Difference between revisions of "Team:SYSU-CHINA/js/appjs"

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SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"description-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What is Intrauterine adhesion?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Intrauterine adhesion (IUA) is a common gynecological disease defined by adhesions inside uterine cavity and/or endocervix whereby derives amenorrhea, hypomenorrhea, recurrent pregnancy loss, infertility and history of abnormal placentation"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(". IUA is mainly caused by the wound formed in uterine because of artificial abortion (13,000,000/year in China) and hysteroscopic surgery (1,000,000/year in China). Therefore, IUA is a hyperendemic disease in China, for which our team aims to provide a better therapy this year.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/f/fc/Description-1.png"}})]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are the problems of current therapies?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The current treatment of IUA is hysteroscopic surgery. The doctors use hysteroscopy to directly view the adhesion inside the uterine and break it down with a sharp needle (Touhy needle) or powered instruments (electric surgery or laser) 2. However, surgery is associated with potential damage to the residual endometrium, which lead to the high post-surgical recurrence of the adhesions (3.1% to 23.5%)"),n("sup",[n("a",{attrs:{href:"#reference-3"}},[e._v("3")]),e._v("-"),n("a",{attrs:{href:"#reference-4"}},[e._v("4")])]),e._v(". ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Several methods to prevent IUA reformations after surgery have been proposed, such as intrauterine device (IUD), intrauterine balloon stent, foley catheter and hyaluronic acid barriers"),n("sup",[n("a",{attrs:{href:"#reference-5"}},[e._v("5")])]),e._v(". All these mechanical devices are used to separate the uterine walls physically. Besides, several drugs have been used to improve the regeneration of the endometrium, such as hormonal treatment using estrogens, oestrogen and type 5 specific phosphodiesterase inhibitor"),n("sup",[n("a",{attrs:{href:"#reference-5"}},[e._v("6")])]),e._v(".")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("However, most of these efforts were less effective and in most of the situation, these results were controversial due to diverse treatment schedule, different population and measurement involved. A good idea to improve the effect is to combine the mechanical devices and drugs together to sperate uterine walls and regenerate endometrium simultaneously.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/9/91/Description-2.png",width:"60%"}}),e._v(" "),n("figure",[e._v("From "),n("a",{attrs:{href:"https://www.youtube.com/watch?v=GRHVmYsk7eo"}},[e._v("YouTube")])])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are the advantages of cell therapy?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Cell therapy is an alternative choice for endometrium regeneration because endometrial tissue had an intrinsic capacity of regeneration. Recently a case report of a severe IUA treated with autologous stem cells isolated from a women’s own bone marrow has been reported"),n("sup",[n("a",{attrs:{href:"#reference-7"}},[e._v("7")])]),e._v(". She was treated hysteroscopically for severe IUA and a T-shaped IUD was place inside the uterine for 6 months. After the failure of hormonal therapy, endometrial stem cells were implanted inside the uterine. Then a clinical pregnancy was obtained. These pioneering discoveries infer that cell therapy with stem cells may be a good choice for endometrium regeneration.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Why do we choose BMSCs?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Several sources of stem cells have been proposed for tissue regeneration, and bone marrow mesenchymal stem cells is the most promising cell source of regeneration medicine due to their easy acquisition, self-renewal ability, multi-potential differentiation and weak immunogenicity"),n("sup",[n("a",{attrs:{href:"#reference-8"}},[e._v("8")])]),e._v(".")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Bone marrow mesenchymal stem cells also has some inherent problems, such as low abundance (0.001-0.01%) in bone marrow population, low overall number, decreased differentiation potential with age and the invasive isolation procedures"),n("sup",[n("a",{attrs:{href:"#reference-9"}},[e._v("9")])]),e._v(". These traits make bone marrow mesenchymal stem cells not enough for clinical therapy, therefore, an alternative convenient cell source would be in favor for clinic interest.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Bone marrow stromal cells (BMSCs) are a heterogeneous population of cells that reside in the bone marrow, which contain a small portion of mesenchymal stem cells. BMSCs can be distinguished from hematopoietic cells in bone marrow by plastic adherence, and can also be easily expanded in culture. BMSCs have immune modulatory properties and can induce angiogenesis and tissue repair, which makes them diverse applications in regeneration medicine"),n("sup",[n("a",{attrs:{href:"#reference-10"}},[e._v("10")])]),e._v(".")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("How to support the cells in the therapy?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Considering the low percentage of mesenchymal stem cell in bone marrow, we plan to transplant a high density of BMSCs in the damaged rat uterine to achieve better curative effect on endometrium regeneration. Therefore, an injectable material for BMSC encapsulation is urgently required for supporting the cells in the therapy. ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Pluronic F-127 (PF-127) is a synthetic FDA-approved compound, which has several therapeutic advantages including low-toxicity, biocompatibility, and thermo-reversibility"),n("sup",[n("a",{attrs:{href:"#reference-11"}},[e._v("11")]),e._v("-"),n("a",{attrs:{href:"#reference-12"}},[e._v("12")])]),e._v(". Moderately concentrated solution of PF-127 in aqueous media (15-30%, w/w) is liquid at room temperature, but could form hydrogel at physiological temperatures. Hence, PF-127 is widely used in drug delivery and in vivo tissue engineering. Growing evidences have suggested that PF-127 might be a suitable scaffold for cell therapy of BMSCs. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel approach of treating IUA with bone marrow stem cells (BMSCs) as a chassis. We engineered BMSCs by inserting a growth factor overexpressing circuit to promote wound healing in the uterus. To stick our engineered BMSCs (eBMSCs) to the wound in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix to form a “stem cell woundplast”.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(34);var i=n(14)(n(36),n(37),"data-v-18f10f7d",null);e.exports=i.exports},function(e,t,n){var i=n(35);"string"==typeof i&&(i=[[e.id,i,""]]),i.locals&&(e.exports=i.locals);n(12)("543365e3",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#design img[data-v-18f10f7d]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"design"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"design-header"}},[n("p",{staticClass:"page-title"},[e._v("Design")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"design-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel treatment for Intrauterine adhesion (IUA) with bone marrow stem cells (BMSCs) as a chassis. We engineered BMSCs by inserting a growth factor overexpressing circuit to promote wound healing in the uterus. To target our engineered BMSCs (eBMSCs) to the wounds in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix (imagine cells on a woundplast). Additionally, we also added Vitamin C (Vc) to enhance wound healing. What’s more, PF-127 can be poisonous to eBMSCs and Vc can also support eBMSCs. The optimal concentration of PF-127 and Vc was determined with orthogonal experiment and the aid of mathematical models.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we chose rat BMSCs as the chassis. Because growth factors have been shown to improve wound healing, so we engineered BMSCs to overexpress various growth factors for AS treatment. The growth factors were expressed constitutively with a strong cmv promoter, fused with eGFP and 3xFLAG.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("The circuits")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Chronic wounds may suffer from hypoxia and impaired vascularity, which is absolutely not good for healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(". Angiogenic growth factors can stimulate dysfunctional components in chronic healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we chose them as our primary therapeutic components in our Stem Cell Woundplast. We engineered the growth factor genes downstream of CMV promoter, making it constitutively expressed in most eukaryotic cells. Additionally, we fused the gene with an eGFP and 3xFLAG to track and test the protein expression with microscopy or Western blot.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/4/41/Design-1.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("VEGF"),n("sub",[e._v("121")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vascular endothelial growth factor (VEGF) is secreted by many types of cells that naturally participated in wound healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we believe it would be safe and efficient to overexpress it in our eBMSCs. VEGF is unique compared to other growth factors, for it functions on various components of the wound healing cascade"),n("sup",[n("a",{attrs:{href:"#reference-2"}},[e._v("2")])]),e._v(". There are five isoforms of VEGF, the chain lengths of which are 121, 145, 165, 189, and 206 amino acids, respectfully"),n("sup",[n("a",{attrs:{href:"#reference-3"}},[e._v("3")])]),e._v(". VEGF121 is freely secreted outward of the cell. In this case, the VEGF121 molecules are secreted into the PF-127 supporting matrix and diffuse to uterus epithelial, so it is the best choice for our eBMSCs.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("bFGF")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another choice is basic fibroblast growth factor (bFGF). bFGF may be an initiator in angiogenesis"),n("sup",[n("a",{attrs:{href:"#reference-4"}},[e._v("4")])]),e._v(" and is activated by sulfate-degrading enzymes. It may also induce VEGF expression. More importantly, bFGF is necessary to keep BMSCs undifferentiated, making our therapy safer and more controllable. Thus, bFGF is an indispensable component of our Woundplast.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("PDGFA")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Prior studies show that adding Platelet-derived growth factor (PDGF) directly to experimentally designed wounds enhances wound healing"),n("sup",[n("a",{attrs:{href:"#reference-5"}},[e._v("5")])]),e._v(". So, we also included it in our Woundplast together with VEGF121 and bFGF.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Promoter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We designed a combination of three promoters and three growth factors and were planning to characterize their expression one by one. The three promoters are CMV promoter (BBa_K404102), EF1a promoter and Ubc promoter. All of them are constitutively-expressed. CMV promoter can be used in most mammalian cells and allows adaptability in transient or stable expression, cytoplasmic expression or secretion. EF1a can be used in most cell types, and the expression level of is stable. Ubc, as the name suggests, is quite ubiquitous in mammals.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/2/2d/Design-2.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("eGFP and 3xFLAG Dual Reporter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("It would be of vital importance to visualize and track the expression of the parts, so we fused the growth factor genes with a eGFP gene and a 3xFLAG and constructed a dual reporter. The eGFP allows us to track the expression of the growth factors during the whole experiments including transfection, lentivirus production and infection. The 3xFLAG makes it easier to purify and detect the expression of the growth factors.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vitamin C to promote wound healing and eBMSC vitality")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vitamin C (Vc), also called ascorbid acid (AA), is a crucial antioxidant"),n("sup",[e._v("6")]),e._v(". More importantly, it is involved in all phases of wound healing"),n("sup",[e._v("7")]),e._v(". Thus, we added it to the PF-127 gel to enhance wound healing in combination with other growth factors. Besides, PF-127 can be poisonous to cells. Thus, eBMSCs located in the uterus with PF-127 matrix are prone to apoptosis and cell death. Vc is also able to promote cells from apoptosis and death. However, Vc is acidic, and a low pH is not good for cell growth. Thus, we conducted an orthogonal experiment with PF-127 concentration and Vc concentration gradients to find the optimal condition. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(39);var i=n(14)(n(41),n(42),"data-v-1ea89e47",null);e.exports=i.exports},function(e,t,n){var i=n(40);"string"==typeof i&&(i=[[e.id,i,""]]),i.locals&&(e.exports=i.locals);n(12)("4ba9c3c2",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#results img[data-v-1ea89e47]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"results"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"results-header"}},[n("p",{staticClass:"page-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"results-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Gel Formation Analysis of PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Before all the experiments on cells, we want to find the lowest concentration needed for PF-127 to form gel at 37℃ but not at room temperature. PF-127 has cytotoxicity (although low), so a lowest concentration is a better choice for application. Besides, if PF-127 at a concentration can only form at 37℃ but not at room temperature, it would be more convenient for us to apply it for clinical use.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We dissolved PF-127 in DMEM/F12 at 4℃ overnight to prepare 40% (w/v) solution, then filter the solution through a 0.45 μM filter and finally kept at 4℃ for use. Then we dissolved 40% (w/v) PF-127 into 5% (w/v), 10% (w/v), 15% (w/v), 20% (w/v), 25% (w/v), 30% (w/v), 35% (w/v), 40% (w/v). Separate each 100μl into 1.5ml EP tube. These tubes were kept at room temperature and at 37℃ for 2min, 5min, 10min. Then we test whether PF-127 form gel by put the tube upside down.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("According to the formation analysis result, PF-127 cannot form gel at 4℃. At 25℃, 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min and 25% (w/v) PF-127 can form gel in 10min. At 37℃, 40% (w/v) PF-127 can form gel in 2min. 25% (w/v), 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min at 37℃. Importantly, 20% (w/v) PF-127 can form gel at 37℃ in 10min, but not form gel at room temperature (Figure 1). Therefore, we came up with a conclusion that 20% (w/v) is the concentration we wanted to find.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/b/b0/Results-1.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 1. Gel formation analysis of PF-127.")]),e._v(" "),n("p",{
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She was treated hysteroscopically for severe IUA and a T-shaped IUD was placed inside the uterine for 6 months. After the failure of hormonal therapy, endometrial stem cells were implanted inside the uterine. Then a clinical pregnancy was obtained. 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")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Pluronic F-127 (PF-127) is a synthetic FDA-approved compound, which has several therapeutic advantages including low-toxicity, biocompatibility, and thermo-reversibility"),n("sup",[n("a",{attrs:{href:"#reference-11"}},[e._v("11")]),e._v("-"),n("a",{attrs:{href:"#reference-12"}},[e._v("12")])]),e._v(". Moderately concentrated solution of PF-127 in aqueous media (15-30%, w/w) is liquid at room temperature, but could form hydrogel at physiological temperatures. Hence, PF-127 is widely used in drug delivery and in vivo tissue engineering. Growing evidences have suggested that PF-127 might be a suitable scaffold for cell therapy of BMSCs. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel approach of treating IUA with bone marrow stem cells (BMSCs) as a chassis. 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To stick our engineered BMSCs (eBMSCs) to the wound in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix to form a “stem cell woundplast”.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(34);var i=n(14)(n(36),n(37),"data-v-18f10f7d",null);e.exports=i.exports},function(e,t,n){var i=n(35);"string"==typeof i&&(i=[[e.id,i,""]]),i.locals&&(e.exports=i.locals);n(12)("543365e3",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#design img[data-v-18f10f7d]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"design"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"design-header"}},[n("p",{staticClass:"page-title"},[e._v("Design")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"design-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel treatment for Intrauterine adhesion (IUA) with bone marrow stem cells (BMSCs) as a chassis. We engineered BMSCs by inserting a growth factor overexpressing circuit to promote wound healing in the uterus. To target our engineered BMSCs (eBMSCs) to the wounds in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix (imagine cells on a woundplast). Additionally, we also added Vitamin C (Vc) to enhance wound healing. What’s more, PF-127 can be poisonous to eBMSCs and Vc can also support eBMSCs. The optimal concentration of PF-127 and Vc was determined with orthogonal experiment and the aid of mathematical models.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we chose rat BMSCs as the chassis. Because growth factors have been shown to improve wound healing, so we engineered BMSCs to overexpress various growth factors for AS treatment. The growth factors were expressed constitutively with a strong cmv promoter, fused with eGFP and 3xFLAG.