Difference between revisions of "Team:NJU-China/Modeling"

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<style type="text/css">  
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<div class="content">
 
<div class="content">
 
<nav>
 
<nav>
−
 
 
<ul>
 
<ul>
−
<li><a href="aknow.html" style="font-weight:bold;font-family:Microsoft YaHei">acknowledgement</a></li>
+
<li><a class="button" href="#detail" style="font-weight:bold;font-family:Microsoft YaHei">content</a></li>
−
<li><a href="human-practice.html" style="font-weight:bold;font-family:Microsoft YaHei">humanpractice</a></li>
+
−
<li><a href="project.html" style="font-weight:bold;font-family:Microsoft YaHei">project</a></li>
+
−
<li><a href="notebook.html" style="font-weight:bold;font-family:Microsoft YaHei">notebook</a></li>
+
−
<li><a href="safty.html" style="font-weight:bold;font-family:Microsoft YaHei">safty</a></li>
+
−
<li><a href="team.html" style="font-weight:bold;font-family:Microsoft YaHei">team</a></li>
+
−
<li><a href="model.html" style="font-weight:bold;font-family:Microsoft YaHei">model</a></li>
+
−
<li><a class="button" href="#detail" style="font-weight:bold;font-family:Microsoft YaHei">home</a></li>
+
 
</ul>
 
</ul>
 
</nav>
 
</nav>
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<div class='menu-content'>
 
<div class='menu-content'>
 
<ul>
 
<ul>
−
<li><a href="aknow.html" style="font-weight:bold;font-family:Microsoft YaHei">acknowledge</a></li>
+
<li><a href="NJU-China-aknow.html" style="font-weight:bold;font-family:Microsoft YaHei">acknowledgement</a></li>
−
<li><a href="human-practice.html" style="font-weight:bold;font-family:Microsoft YaHei">humanpractice</a></li>
+
<li><a href="NJU-China-human-practice.html" style="font-weight:bold;font-family:Microsoft YaHei">humanpractice</a></li>
−
<li><a href="project.html" style="font-weight:bold;font-family:Microsoft YaHei">project</a></li>
+
<li><a href="NJU-China-project.html" style="font-weight:bold;font-family:Microsoft YaHei">project</a></li>
−
<li><a href="notebook.html" style="font-weight:bold;font-family:Microsoft YaHei">notebook</a></li>
+
<li><a href="NJU-China-notebook.html" style="font-weight:bold;font-family:Microsoft YaHei">notebook</a></li>
−
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+
<li><a href="NJU-China-safty.html" style="font-weight:bold;font-family:Microsoft YaHei">safty</a></li>
−
<li><a href="team.html" style="font-weight:bold;font-family:Microsoft YaHei">team</a></li>
+
<li><a href="NJU-China-team.html" style="font-weight:bold;font-family:Microsoft YaHei">team</a></li>
−
<li><a href="module.html" style="font-weight:bold;font-family:Microsoft YaHei">model</a></li>
+
<li><a href="NJU-China-model.html" style="font-weight:bold;font-family:Microsoft YaHei">model</a></li>
−
<li><a class="button" href="#detail" style="font-weight:bold;font-family:Microsoft YaHei">home</a></li>
+
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</ul>
 
</div>
 
</div>
 
</div>
 
</div>
  
−
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+
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<div class="header-content">
 
<div class="container">
 
<div class="container">
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<div class="col-md-12">
 
<div class="col-md-12">
 
<div class="scroll-link-wrapper" style="visibility: visible;margin-top:500px ">
 
<div class="scroll-link-wrapper" style="visibility: visible;margin-top:500px ">
−
<a class="scroll-link" href="#detail"><img src="./file-arrow_down.png">
+
<a class="scroll-link" href="#detail"><img src="https://static.igem.org/mediawiki/2015/1/16/NJU-China-file-arrow_down.png">
 
