<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article  PUBLIC "-//NLM//DTD Journal Publishing DTD v3.0 20080202//EN" "http://dtd.nlm.nih.gov/publishing/3.0/journalpublishing3.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="3.0" xml:lang="en" article-type="research article"><front><journal-meta><journal-id journal-id-type="publisher-id">AM</journal-id><journal-title-group><journal-title>Applied Mathematics</journal-title></journal-title-group><issn pub-type="epub">2152-7385</issn><publisher><publisher-name>Scientific Research Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.4236/am.2013.48A001</article-id><article-id pub-id-type="publisher-id">AM-34604</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Physics&amp;Mathematics</subject></subj-group></article-categories><title-group><article-title>
 
 
  Mathematical Modeling of Cardiomyocytes’ and Skeletal Muscle Fibers’ Membrane: Interaction with External Mechanical Field
 
</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>rina</surname><given-names>V. Ogneva</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Nikolay</surname><given-names>S. Biryukov</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><addr-line>Department of Molecular Biomedicine, State Scientific Center of Russian Federation, Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia</addr-line></aff><author-notes><corresp id="cor1">* E-mail:<email>iogneva@yandex.ru(RVO)</email>;</corresp></author-notes><pub-date pub-type="epub"><day>24</day><month>07</month><year>2013</year></pub-date><volume>04</volume><issue>08</issue><fpage>1</fpage><lpage>6</lpage><history><date date-type="received"><day>March</day>	<month>25,</month>	<year>2013</year></date><date date-type="rev-recd"><day>April</day>	<month>25,</month>	<year>2013</year>	</date><date date-type="accepted"><day>May</day>	<month>3,</month>	<year>2013</year></date></history><permissions><copyright-statement>&#169; Copyright  2014 by authors and Scientific Research Publishing Inc. </copyright-statement><copyright-year>2014</copyright-year><license><license-p>This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/</license-p></license></permissions><abstract><p>
 
 
   We propose a mathematic model of muscle cell membrane based on thin-walled elastic rod theory. A deformation occurs in rodents’ skeletal and cardiac cells during a period of antiorthostatic suspension. We carried out a quantitative evaluation of the deformation using this model. The calculations showed the deformation in cardiac cells to be greater than in skeletal ones. This data corresponds to experimental results of cell response that appears intense in cardiomyocytes than in skeletal muscle cells. Moreover, the deformation in skeletal and heart muscle cells has a different direction (stretching vs. compression), corresponding to experimental data of different adaptive response generation pathways in cells because of external mechanical condition changes. 
 
</p></abstract><kwd-group><kwd>Mathematical Modeling in Biology; Muscle Cell; Cell Mechanosensitivity; Microgravity</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>1. Introduction</title><p>Every mechanical system, including living cells, in an external mechanical field is exposed to forces intrinsic to this field. The action of these forces results in mechanical tension that appears in cells. An external influence change (in direction or magnitude) leads to mechanical tension changes in cells and to deformation. The significance of the deformation for the cell depends on its inherent mechanical characteristics and the sensitivity of its mechanosensors.