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Trolle, Carl
Publications (10 of 13) Show all publications
Hoeber, J., König, N., Trolle, C., Lekholm, E., Zhou, C., Pankratova, S., . . . Kozlova, E. (2017). A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. Stem Cells and Development, 26(14), 1065-1077
Open this publication in new window or tab >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed) Published
Abstract [en]

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 restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), 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 MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting 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 alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

Keywords
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareSwedish Research Council, 20716
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Trolle, C., Ivert, P., Hoeber, J., Rocamonde-Lago, I., Vasylovska, S., Lukanidin, E. & Kozlova, E. N. (2017). Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar. Regenerative Medicine, 12(4), 339-351
Open this publication in new window or tab >>Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
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2017 (English)In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 12, no 4, p. 339-351Article in journal (Refereed) Published
Abstract [en]

AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.

MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.

RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.

CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.

Keywords
calcium-binding protein, glia, nerve degeneration, neural stem cell, sensory neuron, spinal cord
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-328589 (URN)10.2217/rme-2016-0163 (DOI)000406147100006 ()28621171 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
König, N., Trolle, C., Kapuralin, K., Adameyko, I., Mitrecic, D., Aldskogius, H., . . . Kozlova, E. (2017). Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion. Journal of Tissue Engineering and Regenerative Medicine, 11(1), 129-137
Open this publication in new window or tab >>Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion
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2017 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 1, p. 129-137Article in journal (Refereed) Published
Abstract [en]

Spinal root avulsion results in paralysis and sensory loss, and is commonly associated with chronic pain. In addition to the failure of avulsed dorsal root axons to regenerate into the spinal cord, avulsion injury leads to extensive neuroinflammation and degeneration of second order neurons in the dorsal horn. The ultimate objective with the treatment of this condition is to counteract degeneration of spinal cord neurons and to achieve functionally useful regeneration/reconnection of sensory neurons with spinal cord neurons. Here we explore if stem cells transplanted on the surface of avulsed spinal cord can survive, differentiate and migrate into the damaged spinal cord during the first few weeks after this intervention. Murine boundary cap neural crest stem cells (bNCSCs) or embryonic stem cell (ESC)-derived, pre-differentiated neuron precursors were implanted acutely at the junction between avulsed dorsal roots L3-L6 and the spinal cord. Both types of cells survived transplantation, but showed distinctly different modes of differentiation. Thus, bNCSCs migrated into the spinal cord, expressed glial markers, and formed elongated tubes in the peripheral nervous system (PNS) compartment of the avulsed dorsal root transitional zone(DRTZ) area. In contrast, the ESC-transplants remained at the site of implantation and differentiated to motor neurons and interneurons. These data show that both stem cell types successfully survive implantation to the acutely injured spinal cord and maintained their differentiation and migration potential. These data suggest that depending on the source of neural stem cells, they can play different beneficial roles for recovery after dorsal root avulsion.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
sensory neuron, spinal cord, dorsal root transitional zone, regeneration, migration, glial cells, Schwann cells, motor neurons
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218684 (URN)10.1002/term.1893 (DOI)000394173600012 ()24753366 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2018-01-11Bibliographically approved
Trolle, C. (2016). Stem cell transplantation and regeneration after dorsal root avulsion. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Stem cell transplantation and regeneration after dorsal root avulsion
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spinal root avulsion leads to paralysis and loss of sensory function. Surgical methods can improve motor function and ameliorate pain but sensory recovery in adults is poor. Previous studies have shown that cell transplantation or treatment with trophic factors can improve functional outcome in rodents after dorsal root transection or crush. Here, a dorsal root injury model, more similar to human avulsion injuries, was used. The aims of this thesis were to investigate the behaviour of different stem cells following transplantation to avulsed dorsal roots and asses their potential to serve as possible regenerative therapy. In paper I, different murine stem cell types were transplanted to avulsed dorsal roots in rats. Murine embryonic stem cells remained outside the spinal cord and were surrounded by glutamatergic terminals. Boundary cap neural crest stem cells (bNCSC) formed elongated bands outside the spinal cord and migrated to the spinal cord as single cells. In paper II, transplanted bNCSC were further characterized. bNCSC remaining outside the spinal cord expressed glial markers and were associated with different types of sensory fibres. bNCSC that migrated into the injured spinal cord expressed different neuronal markers. In paper III, effects of bNCSC transplantation on local vasculature and glial scar formation were studied. bNCSC increase angiogenesis in a non dose response manner and participate in boundary glial scar formation. In paper IV, bNCSC spinal migration was analysed using two different injury models - dorsal root transection and dorsal root avulsion. In addition, bNCSC capacity to support sensory regeneration was assessed and the results suggest that bNCSC do not support robust regeneration of avulsed afferents. In paper V, an in vitro stem cell model system was used to assess the possibility of using artificial nanomaterials to deliver differentiation factors. Cells treated with either soluble factors or particle-delivered factors showed similar differentiation patterns. Stem cell transplantation offers several opportunities following dorsal root avulsion, including cell replacement and regenerative support. By elucidating the mechanisms by which stem cells can assist regeneration of avulsed afferents will allow for more targeted or combinatorial approaches, including growth factor treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1162
Keywords
Regeneration, dorsal root, sensory nerve, nerve injury, cell transplantation
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-265853 (URN)978-91-554-9410-0 (ISBN)
Public defence
2016-01-08, B/C2:301, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2015-12-17 Created: 2015-11-03 Last updated: 2018-01-10
Hoeber, J., Trolle, C., König, N., Du, Z., Gallo, A., Hermans, E., . . . Kozlova, E. N. (2015). Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. Scientific Reports, 5, Article ID 10666.
Open this publication in new window or tab >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10666Article in journal (Refereed) Published
Abstract [en]