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</a></div>
 
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     <TR height="100%">
 
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<TD width="27%" bgColor=#EEE8AA style="vertical-align:top">
−
  <ul id="nav" style="height:100px;line-height:100px;margin-top:20%;margin-left:10%;list-style-type:none" class="dyn">
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<h2 align="center">Delivery Module</h2>
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你在火中涅槃，灵魂不死；你在花间长眠，记忆不消。绚烂的阳光是迎接你西去的光环，不知你独自一人去那方可会感到孤单？
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<h3>Introduction:</h3></br>
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[一]魂去
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Pharmacokinetics is the quantitative study of drug absorption, distribution and metabolism in the body. We created pharmacokinetic model to simulate the time-dependent tissue distribution of exosomes. To construct a strategy for developing efficient and safe in vivo RNAi therapy systems, pharmacokinetics at whole body, organ, cellular and sub-cellular level need to be considered.</br></br>
+
      起初听到你的死，我是愕然的。毕竟听说你的病情好了不少，却不料那只是最后的回光返照。
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+
      我没有流泪，甚至没有悲伤，脑子里只是混混沌沌的一团。死？那是我们所有人最后的归宿吧。或许于你更是能够减少痛苦，未尝不是一件好事。
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In our preliminary wet lab study(GFP experiment), we obtain qualitative description of in vivo drug distribution after systematic administration. A computational and compartmental model can be built to give mechanistic insights into quantitative explanation of the experiment results.</br></br>
+
       一切被我想得太简单，甚至太过理所当然了。理智，真是一个可怕的局。
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+
[二]席间
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There are three main aspects we take into account in this pharmacokinetic model:</br></br>
+
       小号、大鼓敲个不停，那种声音不得不说是一种噪音。良久声止，开始一个个念悼词。
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+
       我这时才发现，原来我并没有那么冷漠，缘是城市的喧嚣麻木了我的心。想起那年你的温言软语、慈爱笑容，泪竟是就这样忍不住地从眼眶中溢出了。我撇过头，不愿让人看见，嘴角仍是挂着笑容。
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Theoretically predicting the effect of RVG-modification of exosome on its target ability</br></br>
+
       呵呵，我竟觉着在这葬礼上哭泣都是可耻的。望着周围人谈笑风生，我的心有点寒。到场的那么多人，究竟又有几个是真心的呢？可怜，还是可悲啊？
−
 
+
       原来人可以铁石心肠这种程度，可毕竟他们中很多人比我和你的关系更近啊！听着那个花钱雇来哭的人呜咽，看着那人热泪纵横，我终是忍不住苦笑，竟是一个毫不相识的外人哭得最伤心。这是讽刺，还是笑话？
−
Approximating time-series exosome(siRNA) concentration data for use in modeling RNAi kinetics in target tissue and subsequently calculating the effective dose</br></br>
+
  [三]送葬
−
 
+
      你说，为什么他们还能那样淡然，可我偏偏忍不住泪流满面？为什么他们那个惊讶的表情让我竟是感到羞愧？好像自己做了什么惊天动地的事一样？
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Finding out part of delivery system that could be improved based on simulation data</br></br></br>
+
      执着一根香，撒下一碗酒，三拜三叩，泪融于酒，我如若痴人。
−
 
+
      照礼我是不必披麻戴孝的，只需戴着那顶白色的帽子即可。沿着幽僻的小路，我跟着吹着小号开路的队伍走在末尾。
−
<h3>Model Methods:</h3> </br>
+
       风景甚好，埋在那棵大树底下，你会不会成为那树的枝，树的叶？
−
The process of drug delivery in human and mouse is quite complex. Physiologically speaking, drug delivery after administration can be simplified into two separate phases: </br>
+
[四]感怀
−
1) circulation from central compartment(blood) to peripheral compartment(body tissues)  </br>
+
      死生有命，无可更改。谋事在人，成事在天。任你生前浮华万千，到头来不过一抔尘土，一捧青灰。愿逝者安息，生者恬淡。
−
2)  uptake and trafficking at cellular and sub-cellular level in target tissues. </br></br></br>
+
      有时候我们看不到自己拥有的美好，直到失去才恍然叹息。逝者已矣，页已掀过，惜福、感恩，生活其实温暖如花。
−
 
