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Old page wikitext, before the edit (old_wikitext) | ''''CLARITY''' <ref name="Chung 2013">{{cite journal | vauthors = Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K | title = Structural and molecular interrogation of intact biological systems | journal = Nature | volume = 497 | issue = 7449 | pages = 332–7 | date = May 2013 | pmid = 23575631 | pmc = 4092167 | doi = 10.1038/nature12107 }}</ref> is a method of making brain tissue transparent using [[acrylamide]]-based hydrogels built from within, and linked to, the tissue, and as defined in the initial paper, represents "transformation of intact biological tissue into a hybrid form in which specific components are replaced with exogenous elements that provide new accessibility or functionality".<ref name="Chung 2013" /> When accompanied with [[antibody]] or gene-based labeling, CLARITY enables highly detailed pictures of the protein and nucleic acid structure of organs, especially the [[brain]]. It was developed by Kwanghun Chung and [[Karl Deisseroth]] at the [[Stanford University School of Medicine]].<ref>{{cite journal | vauthors = Underwood E | title = Neuroscience. Tissue imaging method makes everything clear | journal = Science | volume = 340 | issue = 6129 | pages = 131–2 | date = April 2013 | pmid = 23580500 | pmc = | doi = 10.1126/science.340.6129.131 }}</ref>
Subsequent published papers have applied the CLARITY method of building acrylamide-based tissue-gel hybrids within tissue for improved optical and molecular access to [[Alzheimer's disease]] human brains,<ref>{{cite journal | vauthors = Ando K, Laborde Q, Lazar A, Godefroy D, Youssef I, Amar M, Pooler A, Potier MC, Delatour B, Duyckaerts C | title = Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D | journal = Acta Neuropathologica | volume = 128 | issue = 3 | pages = 457–9 | date = September 2014 | pmid = 25069432 | pmc = 4131133 | doi = 10.1007/s00401-014-1322-y }}</ref> mouse spinal cords,<ref>{{cite journal | vauthors = Zhang MD, Tortoriello G, Hsueh B, Tomer R, Ye L, Mitsios N, Borgius L, Grant G, Kiehn O, Watanabe M, Uhlén M, Mulder J, Deisseroth K, Harkany T, Hökfelt TG | title = Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 12 | pages = E1149-58 | date = March 2014 | pmid = 24616509 | pmc = 3970515 | doi = 10.1073/pnas.1402318111 }}</ref> [[multiple sclerosis]] animal models,<ref>{{cite journal | vauthors = Spence RD, Kurth F, Itoh N, Mongerson CR, Wailes SH, Peng MS, MacKenzie-Graham AJ | title = Bringing CLARITY to gray matter atrophy | journal = NeuroImage | volume = 101 | issue = | pages = 625–32 | date = November 2014 | pmid = 25038439 | pmc = 4437539 | doi = 10.1016/j.neuroimage.2014.07.017 }}</ref> and plants.<ref>{{cite journal | vauthors = Palmer WM, Martin AP, Flynn JR, Reed SL, White RG, Furbank RT, Grof CP | title = PEA-CLARITY: 3D molecular imaging of whole plant organs | journal = Scientific Reports | volume = 5 | pages = 13492 | date = September 2015 | pmid = 26328508 | doi = 10.1038/srep13492 | pmc = 4556961 }}</ref> CLARITY has also been combined with other technologies to develop new microscopy methods including confocal [[expansion microscopy]] and CLARITY-optimized light sheet microscopy (COLM).<ref>{{cite journal | vauthors = Tomer R, Ye L, Hsueh B, Deisseroth K | title = Advanced CLARITY for rapid and high-resolution imaging of intact tissues | journal = Nature Protocols | volume = 9 | issue = 7 | pages = 1682–97 | date = July 2014 | pmid = 24945384 | pmc = 4096681 | doi = 10.1038/nprot.2014.123 }}</ref>
==Procedure==
[[File:CLARITY Brain Imaging.jpg|350px|thumbnail|A 3-dimensional image taken via the CLARITY technique showing a 1 millimeter slice of mouse [[Hippocampus]]. The different colors represent proteins stained with fluorescent antibodies. Excitatory neurons are labeled in green, Inhibitory neurons in red, and [[Astrocytes]] in blue.]]
