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[[File:LTP.png|thumb|LTP in hippocampal CA1 region Unpublished data.]]
[[File:LTP.png|thumb|LTP in hippocampal CA1 region. Unpublished data.]]
 
[[File:Ampa-trafficking.jpg|thumb|Activity-dependent synaptic translocation of AMPA receptor<ref name=ref1 />. AMPA receptors are visualized by GFP tagging.]]
[[File:Ampa-trafficking.jpg|thumb|Activity-dependent synaptic translocation of AMPA receptor<ref name=ref1 />. AMPA receptor is visualized by tagging it with GFP.]]


== Protein Trafficking and Long-term Potentiation ==
== Protein Trafficking and Long-term Potentiation ==
When hippocampal neurons fire intensely, the synaptic transmission between the neurons is strengthened for a long-term. This phenomenon is called long-term potentiation (LTP) and is considered as a cellular counterpart of learning and memory. But how synaptic transmission is enhanced for long-term had not been clarified.
Long-term potentiation (LTP), a persistent enhancement of synaptic transmission following strong neuronal activation, is widely regarded as a cellular substrate of learning and memory. Despite decades of investigation, the molecular processes that sustain this long-lasting increase in synaptic efficacy have remained incompletely understood.


We tested a novel hypothesis that LTP induction recruits new AMPA type glutamate receptor molecules to the synapse, thereby increasing the postsynaptic sensitivity to released glutamate. Using both optically and electrophysiologically tagged glutamate receptors, we showed that LTP induction delivers new AMPA receptor molecules to the synapse<ref name=ref1><pubmed>10364548</pubmed></ref><ref name=ref2><pubmed>10731148</pubmed></ref><ref name=ref3><pubmed>11348590</pubmed></ref>[1] [2] [3]. Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) and a putative PDZ domain binding protein are both required for this process. The trafficking is not limited to AMPA receptors. We found multiple proteins are trafficked to the synapse in a temporally ordered fashion<ref name=ref4><pubmed>24742465</pubmed></ref>.
We proposed that LTP is mediated, at least in part, by the activity-dependent recruitment of AMPA-type glutamate receptors to synapses, thereby increasing postsynaptic responsiveness to glutamate. Using a combination of optical imaging and electrophysiological approaches, we demonstrated that LTP induction drives the delivery of new AMPA receptor molecules to synaptic sites<ref name=ref1><pubmed>10364548</pubmed></ref><ref name=ref2><pubmed>10731148</pubmed></ref><ref name=ref3><pubmed>11348590</pubmed></ref>[1][2][3]. This process requires Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) and interactions with PDZ domain–containing proteins.


Instead, it does not require phosphorylation of AMPA receptor itself<ref name=ref2 />[2]. As opposed to the widely prevailing view, the proportion of phosphorylated AMPA receptors is too low to explain synaptic plasticity<ref name=ref5><pubmed>25533481</pubmed></ref>[5]. Therefore, what triggers AMPA receptor trafficking and what retains the trafficked receptor are still questions to be answered.
Importantly, synaptic trafficking during LTP is not limited to AMPA receptors. Multiple synaptic proteins are delivered to postsynaptic sites in a temporally coordinated manner<ref name=ref4><pubmed>24742465</pubmed></ref>, suggesting that LTP involves a broader reorganization of the synaptic proteome.


Notably, this process does not depend on phosphorylation of the AMPA receptor itself<ref name=ref2 />[2]. In contrast to earlier models, the fraction of phosphorylated AMPA receptors appears insufficient to account for the magnitude of synaptic potentiation<ref name=ref5><pubmed>25533481</pubmed></ref>[5]. These findings raise fundamental questions regarding the upstream triggers of receptor trafficking and the mechanisms that stabilize receptors at potentiated synapses.