+
       花开半夏，倾尽繁华，愿你回眸半刹。你可听到我在同你夜话？
−
<h3>Modeling Multi-compartmental Transport:</h3></br>
+
−
In our lab work, we measured relatve level of GFP in brain, liver, lung and spleen after injecting anti-GFP siRNA into mouse. Thus, we decided to follow our lab work and separate compartments for brain, liver, lung and spleen. Other tissues are merged into one compartment. Each peripheral compartment has blood exchange with the central blood circulation, during which certain percentage of exosomes were captured into extracellular matrix of endothelial cells in different tissues.</br></br>
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+
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+
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+
−
<img src="model1.png" height="500" style="padding-left:170px;padding-right:170px" /></br>
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<p style="padding-left:80px;padding-right:80px;">Figure1. Schematic diagram of the arrangement of the different tissues in the pharmacokinetic model. The blood, along with exosomes, circulates from central compartment to five peripheral compartments.</p></br></br>
+
−
Exosomes differ from conventional chemical drugs for its distinct biological characteristics as microvesicles(1).As membrane vesicles, exosomes may rapidly shift from associating with other complex and disassociating into free format during blood circulation. Besides, the ultimate fate of exosomes, similar to other microvesicles, is degradation by lysosomes after internalization via a common process discussed later. Research has shown that microvesicles, containing miRNAs or siRNAs, are stable in serum and play significant biological roles in cell communication(2).Furthermore, the elimination of exosomes occurs mainly in specific tissues rather than during blood circulation, albeit that the half life of exosomes during blood circulation is much shorter(3).These two findings suggest the elimination rate of exosomes during blood circulation is negligible compared with that in target tissues and may not be considered in this part of pharmacokinetic model.</br></br>
+
−
 
+
−
Using standard mass action kinetics, the equations below describe the change of concentration(mass) of free exosomes over time in blood and target tissues.</br></br>
+
−
 
+
−
 
+
−
 
+
−
 
+
−
 
+
−
We would like to note that not all portion of exosomes is effective and totally absorbed by tissues. Therefore, paritiontissue is included to describe effective fraction of dose. Also, Et represents quantity of exosomes captured by extracellular matrix of cells in tissues. It does not represent the final quantity of exosomes in tissues, which will be discussed in next part of the model.</br>
+
−
This work is supported by model of IGEM Slovenia 2012, IGEM NJU-China 2013 and other literatures(4,5).</br></br></br>
+
−
<h3>Modeling Cellular Uptake and Intracellular Trafficking:</h3></br>
+
−
There are variety of pathways for extracellular vesicles to be internalized by cells, namely phagocytosis, clathrin and caveolin-mediated endocytosis and macropinocytosis(6).We assume that receptor-mediated endocytosis is the major pathway of primary exosome internalization. </br></br>
+
−
 
+
−
The cellular uptake pathway can be summarized as depicted in Figure2. Exosomes bind to membrane of target cells after being captured by extracellular matrix and then internalized through endocytosis. The receptor-ligand interaction may facilitate this process. After internalization, RISC complex may escape from endosomes and endosomes may be ultimately eliminated by lysosomes. Although other pathways such as transcytosis and exocytosis following endocytosis might happen, we do not take them into account for simplification.</br></br>
+
−
<img src="model2.png" height="600" style="padding-left:120px;padding-right:120px" /></br>
+
−
<p style="padding-left:80px;padding-right:80px;">Figure2. Pathways shown to participate in exosomes uptake by target cells. Exosomes transport from extracellular matrix to cell surface and undergo intracellular trafficking after internalization. The RISC complex in exosomes is released and exosomes are ultimately degraded.</p></br>
+
−
We can now define equations to describe above pathway. RVG modification helps exosomes bind to acetylcholine receptors specifically expressed in neuronal cells. Much easier are exosomes to be internalized provided that more exosomes bind to target cells. The binding process is modeled using mass action kinetics. AR denotes to number of acetylcholine receptors on target cells and km represents specific binding constant. Non receptor-ligand interaction mediated binding is summarized using kbindtissue.</br></br>
+
−
 