The process of applying CLARITY imaging begins with a [[postmortem]] tissue sample. Next a series of chemical treatments must be applied to achieve transparency, in which the [[lipid]] content of the sample is removed, while almost all of the original [[proteins]] and [[nucleic acids]] are left in place.<ref name="Chung 2013"/> The purpose of this is to make the tissue transparent and thus amenable to detailed microscopic investigation of its constituent functional parts (which are predominantly proteins and nucleic acids). To accomplish this, the preexisting protein structure has to be placed in a transparent scaffolding which preserves it, while the lipid components are removed. This 'scaffolding' is made up of hydrogel monomers such as acrylamide. The addition of molecules like [[formaldehyde]], [[paraformaldehyde]], or [[glutaraldehyde]] can facilitate attachment of the scaffolding to the proteins and nucleic acids that are to be preserved, and the addition of heat is necessary to establish the actual linkages between the cellular components and the acrylamide.<ref name="CLARITY Project">{{cite web| first = Charlotte | last = Geaghan-Breiner | name-list-format = vanc |year = 2013|title =CLARITY Brain Imaging|url =https://www.youtube.com/watch?v=ELhA0OQwW9c|publisher =Stanford University}}</ref>
Once this step is complete, the protein and nucleic acid components of the target tissue's cells are held firmly in place, while the lipid components remain detached. Lipids are then removed over 1–2 weeks of passive diffusion in detergent, or accelerated by [[Electrophoresis |electrophoretic methods]] to only hours to days.<ref name=":0" /><ref>{{cite journal | vauthors = Lee E, Choi J, Jo Y, Kim JY, Jang YJ, Lee HM, Kim SY, Lee HJ, Cho K, Jung N, Hur EM, Jeong SJ, Moon C, Choe Y, Rhyu IJ, Kim H, Sun W | title = ACT-PRESTO: Rapid and consistent tissue clearing and labeling method for 3-dimensional (3D) imaging | language = En | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 18631 | date = January 2016 | pmid = 26750588 | pmc = 4707495 | doi = 10.1038/srep18631 }}</ref> As they pass through, the detergent's lipophilic properties enable it to pick up and excise any lipids encountered along the way. Lipophilic dyes as [[DiI]] are removed, however there are CLARITY-compatible lipophilic dyes that can be fixated to neighbouring proteins.<ref>{{cite journal | vauthors = Jensen KH, Berg RW | title = CLARITY-compatible lipophilic dyes for electrode marking and neuronal tracing | journal = Scientific Reports | volume = 6 | pages = 32674 | date = September 2016 | pmid = 27597115 | pmc = 5011694 | doi = 10.1038/srep32674 }}</ref> The large majority of non-lipid molecules, such as proteins and DNA, remain unaffected by this procedure, thanks to the acrylamide gel and chemical properties of the molecules involved.<ref name="CLARITY Project"/>
As reported in the initial paper, the tissue expands during this process, but as needed can be restored to its initial dimensions with a final step of incubation in refractive index matching solution.<ref name="Chung 2013"/>
By this stage in the process, the sample has been fully prepared for imaging. The contrast for imaging can come from endogenous fluorescent molecules, from nucleic acid (DNA or RNA) labels, or from [[immunostaining]], whereby [[antibodies]] that bind specifically to a certain target substance are used. In addition, these antibodies are labeled with [[Fluorescence|Fluorescent]] tags that are the key to final imaging result. Standard confocal, two-photon, or light-sheet imaging methods are all suitable to then detect the fluorescence emitted down to the scale of protein localization, thus resulting in the final highly detailed and three-dimensional images that CLARITY produces.<ref name="CLARITY Project"/>
After a sample has been immunostained for an image, it is possible to remove the antibodies and re-apply new ones, thus enabling a sample to be imaged multiple times and targeting multiple protein types.<ref name="Nature News">{{cite news|last=Shen|first=Helen|title=See-through brains clarify connections|url=http://www.nature.com/news/see-through-brains-clarify-connections-1.12768|newspaper=Nature News|date=April 10, 2013}}</ref><ref>{{cite journal | vauthors = Murray E, Cho JH, Goodwin D, Ku T, Swaney J, Kim SY, Choi H, Park YG, Park JY, Hubbert A, McCue M, Vassallo S, Bakh N, Frosch MP, Wedeen VJ, Seung HS, Chung K | title = Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems | journal = Cell | volume = 163 | issue = 6 | pages = 1500–14 | date = December 2015 | pmid = 26638076 | pmc = 5275966 | doi = 10.1016/j.cell.2015.11.025 }}</ref>
==Applications==
In terms of brain imaging, the ability for CLARITY imaging to reveal specific structures in such unobstructed detail has led to promising avenues of future applications including local [[Neural circuit|circuit]] wiring (especially as it relates to the [[Connectome|Connectome Project]]), relationships between neural cells, roles of subcellular structures, better understanding of protein complexes, and imaging of nucleic acids and [[neurotransmitters]].<ref name="Chung 2013"/> An example of a discovery made through CLARITY imaging is a peculiar 'ladder' pattern where neurons connected back to themselves and their neighbors, which has been observed in animals to be connected to [[autism]]-like behaviors.<ref name="Nature Video">{{cite web|title=See-through brains|url=https://www.youtube.com/watch?v=c-NMfp13Uug|publisher=Nature Video}}</ref>
CLARITY can be used with little or no modifications to clear most other organs such as liver, pancreas, spleen, testis, and ovaries and other species such as zebrafish. While bone requires a simple decalcification step, similarly, plant tissue requires an enzymatic degradation of the cell wall.<ref name=":0">{{cite journal | vauthors = Jensen KH, Berg RW | title = Advances and perspectives in tissue clearing using CLARITY | journal = Journal of Chemical Neuroanatomy | volume = 86 | pages = 19–34 | date = December 2017 | pmid = 28728966 | doi = 10.1016/j.jchemneu.2017.07.005 | s2cid = 27575056 | url = https://ora.ox.ac.uk/objects/uuid:db6cce8c-33eb-4d99-a3c1-fc0575fab499 }}</ref>
[[National Institutes of Health|NIH]] director [[Francis Collins]] has already expressed his hopes for this emergent technology, saying:<ref>{{cite web|last=Collins|first=Francis | name-list-format = vanc |title=The Brain: Now You See It, Soon You Won't|url=http://directorsblog.nih.gov/the-brain-now-you-see-it-soon-you-wont/#more-1088|work=NIH Directors Blog|publisher=NIH}}</ref>
{{Quote|text="CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions."|sign=[[Francis Collins]]}}
==Limitations==
Although the CLARITY procedure has attained unprecedented levels of protein retention after lipid extraction, the technique still loses an estimated 8% of proteins per instance of detergent electrophoresis.<ref name="Nature News"/> Repeated imaging of a single sample would only amplify this loss, as antibody removal is commonly accomplished via the same detergent process that creates the original sample.<ref name="CLARITY Project"/>
Other disadvantages of the technique are the length of time it takes to create and image a sample (the [[immunohistochemistry|immunohistochemical staining]] alone takes up to six weeks to perform), and the fact that the [[acrylamide]] used is highly toxic and [[carcinogenic]].
