one of the cellular mechanisms contributing to the therapeutic effects of these treatments. This review examines evidence showing that genes and gene networks important for myelination can be regulated by functional activity in axons.

  16. From the "little brain" gastrointestinal infection to the "big brain" neuroinflammation: a proposed fast axonal transport pathway involved in multiple sclerosis.

    Science.gov (United States)

    Deretzi, Georgia; Kountouras, Jannis; Grigoriadis, Nikolaos; Zavos, Christos; Chatzigeorgiou, Stavros; Koutlas, Evangelos; Tsiptsios, Iakovos

    2009-11-01

    The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.

  17. Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

    Science.gov (United States)

    Erickson, Susan L.; Gandhi, Anjalika R.; Asafu-Adjei, Josephine K.; Sampson, Allan R.; Miner, LeeAnn; Blakely, Randy D.; Sesack, Susan R.

    2011-01-01

    Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance. PMID:21208501

  18. 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

  19. A cAMP/PKA/Kinesin-1 Axis Promotes the Axonal Transport of Mitochondria in Aging Drosophila Neurons.

    Science.gov (United States)

    Vagnoni, Alessio; Bullock, Simon L

    2018-04-23

    Mitochondria play fundamental roles within cells, including energy provision, calcium homeostasis, and the regulation of apoptosis. The transport of mitochondria by microtubule-based motors is critical for neuronal structure and function. This process allows local requirements for mitochondrial functions to be met and also facilitates recycling of these organelles [1, 2]. An age-related reduction in mitochondrial transport has been observed in neurons of mammalian and non-mammalian organisms [3-6], and has been proposed to contribute to the broader decline in neuronal function that occurs during aging [3, 5-7]. However, the factors that influence mitochondrial transport in aging neurons are poorly understood. Here we provide evidence using the tractable Drosophila wing nerve system that the cyclic AMP/protein kinase A (cAMP/PKA) pathway promotes the axonal transport of mitochondria in adult neurons. The level of the catalytic subunit of PKA decreases during aging, and acute activation of the cAMP/PKA pathway in aged flies strongly stimulates mitochondrial motility. Thus, the age-related impairment of transport is reversible. The expression of many genes is increased by PKA activation in aged flies. However, our results indicate that elevated mitochondrial transport is due in part to upregulation of the heavy chain of the kinesin-1 motor, the level of which declines during aging. Our study identifies evolutionarily conserved factors that can strongly influence mitochondrial motility in aging neurons. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  20. In vivo high-affinity uptake and axonal transport of D-(2,3-/sup 3/H)aspartate in excitatory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Storm-Mathisen, J.; Wold, J.E. (Oslo Univ. (Norway))

    1981-12-28

    D-(2,3-/sup 3/H)aspartate ((/sup 3/H)D-Asp) at ..mu..M concentrations in Krebs' solution was infused intracerebrally in rats, mice and hamsters. Neuropil sites in the hippocampal formation, septum and neostriatum, known to receive excitatory nerve inputs with glutamate and aspartate as putative transmitters, showed strong autoradiographic labeling after intraventricular infusions. There was evidence for retrograde axonal transport to pyramidal cell bodies in hippocampus CA3 and neocortex. Infusions into the hilus fasciae dentatae led to anterograde axonal transport of (/sup 3/H)D-Asp in the mossy fibers.

  1. 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.

  2. Studies on Axonal Transport in an Animal Model for Gulf War Syndrome

    National Research Council Canada - National Science Library

    Baas, Peter W

    2008-01-01

    .... The hypothesis of the project was that these toxins might adversely affect the transport of subcellular elements called microtubules within the nerves, and that potential therapies could be developed accordingly...

  3. Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3β signaling.

    Directory of Open Access Journals (Sweden)

    Jillian L Shaw

    Full Text Available Post-mortem brains from Down syndrome (DS and Alzheimer's disease (AD patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1, but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP, which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.

  4. Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3β signaling.

    Science.gov (United States)

    Shaw, Jillian L; Chang, Karen T

    2013-01-01

    Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.

  5. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles

    NARCIS (Netherlands)

    de Jong, Eiko K.; Vinet, Jonathan; Stanulovic, Vesna S.; Meijer, Michel; Wesseling, Evelyn; Sjollema, Klaas; Boddeke, Hendrikus W. G. M.; Biber, Knut

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  6. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles.

    NARCIS (Netherlands)

    Jong, E.K. de; Vinet, J.; Stanulovic, V.S.; Meijer, M.; Wesseling, E.; Sjollema, K.; Boddeke, H.W.; Biber, K.

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  7. 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

  8. Anterograde axonal transport and intercellular transfer of WGA-HRP in trigeminal-innervated sensory receptors of rat incisive papilla.

    Science.gov (United States)

    Chan, K Y; Byers, M R

    1985-04-08

    The ultrastructure and identification of WGA-HRP-labeled sensory receptors in the rat incisive papilla (the most anterior part of hard palate) were studied using semiserial thin sections. Various sensory receptors were organized according to three locations: dome region (ventral), chemosensory corpuscle region (medial to orifice of incisive canal), and lateral labium (apposing the incisive canal). In the dome region, the sensory receptors were localized in three sensory zones that were associated with surface ridges (one medial and two lateral). In each of these zones, intraepithelial receptor axons and Merkel receptors occurred in the epithelium, while simple unencapsulated corpuscles, glomerular-Meissner corpuscles, and incisive (encapsulated) corpuscles occurred in the lamina propria. In the chemosensory corpuscle region, chemosensory corpuscles and intraepithelial receptor axons were located in the epithelium, and incisive corpuscles were present in the lamina propria. In the lateral labium, only intraepithelial receptor axons were prominent. In all these sensory receptors, the preterminal axons and axon terminals were labeled with the tracer protein. In addition, some nonneuronal cells closely associated with the axon terminals were selectively labeled, e.g., terminal Schwann cells, lamellar Schwann cells, Merkel cells, corpuscular basal cells and chemosensory cells. Other adjacent cells were not labeled, e.g., unspecialized epithelial cells, capsular cells, corpuscular sustentacular cells, and fibroblasts. In both labeled axons and cells, WGA-HRP was incorporated into vesicles, tubules, and vacuolar organelles. The specific intercellular transfer of tracer protein may indicate trophic interactions between axon terminals and support cells in sensory receptors. The specific organization of multiple sensory receptors in the rat incisive papilla may provide a useful alternative system for studying somatosensory physiology.

  9. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.

    Science.gov (United States)

    Rivière, Jean-Baptiste; Ramalingam, Siriram; Lavastre, Valérie; Shekarabi, Masoud; Holbert, Sébastien; Lafontaine, Julie; Srour, Myriam; Merner, Nancy; Rochefort, Daniel; Hince, Pascale; Gaudet, Rébecca; Mes-Masson, Anne-Marie; Baets, Jonathan; Houlden, Henry; Brais, Bernard; Nicholson, Garth A; Van Esch, Hilde; Nafissi, Shahriar; De Jonghe, Peter; Reilly, Mary M; Timmerman, Vincent; Dion, Patrick A; Rouleau, Guy A

    2011-08-12

    Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. One and two-dimensional electrophoresis of fast axonally-transported proteins in rat nerves following acrylamide and 2,5-hexanedione exposure

    International Nuclear Information System (INIS)

    Sickles, D.W.

    1990-01-01

    Transient and repeated deficiencies in protein delivery to the axon are observed following injections of acrylamide (ACR) and 2,5-hexanedione (2,5-HD) (Sickles DW, Neurotoxicology 10: 91;103, 1989; Neurosci Abstr 14:1219, 1988). We have furthered these studies by measuring the effects of single 50 mg/kg ACR and 4 nmole/kg 2,5-HD injections on the quantity of select fast-transported proteins. Proteins were radiolabelled with 3H-leucine injections of the DRG; 1 and 2 dimensional gels were used for separation of the sciatic nerve (9-45mm distal to the ganglion) homogenates. Scintillation counting demonstrated that transport of all proteins studied were affected by both toxicants. Some variation in effect was observed; a direct correlation between molecular weight (r=0.71) and original quantity of radiolabel (r=0.80) with the percent reduction in transport was observed. Some apparent increases in transport of certain proteins were observed on the 2D gels; but this may indicate a change in the isoelectric points of these transported proteins

  11. 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

  12. 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.

  13. 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.

  14. Big data's implications for transportation operations : an exploration.

    Science.gov (United States)

    The purpose of this white paper is to expand the understanding of big data for transportation operations, the value it could provide, and the implications for the : future direction of the U.S. Department of Transportation (USDOT) Connected Vehicle R...

  15. School Transportation Issues, Laws and Concerns: Implications for Future Administrators

    Science.gov (United States)

    Durick, Jody M.

    2010-01-01

    Nearly all building administrators are confronted with a variety of transportation issues. Challenges, concerns and questions can arise from various aspects, including student misbehaviors, transportation laws and its implications at the school level, to importance and implementation of a school bus safety program. As new and upcoming future…

  16. 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.

  17. Dync1h1 Mutation Causes Proprioceptive Sensory Neuron Loss and Impaired Retrograde Axonal Transport of Dorsal Root Ganglion Neurons.

    Science.gov (United States)

    Zhao, Jing; Wang, Yi; Xu, Huan; Fu, Yuan; Qian, Ting; Bo, Deng; Lu, Yan-Xin; Xiong, Yi; Wan, Jun; Zhang, Xiang; Dong, Qiang; Chen, Xiang-Jun

    2016-07-01

    Sprawling (Swl) is a radiation-induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. To display the phenotype of Swl mutant mice, we examined the embryos of homozygous (Swl/Swl) and heterozygous (Swl/+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl/+ mice. The Swl/+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/+ DRG neurons was revealed during E11.5-E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein-driven nerve growth factor (NGF). Mitochondria, another dynein-driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild-type (WT) neurons. Nevertheless, the Swl, Loa, and Cra mutations did not affect homodimerization of DYNC1H1. The Swl/Swl mutation of Dync1h1 gene led to embryonic mal-development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein-driven cargos and excessive apoptosis during mid- to late-developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1. © 2016 John Wiley & Sons Ltd.

  18. Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations

    Science.gov (United States)

    Carrasco, Monica A.; Williams, Luis A.; Winborn, Christina S.; Han, Steve S. W.; Kiskinis, Evangelos; Winborn, Brett; Freibaum, Brian D.; Kanagaraj, Anderson; Clare, Alison J.; Badders, Nisha M.; Bilican, Bilada; Chaum, Edward; Chandran, Siddharthan; Shaw, Christopher E.; Eggan, Kevin C.; Maniatis, Tom; Taylor, J. Paul

    2014-01-01

    Summary The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. PMID:24507191

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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)

  5. 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.

  6. Transportation planning implications of automated/connected vehicles on Texas highways.

    Science.gov (United States)

    2017-04-01

    This research project was focused on the transportation planning implications of automated/connected : vehicles (AV/CVs) on Texas highways. The research assessed how these potentially transformative : technologies can be included in transportation pl...

  7. Implications of Lagrangian transport for coupled chemistry-climate simulations

    Science.gov (United States)

    Stenke, A.; Dameris, M.; Grewe, V.; Garny, H.

    2008-10-01

    For the first time a purely Lagrangian transport algorithm is applied in a fully coupled chemistry-climate model (CCM). We use the Lagrangian scheme ATTILA for the transport of water vapour, cloud water and chemical trace species in the ECHAM4.L39(DLR)/CHEM (E39C) CCM. The advantage of the Lagrangian approach is that it is numerically non-diffusive and therefore maintains steeper and more realistic gradients than the operational semi-Lagrangian transport scheme. In case of radiatively active species changes in the simulated distributions feed back to model dynamics which in turn affect the modelled transport. The implications of the Lagrangian transport scheme for stratospheric model dynamics and tracer distributions in the upgraded model version E39C-ATTILA (E39C-A) are evaluated by comparison with observations and results of the E39C model with the operational semi-Lagrangian advection scheme. We find that several deficiencies in stratospheric dynamics in E39C seem to originate from a pronounced modelled wet bias and an associated cold bias in the extra-tropical lowermost stratosphere. The reduction of the simulated moisture and temperature bias in E39C-A leads to a significant advancement of stratospheric dynamics in terms of the mean state as well as annual and interannual variability. As a consequence of the favourable numerical characteristics of the Lagrangian transport scheme and the improved model dynamics, E39C-A generally shows more realistic stratospheric tracer distributions: Compared to E39C high stratospheric chlorine (Cly) concentrations extend further downward and agree now well with analyses derived from observations. Therefore E39C-A realistically covers the altitude of maximum ozone depletion in the stratosphere. The location of the ozonopause, i.e. the transition from low tropospheric to high stratospheric ozone values, is also clearly improved in E39C-A. Furthermore, the simulated temporal evolution of stratospheric Cly in the past is

  8. Hyporheic flow and transport processes: mechanisms, models, and biogeochemical implications

    Science.gov (United States)

    Boano, Fulvio; Harvey, Judson W.; Marion, Andrea; Packman, Aaron I.; Revelli, Roberto; Ridolfi, Luca; Anders, Wörman

    2014-01-01

    Fifty years of hyporheic zone research have shown the important role played by the hyporheic zone as an interface between groundwater and surface waters. However, it is only in the last two decades that what began as an empirical science has become a mechanistic science devoted to modeling studies of the complex fluid dynamical and biogeochemical mechanisms occurring in the hyporheic zone. These efforts have led to the picture of surface-subsurface water interactions as regulators of the form and function of fluvial ecosystems. Rather than being isolated systems, surface water bodies continuously interact with the subsurface. Exploration of hyporheic zone processes has led to a new appreciation of their wide reaching consequences for water quality and stream ecology. Modern research aims toward a unified approach, in which processes occurring in the hyporheic zone are key elements for the appreciation, management, and restoration of the whole river environment. In this unifying context, this review summarizes results from modeling studies and field observations about flow and transport processes in the hyporheic zone and describes the theories proposed in hydrology and fluid dynamics developed to quantitatively model and predict the hyporheic transport of water, heat, and dissolved and suspended compounds from sediment grain scale up to the watershed scale. The implications of these processes for stream biogeochemistry and ecology are also discussed."

  9. 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.

  10. IMPLICATIONS OF NON-LOCALITY OF TRANSPORT IN GEOMORPHIC TRANSPORT LAWS: HILLSLOPES AND LANDSCAPE EVOLUTION MODELING

    Science.gov (United States)

    Foufoula-Georgiou, E.; Ganti, V. K.; Dietrich, W. E.

    2009-12-01

    Sediment transport on hillslopes can be thought of as a hopping process, where the sediment moves in a series of jumps. A wide range of processes shape the hillslopes which can move sediment to a large distance in the downslope direction, thus, resulting in a broad-tail in the probability density function (PDF) of hopping lengths. Here, we argue that such a broad-tailed distribution calls for a non-local computation of sediment flux, where the sediment flux is not only a function of local topographic quantities but is an integral flux which takes into account the upslope topographic “memory” of the point of interest. We encapsulate this non-local behavior into a simple fractional diffusive model that involves fractional (non-integer) derivatives. We present theoretical predictions from this nonlocal model and demonstrate a nonlinear dependence of sediment flux on local gradient, consistent with observations. Further, we demonstrate that the non-local model naturally eliminates the scale-dependence exhibited by any local (linear or nonlinear) sediment transport model. An extension to a 2-D framework, where the fractional derivative can be cast into a mixture of directional derivatives, is discussed together with the implications of introducing non-locality into existing landscape evolution models.

  11. 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.

  12. 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....

  13. 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.

  14. 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.

  15. 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.

  16. Fiber tractography of the axonal pathways linking the basal ganglia and cerebellum in Parkinson disease: implications for targeting in deep brain stimulation.

    Science.gov (United States)

    Sweet, Jennifer A; Walter, Benjamin L; Gunalan, Kabilar; Chaturvedi, Ashutosh; McIntyre, Cameron C; Miller, Jonathan P

    2014-04-01

    Stimulation of white matter pathways near targeted structures may contribute to therapeutic effects of deep brain stimulation (DBS) for patients with Parkinson disease (PD). Two tracts linking the basal ganglia and cerebellum have been described in primates: the subthalamopontocerebellar tract (SPCT) and the dentatothalamic tract (DTT). The authors used fiber tractography to evaluate white matter tracts that connect the cerebellum to the region of the basal ganglia in patients with PD who were candidates for DBS. Fourteen patients with advanced PD underwent 3-T MRI, including 30-directional diffusion-weighted imaging sequences. Diffusion tensor tractography was performed using 2 regions of interest: ipsilateral subthalamic and red nuclei, and contralateral cerebellar hemisphere. Nine patients underwent subthalamic DBS, and the course of each tract was observed relative to the location of the most effective stimulation contact and the volume of tissue activated. In all patients 2 distinct tracts were identified that corresponded closely to the described anatomical features of the SPCT and DTT, respectively. The mean overall distance from the active contact to the DTT was 2.18 ± 0.35 mm, and the mean proportional distance relative to the volume of tissue activated was 1.35 ± 0.48. There was a nonsignificant trend toward better postoperative tremor control in patients with electrodes closer to the DTT. The SPCT and the DTT may be related to the expression of symptoms in PD, and this may have implications for DBS targeting. The use of tractography to identify the DTT might assist with DBS targeting in the future.

  17. Economic implications of oil crisis and transport sector in India

    Energy Technology Data Exchange (ETDEWEB)

    Pathak, M G

    1980-01-01

    Efforts towards fuel economy in the transport sector have heavily stressed engineering aspects of the automobile. Better roads and better traffic planning too, go a long way in conserving energy. The paper outlines the economic implementations of the hike in oil prices with reference to the transportation sector.

  18. 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.

  19. Transport mechanisms at the pulmonary mucosa: implications for drug delivery.

    Science.gov (United States)

    Nickel, Sabrina; Clerkin, Caoimhe G; Selo, Mohammed Ali; Ehrhardt, Carsten

    2016-01-01

    Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.

  20. Intermittent random walks: transport regimes and implications on search strategies

    International Nuclear Information System (INIS)

    Gomez Portillo, Ignacio; Campos, Daniel; Méndez, Vicenç

    2011-01-01

    We construct a transport model for particles that alternate rests of random duration and flights with random velocities. The model provides a balance equation for the mesoscopic particle density obtained from the continuous-time random walk framework. By assuming power laws for the distributions of waiting times and flight durations (for any velocity distribution with finite moments) we have found that the model can yield all the transport regimes ranging from subdiffusion to ballistic depending on the values of the characteristic exponents of the distributions. In addition, if the exponents satisfy a simple relationship it is shown how the competition between the tails of the distributions gives rise to a diffusive transport. Finally, we explore how the details of this intermittent transport process affect the success probability in an optimal search problem where an individual searcher looks for a target distributed (heterogeneously) in space. All the results are conveniently checked with numerical simulations

  1. Meridional Flow Observations: Implications for the current Flux Transport Models

    International Nuclear Information System (INIS)

    Gonzalez Hernandez, Irene; Komm, Rudolf; Kholikov, Shukur; Howe, Rachel; Hill, Frank

    2011-01-01

    Meridional circulation has become a key element in the solar dynamo flux transport models. Available helioseismic observations from several instruments, Taiwan Oscillation Network (TON), Global Oscillation Network Group (GONG) and Michelson Doppler Imager (MDI), have made possible a continuous monitoring of the solar meridional flow in the subphotospheric layers for the last solar cycle, including the recent extended minimum. Here we review some of the meridional circulation observations using local helioseismology techniques and relate them to magnetic flux transport models.

  2. Implications for the management of R A materials transport

    International Nuclear Information System (INIS)

    Devine, I.R.

    1997-01-01

    This paper attempts to describe some Exclusions and Exemptions from the current and proposed transport regulations and describes those requirements applicable to low active material. It concludes that Clearance is the dominant issue and that within the UK nuclear sector, the current (1985 as amended 1990) transport regulations have no significant impact on the management of low active materials. Nor will the proposed (1996) Regulations. (author)

  3. Particle and energy transport studies on TFTR and implications for helium ash in future fusion devices

    International Nuclear Information System (INIS)

    Synakowski, E.J.; Efthimion, P.C.; Rewoldt, G.; Stratton, B.C.; Tang, W.M.; Bell, R.E.; Grek, B.; Hulse, R.A.; Johnson, D.W.; Hill, K.W.; Mansfield, D.K.; McCune, D.; Mikkelsen, D.R.; Park, H.K.; Ramsey, A.T.; Scott, S.D.; Taylor, G.; Timberlake, J.; Zarnstorff, M.C.

    1992-01-01

    Particle and energy transport in tokamak plasmas have long been subjects of vigorous investigation. Present-day measurement techniques permit radially resolved studies of the transport of electron perturbations, low- and high-Z impurities, and energy. In addition, developments in transport theory provide tools that can be brought to bear on transport issues. Here, we examine local particle transport measurements of electrons, fully-stripped thermal helium, and helium-like iron in balanced-injection L-mode and enhanced confinement deuterium plasmas on TFTR of the same plasma current, toroidal field, and auxiliary heating power. He 2+ and Fe 24+ transport has been studied with charge exchange recombination spectroscopy, while electron transport has been studied by analyzing the perturbed electron flux following the same helium puff used for the He 2+ studies. By examining the electron and He 2+ responses following the same gas puff in the same plasmas, an unambiguous comparison of the transport of the two species has been made. The local energy transport has been examined with power balance analysis, allowing for comparisons to the local thermal fluxes. Some particle and energy transport results from the Supershot have been compared to a transport model based on a quasilinear picture of electrostatic toroidal drift-type microinstabilities. Finally, implications for future fusion reactors of the observed correlation between thermal transport and helium particle transport is discussed

  4. Intercontinental Transport of Aerosols: Implication for Regional Air Quality

    Science.gov (United States)

    Chin, Mian; Diehl, Thomas; Ginoux, Paul

    2006-01-01

    Aerosol particles, also known as PM2.5 (particle diameter less than 2.5 microns) and PM10 (particle diameter less than 10 microns), is one of the key atmospheric components that determine ambient air quality. Current US air quality standards for PM10 (particles with diameter air pollution problems, aerosols can be transported on a hemispheric or global scale. In this study, we use the Goddard Chemistry Aerosol Radiation and Transport (GOCART) model to quantify contributions of long-range transport vs. local/regional pollution sources and from natural vs. anthropogenic sources to PM concentrations different regions. In particular, we estimate the hemispheric impact of anthropogenic sulfate aerosols and dust from major source areas on other regions in the world. The GOCART model results are compared with satellite remote sensing and ground-based network measurements of aerosol optical depth and concentrations.

  5. 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

  6. 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

  7. 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.

  8. Carbon dioxide emissions from passenger transport in China since 1949: Implications for developing sustainable transport

    International Nuclear Information System (INIS)

    Loo, Becky P.Y.; Li, Linna

    2012-01-01

    This paper traces the historical evolution and spatial disparity of CO 2 emissions from passenger transport in China. The general trends of CO 2 emissions from four passenger transport modes are estimated by both the distance-based and fuel-based methods. The results suggest that CO 2 emissions from road transport represented the leading source of passenger transport CO 2 emissions in China. Moreover, they have continued to grow rapidly. Air transport was the second largest contributor since 1998. Emissions from rail and water transport have remained relatively stable with lower emission intensity. At the provincial level, great regional disparity was noticeable, especially in road transport. Moreover, the decomposition analysis shows that income growth was the principal factor leading to the growth of passenger transport CO 2 emissions in China for both the 1949–1979 and 1980–2009 periods. The second most important factor was increased transport intensity and modal shifts for the former and the latter period, respectively. The main factor contributed to emission reduction was the lower emission intensity supported by policies, although the effect was weak. In the future, more policies to encourage modal shifts toward sustainable transport modes and travel reduction should be encouraged. - Highlights: ► CO 2 emissions from passenger transport in China were estimated. ► Road transport was the largest contributor to CO 2 emission. Air transport followed. ► Factors influencing CO 2 emissions growth are analyzed by decomposition analysis. ► Income growth, higher travel intensity and modal shift were driving CO 2 emissions up. ► Policies to promote modal shifts and travel demand reduction should be encouraged.

  9. 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.

  10. 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

  11. 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.

  12. Classical transport in field reversed mirrors: reactor implications

    International Nuclear Information System (INIS)

    Auerbach, S.P.; Condit, W.C.

    1980-01-01

    Assuming that the field-reversed mirror (or the closely related spheromak) turns out to be stable, the next crucial issue is transport of particles and heat. Of particular concern is the field null on axis (the X-point), which at first glance seems to allow particles to flow out unhindered. We have evaluated the classical diffusion coefficients for particles and heat in field-reversed mirrors, with particular reference to a class of Hill's vortex models. Two fairly surprising results emerge from this study. First, the diffusion-driven flow of particles and heat is finite at the X-points. This may be traced to the geometrical constraint that the current (and hence the ion-electron drag force, which causes cross-field transport) must vanish on axis. This conclusion holds for any transport model. Second, the classical diffusion coefficient D(psi), which governs both particle and heat flux, is finite on the separatrix. Indeed, in a wide class of Hill's vortex equilibria (spherical, oblate, or prolate) D(psi) is essentially independent of psi (except for the usual factor of n

  13. IMPLICATIONS ON THE NUMBER AND CONCENTRATION OF SUPPLIERS ON ROMANIAN TRANSPORT SERVICES

    Directory of Open Access Journals (Sweden)

    PĂUN IULIAN GABRIEL

    2017-02-01

    Full Text Available This paper aims to capture the current situation characterizing the transport sector in Romania by degree of concentration of transport service providers. Market analysis covers road, rail and air transport. Knowing the concentration of these markets is useful when it realizes development strategy of these sectors with profound implications on the national economy. There is a decreasing degree of concentration in the road transport sector due to growing number of enterprises in this market. Air transport has similar trend the road transport, the concentration declining during the span of years analyzed. Regarding the Herfindahl-Hirschmann index in the railway sector, we find that it reveals for the year 2012 a very high degree of concentration.

  14. 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.

  15. 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.

  16. Transport of Aerosols: Regional and Global Implications for Climate, Weather, and Air Quality

    Science.gov (United States)

    Chin, Mian; Diehl, Thomas; Yu, Hongbin; Bian, Huisheng; Remer, Lorraine; Kahn, Ralph

    2008-01-01

    Long-range transport of atmospheric aerosols can have a significant impact on global climate, regional weather, and local air quality. In this study, we use a global model GOCART together with satellite data and ground-based measurements to assess the emission and transport of pollution, dust, biomass burning, and volcanic aerosols and their implications. In particular, we will show the impact of emissions and long-range transport of aerosols from major pollution and dust source regions to (1) the surface air quality, (2) the atmospheric heating rates, and (3) surface radiation change near the source and downwind regions.

  17. Lithium battery fires: implications for air medical transport.

    Science.gov (United States)

    Thomas, Frank; Mills, Gordon; Howe, Robert; Zobell, Jim

    2012-01-01

    Lithium-ion batteries provide more power and longer life to electronic medical devices, with the benefits of reduced size and weight. It is no wonder medical device manufacturers are designing these batteries into their products. Lithium batteries are found in cell phones, electronic tablets, computers, and portable medical devices such as ventilators, intravenous pumps, pacemakers, incubators, and ventricular assist devices. Yet, if improperly handled, lithium batteries can pose a serious fire threat to air medical transport personnel. Specifically, this article discusses how lithium-ion batteries work, the fire danger associated with them, preventive measures to reduce the likelihood of a lithium battery fire, and emergency procedures that should be performed in that event. Copyright © 2012 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

  18. 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.

  19. Medical complications of intra-hospital patient transports: implications for architectural design and research.

    Science.gov (United States)

    Ulrich, Roger S; Zhu, Xuemei

    2007-01-01

    Literature on healthcare architecture and evidence-based design has rarely considered explicitly that patient outcomes may be worsened by intra-hospital transport (IHT), which is defined as transport of patients within the hospital. The article focuses on the effects of IHTs on patient complications and outcomes, and the implications of such impacts for designing safer, better hospitals. A review of 22 scientific studies indicates that IHTs are subject to a wide range of complications, many of which occur frequently and have distinctly detrimental effects on patient stability and outcomes. The research suggests that higher patient acuity and longer transport durations are associated with more frequent and serious IHT-related complications and outcome effects. It appears no rigorous research has compared different hospital designs and layouts with respect to having possibly differential effects on transport-related complications and worsened outcomes. Nonetheless, certain design implications can be extracted from the existing research literature, including the importance of minimizing transport delays due to restricted space and congestion, and creating layouts that shorten IHT times for high-acuity patients. Limited evidence raises the possibility that elevator-dependent vertical building layouts may increase susceptibility to transport delays that worsen complications. The strong evidence indicating that IHTs trigger complications and worsen outcomes suggests a powerful justification for adopting acuity-adaptable rooms and care models that substantially reduce transports. A program of studies is outlined to address gaps in knowledge.Key WordsPatient transports, transports within hospitals, patient safety, evidence-based design, hospital design, healthcare architecture, intra-hospital transport complications, acuity-adaptable care, elevators, outcomes.

  20. Coupled Transport Phenomena in the Opalinus Clay: Implications for Radionuclide Transport

    International Nuclear Information System (INIS)

    Soler, J.M.

    1999-09-01

    Coupled phenomena (thermal and chemical osmosis, hyperfiltration, coupled diffusion, thermal diffusion, thermal filtration, Dufour effect) may play an important role in fluid, solute and heat transport in clay-rich formations, such as the Opalinus Clay (OPA), which are being considered as potential hosts for radioactive waste repositories. In this study, the potential effects of coupled phenomena on radionuclide transport in the vicinity of a repository for vitrified high-level radioactive waste (HLW) and spent nuclear fuel (SF) hosted by the Opalinus Clay, at times equal to or greater than the expected lifetime of the waste canisters (about 1000 years), have been addressed. Firstly, estimates of the solute fluxes associated with chemical osmosis, hyperfiltration, thermal diffusion and thermal osmosis have been calculated. Available experimental data concerning coupled transport phenomena in compacted clays, and the hydrogeological and geochemical conditions to which the Opalinus Clay is subject, have been used for these estimates. These estimates suggest that thermal osmosis is the only coupled transport mechanism that could have a strong impact on solute and fluid transport in the vicinity of the repository. Secondly, estimates of the heat fluxes associated with thermal filtration and the Dufour effect in the vicinity of the repository have been calculated. The calculated heat fluxes are absolutely negligible compared to the heat flux caused by thermal conduction. As a further step to obtain additional insight into the effects of coupled phenomena on solute transport, the solute fluxes associated with advection, chemical diffusion, thermal and chemical osmosis, hyperfiltration and thermal diffusion have been incorporated into a simple one-dimensional transport equation. The analytical solution of this equation, with appropriate parameters, shows again that thermal osmosis is the only coupled transport mechanism that could have a strong effect on repository

  1. Coupled Transport Phenomena in the Opalinus Clay: Implications for Radionuclide Transport

    Energy Technology Data Exchange (ETDEWEB)

    Soler, J.M.