+
−
 
+
−
 
+
−
The internalization and elimination of exosomes are formulated below. Note that different tissues have different internalization and elimination rate. </br></br></br>
+
−
 
+
−
 
+
−
 
+
−
The quantity of endosomal RISC complex and escape behavior is modeled using following equation. The concentration of siRNA in exosome is determined by Real Time RT-PCR and represented by kc.</br></br></br>
+
−
 
+
−
 
+
−
 
+
−
This part of work is based on literature(4).</br></br></br>
+
−
 
+
−
<h3>Model Variables</h3>
+
−
<table>
+
−
<tr><td style="width:100px">Name</td>      <td style="width:200px">Model Compartment      <td style="width:500px">Description(Units)</tr>
+
−
 
+
−
<tr><td>Bcf</td>  <td>Plasma</td>   <td>Free exosomes in circulation(ug)</td> </tr>
+
−
 
+
−
<tr><td>Bcb</td> <td> Plasma</td>   <td>Bound exosomes in circulation(ug)</td> </tr>
+
−
 
+
−
<tr><td>Et</td>        <td>Extracellular</td>        <td>Free exosomes in extracellular matrix of cells in tissues(ug)</td> </tr>
+
−
 
+
−
<tr><td>Tb</td>        <td> Tissue</td>                  <td> Bound exosomes to cells in tissues(ug)</td> </tr>
+
−
 
+
−
<tr><td>brain</td>   <td>Brain cytoplasm</td> <td>Free exosomes in brain(ug)*</td> </tr>
+
−
 
+
−
<tr><td>liver</td>       <td>Liver cytoplasm</td>       <td> Free exosomes in liver(ug) *</td> </tr>
+
−
 
+
−
<tr><td>lung</td>       <td>Lung cytoplasm</td>      <td>Free exosomes in lung(ug) *</td> </tr>
+
−
 
+
−
<tr><td>spleen</td>    <td>Spleen cytoplasm</td>   <td>Free exosomes in spleen(ug) *</td> </tr>
+
−
 
+
−
<tr><td>other</td>      <td>Other tissues cytoplasm </td>       <td>Free exosomes in other tissues(ug) *</td> </tr>
+
−
 
+
−
<tr><td>Enc</td>       <td>Brain cytoplasm</td> <td>Free endosomal RISC complex in exosomes(ug) *</td> </tr>
+
−
</table>
+
−
 
+
−
*: Exosomes become endosomes after interanalization. Here we still use term exosomes for clear illustration.</br></br>
+
−
 
+
−
<h3>Parameter Finding and Adjusting</h3>
+
−
The most challenging part of modeling work is finding and adjusting parameters. After literature review, we are unfortunate to find that few of parameters have been measured or reported directly. The original paper written by Bartlett and Davis uses synthetic polyplexes as carrier to deliver siRNA(4). The stability and target ability of synthetic polyplexes diverge considerably from exosomes due to its chemical and biological nature. It is not appropriate if we just use all the parameters in the original paper without adjustment regardless of different biological nature and consequences. </br></br>
+
−
 
+
−
Parameter adjustment is not unusual in modeling biological process. This is a somewhat uncertain endeavor and lack of convincingness. In an iterative process, each set of parameters must be run through the model and modified to bring the output of the model into better and better agreement with observed experiment and literature results(7).Following this doctrine, we run our simulation and try to fit the result to the experimental and literature data.</br></br>
+
−
<table>
+
−
<tr><td>Model Parameters</td>  <td>Decription(units)</td>      <td>Determination</td>        <td>Value</td></tr>
+
−
 