== See also ==
*[[Brainbow]]
*[[Diffusion Tensor Imaging]]
*[[3DISCO]]
== References ==
{{reflist}}
[[Category:Neuroimaging]]
[[Category:Stanford University medicine]]' |
New page wikitext, after the edit (new_wikitext) | ''''CLARITY''' <ref name="Chung 2013">{{cite journal | vauthors = Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K | title = Structural and molecular interrogation of intact biological systems | journal = Nature | volume = 497 | issue = 7449 | pages = 332–7 | date = May 2013 | pmid = 23575631 | pmc = 4092167 | doi = 10.1038/nature12107 }}</ref> is a method of making brain tissue transparent using [[acrylamide]]-based hydrogels built from within, and linked to, the tissue, and as defined in the initial paper, represents "transformation of intact biological tissue into a hybrid form in which specific components are replaced with exogenous elements that provide new accessibility or functionality".<ref name="Chung 2013" /> When accompanied with [[antibody]] or gene-based labeling, CLARITY enables highly detailed pictures of the protein and nucleic acid structure of organs, especially the [[brain]]. It was developed by Kwanghun Chung and [[Karl Deisseroth]] at the [[Stanford University School of Medicine]].<ref>{{cite journal | vauthors = Underwood E | title = Neuroscience. Tissue imaging method makes everything clear | journal = Science | volume = 340 | issue = 6129 | pages = 131–2 | date = April 2013 | pmid = 23580500 | pmc = | doi = 10.1126/science.340.6129.131 }}</ref>
Subsequent published papers have applied the CLARITY method of building acrylamide-based tissue-gel hybrids within tissue for improved optical and molecular access to [[Alzheimer's disease]] human brains,<ref>{{cite journal | vauthors = Ando K, Laborde Q, Lazar A, Godefroy D, Youssef I, Amar M, Pooler A, Potier MC, Delatour B, Duyckaerts C | title = Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D | journal = Acta Neuropathologica | volume = 128 | issue = 3 | pages = 457–9 | date = September 2014 | pmid = 25069432 | pmc = 4131133 | doi = 10.1007/s00401-014-1322-y }}</ref> mouse spinal cords,<ref>{{cite journal | vauthors = Zhang MD, Tortoriello G, Hsueh B, Tomer R, Ye L, Mitsios N, Borgius L, Grant G, Kiehn O, Watanabe M, Uhlén M, Mulder J, Deisseroth K, Harkany T, Hökfelt TG | title = Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 12 | pages = E1149-58 | date = March 2014 | pmid = 24616509 | pmc = 3970515 | doi = 10.1073/pnas.1402318111 }}</ref> [[multiple sclerosis]] animal models,<ref>{{cite journal | vauthors = Spence RD, Kurth F, Itoh N, Mongerson CR, Wailes SH, Peng MS, MacKenzie-Graham AJ | title = Bringing CLARITY to gray matter atrophy | journal = NeuroImage | volume = 101 | issue = | pages = 625–32 | date = November 2014 | pmid = 25038439 | pmc = 4437539 | doi = 10.1016/j.neuroimage.2014.07.017 }}</ref> and plants.<ref>{{cite journal | vauthors = Palmer WM, Martin AP, Flynn JR, Reed SL, White RG, Furbank RT, Grof CP | title = PEA-CLARITY: 3D molecular imaging of whole plant organs | journal = Scientific Reports | volume = 5 | pages = 13492 | date = September 2015 | pmid = 26328508 | doi = 10.1038/srep13492 | pmc = 4556961 }}</ref> CLARITY has also been combined with other technologies to develop new microscopy methods including confocal [[expansion microscopy]] and CLARITY-optimized light sheet microscopy (COLM).<ref>{{cite journal | vauthors = Tomer R, Ye L, Hsueh B, Deisseroth K | title = Advanced CLARITY for rapid and high-resolution imaging of intact tissues | journal = Nature Protocols | volume = 9 | issue = 7 | pages = 1682–97 | date = July 2014 | pmid = 24945384 | pmc = 4096681 | doi = 10.1038/nprot.2014.123 }}</ref>
==Applications==
In terms of brain imaging, the ability for CLARITY imaging to reveal specific structures in such unobstructed detail has led to promising avenues of future applications including local [[Neural circuit|circuit]] wiring (especially as it relates to the [[Connectome|Connectome Project]]), relationships between neural cells, roles of subcellular structures, better understanding of protein complexes, and imaging of nucleic acids and [[neurotransmitters]].<ref name="Chung 2013"/> An example of a discovery made through CLARITY imaging is a peculiar 'ladder' pattern where neurons connected back to themselves and their neighbors, which has been observed in animals to be connected to [[autism]]-like behaviors.<ref name="Nature Video">{{cite web|title=See-through brains|url=https://www.youtube.com/watch?v=c-NMfp13Uug|publisher=Nature Video}}</ref>
