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  • 1
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    Regeneration in the era of functional genomics and gene network analysis (2011)
    Marine Biological Laboratory
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © Marine Biological Laboratory, 2011. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 221 (2011): 18-34.
    Description: What gives an organism the ability to regrow tissues and to recover function where another organism fails is the central problem of regenerative biology. The challenge is to describe the mechanisms of regeneration at the molecular level, delivering detailed insights into the many components that are cross-regulated. In other words, a broad, yet deep dissection of the system-wide network of molecular interactions is needed. Functional genomics has been used to elucidate gene regulatory networks (GRNs) in developing tissues, which, like regeneration, are complex systems. Therefore, we reason that the GRN approach, aided by next generation technologies, can also be applied to study the molecular mechanisms underlying the complex functions of regeneration. We ask what characteristics a model system must have to support a GRN analysis. Our discussion focuses on regeneration in the central nervous system, where loss of function has particularly devastating consequences for an organism. We examine a cohort of cells conserved across all vertebrates, the reticulospinal (RS) neurons, which lend themselves well to experimental manipulations. In the lamprey, a jawless vertebrate, there are giant RS neurons whose large size and ability to regenerate make them particularly suited for a GRN analysis. Adding to their value, a distinct subset of lamprey RS neurons reproducibly fail to regenerate, presenting an opportunity for side-by-side comparison of gene networks that promote or inhibit regeneration. Thus, determining the GRN for regeneration in RS neurons will provide a mechanistic understanding of the fundamental cues that lead to success or failure to regenerate.
    Description: The authors gratefully acknowledge support from The Marine Biological Laboratory, The Charles Evans Foundation (OB, JDB, JRM), AG005138 (JDB), and G. Harold and Leila Y. Mathers Research Professorship of Geriatrics and Adult Development (JDB); University of Texas, Austin start-up funds (JM), the Paralyzed Veterans of America Research Grant #2586 (JM) and the Morton Cure Paralysis Fund (JM); The Feinstein Institute for Medical Research (OB); The Essel Foundation (SJZ) and The Howard Hughes Medical Institute (Williams College).
    Repository Name: Woods Hole Open Access Server
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  • 2
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    How the bending kinematics of swimming lampreys build negative pressure fields for suction thrust (2016)
    Company of Biologists
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    Publication Date: 2022-05-25
    Description: Author Posting. © Company of Biologists, 2016. This article is posted here by permission of Company of Biologists for personal use, not for redistribution. The definitive version was published in Journal of Experimental Biology 219 (2016): 3884-3895, doi:10.1242/jeb.144642.
    Description: Swimming animals commonly bend their bodies to generate thrust. For undulating animals such as eels and lampreys, their bodies bend in the form of waves that travel from head to tail. These kinematics accelerate the flow of adjacent fluids, which alters the pressure field in a manner that generates thrust. We used a comparative approach to evaluate the cause-and-effect relationships in this process by quantifying the hydrodynamic effects of body kinematics at the body–fluid interface of the lamprey, Petromyzon marinus, during steady-state swimming. We compared the kinematics and hydrodynamics of healthy control lampreys to lampreys whose spinal cord had been transected mid-body, resulting in passive kinematics along the posterior half of their body. Using high-speed particle image velocimetry (PIV) and a method for quantifying pressure fields, we detail how the active bending kinematics of the control lampreys were crucial for setting up strong negative pressure fields (relative to ambient fields) that generated high-thrust regions at the bends as they traveled all along the body. The passive kinematics of the transected lamprey were only able to generate significant thrust at the tail, relying on positive pressure fields. These different pressure and thrust scenarios are due to differences in how active versus passive body waves generated and controlled vorticity. This demonstrates why it is more effective for undulating lampreys to pull, rather than push, themselves through the fluid.
    Description: This work was funded by a National Science Foundation (NSF) CBET grant awarded to S.P.C., J.H.C., B.J.G. and J.O.D. (award numbers 1510929, 1511996), by the Marine Biological Laboratory (J.R.M.) and by the Roger Williams University Foundation to Promote Teaching and Scholarship.
    Description: 2017-12-14
    Repository Name: Woods Hole Open Access Server
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  • 3
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    A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis (2013)
    Society for Neuroscience
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    Publication Date: 2022-05-25
    Description: © The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 33 (2013): 8009-8021, doi:10.1523/JNEUROSCI.4505-12.2013.
