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  1. Article ; Online: Rebuttal from Alex J. Smith and Alan S. Verkman.

    Smith, Alex J / Verkman, Alan S

    The Journal of physiology

    2019  Volume 597, Issue 17, Page(s) 4427–4428

    MeSH term(s) Aquaporin 4 ; Brain ; Extracellular Fluid ; Glymphatic System
    Chemical Substances Aquaporin 4
    Language English
    Publishing date 2019-08-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP278461
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica.

    Ratelade, Julien / Verkman, A S

    Molecular immunology

    2014  Volume 62, Issue 1, Page(s) 104–113

    Abstract: ... complement inhibitor(s) in mouse serum. Sera from different strains of mice produced almost no AQP4-IgG ... Hemolysis assays indicated that the inhibitor(s) in mouse serum target the classical and not the alternative ... complement pathway. We found that the complement inhibitor(s) in mouse serum were contained in a serum ...

    Abstract Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which anti-aquaporin-4 (AQP4) autoantibodies (AQP4-IgG) cause damage to astrocytes by complement-dependent cytotoxicity (CDC). Various approaches have been attempted to produce NMO lesions in rodents, some involving genetically modified mice with altered immune cell function. Here, we found that mouse serum strongly inhibits complement from multiple species, preventing AQP4-IgG-dependent CDC. Effects of mouse serum on complement activation were tested in CDC assays in which AQP4-expressing cells were incubated with AQP4-IgG and complement from different species. Biochemical assays and mass spectrometry were used to characterize complement inhibitor(s) in mouse serum. Sera from different strains of mice produced almost no AQP4-IgG-dependent CDC compared with human, rat and guinea pig sera. Remarkably, addition of mouse serum prevented AQP4-IgG-dependent CDC caused by human, rat or guinea pig serum, with 50% inhibition at <5% mouse serum. Hemolysis assays indicated that the inhibitor(s) in mouse serum target the classical and not the alternative complement pathway. We found that the complement inhibitor(s) in mouse serum were contained in a serum fraction purified with protein-A resin; however, the inhibitor was not IgG as determined using serum from IgG-deficient mice. Mass spectrometry on the protein A-purified fraction produced several inhibitor candidates. The low intrinsic complement activity of mouse serum and the presence of complement inhibitor(s) limit the utility of mouse models to study disorders, such as NMO, involving the classical complement pathway.
    MeSH term(s) Animals ; Aquaporin 4/immunology ; Autoantibodies/blood ; CHO Cells ; Complement Inactivating Agents/blood ; Complement Inactivating Agents/immunology ; Complement Pathway, Classical/immunology ; Cricetulus ; Disease Models, Animal ; Guinea Pigs ; Humans ; Immunoglobulin G/blood ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuromyelitis Optica/blood ; Neuromyelitis Optica/immunology ; Rats ; Rats, Wistar
    Chemical Substances Aquaporin 4 ; Autoantibodies ; Complement Inactivating Agents ; Immunoglobulin G
    Language English
    Publishing date 2014-06-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2014.06.003
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  3. Article: Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica

    Ratelade, Julien / A.S. Verkman

    Molecular Immunology. 2014 Nov., v. 62

    2014  

    Abstract: ... complement inhibitor(s) in mouse serum. Sera from different strains of mice produced almost no AQP4-IgG ... Hemolysis assays indicated that the inhibitor(s) in mouse serum target the classical and not the alternative ... complement pathway. We found that the complement inhibitor(s) in mouse serum were contained in a serum ...

    Abstract Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which anti-aquaporin-4 (AQP4) autoantibodies (AQP4-IgG) cause damage to astrocytes by complement-dependent cytotoxicity (CDC). Various approaches have been attempted to produce NMO lesions in rodents, some involving genetically modified mice with altered immune cell function. Here, we found that mouse serum strongly inhibits complement from multiple species, preventing AQP4-IgG-dependent CDC. Effects of mouse serum on complement activation were tested in CDC assays in which AQP4-expressing cells were incubated with AQP4-IgG and complement from different species. Biochemical assays and mass spectrometry were used to characterize complement inhibitor(s) in mouse serum. Sera from different strains of mice produced almost no AQP4-IgG-dependent CDC compared with human, rat and guinea pig sera. Remarkably, addition of mouse serum prevented AQP4-IgG-dependent CDC caused by human, rat or guinea pig serum, with 50% inhibition at <5% mouse serum. Hemolysis assays indicated that the inhibitor(s) in mouse serum target the classical and not the alternative complement pathway. We found that the complement inhibitor(s) in mouse serum were contained in a serum fraction purified with protein-A resin; however, the inhibitor was not IgG as determined using serum from IgG-deficient mice. Mass spectrometry on the protein A-purified fraction produced several inhibitor candidates. The low intrinsic complement activity of mouse serum and the presence of complement inhibitor(s) limit the utility of mouse models to study disorders, such as NMO, involving the classical complement pathway.
    Keywords animal models ; astrocytes ; autoantibodies ; blood serum ; central nervous system ; complement ; cytotoxicity ; guinea pigs ; hemolysis ; humans ; immunoglobulin G ; mass spectrometry ; mice ; rats ; transgenic animals
    Language English
    Dates of publication 2014-11
    Size p. 104-113.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2014.06.003
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  4. Article ; Online: Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy.