CLARITY can be used with little or no modifications to clear most other organs such as liver, pancreas, spleen, testis, and ovaries and other species such as zebrafish. While bone requires a simple decalcification step, similarly, plant tissue requires an enzymatic degradation of the cell wall.<ref name=":0">{{cite journal | vauthors = Jensen KH, Berg RW | title = Advances and perspectives in tissue clearing using CLARITY | journal = Journal of Chemical Neuroanatomy | volume = 86 | pages = 19–34 | date = December 2017 | pmid = 28728966 | doi = 10.1016/j.jchemneu.2017.07.005 | s2cid = 27575056 | url = https://ora.ox.ac.uk/objects/uuid:db6cce8c-33eb-4d99-a3c1-fc0575fab499 }}</ref>
[[National Institutes of Health|NIH]] director [[Francis Collins]] has already expressed his hopes for this emergent technology, saying:<ref>{{cite web|last=Collins|first=Francis | name-list-format = vanc |title=The Brain: Now You See It, Soon You Won't|url=http://directorsblog.nih.gov/the-brain-now-you-see-it-soon-you-wont/#more-1088|work=NIH Directors Blog|publisher=NIH}}</ref>
{{Quote|text="CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions."|sign=[[Francis Collins]]}}
==Limitations==
Although the CLARITY procedure has attained unprecedented levels of protein retention after lipid extraction, the technique still loses an estimated 8% of proteins per instance of detergent electrophoresis.<ref name="Nature News"/> Repeated imaging of a single sample would only amplify this loss, as antibody removal is commonly accomplished via the same detergent process that creates the original sample.<ref name="CLARITY Project"/>
Other disadvantages of the technique are the length of time it takes to create and image a sample (the [[immunohistochemistry|immunohistochemical staining]] alone takes up to six weeks to perform), and the fact that the [[acrylamide]] used is highly toxic and [[carcinogenic]].
== See also ==
*[[Brainbow]]
*[[Diffusion Tensor Imaging]]
*[[3DISCO]]
== References ==
{{reflist}}
[[Category:Neuroimaging]]
[[Category:Stanford University medicine]]' |
Unified diff of changes made by edit (edit_diff) | '@@ -2,16 +2,4 @@
Subsequent published papers have applied the CLARITY method of building acrylamide-based tissue-gel hybrids within tissue for improved optical and molecular access to [[Alzheimer's disease]] human brains,<ref>{{cite journal | vauthors = Ando K, Laborde Q, Lazar A, Godefroy D, Youssef I, Amar M, Pooler A, Potier MC, Delatour B, Duyckaerts C | title = Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D | journal = Acta Neuropathologica | volume = 128 | issue = 3 | pages = 457–9 | date = September 2014 | pmid = 25069432 | pmc = 4131133 | doi = 10.1007/s00401-014-1322-y }}</ref> mouse spinal cords,<ref>{{cite journal | vauthors = Zhang MD, Tortoriello G, Hsueh B, Tomer R, Ye L, Mitsios N, Borgius L, Grant G, Kiehn O, Watanabe M, Uhlén M, Mulder J, Deisseroth K, Harkany T, Hökfelt TG | title = Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 12 | pages = E1149-58 | date = March 2014 | pmid = 24616509 | pmc = 3970515 | doi = 10.1073/pnas.1402318111 }}</ref> [[multiple sclerosis]] animal models,<ref>{{cite journal | vauthors = Spence RD, Kurth F, Itoh N, Mongerson CR, Wailes SH, Peng MS, MacKenzie-Graham AJ | title = Bringing CLARITY to gray matter atrophy | journal = NeuroImage | volume = 101 | issue = | pages = 625–32 | date = November 2014 | pmid = 25038439 | pmc = 4437539 | doi = 10.1016/j.neuroimage.2014.07.017 }}</ref> and plants.<ref>{{cite journal | vauthors = Palmer WM, Martin AP, Flynn JR, Reed SL, White RG, Furbank RT, Grof CP | title = PEA-CLARITY: 3D molecular imaging of whole plant organs | journal = Scientific Reports | volume = 5 | pages = 13492 | date = September 2015 | pmid = 26328508 | doi = 10.1038/srep13492 | pmc = 4556961 }}</ref> CLARITY has also been combined with other technologies to develop new microscopy methods including confocal [[expansion microscopy]] and CLARITY-optimized light sheet microscopy (COLM).<ref>{{cite journal | vauthors = Tomer R, Ye L, Hsueh B, Deisseroth K | title = Advanced CLARITY for rapid and high-resolution imaging of intact tissues | journal = Nature Protocols | volume = 9 | issue = 7 | pages = 1682–97 | date = July 2014 | pmid = 24945384 | pmc = 4096681 | doi = 10.1038/nprot.2014.123 }}</ref>
-
-==Procedure==
-[[File:CLARITY Brain Imaging.jpg|350px|thumbnail|A 3-dimensional image taken via the CLARITY technique showing a 1 millimeter slice of mouse [[Hippocampus]]. The different colors represent proteins stained with fluorescent antibodies. Excitatory neurons are labeled in green, Inhibitory neurons in red, and [[Astrocytes]] in blue.]]