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("The circuits")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Chronic wounds may suffer from hypoxia and impaired vascularity, which is absolutely not good for healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(". Angiogenic growth factors can stimulate dysfunctional components in chronic healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we chose them as our primary therapeutic components in our Stem Cell Woundplast. We engineered the growth factor genes downstream of CMV promoter, making it constitutively expressed in most eukaryotic cells. Additionally, we fused the gene with an eGFP and 3xFLAG to track and test the protein expression with microscopy or Western blot.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/4/41/Design-1.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("VEGF"),n("sub",[e._v("121")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vascular endothelial growth factor (VEGF) is secreted by many types of cells that naturally participated in wound healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we believe it would be safe and efficient to overexpress it in our eBMSCs. VEGF is unique compared to other growth factors, for it functions on various components of the wound healing cascade"),n("sup",[n("a",{attrs:{href:"#reference-2"}},[e._v("2")])]),e._v(". There are five isoforms of VEGF, the chain lengths of which are 121, 145, 165, 189, and 206 amino acids, respectfully"),n("sup",[n("a",{attrs:{href:"#reference-3"}},[e._v("3")])]),e._v(". VEGF121 is freely secreted outward of the cell. In this case, the VEGF121 molecules are secreted into the PF-127 supporting matrix and diffuse to uterus epithelial, so it is the best choice for our eBMSCs.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("bFGF")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another choice is basic fibroblast growth factor (bFGF). bFGF may be an initiator in angiogenesis"),n("sup",[n("a",{attrs:{href:"#reference-4"}},[e._v("4")])]),e._v(" and is activated by sulfate-degrading enzymes. It may also induce VEGF expression. More importantly, bFGF is necessary to keep BMSCs undifferentiated, making our therapy safer and more controllable. Thus, bFGF is an indispensable component of our Woundplast.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("PDGFA")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Prior studies show that adding Platelet-derived growth factor (PDGF) directly to experimentally designed wounds enhances wound healing"),n("sup",[n("a",{attrs:{href:"#reference-5"}},[e._v("5")])]),e._v(". So, we also included it in our Woundplast together with VEGF121 and bFGF.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Promoter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We designed a combination of three promoters and three growth factors and were planning to characterize their expression one by one. The three promoters are CMV promoter (BBa_K404102), EF1a promoter and Ubc promoter. All of them are constitutively-expressed. CMV promoter can be used in most mammalian cells and allows adaptability in transient or stable expression, cytoplasmic expression or secretion. EF1a can be used in most cell types, and the expression level of is stable. Ubc, as the name suggests, is quite ubiquitous in mammals.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/2/2d/Design-2.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("eGFP and 3xFLAG Dual Reporter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("It would be of vital importance to visualize and track the expression of the parts, so we fused the growth factor genes with a eGFP gene and a 3xFLAG and constructed a dual reporter. The eGFP allows us to track the expression of the growth factors during the whole experiments including transfection, lentivirus production and infection. The 3xFLAG makes it easier to purify and detect the expression of the growth factors.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vitamin C to promote wound healing and eBMSC vitality")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vitamin C (Vc), also called ascorbid acid (AA), is a crucial antioxidant"),n("sup",[e._v("6")]),e._v(". More importantly, it is involved in all phases of wound healing"),n("sup",[e._v("7")]),e._v(". Thus, we added it to the PF-127 gel to enhance wound healing in combination with other growth factors. Besides, PF-127 can be poisonous to cells. Thus, eBMSCs located in the uterus with PF-127 matrix are prone to apoptosis and cell death. Vc is also able to promote cells from apoptosis and death. However, Vc is acidic, and a low pH is not good for cell growth. Thus, we conducted an orthogonal experiment with PF-127 concentration and Vc concentration gradients to find the optimal condition. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(39);var i=n(14)(n(41),n(42),"data-v-1ea89e47",null);e.exports=i.exports},function(e,t,n){var i=n(40);"string"==typeof i&&(i=[[e.id,i,""]]),i.locals&&(e.exports=i.locals);n(12)("4ba9c3c2",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#results img[data-v-1ea89e47]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"results"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"results-header"}},[n("p",{staticClass:"page-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"results-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Gel Formation Analysis of PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Before all the experiments on cells, we want to find the lowest concentration needed for PF-127 to form gel at 37℃ but not at room temperature. PF-127 has cytotoxicity (although low), so a lowest concentration is a better choice for application. Besides, if PF-127 at a concentration can only form at 37℃ but not at room temperature, it would be more convenient for us to apply it for clinical use.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We dissolved PF-127 in DMEM/F12 at 4℃ overnight to prepare 40% (w/v) solution, then filter the solution through a 0.45 μM filter and finally kept at 4℃ for use. Then we dissolved 40% (w/v) PF-127 into 5% (w/v), 10% (w/v), 15% (w/v), 20% (w/v), 25% (w/v), 30% (w/v), 35% (w/v), 40% (w/v). Separate each 100μl into 1.5ml EP tube. These tubes were kept at room temperature and at 37℃ for 2min, 5min, 10min. Then we test whether PF-127 form gel by put the tube upside down.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("According to the formation analysis result, PF-127 cannot form gel at 4℃. At 25℃, 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min and 25% (w/v) PF-127 can form gel in 10min. At 37℃, 40% (w/v) PF-127 can form gel in 2min. 25% (w/v), 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min at 37℃. Importantly, 20% (w/v) PF-127 can form gel at 37℃ in 10min, but not form gel at room temperature (Figure 1). Therefore, we came up with a conclusion that 20% (w/v) is the concentration we wanted to find.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/b/b0/Results-1.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 1. Gel formation analysis of PF-127.")]),e._v(" "),n("p",{
 
staticClass:"card-subheader"},[e._v("Preparation of BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we isolated BMSCs from rats with flow cytometry. There are two main types of cells in bone marrow: stromal cells and hematopoietic cells, so we need to isolate stromal cells for future use.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We isolated BMSCs according to a modified protocol from previous work . Briefly, eight-week old female Sprague-Dawley rats were sacrificed by intraperitoneal injecting 50% chloral hydrate solution, and were then sterilized in 75% ethanol. The femurs and tibiae were collected and bone marrow stromal cells were flushed out using DMEM/F12 medium. The suspended cells were centrifuged at 200 g for 5 minutes, and then seeded in DMEM/F12 media with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin and were incubated at 37℃ with 5% CO2. 2 days later, the non-adherent cells were removed and the culture medium was changed every 3 days.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To confirm we isolated BMSCs successfully, we analyzed the cells with flow cytometry. We used CD34 and CD45 as the markers, both of which are typical of hematopoietic cells. As the figure below shows, the majority of the isolated cells were CD34 and CD45 negative, demonstrating they are indeed stromal cells (Figure 2A). The morphology of BMSCs under light microscope was shown on the right panel (Figure 2B).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/8/89/Results-2.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 2. Isolation of BMSCs.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Based on our design, we chose CMV promoter for future experiments. CMV promoter is widely used in almost all types of mammalian cells and allows for high-level constitutive expression. We used quantitative reverse-transcription PCR (qRT-PCR) to demonstrate on the RNA level.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("On day 1, HEK293T cells were transfected with psPAX2, pMD2.G and our overexpression vector for lentivirus production. BMSCs were plated on 6-well plates on day 2. From day 3, lentivirus particles were harvested every 2 days. The BMSCs were infected for two times. Then, we used 1 μg/mL of puromycin to screen for stably-transfected BMSCs. ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We analyzed growth factor overexpression with qRT-PCR.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("qRT-PCR analysis demonstrated that we successfully overexpressed bFGF and VEGF121 in BMSCs (Figure 3). ")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5a/Results-3.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 3. qRT-PCR analysis result of BMSCs overexpressing bFGF and VEGF121.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Establishing rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test the efficacy of our Woundplast in vivo, we establish a rat model, for no model was developed by others before. The model was evaluated by Hematoxylin-eosin (H&E) staining, Masson staining, measuring endometrial glands number and by calculating percentage of endometrial fibrotic area in rats’ uterine.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The whole procedure of establishing IUA rat model is shown in Figure 4.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5a/Results-4.png"}}),e._v(" "),n("figure",[e._v("Figure 4. Procedure of establishing rat IUA model.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate (300 mg/kg), and a vertical incision was made at low abdomen to expose uterine horns. The uterine wall of approximately 0.2 cm was excised 0.5 cm from the left uterine horn, and then mechanical damage of the upper 1.5-2.0 cm endometrium was generated with the spoon scratching, until the inner membrane gave a rough feeling. Finally, the rectus fascia and skin were sealed with a 4-0 nylon suture.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the sham control rats, the glands were uniformly distributed in the surface of uterine endometrial cavity, and collagen fibers were barely observed by Masson staining. Histologic evaluation of the IUA uterine revealed that there was a significant decrease of number of glands in the IUA uterine cavities compared with the sham counterparts (Figure 5A). By contrast, the fibrotic area in the IUA uterine was significantly increased by Masson staining (Figure 5B).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/0/06/Results-5.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 5. Analysis of gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Together, these results showed that mechanical damage leads to severe intrauterine abnormality, suggesting a successful establishment of rat IUA model.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Demonstrate")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Cell migration and proliferation are two main aspects in wound healing. To demonstrate that our Woundplast indeed accelerated wound healing in vitro, we designed wound healing assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay to evaluate cell migration and proliferation, respectfully. Furthermore, we used AS rat model to validate previous achievements in "),n("em",[e._v("vivo")]),e._v(".")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vc enhanced BMSC survival in PF-127 in "),n("em",[e._v("vitro")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test if adding Vc to BMSCs indeed promoted BMSC survival rate, we analyzed BMSC apoptosis rate and proliferation with flow cytometry and CCK-8 growth test.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Annexin V-FITC/PI apoptosis detection assay was carried under manufacturer’s instructions to evaluate cellular apoptosis according to. Briefly, BMSCs were seeded with different encapsulation conditions for 3 days and 7 days, the cells were trypsinized and suspended in binding buffer, labeled with 5 μL Annexin V-FITC and 5 μL PI for 15 minutes in the dark on ice. Then, 300 μL binding buffer was added to each sample and the cells were evaluated by flow cytometer. Positive control was carried out using 100 μM H2O2 treated for 15 min.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For CCK-8 growth test, the BMSCs were seeded with different encapsulation conditions. Cell growth of the 3rd day and 7th day after seeding were tested by adding 10% CCK to each well and incubated for 2 hours before measuring the absorbance at 450 nm using a microplate reader.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the early stage, there was a short period of survival enhancement (68.3% versus 51.2%) in PF-127 encapsulation on the first day after seeding. However, after 3 days of culture, majority stromal cells encapsulated in PF-127 started undergoing apoptosis (43.6% versus 62.9%). After 7 days of culture, majority of cells encapsulated in PF-127 with no addition of Vc underwent apoptosis (44.8% versus 77.3%) and detached due to PF-127 cytotoxicity. However, Vc significantly improved in vitro cell attachment at 7 days, while adding 50 μM Vc showed better effect than 100 μM.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/6/62/Results-6.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 6. Flow cytometry analysis of BMSCs apoptosis rate in PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("CCK test also showed that cells encapsulated in PF-127 supplemented with 50 μM Vc proliferated faster in a long term of 7 days culture (Figure 2D), indicating that 50 μM Vc improved cell viability.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/f/fb/Results-7.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 7. CCK-8 growth test of BMSCs with Vc in PF-127")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs promoted wound healing and cell migration")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In order to demonstrate that the Woundplast indeed promote wound healing, we conducted the wound healing assay, which is a typical way of testing wound healing ability in vitro. Artificial wounds were created and treated with supernatants from cultured eBMSCs. Then, we calculated wound healing percentage and migration velocity.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("HEK293T cells were plated on a 6-well plate. 24 h later, artificial wounds were created by scraping the cell monolayer with a 10 μL pipette tip. Debris were washed with PBS buffer. Because the growth factors are supposed to be secreted from the cell, culture supernatants from eBMSCs were then added. Images were acquired with microscopy.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we calculated wound healing percentage after 24 h. The detailed procedures are as follow (Figure 8).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/4/4e/Results-8.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 8. Procedure of wound healing assay data analysis")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The first step was to load the image. Then the image was processed by enhancing contrast, finding edges and adjusting threshold. Finally, the healing area was measured and calculated.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For measurement of cell migration velocity, we rationalized that only movements perpendicular to the wound matter in healing. So, cells were marked manually and the distance between their original sites (estimated) and migrated sites after 24 h were measured.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To measure cell migration velocity rate, the wound at 0 h was marked with dashed red line and the position of 20 cells after 24 h of migration was circled (Figure 9). The distance was measured and velocity was calculated as μM/min.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5c/Results-9.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 9. Methods of measuring cell migration distance")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("As we expected, the wounds treated with eBMSC supernatant showed a significant higher wound healing percentage compared to control group (CTR). Additionally, cells treated with bFGF presented a higher wound healing percentage compared to VEGF121(Figure 10A).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/3/3e/Results-10.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 10. Results of wound healing assay and cell migration velocity.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In terms of migration velocity, the control group migrated at the speed of xx averagely, while bFGF and VEGF121 migrated at about 0.49 μm/min and 0.80 μm/min, respectively (Figure 10B). ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The results demonstrated that eBMSCs successfully expressed and secreted growth factors to the culture media. The secreted growth factors significantly promoted wound healing and cell migration. ")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs enhanced human uterine epithelial proliferation")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another important aspect of wound healing is cell proliferation. We conducted MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to further investigate how our Woundplast would affect human uterus epithelial cell proliferation. MTT assay is a common-used colorimetric assay for measuring cell proliferation. NAD(P)H-dependent cellular oxidoreductase enzymes are capable of reducing the tetrazolium dye MTT to formazan, an insoluble purple substance. Formazan is soluble in DMSO, so the quantity can then be measured by absorbance.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Human uterine epithelial cells were plated on a 96-well plate with five replicates in each group. 