+
−
<tr><td>kblooddis</td>    <td> Exosomes dissociation from blood components(min-1)</td>    <td>Literature(4)</td>       <td> 1.7×10-4</td></tr>
+
−
 
+
−
 
+
−
<tr><td>kbloodbind</td>  <td> Exosomes binding to blood components(min-1)</td>   <td>Literature(4)</td>   <td>1.7×10-6</td></tr>
+
−
 
+
−
 
+
−
<tr><td>ktransblood</td>  <td>Exosomestransport from plasma to  extracellular fluid(min-1)</td>  <td> Literature(3,4)</td>    <td> 0.4</td></tr>
+
−
+
−
 
+
−
<tr><td>Qc</td>       <td> Cardiac Output(L/min)</td>            <td>IGEM Slovenia 2012</td>  <td>5.6</td></tr>
+
−
 
+
−
<tr><td>Qbrain</td> <td> blood flowing through brain(L/min)</td>   <td>Literature(5)</td>    <td>7.8×10-1</td></tr>
+
−
 
+
−
<tr><td>Qlung</td> <td>blood flowing through lung(L/min)</td> <td>IGEM Slovenia 2012</td>  <td>5.6</td></tr>
+
−
 
+
−
<tr><td>Qliver</td>   <td>blood flowing through liver(L/min)</td>     <td>IGEM Slovenia 2012</td>  <td>1.4</td></tr>
+
−
 
+
−
<tr><td>Qspleen</td>   <td>blood flowing through spleen (L/min)</td>    <td>Estimated?</td> <td> 0.6</td></tr>
+
−
+
−
<tr><td>Qother</td>   <td>blood flowing through other tissues(L/min)</td>    <td>Determined logically</td>    <td> 2.8</td></tr>
+
−
     
+
−
<tr><td>parititionbrain</td>  <td>Effective fraction of dose available to brain</td>   <td>Estimated from literature(3,4,8,9)</td>    <td>1×10-1</td></tr>
+
−
+
−
  <tr><td>parititionlung</td>  <td>Effective fraction of dose available to lung</td> <td>Estimated from literature(3,4,8,9)</td>    <td>1.8×10-2</td></tr>
+
−
 
+
−
  <tr><td>parititionliver</td>  <td>Effective fraction of dose available to liver</td>  <td>Estimated from literature(3,4,8,9)</td>  <td>3.5×10-1</td></tr>
+
−
 
+
−
  <tr><td>parititionspleen</td>  <td>Effective fraction of dose available to spleen</td> <td>Estimated from literature(3,4,8,9)</td>  <td>2×10-1</td></tr>
+
−
             
+
−
  <tr><td>parititionother </td> <td>Effective fraction of dose available to other tissues</td> <td>Estimated from literature(3,4,8,9)</td>  <td>1×10-3</td></tr>
+
−
 
+
−
  <tr><td>kbindbrain</td>    <td>exosomes binding to extracellular matrix of endothelial cells in brain(min-1)</td>    <td>Estimated from literature(3,8,9) </td>    <td>1</td></tr>
+
−
 
+
−
<tr><td>kbindlung</td>    <td>exosomes binding to extracellular matrix of endothelial cells in lung(min-1) </td>    <td>Estimated from literature(3,8,9) </td>  <td>2×10-1</td></tr>
+
−
 
+
−
<tr><td>kbindliver</td>    <td>exosomes binding to extracellular matrix of endothelial cells in lung (min-1)</td>  <td>Estimated from literature(3,8,9)</td>  <td>1×102</td></tr>
+
−
 
+
−
<tr><td>kbindspleen </td>    <td>exosomes binding to extracellular matrix of endothelial cells in spleen(min-1)</td>  <td>Estimated from literature(3,8,9)</td>      <td>1</td></tr>
+
−
 
+
−
<tr><td>kbindother</td>    <td>exosomes binding to extracellular matrix of brain endothelial cells in other tissues(min-1)</td>    <td>Estimated from literature(3,8,9)</td>  <td>1×10-1</td></tr>
+
−
 