    1999-09-01

    Coupled phenomena (thermal and chemical osmosis, hyperfiltration, coupled diffusion, thermal diffusion, thermal filtration, Dufour effect) may play an important role in fluid, solute and heat transport in clay-rich formations, such as the Opalinus Clay (OPA), which are being considered as potential hosts for radioactive waste repositories. In this study, the potential effects of coupled phenomena on radionuclide transport in the vicinity of a repository for vitrified high-level radioactive waste (HLW) and spent nuclear fuel (SF) hosted by the Opalinus Clay, at times equal to or greater than the expected lifetime of the waste canisters (about 1000 years), have been addressed. Firstly, estimates of the solute fluxes associated with chemical osmosis, hyperfiltration, thermal diffusion and thermal osmosis have been calculated. Available experimental data concerning coupled transport phenomena in compacted clays, and the hydrogeological and geochemical conditions to which the Opalinus Clay is subject, have been used for these estimates. These estimates suggest that thermal osmosis is the only coupled transport mechanism that could have a strong impact on solute and fluid transport in the vicinity of the repository. Secondly, estimates of the heat fluxes associated with thermal filtration and the Dufour effect in the vicinity of the repository have been calculated. The calculated heat fluxes are absolutely negligible compared to the heat flux caused by thermal conduction. As a further step to obtain additional insight into the effects of coupled phenomena on solute transport, the solute fluxes associated with advection, chemical diffusion, thermal and chemical osmosis, hyperfiltration and thermal diffusion have been incorporated into a simple one-dimensional transport equation. The analytical solution of this equation, with appropriate parameters, shows again that thermal osmosis is the only coupled transport mechanism that could have a strong effect on repository

  2. 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.

  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. 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.

  5. Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

    Science.gov (United States)

    German, Christopher L; Baladi, Michelle G; McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

    2015-10-01

    Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  7. 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...

  8. 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

  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. Driving forces: Motor vehicle trends and their implications for global warming, energy strategies, and transportation planning

    International Nuclear Information System (INIS)

    MacKenzie, J.J.; Walsh, M.P.

    1990-01-01

    Cars, trucks, and other vehicles have long been linked to smog and other urban pollution, but the part they play in the larger complex of atmospheric and energy ills that we now face is often overlooked. In Driving Forces: Motor Vehicle Trends and Their Implications for Global Warming, Energy Strategies, and Transportation Planning, James J. MacKenzie, senior associate in World Resources Institute's Program in Climate, Energy, and Pollution, and Michael P. Walsh, an international consultant on transportation and environmental issues, fill in this knowledge gap with new data and analyses. They spell out four policy shifts that can help hold the line on global warming: improve new-vehicle efficiency; make transportation more efficient; cut other greenhouse gas emissions; create the green car of the future. The report focuses especially on the US, which pioneered the automotive revolution and leads the world in oil imports and emissions

  11. The transport implications of siting policies for the disposal of low-level radioactive wastes

    International Nuclear Information System (INIS)

    James, I.A.

    1986-01-01

    This report has been produced to be complementary to the previously issued report ''The Transport Implications of Regional Policies for The Disposal of Intermediate Level Radioactive Wastes''. The same combinations of disposal facilities have been used so that direct comparison with intermediate waste results can be made. Low level wastes and short-lived intermediate level wastes for near-surface disposal are assumed to share a common infrastructure on the rail system and hence a methodology of separating total costs between these two waste types has been derived. Two transport modes, road and rail have been analysed. Hybrid transport, a combination of road and rail systems, has not been examined since no site is considered to produce sufficient waste to justify a dedicated rail service. Sellafield, has not been included in this examination since it is assumed to be served by its own disposal site at Drigg. (author)

  12. 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.

  13. 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.

  14. Electron transport chains in organohalide-respiring bacteria and bioremediation implications.

    Science.gov (United States)

    Wang, Shanquan; Qiu, Lan; Liu, Xiaowei; Xu, Guofang; Siegert, Michael; Lu, Qihong; Juneau, Philippe; Yu, Ling; Liang, Dawei; He, Zhili; Qiu, Rongliang

    2018-04-06

    In situ remediation employing organohalide-respiring bacteria represents a promising solution for cleanup of persistent organohalide pollutants. The organohalide-respiring bacteria conserve energy by utilizing H 2 or organic compounds as electron donors and organohalides as electron acceptors. Reductive dehalogenase (RDase), a terminal reductase of the electron transport chain in organohalide-respiring bacteria, is the key enzyme that catalyzes halogen removal. Accumulating experimental evidence thus far suggests that there are distinct models for respiratory electron transfer in organohalide-respirers of different lineages, e.g., Dehalococcoides, Dehalobacter, Desulfitobacterium and Sulfurospirillum. In this review, to connect the knowledge in organohalide-respiratory electron transport chains to bioremediation applications, we first comprehensively review molecular components and their organization, together with energetics of the organohalide-respiratory electron transport chains, as well as recent elucidation of intramolecular electron shuttling and halogen elimination mechanisms of RDases. We then highlight the implications of organohalide-respiratory electron transport chains in stimulated bioremediation. In addition, major challenges and further developments toward understanding the organohalide-respiratory electron transport chains and their bioremediation applications are identified and discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications

    Science.gov (United States)

    Ferro, Suellen; Azevedo-Silva, João; Casal, Margarida; Côrte-Real, Manuela; Baltazar, Fatima; Preto, Ana

    2016-01-01

    Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID:28874966

  16. Mobility as a positional good : implications for transport policy and planning

    Energy Technology Data Exchange (ETDEWEB)

    Litman, T. [Victoria Transport Policy Institute, Victoria, BC (Canada)

    2007-01-17

    Social position refers to a person's social rank. Many goods have positional value because they increase the status of their consumers. Positional goods include fashionable jewellery and clothing, luxurious homes and vehicles, and extravagant entertainment. Many motorists choose vehicles with greater potential speeds and off-road abilities than actually needed because these features are considered prestigious. This paper examined how positional value affects transportation decisions and investigated the resulting economic impacts. These included impacts on social welfare and external costs. The paper also discussed implications for transport policy and planning. The paper discussed the science of happiness and included an excerpt from a newspaper article on money and happiness. The paper also included an analysis of popular television shows and Internet blogs. Transportation impacts were also examined, with reference to motor vehicle ownership, luxury vehicles, mode choice, long-distance recreation travel, planning practices, and industrial development policy. A table was also presented that summarized the categories of prestige value travel impacts. The paper also presented possible offsetting benefits and implications for planning. 40 refs., 1 tab., 11 figs.

  17. Dopamine transporter and vesicular monoamine transporter knockout mice : implications for Parkinson's disease.

    Science.gov (United States)

    Miller, G W; Wang, Y M; Gainetdinov, R R; Caron, M G

    2001-01-01

    One of the most valuable methods for understanding the function of a particular protein is the generation of animals that have had the gene encoding for the protein of interest disrupted, commonly known as a "quo;knockout"quo; or null mutant. By incorporating a sequence of DNA (typically encoding antibiotic resistance to aid in the selection of the mutant gene) into embryonic stem cells by homologous recombination, the normal transcription of the gene is effectively blocked (Fig. 1). Since a particular protein is encoded by two copies of a gene, it is necessary to have the gene on both alleles "quo;knocked out."quo; This is performed by cross-breeding animals with one affected allele (heterozygote) to generate offspring that have inherited two mutant alleles (homozygote). This procedure has been used to generate animals lacking either the plasma membrane dopamine transporter (DAT; Fig. 2) or the vesicular monoamine transporter (VMAT2; Fig. 3). Both DAT and VMAT2 are essential for dopamine homeostasis and are thought to participate in the pathogenesis of Parkinson's disease (1-5). Fig. 1. Maps of the targeting vector and the mock construct. The mouse genomic fragment (clone 11) was isolated from a Stratagene 129 SvJ library by standard colony hybridization using a PCR probe from the 5' end of rat cDNA. The restriction site abbreviations are as follows: H, HindIII; N, NotI; Sc, SacI; Sn, SnaI; X, XbaI; and Xh, XhoI. The region between HindIII and SnaI on clone 11 containing the coding sequence from transmembrane domains 3 and 4 of VMAT2 was deleted and replaced with PGK-neo. The 3' fragment of clone 11 was reserved as an external probe for Southern analysis. To facilitate PCR screening of embryonic stem cell clones, a mock construct containing the SnaI/XbaI fragment and part of the Neo cassette was generated as a positive control. pPNT and pGEM4Z were used to construct knockout and mock vectors, respectively. (Reproduced with permission from ref. 1). Fig. 2. DAT and

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. In Vitro Analysis of the Role of Schwann Cells on Axonal Degeneration and Regeneration Using Sensory Neurons from Dorsal Root Ganglia.

    Science.gov (United States)

    López-Leal, Rodrigo; Diaz, Paula; Court, Felipe A

    2018-01-01

    Sensory neurons from dorsal root ganglion efficiently regenerate after peripheral nerve injuries. These neurons are widely used as a model system to study degenerative mechanisms of the soma and axons, as well as regenerative axonal growth in the peripheral nervous system. This chapter describes techniques associated to the study of axonal degeneration and regeneration using explant cultures of dorsal root ganglion sensory neurons in vitro in the presence or absence of Schwann cells. Schwann cells are extremely important due to their involvement in tissue clearance during axonal degeneration as well as their known pro-regenerative effect during regeneration in the peripheral nervous system. We describe methods to induce and study axonal degeneration triggered by axotomy (mechanical separation of the axon from its soma) and treatment with vinblastine (which blocks axonal transport), which constitute clinically relevant mechanical and toxic models of axonal degeneration. In addition, we describe three different methods to evaluate axonal regeneration using quantitative methods. These protocols constitute a valuable tool to analyze in vitro mechanisms associated to axonal degeneration and regeneration of sensory neurons and the role of Schwann cells in these processes.

  6. The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease

    Science.gov (United States)

    Sabeva, Nadezhda S.; Liu, Jingjing; Graf, Gregory A.

    2014-01-01

    Purpose of review This review summarizes recent developments in the activity, regulation, and physiology of the ABCG5 ABCG8 (G5G8) transporter and the use of its xenobiotic substrates, phytosterols, as cholesterol lowering agents in the treatment of cardiovascular disease. Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome. Recent findings Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction. The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility. Finally, the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction, suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit. Summary Insulin resistance elevates G5G8 and increases susceptibility to cholesterol gallstones. However, this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine. Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease. PMID:19306529

  7. 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

  8. The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo

    Directory of Open Access Journals (Sweden)

    Martin Veronica

    2008-04-01

    Full Text Available Abstract Background Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. Results We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. Conclusion We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the

  9. 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.

  10. 3D Airflow patterns over coastal foredunes: implications for aeolian sediment transport

    Science.gov (United States)

    Jackson, Derek W. T.; Cooper, Andrew G.; Baas, Andreas C. W.; Lynch, Kevin; Beyers, Meiring

    2010-05-01

    A fundamental criterion for the development of coastal sand dunes is usually highlighted as a significant onshore wind component of the local wind field. The presence of large sand dune systems on coasts where the predominant wind blows offshore is therefore difficult to explain and usually they are attributed to the past occurrence of onshore winds and, by implication, subsequent changes in climate. Recent studies have shown that offshore winds can be deflected or 'steered' by existing dunes so that their direction changes. This can occur to such an extent that a process known as 'flow reversal' can arise, whereby the initially offshore wind actually flows onshore at the beach. This process is important because it can cause sand to be blown from the beach and into the dunes, causing them to grow. This may be central in explaining the presence of extensive dunes on coasts where the dominant wind is offshore, but is also important in how dunes recover after periods of wave erosion during storms. Offshore winds have traditionally been excluded from sediment budget calculations for coastal dunes, but when they do transport sand onshore, this may have been an important oversight leading to significant underestimates of the volume of sand being transported by wind. This work investigates the controls on the processes and the mechanisms involved in deformation of the flow and resulting sediment transport at coastal foredunes in Northern Ireland. We use a combination of field measurement of wind and sediment transport coupled with state-of-the-art aerodynamic modelling using computational fluid dynamics (CFD) and 3-D sonic anemometry. Our working hypothesis is that offshore winds contribute substantially to foredune behaviour on leeside coasts. Preliminary results show strong reverse flow eddies in the seaward side of the foredunes during offshore wind events. These secondary flow reversals have been above velocity threshold and are transport capable. Using CFD modelling

  11. 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.

  12. 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.

  13. Implications of transportation policies on energy and environment in Kathmandu Valley, Nepal

    International Nuclear Information System (INIS)

    Dhakal, Shobhakar

    2003-01-01

    This paper estimates and analyzes the historical and future trends of energy demand and environmental emissions from passenger transportation of the Kathmandu Valley covering CO 2 , CO, HC, NO x , SO 2 , total suspended particles (TSP) and lead (Pb). It uses the Long-range Energy Alternatives Planning System framework for constructing future scenarios up to year 2020 and analyzing their implications; these scenarios mainly deal with the traffic improvement measures, promotion of public transportation and electric vehicles. The results estimate over a four-fold increase in energy demand in 1988-2000. TSP increase of 4.5 times in this period is the major concern since high particulate concentration is already above World Health Organization guidelines. Under the non-intervention scenario, energy demand in 2020 is estimated to be 2.7 times that in the year 2000. Similarly, 2.5 times increase of TSP in 2020 from the year 2000 is estimated that would further increase the TSP concentrations. The scenario analyses suggest that increasing vehicle speed, promoting public transportation and promoting electric vehicles could reduce energy demand by 28%, 28% and 18%, respectively, while promoting a reasonably comfortable condition on overcrowded public transportation could increase energy demand by 10% from non-intervention scenario. For TSP, any future measures would not be enough unless the attention is not paid to in-use vehicle stock. A mix of all the policies mentioned above has potentials to cut down CO 2 emissions to over 60% from the non-intervention case in 2020

  14. Long term energy and emission implications of a global shift to electricity-based public rail transportation system

    International Nuclear Information System (INIS)

    Chaturvedi, Vaibhav; Kim, Son H.

    2015-01-01

    With high reliance on light-duty vehicles in the present, the future of global transportation system is also geared towards private modes, which has significant energy and emission implications. Public transportation has been argued as an alternative strategy for meeting the rising transportation demands of the growing world, especially the poor, in a sustainable and energy efficient way. The present study analyzes an important yet under-researched question – what are the long-term energy and emission implications of an electric rail based passenger transportation system for meeting both long and short distance passenter transportation needs? We analyze a suite of electric rail share scenarios with and without climate policy. In the reference scenario, the transportation system will evolve towards dominance of fossil based light-duty vehicles. We find that an electric rail policy is more successful than an economy wide climate policy in reducing transport sector energy demand and emissions. Economy wide emissions however can only be reduced through a broader climate policy, the cost of which can be reduced by hundreds of billions of dollars across the century when implemented in combination with the transport sector focused electric rail policy. Moreover, higher share of electric rail enhances energy security for oil importing nations and reduces vehicular congestion and road infrastructure requirement as well. -- Highlights: •Economy wide carbon price policy will have little impact on transportation emissions. •Focused energy and emission mitigation policies required for transportation sector. •Large global shift towards electric rail based public transport is one possible option. •Transport sector focused policy will have marginal impact on total global emissions. •A combined transport sector and economy wide policy can reduce costs significantly

  15. Implications of the quasi-neutrality condition for neoclassical transport in stellarators

    International Nuclear Information System (INIS)

    Beidler, C.D.; Maassberg, H.

    2005-01-01

    In conventional stellarator neoclassical theory, the transport coefficients are determined so as to satisfy the so-called ambipolarity constraint on the radial particle fluxes but without regard to the additional requirement that the underlying solutions of the kinetic equation also fulfill local quasi-neutrality. This neglect is consistent with the assumption that density, n and electrostatic potential, Φ, are constant on a flux surface and is justified in the literature with analytic scaling arguments which demonstrate that quasi-neutrality introduces variations of n and Φ on a flux surface which have only a modest impact on bulk-plasma transport. The consequences for impurity transport have not been considered. In this contribution, the implications which the quasi-neutrality condition has for neoclassical transport in stellarators are investigated using a version of the General Solution of the Ripple-Averaged Kinetic Equation (GSRAKE) which accounts for the variation of Φ on flux surfaces. Solutions of the kinetic equation which simultaneously fulfill the ambipolarity and the quasi-neutrality conditions are determined iteratively using standard methods for solving systems of non-linear equations, given specified density and temperature profiles for pure hydrogen plasmas. For a conventional heliotron device, it is shown that quasi-neutrality significantly reduces the radial extent of the region in which multiple solutions of the ambipolarity condition can exist. Especially in the plasma periphery, where strong density and temperature gradients are found, the magnitude of the 'ion' root is reduced significantly leading to increased particle and energy fluxes. For strongly drift-optimized stellarators, on the other hand, bulk plasma transport is much less affected. In a small number of cases, the non-linear system of equations produces additional solutions which are not possible when only ambipolarity is enforced, but such cases are rare. Finally, it is

  16. Vesicular trafficking of semaphorin 3A is activity-dependent and differs between axons and dendrites

    NARCIS (Netherlands)

    de Wit, Joris; Toonen, Ruud F; Verhaagen, J.; Verhage, Matthijs

    Secreted semaphorins act as guidance cues in the developing nervous system and may have additional functions in mature neurons. How semaphorins are transported and secreted by neurons is poorly understood. We find that endogenous semaphorin 3A (Sema3A) displays a punctate distribution in axons and

  17. Pollution abatement from road transport: cross-sectoral implications, climate co-benefits and behavioural change

    International Nuclear Information System (INIS)

    Oxley, T.; Elshkaki, A.; Kwiatkowski, L.; Castillo, A.; Scarbrough, T.; ApSimon, H.

    2012-01-01

    With the abatement potential of end-of-pipe technologies for road transport becoming increasingly marginal, and with greater emissions reductions still needed in order to reduce pollution, alternative strategies involving behavioural change and choices between fossil fuelled or low carbon vehicles becomes more important. The environmental requirements include local air quality objectives, meeting national emissions ceilings to limit transboundary effects, and to aspire to significant reductions in greenhouse gas emissions. In this paper we use the BRUTAL sub-model of the UK integrated Assessment Model (UKIAM) to investigate a selection of alternative strategies including downsizing of cars, switching from petrol to diesel, and the introduction of electric, bio-fuelled or hydrogen vehicles into the fleet, relative to a business-as-usual projection for 2020. Projected impacts upon air quality limit values, national emissions ceilings and CO 2 emissions are assessed in relation to local, national and international objectives. We discuss related life-cycle impacts, implications for infrastructure, and potential impacts upon emissions from other sectors in order to highlight the full potential implications of the different strategies within the context of changes resulting from other policy developments at different scales.

  18. 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

  19. 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, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.

  20. Polyamines control of cation transport across plant membranes: implications for ion homeostasis and abiotic stress signaling.

    Science.gov (United States)

    Pottosin, Igor; Shabala, Sergey

    2014-01-01

    Polyamines are unique polycationic metabolites, controlling a variety of vital functions in plants, including growth and stress responses. Over the last two decades a bulk of data was accumulated providing explicit evidence that polyamines play an essential role in regulating plant membrane transport. The most straightforward example is a blockage of the two major vacuolar cation channels, namely slow (SV) and fast (FV) activating ones, by the micromolar concentrations of polyamines. This effect is direct and fully reversible, with a potency descending in a sequence Spm(4+) > Spd(3+) > Put(2+). On the contrary, effects of polyamines on the plasma membrane (PM) cation and K(+)-selective channels are hardly dependent on polyamine species, display a relatively low affinity, and are likely to be indirect. Polyamines also affect vacuolar and PM H(+) pumps and Ca(2+) pump of the PM. On the other hand, catabolization of polyamines generates H2O2 and other reactive oxygen species (ROS), including hydroxyl radicals. Export of polyamines to the apoplast and their oxidation there by available amine oxidases results in the induction of a novel ion conductance and confers Ca(2+) influx across the PM. This mechanism, initially established for plant responses to pathogen attack (including a hypersensitive response), has been recently shown to mediate plant responses to a variety of abiotic stresses. In this review we summarize the effects of polyamines and their catabolites on cation transport in plants and discuss the implications of these effects for ion homeostasis, signaling, and plant adaptive responses to environment.

  1. Autonomous vehicles:challenges, opportunities, and future implications for transportation policies

    Institute of Scientific and Technical Information of China (English)

    Saeed Asadi Bagloee; Madjid Tavana; Mohsen Asadi; Tracey Oliver

    2016-01-01

    This study investigates the challenges and opportunities pertaining to transportation policies that may arise as a result of emerging autonomous vehicle (AV) technologies. AV technologies can decrease the trans-portation cost and increase accessibility to low-income households and persons with mobility issues. This emerg-ing technology also has far-reaching applications and implications beyond all current expectations. This paper provides a comprehensive review of the relevant literature and explores a broad spectrum of issues from safety to machine ethics. An indispensable part of a prospective AV development is communication over cars and infrastructure (connected vehicles). A major knowledge gap exists in AV technology with respect to routing behaviors. Connected-vehicle technology provides a great opportunity to imple-ment an efficient and intelligent routing system. To this end, we propose a conceptual navigation model based on a fleet of AVs that are centrally dispatched over a network seeking system optimization. This study contributes to the literature on two fronts: (i) it attempts to shed light on future opportunities as well as possible hurdles associated with AV technology;and (ii) it conceptualizes a navigation model for the AV which leads to highly efficient traffic circulations.

  2. ``Phantom'' Modes in Ab Initio Tunneling Calculations: Implications for Theoretical Materials Optimization, Tunneling, and Transport

    Science.gov (United States)

    Barabash, Sergey V.; Pramanik, Dipankar

    2015-03-01

    Development of low-leakage dielectrics for semiconductor industry, together with many other areas of academic and industrial research, increasingly rely upon ab initio tunneling and transport calculations. Complex band structure (CBS) is a powerful formalism to establish the nature of tunneling modes, providing both a deeper understanding and a guided optimization of materials, with practical applications ranging from screening candidate dielectrics for lowest ``ultimate leakage'' to identifying charge-neutrality levels and Fermi level pinning. We demonstrate that CBS is prone to a particular type of spurious ``phantom'' solution, previously deemed true but irrelevant because of a very fast decay. We demonstrate that (i) in complex materials, phantom modes may exhibit very slow decay (appearing as leading tunneling terms implying qualitative and huge quantitative errors), (ii) the phantom modes are spurious, (iii) unlike the pseudopotential ``ghost'' states, phantoms are an apparently unavoidable artifact of large numerical basis sets, (iv) a presumed increase in computational accuracy increases the number of phantoms, effectively corrupting the CBS results despite the higher accuracy achieved in resolving the true CBS modes and the real band structure, and (v) the phantom modes cannot be easily separated from the true CBS modes. We discuss implications for direct transport calculations. The strategy for dealing with the phantom states is discussed in the context of optimizing high-quality high- κ dielectric materials for decreased tunneling leakage.

  3. 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.

  4. Low-Z impurity transport in DIII-D - observations and implications

    International Nuclear Information System (INIS)

    Wade, M.R.; Houlberg, W.A.; Baylor, L.R.; West, W.P.; Baker, D.R.

    2001-01-01

    Impurity transport studies on DIII-D have revealed transport phenomena that are qualitatively consistent with that expected from turbulence transport theory in some cases and neoclassical transport theory in other cases. The transport model proposed here, which assumes that the total impurity transport is a linear sum of turbulence-driven transport and neoclassical transport, is shown to reproduce many of these observed features. This transport model is then applied to burn condition calculations, revealing that profile effects associated with neoclassical transport have a large effect on the maximum allowable impurity fraction in machines based on achieving neoclassical transport levels

  5. 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.

  6. Inner tegument proteins of Herpes Simplex Virus are sufficient for intracellular capsid motility in neurons but not for axonal targeting

    Science.gov (United States)

    Müller, Oliver; Ivanova, Lyudmila; Bialy, Dagmara; Pohlmann, Anja; Binz, Anne; Hegemann, Maike; Viejo-Borbolla, Abel; Rosenhahn, Bodo; Bauerfeind, Rudolf; Sodeik, Beate

    2017-01-01

    Upon reactivation from latency and during lytic infections in neurons, alphaherpesviruses assemble cytosolic capsids, capsids associated with enveloping membranes, and transport vesicles harboring fully enveloped capsids. It is debated whether capsid envelopment of herpes simplex virus (HSV) is completed in the soma prior to axonal targeting or later, and whether the mechanisms are the same in neurons derived from embryos or from adult hosts. We used HSV mutants impaired in capsid envelopment to test whether the inner tegument proteins pUL36 or pUL37 necessary for microtubule-mediated capsid transport were sufficient for axonal capsid targeting in neurons derived from the dorsal root ganglia of adult mice. Such neurons were infected with HSV1-ΔUL20 whose capsids recruited pUL36 and pUL37, with HSV1-ΔUL37 whose capsids associate only with pUL36, or with HSV1-ΔUL36 that assembles capsids lacking both proteins. While capsids of HSV1-ΔUL20 were actively transported along microtubules in epithelial cells and in the somata of neurons, those of HSV1-ΔUL36 and -ΔUL37 could only diffuse in the cytoplasm. Employing a novel image analysis algorithm to quantify capsid targeting to axons, we show that only a few capsids of HSV1-ΔUL20 entered axons, while vesicles transporting gD utilized axonal transport efficiently and independently of pUL36, pUL37, or pUL20. Our data indicate that capsid motility in the somata of neurons mediated by pUL36 and pUL37 does not suffice for targeting capsids to axons, and suggest that capsid envelopment needs to be completed in the soma prior to targeting of herpes simplex virus to the axons, and to spreading from neurons to neighboring cells. PMID:29284065

  7. In vivo phosphorylation of axonal proteins in goldfish optic nerve during regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Larrivee, D.C.; Grafstein, B.

    1987-01-01

    In vivo phosphorylation of axonal proteins was investigated in normal and regenerating optic nerves of goldfish by two-dimensional gel electrophoresis. By 6-24 h after intraocular injection of H/sub 3/(32)PO/sub 4/, approximately 20 optic nerve proteins ranging in size from 19 to 180 kilodaltons and in pI from 4.4 to 6.8 were seen to have incorporated radiolabel. Five of these proteins showed a robust increase in incorporation of phosphate during regeneration. Among the latter was an acidic (pI 4.5) 45-kilodalton protein, which has previously been shown to be conveyed by fast axonal transport and to increase dramatically in its rate of synthesis during regeneration of goldfish optic axons.

  8. 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

  9. A justice-theoretic approach to the distribution of transportation benefits: Implications for transportation planning practice in the United States

    NARCIS (Netherlands)

    Martens, C.J.C.M.; Golub, A.; Robinson, G.

    2012-01-01

    Transportation improvements inevitably lead to an uneven distribution of user benefits, in space and by network type (private and public transport). This paper makes a moral argument for what would be a fair distribution of these benefits. The argument follows Walzer’s ‘‘Spheres of Justice’’

  10. Angular momentum transport and dynamo action in the sun - Implications of recent oscillation measurements

    International Nuclear Information System (INIS)

    Gilman, P. A.; Morrow, C. A.; Deluca, E. E.

    1989-01-01

    The implications of a newly proposed picture of the sun's internal rotation (Brown et al., 1989; Morrow, 1988) for the distribution and transport of angular momentum and for the solar dynamo are considered. The new results, derived from an analysis of solar acoustic oscillations, affect understanding of how momentum is cycled in the sun and provide clues as to how and where the solar dynamo is driven. The data imply that the only significant radial gradient of angular velocity exists in a transitional region between the bottom of the convection zone, which is rotating like the solar surface, and the top of the deep interior, which is rotating rigidly at a rate intermediate between the equatorial and polar rates at the surface. Thus the radial gradient must change sign at the latitude where the angular velocity of the surface matches that of the interior. These inferences suggest that the cycle of angular momentum that produces the observed latitudinal differential rotation in the convection zone may be coupled to layers of the interior beneath the convection zone. 35 refs

  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. 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

  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

    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

  14. 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

  15. Opioid transport by ATP-binding cassette transporters at the blood-brain barrier: implications for neuropsychopharmacology.

    Science.gov (United States)

    Tournier, Nicolas; Declèves, Xavier; Saubaméa, Bruno; Scherrmann, Jean-Michel; Cisternino, Salvatore

    2011-01-01

    Some of the ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp; ABCB1, MDR1), BCRP (ABCG2) and MRPs (ABCCs) that are present at the blood-brain barrier (BBB) influence the brain pharmacokinetics (PK) of their substrates by restricting their uptake or enhancing their clearance from the brain into the blood, which has consequences for their CNS pharmacodynamics (PD). Opioid drugs have been invaluable tools for understanding the PK-PD relationships of these ABC-transporters. The effects of morphine, methadone and loperamide on the CNS are modulated by P-gp. This review examines the ways in which other opioid drugs and some of their active metabolites interact with ABC transporters and suggests new mechanisms that may be involved in the variability of the response of the CNS to these drugs like carrier-mediated system belonging to the solute carrier (SLC) superfamily. Exposure to opioids may also alter the expression of ABC transporters. P-gp can be overproduced during morphine treatment, suggesting that the drug has a direct or, more likely, an indirect action. Variations in cerebral neurotransmitters during exposure to opioids and the release of cytokines during pain could be new endogenous stimuli affecting transporter synthesis. This review concludes with an analysis of the pharmacotherapeutic and clinical impacts of the interactions between ABC transporters and opioids.

  16. The effects of voluntary running exercise coincidence with social isolation after early weaning on monoaminergic axonal development.