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
Funder
Swedish Research Council, 5420, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2018-01-11Bibliographically approved
Kosykh, A., Ngamjariyawat, A., Vasylovska, S., König, N., Trolle, C., Lau, J., . . . N. Kozlova, E. (2015). Neural crest stem cells from hair follicles and boundary cap have different  effects on pancreatic islets in vitro. International Journal of Neuroscience, 125(7), 547-554
Open this publication in new window or tab >>Neural crest stem cells from hair follicles and boundary cap have different  effects on pancreatic islets in vitro
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2015 (English)In: International Journal of Neuroscience, ISSN 0020-7454, E-ISSN 1563-5279, Vol. 125, no 7, p. 547-554Article in journal (Refereed) Published
Abstract [en]

Purpose:

Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells.

Materials and Methods:

We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry.

Results:

Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected.

Conclusions:

These observations indicate that HF-NCSCs do not confer the same positive effect on β-cells as demonstrated for bNCSCs. Furthermore, these data suggest that induction of cadherin expression by HF-NCSCs may be useful for their ability to support β-cells in coculture and after transplantation.

Place, publisher, year, edition, pages
London: Informa Healthcare, 2015
Keywords
Diabetes, cell culture, coculture, intercellular contacts, migration
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-233149 (URN)10.3109/00207454.2014.950373 (DOI)000359884200011 ()25077520 (PubMedID)
Funder
Swedish Research Council, 20716
Note

De 2 första författarna delar förstaförfattarskapet

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2018-01-11
Trolle, C., Abrahamsson, N., König, N., Vasylovska, S. & Kozlova, E. (2014). Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents. BMC neuroscience (Online), 15, 60
Open this publication in new window or tab >>Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents
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2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, p. 60-Article in journal (Refereed) Published
Abstract [en]

The boundary cap is a transient group of neural crest-derived cells located at the presumptive dorsal root transitional zone (DRTZ) when sensory axons enter the spinal cord during development. Later, these cells migrate to dorsal root ganglia and differentiate into subtypes of sensory neurons and glia. After birth when the DRTZ is established, sensory axons are no longer able to enter the spinal cord. Here we explored the fate of mouse bNCSCs implanted to the uninjured DRTZ after dorsal root avulsion for their potential to assist sensory axon regeneration. Grafted cells showed extensive survival and differentiation after transplantation to the avulsed DRTZ. Transplanted cells located outside the spinal cord organized elongated tubes of Sox2/GFAP expressing cells closely associated with regenerating sensory axons or appeared as small clusters on the surface of the spinal cord. Others, migrating into the host spinal cordas single cells, differentiated to spinal cord neurons with different neurotransmitter characteristics, extensive fiber organization, and in some cases surrounded by glutamatergic terminal-like profiles. These findings demonstrate that bNCSCs implanted at the site of dorsal root avulsion injury display remarkable differentiation plasticity inside the spinal cord and in the peripheral compartment where they organize tubes associated with regenerating sensory fibers. These properties offer a basis for exploring the ability of bNCSCs to assist regeneration of sensory axons into the spinal cord and replace lost neurons in the injured spinal cord.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keywords
neural stem cell, sensory neuron, spinal cord injury, cell differentiation, nerve regeneration, cell replacement
National Category
Neurosciences Neurology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218685 (URN)10.1186/1471-2202-15-60 (DOI)000337318200001 ()
Funder
Swedish Research Council, 20716Swedish Research Council, 5420
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2018-01-11Bibliographically approved
Garcia-Bennett, A., König, N., Abrahamsson, N., Kozhevnikova, M., Zhou, C., Trolle, C., . . . Kozlova, E. (2014). In vitro generation of motor neuron precursors from mouse embryonic stem cells using mesoporous nanoparticles. Nanomedicine, 9(16), 2457-2466
Open this publication in new window or tab >>In vitro generation of motor neuron precursors from mouse embryonic stem cells using mesoporous nanoparticles
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2014 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 16, p. 2457-2466Article in journal (Refereed) Published
Abstract [en]

Aim: Stem cell-derived motor neurons (MNs) are utilized to develop replacement strategies for spinal cord disorders. Differentiation of embryonic stem cells into MN precursors involves factors and their repeated administration. We investigated if delivery of factors loaded into mesoporous nanoparticles could be effective for stem cell differentiation in vitro.