1 day later, supernatants from corresponding eBMSC group were added. The cells were then incubated for another two days. MTT assay was conducted following instructions from manufactures. ")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Culture supernatants from eBMSCs overexpressing bFGF and VEGF121 significantly enhances human uterine epithelial proliferation. Notably, bFGF in combination with VEGF121 showed the greatest proliferation rate (Figure 11). This is consistent with previous findings that bFGF and VEGF121 work together during wound healing.  ")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/a/ab/Results-11.png",width:"40%"}}),e._v(" "),n("figure",[e._v("Figure 11. Results of MTT human uterine epithelial cell proliferation assay")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("PF-127 encapsulated BMSCs restored gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We used rat model to test if BMSCs cures IUA in vivo. Because of time, we used WT BMSCs instead of our BMSCs in this part.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In order to test whether BMSCs encapsulated with PF-127 and Vc would improve IUA recovery in vivo, the IUA rat model was transplanted with BMSCs encapsulated in PF-127 supplemented with 50 μM Vc (BMSCs/PF-127/Vc) on the left uterine immediately after IUA establishment. In addition to IUA control group, injured rats were also injected with BMSCs plus 50 μM Vc (BMSCs/Vc) or only with PF-127 plus 50 μM Vc (PF-127/Vc) as strict control. Two weeks after the transplantation, rats were sacrificed for histopathological analysis. ")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("H&E staining showed that IUA rat uterine in BMSCs/PF-127/Vc group recovered best, as the number of glands were very similar to the sham group. 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The suspended cells were centrifuged at 200 g for 5 minutes, and then seeded in DMEM/F12 media with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin and were incubated at 37℃ with 5% CO2. 2 days later, the non-adherent cells were removed and the culture medium was changed every 3 days.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To confirm we isolated BMSCs successfully, we analyzed the cells with flow cytometry. We used CD34 and CD45 as the markers, both of which are typical of hematopoietic cells. As the figure below shows, the majority of the isolated cells were CD34 and CD45 negative, demonstrating they are indeed stromal cells (Figure 2A). The morphology of BMSCs under light microscope was shown on the right panel (Figure 2B).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/8/89/Results-2.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 2. Isolation of BMSCs.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Based on our design, we chose CMV promoter for future experiments. CMV promoter is widely used in almost all types of mammalian cells and allows for high-level constitutive expression. We used quantitative reverse-transcription PCR (qRT-PCR) to demonstrate on the RNA level.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("On day 1, HEK293T cells were transfected with psPAX2, pMD2.G and our overexpression vector for lentivirus production. BMSCs were plated on 6-well plates on day 2. From day 3, lentivirus particles were harvested every 2 days. The BMSCs were infected for two times. Then, we used 1 μg/mL of puromycin to screen for stably-transfected BMSCs. ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We analyzed growth factor overexpression with qRT-PCR.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("qRT-PCR analysis demonstrated that we successfully overexpressed bFGF and VEGF121 in BMSCs (Figure 3). ")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5a/Results-3.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 3. qRT-PCR analysis result of BMSCs overexpressing bFGF and VEGF121.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Establishing rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test the efficacy of our Woundplast in vivo, we establish a rat model, for no model was developed by others before. The model was evaluated by Hematoxylin-eosin (H&E) staining, Masson staining, measuring endometrial glands number and by calculating percentage of endometrial fibrotic area in rats’ uterine.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The whole procedure of establishing IUA rat model is shown in Figure 4.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5a/Results-4.png"}}),e._v(" "),n("figure",[e._v("Figure 4. Procedure of establishing rat IUA model.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate (300 mg/kg), and a vertical incision was made at low abdomen to expose uterine horns. The uterine wall of approximately 0.2 cm was excised 0.5 cm from the left uterine horn, and then mechanical damage of the upper 1.5-2.0 cm endometrium was generated with the spoon scratching, until the inner membrane gave a rough feeling. Finally, the rectus fascia and skin were sealed with a 4-0 nylon suture.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the sham control rats, the glands were uniformly distributed in the surface of uterine endometrial cavity, and collagen fibers were barely observed by Masson staining. Histologic evaluation of the IUA uterine revealed that there was a significant decrease of number of glands in the IUA uterine cavities compared with the sham counterparts (Figure 5A). By contrast, the fibrotic area in the IUA uterine was significantly increased by Masson staining (Figure 5B).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/0/06/Results-5.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 5. Analysis of gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Together, these results showed that mechanical damage leads to severe intrauterine abnormality, suggesting a successful establishment of rat IUA model.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Demonstrate")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Cell migration and proliferation are two main aspects in wound healing. To demonstrate that our Woundplast indeed accelerated wound healing in vitro, we designed wound healing assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay to evaluate cell migration and proliferation, respectfully. Furthermore, we used AS rat model to validate previous achievements in "),n("em",[e._v("vivo")]),e._v(".")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vc enhanced BMSC survival in PF-127 in "),n("em",[e._v("vitro")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test if adding Vc to BMSCs indeed promoted BMSC survival rate, we analyzed BMSC apoptosis rate and proliferation with flow cytometry and CCK-8 growth test.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Annexin V-FITC/PI apoptosis detection assay was carried under manufacturer’s instructions to evaluate cellular apoptosis according to. Briefly, BMSCs were seeded with different encapsulation conditions for 3 days and 7 days, the cells were trypsinized and suspended in binding buffer, labeled with 5 μL Annexin V-FITC and 5 μL PI for 15 minutes in the dark on ice. Then, 300 μL binding buffer was added to each sample and the cells were evaluated by flow cytometer. Positive control was carried out using 100 μM H2O2 treated for 15 min.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For CCK-8 growth test, the BMSCs were seeded with different encapsulation conditions. Cell growth of the 3rd day and 7th day after seeding were tested by adding 10% CCK to each well and incubated for 2 hours before measuring the absorbance at 450 nm using a microplate reader.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the early stage, there was a short period of survival enhancement (68.3% versus 51.2%) in PF-127 encapsulation on the first day after seeding. However, after 3 days of culture, majority stromal cells encapsulated in PF-127 started undergoing apoptosis (43.6% versus 62.9%). After 7 days of culture, majority of cells encapsulated in PF-127 with no addition of Vc underwent apoptosis (44.8% versus 77.3%) and detached due to PF-127 cytotoxicity. However, Vc significantly improved in vitro cell attachment at 7 days, while adding 50 μM Vc showed better effect than 100 μM.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/6/62/Results-6.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 6. Flow cytometry analysis of BMSCs apoptosis rate in PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("CCK test also showed that cells encapsulated in PF-127 supplemented with 50 μM Vc proliferated faster in a long term of 7 days culture (Figure 2D), indicating that 50 μM Vc improved cell viability.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/f/fb/Results-7.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 7. CCK-8 growth test of BMSCs with Vc in PF-127")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs promoted wound healing and cell migration")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In order to demonstrate that the Woundplast indeed promote wound healing, we conducted the wound healing assay, which is a typical way of testing wound healing ability in vitro. Artificial wounds were created and treated with supernatants from cultured eBMSCs. Then, we calculated wound healing percentage and migration velocity.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("HEK293T cells were plated on a 6-well plate. 24 h later, artificial wounds were created by scraping the cell monolayer with a 10 μL pipette tip. Debris were washed with PBS buffer. Because the growth factors are supposed to be secreted from the cell, culture supernatants from eBMSCs were then added. Images were acquired with microscopy.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we calculated wound healing percentage after 24 h. The detailed procedures are as follow (Figure 8).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/4/4e/Results-8.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 8. Procedure of wound healing assay data analysis")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The first step was to load the image. Then the image was processed by enhancing contrast, finding edges and adjusting threshold. Finally, the healing area was measured and calculated.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For measurement of cell migration velocity, we rationalized that only movements perpendicular to the wound matter in healing. So, cells were marked manually and the distance between their original sites (estimated) and migrated sites after 24 h were measured.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To measure cell migration velocity rate, the wound at 0 h was marked with dashed red line and the position of 20 cells after 24 h of migration was circled (Figure 9). The distance was measured and velocity was calculated as μM/min.")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/5/5c/Results-9.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 9. Methods of measuring cell migration distance")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("As we expected, the wounds treated with eBMSC supernatant showed a significant higher wound healing percentage compared to control group (CTR). Additionally, cells treated with bFGF presented a higher wound healing percentage compared to VEGF121(Figure 10A).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/3/3e/Results-10.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 10. Results of wound healing assay and cell migration velocity.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In terms of migration velocity, the control group migrated at the speed of xx averagely, while bFGF and VEGF121 migrated at about 0.49 μm/min and 0.80 μm/min, respectively (Figure 10B). ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The results demonstrated that eBMSCs successfully expressed and secreted growth factors to the culture media. The secreted growth factors significantly promoted wound healing and cell migration. ")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs enhanced human uterine epithelial proliferation")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another important aspect of wound healing is cell proliferation. We conducted MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to further investigate how our Woundplast would affect human uterus epithelial cell proliferation. MTT assay is a common-used colorimetric assay for measuring cell proliferation. NAD(P)H-dependent cellular oxidoreductase enzymes are capable of reducing the tetrazolium dye MTT to formazan, an insoluble purple substance. Formazan is soluble in DMSO, so the quantity can then be measured by absorbance.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Human uterine epithelial cells were plated on a 96-well plate with five replicates in each group. 1 day later, supernatants from corresponding eBMSC group were added. The cells were then incubated for another two days. MTT assay was conducted following instructions from manufactures. ")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Culture supernatants from eBMSCs overexpressing bFGF and VEGF121 significantly enhances human uterine epithelial proliferation. Notably, bFGF in combination with VEGF121 showed the greatest proliferation rate (Figure 11). This is consistent with previous findings that bFGF and VEGF121 work together during wound healing.  ")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/a/ab/Results-11.png",width:"40%"}}),e._v(" "),n("figure",[e._v("Figure 11. Results of MTT human uterine epithelial cell proliferation assay")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("PF-127 encapsulated BMSCs restored gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We used rat model to test if BMSCs cures IUA in vivo. Because of time, we used WT BMSCs instead of our BMSCs in this part.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In order to test whether BMSCs encapsulated with PF-127 and Vc would improve IUA recovery in vivo, the IUA rat model was transplanted with BMSCs encapsulated in PF-127 supplemented with 50 μM Vc (BMSCs/PF-127/Vc) on the left uterine immediately after IUA establishment. In addition to IUA control group, injured rats were also injected with BMSCs plus 50 μM Vc (BMSCs/Vc) or only with PF-127 plus 50 μM Vc (PF-127/Vc) as strict control. Two weeks after the transplantation, rats were sacrificed for histopathological analysis. ")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("H&E staining showed that IUA rat uterine in BMSCs/PF-127/Vc group recovered best, as the number of glands were very similar to the sham group. On the contrary, the number of glands in the BMSCs/Vc group were partially rescued, but is significantly less satisfactory without the hydrogel encapsulation. For the PF-127/Vc group without BMSCs, there was no rescue effect at all (Figure 12A).")]),e._v(" "),n("img",{attrs:{src:"https://static.igem.org/mediawiki/2017/3/3b/Results-12.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 12. 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Revision as of 10:34, 1 November 2017

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")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Pluronic F-127 (PF-127) is a synthetic FDA-approved compound, which has several therapeutic advantages including low-toxicity, biocompatibility, and thermo-reversibility"),n("sup",[n("a",{attrs:{href:"#reference-11"}},[e._v("11")]),e._v("-"),n("a",{attrs:{href:"#reference-12"}},[e._v("12")])]),e._v(". Moderately concentrated solution of PF-127 in aqueous media (15-30%, w/w) is liquid at room temperature, but could form hydrogel at physiological temperatures. Hence, PF-127 is widely used in drug delivery and in vivo tissue engineering. Growing evidences have suggested that PF-127 might be a suitable scaffold for cell therapy of BMSCs. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel approach of treating IUA with bone marrow stem cells (BMSCs) as a chassis. We engineered BMSCs by inserting a growth factor overexpressing circuit to promote wound healing in the uterus. To stick our engineered BMSCs (eBMSCs) to the wound in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix to form a “stem cell woundplast”.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(34);var i=n(14)(n(36),n(37),"data-v-18f10f7d",null);e.exports=i.exports},function(e,t,n){var i=n(35);"string"==typeof i&&(i=e.id,i,""),i.locals&&(e.exports=i.locals);n(12)("543365e3",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#design img[data-v-18f10f7d]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"design"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"design-header"}},[n("p",{staticClass:"page-title"},[e._v("Design")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"design-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("What are we doing?")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("This year, we came up a novel treatment for Intrauterine adhesion (IUA) with bone marrow stem cells (BMSCs) as a chassis. We engineered BMSCs by inserting a growth factor overexpressing circuit to promote wound healing in the uterus. To target our engineered BMSCs (eBMSCs) to the wounds in the uterus, we used the FDA-approved Pluronic F-127 (PF-127) gel as supporting matrix (imagine cells on a woundplast). Additionally, we also added Vitamin C (Vc) to enhance wound healing. What’s more, PF-127 can be poisonous to eBMSCs and Vc can also support eBMSCs. The optimal concentration of PF-127 and Vc was determined with orthogonal experiment and the aid of mathematical models.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we chose rat BMSCs as the chassis. Because growth factors have been shown to improve wound healing, so we engineered BMSCs to overexpress various growth factors for AS treatment. The growth factors were expressed constitutively with a strong cmv promoter, fused with eGFP and 3xFLAG.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("The circuits")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Chronic wounds may suffer from hypoxia and impaired vascularity, which is absolutely not good for healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(". Angiogenic growth factors can stimulate dysfunctional components in chronic healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we chose them as our primary therapeutic components in our Stem Cell Woundplast. We engineered the growth factor genes downstream of CMV promoter, making it constitutively expressed in most eukaryotic cells. Additionally, we fused the gene with an eGFP and 3xFLAG to track and test the protein expression with microscopy or Western blot.")]),e._v(" "),n("img",{attrs:{src:"Design-1.