-The process of applying CLARITY imaging begins with a [[postmortem]] tissue sample. Next a series of chemical treatments must be applied to achieve transparency, in which the [[lipid]] content of the sample is removed, while almost all of the original [[proteins]] and [[nucleic acids]] are left in place.<ref name="Chung 2013"/> The purpose of this is to make the tissue transparent and thus amenable to detailed microscopic investigation of its constituent functional parts (which are predominantly proteins and nucleic acids). To accomplish this, the preexisting protein structure has to be placed in a transparent scaffolding which preserves it, while the lipid components are removed. This 'scaffolding' is made up of hydrogel monomers such as acrylamide. The addition of molecules like [[formaldehyde]], [[paraformaldehyde]], or [[glutaraldehyde]] can facilitate attachment of the scaffolding to the proteins and nucleic acids that are to be preserved, and the addition of heat is necessary to establish the actual linkages between the cellular components and the acrylamide.<ref name="CLARITY Project">{{cite web| first = Charlotte | last = Geaghan-Breiner | name-list-format = vanc |year = 2013|title =CLARITY Brain Imaging|url =https://www.youtube.com/watch?v=ELhA0OQwW9c|publisher =Stanford University}}</ref>
-
-Once this step is complete, the protein and nucleic acid components of the target tissue's cells are held firmly in place, while the lipid components remain detached. Lipids are then removed over 1–2 weeks of passive diffusion in detergent, or accelerated by [[Electrophoresis |electrophoretic methods]] to only hours to days.<ref name=":0" /><ref>{{cite journal | vauthors = Lee E, Choi J, Jo Y, Kim JY, Jang YJ, Lee HM, Kim SY, Lee HJ, Cho K, Jung N, Hur EM, Jeong SJ, Moon C, Choe Y, Rhyu IJ, Kim H, Sun W | title = ACT-PRESTO: Rapid and consistent tissue clearing and labeling method for 3-dimensional (3D) imaging | language = En | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 18631 | date = January 2016 | pmid = 26750588 | pmc = 4707495 | doi = 10.1038/srep18631 }}</ref> As they pass through, the detergent's lipophilic properties enable it to pick up and excise any lipids encountered along the way. Lipophilic dyes as [[DiI]] are removed, however there are CLARITY-compatible lipophilic dyes that can be fixated to neighbouring proteins.<ref>{{cite journal | vauthors = Jensen KH, Berg RW | title = CLARITY-compatible lipophilic dyes for electrode marking and neuronal tracing | journal = Scientific Reports | volume = 6 | pages = 32674 | date = September 2016 | pmid = 27597115 | pmc = 5011694 | doi = 10.1038/srep32674 }}</ref> The large majority of non-lipid molecules, such as proteins and DNA, remain unaffected by this procedure, thanks to the acrylamide gel and chemical properties of the molecules involved.<ref name="CLARITY Project"/>
-
-As reported in the initial paper, the tissue expands during this process, but as needed can be restored to its initial dimensions with a final step of incubation in refractive index matching solution.<ref name="Chung 2013"/>
-
-By this stage in the process, the sample has been fully prepared for imaging. The contrast for imaging can come from endogenous fluorescent molecules, from nucleic acid (DNA or RNA) labels, or from [[immunostaining]], whereby [[antibodies]] that bind specifically to a certain target substance are used. In addition, these antibodies are labeled with [[Fluorescence|Fluorescent]] tags that are the key to final imaging result. Standard confocal, two-photon, or light-sheet imaging methods are all suitable to then detect the fluorescence emitted down to the scale of protein localization, thus resulting in the final highly detailed and three-dimensional images that CLARITY produces.<ref name="CLARITY Project"/>
-
-After a sample has been immunostained for an image, it is possible to remove the antibodies and re-apply new ones, thus enabling a sample to be imaged multiple times and targeting multiple protein types.<ref name="Nature News">{{cite news|last=Shen|first=Helen|title=See-through brains clarify connections|url=http://www.nature.com/news/see-through-brains-clarify-connections-1.12768|newspaper=Nature News|date=April 10, 2013}}</ref><ref>{{cite journal | vauthors = Murray E, Cho JH, Goodwin D, Ku T, Swaney J, Kim SY, Choi H, Park YG, Park JY, Hubbert A, McCue M, Vassallo S, Bakh N, Frosch MP, Wedeen VJ, Seung HS, Chung K | title = Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems | journal = Cell | volume = 163 | issue = 6 | pages = 1500–14 | date = December 2015 | pmid = 26638076 | pmc = 5275966 | doi = 10.1016/j.cell.2015.11.025 }}</ref>
==Applications==
' |
New page size (new_size) | 7014 |
Old page size (old_size) | 12085 |
Size change in edit (edit_delta) | -5071 |
Lines added in edit (added_lines) | [] |
Lines removed in edit (removed_lines) | [
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1 => '==Procedure==',
2 => '[[File:CLARITY Brain Imaging.jpg|350px|thumbnail|A 3-dimensional image taken via the CLARITY technique showing a 1 millimeter slice of mouse [[Hippocampus]]. The different colors represent proteins stained with fluorescent antibodies. Excitatory neurons are labeled in green, Inhibitory neurons in red, and [[Astrocytes]] in blue.]]',