    Science.gov (United States)

    Ishikawa, J; Ishikawa, A

    2013-01-29

    The axonal development of serotonin (5-HT)-, noradrenaline (NA)-, or tyrosine hydroxylase (TH)-containing monoaminergic neurons is affected by rearing conditions during the juvenile period. Impaired monoaminergic axonal development is implicated in the pathophysiology of emotional and cognitive dysfunction. On the other hand, exercise may have beneficial effects on emotional and learning performance in adults. We have examined whether voluntary running exercise during social isolation after early weaning (early weaning/social isolation; EI) from postnatal day (PD) 14-28 could prevent the impaired monoaminergic axonal development associated with EI. Compared with control animals reared with their dam and siblings until PD28, the EI animals showed lower density of 5-HT and NA axons in the dorsal-medial prefrontal cortex (mPFC) and basolateral nucleus of the amygdala and of NA- and TH-containing axons in the ventral-mPFC. These adverse effects of EI were not observed in rats taking part in voluntary running (EI+R) when these animals were compared to controls. The 5-HT axon density in the ventral-mPFC was significantly higher in the EI+R rats than that in the EI rats, although both these values were significantly lower than those in the control rats. The density of monoaminergic axons in the dentate gyrus and CA3 of the hippocampus was not affected by either EI or EI+R. These results suggest that the beneficial effects of voluntary running may be because of the modulation of monoaminergic axonal morphology. Our findings will hopefully provide the basis for future research into the beneficial effects of voluntary exercise during the juvenile period on brain development and emotional and cognitive performance. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Specific effects of c-Jun NH2-terminal kinase-interacting protein 1 in neuronal axons

    Directory of Open Access Journals (Sweden)

    Shu Tang

    2016-01-01

    Full Text Available c-Jun NH2-terminal kinase (JNK-interacting protein 3 plays an important role in brain-derived neurotrophic factor/tropomyosin-related kinase B (TrkB anterograde axonal transport. It remains unclear whether JNK-interacting protein 1 mediates similar effects, or whether JNK-interacting protein 1 affects the regulation of TrkB anterograde axonal transport. In this study, we isolated rat embryonic hippocampus and cultured hippocampal neurons in vitro. Coimmunoprecipitation results demonstrated that JNK-interacting protein 1 formed TrkB complexes in vitro and in vivo. Immunocytochemistry results showed that when JNK-interacting protein 1 was highly expressed, the distribution of TrkB gradually increased in axon terminals. However, the distribution of TrkB reduced in axon terminals after knocking out JNK-interacting protein 1. In addition, there were differences in distribution of TrkB after JNK-interacting protein 1 was knocked out compared with not. However, knockout of JNK-interacting protein 1 did not affect the distribution of TrkB in dendrites. These findings confirm that JNK-interacting protein 1 can interact with TrkB in neuronal cells, and can regulate the transport of TrkB in axons, but not in dendrites.

  18. Neuron-glia signaling and the protection of axon function by Schwann cells.

    Science.gov (United States)

    Quintes, Susanne; Goebbels, Sandra; Saher, Gesine; Schwab, Markus H; Nave, Klaus-Armin

    2010-03-01

    The interaction between neurons and glial cells is a feature of all higher nervous systems. In the vertebrate peripheral nervous system, Schwann cells ensheath and myelinate axons thereby allowing rapid saltatory conduction and ensuring axonal integrity. Recently, some of the key molecules in neuron-Schwann cell signaling have been identified. Neuregulin-1 (NRG1) type III presented on the axonal surface determines the myelination fate of axons and controls myelin sheath thickness. Recent observations suggest that NRG1 regulates myelination via the control of Schwann cell cholesterol biosynthesis. This concept is supported by the finding that high cholesterol levels in Schwann cells are a rate-limiting factor for myelin protein production and transport of the major myelin protein P0 from the endoplasmic reticulum into the growing myelin sheath. NRG1 type III activates ErbB receptors on the Schwann cell, which leads to an increase in intracellular PIP3 levels via the PI3-kinase pathway. Surprisingly, enforced elevation of PIP3 levels by inactivation of the phosphatase PTEN in developing and mature Schwann cells does not entirely mimic NRG1 type III stimulated myelin growth, but predominantly causes focal hypermyelination starting at Schmidt-Lanterman incisures and nodes of Ranvier. This indicates that the glial transduction of pro-myelinating signals has to be under tight and life-long control to preserve integrity of the myelinated axon. Understanding the cross talk between neurons and Schwann cells will help to further define the role of glia in preserving axonal integrity and to develop therapeutic strategies for peripheral neuropathies such as CMT1A.

  19. Independent signaling by Drosophila insulin receptor for axon guidance and growth.

    Science.gov (United States)

    Li, Caroline R; Guo, Dongyu; Pick, Leslie

    2013-01-01

    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 five NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. These animals resembled chico mutants, supporting the notion that DInR interacts directly with Chico in vivo to control body size. Mutation of these five NPXY motifs did not affect photoreceptor axon guidance, segregating the roles of DInR in the

  20. Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity.

    Science.gov (United States)

    Truong, Jannine G; Wilkins, Diana G; Baudys, Jakub; Crouch, Dennis J; Johnson-Davis, Kamisha L; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

    2005-09-01

    Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

  1. 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.

  2. 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.

  3. MicroRNA-338 Attenuates Cortical Neuronal Outgrowth by Modulating the Expression of Axon Guidance Genes.

    Science.gov (United States)

    Kos, Aron; Klein-Gunnewiek, Teun; Meinhardt, Julia; Loohuis, Nikkie F M Olde; van Bokhoven, Hans; Kaplan, Barry B; Martens, Gerard J; Kolk, Sharon M; Aschrafi, Armaz

    2017-07-01

    MicroRNAs (miRs) are small non-coding RNAs that confer robustness to gene networks through post-transcriptional gene regulation. Previously, we identified miR-338 as a modulator of axonal outgrowth in sympathetic neurons. In the current study, we examined the role of miR-338 in the development of cortical neurons and uncovered its downstream mRNA targets. Long-term inhibition of miR-338 during neuronal differentiation resulted in reduced dendritic complexity and altered dendritic spine morphology. Furthermore, monitoring axon outgrowth in cortical cells revealed that miR-338 overexpression decreased, whereas inhibition of miR-338 increased axonal length. To identify gene targets mediating the observed phenotype, we inhibited miR-338 in cortical neurons and performed whole-transcriptome analysis. Pathway analysis revealed that miR-338 modulates a subset of transcripts involved in the axonal guidance machinery by means of direct and indirect gene targeting. Collectively, our results implicate miR-338 as a novel regulator of cortical neuronal maturation by fine-tuning the expression of gene networks governing cortical outgrowth.

  4. Effect of climate change on crop production patterns with implications to transport flows and inland waterways.

    Science.gov (United States)

    2011-12-01

    This project analyzed the demand for transportation capacity and changes in transportation flows on : inland waterways due to shifts in crop production patterns induced by climate change. Shifts in the crop : production mix have been observed in rece...

  5. The smart/connected city and its implications for connected transportation.

    Science.gov (United States)

    2014-10-14

    This white paper outlines the potential for the emerging connected transportation system to interface with smart/connected cities. Its aim is to lay the foundation for defining steps that the U.S. Department of Transportation (USDOT) Connected Vehicl...

  6. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques.

    Science.gov (United States)

    Gowrishankar, Swetha; Yuan, Peng; Wu, Yumei; Schrag, Matthew; Paradise, Summer; Grutzendler, Jaime; De Camilli, Pietro; Ferguson, Shawn M

    2015-07-14

    Through a comprehensive analysis of organellar markers in mouse models of Alzheimer's disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer's disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer's disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

  7. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

    Science.gov (United States)

    Gowrishankar, Swetha; Yuan, Peng; Wu, Yumei; Schrag, Matthew; Paradise, Summer; Grutzendler, Jaime; De Camilli, Pietro; Ferguson, Shawn M.

    2015-01-01

    Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology. PMID:26124111

  8. Alternative transport network designs and their implications for intermodal transhipment technologies

    OpenAIRE

    Woxenius, Johan

    2007-01-01

    Six principles for operation of the rail part of intermodal rail freight transport systems are described: direct link, corridor, hub-and-spoke, connected hubs, static routes, and dynamic routes. The first part is a theoretical discussion of the characteristics of the transport network designs. The theory is then applied to intermodal freight transport by analysing how each transport network design affects the need for terminal performance. The discussion includes a classification of existing ...

  9. The cyanobacterial bicarbonate transporter BicA: its physiological role and the implications of structural similarities with human SLC26 transporters.

    Science.gov (United States)

    Price, G Dean; Howitt, Susan M

    2011-04-01

    The cyanobacterial Na+-dependent HCO3- transporter BicA is a member of the ubiquitous and important SulP/SLC26 family of anion transporters found in eukaryotes and prokaryotes. BicA is an important component of the cyanobacterial CO2 concentrating mechanism, an adaptation that contributes to cyanobacteria being able to achieve an estimated 25% of global primary productivity, largely in the oceans. The human SLC26 members are involved in a range of key cellular functions involving a diverse range of anion transport activities including Cl-/HCO3-, I-/HCO3-, and SO42-/HCO3- exchange; mutations in SLC26 members are known to be associated with debilitating diseases such as Pendred syndrome, chondrodysplasias, and congenital chloride diarrhoea. We have recently experimentally determined the membrane topology of BicA using the phoA-lacZ reporter system and here consider some of the extrapolated implications for topology of the human SLC26 family and the Sultr plant sulphate transporters.

  10. 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.

  11. 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.

  12. Macrophage mitochondrial damage from StAR transport of 7-hydroperoxycholesterol: implications for oxidative stress-impaired reverse cholesterol transport.

    Science.gov (United States)

    Korytowski, Witold; Wawak, Katarzyna; Pabisz, Pawel; Schmitt, Jared C; Girotti, Albert W

    2014-01-03

    StAR family proteins in vascular macrophages participate in reverse cholesterol transport (RCT). We hypothesize that under pathophysiological oxidative stress, StARs will transport not only cholesterol to macrophage mitochondria, but also pro-oxidant cholesterol hydroperoxides (7-OOHs), thereby impairing early-stage RCT. Upon stimulation with dibutyryl-cAMP, RAW264.7 macrophages exhibited a strong time-dependent induction of mitochondrial StarD1 and plasma membrane ABCA1, which exports cholesterol. 7α-OOH uptake by stimulated RAW cell mitochondria (like cholesterol uptake) was strongly reduced by StarD1 knockdown, consistent with StarD1 involvement. Upon uptake by mitochondria, 7α-OOH (but not redox-inactive 7α-OH) triggered lipid peroxidation and membrane depolarization while reducing ABCA1 upregulation. These findings provide strong initial support for our hypothesis. Copyright © 2013. Published by Elsevier B.V.

  13. 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.

  14. 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.

  15. Effect of water soluble vitamins on Zn transport of Caco-2 cells and their implications under oxidative stress conditions.

    Science.gov (United States)

    Tupe, Rashmi Santosh; Agte, Vaishali Vilas

    2010-02-01

    The role of different water soluble vitamins in Zn metabolism beyond intestinal Zn absorption is poorly explored. Using Caco-2 cells, effects of different vitamins on intestinal Zn transport and their implications under oxidative stress (OS) were investigated. Cells were apically treated with Zn (25 muM) and vitamins (Folic acid (FA), Nicotinic acid (NA), Ascorbic acid (AA), riboflavin, thiamine, pyridoxine) for 60 min. The effect of most promising vitamins on zinc transport, antioxidant enzymes (Catalase, Glutathione peroxidase, and superoxide dismutase), and intracellular OS status (ROS generation and mitochondrial transmembrane potential) were investigated. OS was generated by tert-butyl hydro peroxide and results for each vitamin were compared with respective Zn containing controls with and without OS. Without OS, Zn transport was slightly enhanced in presence of NA, while it was significantly reduced by thiamine, riboflavin, and pyridoxine. Under OS, NA significantly (P vitamins. With Zn + FA + OS, enzyme activities decreased maximally, with twofold increase in 2',7'-dichlorofluorescin diacetate (DCF-DA) (P < 0.01) and lowering of rhodamine fluorescence (P < 0.05). In Zn + AA + OS, DCF-DA fluorescence increased (P < 0.05) but with NA, cellular enzymes, and antioxidant profile were improved. Results for the first time demonstrate advantageous effects of NA and deleterious consequences of FA with no effect by AA on Zn transport, especially under OS. These observed changes in the transport of Zn seem to have an impact on OS markers.

  16. Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia

    Science.gov (United States)

    Denton, Kyle R.; Lei, Ling; Grenier, Jeremy; Rodionov, Vladimir; Blackstone, Craig; Li, Xue-Jun

    2013-01-01

    Human neuronal models of hereditary spastic paraplegias (HSP) that recapitulate disease-specific axonal pathology hold the key to understanding why certain axons degenerate in patients and to developing therapies. SPG4, the most common form of HSP, is caused by autosomal dominant mutations in the SPAST gene, which encodes the microtubule-severing ATPase spastin. Here, we have generated a human neuronal model of SPG4 by establishing induced pluripotent stem cells (iPSCs) from an SPG4 patient and differentiating these cells into telencephalic glutamatergic neurons. The SPG4 neurons displayed a significant increase in axonal swellings, which stained strongly for mitochondria and tau, indicating the accumulation of axonal transport cargoes. In addition, mitochondrial transport was decreased in SPG4 neurons, revealing that these patient iPSC-derived neurons recapitulate disease-specific axonal phenotypes. Interestingly, spastin protein levels were significantly decreased in SPG4 neurons, supporting a haploinsufficiency mechanism. Furthermore, cortical neurons derived from spastin-knockdown human embryonic stem cells (hESCs) exhibited similar axonal swellings, confirming that the axonal defects can be caused by loss of spastin function. These spastin-knockdown hESCs serve as an additional model for studying HSP. Finally, levels of stabilized acetylated-tubulin were significantly increased in SPG4 neurons. Vinblastine, a microtubule-destabilizing drug, rescued this axonal swelling phenotype in neurons derived from both SPG4 iPSCs and spastin-knockdown hESCs. Thus, this study demonstrates the successful establishment of human pluripotent stem cell-based neuronal models of SPG4, which will be valuable for dissecting the pathogenic cellular mechanisms and screening compounds to rescue the axonal degeneration in HSP. PMID:24123785

  17. Entanglements in Marginal Solutions: A Means of Tuning Pre-Aggregation of Conjugated Polymers with Positive Implications for Charge Transport

    KAUST Repository

    Hu, Hanlin

    2015-06-17

    The solution-processing of conjugated polymers, just like commodity polymers, is subject to solvent and molecular weight-dependent solubility, interactions and chain entanglements within the polymer, all of which can influence the crystallization and microstructure development in semi-crystalline polymers and consequently affect charge transport and optoelectronic properties. Disentanglement of polymer chains in marginal solvents was reported to work via ultrasonication, facilitating the formation of photophysically ordered polymer aggregates. In this contribution, we explore how a wide range of technologically relevant solvents and formulations commonly used in organic electronics influence chain entanglement and the aggregation behaviour of P3HT using a combination of rheological and spectrophotometric measurements. The specific viscosity of the solution offers an excellent indication of the degree of entanglements in the solution, which is found to be related to the solubility of P3HT in a given solvent. Moreover, deliberately disentangling the solution in the presence of solvophobic driving forces, leads consistently to formation of photophysically visible aggregates which is indicative of local and perhaps long range order in the solute. We show for a broad range of solvents and molecular weights that disentanglement ultimately leads to significant ordering of the polymer in the solid state and a commensurate increase in charge transport properties. In doing so we demonstrate a remarkable ability to tune the microstructure which has important implications for transport properties. We discuss its potential implications in the context of organic photovoltaics.

  18. Spatial and temporal patterns of airflow across a foredune and beach surface under offshore winds: implications for aeolian sediment transport

    Science.gov (United States)

    Jackson, D.; Delgado-Fernandez, I.; Lynch, K.; Baas, A. C.; Cooper, J. A.; Beyers, M.

    2010-12-01

    The input of aeolian sediment into foredune systems from beaches represents a key component of sediment budget analysis along many soft sedimentary coastlines. Where there are significant offshore wind components in local wind regimes this is normally excluded from analysis. However, recent work has shown that if the topography of the foredune is favourable then this offshore component is steered or undergoes flow reversal through leeside eddying to give onshore transport events at the back beach under offshore flow conditions. At particular distances from the foredune crest flow reattaches to the surface to continue its incident offshore direction. The location of this reattachment point has important implications for aeolian transport of sand on the back beach and foredune toe locations. This study reports initial results where the positioning of the reattachment point is mobile and is driven by incident wind velocity (at the foredune crest) and the actual undulations of the foredune crest’s topography, dictating heterogeneous flow behaviour at the beach. Using detailed field measurements (25 Hz, three-dimensional sonic anemometry) and computational fluid dynamic modelling, a temporal and spatial pattern of reattachment positions are described. Implications for aeolian transport and dune evolution are also examined.

  19. Entanglements in Marginal Solutions: A Means of Tuning Pre-Aggregation of Conjugated Polymers with Positive Implications for Charge Transport

    KAUST Repository

    Hu, Hanlin; Zhao, Kui; Fernandes, Nikhil J.; Boufflet, Pierre; Bannock, James Henry; Yu, Liyang; de Mello, John C; Stingelin, Natalie; Heeney, Martin; Giannelis, Emmanuel P.; Amassian, Aram

    2015-01-01

    The solution-processing of conjugated polymers, just like commodity polymers, is subject to solvent and molecular weight-dependent solubility, interactions and chain entanglements within the polymer, all of which can influence the crystallization and microstructure development in semi-crystalline polymers and consequently affect charge transport and optoelectronic properties. Disentanglement of polymer chains in marginal solvents was reported to work via ultrasonication, facilitating the formation of photophysically ordered polymer aggregates. In this contribution, we explore how a wide range of technologically relevant solvents and formulations commonly used in organic electronics influence chain entanglement and the aggregation behaviour of P3HT using a combination of rheological and spectrophotometric measurements. The specific viscosity of the solution offers an excellent indication of the degree of entanglements in the solution, which is found to be related to the solubility of P3HT in a given solvent. Moreover, deliberately disentangling the solution in the presence of solvophobic driving forces, leads consistently to formation of photophysically visible aggregates which is indicative of local and perhaps long range order in the solute. We show for a broad range of solvents and molecular weights that disentanglement ultimately leads to significant ordering of the polymer in the solid state and a commensurate increase in charge transport properties. In doing so we demonstrate a remarkable ability to tune the microstructure which has important implications for transport properties. We discuss its potential implications in the context of organic photovoltaics.

  20. Spider silk constructs enhance axonal regeneration and remyelination in long nerve defects in sheep.

    Directory of Open Access Journals (Sweden)

    Christine Radtke

    Full Text Available BACKGROUND: Surgical reapposition of peripheral nerve results in some axonal regeneration and functional recovery, but the clinical outcome in long distance nerve defects is disappointing and research continues to utilize further interventional approaches to optimize functional recovery. We describe the use of nerve constructs consisting of decellularized vein grafts filled with spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect in adult sheep. METHODOLOGY/PRINCIPAL FINDINGS: The nerve constructs were compared to autologous nerve grafts. Regeneration was evaluated for clinical, electrophysiological and histological outcome. Electrophysiological recordings were obtained at 6 months and 10 months post surgery in each group. Ten months later, the nerves were removed and prepared for immunostaining, electrophysiological and electron microscopy. Immunostaining for sodium channel (NaV 1.6 was used to define nodes of Ranvier on regenerated axons in combination with anti-S100 and neurofilament. Anti-S100 was used to identify Schwann cells. Axons regenerated through the constructs and were myelinated indicating migration of Schwann cells into the constructs. Nodes of Ranvier between myelin segments were observed and identified by intense sodium channel (NaV 1.6 staining on the regenerated axons. There was no significant difference in electrophysiological results between control autologous experimental and construct implantation indicating that our construct are an effective alternative to autologous nerve transplantation. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that spider silk enhances Schwann cell migration, axonal regrowth and remyelination including electrophysiological recovery in a long-distance peripheral nerve gap model resulting in functional recovery. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery.

  1. Price and income elasticities of demand for passenger transport fuels in Spain. Implications for public policies

    International Nuclear Information System (INIS)

    Romero-Jordan, Desiderio; Del Rio, Pablo; Jorge-Garcia, Marta; Burguillo, Mercedes

    2010-01-01

    The significant increase in passenger transport activity (cars) experienced by Spain and its associated increase in energy consumption have several associated negative aspects, including a greater dependence on foreign energy sources and higher GHG emissions. Therefore, reducing the level of transport activity would bring important socioeconomic and environmental benefits. The aim of this paper, which focuses on energy consumption in the passenger transport, is fourfold: (1) to provide a diagnostic of energy consumption in the Spanish passenger transport system and the related problems; (2) to develop a model to calculate price and income elasticities of demand for transport fuel; (3) to apply this model to the Spanish passenger transport sector; (4) to infer policy recommendations derived from the results of the diagnostic and the model. It is claimed that, in view of those low price elasticities and high income elasticities and if a reduction in the scale of transport activity is deemed socially desirable, a combination of instruments is necessary. Fuel taxes play an important role within this combination. Apart from their long-term effects, the low price elasticity of demand for transport fuel would allow the collection of a significant amount of revenues, which could eventually be earmarked to encourage reductions in private transport demand and modal shifts with other instruments. (author)

  2. Price and income elasticities of demand for passenger transport fuels in Spain. Implications for public policies

    Energy Technology Data Exchange (ETDEWEB)

    Romero-Jordan, Desiderio [Universidad Rey Juan Carlos, Madrid (Spain); Del Rio, Pablo [Institute for Public Goods and Policies (IPP), Consejo Superior de Investigaciones Cientificas (CSIC), C/Albasanz, 26-28, Madrid 28037 (Spain); Jorge-Garcia, Marta [Universidad de Leon (Spain); Burguillo, Mercedes [Universidad de Alcala (Spain)

    2010-08-15

    The significant increase in passenger transport activity (cars) experienced by Spain and its associated increase in energy consumption have several associated negative aspects, including a greater dependence on foreign energy sources and higher GHG emissions. Therefore, reducing the level of transport activity would bring important socioeconomic and environmental benefits. The aim of this paper, which focuses on energy consumption in the passenger transport, is fourfold: (1) to provide a diagnostic of energy consumption in the Spanish passenger transport system and the related problems; (2) to develop a model to calculate price and income elasticities of demand for transport fuel; (3) to apply this model to the Spanish passenger transport sector; (4) to infer policy recommendations derived from the results of the diagnostic and the model. It is claimed that, in view of those low price elasticities and high income elasticities and if a reduction in the scale of transport activity is deemed socially desirable, a combination of instruments is necessary. Fuel taxes play an important role within this combination. Apart from their long-term effects, the low price elasticity of demand for transport fuel would allow the collection of a significant amount of revenues, which could eventually be earmarked to encourage reductions in private transport demand and modal shifts with other instruments. (author)

  3. The C-terminal domains of NF-H and NF-M subunits maintain axonal neurofilament content by blocking turnover of the stationary neurofilament network.

    Directory of Open Access Journals (Sweden)

    Mala V Rao

    Full Text Available Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M(tailΔ] mice that the deletion of both of these domains selectively lowers NF levels 3-6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M(tailΔ mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M(tailΔ axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons.

  4. Short communication: expression of transporters and metabolizing enzymes in the female lower genital tract: implications for microbicide research.

    Science.gov (United States)

    Zhou, Tian; Hu, Minlu; Cost, Marilyn; Poloyac, Samuel; Rohan, Lisa

    2013-11-01

    Topical vaginal microbicides have been considered a promising option for preventing the male-to-female sexual transmission of HIV; however, clinical trials to date have not clearly demonstrated robust and reproducible effectiveness results. While multiple approaches may help enhance product effectiveness observed in clinical trials, increasing the drug exposure in lower genital tract tissues is a compelling option, given the difficulty in achieving sufficient drug exposure and positive correlation between tissue exposure and microbicide efficacy. Since many microbicide drug candidates are substrates of transporters and/or metabolizing enzymes, there is emerging interest in improving microbicide exposure and efficacy through local modulation of transporters and enzymes in the female lower genital tract. However, no systematic information on transporter/enzyme expression is available for ectocervical and vaginal tissues of premenopausal women, the genital sites most relevant to microbicide drug delivery. The current study utilized reverse transcriptase polymerase chain reaction (RT-PCR) to examine the mRNA expression profile of 22 transporters and 19 metabolizing enzymes in premenopausal normal human ectocervix and vagina. Efflux and uptake transporters important for antiretroviral drugs, such as P-gp, BCRP, OCT2, and ENT1, were found to be moderately or highly expressed in the lower genital tract as compared to liver. Among the metabolizing enzymes examined, most CYP isoforms were not detected while a number of UGTs such as UGT1A1 were highly expressed. Moderate to high expression of select transporters and enzymes was also observed in mouse cervix and vagina. The implications of this information on microbicide research is also discussed, including microbicide pharmacokinetics, the utilization of the mouse model in microbicide screening, as well as the in vivo functional studies of cervicovaginal transporters and enzymes.

  5. Quantitative analysis of microtubule transport in growing nerve processes

    DEFF Research Database (Denmark)

    Ma*, Ytao; Shakiryanova*, Dinara; Vardya, Irina

    2004-01-01

    assumed that only a small fraction of MTs translocates along the axon by saltatory movement reminiscent of the fast axonal transport. Such intermittent "stop and go" MT transport has been difficult to detect or to exclude by using direct video microscopy methods. In this study, we measured...

  6. Modeling Np and Pu transport with a surface complexation model and spatially variant sorption capacities: Implications for reactive transport modeling and performance assessments of nuclear waste disposal sites

    Science.gov (United States)

    Glynn, P.D.

    2003-01-01

    simulation conditions. Functional behaviors that cannot be fit include concentration trend reversals and radionuclide desorption spikes. Other simulation results are fit successfully but the fitted parameters (Kd and dispersivity) vary significantly depending on simulation conditions (e.g. "infiltration" vs. "cleanup" conditions). Notably, an increase in the variance of the specified sorption capacities results in a marked increase in the dispersion of the radionuclides. The results presented have implications for the simulation of radionuclide migration in performance assessments of nuclear waste-disposal sites, for the future monitoring of those sites, and more generally for modeling contaminant transport in ground-water environments. ?? 2003 Published by Elsevier Science Ltd.

  7. Development and transport implications of automated vehicles in the Netherlands : Scenarios for 2030 and 2050

    NARCIS (Netherlands)

    Milakis, D.; Snelder, M.; van Arem, B.; van Wee, G.P.; Homem de Almeida Correia, G.

    2017-01-01

    Automated driving technology is emerging. Yet, little is known in the literature about when automated vehicles will reach the market, how penetration rates will evolve and to what extent this new transport technology will affect transport demand and planning. This study uses scenario analysis to

  8. Development and transport implications of automated vehicles in the Netherlands: Scenarios for 2030 and 2050

    NARCIS (Netherlands)

    Milakis, D.; Snelder, M.; Arem, B. van; Wee, B. van; Almeida Correia, G.H. de

    2017-01-01

    Automated driving technology is emerging. Yet, little is known in the literature about when automated vehicles will reach the market, how penetration rates will evolve and to what extent this new transport technology will affect transport demand and planning. This study uses scenario analysis to

  9. Transport-related fringe benefits: implications for moving and the journey to work

    NARCIS (Netherlands)

    van Ommeren, J.N.; van der Vlist, A.J.; Nijkamp, P.

    2006-01-01

    Firms offer compensation not only through wages, but also offer transport-related fringe benefits such as transport benefits (company cars, travel, and parking benefits) and relocation benefits to job applicants. We argue that these benefits are not randomly offered to employees, but depend on the

  10. Aerosol transport from Chiang Mai, Thailand to Mt. Lulin, Taiwan - Implication of aerosol aging during long-range transport

    Science.gov (United States)

    Chuang, Ming-Tung; Lee, Chung-Te; Chou, Charles C.-K.; Engling, Guenter; Chang, Shih-Yu; Chang, Shuenn-Chin; Sheu, Guey-Rong; Lin, Neng-Huei; Sopajaree, Khajornsak; Chang, You-Jia; Hong, Guo-Jun

    2016-07-01

    The transport of biomass burning (BB) aerosol from Indochina may cause a potential effect on climate change in Southeast Asia, East Asia, and the Western Pacific. Up to now, the understanding of BB aerosol composition modification during long-range transport (LRT) is still very limited due to the lack of observational data. In this study, atmospheric aerosols were collected at the Suthep/Doi Ang Khang (DAK) mountain sites in Chiang Mai, Thailand and the Lulin Atmospheric Background Station (Mt. Lulin) in central Taiwan from March to April 2010 and from February to April 2013, respectively. During the study period, an upwind and downwind relationship between the Suthep/DAK and Lulin sites (2400 km apart) was validated by backward trajectories. Comprehensive aerosol properties were resolved for PM2.5 water-soluble inorganic ions, carbonaceous content, water-soluble/insoluble organic carbon (WSOC/WIOC), dicarboxylic acids and their salts (DCAS), and anhydrosugars. A Modification Factor (MF) is proposed by employing non-sea-salt potassium ion (nss-K+) or fractionalized elemental carbon evolved at 580 °C after pyrolized OC correction (EC1-OP) as a BB aerosol tracer to evaluate the mass fraction changes of aerosol components from source to receptor regions during LRT. The MF values of nss-SO42-, NH4+, NO3-, OC1 (fractionalized organic carbon evolved from room temperature to 140 °C), OP (pyrolized OC fraction), DCAS, and WSOC were above unity, which indicated that these aerosol components were enhanced during LRT as compared with those in the near-source region. In contrast, the MF values of anhydrosugars ranged from 0.1 to 0.3, indicating anhydrosugars have degraded during LRT.

  11. 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

  12. The Pricing Evolution in the Air Transportation Industry. Implication for the Romanian Tourism Sector in the Era of Globalization

    Directory of Open Access Journals (Sweden)

    Andreea Marin-Pantelescu

    2016-06-01

    Full Text Available The globalization process involves the liberalization of the services and the air transportation industry is responsive to this reality. There is a developing tendency for global alliances and strategies in major airline companies. The globalization implies extending service networks in the whole world. Currently we are witnessing lower prices for domestic and foreign airline flights with benefits for the tourists’ business and leisure activities. The last minute offers and early booking prices provide a win-win situation, for the airline companies on one side and for the customers on the other side. The positive online reviews influence people buying decision because customers are more sensitive than ever to the services prices. Under this condition it is very interesting to see the evolution of pricing in the air transportation industry and the implication for the Romanian tourism sector.

  13. Impact of Emissions and Long-Range Transport on Multi-Decadal Aerosol Trends: Implications for Air Quality and Climate

    Science.gov (United States)

    Chin, Mian

    2012-01-01

    We present a global model analysis of the impact of long-range transport and anthropogenic emissions on the aerosol trends in the major pollution regions in the northern hemisphere and in the Arctic in the past three decades. We will use the Goddard Chemistry Aerosol Radiation and Transport (GOCART) model to analyze the multi-spatial and temporal scale data, including observations from Terra, Aqua, and CALIPSO satellites and from the long-term surface monitoring stations. We will analyze the source attribution (SA) and source-receptor (SR) relationships in North America, Europe, East Asia, South Asia, and the Arctic at the surface and free troposphere and establish the quantitative linkages between emissions from different source regions. We will discuss the implications for regional air quality and climate change.

  14. 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.

  15. 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...