    Yu, Gui Jun / Yoo, Choong L / Yang, Baoxue / Lodewyk, Michael W / Meng, Liping / El-Idreesy, Tamer T / Fettinger, James C / Tantillo, Dean J / Verkman, A S / Kurth, Mark J

    Journal of medicinal chemistry

    2008  Volume 51, Issue 19, Page(s) 6044–6054

    Abstract: ... on corrector activity. For example, constraining the C4'-C5 bithiazole tether in the s-cis conformation [N-(2 ... critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2 ... our analysis, the " s-cis-locked" cycloheptathiazolothiazole 29 was found to be the most potent bithiazole ...

    Abstract N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein DeltaF508-CFTR. Eight C4'-C5 C,C-bond-controlling bithiazole analogues of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4'-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenylamino)-7,8-dihydro-6 H-cyclohepta[1,2- d:3,4- d']bithiazole-2'-yl)pivalamide, 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4 H-cyclohepta[1,2- d:3,4- d']bithiazole-2'-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the " s-cis-locked" cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of approximately 450 nM.
    MeSH term(s) Cystic Fibrosis/drug therapy ; Cystic Fibrosis/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/drug effects ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Epithelial Cells/metabolism ; Humans ; Models, Chemical ; Molecular Structure ; Protein Processing, Post-Translational/drug effects ; Stereoisomerism ; Thiazoles/chemistry ; Thiazoles/pharmacology
    Chemical Substances Thiazoles ; cystic fibrosis transmembrane conductance regulator delta F508 ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
    Language English
    Publishing date 2008-09-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm800533c
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Large molecules from the cerebrospinal fluid enter the optic nerve but not the retina of mice.

    Tong, Xiao J / Akdemir, Gokhan / Wadhwa, Meetu / Verkman, Alan S / Smith, Alex J

    Fluids and barriers of the CNS

    2024  Volume 21, Issue 1, Page(s) 1

    Abstract: It has been proposed that cerebrospinal fluid (CSF) can enter and leave the retina and optic nerve along perivascular spaces surrounding the central retinal vessels as part of an aquaporin-4 (AQP4) dependent ocular 'glymphatic' system. Here, we injected ... ...

    Abstract It has been proposed that cerebrospinal fluid (CSF) can enter and leave the retina and optic nerve along perivascular spaces surrounding the central retinal vessels as part of an aquaporin-4 (AQP4) dependent ocular 'glymphatic' system. Here, we injected fluorescent dextrans and antibodies into the CSF of mice at the cisterna magna and measured their distribution in the optic nerve and retina. We found that uptake of dextrans in the perivascular spaces and parenchyma of the optic nerve is highly sensitive to the cisternal injection rate, where high injection rates, in which dextran disperses fully in the sub-arachnoid space, led to uptake along the full length of the optic nerve. Accumulation of dextrans in the optic nerve did not differ significantly in wild-type and AQP4 knockout mice. Dextrans did not enter the retina, even when intracranial pressure was greatly increased over intraocular pressure. However, elevation of intraocular pressure reduced accumulation of fluorescent dextrans in the optic nerve head, and intravitreally injected dextrans left the retina via perivascular spaces surrounding the central retinal vessels. Human IgG distributed throughout the perivascular and parenchymal areas of the optic nerve to a similar extent as dextran following cisternal injection. However, uptake of a cisternally injected AQP4-IgG antibody, derived from a seropositive neuromyelitis optica spectrum disorder subject, was limited by AQP4 binding. We conclude that large molecules injected in the CSF can accumulate along the length of the optic nerve if they are fully dispersed in the optic nerve sub-arachnoid space but that they do not enter the retina.
    MeSH term(s) Mice ; Humans ; Animals ; Dextrans/metabolism ; Optic Nerve/metabolism ; Retina/metabolism ; Neuromyelitis Optica/metabolism ; Aquaporin 4/metabolism ; Autoantibodies/metabolism
    Chemical Substances Dextrans ; Aquaporin 4 ; Autoantibodies
    Language English
    Publishing date 2024-01-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118 ; 2045-8118
    ISSN (online) 2045-8118
    ISSN 2045-8118
    DOI 10.1186/s12987-023-00506-4
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  6. Article ; Online: Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder.