</p><p>An external physical signal transformation results in proper cell response generation. At the same time, the clue is the magnitude of the applied force that is able to induce cell response.</p><p>All living cells can be divided into two groups: cells that form internal tension only against external influence and cells that can additionally generate force themselves —muscle cells. Muscle cells have a specific structure, a developed cytoskeleton, which occupies most of the cell volume and forms a contractile apparatus. Taking these features into account, one can suppose that a muscle cell mechanosensor is connected to the contractile apparatus, for example with the M-line [<xref ref-type="bibr" rid="scirp.34604-ref1">1</xref>].</p><p>However, the muscle cell submembrane cytoskeleton is quite similar to that in non-muscle cells except for certain areas (particularly in areas of M-line and Z-disk projections on the membrane). Hence, cell formation takes place under constant external force action, so one can assume that the first mechanoreception acts to connect with the cell compartment, typical for every living cell. This compartment appears to comprise a membrane and a cortical (submembrane) cytoskeleton. Therefore, the question is what deformations emerge in the muscle fiber membrane after the gravity vector or the fiber contraction rate changes and whether these changes can result in muscle fiber mechanical characteristic change and cell response initiation.</p><p>To answer these questions, we need a numerical evaluation of deformations that arise in the sarcolemma after external mechanical conditions change. Such an evaluation requires data about longitudinal and transversal stiffness because muscle cells appear to have a three-dimensional structure [<xref ref-type="bibr" rid="scirp.34604-ref2">2</xref>]. However, this problem turns out to be hard to solve because the contractile apparatus contribution to linear stiffness is several orders greater than the contribution of the sarcolemma. Previously, we succeeded in determining the transversal stiffness of the sarcolemma using atomic force microscopy [<xref ref-type="bibr" rid="scirp.34604-ref3">3</xref>], changing mechanical conditions for both skeletal and cardiac muscles in rodents (<xref ref-type="fig" rid="fig1">Figure 1</xref>) [<xref ref-type="bibr" rid="scirp.34604-ref4">4</xref>].</p><p>An external mechanical condition change was implemented through the common animal antiorthostatic suspension method by tail at an angle of 30˚ respective to the cage floor (the Ilyin-Novikov method with the MoreyHolton modification is widely used in space physiology to model microgravity effects on a surface [<xref ref-type="bibr" rid="scirp.34604-ref5">5</xref>]). Animal suspension resulted, on the one hand, in a reduction of the external mechanical field on the hind limbs and, on the other hand, in increased mechanical tension in cardiomyocytes. The orientation of the muscle cells (muscle fibers) in the gravity field changed, too.</p><p>Nevertheless, the data for only the transversal stiffness of the membrane and cortical cytoskeleton do not afford us the influence of the gravity vector change on the muscle cell membrane and its probable involvement in primary mechanoreception acts. All of the above indicates the necessity of developing a membrane mathematical model.</p></sec><sec id="s2"><title>2. Mathematical Model</title><sec id="s2_1"><title>2.1. Statement of the Problem</title><p>Let δ define the thickness of the membrane and cortical cytoskeleton, d is the muscle fiber diameter, and l is its length. Then, we can write the following relations:</p><p><img src="1-7401459\46390f51-f229-46be-b05e-74e9e93f1f01.jpg" />, <img src="1-7401459\2bf54210-5e87-42ed-b621-f7e20f412df3.jpg" /></p><p>This enables us to consider the fiber a long, cylindrical envelope called a thin-walled rod [<xref ref-type="bibr" rid="scirp.34604-ref6">6</xref>].