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Lagerström, Malin C.
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Publications (10 of 35) Show all publications
Jakobsson, J. E. T., Ma, H. & Lagerström, M. C. (2019). Neuropeptide Y in itch regulation. Neuropeptides, 78, Article ID 101976.
Open this publication in new window or tab >>Neuropeptide Y in itch regulation
2019 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 78, article id 101976Article, review/survey (Refereed) Published
Abstract [en]

Itch is a somatosensory sensation that informs the organism about the presence of potentially harmful substances or parasites, and initiates scratching to remove the threat. Itch-inducing (pruritogenic) substances activate primary afferent neurons in the skin through interactions with specific receptors that converts the stimulus into an electrical signal. These signals are conveyed to the dorsal horn of the spinal cord through the release of neurotransmitters such as natriuretic polypeptide b and somatostatin, leading to an integrated response within a complex spinal inteneuronal network. A large sub-population of somatostatin-expressing spinal interneurons also carry the Neuropeptide Y (NPY) Y1 receptor, indicating that NPY and somatostatin partly regulate the same neuronal pathway. This review focuses on recent findings regarding the role of the NPY/Y1 and somatostatin/SST2A receptor in itch, and also presents data integrating the two neurotransmitter systems.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398793 (URN)10.1016/j.npep.2019.101976 (DOI)000497598400001 ()31668651 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationStiftelsen Olle Engkvist ByggmästareRagnar Söderbergs stiftelse
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved
Freitag, F. B., Ahemaiti, A., Jakobsson, J. E. T., Weman, H. M. & Lagerström, M. C. (2019). Spinal gastrin releasing peptide receptor expressing interneurons are controlled by local phasic and tonic inhibition. Scientific Reports, 9, Article ID 16573.
Open this publication in new window or tab >>Spinal gastrin releasing peptide receptor expressing interneurons are controlled by local phasic and tonic inhibition
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 16573Article in journal (Refereed) Published
Abstract [en]

Dorsal horn gastrin-releasing peptide receptor (GRPR) neurons have a central role in itch transmission. Itch signaling has been suggested to be controlled by an inhibitory network in the spinal dorsal horn, as increased scratching behavior can be induced by pharmacological disinhibition or ablation of inhibitory interneurons, but the direct influence of the inhibitory tone on the GRPR neurons in the itch pathway have not been explored. Here we have investigated spinal GRPR neurons through in vitro and bioinformatical analysis. Electrophysiological recordings revealed that GRPR neurons receive local spontaneous excitatory inputs transmitted by glutamate and inhibitory inputs by glycine and GABA, which were transmitted either by separate glycinergic and GABAergic synapses or by glycine and GABA co-releasing synapses. Additionally, all GRPR neurons received both glycine- and GABA-induced tonic currents. The findings show a complex inhibitory network, composed of synaptic and tonic currents that gates the excitability of GRPR neurons, which provides direct evidence for the existence of an inhibitory tone controlling spontaneous discharge in an itch-related neuronal network in the spinal cord. Finally, calcium imaging revealed increased levels of neuronal activity in Grpr-Cre neurons upon application of somatostatin, which provides direct in vitro evidence for disinhibition of these dorsal horn interneurons.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-397943 (URN)10.1038/s41598-019-52642-3 (DOI)000495857600027 ()31719558 (PubMedID)
Funder
Swedish Research Council
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Spencer, N. J., Magnúsdóttir, E. I., Jakobsson, J. E. T., Kestell, G., Chen, B. N., Morris, D., . . . Lagerström, M. C. (2018). CGRP alpha within the Trpv1-Cre population contributes to visceral nociception. American Journal of Physiology - Gastrointestinal and Liver Physiology, 314(2), G188-G200
Open this publication in new window or tab >>CGRP alpha within the Trpv1-Cre population contributes to visceral nociception
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2018 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 314, no 2, p. G188-G200Article in journal (Refereed) Published
Abstract [en]

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRP alpha is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRP alpha from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRP alpha-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRP alpha- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRP alpha specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRP alpha from TRPV1-expressing neurons in mice. We show that CGRP alpha from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
calcitonin gene-related peptide, nociception, pain, transient receptor potential cation channel subfamily V member 1, visceral
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-349363 (URN)10.1152/ajpgi.00188.2017 (DOI)000425923800005 ()28971837 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseÅke Wiberg Foundation
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2019-09-08Bibliographically approved
Magnúsdóttir, E. I., Grujic, M., Roers, A., Hartmann, K., Pejler, G. & Lagerström, M. C. (2018). Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin. Molecular Pain, 14, Article ID 1744806918808161.
Open this publication in new window or tab >>Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
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2018 (English)In: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 14, article id 1744806918808161Article in journal (Refereed) Published
Abstract [en]