    Description: Neurotransmission requires a continuously available pool of synaptic vesicles (SVs) that can fuse with the plasma membrane and release their neurotransmitter contents upon stimulation. After fusion, SV membranes and membrane proteins are retrieved from the presynaptic plasma membrane by clathrin-mediated endocytosis. After the internalization of a clathrin-coated vesicle, the vesicle must uncoat to replenish the pool of SVs. Clathrin-coated vesicle uncoating requires ATP and is mediated by the ubiquitous molecular chaperone Hsc70. In vitro, depolymerized clathrin forms a stable complex with Hsc70*ADP. This complex can be dissociated by nucleotide exchange factors (NEFs) that release ADP from Hsc70, allowing ATP to bind and induce disruption of the clathrin:Hsc70 association. Whether NEFs generally play similar roles in vesicle trafficking in vivo and whether they play such roles in SV endocytosis in particular is unknown. To address this question, we used information from recent structural and mechanistic studies of Hsp70:NEF and Hsp70:co-chaperone interactions to design a NEF inhibitor. Using acute perturbations at giant reticulospinal synapses of the sea lamprey (Petromyzon marinus), we found that this NEF inhibitor inhibited SV endocytosis. When this inhibitor was mutated so that it could no longer bind and inhibit Hsp110 (a NEF that we find to be highly abundant in brain cytosol), its ability to inhibit SV endocytosis was eliminated. These observations indicate that the action of a NEF, most likely Hsp110, is normally required during SV trafficking to release clathrin from Hsc70 and make it available for additional rounds of endocytosis.
    Description: This work was supported by the National Institutes of Health (Grant #NS029051 to E.M.L. and Grant #NS078165 to J.R.M.).
    Description: 2013-11-01
    Repository Name: Woods Hole Open Access Server
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  • 4
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    Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation (2015)
    American Society for Cell Biology
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    Publication Date: 2022-05-25
    Description: © The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Molecular Biology of the Cell 25 (2014): 3926-3941, doi:10.1091/mbc.E14-02-0708.
    Description: Parkinson's disease is associated with multiplication of the α-synuclein gene and abnormal accumulation of the protein. In animal models, α-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess α-synuclein and the underlying molecular mechanisms remain unknown. Therefore we acutely increased synuclein levels at a vertebrate synapse and performed a detailed ultrastructural analysis of the effects on presynaptic membranes. At stimulated synapses (20 Hz), excess synuclein caused a loss of synaptic vesicles and an expansion of the plasma membrane, indicating an impairment of vesicle recycling. The N-terminal domain (NTD) of synuclein, which folds into an α-helix, was sufficient to reproduce these effects. In contrast, α-synuclein mutants with a disrupted N-terminal α-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another α-synuclein mutant (A53T) with a properly folded NTD phenocopied the synaptic vesicle recycling defects observed with wild type. Interestingly, the vesicle recycling defects were not observed when the stimulation frequency was reduced (5 Hz). Thus excess α-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal α-helix.
    Description: This work was supported by grants from the NIH/National Institute of Neurological Disorder and Stroke RO1 NS078165 (to J.R.M.), the Morton Cure Paralysis Fund (to J.R.M.), and the Branfman Family Foundation (to J.M.G.) and by a Dorothea Bennett graduate fellowship (to D.J.B.).
    Repository Name: Woods Hole Open Access Server
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  • 5
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    Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses : implications for neurodegenerative diseases (2018)
    Wolters Kluwer
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    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Neural Regeneration Research 13 (2018): 647-648, doi:10.4103/1673-5374.230289.
    Description: Parkinson's disease (PD) is a neurodegenerative disease that impacts the lives of millions of people worldwide. A pathological hallmark of PD, as well as dementia with Lewy bodies (DLB) and several Alzheimer's disease variants, is the appearance of intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein. α-Synuclein is a presynaptic protein that normally associates with synaptic vesicle membranes and regulates synaptic vesicle trafficking under physiological conditions (Calo et al., 2016). However, in familial PD, multiplication and several point mutations in the α-synuclein gene (SNCA) ultimately lead to toxic aggregation of the α-synuclein protein and subsequent degeneration of dopaminergic neurons in the substantia nigra, although other brain areas are also affected (Schulz-Schaeffer, 2010).
    Description: This research was supported by a grant from National Institutes of Health (NINDS/NIA R01NS078165 to JRM), research funds from the Marine Biological Laboratory (to JRM), and a research grant from Horizon 2020 Grant No. InCure EU Joint Programme-JPND (to LB).
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  • 6
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    Regenerative capacity in the lamprey spinal cord is not altered after a repeated transection (2019)
    Public Library of Science
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    Publication Date: 2022-05-25
    Description: © The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 14(1), (2019):e0204193, doi: 10.1371/journal.pone.0204193.