3 => 'The process of applying CLARITY imaging begins with a [[postmortem]] tissue sample. Next a series of chemical treatments must be applied to achieve transparency, in which the [[lipid]] content of the sample is removed, while almost all of the original [[proteins]] and [[nucleic acids]] are left in place.<ref name="Chung 2013"/> The purpose of this is to make the tissue transparent and thus amenable to detailed microscopic investigation of its constituent functional parts (which are predominantly proteins and nucleic acids). To accomplish this, the preexisting protein structure has to be placed in a transparent scaffolding which preserves it, while the lipid components are removed. This 'scaffolding' is made up of hydrogel monomers such as acrylamide. The addition of molecules like [[formaldehyde]], [[paraformaldehyde]], or [[glutaraldehyde]] can facilitate attachment of the scaffolding to the proteins and nucleic acids that are to be preserved, and the addition of heat is necessary to establish the actual linkages between the cellular components and the acrylamide.<ref name="CLARITY Project">{{cite web| first = Charlotte | last = Geaghan-Breiner | name-list-format = vanc |year = 2013|title =CLARITY Brain Imaging|url =https://www.youtube.com/watch?v=ELhA0OQwW9c|publisher =Stanford University}}</ref>',
4 => '',
5 => 'Once this step is complete, the protein and nucleic acid components of the target tissue's cells are held firmly in place, while the lipid components remain detached. Lipids are then removed over 1–2 weeks of passive diffusion in detergent, or accelerated by [[Electrophoresis |electrophoretic methods]] to only hours to days.<ref name=":0" /><ref>{{cite journal | vauthors = Lee E, Choi J, Jo Y, Kim JY, Jang YJ, Lee HM, Kim SY, Lee HJ, Cho K, Jung N, Hur EM, Jeong SJ, Moon C, Choe Y, Rhyu IJ, Kim H, Sun W | title = ACT-PRESTO: Rapid and consistent tissue clearing and labeling method for 3-dimensional (3D) imaging | language = En | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 18631 | date = January 2016 | pmid = 26750588 | pmc = 4707495 | doi = 10.1038/srep18631 }}</ref> As they pass through, the detergent's lipophilic properties enable it to pick up and excise any lipids encountered along the way. Lipophilic dyes as [[DiI]] are removed, however there are CLARITY-compatible lipophilic dyes that can be fixated to neighbouring proteins.<ref>{{cite journal | vauthors = Jensen KH, Berg RW | title = CLARITY-compatible lipophilic dyes for electrode marking and neuronal tracing | journal = Scientific Reports | volume = 6 | pages = 32674 | date = September 2016 | pmid = 27597115 | pmc = 5011694 | doi = 10.1038/srep32674 }}</ref> The large majority of non-lipid molecules, such as proteins and DNA, remain unaffected by this procedure, thanks to the acrylamide gel and chemical properties of the molecules involved.<ref name="CLARITY Project"/>',
6 => '',
7 => 'As reported in the initial paper, the tissue expands during this process, but as needed can be restored to its initial dimensions with a final step of incubation in refractive index matching solution.<ref name="Chung 2013"/>',
8 => '',
9 => 'By this stage in the process, the sample has been fully prepared for imaging. The contrast for imaging can come from endogenous fluorescent molecules, from nucleic acid (DNA or RNA) labels, or from [[immunostaining]], whereby [[antibodies]] that bind specifically to a certain target substance are used. In addition, these antibodies are labeled with [[Fluorescence|Fluorescent]] tags that are the key to final imaging result. Standard confocal, two-photon, or light-sheet imaging methods are all suitable to then detect the fluorescence emitted down to the scale of protein localization, thus resulting in the final highly detailed and three-dimensional images that CLARITY produces.<ref name="CLARITY Project"/>',
10 => '',
11 => 'After a sample has been immunostained for an image, it is possible to remove the antibodies and re-apply new ones, thus enabling a sample to be imaged multiple times and targeting multiple protein types.<ref name="Nature News">{{cite news|last=Shen|first=Helen|title=See-through brains clarify connections|url=http://www.nature.com/news/see-through-brains-clarify-connections-1.12768|newspaper=Nature News|date=April 10, 2013}}</ref><ref>{{cite journal | vauthors = Murray E, Cho JH, Goodwin D, Ku T, Swaney J, Kim SY, Choi H, Park YG, Park JY, Hubbert A, McCue M, Vassallo S, Bakh N, Frosch MP, Wedeen VJ, Seung HS, Chung K | title = Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems | journal = Cell | volume = 163 | issue = 6 | pages = 1500–14 | date = December 2015 | pmid = 26638076 | pmc = 5275966 | doi = 10.1016/j.cell.2015.11.025 }}</ref>'
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Parsed HTML source of the new revision (new_html) | '<div class="mw-parser-output"><p><b>CLARITY</b> <sup id="cite_ref-Chung_2013_1-0" class="reference"><a href="#cite_note-Chung_2013-1">[1]</a></sup> is a method of making brain tissue transparent using <a href="/enwiki/wiki/Acrylamide" title="Acrylamide">acrylamide</a>-based hydrogels built from within, and linked to, the tissue, and as defined in the initial paper, represents "transformation of intact biological tissue into a hybrid form in which specific components are replaced with exogenous elements that provide new accessibility or functionality".<sup id="cite_ref-Chung_2013_1-1" class="reference"><a href="#cite_note-Chung_2013-1">[1]</a></sup> When accompanied with <a href="/enwiki/wiki/Antibody" title="Antibody">antibody</a> or gene-based labeling, CLARITY enables highly detailed pictures of the protein and nucleic acid structure of organs, especially the <a href="/enwiki/wiki/Brain" title="Brain">brain</a>. It was developed by Kwanghun Chung and <a href="/enwiki/wiki/Karl_Deisseroth" title="Karl Deisseroth">Karl Deisseroth</a> at the <a href="/enwiki/wiki/Stanford_University_School_of_Medicine" title="Stanford University School of Medicine">Stanford University School of Medicine</a>.<sup id="cite_ref-2" class="reference"><a href="#cite_note-2">[2]</a></sup>