Materials & methods: We used a mouse embryonic stem cell line expressing green fluorescent protein under the promoter for the MN-specific gene Hb9 to visualize the level of MN differentiation. The differentiation of stem cells was evaluated by expression of MN-specific transcription factors monitored by quantitative real-time PCR reactions and immunocytochemistry.

Results: Mesoporous nanoparticles have strong affiliation to the embryoid bodies, penetrate inside the embryoid bodies and come in contact with differentiating cells.

Conclusion: Repeated administration of soluble factors into a culture medium can be avoided due to a sustained release effect using mesoporous silica.

National Category
Neurosciences Medical Biotechnology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-224650 (URN)10.2217/nnm.14.23 (DOI)000346177600004 ()
Note

De 2 förstaförfattarna delar förstaförfattarskapet

Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2018-01-11Bibliographically approved
Trolle, C. (2014). Stem Cell Transplantation in Dorsal Root Injury. (Licentiate dissertation). Uppsala: Institutionen för neurovetenskap
Open this publication in new window or tab >>Stem Cell Transplantation in Dorsal Root Injury
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

After traumatic injuries to the brachial plexus there is a risk that one or more of the spinal roots are torn from the spinal cord, known as avulsion injury. This often leads to paralysis and chronic pain, notoriously difficult to treat with current pharmacotherapy. Surgical treatment may improve motor function but sensory recovery is usually poor as sensory axons fail to establish functional connections inside the spinal cord. The aims of this thesis were to develop a model for dorsal root avulsion in rodents in order to investigate the potentials of stem cell therapy for enhancing sensory regeneration after spinal root avulsion. Two different types of stem cells, embryonic and neural crest stem cells, have been transplanted to the avulsion model and analysed using immunohistochemical methods. The results indicate that stem cells survive after transplantation to the avulsed dorsal root and associate with regenerating axons. Furthermore, the different stem cells display different phenotypes after transplantation where embryonic stem cells give rise to neurons located outside the spinal cord that could serve as projection neurons whereas the neural crest stem cells form elongated tubes outlining the avulsed dorsal root and are associated with regenerating neuronal fibers. We have also discovered that the neural crest stem cells migrate into the damaged spinal cord as single cells. The neural crest stem cells also display a diversity in generating both neuronal and glial cells that may have different beneficial effects in neural repair following dorsal root avulsion. To improve the survival of stem cell transplants, the potentials of co-transplanting embryonic stem cells together with nanoparticle delivered growth factor mimetics has been investigated. The results indicate that nanoparticle delivered growth factors improve both transplant survival and maturation in comparison to untreated controls and may be a promising strategy in stem cell transplantation.

Place, publisher, year, edition, pages
Uppsala: Institutionen för neurovetenskap, 2014. p. x+46
Keywords
Sensory Neuron, Regeneration, Spinal Root, Stem Cell
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218686 (URN)
Presentation
2014-03-18, BMC A7:115, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2014-02-26 Created: 2014-02-14 Last updated: 2018-01-11Bibliographically approved
Garcia-Bennett, A. E., Kozhevnikova, M., König, N., Zhou, C., Leao, R., Knöpfel, T., . . . Kozlova, E. N. (2013). Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells. Stem Cells Translational Medicine, 2(11), 906-915
Open this publication in new window or tab >>Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells
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2013 (English)In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 2, no 11, p. 906-915Article in journal (Refereed) Published
Abstract [en]

Stem cell transplantation holds great hope for the replacement of damaged cells in the nervous system. However, poor long-term survival after transplantation and insufficiently robust differentiation of stem cells into specialized cell types in vivo remain major obstacles for clinical application. Here, we report the development of a novel technological approach for the local delivery of exogenous trophic factor mimetics to transplanted cells using specifically designed silica nanoporous particles. We demonstrated that delivering Cintrofin and Gliafin, established peptide mimetics of the ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, respectively, with these particles enabled not only robust functional differentiation of motor neurons from transplanted embryonic stem cells but also their long-term survival in vivo. We propose that the delivery of growth factors by mesoporous nanoparticles is a potentially versatile and widely applicable strategy for efficient differentiation and functional integration of stem cell derivatives upon transplantation.

Keywords
Cell transplantation, Differentiation, Embryonic stem cells, Nervous system, Neural differentiation, Neural stem cell, Stem cell culture, Transplantation
National Category
Natural Sciences Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-211443 (URN)10.5966/sctm.2013-0072 (DOI)000326312000017 ()
Note

De 3 första författarna delar förstaförfattarskapet

Available from: 2013-11-27 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
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