</p><p>It is typical for transversal sections of this kind of objects to initially be plane distorted on a surface: W(x, z). W(x, z) is usually called a sectional warping. For closed envelope rods, including muscle fibers, axial uniform warping is also typical, so we can rewrite W(x, z) as W(x). We have <img src="1-7401459\e5a3bc77-cdf6-4ac7-9349-b0f84507a969.jpg" /> in Saint-Venant’s prob-</p><p>lem, where Ф is the Prandtl function (underlining indicates that the underlined value is a vector). We can take a sectorial area as W for a thin section. Then, for the part of membrane between the Z-disk and M-line to be considered, we use the thin-walled theory statements. We will consider the cylindrical rod with thin simply connected section F and with volume load f. For simplicity, we suppose the <img src="1-7401459\3839236a-4a61-47a8-b54e-f5234efa6c73.jpg" /> end to be fixed, and we have the surface load<img src="1-7401459\9b946a26-2e84-4b31-a5ea-66f64182974c.jpg" />, which is a net load between the Zdisk and M-line (to be determined later) on the other end<img src="1-7401459\72510931-933b-4b7e-9e2b-a7d8399550bc.jpg" />. We describe this three-dimensional case using the method of variations [<xref ref-type="bibr" rid="scirp.34604-ref7">7</xref>]:</p><disp-formula id="scirp.34604-formula10285"><label>, (1)</label><graphic position="anchor" xlink:href="1-7401459\553b1c8e-eccb-4fc9-a65a-5428b6450663.jpg"  xlink:type="simple"/></disp-formula><p><img src="1-7401459\0d70203e-c404-440d-abb1-a9b98e26bcac.jpg" />, <img src="1-7401459\54e58a96-ad2c-4cfe-8e6a-ba2165ed154d.jpg" />where <img src="1-7401459\70066de5-c702-4436-a8c0-fd26e14ca2e0.jpg" /> is the translation vector, <img src="1-7401459\592b47fc-ca50-4a49-8601-0eed712dd4e1.jpg" />is the volumetric energy, <img src="1-7401459\d150ee7a-74a5-44e1-9edb-fcf109a8dcfd.jpg" />is the Lam&#233; constant, <img src="1-7401459\6a6474cf-0f91-406b-8632-4e2c519de9e3.jpg" />is the Poisson ratio, <img src="1-7401459\1a796a2a-a03a-4ba1-b0cb-61a6d1f6fdcd.jpg" />is the deformation tensor, and <img src="1-7401459\89107dfc-8e3a-474b-a681-9b5de24cc44a.jpg" /> is the trace of deformation tensor, the first invariant (double underlining indicates tensors).</p><p>To derive equations from the variation principle, we approximate the translation as:</p><disp-formula id="scirp.34604-formula10286"><label>, (2)</label><graphic position="anchor" xlink:href="1-7401459\67cd63ec-4be9-4e1d-bcf1-b8f3c42de8cf.jpg"  xlink:type="simple"/></disp-formula><p>where <img src="1-7401459\e40b663f-edfb-4502-9158-9e58d75940c6.jpg" /> is the linear translation, <img src="1-7401459\f4f463dc-0598-478b-af2f-f7dbce780e4d.jpg" />is the rotation vector, <img src="1-7401459\1a01aec4-a698-44ba-b701-a0c98be51b1c.jpg" />is the rotation angle per unit length, and <img src="1-7401459\f2831619-c3df-4f72-afdb-e101534caf39.jpg" /> is the warping function:</p><p><img src="1-7401459\0a4e8e05-8007-4d11-b037-e3180cde66c9.jpg" />, <img src="1-7401459\3f01d2ad-58a5-48b8-b6bf-25b2929e6c7d.jpg" />,</p><p><img src="1-7401459\e6d46df6-5b7c-4f0a-9232-2cf2d63d71c9.jpg" />is the basis vector of the Lagrangian coordinate.