[[File:Phase separation.jpg|thumb|Liquid-liquid phase separation of CaMKII<ref name=ref6><pubmed>33927400</pubmed></ref>[6]. Activation of CaMKII induces segregation of NMDA receptors (green) and AMPA receptors (red).]]
[[File:Phase separation.jpg|thumb|Liquid–liquid phase separation of CaMKII<ref name=ref6><pubmed>33927400</pubmed></ref>[6]. Activation of CaMKII induces segregation of NMDA receptors (green) and AMPA receptors (red).]]
== Liquid-liquid phase separation and synaptic plasticity ==
Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity<ref name=ref7><pubmed>27207106</pubmed></ref>[7]. It is highly enriched in the postsynaptic density (PSD), at levels comparable to structural proteins, a feature that is difficult to reconcile with its canonical role as a catalytic enzyme. In addition, CaMKII forms a unique dodecameric assembly, the functional significance of which has remained elusive.


== Liquid-liquid phase separation and synaptic plasticity ==
We identified that Tiam1, a guanine nucleotide exchange factor for Rac, forms a stable complex with CaMKII<ref name=ref8><pubmed>31078368</pubmed></ref>[8], and further found that CaMKII interacts with and cross-links multiple synaptic proteins. These observations led us to propose that CaMKII undergoes liquid–liquid phase separation, generating condensed protein assemblies within the synapse.
Ca2+/calodulin-dependent protein kinase II (CaMKII) is a serine/threonine protein kinase critically involved in synaptic plasticity in the brain<ref name=ref7><pubmed>27207106</pubmed></ref>[7]. It is highly concentrated in the postsynaptic density (PSD) fraction, exceeding the amount of any other signal transduction molecule, almost comparable with cytoskeletal proteins<ref name=ref7 />[7]. Because kinase signaling can be amplified by catalytic reaction, it does not have to exist in such a large quantity. Also CaMKII forms a unique dodecameric structure not seen in other kinases. These remained mysteries.


We recently found that Tiam1, an activator of small G-protein Rac, forms a persistent complex with CaMKII<ref name=ref8><pubmed>31078368</pubmed></ref>[8]. We also found that CaMKII interacts with multiple other proteins and cross-links them together (unpublished). From these results, we speculated that CaMKII may undergo liquid-liquid phase separation, a phenomenon where protein solution is segregated into condensed and diluted phases, like water and oil<ref name=ref9><pubmed>33472825</pubmed></ref>[9]. CaMKII did not undergo separation in inactive form. However, when activated with Ca2+, CaMKII undergoes phase separation and forms a condensed phase. Furthermore, it triggers the condensation of other proteins as well<ref name=ref6 />[6]. This property of CaMKII may be a mechanism to trigger translocation and accumulation upon induction of LTP<ref name=ref10><pubmed>33752045</pubmed></ref>[10].
Consistent with this model, inactive CaMKII remains diffusely distributed, whereas Ca<sup>2+</sup>-dependent activation induces its transition into a condensed phase. Moreover, activated CaMKII promotes the co-condensation of interacting proteins<ref name=ref6 />[6]. Such phase-separated assemblies provide a plausible physical mechanism for the rapid accumulation and spatial organization of synaptic proteins during LTP<ref name=ref10><pubmed>33752045</pubmed></ref>[10].


This framework suggests that synaptic plasticity is not solely governed by biochemical signaling, but also by emergent physicochemical processes that organize synaptic components at the nanoscale.
== Molecular Mechanisms of Structural Plasticity of Dendritic Spines ==
== Molecular Mechanisms of Structural Plasticity of Dendritic Spines ==
Synaptic activity also induces postsynaptic structural enlargement of dendritic spines, tiny protrusions on dendrites where synapses are formed <ref name=ref4 /><ref name=ref11><pubmed>15944122</pubmed></ref><ref name=ref12><pubmed>21963169</pubmed></ref>[11][12][4](Movie 1). By using a FRET sensor, we found that actin is polymerized rapidly in response to a LTP-inducing stimulation protocol moving the equilibrium towards polymerization <ref name=ref13><pubmed>15361876</pubmed></ref><ref name=ref14><pubmed>17406324</pubmed></ref>[13] [14]. The change persists notably for at least 30 minutes after the stimulation. The regulation of actin can provide a mechanism for synaptic, activity-dependent delivery of postsynaptic proteins as well as cytoskeletal role.
Synaptic potentiation is accompanied by structural remodeling of dendritic spines, the postsynaptic sites of excitatory synapses<ref name=ref4 /><ref name=ref11><pubmed>15944122</pubmed></ref><ref name=ref12><pubmed>21963169</pubmed></ref>[11][12][4] (Movie 1). These morphological changes are closely linked to functional plasticity.