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("VEGF"),n("sub",[e._v("121")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vascular endothelial growth factor (VEGF) is secreted by many types of cells that naturally participated in wound healing"),n("sup",[n("a",{attrs:{href:"#reference-1"}},[e._v("1")])]),e._v(", so we believe it would be safe and efficient to overexpress it in our eBMSCs. VEGF is unique compared to other growth factors, for it functions on various components of the wound healing cascade"),n("sup",[n("a",{attrs:{href:"#reference-2"}},[e._v("2")])]),e._v(". There are five isoforms of VEGF, the chain lengths of which are 121, 145, 165, 189, and 206 amino acids, respectfully"),n("sup",[n("a",{attrs:{href:"#reference-3"}},[e._v("3")])]),e._v(". VEGF121 is freely secreted outward of the cell. In this case, the VEGF121 molecules are secreted into the PF-127 supporting matrix and diffuse to uterus epithelial, so it is the best choice for our eBMSCs.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("bFGF")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another choice is basic fibroblast growth factor (bFGF). bFGF may be an initiator in angiogenesis"),n("sup",[n("a",{attrs:{href:"#reference-4"}},[e._v("4")])]),e._v(" and is activated by sulfate-degrading enzymes. It may also induce VEGF expression. More importantly, bFGF is necessary to keep BMSCs undifferentiated, making our therapy safer and more controllable. Thus, bFGF is an indispensable component of our Woundplast.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("PDGFA")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Prior studies show that adding Platelet-derived growth factor (PDGF) directly to experimentally designed wounds enhances wound healing"),n("sup",[n("a",{attrs:{href:"#reference-5"}},[e._v("5")])]),e._v(". So, we also included it in our Woundplast together with VEGF121 and bFGF.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Promoter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We designed a combination of three promoters and three growth factors and were planning to characterize their expression one by one. The three promoters are CMV promoter (BBa_K404102), EF1a promoter and Ubc promoter. All of them are constitutively-expressed. CMV promoter can be used in most mammalian cells and allows adaptability in transient or stable expression, cytoplasmic expression or secretion. EF1a can be used in most cell types, and the expression level of is stable. Ubc, as the name suggests, is quite ubiquitous in mammals.")]),e._v(" "),n("img",{attrs:{src:"Design-2.png",width:"60%"}}),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("eGFP and 3xFLAG Dual Reporter")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("It would be of vital importance to visualize and track the expression of the parts, so we fused the growth factor genes with a eGFP gene and a 3xFLAG and constructed a dual reporter. The eGFP allows us to track the expression of the growth factors during the whole experiments including transfection, lentivirus production and infection. The 3xFLAG makes it easier to purify and detect the expression of the growth factors.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vitamin C to promote wound healing and eBMSC vitality")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Vitamin C (Vc), also called ascorbid acid (AA), is a crucial antioxidant"),n("sup",[e._v("6")]),e._v(". More importantly, it is involved in all phases of wound healing"),n("sup",[e._v("7")]),e._v(". Thus, we added it to the PF-127 gel to enhance wound healing in combination with other growth factors. Besides, PF-127 can be poisonous to cells. Thus, eBMSCs located in the uterus with PF-127 matrix are prone to apoptosis and cell death. Vc is also able to promote cells from apoptosis and death. However, Vc is acidic, and a low pH is not good for cell growth. Thus, we conducted an orthogonal experiment with PF-127 concentration and Vc concentration gradients to find the optimal condition. ")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("References")]),e._v(" "),n("p",{staticClass:"card-text"})])])}]}},function(e,t,n){n(39);var i=n(14)(n(41),n(42),"data-v-1ea89e47",null);e.exports=i.exports},function(e,t,n){var i=n(40);"string"==typeof i&&(i=e.id,i,""),i.locals&&(e.exports=i.locals);n(12)("4ba9c3c2",i,!0)},function(e,t,n){t=e.exports=n(11)(),t.push([e.id,"#results img[data-v-1ea89e47]{margin-top:20px;margin-left:auto;margin-right:auto;display:block}",""])},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}Object.defineProperty(t,"__esModule",{value:!0});var r=n(16),a=i(r);t.default={components:{MyFooter:a.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"igem-page Project",attrs:{id:"results"}},[e._m(0),e._v(" "),e._m(1),e._v(" "),n("my-footer")],1)},staticRenderFns:[function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-header",attrs:{id:"results-header"}},[n("p",{staticClass:"page-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"page-subheader"},[e._v("MSCs of Next Generation is coming. SYSU-MEDICINE decided to engineer a set of MSCs (homo sapiens) with higher accuracy.")])])},function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"page-content",attrs:{id:"results-content"}},[n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Gel Formation Analysis of PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Before all the experiments on cells, we want to find the lowest concentration needed for PF-127 to form gel at 37℃ but not at room temperature. PF-127 has cytotoxicity (although low), so a lowest concentration is a better choice for application. Besides, if PF-127 at a concentration can only form at 37℃ but not at room temperature, it would be more convenient for us to apply it for clinical use.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We dissolved PF-127 in DMEM/F12 at 4℃ overnight to prepare 40% (w/v) solution, then filter the solution through a 0.45 μM filter and finally kept at 4℃ for use. Then we dissolved 40% (w/v) PF-127 into 5% (w/v), 10% (w/v), 15% (w/v), 20% (w/v), 25% (w/v), 30% (w/v), 35% (w/v), 40% (w/v). Separate each 100μl into 1.5ml EP tube. These tubes were kept at room temperature and at 37℃ for 2min, 5min, 10min. Then we test whether PF-127 form gel by put the tube upside down.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("According to the formation analysis result, PF-127 cannot form gel at 4℃. At 25℃, 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min and 25% (w/v) PF-127 can form gel in 10min. At 37℃, 40% (w/v) PF-127 can form gel in 2min. 25% (w/v), 30% (w/v), 35% (w/v) and 40% (w/v) PF-127 can form gel in 5min at 37℃. Importantly, 20% (w/v) PF-127 can form gel at 37℃ in 10min, but not form gel at room temperature (Figure 1). Therefore, we came up with a conclusion that 20% (w/v) is the concentration we wanted to find.")]),e._v(" "),n("img",{attrs:{src:"Results-1.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 1. Gel formation analysis of PF-127.")]),e._v(" "),n("p",{

staticClass:"card-subheader"},[e._v("Preparation of BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we isolated BMSCs from rats with flow cytometry. There are two main types of cells in bone marrow: stromal cells and hematopoietic cells, so we need to isolate stromal cells for future use.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We isolated BMSCs according to a modified protocol from previous work . Briefly, eight-week old female Sprague-Dawley rats were sacrificed by intraperitoneal injecting 50% chloral hydrate solution, and were then sterilized in 75% ethanol. The femurs and tibiae were collected and bone marrow stromal cells were flushed out using DMEM/F12 medium. The suspended cells were centrifuged at 200 g for 5 minutes, and then seeded in DMEM/F12 media with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin and were incubated at 37℃ with 5% CO2. 2 days later, the non-adherent cells were removed and the culture medium was changed every 3 days.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To confirm we isolated BMSCs successfully, we analyzed the cells with flow cytometry. We used CD34 and CD45 as the markers, both of which are typical of hematopoietic cells. As the figure below shows, the majority of the isolated cells were CD34 and CD45 negative, demonstrating they are indeed stromal cells (Figure 2A). The morphology of BMSCs under light microscope was shown on the right panel (Figure 2B).")]),e._v(" "),n("img",{attrs:{src:"Results-2.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 2. Isolation of BMSCs.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Engineering BMSCs")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Based on our design, we chose CMV promoter for future experiments. CMV promoter is widely used in almost all types of mammalian cells and allows for high-level constitutive expression. We used quantitative reverse-transcription PCR (qRT-PCR) to demonstrate on the RNA level.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("On day 1, HEK293T cells were transfected with psPAX2, pMD2.G and our overexpression vector for lentivirus production. BMSCs were plated on 6-well plates on day 2. From day 3, lentivirus particles were harvested every 2 days. The BMSCs were infected for two times. Then, we used 1 μg/mL of puromycin to screen for stably-transfected BMSCs. ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We analyzed growth factor overexpression with qRT-PCR.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("qRT-PCR analysis demonstrated that we successfully overexpressed bFGF and VEGF121 in BMSCs (Figure 3). ")]),e._v(" "),n("img",{attrs:{src:"Results-3.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 3. qRT-PCR analysis result of BMSCs overexpressing bFGF and VEGF121.")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Establishing rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test the efficacy of our Woundplast in vivo, we establish a rat model, for no model was developed by others before. The model was evaluated by Hematoxylin-eosin (H&E) staining, Masson staining, measuring endometrial glands number and by calculating percentage of endometrial fibrotic area in rats’ uterine.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The whole procedure of establishing IUA rat model is shown in Figure 4.")]),e._v(" "),n("img",{attrs:{src:"Results-4.png"}}),e._v(" "),n("figure",[e._v("Figure 4. Procedure of establishing rat IUA model.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate (300 mg/kg), and a vertical incision was made at low abdomen to expose uterine horns. The uterine wall of approximately 0.2 cm was excised 0.5 cm from the left uterine horn, and then mechanical damage of the upper 1.5-2.0 cm endometrium was generated with the spoon scratching, until the inner membrane gave a rough feeling. Finally, the rectus fascia and skin were sealed with a 4-0 nylon suture.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the sham control rats, the glands were uniformly distributed in the surface of uterine endometrial cavity, and collagen fibers were barely observed by Masson staining. Histologic evaluation of the IUA uterine revealed that there was a significant decrease of number of glands in the IUA uterine cavities compared with the sham counterparts (Figure 5A). By contrast, the fibrotic area in the IUA uterine was significantly increased by Masson staining (Figure 5B).")]),e._v(" "),n("img",{attrs:{src:"Results-5.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 5. Analysis of gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Together, these results showed that mechanical damage leads to severe intrauterine abnormality, suggesting a successful establishment of rat IUA model.")])]),e._v(" "),n("div",{staticClass:"content-card"},[n("p",{staticClass:"card-title"},[e._v("Demonstrate")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Cell migration and proliferation are two main aspects in wound healing. To demonstrate that our Woundplast indeed accelerated wound healing in vitro, we designed wound healing assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay to evaluate cell migration and proliferation, respectfully. Furthermore, we used AS rat model to validate previous achievements in "),n("em",[e._v("vivo")]),e._v(".")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("Vc enhanced BMSC survival in PF-127 in "),n("em",[e._v("vitro")])]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To test if adding Vc to BMSCs indeed promoted BMSC survival rate, we analyzed BMSC apoptosis rate and proliferation with flow cytometry and CCK-8 growth test.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Annexin V-FITC/PI apoptosis detection assay was carried under manufacturer’s instructions to evaluate cellular apoptosis according to. Briefly, BMSCs were seeded with different encapsulation conditions for 3 days and 7 days, the cells were trypsinized and suspended in binding buffer, labeled with 5 μL Annexin V-FITC and 5 μL PI for 15 minutes in the dark on ice. Then, 300 μL binding buffer was added to each sample and the cells were evaluated by flow cytometer. Positive control was carried out using 100 μM H2O2 treated for 15 min.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For CCK-8 growth test, the BMSCs were seeded with different encapsulation conditions. Cell growth of the 3rd day and 7th day after seeding were tested by adding 10% CCK to each well and incubated for 2 hours before measuring the absorbance at 450 nm using a microplate reader.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In the early stage, there was a short period of survival enhancement (68.3% versus 51.2%) in PF-127 encapsulation on the first day after seeding. However, after 3 days of culture, majority stromal cells encapsulated in PF-127 started undergoing apoptosis (43.6% versus 62.9%). After 7 days of culture, majority of cells encapsulated in PF-127 with no addition of Vc underwent apoptosis (44.8% versus 77.3%) and detached due to PF-127 cytotoxicity. However, Vc significantly improved in vitro cell attachment at 7 days, while adding 50 μM Vc showed better effect than 100 μM.")]),e._v(" "),n("img",{attrs:{src:"Results-6.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 6. Flow cytometry analysis of BMSCs apoptosis rate in PF-127")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("CCK test also showed that cells encapsulated in PF-127 supplemented with 50 μM Vc proliferated faster in a long term of 7 days culture (Figure 2D), indicating that 50 μM Vc improved cell viability.")]),e._v(" "),n("img",{attrs:{src:"Results-7.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 7. CCK-8 growth test of BMSCs with Vc in PF-127")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs promoted wound healing and cell migration")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In order to demonstrate that the Woundplast indeed promote wound healing, we conducted the wound healing assay, which is a typical way of testing wound healing ability in vitro. Artificial wounds were created and treated with supernatants from cultured eBMSCs. Then, we calculated wound healing percentage and migration velocity.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("HEK293T cells were plated on a 6-well plate. 24 h later, artificial wounds were created by scraping the cell monolayer with a 10 μL pipette tip. Debris were washed with PBS buffer. Because the growth factors are supposed to be secreted from the cell, culture supernatants from eBMSCs were then added. Images were acquired with microscopy.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To begin with, we calculated wound healing percentage after 24 h. The detailed procedures are as follow (Figure 8).")]),e._v(" "),n("img",{attrs:{src:"Results-8.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 8. Procedure of wound healing assay data analysis")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The first step was to load the image. Then the image was processed by enhancing contrast, finding edges and adjusting threshold. Finally, the healing area was measured and calculated.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("For measurement of cell migration velocity, we rationalized that only movements perpendicular to the wound matter in healing. So, cells were marked manually and the distance between their original sites (estimated) and migrated sites after 24 h were measured.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("To measure cell migration velocity rate, the wound at 0 h was marked with dashed red line and the position of 20 cells after 24 h of migration was circled (Figure 9). The distance was measured and velocity was calculated as μM/min.")]),e._v(" "),n("img",{attrs:{src:"Results-9.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 9. Methods of measuring cell migration distance")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("As we expected, the wounds treated with eBMSC supernatant showed a significant higher wound healing percentage compared to control group (CTR). Additionally, cells treated with bFGF presented a higher wound healing percentage compared to VEGF121(Figure 10A).")]),e._v(" "),n("img",{attrs:{src:"Results-10.png",width:"60%"}}),e._v(" "),n("figure",[e._v("Figure 10. Results of wound healing assay and cell migration velocity.")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("In terms of migration velocity, the control group migrated at the speed of xx averagely, while bFGF and VEGF121 migrated at about 0.49 μm/min and 0.80 μm/min, respectively (Figure 10B). ")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("The results demonstrated that eBMSCs successfully expressed and secreted growth factors to the culture media. The secreted growth factors significantly promoted wound healing and cell migration. ")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("eBMSCs enhanced human uterine epithelial proliferation")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Another important aspect of wound healing is cell proliferation. We conducted MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to further investigate how our Woundplast would affect human uterus epithelial cell proliferation. MTT assay is a common-used colorimetric assay for measuring cell proliferation. NAD(P)H-dependent cellular oxidoreductase enzymes are capable of reducing the tetrazolium dye MTT to formazan, an insoluble purple substance. Formazan is soluble in DMSO, so the quantity can then be measured by absorbance.")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Experimental Design")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Human uterine epithelial cells were plated on a 96-well plate with five replicates in each group. 