</p><p>Let us suppose that there is a lack of transversal shifts; then:</p><disp-formula id="scirp.34604-formula10287"><label>. (3)</label><graphic position="anchor" xlink:href="1-7401459\2f09fecb-bdca-4eea-89d0-0c07172217dc.jpg"  xlink:type="simple"/></disp-formula><p>Taking into account Equation (3), approximation (2) becomes:</p><disp-formula id="scirp.34604-formula10288"><label>, (4)</label><graphic position="anchor" xlink:href="1-7401459\f78e8e20-d5f0-45ae-a9c2-b9a638209f06.jpg"  xlink:type="simple"/></disp-formula><p>That is:</p><disp-formula id="scirp.34604-formula10289"><label>. (5)</label><graphic position="anchor" xlink:href="1-7401459\22711dc0-1b5f-40b9-bd46-30598d56cb19.jpg"  xlink:type="simple"/></disp-formula><p>From the classical theory of elasticity, we know that:</p><disp-formula id="scirp.34604-formula10290"><label>, (6)</label><graphic position="anchor" xlink:href="1-7401459\6247d864-d507-4941-b883-553fdf51c4a1.jpg"  xlink:type="simple"/></disp-formula><p>where S is the symmetrization symbol.</p><p>Using (4), Equation (6) can be rewritten:</p><disp-formula id="scirp.34604-formula10291"><label>, (7)</label><graphic position="anchor" xlink:href="1-7401459\d0a4e3b6-3510-4f80-8f20-680e27fcfff4.jpg"  xlink:type="simple"/></disp-formula><p>where <img src="1-7401459\6409dac9-1c2c-425e-96cd-06bede4cef38.jpg" /> and <img src="1-7401459\d7c2d8de-5c1f-47c8-8873-3589c388cc76.jpg" />.</p><p>Then:</p><disp-formula id="scirp.34604-formula10292"><label>(8)</label><graphic position="anchor" xlink:href="1-7401459\79a10ad3-7573-455d-a584-8080c0bc8652.jpg"  xlink:type="simple"/></disp-formula><p>Substituting (8) into (1), we obtain a new volumetrical energy density:</p><p><img src="1-7401459\c34faba9-5df8-441c-a661-3ea0def865b2.jpg" /></p><p>Since <img src="1-7401459\80eef5ab-29b8-416d-aa65-c4b6b42274a6.jpg" />:</p><disp-formula id="scirp.34604-formula10293"><label>, (9)</label><graphic position="anchor" xlink:href="1-7401459\dcc7bcb9-8dc3-40cd-b1f7-e3b78fb64478.jpg"  xlink:type="simple"/></disp-formula><p>where<img src="1-7401459\6f6e2aa7-fe98-43be-bfbe-e9d65d255b20.jpg" />, and <img src="1-7401459\2c99da37-a964-498e-9fff-aa1b6a2994b6.jpg" /> is Young’s modulus.</p><p>Taking into account (7), (9) becomes:</p><disp-formula id="scirp.34604-formula10294"><label>. (10)</label><graphic position="anchor" xlink:href="1-7401459\782ec05e-5f64-404b-a0b3-b051ff0bd658.jpg"  xlink:type="simple"/></disp-formula><p>Integrating (10) in the section:</p><disp-formula id="scirp.34604-formula10295"><label>, (11)</label><graphic position="anchor" xlink:href="1-7401459\3c56145f-210e-4790-b995-79717d1635fd.jpg"  xlink:type="simple"/></disp-formula><p>where<img src="1-7401459\7d859001-ecef-4201-b8a6-79bcda7f748b.jpg" />, <img src="1-7401459\b10c4cdd-4d37-4f24-8cf4-78cdf186d84c.jpg" />, <img src="1-7401459\96c5c7f6-13cd-4f65-8c9b-b9465ece0192.jpg" />, <img src="1-7401459\1c4abea9-e66a-4ccd-aad2-60c72771fdae.jpg" />, <img src="1-7401459\c2d91b4a-e7d5-40da-9b60-862166d80cd8.jpg" />.</p><p>Let us now determine the work of volume loads:</p><disp-formula id="scirp.34604-formula10296"><label>, (12)</label><graphic position="anchor" xlink:href="1-7401459\ebed540e-a919-4a28-8bc1-bfe0b706132e.jpg"  xlink:type="simple"/></disp-formula><p>where<img src="1-7401459\2486813f-0f83-4161-a7de-877ed50aaa42.jpg" />, <img src="1-7401459\aa228e70-9ba8-4b9f-9ce2-6d6c936bbe6b.jpg" />, <img src="1-7401459\6f019f4a-74ed-4ae6-82ac-6536ea44075d.jpg" />, <img src="1-7401459\c8657ace-05bc-41f3-9ebb-84fd68b9789d.jpg" />is the distributed bimoment per unit length.</p><p>Similarly, a work of the volume load on the end:</p><disp-formula id="scirp.34604-formula10297"><label>, (13)</label><graphic position="anchor" xlink:href="1-7401459\bb3f9655-5bf8-4390-b44f-d527bd1a959a.jpg"  xlink:type="simple"/></disp-formula><p>where<img src="1-7401459\b2943c6b-f3c9-4898-9a54-2142665ab321.jpg" />, <img src="1-7401459\3cd7ce32-7034-49e0-866c-2e47aa3e82b2.jpg" />, <img src="1-7401459\4a31decd-c4da-4352-9013-34f0e9de09ce.jpg" />, <img src="1-7401459\83b658a0-9237-410e-8d0d-74c55c356f93.jpg" />&#160;is the bimoment on the end.