    Description: The resilience of regeneration in vertebrates is not very well understood. Yet understanding if tissues can regenerate after repeated insults, and identifying limitations, is important for elucidating the underlying mechanisms of tissue plasticity. This is particularly challenging in tissues, such as the nervous system, which possess a large number of terminally differentiated cells and often exhibit limited regeneration in the first place. However, unlike mammals, which exhibit very limited regeneration of spinal cord tissues, many non-mammalian vertebrates, including lampreys, bony fishes, amphibians, and reptiles, regenerate their spinal cords and functionally recover even after a complete spinal cord transection. It is well established that lampreys undergo full functional recovery of swimming behaviors after a single spinal cord transection, which is accompanied by tissue repair at the lesion site, as well as axon and synapse regeneration. Here we begin to explore the resilience of spinal cord regeneration in lampreys after a second spinal transection (re-transection). We report that by all functional and anatomical measures tested, lampreys regenerate after spinal re-transection just as robustly as after single transections. Recovery of swimming, synapse and cytoskeletal distributions, axon regeneration, and neuronal survival were nearly identical after spinal transection or re-transection. Only minor differences in tissue repair at the lesion site were observed in re-transected spinal cords. Thus, regenerative potential in the lamprey spinal cord is largely unaffected by spinal re-transection, indicating a greater persistent regenerative potential than exists in some other highly regenerative models. These findings establish a new path for uncovering pro-regenerative targets that could be deployed in non-regenerative conditions.
    Description: The authors would like to thank Dr. Cristina Roman-Vendrell and Louie Kerr, Director of the Central Microscopy Facility at the MBL, for technical support. We also thank Dr. Juan Diaz-Quiroz for helpful comments on the manuscript. EG was supported in part by an NSF REU Award (#1659604: Biological Discovery in Woods Hole at the Marine Biological Laboratory).
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  • 7
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    GABA promotes survival and axonal regeneration in identifiable descending neurons after spinal cord injury in larval lampreys (2018)
    Nature Publishing Group
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    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Cell Death and Disease 9 (2018): 663, doi:10.1038/s41419-018-0704-9.
    Description: The poor regenerative capacity of descending neurons is one of the main causes of the lack of recovery after spinal cord injury (SCI). Thus, it is of crucial importance to find ways to promote axonal regeneration. In addition, the prevention of retrograde degeneration leading to the atrophy/death of descending neurons is an obvious prerequisite to activate axonal regeneration. Lampreys show an amazing regenerative capacity after SCI. Recent histological work in lampreys suggested that GABA, which is massively released after a SCI, could promote the survival of descending neurons. Here, we aimed to study if GABA, acting through GABAB receptors, promotes the survival and axonal regeneration of descending neurons of larval sea lampreys after a complete SCI. First, we used in situ hybridization to confirm that identifiable descending neurons of late-stage larvae express the gabab1 subunit of the GABAB receptor. We also observed an acute increase in the expression of this subunit in descending neurons after SCI, which further supported the possible role of GABA and GABAB receptors in promoting the survival and regeneration of these neurons. So, we performed gain and loss of function experiments to confirm this hypothesis. Treatments with GABA and baclofen (GABAB agonist) significantly reduced caspase activation in descending neurons 2 weeks after a complete SCI. Long-term treatments with GABOB (a GABA analogue) and baclofen significantly promoted axonal regeneration of descending neurons after SCI. These data indicate that GABAergic signalling through GABAB receptors promotes the survival and regeneration of descending neurons after SCI. Finally, we used morpholinos against the gabab1 subunit to knockdown the expression of the GABAB receptor in descending neurons. Long-term morpholino treatments caused a significant inhibition of axonal regeneration. This shows that endogenous GABA promotes axonal regeneration after a complete SCI in lampreys by activating GABAB receptors.
    Description: Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund 2007–2013 (Grant number: BFU2014-56300-P) and Xunta de Galicia (Grant number: GPC2014/030). D.R.-S. was supported by a fellowship from EMBO (Ref.: 7010) to carry out a short-term stay at the laboratory of JRM. A.B.-I. was supported by a grant from the Xunta de Galicia (Grant number: 2016-PG008) and a grant from the crowdfunding platform Precipita (FECYT; Spanish Ministry of Economy and Competitiveness; grant number 2017-CP081).