Among molecules implicated in synaptic plasticity, we found biochemical evidence that CaMKII is capable of bundling F-actin through a stoichiometric interaction<ref name=ref15><pubmed>17404223</pubmed></ref>[15]. Activation of CaMKII detaches it from F-actin, thereby allowing modification of F-actin during LTP<ref name=ref16><pubmed>26291163</pubmed></ref>[16]. CaMKII serves as a central molecule with both signaling and structural role in the excitatory synapse<ref name=ref7 /><ref name=ref17><pubmed>19996366</pubmed></ref>[17][7].
Using FRET-based probes, we demonstrated that actin polymerization is rapidly enhanced following LTP-inducing stimulation, shifting the balance toward filament assembly<ref name=ref13><pubmed>15361876</pubmed></ref><ref name=ref14><pubmed>17406324</pubmed></ref>[13][14]. This reorganization persists for tens of minutes, providing a structural basis for sustained synaptic changes.
[[File:3 spines in one - time-25-360.mov|thumb|Structural LTP<ref name=ref4 />[4]
When a red dot appears, glutamate is uncaged locally on the tip of the dendritic spine of a neuron expression GFP.]]
[[File:Actin-polyemerization.jpg|thumb|Actin polymerization and expansion of the dendritic spine<ref name=ref13 />[13]]]
[[File:Gating of sLTP by CaMKII.jpg|thumb|Gating of sLTP by CaMKII<ref name=ref16></ref>[16]. Autophosphorylation of CaMKII dissociates it from F-actin, thereby allowing its modification.]]


We further showed that CaMKII directly binds and bundles F-actin in a stoichiometric manner<ref name=ref15><pubmed>17404223</pubmed></ref>[15]. Upon activation, CaMKII dissociates from F-actin, permitting dynamic remodeling of the actin cytoskeleton during LTP<ref name=ref16><pubmed>26291163</pubmed></ref>[16]. These findings position CaMKII as a central integrator of signaling and structural processes within the synapse<ref name=ref7 /><ref name=ref17><pubmed>19996366</pubmed></ref>[17][7].
[[File:3 spines in one - time-25-360.mov|thumb|Structural LTP<ref name=ref4 />[4]. Local glutamate uncaging (red dot) induces spine enlargement in a GFP-expressing neuron.]]
[[File:Actin-polyemerization.jpg|thumb|Actin polymerization and dendritic spine expansion<ref name=ref13 />[13]]]
[[File:Gating of sLTP by CaMKII.jpg|thumb|Gating of sLTP by CaMKII<ref name=ref16></ref>[16]. Autophosphorylation of CaMKII releases it from F-actin, enabling cytoskeletal remodeling.]]
== Dynamic Behavior of Cellular Memory Engram ==
== Dynamic Behavior of Cellular Memory Engram ==
In the hippocampus, there are neurons that fire when an animal is at a specific position, called place cells. They are considered to encode a memory of the animal’s position. How they are formed and how long they last have not been fully elucidated. In order to address these questions, we set up a virtual reality system where an animal can run through while we observe the hippocampal neuronal activity by using two-photon Ca2+ imaging<ref name=ref18><pubmed>25946002</pubmed></ref><ref name=ref19><pubmed>28484738</pubmed></ref><ref name=ref20><pubmed>32640229</pubmed></ref> [18] [19] [20]. The Ca2+-events are automatically detected from images and deduced into spike patterns <ref name=ref21><pubmed>21963169</pubmed></ref>[21]. Using this approach, we are trying to elucidate the dynamic behavior of cellular memory engram.
At the systems level, hippocampal place cells encode spatial information by firing selectively when an animal occupies a specific location. These neurons are thought to contribute to the formation of memory engrams; however, their formation, stability, and long-term dynamics remain incompletely understood.
 