  16. Origin, course, and laterality of spinocerebellar axons in the North American opossum, Didelphis virginiana.

    Science.gov (United States)

    Terman, J R; Wang, X M; Martin, G F

    1998-08-01

    Spinocerebellar axons have been studied extensively in placental mammals, but there have been no full reports on their origin, laterality, or spinal course in any marsupial. We have used the North American opossum (Didelphis virginiana) to obtain such information and to ask whether any spinocerebellar neurons innervate both the anterior and posterior lobes of the cerebellum through axonal collaterals. To identify spinal neurons that project to the cerebellum, we employed the retrograde transport of Fluoro-Gold (FG) from the anterior lobe, the main target of spinocerebellar axons. In some cases, cerebellar injections of FG were combined with hemisections of the rostral cervical or midthoracic spinal cord, so that laterality of spinocerebellar connections could be established. To determine whether single neurons project to both the anterior lobe and the posterior lobe, injections of Fast Blue (FB) into the anterior lobe were combined with injections of Diamidino yellow (DY) or rhodamine B dextran (RBD) into the posterior lobe, or vice versa. Following injections of FG into the anterior lobe, neurons were labeled throughout the length of the spinal cord, which differed in laminar distribution and laterality of their projections. Among other areas, neurons were labeled in the central cervical nucleus, the nucleus centrobasalis, Clarke's nucleus, the dorsal horn dorsal spinocerebellar tract area, the spinal border region, and Stilling's nucleus. When anterior lobe injections of FB were combined with injections of RBD or DY into the posterior lobe, or vice versa, some double-labeled neurons were present in all major spinocerebellar groups. Cerebellar injections of FG also retrogradely labeled spinocerebellar axons, allowing us to document their locations in the gray matter as well as within the periphery of the lateral and ventral funiculi at all spinal levels. A few spinocerebellar axons also were found in the dorsal funiculus (a dorsal column-spinocerebellar tract

  17. Determinants of satisfaction with campus transportation services: Implications for service quality

    Directory of Open Access Journals (Sweden)

    Felix Charbatzadeh

    2016-04-01

    Full Text Available Background: In a number of countries, buses are a critical element of public transportation, providing the most inclusive and sustainable mode of transportation to all forms of citizenry, including staff and students of universities. Objectives: The study examines the determinants of satisfaction with campus bus transportation. The article is primarily discursive and based on the synthesis of existing service literature supported by data obtained from a survey of 847 respondents. Method: Structural equation modelling is undertaken using AMOS 19, allowing for the examination of compound relationships between service engagement variables. Results: Results show statistically significant differences between perceived service quality and travel routes. The authors argue that managerial attention to service user experiences does not only hold the key to ongoing competitive success in campus transportation services but also that those services can be significantly enriched through greater managerial attention to the interface between risk of financial loss (which increases when the campus bus transportation service provider becomes less able to compete and service quality. Conclusion: The authors argue that if providers of campus bus transportation services are to rise to their service delivery challenges and also maintain or improve upon their market positions, they must conceptualise their services in a manner that takes into consideration the two-way interrelationship between risk of financial loss and service quality. It must also be noted that, although this study may have relevance for firm–firm scenarios, its focus is primarily on service supplier firm–customer service engagements. Keywords: Modelling; Transportation; Service

  18. Transportation into narrative worlds: implications for entertainment media influences on tobacco use.

    Science.gov (United States)

    Green, Melanie C; Clark, Jenna L

    2013-03-01

    A growing body of research suggests that smoking portrayals in movies influence adolescent tobacco use. However, the mechanism for this influence remains unclear. The aim of this paper is to provide an overview of research on narrative transportation theory, particularly as applied to movies and smoking. We propose that this theory can provide a valuable framework for guiding research on the role of entertainment media in smoking and other addictive behaviors. We review empirical work on transportation theory and highlight the psychological mechanisms underlying transportation effects. 'Transportation into narrative worlds' refers to cognitive, emotional and imagery engagement into a narrative (including movies and entertainment media). We link this work with research on the effects of movie smoking. Research suggests that individuals who are more highly transported into narratives show greater attitude, belief and behavior change. Transportation effects work through reducing counterarguing, creating connections (identification and liking) with characters and increasing perceptions of realism and emotional involvement. We propose several future directions and research challenges for applying a transportation framework to the issue of entertainment media effects on smoking and tobacco disparities. Understanding factors contributing to transportation may provide a more nuanced view of who will be affected by movie smoking, and understanding the psychological processes underlying narrative persuasion may guide intervention efforts. Narrative transportation theory suggests that individuals' cognitive, emotional and imagery immersion in a narrative is a key mechanism of attitude, belief and behavior change. This theory provides a potentially generative and psychologically grounded framework for increasing knowledge about the boundary conditions and processes underlying the effects of entertainment media on tobacco use. © 2012 The Authors, Addiction © 2012 Society for

  19. Transportation

    National Research Council Canada - National Science Library

    Adams, James; Carr, Ron; Chebl, Maroun; Coleman, Robert; Costantini, William; Cox, Robert; Dial, William; Jenkins, Robert; McGovern, James; Mueller, Peter

    2006-01-01

    ...., trains, ships, etc.) and maximizing intermodal efficiency. A healthy balance must be achieved between the flow of international commerce and security requirements regardless of transportation mode...

  20. Implications of a North American grain marketing system for prairie transportation and elevators

    Science.gov (United States)

    1997-09-01

    The balance of this report will examine the experiences U.S. production agriculture has had with deregulation of the transportation industry. It will highlight the evolution of the procurement segment of grain marketing, concentrating on the wheat or...

  1. The U.S.-Brazil-China trade and transportation triangle : implications for the southwest region.

    Science.gov (United States)

    2009-03-01

    The advent of globalization and more integrated international trade has placed increased demands : on transportation infrastructure. This report assesses the impacts of triangular trade between and among : the United States, Brazil and China with an ...

  2. Freight Transportation Information Systems and Their Implications for R&D Policy

    Science.gov (United States)

    1974-03-01

    The current use of computerized management information and control systems in intercity freight transportation are examined. Each of the four modes (railroad, motor carrier, maritime and air cargo industries) is investigated. In each case, computer i...

  3. Future travel demand and its implications for transportation infrastructure investments in the Texas Triangle.

    Science.gov (United States)

    2009-03-01

    This study takes a megaregion approach to project future travel demand and choice of transport : modes in the Texas Triangle, which is encompassed by four major metropolitan areas, Dallas-Fort : Worth, Houston, San Antonio, and Austin. The model was ...

  4. Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers: implications for oral drug delivery.

    Science.gov (United States)

    Sweet, Deborah M; Kolhatkar, Rohit B; Ray, Abhijit; Swaan, Peter; Ghandehari, Hamidreza

    2009-08-19

    The purpose of this work was to assess the impact of PEGylation on transepithelial transport of anionic poly(amidoamine) dendrimers. Cytotoxicity, uptake and transport across Caco-2 cells of PEGylated G3.5 and G4.5 PAMAM dendrimers were studied. Methoxy polyethylene glycol (750 Da) was conjugated to carboxylic acid-terminated PAMAM dendrimers at feed ratios of 1, 2 and 4 PEG per dendrimer. Compared to the control, PEGylation of anionic dendrimers did not significantly alter cytotoxicity up to a concentration of 0.1 mM. PEGylation of G3.5 dendrimers significantly decreased cellular uptake and transepithelial transport while PEGylation of G4.5 dendrimers led to a significant increase in uptake, but also a significant decrease in transport. Dendrimer PEGylation reduced the opening of tight junctions as evidenced by confocal microscopy techniques. Modulation of the tight junctional complex correlated well with changes in PEGylated dendrimer transport and suggests that anionic dendrimers are transported primarily through the paracellular route. PEGylated dendrimers show promise in oral delivery applications where increased functionality for drug conjugation and release is desired.

  5. 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.

  6. Transportation

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    Here is the decree of the thirtieth of July 1998 relative to road transportation, to trade and brokerage of wastes. It requires to firms which carry out a road transportation as well as to traders and to brokers of wastes to declare their operations to the prefect. The declaration has to be renewed every five years. (O.M.)

  7. Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery.

    Science.gov (United States)

    Sadekar, S; Ghandehari, H

    2012-05-01

    This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. 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

  9. 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

  10. 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

  11. Long-term environmental and health implications of morphological change and sediment transport with respect to contaminants

    Science.gov (United States)

    Sneddon, Christopher; Copplestone, David; Tyler, Andrew; Hunter, Peter; Smith, Nick

    2014-05-01

    The EPSRC-funded Adaptation and Resilience of Coastal Energy Supply (ARCoES) project encompasses four research strands, involving 14 institutions and six PhD studentships. ARCoES aims to determine the threats posed to future energy generation and the distribution network by flooding and erosion, changing patterns of coastal sedimentation, water temperature and the distribution of plants and animals in the coastal zone. Whilst this research has direct benefits for the operation of coastal power stations, ARCoES aims to have a wider stakeholder engagement through assessing how the resilience of coastal communities may be altered by five hundred years of coastal evolution. Coastal evolution will have substantial implications for the energy sector of the North West of England as former waste storage sites are eroded and remobilised within the intertidal environment. The current intertidal environmental stores of radioactivity will also experience reworking as ocean chemistry changes and saltmarsh chronologies are reworked in response to rising sea levels. There is a duel requirement to understand mass sediment movement along the North West coast of England as understanding the sediment transport dynamics is key to modelling long term coastal change and understanding how the environmental store of radioactivity will be reworked. The University of Stirling is researching the long-term environmental and health implications of remobilisation and transport of contaminated sediments around the UK coastline. Using a synergy of hyperspectral and topographic information the mobilisation of sediment bound contaminants within the coastal environment will be investigated. Potential hazards posed by contaminants are determined by a set of environmental impact test criteria which evaluate the bio-accessibility and ionising dose of contaminants. These test criteria will be used to comment on the likely environmental impact of modelled sediment transport and anticipated changes in

  12. Implications Of Technology Learning in Energy-Economy Models of the Transport Sector

    International Nuclear Information System (INIS)

    Krzyzanowski, D.A.; Kypreos, S.; Gutzwiller, L.; Barreto, L.

    2005-07-01

    Diffusion of hydrogen fuelled fuel cell vehicles is foreseen by many as the future for the transportation sector. However, high technological advancement over conventional power trains and improved performance of fuel cells as technology, do not guarantee that fuel cell vehicles will actually play a significant role in the transportation sector in the coming decades. In this study, an attempt is made to evaluate selected factors, which may have a stimulating or hindering effect on the market diffusion of fuel cell vehicles. The analysis evaluates the influence of technological learning of fuel cell stack components, prices of fuel cells, hydrogen and crude oil based fuels as well as governmental initiatives to penalise for CO 2 emissions coming from the transportation sector, on market diffusion of fuel cell vehicles in the coming years. (author)

  13. Implications Of Technology Learning in Energy-Economy Models of the Transport Sector

    Energy Technology Data Exchange (ETDEWEB)

    Krzyzanowski, D.A.; Kypreos, S.; Gutzwiller, L.; Barreto, L

    2005-07-01

    Diffusion of hydrogen fuelled fuel cell vehicles is foreseen by many as the future for the transportation sector. However, high technological advancement over conventional power trains and improved performance of fuel cells as technology, do not guarantee that fuel cell vehicles will actually play a significant role in the transportation sector in the coming decades. In this study, an attempt is made to evaluate selected factors, which may have a stimulating or hindering effect on the market diffusion of fuel cell vehicles. The analysis evaluates the influence of technological learning of fuel cell stack components, prices of fuel cells, hydrogen and crude oil based fuels as well as governmental initiatives to penalise for CO{sub 2} emissions coming from the transportation sector, on market diffusion of fuel cell vehicles in the coming years. (author)

  14. Transepithelial Transport of PEGylated Anionic Poly(amidoamine) Dendrimers: Implications for Oral Drug Delivery

    OpenAIRE

    Sweet, Deborah M.; Kolhatkar, Rohit B.; Ray, Abhijit; Swaan, Peter; Ghandehari, Hamidreza

    2009-01-01

    The purpose of this work was to assess the impact of PEGylation on transepithelial transport of anionic poly(amidoamine) dendrimers. Cytotoxicity, uptake and transport across Caco-2 cells of PEGylated G3.5 and G4.5 PAMAM dendrimers were studied. Methoxy polyethylene glycol (750 Da) was conjugated to carboxylic acid-terminated PAMAM dendrimers at feed ratios of 1, 2 and 4 PEG per dendrimer. Compared to the control, PEGylation of anionic dendrimers did not significantly alter cytotoxicity up to...

  15. 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.

  16. 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...

  17. 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

  18. 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...

  19. Automobile dependence in cities: An international comparison of urban transport and land use patterns with implications for sustainability

    International Nuclear Information System (INIS)

    Kenworthy, J.R.; Laube, F.B.

    1996-01-01

    Cities around the world are subject to increasing levels of environmental impact from dependence on the automobile. In the highly auto-dependent cities of the US and Australia, this is manifested in problems such as urban sprawl and its destruction of prime farming land and natural landscapes, photochemical smog that can be primarily attributed to auto emissions. On top of the more local impacts of the automobile, the global dimension should not be forgotten. Perhaps the two most pressing issues in this regard are the oil problem and the greenhouse problem. A comparison of global cities over the period 1980 to 1990 reveals large differences in automobile dependence with implications for the future sustainability of cities in different countries. This study explores some of the underlying land use, transport, and economic reasons for these different transport patterns. It briefly reviews what the sustainability agenda means for transport and land use patterns in cities and suggests a suite of targets or goals for sustainability by which cities might measure their current directions and plans

  20. Transportation

    National Research Council Canada - National Science Library

    Allshouse, Michael; Armstrong, Frederick Henry; Burns, Stephen; Courts, Michael; Denn, Douglas; Fortunato, Paul; Gettings, Daniel; Hansen, David; Hoffman, D. W; Jones, Robert

    2007-01-01

    .... The ability of the global transportation industry to rapidly move passengers and products from one corner of the globe to another continues to amaze even those wise to the dynamics of such operations...

  1. 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

  2. Energy for sustainable road transportation in China: Challenges, initiatives and policy implications

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Xiaojun; Chang, Shiyan; Li, Jingjie; Qin, Yining [Institute of Energy and Environmental Economics, Energy Science Building, Tsinghua University, Beijing 100084 (China)

    2010-11-15

    This paper presents an overview of the initiatives launched in energy supply and consumption and the challenges encountered in sustainable road transportation development in China. It analyzes the main energy challenges related to road transportation development arising in the context of economic development, rapid urbanization, and improvement in living standards. It also discusses technological- and policy initiatives needed to deal with these challenges, drawing comparisons with foreign experience: promoting the development and dissemination of alternative fuels and clean vehicles such as: LPG, CNG, EV, HEV, FCV, ethanol, methanol, DME, bio-diesel, and CTL, strengthening regulations relating to vehicle fuel economy and emission, improving traffic efficiency and facilitating public transport development, and strengthening management of the soaring motor vehicle population. If the current pattern continues, by the year 2030, the vehicle population in China will be 400 million and fuel demand will be 350 million tons. The potential energy saving capacity being 60%, the actual oil demand by 2030 from on-road vehicles might technically be kept at the current level by improving fuel economy, propagating use of HEV and diesel vehicles, improving supply of alternative fuels, and developing public transport. Several uncertainties are identified that could greatly influence the effect of the technical proposals: traffic efficiency, central government's resolve, and consumers' choice. (author)

  3. The circulation of the lower Capibaribe Estuary (Brazil and its implications for the transport of scalars

    Directory of Open Access Journals (Sweden)

    Carlos Augusto França Schettini

    Full Text Available Abstract The Capibaribe Estuary is a water body that crosses the Recife Metropolitan Area (RMA, one of the largest population centers in Brazil, and causes large pollutant loads and poor water quality. The fresh water inflow of wastewater from the RMA can account for three times the volume of the river discharge during the low discharge period. This article assesses the hydrodynamics and potential transport of particulate and dissolved scalars in this estuary. A field experiment was conducted to record the water level, current velocity, salinity, temperature and suspended particulate matter (SPM contents during a full semi-diurnal tidal cycle. This experiment was performed during low river discharge and spring tide conditions. The estuary showed a partially mixed circulation pattern. The residual transport of water and salt were up estuary, while the SPM residual transport was down estuary. The former were understood as the effect of the residual circulation around the islands, while the latter was interpreted as a morphological factor inducing greater resuspension during the ebb, despite the symmetrical ebb and flood currents. This mechanism may transport SPM to the inner shelf, even under tide-dominated conditions when the opposite would be expected.

  4. Transportation planning implications of automated/connected vehicles on Texas highways : project summary.

    Science.gov (United States)

    2017-01-01

    Through outreach to stakeholders during the workshops, researchers found that there is a need to be able to explain AV/CV technology and its impacts on long-range transportation plans. Given that the future is uncertain, planners either choose to ign...

  5. Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+.

    NARCIS (Netherlands)

    Dimke, H.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2010-01-01

    The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes,

  6. Internationalisation in Road Transport of Goods in Norway: Safety Outcomes, Risk Factors and Policy Implications

    Directory of Open Access Journals (Sweden)

    Tor-Olav Nævestad

    2017-09-01

    Full Text Available The European Union (EU promotes a gradual lifting of restrictions on foreign hauliers involved in domestic road transport of goods (cabotage, and liberalization of the current road cabotage rules may further increase the proportion of foreign heavy goods vehicles (HGVs on Norwegian roads. The aims of the present study are to: (1 Examine the safety outcomes of increasing internationalisation in (Norwegian road transport of goods; and (2 Discuss the importance of potential risk factors related to increasing proportions of foreign HGVs on Norwegian roads. We use four data sources to shed light on the aims. Results show that foreign HGVs account for 6% of the average domestic transport in Norway, and 11% of the HGVs involved in personal injury accidents. Additionally, foreign HGVs have a three times higher risk of single vehicle accidents, and twice the risk of head-on collisions. Foreign HGV drivers also seem more likely to trigger fatal accidents. We conclude that two risk factors seem to be important: (1 experience with/competence on Norwegian roads and (2 winter driving. Thus, the safety challenge is not that the drivers are foreign, but that they to some extent lack experience with, and competence on, the Norwegian road networks and the challenges that these roads may pose (e.g., narrow roads with high gradients, many curves, snow and ice. Previous research from other countries has also found that lacking experience with national road networks is an important risk factor. Given our results on risk factors, we may hypothesize that if foreign HGV drivers get more experience and education on Norwegian driving conditions, then increased internationalization could perhaps be of less concern in road safety. When discussing the higher accident risk and lower experience of foreign HGV drivers in Norway, it is important to note that the reason for foreign HGV drivers, working for foreign hauliers, to drive in Norway is that there are customers of the

  7. Transport and Biodistribution of Dendrimers Across Human Fetal Membranes: Implications for Intravaginal Administration of Dendrimers

    Science.gov (United States)

    Menjoge, Anupa R.; Navath, Raghavendra S.; Asad, Abbas; Kannan, Sujatha; Kim, Chong Jai; Romero, Roberto; Kannan, Rangaramanujam M.

    2010-01-01

    Dendrimers are emerging as promising topical antimicrobial agents, and as targeted nanoscale drug delivery vehicles. Topical intravaginal antimicrobial agents are prescribed to treat the ascending genital infections in pregnant women. The fetal membranes separate the extra-amniotic space and fetus. The purpose of the study is to determine if the dendrimers can be selectively used for local intravaginal application to pregnant women without crossing the membranes into the fetus. In the present study, the transport and permeability of PAMAM (poly(amidoamine)) dendrimers, across human fetal membrane (using a side-by-side diffusion chamber), and its biodistribution (using immunofluorescence) are evaluated ex-vivo. Transport across human fetal membranes (from the maternal side) was evaluated using Fluorescein (FITC), an established transplacental marker (positive control, size~ 400 Da) and fluorophore-tagged G4-PAMAM dendrimers (~ 16 kDa). The fluorophore-tagged G4-PAMAM dendrimers were synthesized and characterized using 1H NMR, MALDI TOF-MS and HPLC analysis. Transfer was measured across the intact fetal membrane (chorioamnion), and the separated chorion and amnion layers. Over a five hour period, the dendrimer transport across all the three membranes was less than transport of FITC was relatively fast with as much as 49% transport across the amnion. The permeability of FITC (7.9 × 10-7 cm2/s) through the chorioamnion was 7-fold higher than that of the dendrimer (5.8 × 10-8 cm2/s). The biodistribution showed that the dendrimers were largely present in interstitial spaces in the decidual stromal cells and the chorionic trophoblast cells (in 2.5 to 4 h) and surprisingly, to a smaller extent internalized in nuclei of trophoblast cells and nuclei and cytoplasm of stromal cells. Passive diffusion and paracellular transport appear to be the major route for dendrimer transport. The overall findings further suggest that entry of drugs conjugated to dendrimers would be

  8. Cross-hemispheric transport of central African biomass burning pollutants: implications for downwind ozone production

    Directory of Open Access Journals (Sweden)

    E. Real

    2010-03-01

    Full Text Available Pollutant plumes with enhanced concentrations of trace gases and aerosols were observed over the southern coast of West Africa during August 2006 as part of the AMMA wet season field campaign. Plumes were observed both in the mid and upper troposphere. In this study we examined the origin of these pollutant plumes, and their potential to photochemically produce ozone (O3 downwind over the Atlantic Ocean. Their possible contribution to the Atlantic O3 maximum is also discussed. Runs using the BOLAM mesoscale model including biomass burning carbon monoxide (CO tracers were used to confirm an origin from central African biomass burning fires. The plumes measured in the mid troposphere (MT had significantly higher pollutant concentrations over West Africa compared to the upper tropospheric (UT plume. The mesoscale model reproduces these differences and the two different pathways for the plumes at different altitudes: transport to the north-east of the fire region, moist convective uplift and transport to West Africa for the upper tropospheric plume versus north-west transport over the Gulf of Guinea for the mid-tropospheric plume. Lower concentrations in the upper troposphere are mainly due to enhanced mixing during upward transport. Model simulations suggest that MT and UT plumes are 16 and 14 days old respectively when measured over West Africa. The ratio of tracer concentrations at 600 hPa and 250 hPa was estimated for 14–15 August in the region of the observed plumes and compares well with the same ratio derived from observed carbon dioxide (CO2 enhancements in both plumes. It is estimated that, for the period 1–15 August, the ratio of Biomass Burning (BB tracer concentration transported in the UT to the ones transported in the MT is 0.6 over West Africa and the equatorial South Atlantic.

    Runs using a photochemical trajectory model, CiTTyCAT, initialized with the observations, were used to estimate

  9. Environmental and financial implications of ethanol as a bioethylene feedstock versus as a transportation fuel

    International Nuclear Information System (INIS)

    McKechnie, Jon; Pourbafrani, Mohammad; Saville, Bradley A; MacLean, Heather L

    2015-01-01

    Bulk chemicals production from biomass may compete with biofuels for low-cost and sustainable biomass sources. Understanding how alternative uses of biomass compare in terms of financial and environmental parameters is therefore necessary to help ensure that efficient uses of resources are encouraged by policy and undertaken by industry. In this paper, we compare the environmental and financial performance of using ethanol as a feedstock for bioethylene production or as a transport fuel in the US life cycle-based models are developed to isolate the relative impacts of these two ethanol uses and generate results that are applicable irrespective of ethanol production pathway. Ethanol use as a feedstock for bioethylene production or as a transport fuel leads to comparable greenhouse gas (GHG) emissions and fossil energy consumption reductions relative to their counterparts produced from fossil sources. By displacing gasoline use in vehicles, use of ethanol as a transport fuel is six times more effective in reducing petroleum energy use on a life cycle basis. In contrast, bioethylene predominately avoids consumption of natural gas. Considering 2013 US ethanol and ethylene market prices, our analysis shows that bioethylene is financially viable only if significant price premiums are realized over conventional ethylene, from 35% to 65% depending on the scale of bioethylene production considered (80 000 t yr −1 to 240 000 t yr −1 ). Ethanol use as a transportation fuel is therefore the preferred pathway considering financial, GHG emissions, and petroleum energy use metrics, although bioethylene production could have strategic value if demand-side limitations of ethanol transport fuel markets are reached. (letter)

  10. Environmental and financial implications of ethanol as a bioethylene feedstock versus as a transportation fuel

    Science.gov (United States)

    McKechnie, Jon; Pourbafrani, Mohammad; Saville, Bradley A.; MacLean, Heather L.

    2015-12-01

    Bulk chemicals production from biomass may compete with biofuels for low-cost and sustainable biomass sources. Understanding how alternative uses of biomass compare in terms of financial and environmental parameters is therefore necessary to help ensure that efficient uses of resources are encouraged by policy and undertaken by industry. In this paper, we compare the environmental and financial performance of using ethanol as a feedstock for bioethylene production or as a transport fuel in the US life cycle-based models are developed to isolate the relative impacts of these two ethanol uses and generate results that are applicable irrespective of ethanol production pathway. Ethanol use as a feedstock for bioethylene production or as a transport fuel leads to comparable greenhouse gas (GHG) emissions and fossil energy consumption reductions relative to their counterparts produced from fossil sources. By displacing gasoline use in vehicles, use of ethanol as a transport fuel is six times more effective in reducing petroleum energy use on a life cycle basis. In contrast, bioethylene predominately avoids consumption of natural gas. Considering 2013 US ethanol and ethylene market prices, our analysis shows that bioethylene is financially viable only if significant price premiums are realized over conventional ethylene, from 35% to 65% depending on the scale of bioethylene production considered (80 000 t yr-1 to 240 000 t yr-1). Ethanol use as a transportation fuel is therefore the preferred pathway considering financial, GHG emissions, and petroleum energy use metrics, although bioethylene production could have strategic value if demand-side limitations of ethanol transport fuel markets are reached.

  11. Sigma-1 receptor agonist increases axon outgrowth of hippocampal neurons via voltage-gated calcium ions channels.

    Science.gov (United States)

    Li, Dong; Zhang, Shu-Zhuo; Yao, Yu-Hong; Xiang, Yun; Ma, Xiao-Yun; Wei, Xiao-Li; Yan, Hai-Tao; Liu, Xiao-Yan

    2017-12-01

    Sigma-1 receptors (Sig-1Rs) are unique endoplasmic reticulum proteins that have been implicated in both neurodegenerative and ischemic diseases, such as Alzheimer's disease and stroke. Accumulating evidence has suggested that Sig-1R plays a role in neuroprotection and axon outgrowth. The underlying mechanisms of Sig-1R-mediated neuroprotection have been well elucidated. However, the mechanisms underlying the effects of Sig-1R on axon outgrowth are not fully understood. To clarify this issue, we utilized immunofluorescence to compare the axon lengths of cultured naïve hippocampal neurons before and after the application of the Sig-1R agonist, SA4503. Then, electrophysiology and immunofluorescence were used to examine voltage-gated calcium ion channel (VGCCs) currents in the cell membranes and growth cones. We found that Sig-1R activation dramatically enhanced the axonal length of the naïve hippocampal neurons. Application of the Sig-1R antagonist NE100 and gene knockdown techniques both demonstrated the effects of Sig-1R. The growth-promoting effect of SA4503 was accompanied by the inhibition of voltage-gated Ca 2+ influx and was recapitulated by incubating the neurons with the L-type, N-type, and P/Q-type VGCC blockers, nimodipine, MVIIA and ω-agatoxin IVA, respectively. This effect was unrelated to glial cells. The application of SA4503 transformed the growth cone morphologies from complicated to simple, which favored axon outgrowth. Sig-1R activation can enhance axon outgrowth and may have a substantial influence on neurogenesis and neurodegenerative diseases. © 2017 John Wiley & Sons Ltd.

  12. Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment.

    Science.gov (United States)

    Sohn, Peter Dongmin; Tracy, Tara E; Son, Hye-In; Zhou, Yungui; Leite, Renata E P; Miller, Bruce L; Seeley, William W; Grinberg, Lea T; Gan, Li

    2016-06-29

    Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Loss of polarized distribution of the axonal protein tau is an early sign of Alzheimer's disease (AD) and other neurodegenerative disorders. The cytoskeletal network in the axon initial segment (AIS) forms a barrier between the axon and the somatodentritic compartment, contributing to axonal retention of tau. Although perturbation of the AIS cytoskeleton has been implicated in neurological disorders, the molecular triggers and functional consequence of AIS perturbation are incompletely understood. Here we report that tau acetylation and consequent destabilization of the AIS cytoskeleton promote the somatodendritic mislocalization of tau. AIS cytoskeletal proteins, including ankyrin G and βIV-spectrin, were downregulated in AD brains and negatively correlated with an increase in tau acetylated at K274 and K281. AIS proteins were also diminished in transgenic mice expressing tauK274/281Q, a tau mutant that mimics K274 and K281 acetylation. In primary neuronal cultures, the tauK274/281Q mutant caused hyperdynamic microtubules (MTs) in the AIS, shown by live-imaging of MT mobility and fluorescence recovery after photobleaching. Using photoconvertible tau constructs, we found that axonal tauK274/281Q was missorted into the somatodendritic compartment. Stabilizing MTs with epothilone D to restore the cytoskeletal barrier in the AIS prevented tau mislocalization in primary neuronal cultures. Together, these findings demonstrate that tau acetylation contributes to the pathogenesis of neurodegenerative disease by compromising the cytoskeletal sorting machinery in the AIS.

  13. 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

  14. Natural spatial and temporal variations in groundwater chemistry in fractured, sedimentary rocks: scale and implications for solute transport

    International Nuclear Information System (INIS)

    Hoven, Stephen J. van der; Kip Solomon, D.; Moline, Gerilynn R.

    2005-01-01

    Natural tracers (major ions, δ 18 O, and O 2 ) were monitored to evaluate groundwater flow and transport to a depth of 20 m below the surface in fractured sedimentary (primarily shale and limestone) rocks. Large temporal variations in these tracers were noted in the soil zone and the saprolite, and are driven primarily by individual storm events. During nonstorm periods, an upward flow brings water with high TDS, constant δ 18 O, and low dissolved O 2 to the water table. During storm events, low TDS, variable δ 18 O, and high dissolved O 2 water recharges through the unsaturated zone. These oscillating signals are rapidly transmitted along fracture pathways in the saprolite, with changes occurring on spatial scales of several meters and on a time scale of hours. The variations decreased markedly below the boundary between the saprolite and less weathered bedrock. Variations in the bedrock units occurred on time scales of days and spatial scales of at least 20 m. The oscillations of chemical conditions in the shallow groundwater are hypothesized to have significant implications for solute transport. Solutes and colloids that adsorb onto aquifer solids can be released into solution by decreases in ionic strength and pH. The decreases in ionic strength also cause thermodynamic undersaturation of the groundwater with respect to some mineral species and may result in mineral dissolution. Redox conditions are also changing and may result in mineral dissolution/precipitation. The net result of these chemical variations is episodic transport of a wide range of dissolved solutes or suspended particles, a phenomenon rarely considered in contaminant transport studies

  15. 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.

  16. Savanna burning and convective mixing in Southern Africa: Implications for CO emissions and transport

    International Nuclear Information System (INIS)

    Connors, V.S.; Cahoon, D.R. Jr.; Reichle, H.G. Jr.; Brunke, E.G.; Garstang, M.; Seiler, W.; Scheel, H.E.