1 day later, supernatants from corresponding eBMSC group were added. The cells were then incubated for another two days. MTT assay was conducted following instructions from manufactures. ")]),e._v(" "),n("p",{staticClass:"card-subsubheader"},[e._v("Results")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("Culture supernatants from eBMSCs overexpressing bFGF and VEGF121 significantly enhances human uterine epithelial proliferation. Notably, bFGF in combination with VEGF121 showed the greatest proliferation rate (Figure 11). This is consistent with previous findings that bFGF and VEGF121 work together during wound healing. ")]),e._v(" "),n("img",{attrs:{src:"Results-11.png",width:"40%"}}),e._v(" "),n("figure",[e._v("Figure 11. Results of MTT human uterine epithelial cell proliferation assay")]),e._v(" "),n("p",{staticClass:"card-subheader"},[e._v("PF-127 encapsulated BMSCs restored gland number and fibrosis area in rat IUA model")]),e._v(" "),n("p",{staticClass:"card-text"},[e._v("We used rat model to test if BMSCs cures IUA in vivo. 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this.loading?this.loadingText||this.t("el.select.loading"):(!this.remote||""!==this.query||0!==this.options.length)&&(this.filterable&&this.options.length>0&&0===this.filteredOptionsCount?this.noMatchText||this.t("el.select.noMatch"):0===this.options.length?this.noDataText||this.t("el.select.noData"):null)},showNewOption:function(){var e=this,t=this.options.filter(function(e){return!e.created}).some(function(t){return t.currentLabel===e.query});return this.filterable&&this.allowCreate&&""!==this.query&&!t}},components:{ElInput:c.default,ElSelectMenu:h.default,ElOption:p.default,ElTag:v.default,ElScrollbar:y.default},directives:{Clickoutside:C.default},props:{name:String,value:{required:!0},size:String,disabled:Boolean,clearable:Boolean,filterable:Boolean,allowCreate:Boolean,loading:Boolean,popperClass:String,remote:Boolean,loadingText:String,noMatchText:String,noDataText:String,remoteMethod:Function,filterMethod:Function,multiple:Boolean,multipleLimit:{type:Number,default:0},placeholder:{type:String,default:function(){return(0,S.t)("el.select.placeholder")}},defaultFirstOption:Boolean,valueKey:{type:String,default:"value"}},data:function(){return{options:[],cachedOptions:[],createdLabel:null,createdSelected:!1,selected:this.multiple?[]:{},isSelect:!0,inputLength:20,inputWidth:0,cachedPlaceHolder:"",optionsCount:0,filteredOptionsCount:0,visible:!1,selectedLabel:"",hoverIndex:-1,query:"",optionsAllDisabled:!1,inputHovering:!1,currentPlaceholder:""}},watch:{disabled:function(){var e=this;this.$nextTick(function(){e.resetInputHeight()})},placeholder:function(e){this.cachedPlaceHolder=this.currentPlaceholder=e},value:function(e){this.multiple&&(this.resetInputHeight(),e.length>0||this.$refs.input&&""!==this.query?this.currentPlaceholder="":this.currentPlaceholder=this.cachedPlaceHolder),this.setSelected(),this.filterable&&!this.multiple&&(this.inputLength=20),this.$emit("change",e),this.dispatch("ElFormItem","el.form.change",e)},query:function(e){var t=this;null!==e&&void 0!==e&&(this.$nextTick(function(){t.visible&&t.broadcast("ElSelectDropdown","updatePopper")}),this.hoverIndex=-1,this.multiple&&this.filterable&&(this.inputLength=15*this.$refs.input.value.length+20,this.managePlaceholder(),this.resetInputHeight()),this.remote&&"function"==typeof this.remoteMethod?(this.hoverIndex=-1,this.remoteMethod(e),this.broadcast("ElOption","resetIndex")):"function"==typeof this.filterMethod?(this.filterMethod(e),this.broadcast("ElOptionGroup","queryChange")):(this.filteredOptionsCount=this.optionsCount,this.broadcast("ElOption","queryChange",e),this.broadcast("ElOptionGroup","queryChange")),this.defaultFirstOption&&(this.filterable||this.remote)&&this.filteredOptionsCount&&this.checkDefaultFirstOption())},visible:function(e){var t=this;e?(this.handleIconShow(),this.broadcast("ElSelectDropdown","updatePopper"),this.filterable&&(this.query=this.selectedLabel,this.multiple?this.$refs.input.focus():(this.remote||(this.broadcast("ElOption","queryChange",""),this.broadcast("ElOptionGroup","queryChange")),this.broadcast("ElInput","inputSelect")))):(this.$refs.reference.$el.querySelector("input").blur(),this.handleIconHide(),this.broadcast("ElSelectDropdown","destroyPopper"),this.$refs.input&&this.$refs.input.blur(),this.query="",this.selectedLabel="",this.inputLength=20,this.resetHoverIndex(),this.$nextTick(function(){t.$refs.input&&""===t.$refs.input.value&&0===t.selected.length&&(t.currentPlaceholder=t.cachedPlaceHolder)}),this.multiple||this.selected&&(this.filterable&&this.allowCreate&&this.createdSelected&&this.createdOption?this.selectedLabel=this.createdLabel:this.selectedLabel=this.selected.currentLabel,this.filterable&&(this.query=this.selectedLabel))),this.$emit("visible-change",e)},options:function(e){if(!this.$isServer){this.optionsAllDisabled=e.length===e.filter(function(e){return e.disabled===!0}).length,this.multiple&&this.resetInputHeight();var t=this.$el.querySelectorAll("input");[].indexOf.call(t,document.activeElement)===-1&&this.setSelected(),this.defaultFirstOption&&(this.filterable||this.remote)&&this.filteredOptionsCount&&this.checkDefaultFirstOption()}}},methods:{handleIconHide:function(){var e=this.$el.querySelector(".el-input__icon");e&&(0,w.removeClass)(e,"is-reverse")},handleIconShow:function(){var e=this.$el.querySelector(".el-input__icon");e&&!(0,w.hasClass)(e,"el-icon-circle-close")&&(0,w.addClass)(e,"is-reverse")},scrollToOption:function(e){var t=Array.isArray(e)&&e[0]?e[0].$el:e.$el;if(this.$refs.popper&&t){var n=this.$refs.popper.$el.querySelector(".el-select-dropdown__wrap");(0,T.default)(n,t)}},handleMenuEnter:function(){var e=this;this.$nextTick(function(){return e.scrollToOption(e.selected)})},getOption:function(e){for(var t=void 0,n="[object object]"===Object.prototype.toString.call(e).toLowerCase(),i=this.cachedOptions.length-1;i>=0;i--){var r=this.cachedOptions[i],a=n?(0,E.getValueByPath)(r.value,this.valueKey)===(0,E.getValueByPath)(e,this.valueKey):r.value===e;if(a){t=r;break}}if(t)return t;var s=n?"":e,o={value:e,currentLabel:s};return this.multiple&&(o.hitState=!1),o},setSelected:function(){var e=this;if(!this.multiple){var t=this.getOption(this.value);return t.created?(this.createdLabel=t.currentLabel,this.createdSelected=!0):this.createdSelected=!1,this.selectedLabel=t.currentLabel,this.selected=t,void(this.filterable&&(this.query=this.selectedLabel))}var n=[];Array.isArray(this.value)&&this.value.forEach(function(t){n.push(e.getOption(t))}),this.selected=n,this.$nextTick(function(){e.resetInputHeight()})},handleFocus:function(){this.visible=!0},handleIconClick:function(e){this.iconClass.indexOf("circle-close")>-1?this.deleteSelected(e):this.toggleMenu()},handleMouseDown:function(e){"INPUT"===e.target.tagName&&this.visible&&(this.handleClose(),e.preventDefault())},doDestroy:function(){this.$refs.popper&&this.$refs.popper.doDestroy(),this.dropdownUl=null},handleClose:function(){this.visible=!1},toggleLastOptionHitState:function(e){if(Array.isArray(this.selected)){var t=this.selected[this.selected.length-1];if(t)return e===!0||e===!1?(t.hitState=e,e):(t.hitState=!t.hitState,t.hitState)}},deletePrevTag:function(e){if(e.target.value.length<=0&&!this.toggleLastOptionHitState()){var t=this.value.slice();t.pop(),this.$emit("input",t)}},managePlaceholder:function(){""!==this.currentPlaceholder&&(this.currentPlaceholder=this.$refs.input.value?"":this.cachedPlaceHolder)},resetInputState:function(e){8!==e.keyCode&&this.toggleLastOptionHitState(!1),this.inputLength=15*this.$refs.input.value.length+20,this.resetInputHeight()},resetInputHeight:function(){var e=this;this.$nextTick(function(){if(e.$refs.reference){var t=e.$refs.reference.$el.childNodes,n=[].filter.call(t,function(e){return"INPUT"===e.tagName})[0];n.style.height=Math.max(e.$refs.tags.clientHeight+6,I[e.size]||36)+"px",e.visible&&e.emptyText!==!1&&e.broadcast("ElSelectDropdown","updatePopper")}})},resetHoverIndex:function(){var e=this;setTimeout(function(){e.multiple?e.selected.length>0?e.hoverIndex=Math.min.apply(null,e.selected.map(function(t){return e.options.indexOf(t)})):e.hoverIndex=-1:e.hoverIndex=e.options.indexOf(e.selected)},300)},handleOptionSelect:function(e){var t=this;if(this.multiple){var n=this.value.slice(),i=this.getValueIndex(n,e.value);i>-1?n.splice(i,1):(this.multipleLimit<=0||n.length<this.multipleLimit)&&n.push(e.value),this.$emit("input",n),e.created&&(this.query="",this.inputLength=20),this.filterable&&this.$refs.input.focus()}else this.$emit("input",e.value),this.visible=!1;this.$nextTick(function(){return t.scrollToOption(e)})},getValueIndex:function(){var e=this,t=arguments.length>0&&void 0!==arguments[0]?arguments[0]:[],n=arguments[1],i="[object object]"===Object.prototype.toString.call(n).toLowerCase();if(!i)return t.indexOf(n);var a=function(){var i=e.valueKey,r=-1;return t.some(function(e,t){return(0,E.getValueByPath)(e,i)===(0,E.getValueByPath)(n,i)&&(r=t,!0)}),{v:r}}();return"object"===("undefined"==typeof a?"undefined":r(a))?a.v:void 0},toggleMenu:function(){this.filterable&&""===this.query&&this.visible||this.disabled||(this.visible=!this.visible)},navigateOptions:function(e){var t=this;return this.visible?void(0!==this.options.length&&0!==this.filteredOptionsCount&&(this.optionsAllDisabled=this.options.length===this.options.filter(function(e){return e.disabled===!0}).length,this.optionsAllDisabled||("next"===e&&(this.hoverIndex++,this.hoverIndex===this.options.length&&(this.hoverIndex=0),this.options[this.hoverIndex].disabled!==!0&&this.options[this.hoverIndex].groupDisabled!==!0&&this.options[this.hoverIndex].visible||this.navigateOptions("next")),"prev"===e&&(this.hoverIndex--,this.hoverIndex<0&&(this.hoverIndex=this.options.length-1),this.options[this.hoverIndex].disabled!==!0&&this.options[this.hoverIndex].groupDisabled!==!0&&this.options[this.hoverIndex].visible||this.navigateOptions("prev"))),this.$nextTick(function(){return t.scrollToOption(t.options[t.hoverIndex])}))):void(this.visible=!0)},selectOption:function(){this.options[this.hoverIndex]&&this.handleOptionSelect(this.options[this.hoverIndex])},deleteSelected:function(e){e.stopPropagation(),this.$emit("input",""),this.visible=!1,this.$emit("clear")},deleteTag:function(e,t){var n=this.selected.indexOf(t);if(n>-1&&!this.disabled){var i=this.value.slice();i.splice(n,1),this.$emit("input",i),this.$emit("remove-tag",t)}e.stopPropagation()},onInputChange:function(){this.filterable&&(this.query=this.selectedLabel)},onOptionDestroy:function(e){this.optionsCount--,this.filteredOptionsCount--;var t=this.options.indexOf(e);t>-1&&this.options.splice(t,1),this.broadcast("ElOption","resetIndex")},resetInputWidth:function(){this.inputWidth=this.$refs.reference.$el.getBoundingClientRect().width},handleResize:function(){this.resetInputWidth(),this.multiple&&this.resetInputHeight()},checkDefaultFirstOption:function(){this.hoverIndex=-1;for(var e=0;e!==this.options.length;++e){var t=this.options[e];if(this.query){if(!t.disabled&&!t.groupDisabled&&t.visible){this.hoverIndex=e;break}}else if(t.itemSelected){this.hoverIndex=e;break}}},getValueKey:function(e){return"[object object]"!==Object.prototype.toString.call(e.value).toLowerCase()?e.value:(0,E.getValueByPath)(e.value,this.valueKey)}},created:function(){var e=this;this.cachedPlaceHolder=this.currentPlaceholder=this.placeholder,this.multiple&&!Array.isArray(this.value)&&this.$emit("input",[]),!this.multiple&&Array.isArray(this.value)&&this.$emit("input",""),this.debouncedOnInputChange=(0,x.default)(this.debounce,function(){e.onInputChange()}),this.$on("handleOptionClick",this.handleOptionSelect),this.$on("onOptionDestroy",this.onOptionDestroy),this.$on("setSelected",this.setSelected)},mounted:function(){var e=this;this.multiple&&Array.isArray(this.value)&&this.value.length>0&&(this.currentPlaceholder=""),(0,M.addResizeListener)(this.$el,this.handleResize),this.remote&&this.multiple&&this.resetInputHeight(),this.$nextTick(function(){e.$refs.reference&&e.$refs.reference.$el&&(e.inputWidth=e.$refs.reference.$el.getBoundingClientRect().width)}),this.setSelected()},beforeDestroy:function(){this.$el&&this.handleResize&&(0,M.removeResizeListener)(this.$el,this.handleResize)}}},function(e,t,n){var i=n(5)(n(103),n(104),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(24),a=i(r);t.default={name:"ElSelectDropdown",componentName:"ElSelectDropdown",mixins:[a.default],props:{placement:{default:"bottom-start"},boundariesPadding:{default:0},popperOptions:{default:function(){return{gpuAcceleration:!1}}}},data:function(){return{minWidth:""}},computed:{popperClass:function(){return this.$parent.popperClass}},watch:{"$parent.inputWidth":function(){this.minWidth=this.$parent.$el.getBoundingClientRect().width+"px"}},mounted:function(){var e=this;this.referenceElm=this.$parent.$refs.reference.$el,this.$parent.popperElm=this.popperElm=this.$el,this.$on("updatePopper",function(){e.$parent.visible&&e.updatePopper()}),this.$on("destroyPopper",this.destroyPopper)}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"el-select-dropdown",class:[{"is-multiple":e.$parent.multiple},e.popperClass],style:{minWidth:e.minWidth}},[e._t("default")],2)},staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(106),n(108),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(e){return typeof e}:function(e){return e&&"function"==typeof Symbol&&e.constructor===Symbol&&e!==Symbol.prototype?"symbol":typeof e},a=n(15),s=i(a),o=n(107);t.default={mixins:[s.default],name:"ElOption",componentName:"ElOption",props:{value:{required:!0},label:[String,Number],created:Boolean,disabled:{type:Boolean,default:!1}},data:function(){return{index:-1,groupDisabled:!1,visible:!0,hitState:!1}},computed:{isObject:function(){return"[object object]"===Object.prototype.toString.call(this.value).toLowerCase()},currentLabel:function(){return this.label||(this.isObject?"":this.value)},currentValue:function(){return this.value||this.label||""},parent:function(){for(var e=this.$parent;!e.isSelect;)e=e.$parent;return e},itemSelected:function(){return this.parent.multiple?this.contains(this.parent.value,this.value):this.isEqual(this.value,this.parent.value)},limitReached:function(){return!!this.parent.multiple&&(!this.itemSelected&&this.parent.value.length>=this.parent.multipleLimit&&this.parent.multipleLimit>0)}},watch:{currentLabel:function(){this.created||this.parent.remote||this.dispatch("ElSelect","setSelected")},value:function(){this.created||this.parent.remote||this.dispatch("ElSelect","setSelected")}},methods:{isEqual:function(e,t){if(this.isObject){var n=this.parent.valueKey;return(0,o.getValueByPath)(e,n)===(0,o.getValueByPath)(t,n)}return e===t},contains:function(){var e=this,t=arguments.length>0&&void 0!==arguments[0]?arguments[0]:[],n=arguments[1];if(!this.isObject)return t.indexOf(n)>-1;var i=function(){var i=e.parent.valueKey;return{v:t.some(function(e){return(0,o.getValueByPath)(e,i)===(0,o.getValueByPath)(n,i)})}}();return"object"===("undefined"==typeof i?"undefined":r(i))?i.v:void 0},handleGroupDisabled:function(e){this.groupDisabled=e},hoverItem:function(){this.disabled||this.groupDisabled||(this.parent.hoverIndex=this.parent.options.indexOf(this))},selectOptionClick:function(){this.disabled!==!0&&this.groupDisabled!==!0&&this.dispatch("ElSelect","handleOptionClick",this)},queryChange:function(e){var t=String(e).replace(/(\^|\(|\)|\[|\]|\$|\*|\+|\.|\?|\\|\{|\}|\|)/g,"\\$1");this.visible=new RegExp(t,"i").test(this.currentLabel)||this.created,this.visible||this.parent.filteredOptionsCount--},resetIndex:function(){var e=this;this.$nextTick(function(){e.index=e.parent.options.indexOf(e)})}},created:function(){this.parent.options.push(this),this.parent.cachedOptions.push(this),this.parent.optionsCount++,this.parent.filteredOptionsCount++,this.index=this.parent.options.indexOf(this),this.$on("queryChange",this.queryChange),this.$on("handleGroupDisabled",this.handleGroupDisabled),this.$on("resetIndex",this.resetIndex)},beforeDestroy:function(){this.dispatch("ElSelect","onOptionDestroy",this)}}},function(e,t){e.exports=n(139)},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("li",{directives:[{name:"show",rawName:"v-show",value:e.visible,expression:"visible"}],staticClass:"el-select-dropdown__item",class:{selected:e.itemSelected,"is-disabled":e.disabled||e.groupDisabled||e.limitReached,hover:e.parent.hoverIndex===e.index},on:{mouseenter:e.hoverItem,click:function(t){t.stopPropagation(),e.selectOptionClick(t)}}},[e._t("default",[n("span",[e._v(e._s(e.currentLabel))])])],2)},staticRenderFns:[]}},function(e,t){e.exports=n(148)},function(e,t){e.exports=n(138)},function(e,t){e.exports=n(142)},function(e,t){e.exports=n(140)},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{directives:[{name:"clickoutside",rawName:"v-clickoutside",value:e.handleClose,expression:"handleClose"}],staticClass:"el-select"},[e.multiple?n("div",{ref:"tags",staticClass:"el-select__tags",style:{"max-width":e.inputWidth-32+"px"},on:{click:function(t){t.stopPropagation(),e.toggleMenu(t)}}},[n("transition-group",{on:{"after-leave":e.resetInputHeight}},e._l(e.selected,function(t){return n("el-tag",{key:e.getValueKey(t),attrs:{closable:!e.disabled,hit:t.hitState,type:"primary","close-transition":""},on:{close:function(n){e.deleteTag(n,t)}}},[n("span",{staticClass:"el-select__tags-text"},[e._v(e._s(t.currentLabel))])])})),e.filterable?n("input",{directives:[{name:"model",rawName:"v-model",value:e.query,expression:"query"}],ref:"input",staticClass:"el-select__input",class:"is-"+e.size,style:{width:e.inputLength+"px","max-width":e.inputWidth-42+"px"},attrs:{type:"text",disabled:e.disabled,debounce:e.remote?300:0},domProps:{value:e.query},on:{focus:function(t){e.visible=!0},keyup:e.managePlaceholder,keydown:[e.resetInputState,function(t){return"button"in t||!e._k(t.keyCode,"down",40)?(t.preventDefault(),void e.navigateOptions("next")):null},function(t){return"button"in t||!e._k(t.keyCode,"up",38)?(t.preventDefault(),void e.navigateOptions("prev")):null},function(t){return"button"in t||!e._k(t.keyCode,"enter",13)?(t.preventDefault(),void 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e=this,t=this.$refs,n=t.headerWrapper,i=t.footerWrapper,r=this.$refs;this.bodyWrapper.addEventListener("scroll",function(){n&&(n.scrollLeft=this.scrollLeft),i&&(i.scrollLeft=this.scrollLeft),r.fixedBodyWrapper&&(r.fixedBodyWrapper.scrollTop=this.scrollTop),r.rightFixedBodyWrapper&&(r.rightFixedBodyWrapper.scrollTop=this.scrollTop)});var a=function(t){var n=t.deltaX,i=t.deltaY;Math.abs(n)<Math.abs(i)||(n>0?e.bodyWrapper.scrollLeft+=10:n<0&&(e.bodyWrapper.scrollLeft-=10))};n&&(0,w.mousewheel)(n,(0,o.default)(16,a)),i&&(0,w.mousewheel)(i,(0,o.default)(16,a)),this.fit&&(this.windowResizeListener=(0,o.default)(50,function(){e.$ready&&e.doLayout()}),(0,c.addResizeListener)(this.$el,this.windowResizeListener))},doLayout:function(){var e=this;this.store.updateColumns(),this.layout.update(),this.updateScrollY(),this.