To address these questions, we developed a virtual reality system that enables mice to navigate controlled environments while hippocampal activity is recorded using two-photon Ca<sup>2+</sup> imaging<ref name=ref18><pubmed>25946002</pubmed></ref><ref name=ref19><pubmed>28484738</pubmed></ref><ref name=ref20><pubmed>32640229</pubmed></ref>[18][19][20]. Ca<sup>2+</sup> transients are automatically detected and converted into inferred spike patterns<ref name=ref21><pubmed>21963169</pubmed></ref>[21].
 
This approach enables us to examine how neuronal ensembles evolve over time and how memory representations are stabilized, reorganized, or lost. Through this multi-scale framework, we aim to bridge molecular mechanisms of synaptic plasticity with the emergent dynamics of memory engrams.


Mouse virtual reality system <ref name=ref19><pubmed>28484738</pubmed></ref>[19]
Mouse virtual reality system<ref name=ref19><pubmed>28484738</pubmed></ref>[19]


Hippocampal Ca<sup>2+</sup> events recorded from a behaving mouse
Hippocampal Ca2+-events from behaving mouse


== References ==
== References ==

Revision as of 14:20, 11 April 2026

LTP in hippocampal CA1 region. Unpublished data.
Activity-dependent synaptic translocation of AMPA receptor[1]. AMPA receptors are visualized by GFP tagging.

Protein Trafficking and Long-term Potentiation

Long-term potentiation (LTP), a persistent enhancement of synaptic transmission following strong neuronal activation, is widely regarded as a cellular substrate of learning and memory. Despite decades of investigation, the molecular processes that sustain this long-lasting increase in synaptic efficacy have remained incompletely understood.

We proposed that LTP is mediated, at least in part, by the activity-dependent recruitment of AMPA-type glutamate receptors to synapses, thereby increasing postsynaptic responsiveness to glutamate. Using a combination of optical imaging and electrophysiological approaches, we demonstrated that LTP induction drives the delivery of new AMPA receptor molecules to synaptic sites[1][2][3][1][2][3]. This process requires Ca2+/calmodulin-dependent protein kinase II (CaMKII) and interactions with PDZ domain–containing proteins.

Importantly, synaptic trafficking during LTP is not limited to AMPA receptors. Multiple synaptic proteins are delivered to postsynaptic sites in a temporally coordinated manner[4], suggesting that LTP involves a broader reorganization of the synaptic proteome.

Notably, this process does not depend on phosphorylation of the AMPA receptor itself[2][2]. In contrast to earlier models, the fraction of phosphorylated AMPA receptors appears insufficient to account for the magnitude of synaptic potentiation[5][5]. These findings raise fundamental questions regarding the upstream triggers of receptor trafficking and the mechanisms that stabilize receptors at potentiated synapses.

Liquid–liquid phase separation of CaMKII[6][6]. Activation of CaMKII induces segregation of NMDA receptors (green) and AMPA receptors (red).

Liquid-liquid phase separation and synaptic plasticity

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity[7][7]. It is highly enriched in the postsynaptic density (PSD), at levels comparable to structural proteins, a feature that is difficult to reconcile with its canonical role as a catalytic enzyme. In addition, CaMKII forms a unique dodecameric assembly, the functional significance of which has remained elusive.

We identified that Tiam1, a guanine nucleotide exchange factor for Rac, forms a stable complex with CaMKII[8][8], and further found that CaMKII interacts with and cross-links multiple synaptic proteins. These observations led us to propose that CaMKII undergoes liquid–liquid phase separation, generating condensed protein assemblies within the synapse.

Consistent with this model, inactive CaMKII remains diffusely distributed, whereas Ca2+-dependent activation induces its transition into a condensed phase. Moreover, activated CaMKII promotes the co-condensation of interacting proteins[6][6]. Such phase-separated assemblies provide a plausible physical mechanism for the rapid accumulation and spatial organization of synaptic proteins during LTP[9][10].

This framework suggests that synaptic plasticity is not solely governed by biochemical signaling, but also by emergent physicochemical processes that organize synaptic components at the nanoscale.

Molecular Mechanisms of Structural Plasticity of Dendritic Spines

Synaptic potentiation is accompanied by structural remodeling of dendritic spines, the postsynaptic sites of excitatory synapses[4][10][11][11][12][4] (Movie 1). These morphological changes are closely linked to functional plasticity.