+
−
<tr><td>kintbrain</td>    <td>exosomes internalizing into brain(min-1)</td>  <td>Estimated from literature(4,10)</td>  <td>1×101</td></tr>
+
−
   
+
−
<tr><td>kintlung </td>  <td>exosomes internalizing into lung(min-1)</td>  <td>Estimated from literature(4,10,11)</td>  <td>1×102</td></tr>
+
−
   
+
−
<tr><td>kintliver</td>    <td>exosomes internalizing into liver(min-1)</td>  <td>Estimated from literature(4,10,11)</td>  <td>3×10-2</td></tr>
+
−
   
+
−
<tr><td>kintspleen </td>    <td>exosomes internalizing into spleen(min-1)</td>  <td>Estimated from literature(4,10,11)</td> <td>1×102</td></tr>
+
−
   
+
−
<tr><td>kintother</td>    <td>exosomes internalizing into brain(min-1)</td>  <td>Estimated from literature(4,10,11)</td>  <td>2×10-2</td></tr>
+
−
   
+
−
<tr><td>kelimtbrain</td>  <td>exosomes degradation in brain(min-1)</td>    <td>Estimated from literature(4,10,11)</td>  <td>6×10-2</td></tr>
+
−
+
−
<tr><td>kelimtlung </td> <td>exosomes degradation in lung (min-1)</td>  <td>Estimated from literature</td>  <td>2×10-2</td></tr>
+
−
 
+
−
<tr><td>kelimtliver</td>  <td>exosomes degradation in liver (min-1)</td>    <td>Estimated from literature</td>  <td>6×10-1</td></tr>
+
−
 
+
−
<tr><td>kelimtspleen</td> <td>exosomes degradation in spleen(min-1)</td>    <td>Estimated from literature</td>  <td> 4×10-3</td></tr>
+
−
 