$nextTick(function(){e.height?e.layout.setHeight(e.height):e.maxHeight?e.layout.setMaxHeight(e.maxHeight):e.shouldUpdateHeight&&e.layout.updateHeight(),e.$el&&(e.isHidden=0===e.$el.clientWidth,e.isHidden&&e.layout.bodyWidth&&setTimeout(function(){return e.doLayout()}))})}},created:function(){var e=this;this.tableId="el-table_"+M+"_",this.debouncedLayout=(0,u.default)(50,function(){return e.doLayout()})},computed:{bodyWrapper:function(){return this.$refs.bodyWrapper},shouldUpdateHeight:function(){return"number"==typeof this.height||this.fixedColumns.length>0||this.rightFixedColumns.length>0},selection:function(){return this.store.states.selection},columns:function(){return this.store.states.columns},tableData:function(){return this.store.states.data},fixedColumns:function(){return this.store.states.fixedColumns},rightFixedColumns:function(){return 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v.default({store:e,table:this,fit:this.fit,showHeader:this.showHeader});return{store:e,layout:t,isHidden:!1,renderExpanded:null,resizeProxyVisible:!1}}}},function(e,t){e.exports=n(153)},function(e,t){e.exports=n(147)},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(133),a=i(r),s=n(69),o=i(s),l=n(134),u=function(e,t){var n=t.sortingColumn;return n&&"string"!=typeof n.sortable?(0,l.orderBy)(e,t.sortProp,t.sortOrder,n.sortMethod):e},c=function(e,t){var n={};return(e||[]).forEach(function(e,i){n[(0,l.getRowIdentity)(e,t)]={row:e,index:i}}),n},d=function(e,t,n){var i=!1,r=e.selection,a=r.indexOf(t);return"undefined"==typeof n?a===-1?(r.push(t),i=!0):(r.splice(a,1),i=!0):n&&a===-1?(r.push(t),i=!0):!n&&a>-1&&(r.splice(a,1),i=!0),i},h=function(e){var t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{};if(!e)throw new Error("Table is 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n?s(e,n[0]):null},"undefined"!=typeof navigator&&navigator.userAgent.toLowerCase().indexOf("firefox")>-1);t.mousewheel=function(e,t){e&&e.addEventListener&&e.addEventListener(o?"DOMMouseScroll":"mousewheel",t)},t.getRowIdentity=function(e,t){if(!e)throw new Error("row is required when get row identity");if("string"==typeof t){if(t.indexOf(".")<0)return e[t];for(var n=t.split("."),i=e,r=0;r<n.length;r++)i=i[n[r]];return i}if("function"==typeof t)return t.call(null,e)}},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}function r(e,t){if(!(e instanceof t))throw new TypeError("Cannot call a class as a function")}t.__esModule=!0;var a=n(136),s=i(a),o=function(){function e(t){r(this,e),this.table=null,this.store=null,this.columns=null,this.fit=!0,this.showHeader=!0,this.height=null,this.scrollX=!1,this.scrollY=!1,this.bodyWidth=null,this.fixedWidth=null,this.rightFixedWidth=null,this.tableHeight=null,this.headerHeight=44,this.footerHeight=44,this.viewportHeight=null,this.bodyHeight=null,this.fixedBodyHeight=null,this.gutterWidth=(0,s.default)();for(var n in t)t.hasOwnProperty(n)&&(this[n]=t[n]);if(!this.table)throw new Error("table is required for Table Layout");if(!this.store)throw new Error("store is required for Table Layout")}return e.prototype.updateScrollY=function(){var e=this.height;if("string"==typeof e||"number"==typeof e){var t=this.table.bodyWrapper;if(this.table.$el&&t){var n=t.querySelector(".el-table__body");this.scrollY=n.offsetHeight>t.offsetHeight}}},e.prototype.setHeight=function(e){var t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"height",n=this.table.$el;"string"==typeof e&&/^\d+$/.test(e)&&(e=Number(e)),this.height=e,n&&("number"==typeof e?(n.style[t]=e+"px",this.updateHeight()):"string"==typeof e&&(""===e&&(n.style[t]=""),this.updateHeight()))},e.prototype.setMaxHeight=function(e){return this.setHeight(e,"max-height")},e.prototype.updateHeight=function(){var e=this.tableHeight=this.table.$el.clientHeight,t=!this.table.data||0===this.table.data.length,n=this.table.$refs,i=n.headerWrapper,r=n.footerWrapper,a=this.footerHeight=r?r.offsetHeight:0;if(!this.showHeader||i){if(this.showHeader){var s=this.headerHeight=i.offsetHeight,o=e-s-a+(r?1:0);null===this.height||isNaN(this.height)&&"string"!=typeof this.height||(this.bodyHeight=o),this.fixedBodyHeight=this.scrollX?o-this.gutterWidth:o}else this.headerHeight=0,null===this.height||isNaN(this.height)&&"string"!=typeof this.height||(this.bodyHeight=e-a+(r?1:0)),this.fixedBodyHeight=this.scrollX?e-this.gutterWidth:e;this.viewportHeight=this.scrollX?e-(t?0:this.gutterWidth):e}},e.prototype.update=function(){var e=this.fit,t=this.table.columns,n=this.table.$el.clientWidth,i=0,r=[];t.forEach(function(e){e.isColumnGroup?r.push.apply(r,e.columns):r.push(e)});var a=r.filter(function(e){return"number"!=typeof e.width});if(a.length>0&&e){if(r.forEach(function(e){i+=e.width||e.minWidth||80}),i<n-this.gutterWidth){this.scrollX=!1;var s=n-this.gutterWidth-i;1===a.length?a[0].realWidth=(a[0].minWidth||80)+s:!function(){var e=a.reduce(function(e,t){return e+(t.minWidth||80)},0),t=s/e,n=0;a.forEach(function(e,i){if(0!==i){var r=Math.floor((e.minWidth||80)*t);n+=r,e.realWidth=(e.minWidth||80)+r}}),a[0].realWidth=(a[0].minWidth||80)+s-n}()}else this.scrollX=!0,a.forEach(function(e){e.realWidth=e.minWidth});this.bodyWidth=Math.max(i,n)}else r.forEach(function(e){e.width||e.minWidth?e.realWidth=e.width||e.minWidth:e.realWidth=80,i+=e.realWidth}),this.scrollX=i>n,this.bodyWidth=i;var o=this.store.states.fixedColumns;if(o.length>0){var l=0;o.forEach(function(e){l+=e.realWidth}),this.fixedWidth=l}var u=this.store.states.rightFixedColumns;if(u.length>0){var c=0;u.forEach(function(e){c+=e.realWidth}),this.rightFixedWidth=c}},e}();t.default=o},function(e,t){e.exports=n(135)},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(134),a=n(44),s=n(130),o=i(s),l=n(138),u=i(l),c=n(69),d=i(c);t.default={components:{ElCheckbox:o.default,ElTooltip:u.default},props:{store:{required:!0},stripe:Boolean,context:{},layout:{required:!0},rowClassName:[String,Function],rowStyle:[Object,Function],fixed:String,highlight:Boolean},render:function(e){var t=this,n=this.columns.map(function(e,n){return t.isColumnHidden(n)});return e("table",{class:"el-table__body",attrs:{cellspacing:"0",cellpadding:"0",border:"0"}},[e("colgroup",null,[this._l(this.columns,function(t){return e("col",{attrs:{name:t.id,width:t.realWidth||t.width}},[])})]),e("tbody",null,[this._l(this.data,function(i,r){return[e("tr",{style:t.rowStyle?t.getRowStyle(i,r):null,key:t.table.rowKey?t.getKeyOfRow(i,r):r,on:{dblclick:function(e){return t.handleDoubleClick(e,i)},click:function(e){return t.handleClick(e,i)},contextmenu:function(e){return t.handleContextMenu(e,i)},mouseenter:function(e){return t.handleMouseEnter(r)},mouseleave:function(e){return t.handleMouseLeave()}},class:[t.getRowClass(i,r)]},[t._l(t.columns,function(a,s){return e("td",{class:[a.id,a.align,a.className||"",n[s]?"is-hidden":""],on:{mouseenter:function(e){return t.handleCellMouseEnter(e,i)},mouseleave:t.handleCellMouseLeave}},[a.renderCell.call(t._renderProxy,e,{row:i,column:a,$index:r,store:t.store,_self:t.context||t.table.$vnode.context},n[s])])}),!t.fixed&&t.layout.scrollY&&t.layout.gutterWidth?e("td",{class:"gutter"},[]):""]),t.store.states.expandRows.indexOf(i)>-1?e("tr",null,[e("td",{attrs:{colspan:t.columns.length},class:"el-table__expanded-cell"},[t.table.renderExpanded?t.table.renderExpanded(e,{row:i,$index:r,store:t.store}):""])]):""]}).concat(this._self.$parent.$slots.append).concat(e("el-tooltip",{attrs:{effect:this.table.tooltipEffect,placement:"top",content:this.tooltipContent},ref:"tooltip"},[]))])])},watch:{"store.states.hoverRow":function(e,t){if(this.store.states.isComplex){var n=this.$el;if(n){var i=n.querySelectorAll("tbody > tr.el-table__row"),r=i[t],s=i[e];r&&(0,a.removeClass)(r,"hover-row"),s&&(0,a.addClass)(s,"hover-row")}}},"store.states.currentRow":function(e,t){if(this.highlight){var n=this.$el;if(n){var i=this.store.states.data,r=n.querySelectorAll("tbody > tr.el-table__row"),s=r[i.indexOf(t)],o=r[i.indexOf(e)];s?(0,a.removeClass)(s,"current-row"):r&&[].forEach.call(r,function(e){return(0,a.removeClass)(e,"current-row")}),o&&(0,a.addClass)(o,"current-row")}}}},computed:{table:function(){return this.$parent},data:function(){return this.store.states.data},columnsCount:function(){return this.store.states.columns.length},leftFixedCount:function(){return this.store.states.fixedColumns.length},rightFixedCount:function(){return this.store.states.rightFixedColumns.length},columns:function(){return this.store.states.columns}},data:function(){return{tooltipContent:""}},created:function(){this.activateTooltip=(0,d.default)(50,function(e){return e.handleShowPopper()})},methods:{getKeyOfRow:function(e,t){var n=this.table.rowKey;return n?(0,r.getRowIdentity)(e,n):t},isColumnHidden:function(e){return this.fixed===!0||"left"===this.fixed?e>=this.leftFixedCount:"right"===this.fixed?e<this.columnsCount-this.rightFixedCount:e<this.leftFixedCount||e>=this.columnsCount-this.rightFixedCount},getRowStyle:function(e,t){var n=this.rowStyle;return"function"==typeof n?n.call(null,e,t):n},getRowClass:function(e,t){var n=["el-table__row"];this.stripe&&t%2===1&&n.push("el-table__row--striped");var i=this.rowClassName;return"string"==typeof i?n.push(i):"function"==typeof i&&n.push(i.call(null,e,t)||""),n.join(" ")},handleCellMouseEnter:function(e,t){var n=this.table,i=(0,r.getCell)(e);if(i){var s=(0,r.getColumnByCell)(n,i),o=n.hoverState={cell:i,column:s,row:t};n.$emit("cell-mouse-enter",o.row,o.column,o.cell,e)}var l=e.target.querySelector(".cell");if((0,a.hasClass)(l,"el-tooltip")&&l.scrollWidth>l.offsetWidth){var u=this.$refs.tooltip;this.tooltipContent=i.innerText,u.referenceElm=i,u.$refs.popper&&(u.$refs.popper.style.display="none"),u.doDestroy(),u.setExpectedState(!0),this.activateTooltip(u)}},handleCellMouseLeave:function(e){var t=this.$refs.tooltip;t&&(t.setExpectedState(!1),t.handleClosePopper());var n=(0,r.getCell)(e);if(n){var i=this.table.hoverState;this.table.$emit("cell-mouse-leave",i.row,i.column,i.cell,e)}},handleMouseEnter:function(e){this.store.commit("setHoverRow",e)},handleMouseLeave:function(){this.store.commit("setHoverRow",null)},handleContextMenu:function(e,t){this.handleEvent(e,t,"contextmenu")},handleDoubleClick:function(e,t){this.handleEvent(e,t,"dblclick")},handleClick:function(e,t){this.store.commit("setCurrentRow",t),this.handleEvent(e,t,"click")},handleEvent:function(e,t,n){var i=this.table,a=(0,r.getCell)(e),s=void 0;a&&(s=(0,r.getColumnByCell)(i,a),s&&i.$emit("cell-"+n,t,s,a,e)),i.$emit("row-"+n,t,e,s)},handleExpandClick:function(e){this.store.commit("toggleRowExpanded",e)}}}},function(e,t){e.exports=n(154)},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(44),a=n(130),s=i(a),o=n(109),l=i(o),u=n(133),c=i(u),d=n(140),h=i(d),f=function e(t){var n=[];return t.forEach(function(t){t.children?(n.push(t),n.push.apply(n,e(t.children))):n.push(t)}),n},p=function(e){var t=1,n=function e(n,i){if(i&&(n.level=i.level+1,t<n.level&&(t=n.level)),n.children){var r=0;n.children.forEach(function(t){e(t,n),r+=t.colSpan}),n.colSpan=r}else n.colSpan=1};e.forEach(function(e){e.level=1,n(e)});for(var i=[],r=0;r<t;r++)i.push([]);var a=f(e);return a.forEach(function(e){e.children?e.rowSpan=1:e.rowSpan=t-e.level+1,i[e.level-1].push(e)}),i};t.default={name:"ElTableHeader",render:function(e){var t=this,n=this.store.states.originColumns,i=p(n,this.columns);return e("table",{class:"el-table__header",attrs:{cellspacing:"0",cellpadding:"0",border:"0"}},[e("colgroup",null,[this._l(this.columns,function(t){return e("col",{attrs:{name:t.id,width:t.realWidth||t.width}},[])}),!this.fixed&&this.layout.gutterWidth?e("col",{attrs:{name:"gutter",width:this.layout.scrollY?this.layout.gutterWidth:""}},[]):""]),e("thead",null,[this._l(i,function(n,i){return e("tr",null,[t._l(n,function(r,a){return e("th",{attrs:{colspan:r.colSpan,rowspan:r.rowSpan},on:{mousemove:function(e){return t.handleMouseMove(e,r)},mouseout:t.handleMouseOut,mousedown:function(e){return t.handleMouseDown(e,r)},click:function(e){return t.handleHeaderClick(e,r)}},class:[r.id,r.order,r.headerAlign,r.className||"",0===i&&t.isCellHidden(a,n)?"is-hidden":"",r.children?"":"is-leaf",r.labelClassName,r.sortable?"is-sortable":""]},[e("div",{class:["cell",r.filteredValue&&r.filteredValue.length>0?"highlight":"",r.labelClassName]},[r.renderHeader?r.renderHeader.call(t._renderProxy,e,{column:r,$index:a,store:t.store,_self:t.$parent.$vnode.context}):r.label,r.sortable?e("span",{class:"caret-wrapper",on:{click:function(e){return t.handleSortClick(e,r)}}},[e("i",{class:"sort-caret ascending",on:{click:function(e){return t.handleSortClick(e,r,"ascending")}}},[]),e("i",{class:"sort-caret descending",on:{click:function(e){return t.handleSortClick(e,r,"descending")}}},[])]):"",r.filterable?e("span",{class:"el-table__column-filter-trigger",on:{click:function(e){return t.handleFilterClick(e,r)}}},[e("i",{class:["el-icon-arrow-down",r.filterOpened?"el-icon-arrow-up":""]},[])]):""])])}),!t.fixed&&t.layout.gutterWidth?e("th",{class:"gutter",style:{width:t.layout.scrollY?t.layout.gutterWidth+"px":"0"}},[]):""])})])])},props:{fixed:String,store:{required:!0},layout:{required:!0},border:Boolean,defaultSort:{type:Object,default:function(){return{prop:"",order:""}}}},components:{ElCheckbox:s.default,ElTag:l.default},computed:{isAllSelected:function(){return this.store.states.isAllSelected},columnsCount:function(){return this.store.states.columns.length},leftFixedCount:function(){return this.store.states.fixedColumns.length},rightFixedCount:function(){return this.store.states.rightFixedColumns.length},columns:function(){return this.store.states.columns}},created:function(){this.filterPanels={}},mounted:function(){var e=this;this.defaultSort.prop&&!function(){var t=e.store.states;t.sortProp=e.defaultSort.prop,t.sortOrder=e.defaultSort.order||"ascending",e.$nextTick(function(n){for(var i=0,r=e.columns.length;i<r;i++){var a=e.columns[i];if(a.property===t.sortProp){a.order=t.sortOrder,t.sortingColumn=a;break}}t.sortingColumn&&e.store.commit("changeSortCondition")})}()},beforeDestroy:function(){var e=this.filterPanels;for(var t in e)e.hasOwnProperty(t)&&e[t]&&e[t].$destroy(!0)},methods:{isCellHidden:function(e,t){if(this.fixed===!0||"left"===this.fixed)return e>=this.leftFixedCount;if("right"===this.fixed){for(var n=0,i=0;i<e;i++)n+=t[i].colSpan;return n<this.columnsCount-this.rightFixedCount}return e<this.leftFixedCount||e>=this.columnsCount-this.rightFixedCount},toggleAllSelection:function(){this.store.commit("toggleAllSelection")},handleFilterClick:function(e,t){e.stopPropagation();var n=e.target,i=n.parentNode,r=this.$parent,a=this.filterPanels[t.id];return a&&t.filterOpened?void(a.showPopper=!1):(a||(a=new c.default(h.default),this.filterPanels[t.id]=a,t.filterPlacement&&(a.placement=t.filterPlacement),a.table=r,a.cell=i,a.column=t,!this.$isServer&&a.$mount(document.createElement("div"))),void setTimeout(function(){a.showPopper=!0},16))},handleHeaderClick:function(e,t){!t.filters&&t.sortable?this.handleSortClick(e,t):t.filters&&!t.sortable&&this.handleFilterClick(e,t),this.$parent.$emit("header-click",t,e)},handleMouseDown:function(e,t){var n=this;this.$isServer||t.children&&t.children.length>0||this.draggingColumn&&this.border&&!function(){n.dragging=!0,n.$parent.resizeProxyVisible=!0;var i=n.$parent,a=i.$el,s=a.getBoundingClientRect().left,o=n.$el.querySelector("th."+t.id),l=o.getBoundingClientRect(),u=l.left-s+30;(0,r.addClass)(o,"noclick"),n.dragState={startMouseLeft:e.clientX,startLeft:l.right-s,startColumnLeft:l.left-s,tableLeft:s};var c=i.$refs.resizeProxy;c.style.left=n.dragState.startLeft+"px",document.onselectstart=function(){return!1},document.ondragstart=function(){return!1};var d=function(e){var t=e.clientX-n.dragState.startMouseLeft,i=n.dragState.startLeft+t;c.style.left=Math.max(u,i)+"px"},h=function a(){if(n.dragging){var s=n.dragState,l=s.startColumnLeft,u=s.startLeft,h=parseInt(c.style.left,10),f=h-l;t.width=t.realWidth=f,i.$emit("header-dragend",t.width,u-l,t,e),n.store.scheduleLayout(),document.body.style.cursor="",n.dragging=!1,n.draggingColumn=null,n.dragState={},i.resizeProxyVisible=!1}document.removeEventListener("mousemove",d),document.removeEventListener("mouseup",a),document.onselectstart=null,document.ondragstart=null,setTimeout(function(){(0,r.removeClass)(o,"noclick")},0)};document.addEventListener("mousemove",d),document.addEventListener("mouseup",h)}()},handleMouseMove:function(e,t){if(!(t.children&&t.children.length>0)){for(var n=e.target;n&&"TH"!==n.tagName;)n=n.parentNode;if(t&&t.resizable&&!this.dragging&&this.border){var i=n.getBoundingClientRect(),a=document.body.style;i.width>12&&i.right-e.pageX<8?(a.cursor="col-resize",(0,r.hasClass)(n,"is-sortable")&&(n.style.cursor="col-resize"),this.draggingColumn=t):this.dragging||(a.cursor="",(0,r.hasClass)(n,"is-sortable")&&(n.style.cursor="pointer"),this.draggingColumn=null)}}},handleMouseOut:function(){this.$isServer||(document.body.style.cursor="")},toggleOrder:function(e){return e?"ascending"===e?"descending":null:"ascending"},handleSortClick:function(e,t,n){e.stopPropagation();for(var i=n||this.toggleOrder(t.order),a=e.target;a&&"TH"!==a.tagName;)a=a.parentNode;if(a&&"TH"===a.tagName&&(0,r.hasClass)(a,"noclick"))return void(0,r.removeClass)(a,"noclick");if(t.sortable){var s=this.store.states,o=s.sortProp,l=void 0,u=s.sortingColumn;u!==t&&(u&&(u.order=null),s.sortingColumn=t,o=t.property),i?l=t.order=i:(l=t.order=null,s.sortingColumn=null,o=null),s.sortProp=o,s.sortOrder=l,this.store.commit("changeSortCondition")}}},data:function(){return{draggingColumn:null,dragging:!1,dragState:{}}}}},function(e,t,n){var i=n(5)(n(141),n(144),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(24),a=i(r),s=n(14),o=n(10),l=i(o),u=n(21),c=i(u),d=n(142),h=i(d),f=n(130),p=i(f),m=n(143),v=i(m);t.default={name:"ElTableFilterPanel",mixins:[a.default,l.default],directives:{Clickoutside:c.default},components:{ElCheckbox:p.default,ElCheckboxGroup:v.default},props:{placement:{type:String,default:"bottom-end"}},customRender:function(e){return e("div",{class:"el-table-filter"},[e("div",{class:"el-table-filter__content"},[]),e("div",{class:"el-table-filter__bottom"},[e("button",{on:{click:this.handleConfirm}},[this.t("el.table.confirmFilter")]),e("button",{on:{click:this.handleReset}},[this.t("el.table.resetFilter")])])])},methods:{isActive:function(e){return e.value===this.filterValue},handleOutsideClick:function(){this.showPopper=!1},handleConfirm:function(){this.confirmFilter(this.filteredValue),this.handleOutsideClick()},handleReset:function(){this.filteredValue=[],this.confirmFilter(this.filteredValue),this.handleOutsideClick()},handleSelect:function(e){this.filterValue=e,"undefined"!=typeof e&&null!