    1991-01-01

    This study examines both the emission and the transport of CO from the surface to the free troposphere and the role of convection in redistributing this gas in the free troposphere over southern Africa. Upper-air soundings, the meteorological analyses from the European Center for Medium-Range Weather Forecasts (ECMWF), and the multispectral imagery from the European Space Agency's Meteosat-2 satellite comprise the meteorological data base. The surface measurements of CO were measured at an atmospheric chemistry laboratory in Cape Point, South Africa. The CO in the middle troposphere was measured by the Measurement of Air Pollution from Satellites (MAPS) experiment flown on the space shuttle. This study focuses on the emissions and transport of CO from Africa south of the equator on 5-6 October 1984

  17. The transport implications of regional policies for the disposal of intermediate level radioactive wastes

    International Nuclear Information System (INIS)

    James, I.A.

    1985-09-01

    This report aims to evaluate transport parameters and logistics associated with the disposal of intermediate-level radioactive wastes, as generated by CEGB, SSEB, UKAEA and BNFL. The assumed power scenario is DoE Scheme 3, which approximates to a moderate power generation scenario, with a 15 GWe PWR programme commissioned between 1991 and 2010, existing Magnox and AGR stations are assumed to have a 30 year lifespan. Three transport options are again assumed, namely; road, rail and a hybrid system, as is consistent with previous studies. These three options will be used in investigating regional policies of disposal, initially at the national level and then progressively disaggregating to a system of three regional depositories serving their respective catchment areas. (author)

  18. Chlorpyrifos exerts opposing effects on axonal and dendritic growth in primary neuronal cultures

    International Nuclear Information System (INIS)

    Howard, Angela S.; Bucelli, Robert; Jett, David A.; Bruun, Donald; Yang, Dongren; Lein, Pamela J.

    2005-01-01

    Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that OPs cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations ≥0.001 μM or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (≥1 μM) and CPFO (≥1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system

  19. 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.

  20. Immobilization of Caenorhabditis elegans to Analyze Intracellular Transport in Neurons.

    Science.gov (United States)

    Niwa, Shinsuke

    2017-10-18

    Axonal transport and intraflagellar transport (IFT) are essential for axon and cilia morphogenesis and function. Kinesin superfamily proteins and dynein are molecular motors that regulate anterograde and retrograde transport, respectively. These motors use microtubule networks as rails. Caenorhabditis elegans (C. elegans) is a powerful model organism to study axonal transport and IFT in vivo. Here, I describe a protocol to observe axonal transport and IFT in living C. elegans. Transported cargo can be visualized by tagging cargo proteins using fluorescent proteins such as green fluorescent protein (GFP). C. elegans is transparent and GFP-tagged cargo proteins can be expressed in specific cells under cell-specific promoters. Living worms can be fixed by microbeads on 10% agarose gel without killing or anesthetizing the worms. Under these conditions, cargo movement can be directly observed in the axons and cilia of living C. elegans without dissection. This method can be applied to the observation of any cargo molecule in any cells by modifying the target proteins and/or the cells they are expressed in. Most basic proteins such as molecular motors and adaptor proteins that are involved in axonal transport and IFT are conserved in C. elegans. Compared to other model organisms, mutants can be obtained and maintained more easily in C. elegans. Combining this method with various C. elegans mutants can clarify the molecular mechanisms of axonal transport and IFT.

  1. Implications of high density operation on SOL transport: A multimachine investigation

    Czech Academy of Sciences Publication Activity Database

    Carralero, D.; Müller, H.W.; Groth, M.; Komm, Michael; Adámek, Jiří; Birkenmeier, G.; Brix, M.; Janky, Filip; Háček, Pavel; Marsen, S.; Reimold, F.; Silva, C.; Stroth, U.; Wischmeier, M.; Wolfrum, E.

    2015-01-01

    Roč. 463, August (2015), s. 123-127 ISSN 0022-3115. [PLASMA-SURFACE INTERACTIONS 21: International Conference on Plasma-Surface Interactions in Controlled Fusion Devices. Kanazawa, 26.05.2014-30.05.2014] Institutional support: RVO:61389021 Keywords : SOL transport * tokamak * COMPASS Subject RIV: JF - Nuclear Energetics OBOR OECD: Nuclear related engineering Impact factor: 2.199, year: 2015 http://www.sciencedirect.com/science/article/pii/S002231151400703X

  2. Achieving deep reductions in US transport greenhouse gas emissions: Scenario analysis and policy implications

    International Nuclear Information System (INIS)

    McCollum, David; Yang, Christopher

    2009-01-01

    This paper investigates the potential for making deep cuts in US transportation greenhouse gas (GHG) emissions in the long-term (50-80% below 1990 levels by 2050). Scenarios are used to envision how such a significant decarbonization might be achieved through the application of advanced vehicle technologies and fuels, and various options for behavioral change. A Kaya framework that decomposes GHG emissions into the product of four major drivers is used to analyze emissions and mitigation options. In contrast to most previous studies, a relatively simple, easily adaptable modeling methodology is used which can incorporate insights from other modeling studies and organize them in a way that is easy for policymakers to understand. Also, a wider range of transportation subsectors is considered here-light- and heavy-duty vehicles, aviation, rail, marine, agriculture, off-road, and construction. This analysis investigates scenarios with multiple options (increased efficiency, lower-carbon fuels, and travel demand management) across the various subsectors and confirms the notion that there are no 'silver bullet' strategies for making deep cuts in transport GHGs. If substantial emission reductions are to be made, considerable action is needed on all fronts, and no subsectors can be ignored. Light-duty vehicles offer the greatest potential for emission reductions; however, while deep reductions in other subsectors are also possible, there are more limitations in the types of fuels and propulsion systems that can be used. In all cases travel demand management strategies are critical; deep emission cuts will not likely be possible without slowing growth in travel demand across all modes. Even though these scenarios represent only a small subset of the potential futures in which deep reductions might be achieved, they provide a sense of the magnitude of changes required in our transportation system and the need for early and aggressive action if long-term targets are to be met.

  3. Queueing in a spent fuel transportation system - preliminary analysis of implications for system design

    International Nuclear Information System (INIS)

    Cashwell, J.W.; Wood, T.W.

    1985-01-01

    Compliance with the Nuclear Waste Policy Act of 1982 (PL 97-425) will require the transportation of large volumes of spent fuel to a central receiving facility (either a geologic repository or a monitored retrievable storage facility). Decisions on the transport mode and technology will evolve over the next several years, in anticipation of the deployment of a receiving facility in the late 1990s. Regardless of the particular transportation mode or modes and the details of cask technology, the transport system from many diverse sources to a single point will generate an essentially random arrival pattern. This random arrival pattern will lead to the formation of queues at the receiving facility. As is normal in any queueing system, the waiting time distribution caused by this queueing will depend on the receiving facility input processing rate and the characteristics of the traffic. Since this is a cyclic system, there is also a reverse effect in which (for a given size cask fleet) average wait time affects traffic intensity. Both effects must be accounted for to properly represent the system. This paper develops a simple analytic queueing model which accounts for both of these effects simultaneously. Since both effects are determined by receiving facility input rates and cask fleet size and characteristics, two major sets of system design parameters are linked by the queueing process. The model is used with estimated traffic and service parameters to predict the severity of queueing under plausible reference system conditions, and to establish shadow prices for the trade off between larger cask fleets and more efficient receiving facilities. Since many of the parameter values used in this estimation are quite preliminary, these results are presented primarily in the context of demonstrating the utility of the queueing model for future trade off studies

  4. Surf zone entrainment, along-shore transport, and human health implications of pollution from tidal outlets

    Science.gov (United States)

    Grant, S. B.; Kim, J. H.; Jones, B. H.; Jenkins, S. A.; Wasyl, J.; Cudaback, C.

    2005-10-01

    Field experiments and modeling studies were carried out to characterize the surf zone entrainment and along-shore transport of pollution from two tidal outlets that drain into Huntington Beach and Newport Beach, popular public beaches in southern California. The surf zone entrainment and near-shore transport of pollutants from these tidal outlets appears to be controlled by prevailing wave conditions and coastal currents, and fine-scale features of the flow field around the outlets. An analysis of data from dye experiments and fecal indicator bacteria monitoring studies reveals that the along-shore flux of surf zone water is at least 50 to 300 times larger than the cross-shore flux of surf zone water. As a result, pollutants entrained in the surf zone hug the shore, where they travel significant distances parallel to the beach before diluting to extinction. Under the assumption that all surf zone pollution at Huntington Beach originates from two tidal outlets, the Santa Ana River and Talbert Marsh outlets, models of mass and momentum transport in the surf zone approximately capture the observed tidal phasing and magnitude of certain fecal indicator bacteria groups (total coliform) but not others (Escherichia coli and enterococci), implying the existence of multiple sources of, and/or multiple transport pathways for, fecal pollution at this site. The intersection of human recreation and near-shore pollution pathways implies that, from a human health perspective, special care should be taken to reduce the discharge of harmful pollutants from land-side sources of surface water runoff, such as tidal outlets and storm drains.

  5. Queueing in a spent fuel transportation system: a preliminary analysis of implications for system design

    International Nuclear Information System (INIS)

    Cashwell, J.W.; Wood, T.W.

    1985-03-01

    Compliance with the Nuclear Waste Policy Act of 1982 (PL 97-425) will require the transportation of large volumes of spent fuel to a central receiving facility (Either a geologic repository or a monitored retrievable storage facility). Decisions on the transport mode and technology will evolve over the next several years, in anticipation of the deployment of a receiving facility in the late 1990s. Regardless of the particular transportation mode or modes and the details of cask technology, the transport system from many diverse sources to a single point will generate an essentially random arrival pattern. This random arrival pattern will lead to the formation of queues at the receiving facility. As is normal in any queueing system, the waiting time distribution caused by this queueing will depend on the receiving facility input processing rate and the characteristics of the traffic. Since this is a cyclic system, there is also a reverse effect in which (for a given size cask fleet) average wait time affects traffic intensity. Both effects must be accounted for to properly represent the system. This paper develops a simple analytic queueing model which accounts for both of these effects simultaneously. Since both effects are determined by receiving facility input and cask fleet size characteristics, two major sets of system design parameters are linked by the queueing process. The model is used with estimated traffic and service parameters to predict the severity of queueing under plausible reference system conditions, and to establish ''shadow prices'' for the trade off between larger cask fleets and more efficient receiving facilities. Since many of the parameter values used in this estimation are quite preliminary, these results are presented primarily in the context of demonstrating the utility of the queueing model for future trade off studies. 5 refs., 5 figs., 2 tabs

  6. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  7. 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.

  8. 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.

  9. Oregon inlet: Hydrodynamics, volumetric flux and implications for larval fish transport

    Energy Technology Data Exchange (ETDEWEB)

    Nichols, C.R. [National Oceanic and Atmospheric Administration, Silver Springs, MD (United States); Pietrafesa, L.J. [North Carolina State Univ., Raleigh, NC (United States). Department of Marine, Earth and Atmospheric Sciences

    1997-05-01

    The temporal response of Oregon Inlet currents to atmospheric forcing and sea level fluctuations is analyzed using time and frequency domain analysis. Temporally persistent and spatially extensive ebb and flood events are identified using data sets from both within and outside of Oregon Inlet. Prism estimates are made to generate a time series of volumetric flux of water transported through the inlet. Water masses flooding into the Pamlico Sound via Oregon Inlet are identified in temperature (T) and salinity (S) space to determine their source of origin. Correlations are examined between the atmospheric wind field, the main axial slope of the inlet`s water level, inlet flow and T, S properties. Synoptic scale atmospheric wind events are found to dramatically and directly affect the transport of water towards (away from) the inlet on the ocean side, in concert with the contemporaneous transport away from (towards) the inlet on the estuary side, and a subsequent flooding into (out of) the estuary via Oregon Inlet. Thus, while astronomical tidal flooding and ebbing events are shown to be one-sided as coastal waters either set-up or set-down, synoptic scale wind events are shown to be manifested as a two-sided in-phase response set-up and set-down inside and outside the inlet, and thus are extremely effective in driving currents through the inlet. These subinertial frequency flood events are believed to be essential for both the recruitment and subsequent retention of estuarine dependent larval fish from the coastal ocean into Pamlico Sound. Year class strength of these finish may be determined annually by the relative strength and timing of these climatological wind events.

  10. Structure and damping of toroidal drift waves (and their implications for anomalous transport)

    International Nuclear Information System (INIS)

    Taylor, J.B.; Connor, J.; Wilson, H.R.

    1993-05-01

    The conventional theory of high-n toroidal drift waves, based on the ballooning representation, indicates that shear-damping is generally reduced in a torus compared to its plane-slab value. It therefore describes the most unstable class of toroidal drift waves. However, modes of this type occur only i f the diamagnetic frequency ω*(r) has a maximum in r, and they affect only a small fraction, Ο(1/n l/2 ), of the plasma radius around this maximum. Consequently they may produce little anomalous transport. In the present work we show that, within the ballooning description, there is another class of toroidal drift waves with very different properties to the conventional ones. The new modes have greater shear-damping (closer to that in a plane-slab) than the conventional ones and so have a higher instability threshold. However, they occur for any plasma profile and at all radii, and they have larger radial extent. Consequently they may produce much greater anomalous transport than the possibly benign conventional modes. This suggests a picture of anomalous transport in which the plasma profile is determined by marginal stability, but marginal to the new class of modes not to the conventional ones. This might explain why marginally stable profiles calculated for drift waves with plane-slab damping sometimes agree well with the profiles in toroidal experiments. It is also consistent with the fact that experimental profiles may exceed conventional toroidal instability thresholds. The new modes may also be related to the tong radial structures which appear in some plasma simulations and in experiments

  11. Measurement and Simulation of Radon Transport in East Asia and Their Implication on Source Distribution

    International Nuclear Information System (INIS)

    Hirao, S.; Yamazawa, H.; Moriizumi, J.; Iida, T.

    2012-01-01

    Outlines of the continuous monitoring of atmospheric radon concentration at several locations in East Asia, the development and validation of a long-range atmospheric transport model, and a trial of estimating and reducing uncertainty in radon exhalation flux density maps were presented. Atmospheric radon concentration data observed at a small solitary island in the Pacific Ocean were successfully used to improve the vertical diffusion scheme in the model although the uncertainty in the radon flux density data was the limitation. It was also pointed out that a kind of source-receptor analysis using the radon concentration observed at these islands would reduce uncertainty in the radon flux density maps. (author)

  12. Long-range spatial dependence in fractured rock. Empirical evidence and implications for tracer transport

    International Nuclear Information System (INIS)

    Painter, S.

    1999-02-01

    Nonclassical stochastic continuum models incorporating long-range spatial dependence are evaluated as models for fractured crystalline rock. Open fractures and fracture zones are not modeled explicitly in this approach. The fracture zones and intact rock are modeled as a single stochastic continuum. The large contrasts between the fracture zones and unfractured rock are accounted for by making use of random field models specifically designed for highly variable systems. Hydraulic conductivity data derived from packer tests in the vicinity of the Aespoe Hard Rock Laboratory form the basis for the evaluation. The Aespoe log K data were found to be consistent with a fractal scaling model based on bounded fractional Levy motion (bfLm), a model that has been used previously to model highly variable sedimentary formations. However, the data are not sufficient to choose between this model, a fractional Brownian motion model for the normal-score transform of log K, and a conventional geostatistical model. Stochastic simulations conditioned by the Aespoe data coupled with flow and tracer transport calculations demonstrate that the models with long-range dependence predict earlier arrival times for contaminants. This demonstrates the need to evaluate this class of models when assessing the performance of proposed waste repositories. The relationship between intermediate-scale and large-scale transport properties in media with long-range dependence is also addressed. A new Monte Carlo method for stochastic upscaling of intermediate-scale field data is proposed

  13. A bright intra-dune feature on Titan and its implications for sand formation and transport

    Science.gov (United States)

    MacKenzie, Shannon; Barnes, Jason W.; Rodriguez, Sebastien; Cornet, Thomas; Brossier, Jeremy; Soderblom, Jason M.; Le Mouélic, Stephane; Sotin, Christophe; Brown, Robert H.; Buratti, Bonnie J.; Clark, Roger Nelson; Nicholson, Philip D.; Baines, Kevin

    2017-10-01

    Organic sands cover much of Titan’s equatorial belt, gathered into longitudinal dunes about a kilometer wide and hundreds of kilometers long. At the end of the Cassini era, questions of how such a vast volume of saltable material is or was created on Titan remain unanswered. At least two possible mechanisms suggested for forming sand-sized particles involve liquids: (1) evaporite deposition and erosion and (2) flocculation of material within a lake. Transporting sand from the lakes and seas of Titan’s poles to the equatorial belt is not strongly supported by Cassini observations: the equatorial belt sits higher than the poles and no sheets or corridors of travelling sand have been identified. Thus, previous sites of equatorial surface liquids may be of interest for understanding sand formation, such as the suggested paleoseas Tui and Hotei Regio. A newly identified feature in the VIMS data sits within the Fensal dune field but is distinct from the surrounding sand. We investigate this Bright Fensal Feature (BFF) using data from Cassini VIMS and RADAR. Specifically, we find spectral similarities between the BFF and both sand and Hotei Regio. The RADAR cross sectional backscatter is similar to neighboring dark areas, perhaps sand covered interdunes. We use this evidence to constrain the BFF’s formation history and discuss how this intra-dune feature may contribute to the processes of sand transport and supply.

  14. Interfaces in aquatic ecosystems: Implications for transport and impact of anthropogenic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Knulst, J.

    1996-11-01

    Mechanisms that govern transport, accumulation and toxicity of persistent pollutants at interfaces in aquatic ecosystems were the foci of this thesis. Specific attention was paid to humic substances, their occurrence, composition, and role in exchange processes across interfaces. It was concluded that: The composition of humic substances in aquatic surface microlayers is different from that of the subsurface water and terrestrial humic matter. Levels of dissolved organic carbon (DOC) in the aquatic surface microlayer reflect the DOC levels in the subsurface water. While the levels and enrichment of DOC in the microlayer generally show small variations, the levels and enrichment of particulate organic carbon (POC) vary to a great extent. Similarities exist between aquatic surface films, artificial semi-permeable and biological membranes regarding their structure and functioning. Acidification and liming of freshwater ecosystems affect DOC:POC ratio and humic composition of the surface film, thus influencing the partitioning of pollutants across aquatic interfaces. Properties of lake catchment areas extensively govern DOC:POC ratio both in the surface film and subsurface water. Increased UV-B irradiation changes the DOC:POC ratio in the surface film and thus affect transfer of matter across the interface. Transport of lipophilic, persistent organic pollutants across semi-permeable membranes is influenced by the solutes organic composition. 106 refs, 11 figs, 1 tab

  15. Transport of perfluoroalkyl substances (PFAS) from an arctic glacier to downstream locations: implications for sources.

    Science.gov (United States)

    Kwok, Karen Y; Yamazaki, Eriko; Yamashita, Nobuyoshi; Taniyasu, Sachi; Murphy, Margaret B; Horii, Yuichi; Petrick, Gert; Kallerborn, Roland; Kannan, Kurunthachalam; Murano, Kentaro; Lam, Paul K S

    2013-03-01

    Perfluoroalkyl substances (PFAS) have been globally detected in various environmental matrices, yet their fate and transport to the Arctic is still unclear, especially for the European Arctic. In this study, concentrations of 17 PFAS were quantified in two ice cores (n=26), surface snow (n=9) and surface water samples (n=14) collected along a spatial gradient in Svalbard, Norway. Concentrations of selected ions (Na(+), SO4(2-), etc.) were also determined for tracing the origins and sources of PFAS. Perfluorobutanoate (PFBA), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were the dominant compounds found in ice core samples. Taking PFOA, PFNA and perfluorooctane-sulfonate (PFOS) as examples, higher concentrations were detected in the middle layers of the ice cores representing the period of 1997-2000. Lower concentrations of C8-C12 perfluorocarboxylates (PFCAs) were detected in comparison with concentrations measured previously in an ice core from the Canadian Arctic, indicating that contamination levels in the European Arctic are lower. Average PFAS concentrations were found to be lower in surface snow and melted glacier water samples, while increased concentrations were observed in river water downstream near the coastal area. Perfluorohexanesulfonate (PFHxS) was detected in the downstream locations, but not in the glacier, suggesting existence of local sources of this compound. Long-range atmospheric transport of PFAS was the major deposition pathway for the glaciers, while local sources (e.g., skiing activities) were identified in the downstream locations. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Health initiatives to target obesity in surface transport industries: Review and implications for action

    Directory of Open Access Journals (Sweden)

    Anjum Naweed

    2015-06-01

    Full Text Available Lifestyle-related chronic diseases pose a considerable burden to the individual and the wider society, with correspondingly negative effects on industry. Obesity is a particular problem for the Australasian road and rail industries where it is associated with specific cardiac and fatigue-related safety risks, and levels are higher than those found in the general population. Despite this recognition, and the introduction of National Standards, very little consensus exists regarding approaches to preventative health for surface transport workers. A review of evidence regarding effective health promotion initiatives is urgently needed to inform best practice in this cohort. This review draws together research informing the scope and effectiveness of health promotion programs, initiatives and interventions targeting overweight and obesity in safety critical surface transport domains including the truck, bus and rail industries. A number of health interventions demonstrated measurable successes, including incentivising, peer mentoring, verbal counselling, development of personalised health profiles, and offer of healthier on-site food choices – some of which also resulted in sizeable return on investment over the long term.

  17. Trends in CO2 Emissions from China-Oriented International Marine Transportation Activities and Policy Implications

    Directory of Open Access Journals (Sweden)

    Hualong Yang

    2017-07-01

    Full Text Available The demand for marine transportation and its associated CO2 emissions are growing rapidly as a result of increasing international trade and economic growth. An activity-based approach is developed for forecasting CO2 emissions from the China-oriented international seaborne trade sector. To accurately estimate the aggregated emissions, CO2 emissions are calculated individually for five categories of vessels: crude oil tanker, product tanker, chemical tanker, bulk carrier, and container. A business-as-usual (BAU scenario was developed to describe the current situation without additional mitigation policies, whilst three alternative scenarios were developed to describe scenarios with various accelerated improvements of the key factors. The aggregated CO2 emissions are predicted to reach 419.97 Mt under the BAU scenario, and 258.47 Mt under the optimal case, AD3. These predictions are 4.5 times and 2.8 times that of the aggregated emissions in 2007. Our analysis suggests that regulations for monitoring, reporting, and verifying the activities of vessels should be proposed, in order to quantify the CO2 emissions of marine transportation activities in Chinese territorial waters. In the long-term future, mitigation policies should be employed to reduce CO2 emissions from the marine trade sector and to address the climatic impact of shipping.

  18. 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

  19. 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.

  20. Transportation

    Science.gov (United States)

    2007-01-01

    Faculty ii INDUSTRY TRAVEL Domestic Assistant Deputy Under Secretary of Defense (Transportation Policy), Washington, DC Department of...developed between the railroad and trucking industries. Railroads: Today’s seven Class I freight railroad systems move 42% of the nation’s intercity ...has been successfully employed in London to reduce congestion and observed by this industry study during its travels . It is currently being

  1. Long distance electron transport in marine sediments: Microbial and geochemical implications

    DEFF Research Database (Denmark)

    Risgaard-Petersen, Nils; Larsen, Steffen; Pfeffer, Christian

    and promotes the formation of Mg-calcite and iron oxides in the oxic zone. Oxygen seems to be the major electron acceptor, and more than 40% of the oxygen consumption in sediments can be driven by long distance electron transfer from distant electron donors. The major e-donor is sulfide, which is oxidized......Anaerobic oxidation of organic matter in marine sediment is traditionally considered to be coupled to oxygen reduction via a cascade of redox processes and transport of intermittent electron donors and acceptors. Electric currents have been found to shortcut this cascade and directly couple...... oxidation of sulphide centimeters down in marine sediment to the reduction of oxygen at the very surface1 . This electric coupling of spatially separated redox half-reactions seems to be mediated by centimeter long filamentous Desulfubulbus affiliated bacteria with morphological and ultra...

  2. ATMOS Stratospheric Deuterated Water and Implications for Tropospheric-Stratospheric Transport

    Science.gov (United States)

    Moyer, Elisabeth J.; Irion, Fredrick W.; Yung, Yuk L.; Gunson, Michael R.

    1996-01-01

    Measurements of the isotopic composition of stratospheric water by the ATMOS instrument are used to infer the convective history of stratospheric air. The average water vapor entering the stratosphere is found to be highly depleted of deuterium, with delta-D(sub w) of -670 +/- 80 (67% deuterium loss). Model calculations predict, however, that under conditions of thermodynamic equilibrium, dehydration to stratospheric mixing ratios should produce stronger depletion to delta-D(sub w) of -800 to 900 (80-90% deuterium loss). Deuterium enrichment of water vapor in ascending parcels can occur only in conditions of rapid convection; enrichments persisting into the stratosphere require that those conditions continue to near-tropopause altitudes. We conclude that either the predominant source of water vapor to the uppermost troposphere is enriched convective water, most likely evaporated cloud ice, or troposphere-stratosphere transport occurs closely associated with tropical deep convection.

  3. Baby boomers’ mobility patterns and preferences. What are the implications for future transport? (abstract)

    DEFF Research Database (Denmark)

    Siren, Anu Kristiina; Haustein, Sonja

    2012-01-01

    , and it is expected that they will differ from their parents’ generation when growing old. In order to understand how the aging boomers may impact the future travel demand, their travel behaviour and expectations were analysed based on 1772 standardized telephone interviews. Baby boomers reported in general being......The demographic grand challenge of population ageing will be reflected on most of the areas of society, and to a great extent also on the area of transportation. The large post-II world war cohorts, the so called baby boomers, will comprise a large share of tomorrows older population...... to those observed in the older cohorts. In addition, using cluster analysis, three segments of baby boomers could be differentiated. The segments showed significant differences in current travel behaviour and living circumstances and some similarities to former segmentations of older road users. Results...

  4. Baby boomers’ mobility patterns and preferences: What are the implications for future transport (abstract)

    DEFF Research Database (Denmark)

    Haustein, Sonja

    , the so-called “baby boomers”, will comprise a large share of tomorrow’s older population, and it is expected that they will differ from their parents’ generation when they grow old. In order to better understand how the ageing baby boomers may affect future travel demand, the travel behaviour...... and expectations of Danish baby boomers were analysed based on 1772 standardised telephone interviews. In general, the baby boomers reported being healthy, independent and highly (auto)mobile. They were also optimistic regarding their level of mobility, capability to use a variety of travel modes and ability...... consumers of the transport system also as they age, but that the group is also heterogeneous. Thus, overly optimistic scenarios about independent baby boomers who differ from the previous generations and whose need for external support in old age will be minimal may be unrealistic....

  5. Baby boomers’ mobility patterns and preferences: What are the implications for future transport?

    DEFF Research Database (Denmark)

    Siren, Anu Kristiina; Haustein, Sonja

    2013-01-01

    , the so-called “baby boomers”, will comprise a large share of tomorrow’s older population, and it is expected that they will differ from their parents’ generation when they grow old. In order to better understand how the ageing baby boomers may affect future travel demand, the travel behaviour...... and expectations of Danish baby boomers were analysed based on 1772 standardised telephone interviews. In general, the baby boomers reported being healthy, independent and highly (auto)mobile. They were also optimistic regarding their level of mobility, capability to use a variety of travel modes and ability...... consumers of the transport system also as they age, but that the group is also heterogeneous. Thus, overly optimistic scenarios about independent baby boomers who differ from the previous generations and whose need for external support in old age will be minimal may be unrealistic....

  6. The Association of Cryptosporidium parvum With Suspended Sediments: Implications for Transport in Surface Waters

    Science.gov (United States)

    Searcy, K. E.; Packman, A. I.; Atwill, E. R.; Harter, T.

    2003-12-01

    Understanding the transport and fate of microorganisms in surface waters is of vital concern in protecting the integrity and safety of municipal water supply systems. The human pathogen Cryptosporidium parvum is a particular public health interest, as it is ubiquitous in the surface waters of the United States, it can persist for long periods in the environment, and it is difficult to disinfect in water treatment plants. Due to its small size (5 um), low specific gravity (1.05 g/cm3), and negative surface charge, C. parvum oocysts are generally considered to move through watersheds from their source to drinking water reservoirs with little attenuation. However, the transport of the oocysts in surface waters may be mediated by interactions with suspended sediments. Batch experiments were conducted to determine the extent of C. parvum oocyst attachment to several inorganic and organic sediments under varying water chemical conditions, and settling column experiments were performed to demonstrate how these associations influence the effective settling velocity of C. parvum oocysts. Results from these experiments showed that C. parvum oocysts do associate with inorganic and organic sediments and often settle at the rate of the suspended sediment. The size and surface charge of the host suspended sediment influenced the extent of oocyst attachment as oocysts preferentially associated with particles greater than 3 um, and fewer oocysts associated with particles having a highly negative surface charge. Background water chemical conditions including ionic strength, ion composition, and pH did not have a significant effect on oocyst attachment to suspended sediments.

  7. 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...

  8. 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...

  9. 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.

  10. 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...