    Tradtrantip, Lukmanee / Yeaman, Michael R / Verkman, A S

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 21962

    Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called ... ...

    Abstract Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called AQP4-IgG. AQP4-IgG binding to aquaporin-4 causes complement-dependent cytotoxicity (CDC), leading to inflammation and demyelination. Here, CDC was measured in AQP4-expressing cells exposed to human complement and heat-inactivated sera from 108 AQP4-IgG seropositive NMOSD subjects and 25 non-NMOSD controls. AQP4-IgG positive sera produced a wide range of CDC, with 50% maximum cytotoxicity produced by as low as 0.2% serum concentration. Unexpectedly, 58 samples produced no cytotoxicity, and of those, four sera were cytoprotective against cytotoxic AQP4-IgG. Cytoprotection was found against different cytotoxic monoclonal AQP4-IgGs and NMOSD patient sera, and in primary astrocyte cultures. Mechanistic studies revealed that the protective factor is an IgG antibody that did not inhibit complement directly, but interfered with binding of cytotoxic AQP4-IgG to AQP4 and consequent C1q binding and complement activation. Further studies suggested that non-pathogenic AQP4-IgG, perhaps with altered glycosylation, may contribute to reduced or ineffectual binding of cytotoxic AQP4-IgG, as well as reduced cell-surface AQP4. The presence of natural cytoprotective antibodies in AQP4-IgG seropositive sera reveals an added level of complexity in NMOSD disease pathogenesis, and suggests the potential therapeutic utility of 'convalescent' serum or engineered protective antibody to interfere with pathogenic antibody in AQP4-IgG seropositive NMOSD.
    MeSH term(s) Animals ; Aquaporin 4/blood ; Aquaporin 4/immunology ; Autoantibodies/blood ; Autoantibodies/immunology ; Biomarkers/blood ; CHO Cells ; Cricetulus ; Disease Progression ; Humans ; Immune Sera ; Immunoglobulin G/blood ; Neuromyelitis Optica/blood ; Neuromyelitis Optica/immunology ; Neuromyelitis Optica/pathology
    Chemical Substances AQP4 protein, human ; Aquaporin 4 ; Autoantibodies ; Biomarkers ; Immune Sera ; Immunoglobulin G
    Language English
    Publishing date 2021-11-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-01294-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Ocular Surface Ion Transport and Dry Eye Disease.

    Lindgren, Ethan S / Cil, Onur / Verkman, Alan S / Pasricha, Neel D

    Current ophthalmology reports

    2022  Volume 10, Issue 4, Page(s) 188–197

    Abstract: Purpose of review: To review the role of ocular surface epithelial (corneal and conjunctival) ion transporters in the pathogenesis and treatment of dry eye disease (DED).: Recent findings: Currently, anti-inflammatory agents are the mainstay of DED ... ...

    Abstract Purpose of review: To review the role of ocular surface epithelial (corneal and conjunctival) ion transporters in the pathogenesis and treatment of dry eye disease (DED).
    Recent findings: Currently, anti-inflammatory agents are the mainstay of DED treatment, though there are several agents in development that target ion transport proteins on the ocular surface, acting by pro-secretory or anti-absorptive mechanisms to increase the tear fluid Film volume. Activation or inhibition of selected ion transporters can alter tear fluid osmolality, driving water transport onto the ocular surface via osmosis. Several ion transporters have been proposed as potential therapeutic targets for DED, including the cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channels (CaCCs), and the epithelial sodium channel (ENaC).
    Summary: Ocular surface epithelial cell ion transporters are promising targets for pro-secretory and anti-absorptive therapies of DED.
    Language English
    Publishing date 2022-10-20
    Publishing country United States
    Document type Journal Article
    ISSN 2167-4868
    ISSN 2167-4868
    DOI 10.1007/s40135-022-00295-3
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  8. Article ; Online: CrossTalk opposing view: Going against the flow: interstitial solute transport in brain is diffusive and aquaporin-4 independent.

    Smith, Alex J / Verkman, Alan S

    The Journal of physiology

    2019  Volume 597, Issue 17, Page(s) 4421–4424

    MeSH term(s) Animals ; Aquaporin 4/metabolism ; Biological Transport/physiology ; Brain/metabolism ; Diffusion ; Water/metabolism
    Chemical Substances Aquaporin 4 ; Water (059QF0KO0R)
    Language English
    Publishing date 2019-08-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP277636
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Targeting the complement system in neuromyelitis optica spectrum disorder.