Using FRET-based probes, we demonstrated that actin polymerization is rapidly enhanced following LTP-inducing stimulation, shifting the balance toward filament assembly[12][13][13][14]. This reorganization persists for tens of minutes, providing a structural basis for sustained synaptic changes.

We further showed that CaMKII directly binds and bundles F-actin in a stoichiometric manner[14][15]. Upon activation, CaMKII dissociates from F-actin, permitting dynamic remodeling of the actin cytoskeleton during LTP[15][16]. These findings position CaMKII as a central integrator of signaling and structural processes within the synapse[7][16][17][7].

File:3 spines in one - time-25-360.mov
Structural LTP[4][4]. Local glutamate uncaging (red dot) induces spine enlargement in a GFP-expressing neuron.
Actin polymerization and dendritic spine expansion[12][13]
Gating of sLTP by CaMKII[15][16]. Autophosphorylation of CaMKII releases it from F-actin, enabling cytoskeletal remodeling.

Dynamic Behavior of Cellular Memory Engram

At the systems level, hippocampal place cells encode spatial information by firing selectively when an animal occupies a specific location. These neurons are thought to contribute to the formation of memory engrams; however, their formation, stability, and long-term dynamics remain incompletely understood.

To address these questions, we developed a virtual reality system that enables mice to navigate controlled environments while hippocampal activity is recorded using two-photon Ca2+ imaging[17][18][19][18][19][20]. Ca2+ transients are automatically detected and converted into inferred spike patterns[20][21].

This approach enables us to examine how neuronal ensembles evolve over time and how memory representations are stabilized, reorganized, or lost. Through this multi-scale framework, we aim to bridge molecular mechanisms of synaptic plasticity with the emergent dynamics of memory engrams.

Mouse virtual reality system[18][19]