  11. 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

  12. Imaging and quantifying solute transport across periosteum: implications for muscle-bone crosstalk.

    Science.gov (United States)

    Lai, Xiaohan; Price, Christopher; Lu, Xin Lucas; Wang, Liyun

    2014-09-01

    Muscle and bone are known to act as a functional unit and communicate biochemically during tissue development and maintenance. Muscle-derived factors (myokines) have been found to affect bone functions in vitro. However, the transport times of myokines to penetrate into bone, a critical step required for local muscle-bone crosstalk, have not been quantified in situ or in vivo. In this study, we investigated the permeability of the periosteum, a major barrier to muscle-bone crosstalk by tracking and modeling fluorescent tracers that mimic myokines under confocal microscopy. Periosteal surface boundaries and tracer penetration within the boundaries were imaged in intact murine tibiae using reflected light and time-series xz confocal imaging, respectively. Four fluorescent tracers including sodium fluorescein (376Da) and dextrans (3kDa, 10kDa and 40kDa) were chosen because they represented a wide range of molecular weights (MW) of myokines. We found that i) murine periosteum was permeable to the three smaller tracers while the 40kDa could not penetrate beyond 40% of the outer periosteum within 8h, suggesting that periosteum is semi-permeable with a cut-off MW of approximately 40kDa, and ii) the characteristic penetration time through the periosteum (~60μm thick) increased with tracer MW and fit well with a relationship tcs=-4.43×10(4)-0.57×MWDa-4×10(4)-8.65×10(8)MWDa-4×10(4), from which, the characteristic penetration times of various myokines were extrapolated. To achieve effective muscle-bone crosstalk, likely signaling candidates should have shorter penetration time than their bioactive time, which we assumed to be 5 times of the molecule's half-lifetime in the body. Myokines such as PGE2, IGF-1, IL-15 and FGF-2 were predicted to satisfy this requirement. In summary, a novel imaging approach was developed and used to investigate the transport of myokine mimicking-tracers through the periosteum, enabling further quantitative studies of muscle

  13. Sediments in Arctic sea ice: Implications for entrainment, transport and release

    Science.gov (United States)

    Nurnberg, D.; Wollenburg, I.; Dethleff, D.; Eicken, H.; Kassens, H.; Letzig, T.; Reimnitz, E.; Thiede, Jorn

    1994-01-01

    Despite the Arctic sea ice cover's recognized sensitivity to environmental change, the role of sediment inclusions in lowering ice albedo and affecting ice ablation is poorly understood. Sea ice sediment inclusions were studied in the central Arctic Ocean during the Arctic 91 expedition and in the Laptev Sea (East Siberian Arctic Region Expedition 1992). Results from these investigations are here combined with previous studies performed in major areas of ice ablation and the southern central Arctic Ocean. This study documents the regional distribution and composition of particle-laden ice, investigates and evaluates processes by which sediment is incorporated into the ice cover, and identifies transport paths and probable depositional centers for the released sediment. In April 1992, sea ice in the Laptev Sea was relatively clean. The sediment occasionally observed was distributed diffusely over the entire ice column, forming turbid ice. Observations indicate that frazil and anchor ice formation occurring in a large coastal polynya provide a main mechanism for sediment entrainment. In the central Arctic Ocean sediments are concentrated in layers within or at the surface of ice floes due to melting and refreezing processes. The surface sediment accumulation in central Arctic multi-year sea ice exceeds by far the amounts observed in first-year ice from the Laptev Sea in April 1992. Sea ice sediments are generally fine grained, although coarse sediments and stones up to 5 cm in diameter are observed. Component analysis indicates that quartz and clay minerals are the main terrigenous sediment particles. The biogenous components, namely shells of pelecypods and benthic foraminiferal tests, point to a shallow, benthic, marine source area. Apparently, sediment inclusions were resuspended from shelf areas before and incorporated into the sea ice by suspension freezing. Clay mineralogy of ice-rafted sediments provides information on potential source areas. A smectite

  14. 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.

  15. 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.

  16. Electron microscopic localization of 3H-leucine in the neurons of the hypoglossal nerve during axonal reaction

    International Nuclear Information System (INIS)

    Gylybov, G.P.; Chuchkov, Ch.Kh.; Davidov, M.S.

    1978-01-01

    The uptake of tritium-labelled leucine in the neuronal organelles with the aim of a follow-up of the dynamics in the protein synthesis in the motoneurons affected during axonal reaction was investigated. The experiments were carried out with rats, of which one of the hypoglossal nerve was crushed and the other was left intact. The labelled amino-acid was injected in the lateral cerebral ventricle 30 to 40 min before the sacrificing of each animal. The examination of the histological preparations shows that the neurons of the hypoglossal nerve cumulate to a larger extent the labelled precursor in comparison with the neuroglia. The perinuclear region, the nucleus, the nucleolus and the axonal hillock show preponderance in the accumulation. The activity greatly decreases at the more remote parts of the axon. The electron=microscopic data confirm these results and supplement them by exactly determining the localization of the labels in the individual organelles. The highest activity was found in the mitochondria, in the Golgi apparatus and in the lysosomes. This can be viewed as the result of intensified transfer of proteins from the ribosomes toward these organelles. There is, however, another possibility - the directly elevated biosynthesis. The elevated activity of the protein synthesis in the cell organelles, assume the authors, is related not only to preserving their structural proteins but also to intensifying axonal transport. (A.B.)

  17. Transport of fluid and solutes in the body II. Model validation and implications.

    Science.gov (United States)

    Gyenge, C C; Bowen, B D; Reed, R K; Bert, J L

    1999-09-01

    A mathematical model of short-term whole body fluid, protein, and ion distribution and transport developed earlier [see companion paper: C. C. Gyenge, B. D. Bowen, R. K. Reed, and J. L. Bert. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1215-H1227, 1999] is validated using experimental data available in the literature. The model was tested against data measured for the following three types of experimental infusions: 1) hyperosmolar saline solutions with an osmolarity in the range of 2,000-2,400 mosmol/l, 2) saline solutions with an osmolarity of approximately 270 mosmol/l and composition comparable with Ringer solution, and 3) an isosmotic NaCl solution with an osmolarity of approximately 300 mosmol/l. Good agreement between the model predictions and the experimental data was obtained with respect to the trends and magnitudes of fluid shifts between the intra- and extracellular compartments, extracellular ion and protein contents, and hematocrit values. The model is also able to yield information about inaccessible or difficult-to-measure system variables such as intracellular ion contents, cellular volumes, and fluid fluxes across the vascular capillary membrane, data that can be used to help interpret the behavior of the system.

  18. Zinc Transporters, Mechanisms of Action and Therapeutic Utility: Implications for Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Stephen A. Myers

    2012-01-01

    Full Text Available Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer’s disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc’s dynamic role as a “cellular second messenger” in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy.

  19. Mass-transport limitation to in-cloud reaction rates: Implications of new accommodation coefficient measurements

    International Nuclear Information System (INIS)

    Schwartz, S.E.

    1988-10-01

    Although it has been recognized for some time that the rate of reactive uptake of gases in cloudwater can depend on the value of the mass-accommodation coefficient (α) describing interfacial mass transport (MT), definitive evaluation of such rates is only now becoming possible with the availability of measurements of α for gases of atmospheric interest at air-water interfaces. Examination of MT limitation to the rate of in-cloud aqueous-phase oxidation of SO 2 by O 3 and H 2 O 2 shows that despite the low value of α/sub O3/ (5 /times/ 10/sup /minus/4/), interfacial MT of this species is not limiting under essentially all conditions of interest; the high values of α for SO 2 (≥ 0.2) and H 2 O 2 (≥ 0.08) indicate no interfacial MT limitation for these species also. Although gas- and aqueous-phase MT can be limiting under certain extremes of conditions, treating the system as under chemical kinetic control is generally an excellent approximation. Interfacial MT limitation also is found not to hinder the rate of H 2 O 2 formation by aqueous-phase disproportionation of HO 2 . Finally, the rapid uptake of N 2 O 5 by cloud droplets implies that the yield of aqueous HNO 3 from in-cloud gas-phase oxidation of NO 2 by O 3 can be substantial even under daytime conditions. This report consists of copies of viewgraphs prepared for this presentation

  20. Economic impact and policy implications from urban shared transportation: The case of Pittsburgh's shared bike system.

    Science.gov (United States)

    Pelechrinis, Konstantinos; Zacharias, Christos; Kokkodis, Marios; Lappas, Theodoros

    2017-01-01

    During the last years the number of cities that have installed and started operating shared bike systems has significantly increased. These systems provide an alternative and sustainable mean of transportation to the city dwellers. Apart from the energy sustainability benefits, shared bike systems can have a positive effect on residents' health, air quality and the overall condition of the currently crumbling road network infrastructure. Anecdotal stories and survey studies have also identified that bike lanes have a positive impact on local businesses. In this study, driven by the rapid adoption of shared bike systems by city governments and their potential positive effects on a number of urban life facets we opt to study and quantify the value of these systems. We focus on a specific aspect of this value and use evidence from the real estate market in the city of Pittsburgh to analyze the effect on dwellers' properties of the shared bike system installed in the city in June 2015. We use quasi-experimental techniques and find that the shared bike system led to an increase in the housing prices (both sales and rental prices) in the zip codes where shared bike stations were installed. We further bring into the light potential negative consequences of this impact (i.e., gentrification) and discuss/propose two public policies that can exploit the impact of the system for the benefit of both the local government as well as the city dwellers.

  1. Economic impact and policy implications from urban shared transportation: The case of Pittsburgh's shared bike system.

    Directory of Open Access Journals (Sweden)

    Konstantinos Pelechrinis

    Full Text Available During the last years the number of cities that have installed and started operating shared bike systems has significantly increased. These systems provide an alternative and sustainable mean of transportation to the city dwellers. Apart from the energy sustainability benefits, shared bike systems can have a positive effect on residents' health, air quality and the overall condition of the currently crumbling road network infrastructure. Anecdotal stories and survey studies have also identified that bike lanes have a positive impact on local businesses. In this study, driven by the rapid adoption of shared bike systems by city governments and their potential positive effects on a number of urban life facets we opt to study and quantify the value of these systems. We focus on a specific aspect of this value and use evidence from the real estate market in the city of Pittsburgh to analyze the effect on dwellers' properties of the shared bike system installed in the city in June 2015. We use quasi-experimental techniques and find that the shared bike system led to an increase in the housing prices (both sales and rental prices in the zip codes where shared bike stations were installed. We further bring into the light potential negative consequences of this impact (i.e., gentrification and discuss/propose two public policies that can exploit the impact of the system for the benefit of both the local government as well as the city dwellers.

  2. Energetic O+ and H+ Ions in the Plasma Sheet: Implications for the Transport of Ionospheric Ions

    Science.gov (United States)

    Ohtani, S.; Nose, M.; Christon, S. P.; Lui, A. T.

    2011-01-01

    The present study statistically examines the characteristics of energetic ions in the plasma sheet using the Geotail/Energetic Particle and Ion Composition data. An emphasis is placed on the O+ ions, and the characteristics of the H+ ions are used as references. The following is a summary of the results. (1) The average O+ energy is lower during solar maximum and higher during solar minimum. A similar tendency is also found for the average H+ energy, but only for geomagnetically active times; (2) The O+ -to -H+ ratios of number and energy densities are several times higher during solar maximum than during solar minimum; (3) The average H+ and O+ energies and the O+ -to -H+ ratios of number and energy densities all increase with geomagnetic activity. The differences among different solar phases not only persist but also increase with increasing geomagnetic activity; (4) Whereas the average H+ energy increases toward Earth, the average O+ energy decreases toward Earth. The average energy increases toward dusk for both the H+ and O+ ions; (5) The O+ -to -H+ ratios of number and energy densities increase toward Earth during all solar phases, but most clearly during solar maximum. These results suggest that the solar illumination enhances the ionospheric outflow more effectively with increasing geomagnetic activity and that a significant portion of the O+ ions is transported directly from the ionosphere to the near ]Earth region rather than through the distant tail.

  3. Measurements of mesospheric water vapor in 1984 and 1985 - Results and implications for middle atmospheric transport

    Science.gov (United States)

    Bevilacqua, Richard M.; Schwartz, Philip R.; Wilson, William J.

    1987-01-01

    The detailed results of ground-based mesospheric water vapor measurements obtained by microwave spectroscopy at the Jet Propulsion Laboratory (JPL) from December 1984 to April 1985 (JPL 1984/85), and an overview of results obtained the previous year from April to June 1984 are presented. The JPL 1984/85 spectral data appeared to contain an instrumental baseline curvature which was bracketed and removed. In general, the JPL 1984/85 results are in good agreement with those of previous measurements. They indicate water vapor mixing ratios between 6 and 8 ppmv at 60 or 65 km and falling off steeply with height above this point to values of less than 2 ppmv at 80 km. In addition, there is a large amount of day-to-day variability indicated in the data. A major result of the study is that it is found that both the observed vertical gradient of water vapor mixing ratio and its seasonal variation are consistent with the hypothesis that vertical transport time scales are smaller, perhaps by an order of magnitude, than values currently used in both one- and two-dimensional photochemical/dynamical models.

  4. A significant longshore transport divergence zone at the Northeastern Brazilian coast: implications on coastal Quaternary evolution

    Directory of Open Access Journals (Sweden)

    ABÍLIO C.S.P. BITTENCOURT

    2002-09-01

    Full Text Available By using the mean directions of the wave-fronts approaching the Brazilian northeastern coastal stretch comprised between the localities of Real river (Sergipe State and Galinhos (Rio Grande do Norte State - coincident with those of the main winds occurring in the area - and their periods, we have defined a wave climate model based on the construction of refraction diagrams. The resulting model of sediment transport, as obtained by numerical modelling from the refraction diagrams, taking into consideration the angle of approach and waves heights along the 10-m isobath, was capable of reproducing the patterns of sediment dispersion provided by geomorphic indicators of the longshore drift. All this coastal region, approximately 900 km in length, is characterized by a significant divergence zone in the direction of net longshore drift of sediments, the potential intensity of which increases considerably in value, in almost its entire length, continuously toward downdrift, which might explain the greater or lesser long term susceptibility to erosion, during the Quaternary, along the coastal stretch studied.Utilizando-se as direções médias das principais frentes-de-onda que se aproximam do trecho costeiro do nordeste brasileiro compreendido entre as localidades de Rio Real (Sergipe e Galinhos (Rio Grande do Norte - coincidentes com aquelas dos principais ventos que ocorrem na área - e de seus períodos, nós definimos um modelo de clima de ondas baseado na construção de diagramas de refração. O modelo resultante de transporte de sedimentos, obtido por modelagem numérica feita a partir dos diagramas de refração, considerando o ângulo de aproximação e a altura das ondas ao longo da isóbata de 10m, foi capaz de reproduzir os padrões de dispersão de sedimentos fornecidos pelos indicadores geomórficos de deriva litorânea. Toda essa região costeira, com cerca de 900km de extensão, caracteriza-se por se constituir em uma grande zona de

  5. Mechanism of Crystallization and Implications for Charge Transport in Poly(3-ethylhexylthiophene) Thin Films

    KAUST Repository

    Duong, Duc T.

    2014-04-09

    In this work, crystallization kinetics and aggregate growth of poly(3-ethylhexylthiophene) (P3EHT) thin films are studied as a function of film thickness. X-ray diffraction and optical absorption show that individual aggregates and crystallites grow anisotropically and mostly along only two packing directions: the alkyl stacking and the polymer chain backbone direction. Further, it is also determined that crystallization kinetics is limited by the reorganization of polymer chains and depends strongly on the film thickness and average molecular weight. Time-dependent, field-effect hole mobilities in thin films reveal a percolation threshold for both low and high molecular weight P3EHT. Structural analysis reveals that charge percolation requires bridged aggregates separated by a distance of ≈2-3 nm, which is on the order of the polymer persistence length. These results thus highlight the importance of tie molecules and inter-aggregate distance in supporting charge percolation in semiconducting polymer thin films. The study as a whole also demonstrates that P3EHT is an ideal model system for polythiophenes and should prove to be useful for future investigations into crystallization kinetics. Recrystallization kinetics and its relationship to charge transport in poly(3-ethylhexylthiophene) (P3EHT) thin films are investigated using a combination of grazing incidence X-ray diffraction, optical absorption, and field-effect transistor measurements. These results show that thin film crystallization kinetics is limited by polymer chain reorganization and that charge percolation depends strongly on the edge-to-edge distance between aggregates. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Differential subsidence in Mexico City and implications to its Collective Transport System (Metro).

    Science.gov (United States)

    Solano Rojas, D. E.; Wdowinski, S.; Cabral-Cano, E.; Osmanoglu, B.

    2017-12-01

    Mexico City is one of the fastest subsiding metropolis in the world. At displacement rates ranging from 0 to -380 [mm/yr], the complex geological setting is subjected to differential subsidence, which has led to damage, operation interruptions, and accidents to the Collective Transport System, or Metro. The Metro plays a critical role in Mexico City, carrying more than four million passengers per day. However, no previous study has focused on the deformation monitoring along the 93 km of the Metro surface railways, mainly because of the limitations of the traditional geodetic techniques. In this study, we use high-resolution Interferometric Synthetic Aperture Radar (InSAR) observations to monitor land subsidence throughout the city and quantify differential subsidence along surface Metro lines. Our analysis is based on 34 TerraSAR-X StripMap scenes acquired from May 2011 to June 2013 and 36 COSMO-SkyMed Stripmap scenes acquired from June 2011 to June 2012. The data were processed using the StaMPS InSAR time series technique, obtaining point densities of up to 4827 points/km2. Our post-processing methodologies include the following two components: (1) Detection of differential subsidence along the metro lines by calculating subsidence gradients, and (2) Detection of apparent uplift—areas subsiding slower than their surroundings—by using spatial frequency filtering. The two analyses allow us to recognize four main consequences of differential subsidence in the Metro system: 1. Deflection in elevated railways, 2. Deflection in street-level railways, 3. Columns with decreased loading capacity, and 4. Apparent uplift affecting surrounding infrastructure. Our results aim at shortening the large gap between scientific geodetic studies and applicable engineering parameters that can be used by local authorities in the city for maintenance and new lines development.

  7. Observations of Scour and Transport at Coastal Structures from the 2011 Tohoku Tsunami - Implications for Flow in Natural Terrain

    Science.gov (United States)

    Petroff, C. M.

    2011-12-01

    Before the March 11, 2011 Tohoku tsunami, many communities along the Japan coast had shore protection barriers, some designed specifically to provide protection from tsunamis and others for typhoon and storm surge protection. A vast number of these structures were overtopped, damaged or destroyed by the high inundation and currents generated in the tsunami. Observations are presented about scour features at man-made coastal structures in the Tohoku region as well as the hydraulic transport of debris from these structures. Along with providing lessons for structure design and maintenance, these observations have implications for hydraulic transport in natural terrain, not only at hard points such as rock outcrops but also at other features such as river mouths, barrier islands and coastal dunes. As an example, Photo 1 shows the overtopping flow at the seawall at Noda, in the Iwate prefecture. From the point of view of hydraulics the type of flow seen in the photo is more like that at an in-line weir or spillway than the wave conditions for which the structure was designed. On the lee or downstream side of such structures, the flow is supercritical resulting in a supercritical to subcritical transition near the landward toe of the seawall. High flow velocities along with increased pore pressure and overturning flow create very deep scour in these locations Such as the zone clearly seen in Photo 2 behind the seawall at the Sendai airport. It is anticipated that similar hydraulic conditions would occur for flow over a high coastal dune ridge where the ridge would act as a flow control point and locally high velocities on the landward side of the ridge would result in high erosion and scour. Other examples are given.

  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. 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.

  10. Implications of heterogeneity on transport simulations at large scale: the Morroa aquifer case

    Directory of Open Access Journals (Sweden)

    Anibal Jose Pérez-García

    2014-01-01

    Full Text Available El acuífero Morroa, localizado en el departamento de Sucre (Colombia, representa la única fuente de suministro de agua potable de cerca de 500.000 habitantes que incluyen la totalidad de los habitantes de la capital del departamento Sincelejo. Aunque se han desarrollado muchos estudios en esta zona que incluyen la recolección de gran cantidad de información relacionada con niveles piezométricos, información estratigráfica, pruebas de bombeo, esta información es difusa, heterogénea y fraccionada. La incertidumbre asociada a esta información afecta cualquier intento de cuantificar la respuesta del acuífero, por esta razón el punto de partida de esta investigación es el desarrollo de una metodología capaz de integrar todas las variables en un modelo conceptual. Para considerar la incertidumbre se generaron múltiples realizaciones del acuífero de tal manera que todas respetan las propiedades estadísticas de la información disponible. Para generar estas realizaciones se utilizaron dos metodologías: (1 SISIM, que es un método basado en estadísticas de dos puntos (semivariograma, y (2 SNESIM, que es un algoritmo basado en el concepto de imágenes de entrenamiento (estadística de puntos múltiples. Resultados de las simulaciones muestran la gran capacidad de este último para reproducir geometrías curvilíneas complejas. En una segunda fase, se desarrollaron simulaciones de flujo y transporte de contaminantes de una manera integrada usando los dos modelos conceptuales obtenidos a través de las dos aproximaciones geoestadísticas. Condiciones de flujo estacionario y un contaminante conservativo fueron asumidos para todas las simulaciones. Los resultados obtenidos muestran una influencia notable de la heterogeneidad en general, así como una gran sensibilidad al método geoestadístico usado para generar la heterogeneidad. Las diferencias observadas tendrían un gran efecto en el diseño de políticas de manejo integral del recurso

  11. Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury

    Science.gov (United States)

    2014-03-01

    association with transported herpes simplex virus particles.11 In this study, we tested the efficacy of these axon-targeting motifs to target the fluorophore...Richter D, Kindler S. Identification of a cis-acting dendritic targeting element in the mRNA encoding the alpha subunit of Ca2þ /calmodulin-dependent

  12. Zonal organization of the climbing fiber projection to the flocculus and nodulus of the rabbit: A combined axonal tracing and acetylcholinesterase histochemical study

    NARCIS (Netherlands)

    J. Tan (J.); N.M. Gerrits (N.); R. Nanhoe (R.); J.I. Simpson (John); J. Voogd (Jan)

    1995-01-01

    textabstractThe localization and termination of olivocerebellar fibers in the flocculus and nodulus of the rabbit were studied with anterograde axonal transport methods [wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine] and correlated with the compartments in the white

  13. Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.

    Science.gov (United States)

    Wang, Haicui; Salter, Claire G; Refai, Osama; Hardy, Holly; Barwick, Katy E S; Akpulat, Ugur; Kvarnung, Malin; Chioza, Barry A; Harlalka, Gaurav; Taylan, Fulya; Sejersen, Thomas; Wright, Jane; Zimmerman, Holly H; Karakaya, Mert; Stüve, Burkhardt; Weis, Joachim; Schara, Ulrike; Russell, Mark A; Abdul-Rahman, Omar A; Chilton, John; Blakely, Randy D; Baple, Emma L; Cirak, Sebahattin; Crosby, Andrew H

    2017-11-01

    The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals.

    Science.gov (United States)

    Su, Y C; Maurel-Zaffran, C; Treisman, J E; Skolnik, E Y

    2000-07-01

    We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct

  15. 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.

  16. 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.

  17. Tissue As A Medium For Laser Light Transport-Implications For Photoradiation Therapy

    Science.gov (United States)

    Preuss, L. E.; Bolin, F. P.; Cain, B. W.

    1982-12-01

    An important medical laser application is in the emerging field of photoradiation therapy (PRT). PRT is the process in which malignant tissue is destroyed by administration of light to a specific photosensitized site. Filtered arcs, incandescents and dye lasers have been used as sources of activating light. We have carried out light experiments in tissue to study such PRT light distributions. The results of this research have shown that a number of important optical phenomena occurring within illuminated tissue must be accounted for in order to make good predictions of tumor light dosage. Among these are; tissue type, interface effects and anomalies due to composition. These effects substantially influence light levels in PRT and, thus, the therapeutic effect. The uniqueness of tissue as a medium for light transport presents special problems for optics research and instrumentation. Successful solutions necessarily will involve collaboration between the life sciences and optic specialists. Attempts at treatment of human disease using non-ionizing radiation have a history archaeologically traceable to archaic societies (in which the sun's photons were used and often worshipped).1 Western medicine in the past, has used visible light beneficially, albeit empirically, on a few ailments. However, in this century, a significant development in the understanding and in the therapeutic use of this electromagnetic radiation in the UV, visible and IR has occurred, based on scientific study. This utilization of radiation in the visible and ultraviolet can be by two distinct processes. One is through the direct action of the photons which serve as the sole treatment agent. In this case the photon interacts with the cell, or its components, in a single step, to produce a desired effect. An example is the successful use of blue light for treatment of bilirubinemia in newborns. The second process is a biological effect produced through the combination of electromagnetic radiation

  18. Ozone-surface interactions: Investigations of mechanisms, kinetics, mass transport, and implications for indoor air quality

    Energy Technology Data Exchange (ETDEWEB)

    Morrison, Glenn Charles [Univ. of California, Berkeley, CA (United States)

    1999-12-01

    In this dissertation, results are presented of laboratory investigations and mathematical modeling efforts designed to better understand the interactions of ozone with surfaces. In the laboratory, carpet and duct materials were exposed to ozone and measured ozone uptake kinetics and the ozone induced emissions of volatile organic compounds. To understand the results of the experiments, mathematical methods were developed to describe dynamic indoor aldehyde concentrations, mass transport of reactive species to smooth surfaces, the equivalent reaction probability of whole carpet due to the surface reactivity of fibers and carpet backing, and ozone aging of surfaces. Carpets, separated carpet fibers, and separated carpet backing all tended to release aldehydes when exposed to ozone. Secondary emissions were mostly n-nonanal and several other smaller aldehydes. The pattern of emissions suggested that vegetable oils may be precursors for these oxidized emissions. Several possible precursors and experiments in which linseed and tung oils were tested for their secondary emission potential were discussed. Dynamic emission rates of 2-nonenal from a residential carpet may indicate that intermediate species in the oxidation of conjugated olefins can significantly delay aldehyde emissions and act as reservoir for these compounds. The ozone induced emission rate of 2-nonenal, a very odorous compound, can result in odorous indoor concentrations for several years. Surface ozone reactivity is a key parameter in determining the flux of ozone to a surface, is parameterized by the reaction probability, which is simply the probability that an ozone molecule will be irreversibly consumed when it strikes a surface. In laboratory studies of two residential and two commercial carpets, the ozone reaction probability for carpet fibers, carpet backing and the equivalent reaction probability for whole carpet were determined. Typically reaction probability values for these materials were 10

  19. Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves.

    Directory of Open Access Journals (Sweden)

    Nikki A McLean

    Full Text Available Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.

  20. Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves.

    Science.gov (United States)

    McLean, Nikki A; Popescu, Bogdan F; Gordon, Tessa; Zochodne, Douglas W; Verge, Valerie M K

    2014-01-01

    Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.

  1. 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

  2. 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.

  3. 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.

  4. 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)

  5. 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.

  6. 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.

  7. 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.

  8. Uranium and Cesium sorption to bentonite colloids in high salinity and carbonate-rich environments: Implications for radionuclide transport

    Science.gov (United States)

    Tran, E. L.; Teutsch, N.; Klein-BenDavid, O.; Weisbrod, N.

    2017-12-01

    When radionuclides are leaked into the subsurface due to engineered waste disposal container failure, the ultimate barrier to migration of radionuclides into local aquifers is sorption to the surrounding rock matrix and sediments, which often includes a bentonite backfill. The extent of this sorption is dependent on pH, ionic strength, surface area availability, radionuclide concentration, surface mineral composition, and solution chemistry. Colloidal-sized bentonite particles eroded from the backfill have been shown to facilitate the transport of radionuclides sorbed to them away from their source. Thus, sorption of radionuclides such as uranium and cesium to bentonite surfaces can be both a mobilization or retardation factor. Though numerous studies have been conducted to-date on sorption of radionuclides under low ionic strength and carbonate-poor conditions, there has been little research conducted on the behavior of radionuclides in high salinities and carbonate rich conditions typical of aquifers in the vicinity of some potential nuclear repositories. This study attempts to characterize the sorption properties of U(VI) and Cs to bentonite colloids under these conditions using controlled batch experiments. Results indicated that U(VI) undergoes little to no sorption to bentonite colloids in a high-salinity (TDS= 9000 mg/L) artificial groundwater. This lack of sorption was attributed to the formation of CaUO2(CO3)22- and Ca2UO2(CO3)3 aqueous ions which stabilize the UO22+ ions in solution. In contrast, Cs exhibited greater sorption, the extent to which was influenced greatly by the matrix water's ionic strength and the colloid concentration used. Surprisingly, when both U and Cs were together, the presence of U(VI) in solution decreased Cs sorption, possibly due to the formation of stabilizing CaUO2(CO3)22- anions. The implications of this research are that rather than undergoing colloid-facilitated transport, U(VI) is expected to migrate similarly to a

  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. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum.

    Directory of Open Access Journals (Sweden)

    Alper Okyar

    Full Text Available ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation.Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1 and B6CBAF(1 mice synchronized with light from Zeitgeber Time (ZT0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days was administered at the sex- and strain-specific times corresponding to least (ZT11-15 or largest drug-induced body weight loss (ZT23-03-07. Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05. ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003. Irinotecan was also best tolerated in males (p = 0.05 and in B6CBAF(1 (p = 0.0006.Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

  17. 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.

  18. 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.

  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. ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.

    Science.gov (United States)

    Franco, D Lorena; Rezával, Carolina; Cáceres, Alfredo; Schinder, Alejandro F; Ceriani, M Fernanda

    2010-06-01

    Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration. 2010 Elsevier Inc. All rights reserved.

  1. The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes.

    Science.gov (United States)

    Lundberg, Marcus; Lindqvist, Andreas; Wierup, Nils; Krogvold, Lars; Dahl-Jørgensen, Knut; Skog, Oskar

    2017-01-01

    To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes.

  2. The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Marcus Lundberg

    Full Text Available To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes.

  3. 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.

  4. 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...

  5. 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...

  6. 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)

  7. 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.

  8. 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.

  9. 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)

  10. 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

  11. Passenger transport modal split based on budgets and implication for energy consumption: Approach and application in China

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shuwei; Liu, Deshun [School of Public Policy and Management (SPPM) and Institute of Energy, Environment, and Economy, Tsinghua University, Beijing 100084 (China); Jiang, Kejun [Energy Research Institute, National Development and Reform Commission, Beijing 100084 (China)

    2007-09-15

    Transport will be the strongest growing energy demand sector in the future, especially in developing countries like China, and it needs more attention. The evolution of transport structure is very important in the dynamic of transport development, and therefore worth emphasis. In this study, a modal split model maximizing spatial welfare and constrained by travel money budget and time budget is developed. This approach differs from the general econometric-based approach used in most existing macro transport studies and deals with the cost and speed of transport modes as important variables explicitly. The model is then applied to China's transport sector together with sensitivity test despite many data problems. The decomposition of energy consumption generated from bottom-up model based on this modal split identified the importance of modal split and turnover expansion in the next 30 years, which should be a stronger area of focus in transportation studies. (author)

  12. Passenger transport modal split based on budgets and implication for energy consumption: Approach and application in China

    International Nuclear Information System (INIS)

    Zhang, Shuwei; Liu, Deshun; Jiang, Kejun

    2007-01-01

    Transport will be the strongest growing energy demand sector in the future, especially in developing countries like China, and it needs more attention. The evolution of transport structure is very important in the dynamic of transport development, and therefore worth emphasis. In this study, a modal split model maximizing spatial welfare and constrained by travel money budget and time budget is developed. This approach differs from the general econometric-based approach used in most existing macro transport studies and deals with the cost and speed of transport modes as important variables explicitly. The model is then applied to China's transport sector together with sensitivity test despite many data problems. The decomposition of energy consumption generated from bottom-up model based on this modal split identified the importance of modal split and turnover expansion in the next 30 years, which should be a stronger area of focus in transportation studies. (author)

  13. 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.

  14. Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.