Subcutaneous formalin injections are used as a model for tissue injury-induced pain where formalin induces pain and inflammation indirectly by crosslinking proteins and directly through activation of the transient receptor potential A1 receptor on primary afferents. Activation of primary afferents leads to both central and peripheral release of neurotransmitters. Mast cells are found in close proximity to peripheral sensory nerve endings and express receptors for neurotransmitters released by the primary afferents, contributing to the neuro/immune interface. Mast cell proteases are found in large quantities within mast cell granules and are released continuously in small amounts and upon mast cell activation. They have a wide repertoire of proposed substrates, including Substance P and calcitonin gene-related peptide, but knowledge of their in vivo function is limited. We evaluated the role of mouse mast cell proteases (mMCPs) in tissue injury pain responses induced by formalin, using transgenic mice lacking either mMCP4, mMCP6, or carboxypeptidase A3 (CPA3), or mast cells in their entirety. Further, we investigated the role of mast cells in heat hypersensitivity following a nerve growth factor injection. No statistical difference was observed between the respective mast cell protease knockout lines and wild-type controls in the formalin test. Mast cell deficiency did not have an effect on formalin-induced nociceptive responses nor nerve growth factor-induced heat hypersensitivity. Our data thus show that mMCP4, mMCP6, and CPA3 as well as mast cells as a whole, do not play a significant role in the pain responses associated with acute tissue injury and inflammation in the formalin test. Our data also indicate that mast cells are not essential to heat hypersensitivity induced by nerve growth factor.

Keywords
Pain formalin, transgenic, mast cell, protease
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-372455 (URN)10.1177/1744806918808161 (DOI)000451284400001 ()30280636 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelse
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-09-08Bibliographically approved
Haring, M., Zeisel, A., Hochgerner, H., Rinwa, P., Jakobsson, J. E. T., Lonnerberg, P., . . . Ernfors, P. (2018). Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types. Nature Neuroscience, 21(6), 869-880
Open this publication in new window or tab >>Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types
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2018 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 21, no 6, p. 869-880Article in journal (Refereed) Published
Abstract [en]

The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-357394 (URN)10.1038/s41593-018-0141-1 (DOI)000433232600016 ()29686262 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, PainCells 740491Swedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation, 2015.0041Ragnar Söderbergs stiftelseWellcome trust
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Gao, T., Ma, H., Xu, B., Bergman, J., Larhammar, D. & Lagerström, M. C. (2018). The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch. Journal of Investigative Dermatology, 138(11), 2405-2411
Open this publication in new window or tab >>The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch
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2018 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 138, no 11, p. 2405-2411Article in journal (Refereed) Published
Abstract [en]

Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y-1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y-1 agonist [Leu(31), Pro(34)]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y-1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y-1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y-1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-369040 (URN)10.1016/j.jid.2018.05.008 (DOI)000447794000021 ()29803641 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationRagnar Söderbergs stiftelseStiftelsen Olle Engkvist Byggmästare
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2019-01-03Bibliographically approved
Spencer, N. J., Hibberd, T. J., Lagerström, M., Otsuka, Y. & Kelley, N. (2018). Visceral pain: Novel approaches for optogenetic control of spinal afferents. Brain Research, 1693(part B), 159-164
Open this publication in new window or tab >>Visceral pain: Novel approaches for optogenetic control of spinal afferents
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2018 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1693, no part B, p. 159-164Article in journal (Refereed) Published
Abstract [en]

Painful stimuli arising within visceral organs are detected by peripheral nerve endings of spinal afferents, whose cell bodies are located in dorsal root ganglia (DRG). Recent technical advances have made it possible to reliably expose and inject single DRG with neuronal tracers or viruses in vivo. This has facilitated, for the first time, unequivocal identification of different types of spinal afferent endings in visceral organs. These technical advances paved the way for a very exciting series of in vivo experiments where individual DRG are injected to facilitate opsin expression (e.g. Archaerhodopsin). Organ-specific expression of opsins in sensory neurons may be achieved by retrograde viral transduction. This means activity of target specific populations of sensory neurons, within single DRG, can be modulated by optogenetic photo stimulation. Using this approach we implanted micro light-emitting diodes (micro-LEDs) adjacent to DRG of interest, thereby allowing focal DRG-specific control of visceral and/or somatic afferents in conscious mice. This is vastly different from broad photo-illumination of peripheral nerve endings, which are dispersed over much larger surface areas across an entire visceral organ; and embedded deep within multiple anatomical layers. Focal DRG photo-stimulation also avoids the potential that wide-field illumination of the periphery could inadvertently activate other closely apposed organs, or co-activate different classes of axons in the same organ (e.g. enteric and spinal afferent endings in the gut). It is now possible to selectively control nociceptive and/or non-nociceptive pathways to specific visceral organs in vivo, using wireless optogenetics and micro-LEDs implanted adjacent to DRG, for targeted photo-stimulation.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Adeno-associated Virus (AAV), Nociception, Visceral pain, Spinal afferent, Optogenetics, Channelrhodopsin, Archaerhodopsin, DRG, Pain, Wireless optogenetics, Light emitting diodes (LEDs), Sensory neuron, Trpv1
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-359866 (URN)10.1016/j.brainres.2018.02.002 (DOI)000436913200008 ()29425907 (PubMedID)
Available from: 2018-09-07 Created: 2018-09-07 Last updated: 2018-09-07Bibliographically approved
Aresh, B., Freitag, F. B., Perry, S., Blümel, E., Lau, J., Franck, M. C. .. & Lagerström, M. C. (2017). Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling. Pain, 158(5), 945-961
Open this publication in new window or tab >>Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling
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2017 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 5, p. 945-961Article in journal (Refereed) Published
Abstract [en]

Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

Keywords
Itch, Gastrin-releasing peptide receptor population, Natriuretic polypeptide B, Spinal cord, Vesicular glutamate transporter 2, Neuronal networks, Labeled line of itch, Electrophysiology, Conditional knockout analysis, Tracing, Calcium imaging, Grpr, VGLUT2
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-284058 (URN)10.1097/j.pain.0000000000000861 (DOI)000402430600021 ()28157737 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationThe Royal Swedish Academy of SciencesRagnar Söderbergs stiftelseMagnus Bergvall FoundationGunvor och Josef Anérs stiftelse
Note

Title in thesis list of papers: Spinal Cord Interneurons Expressing the Gastrin Releasing Peptide Receptor Convey Itch through VGLUT2-mediated Signaling

Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-07-10Bibliographically approved
Rogoz, K., Aresh, B., Freitag, F. B., Pettersson, H., Magnúsdóttir, E. I., Larsson Ingwall, L., . . . Lagerström, M. C. (2016). Identification of a Neuronal Receptor Controlling Anaphylaxis. Cell reports, 14(2), 370-379
Open this publication in new window or tab >>Identification of a Neuronal Receptor Controlling Anaphylaxis
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 370-379Article in journal (Refereed) Published
Abstract [en]

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-272637 (URN)10.1016/j.celrep.2015.12.033 (DOI)000368101600019 ()26748715 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationÅke Wiberg FoundationMagnus Bergvall FoundationThe Royal Swedish Academy of Sciences
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2018-01-10Bibliographically approved
Rogóz, K., Stjarne, L., Kullander, K. & Lagerström, M. C. (2015). VGLUT2 controls heat and punctuate hyperalgesia associated with nerve injury via TRPV1-Cre primary afferents. PLoS ONE, 10(1), Article ID e0116568.
Open this publication in new window or tab >>VGLUT2 controls heat and punctuate hyperalgesia associated with nerve injury via TRPV1-Cre primary afferents
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 1, article id e0116568Article in journal (Refereed) Published
Abstract [en]

Nerve injury induces a state of prolonged thermal and mechanical hypersensitivity in the innervated area, causing distress in affected individuals. Nerve injury-induced hypersensitivity is partially due to increased activity and thereby sustained release of neurotransmitters from the injured fibers. Glutamate, a prominent neurotransmitter in primary afferents, plays a major role in development of hypersensitivity. Glutamate is packed in vesicles by vesicular glutamate transporters (VGLUTs) to enable controlled release upon depolarization. While a role for peripheral VGLUTs in nerve injury-induced pain is established, their contribution in specific peripheral neuronal populations is unresolved. We investigated the role of VGLUT2, expressed by transient receptor potential vanilloid (TRPV1) fibers, in nerve injury-induced hypersensitivity. Our data shows that removal of Vglut2 from Trpv1-Cre neurons using transgenic mice abolished both heat and punctuate hyperalgesia associated with nerve injury. In contrast, the development of cold hypersensitivity after nerve injury was unaltered. Here, we show that, VGLUT2-mediated glutamatergic transmission from Trpv1-Cre neurons selectively mediates heat and mechanical hypersensitivity associated with nerve injury. Our data clarifies the role of the Trpv1-Cre population and the dependence of VGLUT2-mediated glutamatergic transmission in nerve injury-induced hyperalgesia.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-247151 (URN)10.1371/journal.pone.0116568 (DOI)000349122100031 ()
Available from: 2015-03-17 Created: 2015-03-13 Last updated: 2018-01-11Bibliographically approved
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