Hippocampal Ca2+ events recorded from a behaving mouse

References

  1. ↑ 1.0 1.1 Shi, S.H., Hayashi, Y., Petralia, R.S., Zaman, S.H., Wenthold, R.J., Svoboda, K., & Malinow, R. (1999).
    Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science (New York, N.Y.), 284(5421), 1811-6. [PubMed:10364548] [WorldCat] [DOI]
  2. ↑ 2.0 2.1 Hayashi, Y., Shi, S.H., Esteban, J.A., Piccini, A., Poncer, J.C., & Malinow, R. (2000).
    Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science (New York, N.Y.), 287(5461), 2262-7. [PubMed:10731148] [WorldCat] [DOI]
  3. ↑ Shi, S., Hayashi, Y., Esteban, J.A., & Malinow, R. (2001).
    Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell, 105(3), 331-43. [PubMed:11348590] [WorldCat] [DOI]
  4. ↑ 4.0 4.1 4.2 Bosch, M., Castro, J., Saneyoshi, T., Matsuno, H., Sur, M., & Hayashi, Y. (2014).
    Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron, 82(2), 444-59. [PubMed:24742465] [PMC] [WorldCat] [DOI]
  5. ↑ Hosokawa, T., Mitsushima, D., Kaneko, R., & Hayashi, Y. (2015).
    Stoichiometry and phosphoisotypes of hippocampal AMPA-type glutamate receptor phosphorylation. Neuron, 85(1), 60-67. [PubMed:25533481] [PMC] [WorldCat] [DOI]
  6. ↑ 6.0 6.1 Hosokawa, T., Liu, P.W., Cai, Q., Ferreira, J.S., Levet, F., Butler, C., ..., & Hayashi, Y. (2021).
    CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation. Nature neuroscience, 24(6), 777-785. [PubMed:33927400] [WorldCat] [DOI]
  7. ↑ 7.0 7.1 Kim, K., Saneyoshi, T., Hosokawa, T., Okamoto, K., & Hayashi, Y. (2016).
    Interplay of enzymatic and structural functions of CaMKII in long-term potentiation. Journal of neurochemistry, 139(6), 959-972. [PubMed:27207106] [WorldCat] [DOI]
  8. ↑ Saneyoshi, T., Matsuno, H., Suzuki, A., Murakoshi, H., Hedrick, N.G., Agnello, E., ..., & Hayashi, Y. (2019).
    Reciprocal Activation within a Kinase-Effector Complex Underlying Persistence of Structural LTP. Neuron, 102(6), 1199-1210.e6. [PubMed:31078368] [PMC] [WorldCat] [DOI]
  9. ↑ Liu, P.W., Hosokawa, T., & Hayashi, Y. (2021).
    Regulation of synaptic nanodomain by liquid-liquid phase separation: A novel mechanism of synaptic plasticity. Current opinion in neurobiology, 69, 84-92. [PubMed:33752045] [WorldCat] [DOI]
  10. ↑ Hayashi, Y., & Majewska, A.K. (2005).
    Dendritic spine geometry: functional implication and regulation. Neuron, 46(4), 529-32. [PubMed:15944122] [WorldCat] [DOI]
  11. ↑ Bosch, M., & Hayashi, Y. (2012).
    Structural plasticity of dendritic spines. Current opinion in neurobiology, 22(3), 383-8. [PubMed:21963169] [PMC] [WorldCat] [DOI]
  12. ↑ 12.0 12.1 Okamoto, K., Nagai, T., Miyawaki, A., & Hayashi, Y. (2004).
    Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nature neuroscience, 7(10), 1104-12. [PubMed:15361876] [WorldCat] [DOI]
  13. ↑ Okamoto, K., & Hayashi, Y. (2006).
    Visualization of F-actin and G-actin equilibrium using fluorescence resonance energy transfer (FRET) in cultured cells and neurons in slices. Nature protocols, 1(2), 911-9. [PubMed:17406324] [WorldCat] [DOI]
  14. ↑ Okamoto, K., Narayanan, R., Lee, S.H., Murata, K., & Hayashi, Y. (2007).
    The role of CaMKII as an F-actin-bundling protein crucial for maintenance of dendritic spine structure. Proceedings of the National Academy of Sciences of the United States of America, 104(15), 6418-23. [PubMed:17404223] [PMC] [WorldCat] [DOI]
  15. ↑ 15.0 15.1 Kim, K., Lakhanpal, G., Lu, H.E., Khan, M., Suzuki, A., Hayashi, M.K., ..., & Okamoto, K. (2015).
    A Temporary Gating of Actin Remodeling during Synaptic Plasticity Consists of the Interplay between the Kinase and Structural Functions of CaMKII. Neuron, 87(4), 813-26. [PubMed:26291163] [PMC] [WorldCat] [DOI]
  16. ↑ Okamoto, K., Bosch, M., & Hayashi, Y. (2009).
    The roles of CaMKII and F-actin in the structural plasticity of dendritic spines: a potential molecular identity of a synaptic tag? Physiology (Bethesda, Md.), 24, 357-66. [PubMed:19996366] [WorldCat] [DOI]
  17. ↑ Sato, M., Kawano, M., Ohkura, M., Gengyo-Ando, K., Nakai, J., & Hayashi, Y. (2015).
    Generation and Imaging of Transgenic Mice that Express G-CaMP7 under a Tetracycline Response Element. PloS one, 10(5), e0125354. [PubMed:25946002] [PMC] [WorldCat] [DOI]
  18. ↑ 18.0 18.1 Sato, M., Kawano, M., Mizuta, K., Islam, T., Lee, M.G., & Hayashi, Y. (2017).
    Hippocampus-Dependent Goal Localization by Head-Fixed Mice in Virtual Reality. eNeuro, 4(3). [PubMed:28484738] [PMC] [WorldCat] [DOI]
  19. ↑ Sato, M., Mizuta, K., Islam, T., Kawano, M., Sekine, Y., Takekawa, T., ..., & Hayashi, Y. (2020).
    Distinct Mechanisms of Over-Representation of Landmarks and Rewards in the Hippocampus. Cell reports, 32(1), 107864. [PubMed:32640229] [PMC] [WorldCat] [DOI]
  20. ↑ Bosch, M., & Hayashi, Y. (2012).
    Structural plasticity of dendritic spines. Current opinion in neurobiology, 22(3), 383-8. [PubMed:21963169] [PMC] [WorldCat] [DOI]
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