    Science.gov (United States)

    Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

    2016-09-06

    CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

  15. Difference in trafficking of brain-derived neurotrophic factor between axons and dendrites of cortical neurons, revealed by live-cell imaging

    Directory of Open Access Journals (Sweden)

    Kohara Keigo

    2005-06-01

    Full Text Available Abstract Background Brain-derived neurotrophic factor (BDNF, which is sorted into a regulated secretory pathway of neurons, is supposed to act retrogradely through dendrites on presynaptic neurons or anterogradely through axons on postsynaptic neurons. Depending on which is the case, the pattern and direction of trafficking of BDNF in dendrites and axons are expected to be different. To address this issue, we analyzed movements of green fluorescent protein (GFP-tagged BDNF in axons and dendrites of living cortical neurons by time-lapse imaging. In part of the experiments, the expression of BDNF tagged with cyan fluorescent protein (CFP was compared with that of nerve growth factor (NGF tagged with yellow fluorescent protein (YFP, to see whether fluorescent protein-tagged BDNF is expressed in a manner specific to this neurotrophin. Results We found that BDNF tagged with GFP or CFP was expressed in a punctated manner in dendrites and axons in about two-thirds of neurons into which plasmid cDNAs had been injected, while NGF tagged with GFP or YFP was diffusely expressed even in dendrites in about 70% of the plasmid-injected neurons. In neurons in which BDNF-GFP was expressed as vesicular puncta in axons, 59 and 23% of the puncta were moving rapidly in the anterograde and retrograde directions, respectively. On the other hand, 64% of BDNF-GFP puncta in dendrites did not move at all or fluttered back and forth within a short distance. The rest of the puncta in dendrites were moving relatively smoothly in either direction, but their mean velocity of transport, 0.47 ± 0.23 (SD μm/s, was slower than that of the moving puncta in axons (0.73 ± 0.26 μm/s. Conclusion The present results show that the pattern and velocity of the trafficking of fluorescence protein-tagged BDNF are different between axons and dendrites, and suggest that the anterograde transport in axons may be the dominant stream of BDNF to release sites.

  16. 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

  17. System-of-Systems Considerations in the Notional Development of a Metropolitan Aerial Transportation System. [Implications as to the Identification of Enabling Technologies and Reference Designs for Extreme Short Haul VTOL Vehicles With Electric Propulsion

    Science.gov (United States)

    Alonso, Juan J.; Arneson, Heather M.; Melton, John E.; Vegh, Michael; Walker, Cedric; Young, Larry A.

    2017-01-01

    There are substantial future challenges related to sustaining and improving efficient, cost-effective, and environmentally friendly transportation options for urban regions. Over the past several decades there has been a worldwide trend towards increasing urbanization of society. Accompanying this urbanization are increasing surface transportation infrastructure costs and, despite public infrastructure investments, increasing surface transportation "gridlock." In addition to this global urbanization trend, there has been a substantial increase in concern regarding energy sustainability, fossil fuel emissions, and the potential implications of global climate change. A recently completed study investigated the feasibility of an aviation solution for future urban transportation (refs. 1, 2). Such an aerial transportation system could ideally address some of the above noted concerns related to urbanization, transportation gridlock, and fossil fuel emissions (ref. 3). A metro/regional aerial transportation system could also provide enhanced transportation flexibility to accommodate extraordinary events such as surface (rail/road) transportation network disruptions and emergency/disaster relief responses.

  18. Orexin A and Orexin Receptor 1 axonal traffic in dorsal roots at the CNS/PNS interface

    Directory of Open Access Journals (Sweden)

    Damien eColas

    2014-02-01

    Full Text Available Hypothalamic orexin/hypocretin neurons send long axonal projections through the dorsal spinal cord in lamina I-II of the dorsal horn at the interface with the peripheral nervous system (PNS. We show that in the dorsal horn OXA fibers colocalize with substance P (SP positive afferents of dorsal root ganglia (DRG neurons known to mediate sensory processing. Further, OR1 is expressed in p75NTR and SP positive DRG neurons, suggesting a potential signaling pathway between orexin and DRG neurons. Interestingly, DRG sensory neurons have a distinctive bifurcating axon where one branch innervates the periphery and the other one the spinal cord (pseudo-unipolar neurons, allowing for potential functional coupling of distinct targets. We observe that OR1 is transported selectively from DRG toward the spinal cord, while OXA is accumulated retrogradely toward the DRG. We hence report a rare situation of asymmetrical neuropeptide receptor distribution between axons projected by a single neuron. This molecular and cellular data are consistent with the role of OXA/OR1 in sensory processing, including DRG neuronal modulation, and support the potential existence of an OX/HCRT circuit between CNS and PNS.

  19. 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

  20. Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease

    OpenAIRE

    Bogdanik, Laurent P.; Sleigh, James N.; Tian, Cong; Samuels, Mark E.; Bedard, Karen; Seburn, Kevin L.; Burgess, Robert W.

    2013-01-01

    SUMMARY Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous condition characterized by peripheral axon degeneration with subsequent motor and sensory deficits. Several CMT gene products function in endosomal sorting and trafficking to the lysosome, suggesting that defects in this cellular pathway might present a common pathogenic mechanism for these conditions. LRSAM1 is an E3 ubiquitin ligase that is implicated in this process, and mutations in LRSAM1 have rece...

  1. Developing a long-term global tourism transport model using a behavioural approach: implications for sustainable tourism policy making.

    NARCIS (Netherlands)

    Peeters, P.M.

    2013-01-01

    This paper explores the creation and use of a long-term global tourism transport model for private and public sector tourism policy makers. Given that technology is unlikely to reduce tourism transport's impact on climate change sufficiently to avoid serious dangers, behavioural change is necessary.

  2. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.

    Science.gov (United States)

    Bonnin, A; Levitt, P

    2011-12-01

    In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.

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    Kara R Barber

    2017-02-01

    Full Text Available Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

  4. 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

  5. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy

    Directory of Open Access Journals (Sweden)

    Khalid J.H. Alzahrani

    2017-08-01

    Full Text Available Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU and 5F,2′deoxyuridine (5F,2′dUrd, and was designated uridine-uracil transporter 1 (UUT1; the other transporter mediated uptake of adenosine, uridine, 5F,2′dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1. To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2′dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2′dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Keywords: Leishmania, Pyrimidine metabolism, Uracil

  6. Inter-compartmental transport of organophosphate and pyrethroid pesticides in South China: Implications for a regional risk assessment

    International Nuclear Information System (INIS)

    Li, Huizhen; Wei, Yanli; Lydy, Michael J.; You, Jing

    2014-01-01

    The dynamic flux of an organophosphate and four pyrethroid pesticides was determined in an air-(soil)-water-sediment system based on monitoring data from Guangzhou, China. The total air–water flux, including air–water gaseous exchange and atmospheric deposition, showed deposition from air to water for chlorpyrifos, bifenthrin and cypermethrin, but volatilization for lambda-cyhalothrin and permethrin. The transport of the pesticides from overlying water to sediment suggested that sediment acted as a sink for the pesticides. Additionally, distinct annual atmospheric depositional fluxes between legacy and current-use pesticides suggested the role of consumer usage in their transport throughout the system. Finally, pesticide toxicity was estimated from annual air–water-sediment flux within an urban stream in Guangzhou. A dynamic flux-based risk assessment indicated that inter-compartmental transport of chlorpyrifos decreased its atmospheric exposure, but had little influence on its aquatic toxicity. Instead, water-to-sediment transport of pyrethroids increased their sediment toxicity, which was supported by previously reported toxicity data. - Highlights: • Transport fluxes of chlorpyrifos and pyrethroids were assessed in Guangzhou, China. • Sediment acted as a sink for chlorpyrifos and pyrethroids. • Air-to-water transport decreased the exposure risk of atmospheric chlorpyrifos. • Dynamic transport might increase the risk of pyrethroids in air and sediment. • Flux-based pesticide concentrations provide a way to estimate sediment toxicity. - Regional risk assessment could be improved by integrating dynamic flux information derived from inter-compartmental models

  7. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

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    Dirk Taubert

    Full Text Available BACKGROUND: The etiology of neurodegenerative disorders, such as the accelerated loss of dopaminergic neurons in Parkinson's disease, is unclear. Current hypotheses suggest an abnormal function of the neuronal sodium-dependent dopamine transporter DAT to contribute to cell death in the dopaminergic system, but it has not been investigated whether sodium-independent amine transporters are implicated in the pathogenesis of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: By the use of a novel tandem-mass spectrometry-based substrate search technique, we have shown that the dopaminergic neuromodulators histidyl-proline diketopiperazine (cyclo(his-pro and salsolinol were the endogenous key substrates of the sodium-independent organic cation transporter OCT2. Quantitative real-time mRNA expression analysis revealed that OCT2 in contrast to its related transporters was preferentially expressed in the dopaminergic regions of the substantia nigra where it colocalized with DAT and tyrosine hydroxylase. By assessing cell viability with the MTT reduction assay, we found that salsolinol exhibited a selective toxicity toward OCT2-expressing cells that was prevented by cyclo(his-pro. A frequent genetic variant of OCT2 with the amino acid substitution R400C reduced the transport efficiency for the cytoprotective cyclo(his-pro and thereby increased the susceptibility to salsolinol-induced cell death. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the OCT2-regulated interplay between cyclo(his-pro and salsolinol is crucial for nigral cell integrity and that a shift in transport efficiency may impact the risk of Parkinson's disease.

  8. 3-D Characterization of Detrital Zircon Grains and its Implications for Fluvial Transport, Mixing, and Preservation Bias

    Science.gov (United States)

    Markwitz, V.; Kirkland, C. L.; Mehnert, A.; Gessner, K.; Shaw, J.

    2017-12-01

    Detrital zircon studies can suffer from selective loss of provenance information due to U-Pb age discordance, metamictization, metamorphic overprinting and fluviatile transport processes. The relationship between isotopic composition and zircon grain shape, and how grain shape is modified during transport, is largely unknown. We combine X-ray tomography with U-Pb geochronology to quantify how fluvial transport affects 3-D zircon shape, detrital age signature, and grain density along the Murchison River, whose catchment comprises Eoarchean to Early Paleozoic source rocks in Western Australia. We acquired tomographic volumes and isotopic data from 373 detrital zircons to document changes in size, shape and density in transport direction, and explore how grain shape, age spectra and the proportion of discordant material vary along the channel. Results show that shape characteristics are sensitive to transport distance, stream gradient, proximity to source material, and whether the source consists of primary or recycled zircons. With increasing transport distance, grain lengths decrease more than their widths. Furthermore, the loss of metamict grains occurs at a near constant rate, resulting in a linear increase of mean calculated zircon density by ca. 0.03 g/cm3 per 100 km transport distance. 3-D grain shape is therefore strongly linked to detrital age signature, and mean grain density is a function of the absolute transport distance. 3-D shape characteristics provide valuable information on detrital zircon populations, including the interaction between source materials with fluvial transport processes, which significantly affects preservation bias and, by inference, the representativeness of the sampled data.

  9. 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.

  10. Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology.

    Science.gov (United States)

    Skjørringe, Tina; Burkhart, Annette; Johnsen, Kasper Bendix; Moos, Torben

    2015-01-01

    Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.

  11. 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

  12. Polyethylene glycol restores axonal conduction after corpus callosum transection

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    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.

  13. 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.

  14. Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.

    Science.gov (United States)

    Tsai, Shang-Yi A; Pokrass, Michael J; Klauer, Neal R; Nohara, Hiroshi; Su, Tsung-Ping

    2015-05-26

    Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.

    Science.gov (United States)

    Alzahrani, Khalid J H; Ali, Juma A M; Eze, Anthonius A; Looi, Wan Limm; Tagoe, Daniel N A; Creek, Darren J; Barrett, Michael P; de Koning, Harry P

    2017-08-01

    Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2'deoxyuridine (5F,2'dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2'dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [ 3 H]-uridine but not of [ 3 H]-inosine. Conversely, the NT2-like genes mediated uptake of [ 3 H]-inosine but not [ 3 H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2'dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2'dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights

  20. 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.

  1. 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

  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. SIMULATION OF ENERGETIC PARTICLE TRANSPORT AND ACCELERATION AT SHOCK WAVES IN A FOCUSED TRANSPORT MODEL: IMPLICATIONS FOR MIXED SOLAR PARTICLE EVENTS

    Energy Technology Data Exchange (ETDEWEB)

    Kartavykh, Y. Y.; Dröge, W. [Institut für Theoretische Physik und Astrophysik, Universität Würzburg, D-97074 Würzburg (Germany); Gedalin, M. [Department of Physics, Ben-Gurion Unversity of the Negev, Beer-Sheva (Israel)

    2016-03-20

    We use numerical solutions of the focused transport equation obtained by an implicit stochastic differential equation scheme to study the evolution of the pitch-angle dependent distribution function of protons in the vicinity of shock waves. For a planar stationary parallel shock, the effects of anisotropic distribution functions, pitch-angle dependent spatial diffusion, and first-order Fermi acceleration at the shock are examined, including the timescales on which the energy spectrum approaches the predictions of diffusive shock acceleration theory. We then consider the case that a flare-accelerated population of ions is released close to the Sun simultaneously with a traveling interplanetary shock for which we assume a simplified geometry. We investigate the consequences of adiabatic focusing in the diverging magnetic field on the particle transport at the shock, and of the competing effects of acceleration at the shock and adiabatic energy losses in the expanding solar wind. We analyze the resulting intensities, anisotropies, and energy spectra as a function of time and find that our simulations can naturally reproduce the morphologies of so-called mixed particle events in which sometimes the prompt and sometimes the shock component is more prominent, by assuming parameter values which are typically observed for scattering mean free paths of ions in the inner heliosphere and energy spectra of the flare particles which are injected simultaneously with the release of the shock.

  4. The Question of Queue: Implications for -Best Practice- in Cross-country Transport of Commercial Spent Nuclear Fuel

    International Nuclear Information System (INIS)

    Williams, J.M.

    2009-01-01

    The 'Standard Contract' authorized by the Nuclear Waste Policy Act of 1982 (Section 302(a)) provides that priority for acceptance of spent nuclear fuel (SNF) shall be based on the date of its discharge from civilian nuclear reactors. Through 2007, about 2,100 discharges of about 58,000 metric tons have created a priority ranking (or 'queue') for US DOE spent fuel acceptance and transport. Since 1982, consideration of the task of large-scale, cross-country SNF transport (by the National Academies and others) has led to several recommendations for 'best practice' in such an unprecedented campaign. Many of these recommendations, however, are inconsistent with the acceptance priority established by the Standard Contract, and in fact cannot be implemented under its provisions. This paper considers the SNF acceptance rankings established by the Standard Contract, and the barrier these place on best practice cross-country transport of the nation's inventory of SNF. Using a series of case studies, the paper explores the challenge of best practice transport from selected shipment origins under current arrangements. The case studies support preliminary conclusions regarding the inconsistency between best practice SNF transport and the Standard Contract acceptance queue, with reference to particular origins sites and their utility owners. The paper concludes with a suggestion for resolving the inconsistencies, and recommended next steps in the inquiry. (authors)

  5. Geographic Access Modeling of Emergency Obstetric and Neonatal Care in Kigoma Region, Tanzania: Transportation Schemes and Programmatic Implications.

    Science.gov (United States)

    Chen, Yi No; Schmitz, Michelle M; Serbanescu, Florina; Dynes, Michelle M; Maro, Godson; Kramer, Michael R

    2017-09-27

    Access to transportation is vital to reducing the travel time to emergency obstetric and neonatal care (EmONC) for managing complications and preventing adverse maternal and neonatal outcomes. This study examines the distribution of travel times to EmONC in Kigoma Region, Tanzania, using various transportation schemes, to estimate the proportion of live births (a proxy indicator of women needing delivery care) with poor geographic access to EmONC services. The 2014 Reproductive Health Survey of Kigoma Region identified 4 primary means of transportation used to travel to health facilities: walking, cycling, motorcycle, and 4-wheeled motor vehicle. A raster-based travel time model was used to map the 2-hour travel time catchment for each mode of transportation. Live birth density distributions were aggregated by travel time catchments, and by administrative council, to estimate the proportion of births with poor access. Of all live births in Kigoma Region, 13% occurred in areas where women can reach EmONC facilities within 2 hours on foot, 33% in areas that can be reached within 2 hours only by motorized vehicles, and 32% where it is impossible to reach EmONC facilities within 2 hours. Over 50% of births in 3 of the 8 administrative councils had poor estimated access. In half the councils, births with poor access could be reduced to no higher than 12% if all female residents had access to motorized vehicles. Significant differences in geographic access to EmONC in Kigoma Region, Tanzania, were observed both by location and by primary transportation type. As most of the population may only have good EmONC access when using mechanized or motorized vehicles, bicycles and motorcycles should be incorporated into the health transportation strategy. Collaboration between private transportation sectors and obstetric service providers could improve access to EmONC services among most populations. In areas where residents may not access EmONC facilities within 2 hours

  6. 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.

  7. 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...

  8. Novel properties of the wheat aluminum tolerance organic acid transporter (TaALMT1) revealed by electrophysiological characterization in Xenopus Oocytes: functional and structural implications.

    Science.gov (United States)

    Piñeros, Miguel A; Cançado, Geraldo M A; Kochian, Leon V

    2008-08-01

    Many plant species avoid the phytotoxic effects of aluminum (Al) by exuding dicarboxylic and tricarboxylic acids that chelate and immobilize Al(3+) at the root surface, thus preventing it from entering root cells. Several novel genes that encode membrane transporters from the ALMT and MATE families recently were cloned and implicated in mediating the organic acid transport underlying this Al tolerance response. Given our limited understanding of the functional properties of ALMTs, in this study a detailed characterization of the transport properties of TaALMT1 (formerly named ALMT1) from wheat (Triticum aestivum) expressed in Xenopus laevis oocytes was conducted. The electrophysiological findings are as follows. Although the activity of TaALMT1 is highly dependent on the presence of extracellular Al(3+) (K(m1/2) of approximately 5 microm Al(3+) activity), TaALMT1 is functionally active and can mediate ion transport in the absence of extracellular Al(3+). The lack of change in the reversal potential (E(rev)) upon exposure to Al(3+) suggests that the "enhancement" of TaALMT1 malate transport by Al is not due to alteration in the transporter's selectivity properties but is solely due to increases in its anion permeability. The consistent shift in the direction of the E(rev) as the intracellular malate activity increases indicates that TaALMT1 is selective for the transport of malate over other anions. The estimated permeability ratio between malate and chloride varied between 1 and 30. However, the complex behavior of the E(rev) as the extracellular Cl(-) activity was varied indicates that this estimate can only be used as a general guide to understanding the relative affinity of TaALMT1 for malate, representing only an approximation of those expected under physiologically relevant ionic conditions. TaALMT1 can also mediate a large anion influx (i.e. outward currents). TaALMT1 is permeable not only to malate but also to other physiologically relevant anions such as Cl

  9. Novel Properties of the Wheat Aluminum Tolerance Organic Acid Transporter (TaALMT1) Revealed by Electrophysiological Characterization in Xenopus Oocytes: Functional and Structural Implications1[OA

    Science.gov (United States)

    Piñeros, Miguel A.; Cançado, Geraldo M.A.; Kochian, Leon V.

    2008-01-01

    Many plant species avoid the phytotoxic effects of aluminum (Al) by exuding dicarboxylic and tricarboxylic acids that chelate and immobilize Al3+ at the root surface, thus preventing it from entering root cells. Several novel genes that encode membrane transporters from the ALMT and MATE families recently were cloned and implicated in mediating the organic acid transport underlying this Al tolerance response. Given our limited understanding of the functional properties of ALMTs, in this study a detailed characterization of the transport properties of TaALMT1 (formerly named ALMT1) from wheat (Triticum aestivum) expressed in Xenopus laevis oocytes was conducted. The electrophysiological findings are as follows. Although the activity of TaALMT1 is highly dependent on the presence of extracellular Al3+ (Km1/2 of approximately 5 μm Al3+ activity), TaALMT1 is functionally active and can mediate ion transport in the absence of extracellular Al3+. The lack of change in the reversal potential (Erev) upon exposure to Al3+ suggests that the “enhancement” of TaALMT1 malate transport by Al is not due to alteration in the transporter's selectivity properties but is solely due to increases in its anion permeability. The consistent shift in the direction of the Erev as the intracellular malate activity increases indicates that TaALMT1 is selective for the transport of malate over other anions. The estimated permeability ratio between malate and chloride varied between 1 and 30. However, the complex behavior of the Erev as the extracellular Cl− activity was varied indicates that this estimate can only be used as a general guide to understanding the relative affinity of TaALMT1 for malate, representing only an approximation of those expected under physiologically relevant ionic conditions. TaALMT1 can also mediate a large anion influx (i.e. outward currents). TaALMT1 is permeable not only to malate but also to other physiologically relevant anions such as Cl−, NO3−, and

  10. Traumatic midline subarachnoid hemorrhage on initial computed tomography as a marker of severe diffuse axonal injury.

    Science.gov (United States)

    Mata-Mbemba, Daddy; Mugikura, Shunji; Nakagawa, Atsuhiro; Murata, Takaki; Ishii, Kiyoshi; Kushimoto, Shigeki; Tominaga, Teiji; Takahashi, Shoki; Takase, Kei

    2018-01-05

    OBJECTIVE The objective of this study was to test the hypothesis that midline (interhemispheric or perimesencephalic) traumatic subarachnoid hemorrhage (tSAH) on initial CT may implicate the same shearing mechanism that underlies severe diffuse axonal injury (DAI). METHODS The authors enrolled 270 consecutive patients (mean age [± SD] 43 ± 23.3 years) with a history of head trauma who had undergone initial CT within 24 hours and brain MRI within 30 days. Six initial CT findings, including intraventricular hemorrhage (IVH) and tSAH, were used as candidate predictors of DAI. The presence of tSAH was determined at the cerebral convexities, sylvian fissures, sylvian vallecula, cerebellar folia, interhemispheric fissure, and perimesencephalic cisterns. Following MRI, patients were divided into negative and positive DAI groups, and were assigned to a DAI stage: 1) stage 0, negative DAI; 2) stage 1, DAI in lobar white matter or cerebellum; 3) stage 2, DAI involving the corpus callosum; and 4) stage 3, DAI involving the brainstem. Glasgow Outcome Scale-Extended (GOSE) scores were obtained in 232 patients. RESULTS Of 270 patients, 77 (28.5%) had DAI; tSAH and IVH were independently associated with DAI (p GOSE score at both hospital discharge and after 6 months. CONCLUSIONS Midline tSAH could implicate the same shearing mechanism that underlies severe DAI, for which midline tSAH on initial CT is a probable surrogate.

  11. Risk Factors for Road Transport-Related Injury among Pedestrians in Rural Ghana: Implications for Road Safety Education

    Science.gov (United States)

    Teye-Kwadjo, Enoch

    2017-01-01

    Objectives: Injuries and mortality resulting from pedestrian road traffic crashes are a major public health problem in Ghana. This study investigated risk factors for road transport-related injury among pedestrians in rural Ghana. Design: Case study design using qualitative data. Method: In-depth interviews were conducted with pedestrians.…

  12. Modelling the transport of suspended particulate matter by the Rhone River plume (France). Implications for pollutant dispersion

    International Nuclear Information System (INIS)

    Perianez, R.

    2005-01-01

    A model to simulate the transport of suspended particulate matter by the Rhone River plume has been developed. The model solves the 3D hydrodynamic equations, including baroclinic terms and a 1-equation turbulence model, and the suspended matter equations including advection/diffusion of particles, settling and deposition. Four particle classes are considered simultaneously according to observations in the Rhone. Computed currents, salinity and particle distributions are, in general, in good agreement with observations or previous calculations. The model also provides sedimentation rates and the distribution of different particle classes over the sea bed. It has been found that high sedimentation rates close to the river mouth are due to coarse particles that sink rapidly. Computed sedimentation rates are also similar to those derived from observations. The model has been applied to simulate the transport of radionuclides by the plume, since suspended matter is the main vector for them. The radionuclide transport model, previously described and validated, includes exchanges of radionuclides between water, suspended matter and bottom sediment described in terms of kinetic rates. A new feature is the explicit inclusion of the dependence of kinetic rates upon salinity. The model has been applied to 137 Cs and 239,240 Pu. Results are, in general, in good agreement with observations. - A model has been developed to simulate transport of suspended particulate matter in the Rhone River plume

  13. Inter-compartmental transport of organophosphate and pyrethroid pesticides in South China: implications for a regional risk assessment.

    Science.gov (United States)

    Li, Huizhen; Wei, Yanli; Lydy, Michael J; You, Jing

    2014-07-01

    The dynamic flux of an organophosphate and four pyrethroid pesticides was determined in an air-(soil)-water-sediment system based on monitoring data from Guangzhou, China. The total air-water flux, including air-water gaseous exchange and atmospheric deposition, showed deposition from air to water for chlorpyrifos, bifenthrin and cypermethrin, but volatilization for lambda-cyhalothrin and permethrin. The transport of the pesticides from overlying water to sediment suggested that sediment acted as a sink for the pesticides. Additionally, distinct annual atmospheric depositional fluxes between legacy and current-use pesticides suggested the role of consumer usage in their transport throughout the system. Finally, pesticide toxicity was estimated from annual air-water-sediment flux within an urban stream in Guangzhou. A dynamic flux-based risk assessment indicated that inter-compartmental transport of chlorpyrifos decreased its atmospheric exposure, but had little influence on its aquatic toxicity. Instead, water-to-sediment transport of pyrethroids increased their sediment toxicity, which was supported by previously reported toxicity data. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. 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...

  15. 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...

  16. 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

  17. 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.

  18. Computational approaches for the study of serotonin and its membrane transporter SERT: implications for drug design in neurological sciences.

    Science.gov (United States)

    Pratuangdejkul, J; Schneider, B; Launay, J-M; Kellermann, O; Manivet, P

    2008-01-01

    Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, "selective" serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.

  19. Transport and biodistribution of dendrimers across human fetal membranes: implications for intravaginal administration of dendrimer-drug conjugates.

    Science.gov (United States)

    Menjoge, Anupa R; Navath, Raghavendra S; Asad, Abbas; Kannan, Sujatha; Kim, Chong J; Romero, Roberto; Kannan, Rangaramanujam M

    2010-06-01

    Dendrimers are emerging as promising topical antimicrobial agents, and as targeted nanoscale drug delivery vehicles. Topical intravaginal antimicrobial agents are prescribed to treat the ascending genital infections in pregnant women. The fetal membranes separate the extra-amniotic space and fetus. The purpose of the study is to determine if the dendrimers can be selectively used for local intravaginal application to pregnant women without crossing the membranes into the fetus. In the present study, the transport and permeability of PAMAM (poly (amidoamine)) dendrimers, across human fetal membrane (using a side by side diffusion chamber), and its biodistribution (using immunofluorescence) are evaluated ex-vivo. Transport across human fetal membranes (from the maternal side) was evaluated using Fluorescein (FITC), an established transplacental marker (positive control, size approximately 400 Da) and fluorophore-tagged G(4)-PAMAM dendrimers (approximately 16 kDa). The fluorophore-tagged G(4)-PAMAM dendrimers were synthesized and characterized using (1)H NMR, MALDI TOF MS and HPLC analysis. Transfer was measured across the intact fetal membrane (chorioamnion), and the separated chorion and amnion layers. Over a 5 h period, the dendrimer transport across all the three membranes was less than dendrimer (5.8 x 10(-8) cm(2)/s). The biodistribution showed that the dendrimers were largely present in interstitial spaces in the decidual stromal cells and the chorionic trophoblast cells (in 2.5-4 h) and surprisingly, to a smaller extent internalized in nuclei of trophoblast cells and nuclei and cytoplasm of stromal cells. Passive diffusion and paracellular transport appear to be the major route for dendrimer transport. The overall findings further suggest that entry of drugs conjugated to dendrimers would be restricted across the human fetal membranes when administered topically by intravaginal route, suggesting new ways of selectively delivering therapeutics to the mother

  20. Air pollution over the North China Plain and its implication of regional transport: A new sight from the observed evidences.

    Science.gov (United States)

    Ge, Baozhu; Wang, Zifa; Lin, Weili; Xu, Xiaobin; Li, Jie; Ji, Dongshen; Ma, Zhiqiang

    2018-03-01

    High concentrations of the fine particles (PM 2.5 ) are frequently observed during all seasons over the North China Plain (NCP) region in recent years. In NCP, the contributions of regional transports to certain area, e.g. Beijing city, are often discussed and estimated by models when considering an effective air pollution controlling strategy. In this study, we selected three sites from southwest to northeast in NCP, in which the concentrations of air pollutants displayed a multi-step decreasing trend in space. An approach based on the measurement results at these sites has been developed to calculate the relative contributions of the minimal local emission (MinLEC) and the maximum regional transport (MaxRTC) to the air pollutants (e.g., SO 2 , NO 2 , CO, PM 2.5 ) in Beijing. The minimal influence of local emission is estimated by the difference of the air pollutants' concentrations between urban and rural areas under the assumption of a similar influence of regional transport. Therefore, it's convenient to estimate the contributions of local emission from regional transport based on the selective measurement results instead of the complex numerical model simulation. For the whole year of 2013, the averaged contributions of MinLEC (MaxRTC) for NO 2 , SO 2 , PM 2.5 and CO are 61.7% (30.7%), 46.6% (48%), 52.1% (40.2%) and 35.8% (45.5%), respectively. The diurnal variation of MaxRTC for SO 2 , PM 2.5 and CO shows an increased pattern during the afternoon and reached a peak (more than 50%) around 18:00, which indicates that the regional transport is the important role for the daytime air pollution in Beijing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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...

  6. 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

  7. 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.

  8. 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.

  9. 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...

  10. Optical conductivity and optical effective mass in a high-mobility organic semiconductor: Implications for the nature of charge transport

    KAUST Repository

    Li, Yuan

    2014-12-03

    We present a multiscale modeling of the infrared optical properties of the rubrene crystal. The results are in very good agreement with the experimental data that point to nonmonotonic features in the optical conductivity spectrum and small optical effective masses. We find that, in the static-disorder approximation, the nonlocal electron-phonon interactions stemming from low-frequency lattice vibrations can decrease the optical effective masses and lead to lighter quasiparticles. On the other hand, the charge-transport and infrared optical properties of the rubrene crystal at room temperature are demonstrated to be governed by localized carriers driven by inherent thermal disorders. Our findings underline that the presence of apparently light carriers in high-mobility organic semiconductors does not necessarily imply bandlike transport.

  11. The implications of megatrends in information and communication technology and transportation for changes in global physical activity.

    Science.gov (United States)

    Pratt, Michael; Sarmiento, Olga L; Montes, Felipe; Ogilvie, David; Marcus, Bess H; Perez, Lilian G; Brownson, Ross C

    2012-07-21

    Physical inactivity accounts for more than 3 million deaths per year, most from non-communicable diseases in low-income and middle-income countries. We used reviews of physical activity interventions and a simulation model to examine how megatrends in information and communication technology and transportation directly and indirectly affect levels of physical activity across countries of low, middle, and high income. The model suggested that the direct and potentiating eff ects of information and communication technology, especially mobile phones, are nearly equal in magnitude to the mean eff ects of planned physical activity interventions. The greatest potential to increase population physical activity might thus be in creation of synergistic policies in sectors outside health including communication and transportation. However, there remains a glaring mismatch between where studies on physical activity interventions are undertaken and where the potential lies in low-income and middle-income countries for population-level effects that will truly affect global health.