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  • 8
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    Effects of excess brain-derived human alpha-synuclein on synaptic vesicle trafficking (2021)
    Frontiers Media
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    Publication Date: 2022-10-27
    Description: © The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Roman-Vendrell, C., Medeiros, A. T., Sanderson, J. B., Jiang, H., Bartels, T., & Morgan, J. R. Effects of excess brain-derived human alpha-synuclein on synaptic vesicle trafficking. Frontiers in Neuroscience, 15, (2021): 639414, https://doi.org/10.3389./fnins.2021.639414
    Description: α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae.” In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.
    Description: This work was supported by the NIH (NINDS/NIA R01NS078165 and R01NS078165-S1 to JM; NINDS U54-NS110435, R01-NS109209, and R21-NS107950 to TB); research funds from the Marine Biological Laboratory (to JM); grants from the UK Dementia Research Institute (DRI), which receives its funding from DRI Ltd., the UK Medical Research Council and Alzheimer’s Society, and Alzheimer’s Research UK (to TB); the Michael J. Fox Foundation (Ken Griffin Imaging Award to TB); a Parkinson’s Disease Foundation Stanley Fahn Award (PF-JFA-1884 to TB); the Eisai Pharmaceutical postdoctoral program to TB; and the Chan Zuckerberg Collaborative Pairs Initiative (to TB).
    Keywords: Clathrin mediated endocytosis ; Electron microscopy ; Endosome ; Lamprey ; Reticulospinal synapse
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  • 9
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    Thrust generation during steady swimming and acceleration from rest in anguilliform swimmers (2020)
    Company of Biologists
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    Publication Date: 2022-05-26
    Description: Author Posting. © Company of Biologists, 2019. This article is posted here by permission of Company of Biologists for personal use, not for redistribution. The definitive version was published in Journal of Experimental Biology 222(22), (2019): jeb212464, doi:10.1242/jeb.212464.
    Description: Escape swimming is a crucial behavior by which undulatory swimmers evade potential threats. The hydrodynamics of escape swimming have not been well studied, particularly for anguilliform swimmers, such as the sea lamprey Petromyzon marinus. For this study, we compared the kinematics and hydrodynamics of larval sea lampreys with those of lampreys accelerating from rest during escape swimming. We used experimentally derived velocity fields to calculate pressure fields and distributions of thrust and drag along the body. Lampreys initiated acceleration from rest with the formation of a high-amplitude body bend at approximately one-quarter body length posterior to the head. This deep body bend produced two high-pressure regions from which the majority of thrust for acceleration was derived. In contrast, steady swimming was characterized by shallower body bends and negative-pressure-derived thrust, which was strongest near the tail. The distinct mechanisms used for steady swimming and acceleration from rest may reflect the differing demands of the two behaviors. High-pressure-based mechanisms, such as the one used for acceleration from rest, could also be important for low-speed maneuvering during which drag-based turning mechanisms are less effective. The design of swimming robots may benefit from the incorporation of such insights from unsteady swimming.
    Description: This research was supported by grants from the National Science Foundation (UNS-1511996 and IDBR-1455471 to B.J.G., J.O.D., S.P.C. and J.H.C.). J.R.M. was funded by the Marine Biological Laboratory.
    Description: 2020-11-18
    Keywords: Petromyzon marinus ; Lamprey ; Undulatory ; Thrust ; Drag
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  • 10
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    Hsc70 ameliorates the vesicle recycling defects caused by excess alpha-synuclein at synapses (2020)
    Society for Neuroscience
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    Publication Date: 2022-10-27
    Description: © The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Banks, S. M. L., Medeiros, A. T., McQuillan, M., Busch, D. J., Ibarraran-Viniegra, A. S., Sousa, R., Lafer, E. M., & Morgan, J. R. Hsc70 ameliorates the vesicle recycling defects caused by excess alpha-synuclein at synapses. Eneuro, 7(1), (2020): ENEURO.0448-19.2020, doi: 10.1523/ENEURO.0448-19.2020.
    Description: α-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal (RS) synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to an increase in endocytic intermediates and a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein, Hsc70 availability was reduced at stimulated synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 along with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the synaptic vesicle trafficking defects associated with excess α-synuclein, which may be of value for improving synaptic function in PD and other synuclein-linked diseases.
    Description: This work was supported by Department of Health and Human Services/National Institutes of Health (HHS/NIH) National Institute of Neurological Disorders and Stroke/National Institute on Aging Grant R01NS078165 (to J.R.M.) and HHS/NIH National Institute of General Medical Sciences Grant R01GM118933 (to E.M.L. and R.S.).
    Keywords: Auxilin ; Chaperone ; Clathrin ; Clathrin-coated vesicles ; Endocytosis ; Lamprey
    Repository Name: Woods Hole Open Access Server
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