</p><p>Taking into account Equations (12) and (13), the variational equation becomes:</p><disp-formula id="scirp.34604-formula10298"><label>. (14)</label><graphic position="anchor" xlink:href="1-7401459\5d7907e6-f2a1-4552-9dc2-6f7fe8b152ff.jpg"  xlink:type="simple"/></disp-formula><p>From (14), we obtain differential equations and limits:</p><p><img src="1-7401459\248c5ee0-57ab-44ae-aa29-bfaed297ca18.jpg" /><img src="1-7401459\dd9852a2-390a-4c04-bb35-26077a18d848.jpg" />,</p><p><img src="1-7401459\d8d49098-b5e3-4c89-a0e7-a5f2748f9882.jpg" />:<img src="1-7401459\3481320c-4db5-4617-ae94-fc4411f551a8.jpg" />, <img src="1-7401459\c85f0009-7dec-4059-95c1-f36f2873d378.jpg" />, <img src="1-7401459\c78aed3d-91f0-4a99-96d6-d95f3d3ce1cc.jpg" />,</p><disp-formula id="scirp.34604-formula10299"><label>, (15)</label><graphic position="anchor" xlink:href="1-7401459\f56933d8-0614-43e7-84a7-fd436d1f51f7.jpg"  xlink:type="simple"/></disp-formula><p><img src="1-7401459\af109714-9ef3-4dac-9b5c-369484eba9c2.jpg" />:<img src="1-7401459\c0144688-c851-436e-974f-5aa0da49a3c7.jpg" />, <img src="1-7401459\0bd64b5e-556b-4146-a4f9-ae075ee5258b.jpg" /></p><p><img src="1-7401459\92eb9ae7-fea2-4c21-a428-e69f5c1d9f49.jpg" />, <img src="1-7401459\508f08a9-4122-4733-b904-9a0de39a0a44.jpg" />,</p><p><img src="1-7401459\421d2673-321c-4a4d-b940-e81e5dc8a8a3.jpg" />,</p><p><img src="1-7401459\957cdeab-a112-40cc-a81f-1b700d8b0b19.jpg" />:<img src="1-7401459\dd061412-5ee2-44b1-b14c-c95642c78be4.jpg" />, <img src="1-7401459\37373890-c752-4c74-8fa4-213fb69d47d7.jpg" />, <img src="1-7401459\63f142c8-e0aa-480a-9af0-602d18ff3b04.jpg" /></p><p>The set of equations derived in (15) gives us a chance to completely describe muscle fiber membrane behavior as a long cylindrical envelope and to find the potential energy <img src="1-7401459\1d243c4d-6ad5-4c92-93d5-03494349a04e.jpg" /> in the case described.</p><p>Let us assume that there is no external moment influence and that section warping and transversal shift contribution are negligible in comparison with the longitudinal component. This assumption is justified because of the specific muscle cell structure. Then, solving (15), we can find<img src="1-7401459\287575f7-4430-49f8-a901-b42c067ad160.jpg" />:</p><disp-formula id="scirp.34604-formula10300"><label>, (16)</label><graphic position="anchor" xlink:href="1-7401459\f772f927-809f-4601-b5ed-536efea590b5.jpg"  xlink:type="simple"/></disp-formula><p>where <img src="1-7401459\decad643-fccc-42d3-8a2d-4c8dc1d079af.jpg" /> is the volume load, <img src="1-7401459\61fba604-93e4-4de8-ba4d-c71584d44142.jpg" />is the surface load, F is the section area, <img src="1-7401459\0f30da55-820e-4b43-a251-2fe87dadaa6a.jpg" />is the adduced Young’s modulus, and <img src="1-7401459\c9f97d47-13e2-4332-aa0c-3fd46d25e27f.jpg" /> is the Poisson ratio.</p></sec><sec id="s2_2"><title>2.2. External Mechanical Loading</title><p>An external mechanical field acts on the whole organism and launches a number of processes, leading to nervous activation change in skeletal muscles, a liquid shift in the cranial direction, and, as a result, to a volume load change in the heart.