  12. Constraints on water transport posed by xylem embolism: implications for drought and frost resistance in woody plants

    OpenAIRE

    Martínez Vilalta, Jordi

    2001-01-01

    Consultable des del TDX Títol obtingut de la portada digitalitzada Introducció L'aigua és un recurs i un factor limitant per la vida de les plantes. El transport d'aigua des de les arrels fins a les fulles té lloc fonamentalment a través del xilema. La capacitat d'aquest teixit per transportar aigua (i.e., la seva conductivitat hidràulica) no és constant sinó que depèn de les condicions en què es produeix el transport. En particular, quan els potencials hídrics es fan molt negatius (seq...

  13. Optical conductivity and optical effective mass in a high-mobility organic semiconductor: Implications for the nature of charge transport

    KAUST Repository

    Li, Yuan; Yi, Yuanping; Coropceanu, Veaceslav; Bredas, Jean-Luc

    2014-01-01

    We present a multiscale modeling of the infrared optical properties of the rubrene crystal. The results are in very good agreement with the experimental data that point to nonmonotonic features in the optical conductivity spectrum and small optical effective masses. We find that, in the static-disorder approximation, the nonlocal electron-phonon interactions stemming from low-frequency lattice vibrations can decrease the optical effective masses and lead to lighter quasiparticles. On the other hand, the charge-transport and infrared optical properties of the rubrene crystal at room temperature are demonstrated to be governed by localized carriers driven by inherent thermal disorders. Our findings underline that the presence of apparently light carriers in high-mobility organic semiconductors does not necessarily imply bandlike transport.

  14. Effects of blood transportation on human peripheral mononuclear cell yield, phenotype and function: implications for immune cell biobanking.

    Directory of Open Access Journals (Sweden)

    Anita Posevitz-Fejfár

    Full Text Available Human biospecimen collection, processing and preservation are rapidly emerging subjects providing essential support to clinical as well as basic researchers. Unlike collection of other biospecimens (e.g. DNA and serum, biobanking of viable immune cells, such as peripheral blood mononuclear cells (PBMC and/or isolated immune cell subsets is still in its infancy. While certain aspects of processing and freezing conditions have been studied in the past years, little is known about the effect of blood transportation on immune cell survival, phenotype and specific functions. However, especially for multicentric and cooperative projects it is vital to precisely know those effects. In this study we investigated the effect of blood shipping and pre-processing delay on immune cell phenotype and function both on cellular and subcellular levels. Peripheral blood was collected from healthy volunteers (n = 9: at a distal location (shipped overnight and in the central laboratory (processed immediately. PBMC were processed in the central laboratory and analyzed post-cryopreservation. We analyzed yield, major immune subset distribution, proliferative capacity of T cells, cytokine pattern and T-cell receptor signal transduction. Results show that overnight transportation of blood samples does not globally compromise T- cell subsets as they largely retain their phenotype and proliferative capacity. However, NK and B cell frequencies, the production of certain PBMC-derived cytokines and IL-6 mediated cytokine signaling pathway are altered due to transportation. Various control experiments have been carried out to compare issues related to shipping versus pre-processing delay on site. Our results suggest the implementation of appropriate controls when using multicenter logistics for blood transportation aiming at subsequent isolation of viable immune cells, e.g. in multicenter clinical trials or studies analyzing immune cells/subsets. One important conclusion might

  15. Effect of Mass Transport in the Synthesis of Partially Acetylated Dendrimer: Implications for Functional Ligand–Nanoparticle Distributions

    OpenAIRE

    Mullen, Douglas G.; Borgmeier, Emilee L.; Fang, Ming; McNerny, Daniel Q.; Desai, Ankur; Baker, James R.; Orr, Bradford G.; Holl, Mark M. Banaszak

    2010-01-01

    Partial acetylation of the amine-terminated poly(amidoamine) dendrimer has been used in the preparation of dendrimer particles conjugated with a wide variety of functional ligands including targeting moieties, therapeutic agents, and dye molecules. The effectiveness of mass transport during the partial acetylation reaction was found to have a major effect on subsequent distributions of dendrimer–ligand components and to be a major source of inconsistency between batches. This study has broad ...

  16. Unusual Sediment Transportation Processes Under Low Pressure Environments and Implications For Gullies and Recurring Slope Lineae (RSL)

    Science.gov (United States)

    Raack, J.; Herny, C.; Conway, S. J.; Balme, M. R.; Carpy, S.; Patel, M.

    2017-12-01

    Recently and presently active mass wasting features such as gullies and recurring slope lineae (RSL) are common on the surface of Mars, but their origin and triggering mechanisms are under intense debate. While several active mass wasting features have been linked to sublimation of CO2ice, dry granular flows (avalanches), or a combination of both effects, others have been more closely linked to liquid water or briny outflows (e.g. for RSL). However, liquid water on the surface of Mars is unstable under present-day low pressures and surface temperatures. Nevertheless, numerical modeling and remote sensing data have shown that maximum surface temperatures can exceed the frost point of water and that liquid water could exist on the surface of actual Mars in a transient state. But to explain the observed spatial extent of RSL and recent modification of gullies, it is estimated that relatively large amounts of liquid water are necessary. It is proving challenging to generate such quantities from the atmosphere. In this contribution we explore the potential effects of boiling water (boiling occurs at martian pressures slightly above the frost point of 273 K) on sediment transport. We will present the outcomes of a series of experiments under low surface and water temperatures (between 278 and 297 K, analogous to surface temperatures observed near RSL) and low pressures (between 8 and 11 mbar). We simulate sediment transport by boiling liquid water over a sloping bed of unconsolidated sediment. Our results reveal a suite of unusual and very reactive sediment transportation processes, which are not produced under terrestrial pressures. We will discuss the impact of these unusual sediment transport processes on estimates of water budgets for active mass wasting processes.

  17. Implications of high altitude desert dust transport from Western Sahara to Nile Delta during biomass burning season

    Energy Technology Data Exchange (ETDEWEB)

    Prasad, Anup K., E-mail: aprasad@chapman.ed [School of Earth and Environmental Sciences, Schmid College of Science, Chapman University, Orange, CA 92866 (United States); Center of Excellence in Earth Observing, Chapman University, Orange, CA 92866 (United States); El-Askary, Hesham [School of Earth and Environmental Sciences, Schmid College of Science, Chapman University, Orange, CA 92866 (United States); Center of Excellence in Earth Observing, Chapman University, Orange, CA 92866 (United States); Department of Environmental Sciences, Faculty of Science, Alexandria University, Moharem Bek, Alexandria 21522 (Egypt); National Authority for Remote Sensing and Space Science (NARSS), Cairo (Egypt); Kafatos, Menas [School of Earth and Environmental Sciences, Schmid College of Science, Chapman University, Orange, CA 92866 (United States); Center of Excellence in Earth Observing, Chapman University, Orange, CA 92866 (United States)

    2010-11-15

    The air over major cities and rural regions of the Nile Delta is highly polluted during autumn which is the biomass burning season, locally known as black cloud. Previous studies have attributed the increased pollution levels during the black cloud season to the biomass or open burning of agricultural waste, vehicular, industrial emissions, and secondary aerosols. However, new multi-sensor observations (column and vertical profiles) from satellites, dust transport models and associated meteorology present a different picture of the autumn pollution. Here we show, for the first time, the evidence of long range transport of dust at high altitude (2.5-6 km) from Western Sahara and its deposition over the Nile Delta region unlike current Models. The desert dust is found to be a major contributor to the local air quality which was previously considered to be due to pollution from biomass burning enhanced by the dominant northerly winds coming from Europe. - New evidence of desert dust transport from Western Sahara to Nile Delta during black cloud season and its significance for regional aerosols, dust models, and potential impact on the regional climate.

  18. The Implication of PGC-1α on Fatty Acid Transport across Plasma and Mitochondrial Membranes in the Insulin Sensitive Tissues

    Directory of Open Access Journals (Sweden)

    Elżbieta Supruniuk

    2017-11-01

    Full Text Available PGC-1α coactivator plays a decisive role in the maintenance of lipid balance via engagement in numerous metabolic processes (i.e., Krebs cycle, β-oxidation, oxidative phosphorylation and electron transport chain. It constitutes a link between fatty acids import and their complete oxidation or conversion into bioactive fractions through the coordination of both the expression and subcellular relocation of the proteins involved in fatty acid transmembrane movement. Studies on cell lines and/or animal models highlighted the existence of an upregulation of the total and mitochondrial FAT/CD36, FABPpm and FATPs content in skeletal muscle in response to PGC-1α stimulation. On the other hand, the association between PGC-1α level or activity and the fatty acids transport in the heart and adipocytes is still elusive. So far, the effects of PGC-1α on the total and sarcolemmal expression of FAT/CD36, FATP1, and FABPpm in cardiomyocytes have been shown to vary in relation to the type of PPAR that was coactivated. In brown adipose tissue (BAT PGC-1α knockdown was linked with a decreased level of lipid metabolizing enzymes and fatty acid transporters (FAT/CD36, FABP3, whereas the results obtained for white adipose tissue (WAT remain contradictory. Furthermore, dysregulation in lipid turnover is often associated with insulin intolerance, which suggests the coactivator's potential role as a therapeutic target.

  19. Implications of high altitude desert dust transport from Western Sahara to Nile Delta during biomass burning season

    International Nuclear Information System (INIS)

    Prasad, Anup K.; El-Askary, Hesham; Kafatos, Menas

    2010-01-01

    The air over major cities and rural regions of the Nile Delta is highly polluted during autumn which is the biomass burning season, locally known as black cloud. Previous studies have attributed the increased pollution levels during the black cloud season to the biomass or open burning of agricultural waste, vehicular, industrial emissions, and secondary aerosols. However, new multi-sensor observations (column and vertical profiles) from satellites, dust transport models and associated meteorology present a different picture of the autumn pollution. Here we show, for the first time, the evidence of long range transport of dust at high altitude (2.5-6 km) from Western Sahara and its deposition over the Nile Delta region unlike current Models. The desert dust is found to be a major contributor to the local air quality which was previously considered to be due to pollution from biomass burning enhanced by the dominant northerly winds coming from Europe. - New evidence of desert dust transport from Western Sahara to Nile Delta during black cloud season and its significance for regional aerosols, dust models, and potential impact on the regional climate.

  20. Trace-metal concentrations in African dust: effects of long-distance transport and implications for human health

    Science.gov (United States)

    Garrison, Virginia; Lamothe, Paul; Morman, Suzette; Plumlee, Geoffrey S.; Gilkes, Robert; Prakongkep, Nattaporn

    2010-01-01

    The Sahara and Sahel lose billions of tons of eroded mineral soils annually to the Americas and Caribbean, Europe and Asia via atmospheric transport. African dust was collected from a dust source region (Mali, West Africa) and from downwind sites in the Caribbean [Trinidad-Tobago (TT) and U.S. Virgin Islands (VI)] and analysed for 32 trace-elements. Elemental composition of African dust samples was similar to that of average upper continental crust (UCC), with some enrichment or depletion of specific trace-elements. Pb enrichment was observed only in dust and dry deposition samples from the source region and was most likely from local use of leaded gasoline. Dust particles transported long-distances (VI and TT) exhibited increased enrichment of Mo and minor depletion of other elements relative to source region samples. This suggests that processes occurring during long-distance transport of dust produce enrichment/depletion of specific elements. Bioaccessibility of trace-metals in samples was tested in simulated human fluids (gastric and lung) and was found to be greater in downwind than source region samples, for some metals (e.g., As). The large surface to volume ratio of the dust particles (<2.5 µm) at downwind sites may be a factor.

  1. αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function.

    Science.gov (United States)

    Huang, Claire Yu-Mei; Zhang, Chuansheng; Ho, Tammy Szu-Yu; Oses-Prieto, Juan; Burlingame, Alma L; Lalonde, Joshua; Noebels, Jeffrey L; Leterrier, Christophe; Rasband, Matthew N

    2017-11-22

    Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1 f/f mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system. SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology. Copyright © 2017 the authors 0270-6474/17/3711311-12$15.00/0.

  2. Locality and nonlocality in geomorphic transport laws: Implications of a particle-based model of hillslope evolution

    Science.gov (United States)

    Tucker, G. E.; Bradley, D. N.

    2008-12-01

    Many geomorphic transport laws assume that the transport process is local, meaning that the space and time scales of particle displacement are short relative to those of the system as a whole. This assumption allows one to express sediment flux in terms of at-a-point properties such as the local surface gradient. However, while this assumption is quite reasonable for some processes (for example, grain displacement by raindrop impact), it is questionable for others (such as landsliding). Moreover, particle displacement distance may also depend on slope angle, becoming longer as gradient increases. For example, the average motion distance during sediment ravel events on very steep slopes may approach the length of the entire hillslope. In such cases, the mass flux through a given point may depend not only on the local topography but also on topography some distance upslope, thus violating the locality assumption. Here we use a stochastic, particle- based model of hillslope evolution to gain insight into the potential for, and consequences of, nonlocality in sediment transport. The model is designed as a simple analogy for a host of different processes that displace sediment grains on hillslopes. The hillslope is represented as a two-dimensional pile of particles. These particles undergo quasi-random motion according to the following rules: (1) during each iteration, a particle and a direction are selected at random; (2) the particle hops in the direction of motion with a probability that depends on the its height relative to that of its immediate neighbor; (3) the particle continues making hops in the same direction and with the same probability dependence, until coming to rest or exiting the base of the slope. The topography and motion statistics that emerge from these rules show a range of behavior that depends on a dimensionless relief parameter. At low relief, hillslope shape is parabolic, mean displacement length is on the order of two particle widths, and the

  3. Cd and Ni transport and accumulation in the halophyte Sesuvium portulacastrum: implication of organic acids in these processes

    Directory of Open Access Journals (Sweden)

    Tahar eGhnaya

    2015-03-01

    Full Text Available The implication of organic acids in Cd and Ni translocation was studied in the halophyte species Sesuvium portulacastrum. Citric, fumaric, malic and ascorbic acids were separated and quantified by HPLC technique in shoots, roots and xylem saps of plants grown on nutrient solutions added with 50 µM Cd, 100 µM Ni and the combination of 50 µM Cd + 100 µM Ni. Results showed that Cd had no significant impact on biomass production while Ni and the combination of both metals drastically affected plant development. Cadmium and Ni concentrations in tissues and xylem sap were higher in plants individually exposed to heavy metal application than in those subjected to the combined treatment Cd + Ni, suggesting a possible competition between these metals for absorption. Both metals applied separately or in combination induced an increase in citrate concentration in shoots and xylem sap but a decrease of this concentration in the roots. However a minor relationship was observed between metal application and fumaric, malic and ascorbic acids. Both observations suggest the implication of citric acid in Cd, Ni translocation and shoot accumulation in S. portulacastrum. The relatively high accumulation of citric acid in xylem sap and shoot of S. portulacastrum could be involved in metal chelation and thus contributes to heavy metal tolerance in this species.

  4. 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

  5. Ammonia gas transport and reactions in unsaturated sediments: Implications for use as an amendment to immobilize inorganic contaminants

    International Nuclear Information System (INIS)

    Zhong, L.; Szecsody, J.E.; Truex, M.J.; Williams, M.D.; Liu, Y.

    2015-01-01

    Highlights: • Ammonia transport can be predicted from gas movement and equilibrium partitioning. • Ammonia diffusion rate in unsaturated sediment is a function of water contents. • High pH induced by ammonia causes mineral dissolution and sequential precipitation. • Ammonia treatment effectively immobilized uranium from contaminated sediments. - Abstract: Use of gas-phase amendments for in situ remediation of inorganic contaminants in unsaturated sediments of the vadose zone may be advantageous, but there has been limited development and testing of gas remediation technologies. Treatment with ammonia gas has a potential for use in treating inorganic contaminants (such as uranium) because it induces a high pore-water pH, causing mineral dissolution and subsequent formation of stable precipitates that decrease the mobility of some contaminants. For field application of this treatment, further knowledge of ammonia transport in porous media and the geochemical reactions induced by ammonia treatment is needed. Laboratory studies were conducted to support calculations needed for field treatment design, to quantify advective and diffusive ammonia transport in unsaturated sediments, to evaluate inter-phase (gas/sediment/pore water) reactions, and to study reaction-induced pore-water chemistry changes as a function of ammonia delivery conditions, such as flow rate, gas concentration, and water content. Uranium-contaminated sediment was treated with ammonia gas to demonstrate U immobilization. Ammonia gas quickly partitions into sediment pore water and increases the pH up to 13.2. Injected ammonia gas advection front movement can be reasonably predicted by gas flow rate and equilibrium partitioning. The ammonia gas diffusion rate is a function of the water content in the sediment. Sodium, aluminum, and silica pore-water concentrations increase upon exposure to ammonia and then decline as aluminosilicates precipitate when the pH declines due to buffering. Up to 85% of

  6. Differential effects of histone deacetylase inhibitors on cellular drug transporters and their implications for using epigenetic modifiers in combination chemotherapy.

    Science.gov (United States)

    Valdez, Benigno C; Li, Yang; Murray, David; Brammer, Jonathan E; Liu, Yan; Hosing, Chitra; Nieto, Yago; Champlin, Richard E; Andersson, Borje S

    2016-09-27

    HDAC inhibitors, DNA alkylators and nucleoside analogs are effective components of combination chemotherapy. To determine a possible mechanism of their synergism, we analyzed the effects of HDAC inhibitors on the expression of drug transporters which export DNA alkylators. Exposure of PEER lymphoma T-cells to 15 nM romidepsin (Rom) resulted in 40%-50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the MDR1 mRNA within 32-48 hrs. MRP1 protein levels concomitantly decreased while MDR1 increased. Other HDAC inhibitors - panobinostat, belinostat and suberoylanilide hydroxamic acid (SAHA) - had similar effects on these transporters. The protein level of MRP1 correlated with cellular resistance to busulfan and chlorambucil, and Rom exposure sensitized cells to these DNA alkylators. The decrease in MRP1 correlated with decreased cellular drug export activity, and increased level of MDR1 correlated with increased export of daunorubicin. A similar decrease in the level of MRP1 protein, and increase in MDR1, were observed when mononuclear cells derived from patients with T-cell malignancies were exposed to Rom. Decreased MRP1 and increased MDR1 expressions were also observed in blood mononuclear cells from lymphoma patients who received SAHA-containing chemotherapy in a clinical trial. This inhibitory effect of HDAC inhibitors on the expression of MRP1 suggests that their synergism with DNA alkylating agents is partly due to decreased efflux of these alkylators. Our results further imply the possibility of antagonistic effects when HDAC inhibitors are combined with anthracyclines and other MDR1 drug ligands in chemotherapy.

  7. 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.

  8. 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.

  9. 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.

  10. W transport and accumulation control in the termination phase of JET H-mode discharges and implications for ITER

    Science.gov (United States)

    Köchl, F.; Loarte, A.; de la Luna, E.; Parail, V.; Corrigan, G.; Harting, D.; Nunes, I.; Reux, C.; Rimini, F. G.; Polevoi, A.; Romanelli, M.; Contributors, JET

    2018-07-01

    Tokamak operation with W PFCs is associated with specific challenges for impurity control, which may be particularly demanding in the transition from stationary H-mode to L-mode. To address W control issues in this phase, dedicated experiments have been performed at JET including the variation of the decrease of the power and current, gas fuelling and central ion cyclotron heating (ICRH), and applying active ELM control by vertical kicks. The experimental results obtained demonstrate the key role of maintaining ELM control to control the W concentration in the exit phase of H-modes with slow (ITER-like) ramp-down of the neutral beam injection power in JET. For these experiments, integrated fully predictive core+edge+SOL transport modelling studies applying discrete models for the description of transients such as sawteeth and ELMs have been performed for the first time with the JINTRAC suite of codes for the entire transition from stationary H-mode until the time when the plasma would return to L-mode focusing on the W transport behaviour. Simulations have shown that the existing models can appropriately reproduce the plasma profile evolution in the core, edge and SOL as well as W accumulation trends in the termination phase of JET H-mode discharges as function of the applied ICRH and ELM control schemes, substantiating the ambivalent effect of ELMs on W sputtering on one side and on edge transport affecting core W accumulation on the other side. The sensitivity with respect to NB particle and momentum sources has also been analysed and their impact on neoclassical W transport has been found to be crucial to reproduce the observed W accumulation characteristics in JET discharges. In this paper the results of the JET experiments, the comparison with JINTRAC modelling and the adequacy of the models to reproduce the experimental results are described and conclusions are drawn regarding the applicability of these models for the extrapolation of the applied W

  11. Response of the global surface ozone distribution to Northern Hemisphere sea surface temperature changes: implications for long-range transport

    Science.gov (United States)

    Yi, Kan; Liu, Junfeng; Ban-Weiss, George; Zhang, Jiachen; Tao, Wei; Cheng, Yanli; Tao, Shu

    2017-07-01

    The response of surface ozone (O3) concentrations to basin-scale warming and cooling of Northern Hemisphere oceans is investigated using the Community Earth System Model (CESM). Idealized, spatially uniform sea surface temperature (SST) anomalies of ±1 °C are individually superimposed onto the North Pacific, North Atlantic, and North Indian oceans. Our simulations suggest large seasonal and regional variability in surface O3 in response to SST anomalies, especially in the boreal summer. The responses of surface O3 associated with basin-scale SST warming and cooling have similar magnitude but are opposite in sign. Increasing the SST by 1 °C in one of the oceans generally decreases the surface O3 concentrations from 1 to 5 ppbv. With fixed emissions, SST increases in a specific ocean basin in the Northern Hemisphere tend to increase the summertime surface O3 concentrations over upwind regions, accompanied by a widespread reduction over downwind continents. We implement the integrated process rate (IPR) analysis in CESM and find that meteorological O3 transport in response to SST changes is the key process causing surface O3 perturbations in most cases. During the boreal summer, basin-scale SST warming facilitates the vertical transport of O3 to the surface over upwind regions while significantly reducing the vertical transport over downwind continents. This process, as confirmed by tagged CO-like tracers, indicates a considerable suppression of intercontinental O3 transport due to increased tropospheric stability at lower midlatitudes induced by SST changes. Conversely, the responses of chemical O3 production to regional SST warming can exert positive effects on surface O3 levels over highly polluted continents, except South Asia, where intensified cloud loading in response to North Indian SST warming depresses both the surface air temperature and solar radiation, and thus photochemical O3 production. Our findings indicate a robust linkage between basin-scale SST

  12. Response of the global surface ozone distribution to Northern Hemisphere sea surface temperature changes: implications for long-range transport

    Directory of Open Access Journals (Sweden)

    K. Yi

    2017-07-01

    Full Text Available The response of surface ozone (O3 concentrations to basin-scale warming and cooling of Northern Hemisphere oceans is investigated using the Community Earth System Model (CESM. Idealized, spatially uniform sea surface temperature (SST anomalies of ±1 °C are individually superimposed onto the North Pacific, North Atlantic, and North Indian oceans. Our simulations suggest large seasonal and regional variability in surface O3 in response to SST anomalies, especially in the boreal summer. The responses of surface O3 associated with basin-scale SST warming and cooling have similar magnitude but are opposite in sign. Increasing the SST by 1 °C in one of the oceans generally decreases the surface O3 concentrations from 1 to 5 ppbv. With fixed emissions, SST increases in a specific ocean basin in the Northern Hemisphere tend to increase the summertime surface O3 concentrations over upwind regions, accompanied by a widespread reduction over downwind continents. We implement the integrated process rate (IPR analysis in CESM and find that meteorological O3 transport in response to SST changes is the key process causing surface O3 perturbations in most cases. During the boreal summer, basin-scale SST warming facilitates the vertical transport of O3 to the surface over upwind regions while significantly reducing the vertical transport over downwind continents. This process, as confirmed by tagged CO-like tracers, indicates a considerable suppression of intercontinental O3 transport due to increased tropospheric stability at lower midlatitudes induced by SST changes. Conversely, the responses of chemical O3 production to regional SST warming can exert positive effects on surface O3 levels over highly polluted continents, except South Asia, where intensified cloud loading in response to North Indian SST warming depresses both the surface air temperature and solar radiation, and thus photochemical O3 production. Our findings indicate a robust linkage

  13. Using column experiments to examine transport of As and other trace elements released from poultry litter: Implications for trace element mobility in agricultural watersheds.

    Science.gov (United States)

    Oyewumi, Oluyinka; Schreiber, Madeline E

    2017-08-01

    Trace elements are added to poultry feed to control infection and improve weight gain. However, the fate of these trace elements in poultry litter is poorly understood. Because poultry litter is applied as fertilizer in many agricultural regions, evaluation of the environmental processes that influence the mobility of litter-derived trace elements is critical for predicting if trace elements are retained in soil or released to water. This study examined the effect of dissolved organic carbon (DOC) in poultry litter leachate on the fate and transport of litter-derived elements (As, Cu, P and Zn) using laboratory column experiments with soil collected from the Delmarva Peninsula (Mid-Atlantic, USA), a region of intense poultry production. Results of the experiments showed that DOC enhanced the mobility of all of the studied elements. However, despite the increased mobility, 60-70% of Zn, As and P mass was retained within the soil. In contrast, almost all of the Cu was mobilized in the litter leachate experiments, with very little retention in soil. Overall, our results demonstrate that the mobility of As, Cu, Zn and P in soils which receive poultry litter application is strongly influenced by both litter leachate composition, specifically organic acids, and adsorption to soil. Results have implications for understanding fate and transport of trace elements released from litter application to soil water and groundwater, which can affect both human health and the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Simulation of a relativistic heavy ions beam transport in the matter: contribution of the fragmentation process and biological implications

    International Nuclear Information System (INIS)

    Ibnouzahir, M.

    1995-03-01

    The study of relativistic heavy ion collisions permit an approach of the properties of dense and not hadronic matter, and an analysis of the reaction mechanisms. Such studies are also interesting on the biological point of view, since there exist now well defined projects concerning the radiotherapy with high LET particles as neutrons, protons, heavy ions. It is thus necessary to have a good understanding of the processes which occur in the propagation of a relativistic heavy ion beam (E≥ 100 A.MeV) in matter. We have elaborated a three dimensional transport code, using a Monte Carlo method, in order to describe the propagation of Ne and Ar ions in water. Violent nuclear collisions giving fragmentation process have been taken into account by use of the FREESCO program. We have tested the validity of our transport model and we show an important change of the energy deposition at the vicinity of the Bragg peak; such a distortion, due mainly to fragmentation reactions, is of a great interest for biological applications. (author)

  15. LABCG2, a New ABC Transporter Implicated in Phosphatidylserine Exposure, Is Involved in the Infectivity and Pathogenicity of Leishmania

    Science.gov (United States)

    González-Rey, Elena; Delgado, Mario; Castanys, Santiago; Pérez-Victoria, José M.; Gamarro, Francisco

    2013-01-01

    Leishmaniasis is a neglected disease produced by the intracellular protozoan parasite Leishmania. In the present study, we show that LABCG2, a new ATP-binding cassette half-transporter (ABCG subfamily) from Leishmania, is involved in parasite virulence. Down-regulation of LABCG2 function upon expression of an inactive mutant version of this half-transporter (LABCG2K/M) is shown to reduce the translocation of short-chain analogues of phosphatidylserine (PS). This dominant-negative phenotype is specific for the headgroup of the phospholipid, as the movement of phospholipid analogues of phosphatidylcholine, phosphatidylethanolamine or sphingomyelin is not affected. In addition, promastigotes expressing LABCG2K/M expose less endogenous PS in the stationary phase than control parasites. Transient exposure of PS at the outer leaflet of the plasma membrane is known to be one of the mechanisms used by Leishmania to infect macrophages and to silence their immune response. Stationary phase/metacyclic promastigotes expressing LABCG2K/M are less infective for macrophages and show decreased pathogenesis in a mouse model of cutaneous leishmaniasis. Thus, mice infected with parasites expressing LABCG2K/M did not develop any lesion and showed significantly lower inflammation and parasite burden than mice infected with control parasites. Our results indicate that LABCG2 function is required for the externalization of PS in Leishmania promastigotes, a process that is involved in the virulence of the parasite. PMID:23638200

  16. Drastic Control of Texture in a High Performance n-Type Polymeric Semiconductor and Implications for Charge Transport

    KAUST Repository

    Rivnay, Jonathan

    2011-07-12

    Control of crystallographic texture from mostly face-on to edge-on is observed for the film morphology of the n-type semicrystalline polymer {[N,N-9-bis(2-octyldodecyl)naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl] -alt-5,59-(2,29-bithiophene)}, P(NDI2OD-T2), when annealing the film to the polymer melting point followed by slow cooling to ambient temperature. A variety of X-ray diffraction analyses, including pole figure construction and Fourier transform peak shape deconvolution, are employed to quantify the texture change, relative degree of crystallinity and lattice order. We find that annealing the polymer film to the melt leads to a shift from 77.5% face-on to 94.6% edge-on lamellar texture as well as to a 2-fold increase in crystallinity and a 40% decrease in intracrystallite cumulative disorder. The texture change results in a significant drop in the electron-only diode current density through the film thickness upon melt annealing, while little change is observed in the in-plane transport of bottom gated thin film transistors. This suggests that the texture change is prevalent in the film interior and that either the (bottom) surface structure is different from the interior structure or the intracrystalline order and texture play a secondary role in transistor transport for this material. © 2011 American Chemical Society.

  17. Path integration of head direction: updating a packet of neural activity at the correct speed using axonal conduction delays.

    Science.gov (United States)

    Walters, Daniel; Stringer, Simon; Rolls, Edmund

    2013-01-01

    The head direction cell system is capable of accurately updating its current representation of head direction in the absence of visual input. This is known as the path integration of head direction. An important question is how the head direction cell system learns to perform accurate path integration of head direction. In this paper we propose a model of velocity path integration of head direction in which the natural time delay of axonal transmission between a linked continuous attractor network and competitive network acts as a timing mechanism to facilitate the correct speed of path integration. The model effectively learns a "look-up" table for the correct speed of path integration. In simulation, we show that the model is able to successfully learn two different speeds of path integration across two different axonal conduction delays, and without the need to alter any other model parameters. An implication of this model is that, by learning look-up tables for each speed of path integration, the model should exhibit a degree of robustness to damage. In simulations, we show that the speed of path integration is not significantly affected by degrading the network through removing a proportion of the cells that signal rotational velocity.

  18. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy

    Directory of Open Access Journals (Sweden)

    Chong-Chong Xu

    2016-01-01

    Full Text Available Spinal muscular atrophy (SMA, characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1 gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

  19. 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.

  20. 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