==e?this.confirmFilter(this.filteredValue):this.confirmFilter([]),this.handleOutsideClick()},confirmFilter:function(e){this.table.store.commit("filterChange",{column:this.column,values:e})}},data:function(){return{table:null,cell:null,column:null}},computed:{filters:function(){return this.column&&this.column.filters},filterValue:{get:function(){return(this.column.filteredValue||[])[0]},set:function(e){this.filteredValue&&("undefined"!=typeof e&&null!==e?this.filteredValue.splice(0,1,e):this.filteredValue.splice(0,1))}},filteredValue:{get:function(){return this.column?this.column.filteredValue||[]:[]},set:function(e){this.column&&(this.column.filteredValue=e)}},multiple:function(){return!this.column||this.column.filterMultiple}},mounted:function(){var e=this;this.popperElm=this.$el,this.referenceElm=this.cell,this.table.bodyWrapper.addEventListener("scroll",function(){e.updatePopper()}),this.$watch("showPopper",function(t){e.column&&(e.column.filterOpened=t),t?h.default.open(e):h.default.close(e)})},watch:{showPopper:function(e){e===!0&&parseInt(this.popperJS._popper.style.zIndex,10)<s.PopupManager.zIndex&&(this.popperJS._popper.style.zIndex=s.PopupManager.nextZIndex())}}}},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(133),a=i(r),s=[];!a.default.prototype.$isServer&&document.addEventListener("click",function(e){s.forEach(function(t){var n=e.target;t&&t.$el&&(n===t.$el||t.$el.contains(n)||t.handleOutsideClick&&t.handleOutsideClick(e))})}),t.default={open:function(e){e&&s.push(e)},close:function(e){var t=s.indexOf(e);t!==-1&&s.splice(e,1)}}},function(e,t){e.exports=n(156)},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-zoom-in-top"}},[e.multiple?n("div",{directives:[{name:"show",rawName:"v-show",value:e.showPopper,expression:"showPopper"}],staticClass:"el-table-filter"},[n("div",{staticClass:"el-table-filter__content"},[n("el-checkbox-group",{staticClass:"el-table-filter__checkbox-group",model:{value:e.filteredValue,callback:function(t){e.filteredValue=t},expression:"filteredValue"}},e._l(e.filters,function(t){return n("el-checkbox",{key:t.value,attrs:{label:t.value}},[e._v(e._s(t.text))])}))],1),n("div",{staticClass:"el-table-filter__bottom"},[n("button",{class:{"is-disabled":0===e.filteredValue.length},attrs:{disabled:0===e.filteredValue.length},on:{click:e.handleConfirm}},[e._v(e._s(e.t("el.table.confirmFilter")))]),n("button",{on:{click:e.handleReset}},[e._v(e._s(e.t("el.table.resetFilter")))])])]):n("div",{directives:[{name:"show",rawName:"v-show",value:e.showPopper,expression:"showPopper"}],staticClass:"el-table-filter"},[n("ul",{staticClass:"el-table-filter__list"},[n("li",{staticClass:"el-table-filter__list-item",class:{"is-active":void 0===e.filterValue||null===e.filterValue},on:{click:function(t){e.handleSelect(null)}}},[e._v(e._s(e.t("el.table.clearFilter")))]),e._l(e.filters,function(t){return n("li",{key:t.value,staticClass:"el-table-filter__list-item",class:{"is-active":e.isActive(t)},attrs:{label:t.value},on:{click:function(n){e.handleSelect(t.value)}}},[e._v(e._s(t.text))])})],2)])])},staticRenderFns:[]}},function(e,t){"use strict";t.__esModule=!0,t.default={name:"ElTableFooter",render:function(e){var t=this,n=[];return this.columns.forEach(function(e,i){if(0===i)return void(n[i]=t.sumText);var r=t.store.states.data.map(function(t){return Number(t[e.property])}),a=[],s=!0;r.forEach(function(e){if(!isNaN(e)){s=!1;var t=(""+e).split(".")[1];a.push(t?t.length:0)}});var o=Math.max.apply(null,a);s?n[i]="":n[i]=r.reduce(function(e,t){var n=Number(t);return isNaN(n)?e:parseFloat((e+t).toFixed(Math.min(o,20)))},0)}),e("table",{class:"el-table__footer",attrs:{cellspacing:"0",cellpadding:"0",border:"0"}},[e("colgroup",null,[this._l(this.columns,function(t){return e("col",{attrs:{name:t.id,width:t.realWidth||t.width}},[])}),!this.fixed&&this.layout.gutterWidth?e("col",{attrs:{name:"gutter",width:this.layout.scrollY?this.layout.gutterWidth:""}},[]):""]),e("tbody",null,[e("tr",null,[this._l(this.columns,function(i,r){return e("td",{attrs:{colspan:i.colSpan,rowspan:i.rowSpan},class:[i.id,i.headerAlign,i.className||"",t.isCellHidden(r,t.columns)?"is-hidden":"",i.children?"":"is-leaf",i.labelClassName]},[e("div",{class:["cell",i.labelClassName]},[t.summaryMethod?t.summaryMethod({columns:t.columns,data:t.store.states.data})[r]:n[r]])])}),!this.fixed&&this.layout.gutterWidth?e("td",{class:"gutter",style:{width:this.layout.scrollY?this.layout.gutterWidth+"px":"0"}},[]):""])])])},props:{fixed:String,store:{required:!0},layout:{required:!0},summaryMethod:Function,sumText:String,border:Boolean,defaultSort:{type:Object,default:function(){return{prop:"",order:""}}}},computed:{isAllSelected:function(){return 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a.default(this.panel).$mount(),this.picker.popperClass=this.popperClass,this.popperElm=this.picker.$el,this.picker.width=this.reference.getBoundingClientRect().width,this.picker.showTime="datetime"===this.type||"datetimerange"===this.type,this.picker.selectionMode=this.selectionMode,this.format&&(this.picker.format=this.format);var t=function(){var t=e.pickerOptions;t&&t.selectableRange&&!function(){var n=t.selectableRange,i=C.datetimerange.parser,r=v.timerange;n=Array.isArray(n)?n:[n],e.picker.selectableRange=n.map(function(t){return i(t,r,e.rangeSeparator)})}();for(var n in t)t.hasOwnProperty(n)&&"selectableRange"!==n&&(e.picker[n]=t[n])};t(),this.unwatchPickerOptions=this.$watch("pickerOptions",function(){return t()},{deep:!0}),this.$el.appendChild(this.picker.$el),this.picker.resetView&&this.picker.resetView(),this.picker.$on("dodestroy",this.doDestroy),this.picker.$on("pick",function(){var t=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",n=arguments.length>1&&void 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r=n(154),a=i(r),s=n(111),o=["sun","mon","tue","wed","thu","fri","sat"],l=["jan","feb","mar","apr","may","jun","jul","aug","sep","oct","nov","dec"],u=function(){return{dayNamesShort:o.map(function(e){return(0,s.t)("el.datepicker.weeks."+e)}),dayNames:o.map(function(e){return(0,s.t)("el.datepicker.weeks."+e)}),monthNamesShort:l.map(function(e){return(0,s.t)("el.datepicker.months."+e)}),monthNames:l.map(function(e,t){return(0,s.t)("el.datepicker.month"+(t+1))}),amPm:["am","pm"]}},c=function(e,t){for(var n=[],i=e;i<=t;i++)n.push(i);return n},d=(t.equalDate=function(e,t){return e===t||new Date(e).getTime()===new Date(t).getTime()},t.toDate=function(e){return h(e)?new Date(e):null}),h=t.isDate=function(e){return null!==e&&void 0!==e&&!isNaN(new Date(e).getTime())},f=(t.formatDate=function(e,t){return e=d(e),e?a.default.format(e,t||"yyyy-MM-dd",u()):""},t.parseDate=function(e,t){return a.default.parse(e,t||"yyyy-MM-dd",u())},t.getDayCountOfMonth=function(e,t){return 3===t||5===t||8===t||10===t?30:1===t?e%4===0&&e%100!==0||e%400===0?29:28:31}),p=(t.getFirstDayOfMonth=function(e){var t=new Date(e.getTime());return t.setDate(1),t.getDay()},t.DAY_DURATION=864e5);t.getStartDateOfMonth=function(e,t){var n=new Date(e,t,1),i=n.getDay();return 0===i?n.setTime(n.getTime()-7*p):n.setTime(n.getTime()-p*i),n},t.getWeekNumber=function(e){var t=new Date(e.getTime());t.setHours(0,0,0,0),t.setDate(t.getDate()+3-(t.getDay()+6)%7);var n=new Date(t.getFullYear(),0,4);return 1+Math.round(((t.getTime()-n.getTime())/864e5-3+(n.getDay()+6)%7)/7)},t.prevMonth=function(e){var t=e.getFullYear(),n=e.getMonth(),i=e.getDate(),r=0===n?t-1:t,a=0===n?11:n-1,s=f(r,a);return s<i&&e.setDate(s),e.setMonth(a),e.setFullYear(r),new Date(e.getTime())},t.nextMonth=function(e){var t=e.getFullYear(),n=e.getMonth(),i=e.getDate(),r=11===n?t+1:t,a=11===n?0:n+1,s=f(r,a);return s<i&&e.setDate(s),e.setMonth(a),e.setFullYear(r),new Date(e.getTime())},t.getRangeHours=function(e){var t=[],n=[];if((e||[]).forEach(function(e){var t=e.map(function(e){return e.getHours()});n=n.concat(c(t[0],t[1]))}),n.length)for(var i=0;i<24;i++)t[i]=n.indexOf(i)===-1;else for(var r=0;r<24;r++)t[r]=!1;return t},t.limitRange=function(e,t){var n=arguments.length>2&&void 0!==arguments[2]?arguments[2]:"yyyy-MM-dd HH:mm:ss";if(!t||!t.length)return e;var i=t.length;e=a.default.parse(a.default.format(e,n),n);for(var r=0;r<i;r++){var s=t[r];if(e>=s[0]&&e<=s[1])return e}var o=t[0][0],l=t[0][0];return t.forEach(function(e){l=new Date(Math.min(e[0],l)),o=new Date(Math.max(e[1],o))}),e<l?l:o}},function(e,t){e.exports=n(157)},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("el-input",{directives:[{name:"clickoutside",rawName:"v-clickoutside",value:e.handleClose,expression:"handleClose"}],ref:"reference",staticClass:"el-date-editor",class:"el-date-editor--"+e.type,attrs:{readonly:!e.editable||e.readonly,disabled:e.disabled,size:e.size,placeholder:e.placeholder,value:e.displayValue,validateEvent:!1},on:{focus:e.handleFocus,blur:e.handleBlur},nativeOn:{keydown:function(t){e.handleKeydown(t)},change:function(t){e.displayValue=t.target.value}}},[e.haveTrigger?n("i",{staticClass:"el-input__icon",class:[e.showClose?"el-icon-close":e.triggerClass],on:{click:e.handleClickIcon,mouseenter:e.handleMouseEnterIcon,mouseleave:function(t){e.showClose=!1}},slot:"icon"}):e._e()])},staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(157),n(173),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(153),a=n(10),s=i(a),o=n(20),l=i(o),u=n(158),c=i(u),d=n(164),h=i(d),f=n(167),p=i(f),m=n(170),v=i(m);t.default={mixins:[s.default],watch:{showTime:function(e){var t=this;e&&this.$nextTick(function(e){var n=t.$refs.input.$el;n&&(t.pickerWidth=n.getBoundingClientRect().width+10)})},value:function(e){if(e&&(e=new Date(e),!isNaN(e))){if("function"==typeof this.disabledDate&&this.disabledDate(new Date(e)))return;this.date=e,this.year=e.getFullYear(),this.month=e.getMonth(),this.$emit("pick",e,!1)}},timePickerVisible:function(e){var t=this;e&&this.$nextTick(function(){return t.$refs.timepicker.ajustScrollTop()})},selectionMode:function(e){"month"===e?"year"===this.currentView&&"month"===this.currentView||(this.currentView="month"):"week"===e&&(this.week=(0,r.getWeekNumber)(this.date))},date:function(e){this.year=e.getFullYear(),this.month=e.getMonth(),"week"===this.selectionMode&&(this.week=(0,r.getWeekNumber)(e))}},methods:{handleClear:function(){this.date=this.$options.defaultValue?new 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t=this.selectionMode;if("month"!==t)this.date.setMonth(e),this.currentView="date",this.resetDate();else{this.date.setMonth(e),this.year&&this.date.setFullYear(this.year),this.resetDate();var n=new Date(this.date.getFullYear(),e,1);this.$emit("pick",n)}},handleDatePick:function(e){"day"===this.selectionMode?(this.showTime||this.$emit("pick",new Date(e.getTime())),this.date.setFullYear(e.getFullYear()),this.date.setMonth(e.getMonth(),e.getDate())):"week"===this.selectionMode&&(this.week=e.week,this.$emit("pick",e.date)),this.resetDate()},handleYearPick:function(e){var t=!(arguments.length>1&&void 0!==arguments[1])||arguments[1];this.year=e,t&&(this.date.setFullYear(e),"year"===this.selectionMode?this.$emit("pick",new Date(e,0,1)):this.currentView="month",this.resetDate())},changeToNow:function(){this.date.setTime(+new Date),this.$emit("pick",new Date(this.date.getTime())),this.resetDate()},confirm:function(){this.date.setMilliseconds(0),this.$emit("pick",this.date)},resetView:function(){"month"===this.selectionMode?this.currentView="month":"year"===this.selectionMode?this.currentView="year":this.currentView="date","week"!==this.selectionMode&&(this.year=this.date.getFullYear(),this.month=this.date.getMonth())}},components:{TimePicker:c.default,YearTable:h.default,MonthTable:p.default,DateTable:v.default,ElInput:l.default},mounted:function(){this.date&&!this.year&&(this.year=this.date.getFullYear(),this.month=this.date.getMonth())},data:function(){return{popperClass:"",pickerWidth:0,date:this.$options.defaultValue?new Date(this.$options.defaultValue):new Date,value:"",showTime:!1,selectionMode:"day",shortcuts:"",visible:!1,currentView:"date",disabledDate:"",firstDayOfWeek:7,year:null,month:null,week:null,showWeekNumber:!1,timePickerVisible:!1,width:0,format:""}},computed:{footerVisible:function(){return this.showTime},visibleTime:{get:function(){return(0,r.formatDate)(this.date,this.timeFormat)},set:function(e){if(e){var t=(0,r.parseDate)(e,this.timeFormat);t&&(t.setFullYear(this.date.getFullYear()),t.setMonth(this.date.getMonth()),t.setDate(this.date.getDate()),this.date=t,this.$refs.timepicker.value=t,this.timePickerVisible=!1)}}},visibleDate:{get:function(){return(0,r.formatDate)(this.date,this.dateFormat)},set:function(e){var t=(0,r.parseDate)(e,this.dateFormat);t&&("function"==typeof this.disabledDate&&this.disabledDate(t)||(t.setHours(this.date.getHours()),t.setMinutes(this.date.getMinutes()),t.setSeconds(this.date.getSeconds()),this.date=t,this.resetView()))}},yearLabel:function(){var e=this.year;if(!e)return"";var t=this.t("el.datepicker.year");if("year"===this.currentView){var n=10*Math.floor(e/10);return t?n+" "+t+" - "+(n+9)+" "+t:n+" - "+(n+9)}return this.year+" "+t},timeFormat:function(){return this.format&&this.format.indexOf("ss")===-1?"HH:mm":"HH:mm:ss"},dateFormat:function(){return this.format?this.format.replace("HH","").replace(":mm","").replace(":ss","").trim():"yyyy-MM-dd"}}}},function(e,t,n){var i=n(5)(n(159),n(163),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(153),a=n(10),s=i(a);t.default={mixins:[s.default],components:{TimeSpinner:n(160)},props:{pickerWidth:{},date:{default:function(){return new Date}},visible:Boolean},watch:{visible:function(e){this.currentVisible=e,e&&(this.oldHours=this.hours,this.oldMinutes=this.minutes,this.oldSeconds=this.seconds)},pickerWidth:function(e){this.width=e},value:function(e){var t=this,n=void 0;e instanceof Date?n=(0,r.limitRange)(e,this.selectableRange):e||(n=new Date),this.handleChange({hours:n.getHours(),minutes:n.getMinutes(),seconds:n.getSeconds()}),this.$nextTick(function(e){return t.ajustScrollTop()})},selectableRange:function(e){this.$refs.spinner.selectableRange=e}},data:function(){return{popperClass:"",format:"HH:mm:ss",value:"",hours:0,minutes:0,seconds:0,oldHours:0,oldMinutes:0,oldSeconds:0,selectableRange:[],currentDate:this.$options.defaultValue||this.date||new Date,currentVisible:this.visible||!1,width:this.pickerWidth||0}},computed:{showSeconds:function(){return(this.format||"").indexOf("ss")!==-1}},methods:{handleClear:function(){this.$emit("pick")},handleCancel:function(){this.currentDate.setHours(this.oldHours),this.currentDate.setMinutes(this.oldMinutes),this.currentDate.setSeconds(this.oldSeconds),this.hours=this.currentDate.getHours(),this.minutes=this.currentDate.getMinutes(),this.seconds=this.currentDate.getSeconds();var e=new Date((0,r.limitRange)(this.currentDate,this.selectableRange,"HH:mm:ss"));this.$emit("pick",e)},handleChange:function(e){void 0!==e.hours&&(this.currentDate.setHours(e.hours),this.hours=this.currentDate.getHours()),void 0!==e.minutes&&(this.currentDate.setMinutes(e.minutes),this.minutes=this.currentDate.getMinutes()),void 0!==e.seconds&&(this.currentDate.setSeconds(e.seconds),this.seconds=this.currentDate.getSeconds()),this.handleConfirm(!0)},setSelectionRange:function(e,t){this.$emit("select-range",e,t)},handleConfirm:function(){var e=arguments.length>0&&void 0!==arguments[0]&&arguments[0],t=arguments[1];if(!t){var n=new Date((0,r.limitRange)(this.currentDate,this.selectableRange,"HH:mm:ss"));this.$emit("pick",n,e,t)}},ajustScrollTop:function(){return this.$refs.spinner.ajustScrollTop()}},created:function(){this.hours=this.currentDate.getHours(),this.minutes=this.currentDate.getMinutes(),this.seconds=this.currentDate.getSeconds()},mounted:function(){var e=this;this.$nextTick(function(){return e.handleConfirm(!0,!0)}),this.$emit("mounted")}}},function(e,t,n){var i=n(5)(n(161),n(162),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(153),a=n(25),s=i(a),o=n(69),l=i(o);t.default={components:{ElScrollbar:s.default},props:{hours:{type:Number,default:0},minutes:{type:Number,default:0},seconds:{type:Number,default:0},showSeconds:{type:Boolean,default:!0}},watch:{hoursPrivate:function(e,t){e>=0&&e<=23||(this.hoursPrivate=t),this.ajustElTop("hour",e),this.$emit("change",{hours:e})},minutesPrivate:function(e,t){e>=0&&e<=59||(this.minutesPrivate=t),this.ajustElTop("minute",e),this.$emit("change",{minutes:e})},secondsPrivate:function(e,t){e>=0&&e<=59||(this.secondsPrivate=t),this.ajustElTop("second",e),this.$emit("change",{seconds:e})}},computed:{hoursList:function(){return(0,r.getRangeHours)(this.selectableRange)},hourEl:function(){return this.$refs.hour.wrap},minuteEl:function(){return this.$refs.minute.wrap},secondEl:function(){return this.$refs.second.wrap}},data:function(){return{hoursPrivate:0,minutesPrivate:0,secondsPrivate:0,selectableRange:[]}},created:function(){var e=this;this.debounceAjustElTop=(0,l.default)(100,function(t){return e.ajustElTop(t,e[t+"s"])})},mounted:function(){var e=this;this.$nextTick(function(){e.bindScrollEvent()})},methods:{handleClick:function(e,t,n){t.disabled||(this[e+"Private"]=t.value>=0?t.value:t,this.emitSelectRange(e))},emitSelectRange:function(e){"hours"===e?this.$emit("select-range",0,2):"minutes"===e?this.$emit("select-range",3,5):"seconds"===e&&this.$emit("select-range",6,8)},bindScrollEvent:function(){var e=this,t=function(t){e[t+"El"].onscroll=function(n){return e.handleScroll(t,n)}};t("hour"),t("minute"),t("second")},handleScroll:function(e){var t={};t[e+"s"]=Math.min(Math.floor((this[e+"El"].scrollTop-80)/32+3),""+e=="hour"?23:59),this.debounceAjustElTop(e),this.$emit("change",t)},ajustScrollTop:function(){this.ajustElTop("hour",this.hours),this.ajustElTop("minute",this.minutes),this.ajustElTop("second",this.seconds)},ajustElTop:function(e,t){this[e+"El"].scrollTop=Math.max(0,32*(t-2.5)+80)}}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"el-time-spinner",class:{"has-seconds":e.showSeconds}},[n("el-scrollbar",{ref:"hour",staticClass:"el-time-spinner__wrapper",attrs:{"wrap-style":"max-height: inherit;","view-class":"el-time-spinner__list",noresize:"",tag:"ul"},nativeOn:{mouseenter:function(t){e.emitSelectRange("hours")}}},e._l(e.hoursList,function(t,i){return n("li",{staticClass:"el-time-spinner__item",class:{active:i===e.hours,disabled:t},attrs:{"track-by":"hour"},domProps:{textContent:e._s(i)},on:{click:function(n){e.handleClick("hours",{value:i,disabled:t},!0)}}})})),n("el-scrollbar",{ref:"minute",staticClass:"el-time-spinner__wrapper",attrs:{"wrap-style":"max-height: inherit;","view-class":"el-time-spinner__list",noresize:"",tag:"ul"},nativeOn:{mouseenter:function(t){e.emitSelectRange("minutes")}}},e._l(60,function(t,i){return n("li",{staticClass:"el-time-spinner__item",class:{active:i===e.minutes},domProps:{textContent:e._s(i)},on:{click:function(t){e.handleClick("minutes",i,!0)}}})})),n("el-scrollbar",{directives:[{name:"show",rawName:"v-show",value:e.showSeconds,expression:"showSeconds"}],ref:"second",staticClass:"el-time-spinner__wrapper",attrs:{"wrap-style":"max-height: inherit;","view-class":"el-time-spinner__list",noresize:"",tag:"ul"},nativeOn:{mouseenter:function(t){e.emitSelectRange("seconds")}}},e._l(60,function(t,i){return n("li",{staticClass:"el-time-spinner__item",class:{active:i===e.seconds},domProps:{textContent:e._s(i)},on:{click:function(t){e.handleClick("seconds",i,!0)}}})}))],1)},staticRenderFns:[]}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-zoom-in-top"},on:{"after-leave":function(t){e.