</p><p>These processes results in the muscle fiber membrane becoming subjected to the following forces: <img src="1-7401459\9ead833a-a2d6-4c80-a966-36a4738d6f4d.jpg" />by the contractile apparatus as a result of nervous activation, <img src="1-7401459\648ac306-c02b-4bf2-85f0-d1412ed9f774.jpg" />, hydrostatic pressure (only for cardiomyocytes), and<img src="1-7401459\849a0116-7c16-461f-af34-439823c94ae5.jpg" />, the gravity. Nervous activation by intracellular signal mechanisms launch results in mechanical tension that arises in a muscle fiber because of myosin head and actin filament interaction, which is transmitted into the sarcolemma by the cortical cytoskeleton. Let us suppose that this interaction is uniform distributed over the length of the contractile apparatus. Therefore, it can be represented as a periodical function with the period of Т, which equals the distance between two successive myosin heads.</p><p>Then<img src="1-7401459\ff410516-94ac-49d5-a62e-2dd12551cc41.jpg" />, where <img src="1-7401459\3493e68e-fb95-4364-90d7-c04cbdb0f161.jpg" /> is the force generated by the single bridge, approximately 3 - 5 pN, n represents a number of bridges, which can be determined as the ratio of the fiber length (l) to the distance between two successive bridges, approximately 43 nm, per fiber volume. Gravity also acts on a muscle cell depending on the cell orientation. The specific volumetric force in this case may be represented as<img src="1-7401459\9c162e99-cc0d-4b7f-85d9-7326470f8edb.jpg" />, where</p><p><img src="1-7401459\b4ac9f70-2e4f-4026-aeff-0a0363e56d13.jpg" />is the angle between the gravity vector and the fiber longitudinal axis direction, <img src="1-7401459\622eaa43-c297-49aa-9614-65e5b55fd635.jpg" />is the free-fall acceleration, and <img src="1-7401459\6e4f36e6-29da-43bf-be28-94dc22948ce8.jpg" /> is the liquid density. The surface load on the end is a net load of gravity and hydrostatic pressure;<img src="1-7401459\81770a0f-4a90-4dd9-9b45-2b0349a08e6b.jpg" />, where d is the fiber diameter.</p><p>Then, the external forces become:</p><p><img src="1-7401459\1bd46bdd-6b2a-4ae6-906b-5ce6c1e7a671.jpg" />,</p><disp-formula id="scirp.34604-formula10301"><label>. (17)</label><graphic position="anchor" xlink:href="1-7401459\7263348d-4a30-4f28-b4f2-e8dadd90f371.jpg"  xlink:type="simple"/></disp-formula></sec></sec><sec id="s3"><title>3. Numerical Examples</title><p>As an experimental model, we use a rodent’s antiorthostatic suspension (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p><p>We have determined in previous experiments Young’s modulus of the sarcolemma of different skeletal muscles [<xref ref-type="bibr" rid="scirp.34604-ref4">4</xref>] and a rat’s left ventricle [8,9]. Moreover, the introduction of the nifedipin system into rats resulted in increased sarcolemma transversal stiffness in skeletal muscles [<xref ref-type="bibr" rid="scirp.34604-ref10">10</xref>]. We have also determined the muscle fiber diameter. Based both on these data and ratio (16), we can find characteristic longitudinal deformations of M. soleus fibers and cardiomyocytes (<xref ref-type="table" rid="table1">Table 1</xref>).</p></sec><sec id="s4"><title>4. Discussion and Conclusions</title><p>Interaction between a cell and an external mechanical field is still an unsolved problem in modern cell biophysics. A case of gravity vector change appears to be</p><p><xref ref-type="table" rid="table1">Table 1</xref>. Longitudinal absolute and relative deformations of different muscle cells after antiorthostatic suspension at an angle of 30˚.</p></sec></body><back><ref-list><title>References</title><ref id="scirp.34604-ref1"><label>1</label><mixed-citation publication-type="other" xlink:type="simple">A. A. Shabarchin and A. K. Tsaturyan, “Proposed Role of the M-Band Sarcomere Mechanics and Mechano-Sensing: A Model Study,” Biomechanics and Modeling in Mech anobiology, Vol. 9, No. 2, 2010, pp. 163-175. 
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