+
−
<tr><td>kelimtother</td> <td>exosomes degradation in other tissue(min-1)</td> <td>Estimated from literature </td>  <td>5×10-3</td></tr>
+
−
+
−
<tr><td>AR</td>   <td>Number of acetylcholine receptors in brain(#)</td>  <td>Estimated? </td>     <td>1×1010</td></tr>
+
−
+
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<tr><td>km</td>       <td>binding rates of RVG peptides to acetylcholine Estimated? </td>  <td>1×10-8</td>   <td>receptors(#-1min-1)</td> </tr>
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<tr><td>kescendvec</td>  <td>endosomal escape for RISC complex(min-1)</td> <td>Literature(4) </td>  <td>1.7×10-4</td></tr>
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<tr><td>kc</td>  <td>concentration of RISC complex(#/ug)</td> <td>Literature(12)</td> <td>6.02×1012</td></tr>
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</table>
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</br>
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?: We are very uncertain about these parameters. However, we determine the magnitude of AR*km is about 102.</br></br>
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<h3>Results:</h3>
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We simulate the pharmacokinetic model and get initial results. Unfortunately, the results show that the model is not accurate. It is hard to distinguish the effects of RVG modification on tissue distribution of exosomes based on the figure below.</br>
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<table>
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</br>
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</br>
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<td>
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<p style="padding-left:80px;padding-right:80px;">Tissue distribution of exosomes without RVG modification</p>
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<img src="model3.png" height="300" style="padding-left:0px" /></td>
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<td>
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<p style="padding-left:80px;padding-right:80px;">Tissue distribution of exosomes with RVG modification</p>
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<img src="model4.png" height="300" style="padding-right:0px" /></td>
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</tr>
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</table>
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</br>
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<p style="padding-left:80px;padding-right:80px;">Figure3. Effect of RVG modification on tissue distribution of exosomes. A: Without RVG modification; B: With RVG modification. The initial results are simulated using the exact parameter set described above.</p></br>
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Why do we get unrealistic simulation results? The answer simply lies in the parameter set we choose. After performing parameter sensitivity analysis, we are surprised to find that it is not binding of exosomes to neuronal cell surface that determines the internalization rate. In contrast, the rate limiting step for exosome internalization is its capacity of being captured by extracellular matrix of endothelial cells.</br></br>
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The blood brain barrier is formed by endothelial cells at the level of cerebral capillaries(13). The cerebral endothelial cells may form complex tight junctions that interfere the permeability. The binding of RVG to acetylcholine receptors, which are present in high density at the neuromuscular junction, would provide a mechanism whereby exosomes could be locally concentrate at sites in proximity to peripheral nerves facilitating subsequent uptake and transfer to the central nervous system(14). The local concentrating of exosomes at proximal sites may significantly increase the effective fraction of dose available to target cells, resulting in more exosomes captured by extracellular matrix. Thus, we hypothesized that partitionbrain may also be influenced by RVG modification.</br>
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With partitionbrain increased by 6 fold, we finally obtain optimized simulation results. </br></br>
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<table>
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</br>
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</br>
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<tr>
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<td>
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<img src="model5.png" height="300" style="padding-left:0px" /></td>
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<td>
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<img src="model6.png" height="300" style="padding-right:0px" /></td>
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<img src="model7.png" height="300" style="padding-left:0px" /></td>
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<td>
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<img src="model8.png" height="300" style="padding-right:0px" /></td>
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</tr>
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</table>
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<p style="padding-left:80px;padding-right:80px;">Figure4. Effect of RVG modification on tissue distribution of exosomes. The results are simulated with partitionbrain increased by 6 fold. A-B: time course of distribution of exosomes without RVG modification. C-D: time course of distribution of exosomes with RVG modification. </p></br>
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We now understand our delivery device better using computational simulation data. The half life of exosome in blood is short, which agrees with literature findings(9).The pattern of tissue distribution of exosome with or without RVG modification is also consistent with literature(11) and our GFP experiment. Furthermore, the simulation data provides a new perspective for improving delivery device—modification of exosome is recommended to inhibit its internalization in non-interested tissues.</br></br>
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References:</br>
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<table>
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<td valign="top">1.</td> <td>El Andaloussi, S., Lakhal, S., Mager, I. and Wood, M.J. (2013) Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev, 65, 391-397.</td>
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</tr>
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<td valign="top">2.</td> <td>Zhang, Y., Liu, D., Chen, X., Li, J., Li, L., Bian, Z., Sun, F., Lu, J., Yin, Y., Cai, X. et al. (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Molecular cell, 39, 133-144.</br></td>
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</tr>
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<tr>
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<td valign="top">3.</td> <td>Takahashi, Y., Nishikawa, M., Shinotsuka, H., Matsui, Y., Ohara, S., Imai, T. and Takakura, Y. (2013) Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. Journal of Biotechnology, 165, 77-84.</br></td>
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</tr>
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<td valign="top">4.</td> <td>Bartlett, D.W. and Davis, M.E. (2006) Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res, 34, 322-333.</br></td>
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</tr>
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<td  valign="top">5.</td> <td>Levitt, D.G. and Schoemaker, R.C. (2006) Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat. BMC clinical pharmacology, 6, 1.</br></td>
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</tr>
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<td valign="top">6.</td><td> Mulcahy, L.A., Pink, R.C. and Carter, D.R. (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles, 3.</br></td>
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</tr>
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<td valign="top">7.</td> <td>Sible, J.C. and Tyson, J.J. (2007) Mathematical modeling as a tool for investigating cell cycle control networks. Methods (San Diego, Calif.), 41, 238-247.</br></td>
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</tr>
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<td valign="top">8.</td><td> Lai, C.P., Mardini, O., Ericsson, M., Prabhakar, S., Maguire, C.A., Chen, J.W., Tannous, B.A. and Breakefield, X.O. (2014) Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano, 8, 483-494.</br></td>
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</tr>
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<td valign="top">9.</td> <td>Morishita, M., Takahashi, Y., Nishikawa, M., Sano, K., Kato, K., Yamashita, T., Imai, T., Saji, H. and Takakura, Y. (2015) Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. Journal of pharmaceutical sciences, 104, 705-713.</br></td>
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</tr>
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<td valign="top">10.</td> <td>Banks, G.A., Roselli, R.J., Chen, R. and Giorgio, T.D. (2003) A model for the analysis of nonviral gene therapy. Gene Ther, 10, 1766-1775.</br></td>
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</tr>
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<td valign="top">11.</td> <td>Kumar, P., Wu, H., McBride, J.L., Jung, K.E., Kim, M.H., Davidson, B.L., Lee, S.K., Shankar, P. and Manjunath, N. (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature, 448, 39-43.</br></td>
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</tr>
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<td valign="top">12.</td> <td>Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S. and Wood, M.J. (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature biotechnology, 29, 341-345.</br></td>
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</tr>
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<tr>
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<td valign="top">13.</td> <td>Cecchelli, R., Berezowski, V., Lundquist, S., Culot, M., Renftel, M., Dehouck, M.P. and Fenart, L. (2007) Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov, 6, 650-661.</br></td>
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</tr>
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<tr>
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<td valign="top">14.</td> <td>Lentz, T.L., Burrage, T.G., Smith, A.L., Crick, J. and Tignor, G.H. (1982) Is the acetylcholine receptor a rabies virus receptor? Science, 215, 182-184.</br></td>
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Revision as of 14:23, 17 September 2015