    Asavapanumas, Nithi / Tradtrantip, Lukmanee / Verkman, Alan S

    Expert opinion on biological therapy

    2021  Volume 21, Issue 8, Page(s) 1073–1086

    Abstract: Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is characterized by central nervous system inflammation and demyelination. In AQP4-IgG seropositive NMOSD, circulating immunoglobulin G (IgG) autoantibodies against astrocyte water channel ... ...

    Abstract Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is characterized by central nervous system inflammation and demyelination. In AQP4-IgG seropositive NMOSD, circulating immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4) cause tissue injury. Compelling evidence supports a pathogenic role for complement activation following AQP4-IgG binding to AQP4. Clinical studies supported the approval of eculizumab, an inhibitor of C5 cleavage, in AQP4-IgG seropositive NMOSD.
    Areas covered: This review covers in vitro, animal models, and human evidence for complement-dependent and complement-independent tissue injury in AQP4-IgG seropositive NMOSD. Complement targets are discussed, including complement proteins, regulators and anaphylatoxin receptors, and corresponding drug candidates.
    Expert opinion: Though preclinical data support a central pathogenic role of complement activation in AQP4-IgG seropositive NMOSD, they do not resolve the relative contributions of complement-dependent vs. complement-independent disease mechanisms such as antibody-dependent cellular cytotoxicity, T cell effector mechanisms, and direct AQP4-IgG-induced cellular injury. The best evidence that complement-dependent mechanisms predominate in AQP4-IgG seropositive NMOSD comes from eculizumab clinical data. Various drug candidates targeting distinct complement effector mechanisms may offer improved safety and efficacy. However, notwithstanding the demonstrated efficacy of complement inhibition in AQP4-IgG seropositive NMOSD, the ultimate niche for complement inhibition is not clear given multiple drug options with alternative mechanisms of action.
    MeSH term(s) Animals ; Aquaporin 4 ; Autoantibodies ; Complement System Proteins/metabolism ; Humans ; Immunoglobulin G ; Neuromyelitis Optica/drug therapy
    Chemical Substances Aquaporin 4 ; Autoantibodies ; Immunoglobulin G ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2021-02-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2052501-1
    ISSN 1744-7682 ; 1471-2598
    ISSN (online) 1744-7682
    ISSN 1471-2598
    DOI 10.1080/14712598.2021.1884223
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Chloride transport modulators as drug candidates.

    Verkman, Alan S / Galietta, Luis J V

    American journal of physiology. Cell physiology

    2021  Volume 321, Issue 6, Page(s) C932–C946

    Abstract: Chloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride-transporting ...

    Abstract Chloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride-transporting proteins with expression in cell plasma or intracellular membranes, which include chloride channels, exchangers, and cotransporters, some having broad anion specificity. Loss-of-function mutations in chloride transporters cause a wide variety of human diseases, including cystic fibrosis, secretory diarrhea, kidney stones, salt-wasting nephropathy, myotonia, osteopetrosis, hearing loss, and goiter. Although impactful advances have been made in the past decade in drug treatment of cystic fibrosis using small molecule modulators of the defective cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, other chloride channels and solute carrier proteins (SLCs) represent relatively underexplored target classes for drug discovery. New opportunities have emerged for the development of chloride transport modulators as potential therapeutics for secretory diarrheas, constipation, dry eye disorders, kidney stones, polycystic kidney disease, hypertension, and osteoporosis. Approaches to chloride transport-targeted drug discovery are reviewed herein, with focus on chloride channel and exchanger classes in which recent preclinical advances have been made in the identification of small molecule modulators and in proof of concept testing in experimental animal models.
    MeSH term(s) Animals ; Antiporters/drug effects ; Antiporters/genetics ; Antiporters/metabolism ; Chloride Channels/drug effects ; Chloride Channels/genetics ; Chloride Channels/metabolism ; Chlorides/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/drug effects ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Drug Design ; Drug Discovery ; Humans ; Ion Transport ; Kinetics ; Membrane Transport Modulators/chemistry ; Membrane Transport Modulators/pharmacology ; Mutation ; Sulfate Transporters/drug effects ; Sulfate Transporters/genetics ; Sulfate Transporters/metabolism
    Chemical Substances Antiporters ; CFTR protein, human ; Chloride Channels ; Chlorides ; Membrane Transport Modulators ; Sulfate Transporters ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
    Language English
    Publishing date 2021-10-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00334.2021
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