</p><p>Subsequent published papers have applied the CLARITY method of building acrylamide-based tissue-gel hybrids within tissue for improved optical and molecular access to <a href="/enwiki/wiki/Alzheimer%27s_disease" title="Alzheimer's disease">Alzheimer's disease</a> human brains,<sup id="cite_ref-3" class="reference"><a href="#cite_note-3">[3]</a></sup> mouse spinal cords,<sup id="cite_ref-4" class="reference"><a href="#cite_note-4">[4]</a></sup> <a href="/enwiki/wiki/Multiple_sclerosis" title="Multiple sclerosis">multiple sclerosis</a> animal models,<sup id="cite_ref-5" class="reference"><a href="#cite_note-5">[5]</a></sup> and plants.<sup id="cite_ref-6" class="reference"><a href="#cite_note-6">[6]</a></sup> CLARITY has also been combined with other technologies to develop new microscopy methods including confocal <a href="/enwiki/wiki/Expansion_microscopy" title="Expansion microscopy">expansion microscopy</a> and CLARITY-optimized light sheet microscopy (COLM).<sup id="cite_ref-7" class="reference"><a href="#cite_note-7">[7]</a></sup>
</p>
<div id="toc" class="toc" role="navigation" aria-labelledby="mw-toc-heading"><input type="checkbox" role="button" id="toctogglecheckbox" class="toctogglecheckbox" style="display:none" /><div class="toctitle" lang="en" dir="ltr"><h2 id="mw-toc-heading">Contents</h2><span class="toctogglespan"><label class="toctogglelabel" for="toctogglecheckbox"></label></span></div>
<ul>
<li class="toclevel-1 tocsection-1"><a href="#Applications"><span class="tocnumber">1</span> <span class="toctext">Applications</span></a></li>
<li class="toclevel-1 tocsection-2"><a href="#Limitations"><span class="tocnumber">2</span> <span class="toctext">Limitations</span></a></li>
<li class="toclevel-1 tocsection-3"><a href="#See_also"><span class="tocnumber">3</span> <span class="toctext">See also</span></a></li>
<li class="toclevel-1 tocsection-4"><a href="#References"><span class="tocnumber">4</span> <span class="toctext">References</span></a></li>
</ul>
</div>
<h2><span class="mw-headline" id="Applications">Applications</span><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/enwiki/w/index.php?title=CLARITY&action=edit&section=1" title="Edit section: Applications">edit</a><span class="mw-editsection-bracket">]</span></span></h2>
<p>In terms of brain imaging, the ability for CLARITY imaging to reveal specific structures in such unobstructed detail has led to promising avenues of future applications including local <a href="/enwiki/wiki/Neural_circuit" title="Neural circuit">circuit</a> wiring (especially as it relates to the <a href="/enwiki/wiki/Connectome" title="Connectome">Connectome Project</a>), relationships between neural cells, roles of subcellular structures, better understanding of protein complexes, and imaging of nucleic acids and <a href="/enwiki/wiki/Neurotransmitters" class="mw-redirect" title="Neurotransmitters">neurotransmitters</a>.<sup id="cite_ref-Chung_2013_1-2" class="reference"><a href="#cite_note-Chung_2013-1">[1]</a></sup> An example of a discovery made through CLARITY imaging is a peculiar 'ladder' pattern where neurons connected back to themselves and their neighbors, which has been observed in animals to be connected to <a href="/enwiki/wiki/Autism" title="Autism">autism</a>-like behaviors.<sup id="cite_ref-Nature_Video_8-0" class="reference"><a href="#cite_note-Nature_Video-8">[8]</a></sup>
</p><p>CLARITY can be used with little or no modifications to clear most other organs such as liver, pancreas, spleen, testis, and ovaries and other species such as zebrafish. While bone requires a simple decalcification step, similarly, plant tissue requires an enzymatic degradation of the cell wall.<sup id="cite_ref-:0_9-0" class="reference"><a href="#cite_note-:0-9">[9]</a></sup>
</p><p><a href="/enwiki/wiki/National_Institutes_of_Health" title="National Institutes of Health">NIH</a> director <a href="/enwiki/wiki/Francis_Collins" title="Francis Collins">Francis Collins</a> has already expressed his hopes for this emergent technology, saying:<sup id="cite_ref-10" class="reference"><a href="#cite_note-10">[10]</a></sup>
</p>
<style data-mw-deduplicate="TemplateStyles:r960796168">.mw-parser-output .templatequote{overflow:hidden;margin:1em 0;padding:0 40px}.mw-parser-output .templatequote .templatequotecite{line-height:1.5em;text-align:left;padding-left:1.6em;margin-top:0}</style><blockquote class="templatequote"><p>"CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions."</p><div class="templatequotecite">— <cite><a href="/enwiki/wiki/Francis_Collins" title="Francis Collins">Francis Collins</a></cite></div></blockquote>
<h2><span class="mw-headline" id="Limitations">Limitations</span><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/enwiki/w/index.php?title=CLARITY&action=edit&section=2" title="Edit section: Limitations">edit</a><span class="mw-editsection-bracket">]</span></span></h2>
<p>Although the CLARITY procedure has attained unprecedented levels of protein retention after lipid extraction, the technique still loses an estimated 8% of proteins per instance of detergent electrophoresis.<sup id="cite_ref-Nature_News_11-0" class="reference"><a href="#cite_note-Nature_News-11">[11]</a></sup> Repeated imaging of a single sample would only amplify this loss, as antibody removal is commonly accomplished via the same detergent process that creates the original sample.<sup id="cite_ref-CLARITY_Project_12-0" class="reference"><a href="#cite_note-CLARITY_Project-12">[12]</a></sup>
</p><p>Other disadvantages of the technique are the length of time it takes to create and image a sample (the <a href="/enwiki/wiki/Immunohistochemistry" title="Immunohistochemistry">immunohistochemical staining</a> alone takes up to six weeks to perform), and the fact that the <a href="/enwiki/wiki/Acrylamide" title="Acrylamide">acrylamide</a> used is highly toxic and <a href="/enwiki/wiki/Carcinogenic" class="mw-redirect" title="Carcinogenic">carcinogenic</a>.