model

你在火中涅槃，灵魂不死；你在花间长眠，记忆不消。绚烂的阳光是迎接你西去的光环，不知你独自一人去那方可会感到孤单？ [一]魂去 起初听到你的死，我是愕然的。毕竟听说你的病情好了不少，却不料那只是最后的回光返照。 我没有流泪，甚至没有悲伤，脑子里只是混混沌沌的一团。死？那是我们所有人最后的归宿吧。或许于你更是能够减少痛苦，未尝不是一件好事。 一切被我想得太简单，甚至太过理所当然了。理智，真是一个可怕的局。 [二]席间 小号、大鼓敲个不停，那种声音不得不说是一种噪音。良久声止，开始一个个念悼词。 我这时才发现，原来我并没有那么冷漠，缘是城市的喧嚣麻木了我的心。想起那年你的温言软语、慈爱笑容，泪竟是就这样忍不住地从眼眶中溢出了。我撇过头，不愿让人看见，嘴角仍是挂着笑容。 呵呵，我竟觉着在这葬礼上哭泣都是可耻的。望着周围人谈笑风生，我的心有点寒。到场的那么多人，究竟又有几个是真心的呢？可怜，还是可悲啊？ 原来人可以铁石心肠这种程度，可毕竟他们中很多人比我和你的关系更近啊！听着那个花钱雇来哭的人呜咽，看着那人热泪纵横，我终是忍不住苦笑，竟是一个毫不相识的外人哭得最伤心。这是讽刺，还是笑话？ [三]送葬 你说，为什么他们还能那样淡然，可我偏偏忍不住泪流满面？为什么他们那个惊讶的表情让我竟是感到羞愧？好像自己做了什么惊天动地的事一样？ 执着一根香，撒下一碗酒，三拜三叩，泪融于酒，我如若痴人。 照礼我是不必披麻戴孝的，只需戴着那顶白色的帽子即可。沿着幽僻的小路，我跟着吹着小号开路的队伍走在末尾。 风景甚好，埋在那棵大树底下，你会不会成为那树的枝，树的叶？ [四]感怀 死生有命，无可更改。谋事在人，成事在天。任你生前浮华万千，到头来不过一抔尘土，一捧青灰。愿逝者安息，生者恬淡。 有时候我们看不到自己拥有的美好，直到失去才恍然叹息。逝者已矣，页已掀过，惜福、感恩，生活其实温暖如花。 花开半夏，倾尽繁华，愿你回眸半刹。你可听到我在同你夜话？