</p>
<h2><span class="mw-headline" id="See_also">See also</span><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/enwiki/w/index.php?title=CLARITY&action=edit&section=3" title="Edit section: See also">edit</a><span class="mw-editsection-bracket">]</span></span></h2>
<ul><li><a href="/enwiki/wiki/Brainbow" title="Brainbow">Brainbow</a></li>
<li><a href="/enwiki/wiki/Diffusion_Tensor_Imaging" class="mw-redirect" title="Diffusion Tensor Imaging">Diffusion Tensor Imaging</a></li>
<li><a href="/enwiki/wiki/3DISCO" title="3DISCO">3DISCO</a></li></ul>
<h2><span class="mw-headline" id="References">References</span><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/enwiki/w/index.php?title=CLARITY&action=edit&section=4" title="Edit section: References">edit</a><span class="mw-editsection-bracket">]</span></span></h2>
<div class="reflist" style="list-style-type: decimal;">
<div class="mw-references-wrap mw-references-columns"><ol class="references">
<li id="cite_note-Chung_2013-1"><span class="mw-cite-backlink">^ <a href="#cite_ref-Chung_2013_1-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-Chung_2013_1-1"><sup><i><b>b</b></i></sup></a> <a href="#cite_ref-Chung_2013_1-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text"><cite id="CITEREFChungWallaceKimKalyanasundaram2013" class="citation journal cs1">Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K (May 2013). <a rel="nofollow" class="external text" href="/enwiki//www.ncbi.nlm.nih.gov/pmc/articles/PMC4092167">"Structural and molecular interrogation of intact biological systems"</a>. <i>Nature</i>. <b>497</b> (7449): 332–7. <a href="/enwiki/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Fnature12107">10.1038/nature12107</a>. <a href="/enwiki/wiki/PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="cs1-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="/enwiki//www.ncbi.nlm.nih.gov/pmc/articles/PMC4092167">4092167</a></span>. <a href="/enwiki/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="/enwiki//pubmed.ncbi.nlm.nih.gov/23575631">23575631</a>.</cite><span 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<li id="cite_note-10"><span class="mw-cite-backlink"><b><a href="#cite_ref-10">^</a></b></span> <span class="reference-text"><cite id="CITEREFCollins" class="citation web cs1">Collins F. <a rel="nofollow" class="external text" href="http://directorsblog.nih.gov/the-brain-now-you-see-it-soon-you-wont/#more-1088">"The Brain: Now You See It, Soon You Won't"</a>. <i>NIH Directors Blog</i>. NIH.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=unknown&rft.jtitle=NIH+Directors+Blog&rft.atitle=The+Brain%3A+Now+You+See+It%2C+Soon+You+Won%27t&rft.aulast=Collins&rft.aufirst=Francis&rft_id=http%3A%2F%2Fdirectorsblog.nih.gov%2Fthe-brain-now-you-see-it-soon-you-wont%2F%23more-1088&rfr_id=info%3Asid%2Fen.wikipedia.org%3ACLARITY" class="Z3988"></span><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r951705291"/></span>
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<li id="cite_note-Nature_News-11"><span class="mw-cite-backlink"><b><a href="#cite_ref-Nature_News_11-0">^</a></b></span> <span class="error mw-ext-cite-error" lang="en" dir="ltr">Cite error: The named reference <code>Nature News</code> was invoked but never defined (see the <a href="/enwiki/wiki/Help:Cite_errors/Cite_error_references_no_text" title="Help:Cite errors/Cite error references no text">help page</a>).
</span></li>
<li id="cite_note-CLARITY_Project-12"><span class="mw-cite-backlink"><b><a href="#cite_ref-CLARITY_Project_12-0">^</a></b></span> <span class="error mw-ext-cite-error" lang="en" dir="ltr">Cite error: The named reference <code>CLARITY Project</code> was invoked but never defined (see the <a href="/enwiki/wiki/Help:Cite_errors/Cite_error_references_no_text" title="Help:Cite errors/Cite error references no text">help page</a>).
</span></li>
</ol></div></div>
' |
Whether or not the change was made through a Tor exit node (tor_exit_node) | false |
Unix timestamp of change (timestamp) | 1601984862 |