$emit("dodestroy")}}},[n("div",{directives:[{name:"show",rawName:"v-show",value:e.currentVisible,expression:"currentVisible"}],staticClass:"el-time-panel",class:e.popperClass,style:{width:e.width+"px"}},[n("div",{staticClass:"el-time-panel__content",class:{"has-seconds":e.showSeconds}},[n("time-spinner",{ref:"spinner",attrs:{"show-seconds":e.showSeconds,hours:e.hours,minutes:e.minutes,seconds:e.seconds},on:{change:e.handleChange,"select-range":e.setSelectionRange}})],1),n("div",{staticClass:"el-time-panel__footer"},[n("button",{staticClass:"el-time-panel__btn cancel",attrs:{type:"button"},on:{click:e.handleCancel}},[e._v(e._s(e.t("el.datepicker.cancel")))]),n("button",{staticClass:"el-time-panel__btn confirm",attrs:{type:"button"},on:{click:function(t){e.handleConfirm()}}},[e._v(e._s(e.t("el.datepicker.confirm")))])])])]); },staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(165),n(166),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";t.__esModule=!0;var i=n(44);t.default={props:{disabledDate:{},date:{},year:{}},computed:{startYear:function(){return 10*Math.floor(this.year/10)}},methods:{getCellStyle:function(e){var t={},n=new Date(e,0,1,0),i=new Date(n);i.setFullYear(e+1);var r=!1;if("function"==typeof this.disabledDate){for(;n<i&&this.disabledDate(n);)n=new Date(n.getTime()+864e5);n-i===0&&(r=!0)}return t.disabled=r,t.current=Number(this.year)===e,t},nextTenYear:function(){this.$emit("pick",Number(this.year)+10,!1)},prevTenYear:function(){this.$emit("pick",Number(this.year)-10,!1)},handleYearTableClick:function(e){var t=e.target;if("A"===t.tagName){if((0,i.hasClass)(t.parentNode,"disabled"))return;var n=t.textContent||t.innerText;this.$emit("pick",Number(n))}}}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("table",{staticClass:"el-year-table",on:{click:e.handleYearTableClick}},[n("tbody",[n("tr",[n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+0)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+1)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+1))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+2)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+2))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+3)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+3))])])]),n("tr",[n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+4)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+4))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+5)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+5))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+6)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+6))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+7)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+7))])])]),n("tr",[n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+8)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+8))])]),n("td",{staticClass:"available",class:e.getCellStyle(e.startYear+9)},[n("a",{staticClass:"cell"},[e._v(e._s(e.startYear+9))])]),n("td"),n("td")])])])},staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(168),n(169),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(10),a=i(r),s=n(44);t.default={props:{disabledDate:{},date:{},month:{type:Number}},mixins:[a.default],methods:{getCellStyle:function(e){var t={},n=this.date.getFullYear(),i=new Date(0);i.setFullYear(n),i.setMonth(e,1),i.setHours(0);var r=new Date(i);r.setMonth(e+1);var a=!1;if("function"==typeof this.disabledDate)for(;i<r;){if(!this.disabledDate(i)){a=!1;break}i=new Date(i.getTime()+864e5),a=!0}return t.disabled=a,t.current=this.month===e,t},handleMonthTableClick:function(e){var t=e.target;if("A"===t.tagName&&!(0,s.hasClass)(t.parentNode,"disabled")){var n=t.parentNode.cellIndex,i=t.parentNode.parentNode.rowIndex,r=4*i+n;this.$emit("pick",r)}}}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("table",{staticClass:"el-month-table",on:{click:e.handleMonthTableClick}},[n("tbody",[n("tr",[n("td",{class:e.getCellStyle(0)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.jan")))])]),n("td",{class:e.getCellStyle(1)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.feb")))])]),n("td",{class:e.getCellStyle(2)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.mar")))])]),n("td",{class:e.getCellStyle(3)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.apr")))])])]),n("tr",[n("td",{class:e.getCellStyle(4)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.may")))])]),n("td",{class:e.getCellStyle(5)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.jun")))])]),n("td",{class:e.getCellStyle(6)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.jul")))])]),n("td",{class:e.getCellStyle(7)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.aug")))])])]),n("tr",[n("td",{class:e.getCellStyle(8)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.sep")))])]),n("td",{class:e.getCellStyle(9)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.oct")))])]),n("td",{class:e.getCellStyle(10)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.nov")))])]),n("td",{class:e.getCellStyle(11)},[n("a",{staticClass:"cell"},[e._v(e._s(e.t("el.datepicker.months.dec")))])])])])])},staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(171),n(172),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(153),a=n(44),s=n(10),o=i(s),l=["sun","mon","tue","wed","thu","fri","sat"],u=function(e){var t=new Date(e);return t.setHours(0,0,0,0),t.getTime()};t.default={mixins:[o.default],props:{firstDayOfWeek:{default:7,type:Number,validator:function(e){return e>=1&&e<=7}},date:{},year:{},month:{},week:{},selectionMode:{default:"day"},showWeekNumber:{type:Boolean,default:!1},disabledDate:{},minDate:{},maxDate:{},rangeState:{default:function(){return{endDate:null,selecting:!1,row:null,column:null}}}},computed:{offsetDay:function(){var e=this.firstDayOfWeek;return e>3?7-e:-e},WEEKS:function(){var e=this.firstDayOfWeek;return l.concat(l).slice(e,e+7)},monthDate:function(){return this.date.getDate()},startDate:function(){return(0,r.getStartDateOfMonth)(this.year,this.month)},rows:function e(){var t=new Date(this.year,this.month,1),n=(0,r.getFirstDayOfMonth)(t),i=(0,r.getDayCountOfMonth)(t.getFullYear(),t.getMonth()),a=(0,r.getDayCountOfMonth)(t.getFullYear(),0===t.getMonth()?11:t.getMonth()-1);n=0===n?7:n;for(var s=this.offsetDay,e=this.tableRows,o=1,l=void 0,c=this.startDate,d=this.disabledDate,h=u(new Date),f=0;f<6;f++){var p=e[f];this.showWeekNumber&&(p[0]||(p[0]={type:"week",text:(0,r.getWeekNumber)(new Date(c.getTime()+r.DAY_DURATION*(7*f+1)))}));for(var m=0;m<7;m++){var v=p[this.showWeekNumber?m+1:m];v||(v={row:f,column:m,type:"normal",inRange:!1,start:!1,end:!1}),v.type="normal";var g=7*f+m,y=c.getTime()+r.DAY_DURATION*(g-s);v.inRange=y>=u(this.minDate)&&y<=u(this.maxDate),v.start=this.minDate&&y===u(this.minDate),v.end=this.maxDate&&y===u(this.maxDate);var b=y===h;b&&(v.type="today"),f>=0&&f<=1?m+7*f>=n+s?(v.text=o++,2===o&&(l=7*f+m)):(v.text=a-(n+s-m%7)+1+7*f,v.type="prev-month"):o<=i?(v.text=o++,2===o&&(l=7*f+m)):(v.text=o++-i,v.type="next-month"),v.disabled="function"==typeof d&&d(new Date(y)),this.$set(p,this.showWeekNumber?m+1:m,v)}if("week"===this.selectionMode){var x=this.showWeekNumber?1:0,_=this.showWeekNumber?7:6,C=this.isWeekActive(p[x+1]);p[x].inRange=C,p[x].start=C,p[_].inRange=C,p[_].end=C}}return e.firstDayPosition=l,e}},watch:{"rangeState.endDate":function(e){this.markRange(e)},minDate:function(e,t){e&&!t?(this.rangeState.selecting=!0,this.markRange(e)):e?this.markRange():(this.rangeState.selecting=!1,this.markRange(e))},maxDate:function(e,t){e&&!t&&(this.rangeState.selecting=!1,this.markRange(e),this.$emit("pick",{minDate:this.minDate,maxDate:this.maxDate}))}},data:function(){return{tableRows:[[],[],[],[],[],[]]}},methods:{getCellClasses:function(e){var t=this.selectionMode,n=this.monthDate,i=[];return"normal"!==e.type&&"today"!==e.type||e.disabled?i.push(e.type):(i.push("available"),"today"===e.type&&i.push("today")),"day"!==t||"normal"!==e.type&&"today"!==e.type||Number(this.year)!==this.date.getFullYear()||this.month!==this.date.getMonth()||n!==Number(e.text)||i.push("current"),!e.inRange||"normal"!==e.type&&"today"!==e.type&&"week"!==this.selectionMode||(i.push("in-range"),e.start&&i.push("start-date"),e.end&&i.push("end-date")),e.disabled&&i.push("disabled"),i.join(" ")},getDateOfCell:function(e,t){var n=this.startDate;return new Date(n.getTime()+(7*e+(t-(this.showWeekNumber?1:0))-this.offsetDay)*r.DAY_DURATION)},getCellByDate:function(e){var t=this.startDate,n=this.rows,i=(e-t)/r.DAY_DURATION,a=n[Math.floor(i/7)];return this.showWeekNumber?a[i%7+1]:a[i%7]},isWeekActive:function(e){if("week"!==this.selectionMode)return!1;var t=new Date(this.year,this.month,1),n=t.getFullYear(),i=t.getMonth();return"prev-month"===e.type&&(t.setMonth(0===i?11:i-1),t.setFullYear(0===i?n-1:n)),"next-month"===e.type&&(t.setMonth(11===i?0:i+1),t.setFullYear(11===i?n+1:n)),t.setDate(parseInt(e.text,10)),(0,r.getWeekNumber)(t)===this.week},markRange:function(e){var t=this.startDate;e||(e=this.maxDate);for(var n=this.rows,i=this.minDate,a=0,s=n.length;a<s;a++)for(var o=n[a],l=0,c=o.length;l<c;l++)if(!this.showWeekNumber||0!==l){var d=o[l],h=7*a+l+(this.showWeekNumber?-1:0),f=t.getTime()+r.DAY_DURATION*(h-this.offsetDay);d.inRange=i&&f>=u(i)&&f<=u(e),d.start=i&&f===u(i.getTime()),d.end=e&&f===u(e.getTime())}},handleMouseMove:function(e){if(this.rangeState.selecting){this.$emit("changerange",{minDate:this.minDate,maxDate:this.maxDate,rangeState:this.rangeState});var t=e.target;if("TD"===t.tagName){var n=t.cellIndex,i=t.parentNode.rowIndex-1,r=this.rangeState,a=r.row,s=r.column;a===i&&s===n||(this.rangeState.row=i,this.rangeState.column=n,this.rangeState.endDate=this.getDateOfCell(i,n))}}},handleClick:function(e){var t=e.target;if("TD"===t.tagName&&!(0,a.hasClass)(t,"disabled")&&!(0,a.hasClass)(t,"week")){var n=this.selectionMode;"week"===n&&(t=t.parentNode.cells[1]);var i=Number(this.year),s=Number(this.month),o=t.cellIndex,l=t.parentNode.rowIndex,u=this.rows[l-1][o],c=u.text,d=t.className,h=new Date(i,s,1);if(d.indexOf("prev")!==-1?(0===s?(i-=1,s=11):s-=1,h.setFullYear(i),h.setMonth(s)):d.indexOf("next")!==-1&&(11===s?(i+=1,s=0):s+=1,h.setFullYear(i),h.setMonth(s)),h.setDate(parseInt(c,10)),"range"===this.selectionMode){if(this.minDate&&this.maxDate){var f=new Date(h.getTime()),p=null;this.$emit("pick",{minDate:f,maxDate:p},!1),this.rangeState.selecting=!0,this.markRange(this.minDate)}else if(this.minDate&&!this.maxDate)if(h>=this.minDate){var m=new Date(h.getTime());this.rangeState.selecting=!1,this.$emit("pick",{minDate:this.minDate,maxDate:m})}else{var v=new Date(h.getTime());this.$emit("pick",{minDate:v,maxDate:this.maxDate},!1)}else if(!this.minDate){var g=new Date(h.getTime());this.$emit("pick",{minDate:g,maxDate:this.maxDate},!1),this.rangeState.selecting=!0,this.markRange(this.minDate)}}else if("day"===n)this.$emit("pick",h);else if("week"===n){var y=(0,r.getWeekNumber)(h),b=h.getFullYear()+"w"+y;this.$emit("pick",{year:h.getFullYear(),week:y,value:b,date:h})}}}}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("table",{staticClass:"el-date-table",class:{"is-week-mode":"week"===e.selectionMode},attrs:{cellspacing:"0",cellpadding:"0"},on:{click:e.handleClick,mousemove:e.handleMouseMove}},[n("tbody",[n("tr",[e.showWeekNumber?n("th",[e._v(e._s(e.t("el.datepicker.week")))]):e._e(),e._l(e.WEEKS,function(t){return n("th",[e._v(e._s(e.t("el.datepicker.weeks."+t)))])})],2),e._l(e.rows,function(t){return n("tr",{staticClass:"el-date-table__row",class:{current:e.isWeekActive(t[1])}},e._l(t,function(t){return n("td",{class:e.getCellClasses(t),domProps:{textContent:e._s("today"===t.type?e.t("el.datepicker.today"):t.text)}})}))})],2)])},staticRenderFns:[]}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-zoom-in-top"},on:{"after-leave":function(t){e.$emit("dodestroy")}}},[n("div",{directives:[{name:"show",rawName:"v-show",value:e.visible,expression:"visible"}],staticClass:"el-picker-panel el-date-picker",class:[{"has-sidebar":e.$slots.sidebar||e.shortcuts,"has-time":e.showTime},e.popperClass],style:{width:e.width+"px"}},[n("div",{staticClass:"el-picker-panel__body-wrapper"},[e._t("sidebar"),e.shortcuts?n("div",{staticClass:"el-picker-panel__sidebar"},e._l(e.shortcuts,function(t){return n("button",{staticClass:"el-picker-panel__shortcut",attrs:{type:"button"},on:{click:function(n){e.handleShortcutClick(t)}}},[e._v(e._s(t.text))])})):e._e(),n("div",{staticClass:"el-picker-panel__body"},[e.showTime?n("div",{staticClass:"el-date-picker__time-header"},[n("span",{staticClass:"el-date-picker__editor-wrap"},[n("el-input",{attrs:{placeholder:e.t("el.datepicker.selectDate"),value:e.visibleDate,size:"small"},nativeOn:{change:function(t){e.visibleDate=t.target.value}}})],1),n("span",{staticClass:"el-date-picker__editor-wrap"},[n("el-input",{ref:"input",attrs:{placeholder:e.t("el.datepicker.selectTime"),value:e.visibleTime,size:"small"},on:{focus:function(t){e.timePickerVisible=!e.timePickerVisible}},nativeOn:{change:function(t){e.visibleTime=t.target.value}}}),n("time-picker",{ref:"timepicker",attrs:{date:e.date,"picker-width":e.pickerWidth,visible:e.timePickerVisible},on:{pick:e.handleTimePick,mounted:function(t){e.$refs.timepicker.format=e.timeFormat}}})],1)]):e._e(),n("div",{directives:[{name:"show",rawName:"v-show",value:"time"!==e.currentView,expression:"currentView !== 'time'"}],staticClass:"el-date-picker__header"},[n("button",{staticClass:"el-picker-panel__icon-btn el-date-picker__prev-btn el-icon-d-arrow-left",attrs:{type:"button"},on:{click:e.prevYear}}),n("button",{directives:[{name:"show",rawName:"v-show",value:"date"===e.currentView,expression:"currentView === 'date'"}],staticClass:"el-picker-panel__icon-btn el-date-picker__prev-btn el-icon-arrow-left",attrs:{type:"button"},on:{click:e.prevMonth}}),n("span",{staticClass:"el-date-picker__header-label",on:{click:e.showYearPicker}},[e._v(e._s(e.yearLabel))]),n("span",{directives:[{name:"show",rawName:"v-show",value:"date"===e.currentView,expression:"currentView === 'date'"}],staticClass:"el-date-picker__header-label",class:{active:"month"===e.currentView},on:{click:e.showMonthPicker}},[e._v(e._s(e.t("el.datepicker.month"+(e.month+1))))]),n("button",{staticClass:"el-picker-panel__icon-btn el-date-picker__next-btn el-icon-d-arrow-right",attrs:{type:"button"},on:{click:e.nextYear}}),n("button",{directives:[{name:"show",rawName:"v-show",value:"date"===e.currentView,expression:"currentView === 'date'"}],staticClass:"el-picker-panel__icon-btn el-date-picker__next-btn el-icon-arrow-right",attrs:{type:"button"},on:{click:e.nextMonth}})]),n("div",{staticClass:"el-picker-panel__content"},[n("date-table",{directives:[{name:"show",rawName:"v-show",value:"date"===e.currentView,expression:"currentView === 'date'"}],attrs:{year:e.year,month:e.month,date:e.date,week:e.week,"selection-mode":e.selectionMode,"first-day-of-week":e.firstDayOfWeek,"disabled-date":e.disabledDate},on:{pick:e.handleDatePick}}),n("year-table",{directives:[{name:"show",rawName:"v-show",value:"year"===e.currentView,expression:"currentView === 'year'"}],ref:"yearTable",attrs:{year:e.year,date:e.date,"disabled-date":e.disabledDate},on:{pick:e.handleYearPick}}),n("month-table",{directives:[{name:"show",rawName:"v-show",value:"month"===e.currentView,expression:"currentView === 'month'"}],attrs:{month:e.month,date:e.date,"disabled-date":e.disabledDate},on:{pick:e.handleMonthPick}})],1)])],2),n("div",{directives:[{name:"show",rawName:"v-show",value:e.footerVisible&&"date"===e.currentView,expression:"footerVisible && currentView === 'date'"}],staticClass:"el-picker-panel__footer"},[n("a",{staticClass:"el-picker-panel__link-btn",attrs:{href:"JavaScript:"},on:{click:e.changeToNow}},[e._v(e._s(e.t("el.datepicker.now")))]),n("button",{staticClass:"el-picker-panel__btn",attrs:{type:"button"},on:{click:e.confirm}},[e._v(e._s(e.t("el.datepicker.confirm")))])])])])},staticRenderFns:[]}},function(e,t,n){var i=n(5)(n(175),n(176),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(153),a=n(10),s=i(a),o=n(158),l=i(o),u=n(170),c=i(u),d=n(20),h=i(d),f=function(e){return Array.isArray(e)?e[0]?new Date(e[0]):new Date:new Date(e)};t.default={mixins:[s.default],computed:{btnDisabled:function(){return!(this.minDate&&this.maxDate&&!this.selecting)},leftLabel:function(){return this.date.getFullYear()+" "+this.t("el.datepicker.year")+" "+this.t("el.datepicker.month"+(this.date.getMonth()+1))},rightLabel:function(){return this.rightDate.getFullYear()+" "+this.t("el.datepicker.year")+" "+this.t("el.datepicker.month"+(this.rightDate.getMonth()+1))},leftYear:function(){return this.date.getFullYear()},leftMonth:function(){return this.date.getMonth()},rightYear:function(){return this.rightDate.getFullYear()},rightMonth:function(){return this.rightDate.getMonth()},minVisibleDate:function(){return this.minDate?(0,r.formatDate)(this.minDate):""},maxVisibleDate:function(){return this.maxDate||this.minDate?(0,r.formatDate)(this.maxDate||this.minDate):""},minVisibleTime:function(){return this.minDate?(0,r.formatDate)(this.minDate,"HH:mm:ss"):""},maxVisibleTime:function(){return this.maxDate||this.minDate?(0,r.formatDate)(this.maxDate||this.minDate,"HH:mm:ss"):""},rightDate:function(){var e=new Date(this.date),t=e.getMonth();return e.setDate(1),11===t?(e.setFullYear(e.getFullYear()+1),e.setMonth(0)):e.setMonth(t+1),e}},data:function(){return{popperClass:"",minPickerWidth:0,maxPickerWidth:0,date:this.$options.defaultValue?f(this.$options.defaultValue):new Date,minDate:"",maxDate:"",rangeState:{endDate:null,selecting:!1,row:null,column:null},showTime:!1,shortcuts:"",value:"",visible:"",disabledDate:"",firstDayOfWeek:7,minTimePickerVisible:!1,maxTimePickerVisible:!1,width:0}},watch:{showTime:function(e){var t=this;e&&this.$nextTick(function(e){var n=t.$refs.minInput.$el,i=t.$refs.maxInput.$el;n&&(t.minPickerWidth=n.getBoundingClientRect().width+10),i&&(t.maxPickerWidth=i.getBoundingClientRect().width+10)})},minDate:function(){var e=this;this.$nextTick(function(){if(e.maxDate&&e.maxDate<e.minDate){var t="HH:mm:ss";e.$refs.maxTimePicker.selectableRange=(0,r.parseDate)((0,r.formatDate)(e.minDate,t),t),(0,r.parseDate)("23:59:59",t)}})},minTimePickerVisible:function(e){var t=this;e&&this.$nextTick(function(){return t.$refs.minTimePicker.ajustScrollTop()})},maxTimePickerVisible:function(e){var t=this;e&&this.$nextTick(function(){return t.$refs.maxTimePicker.ajustScrollTop()})},value:function(e){e?Array.isArray(e)&&(this.minDate=e[0]?(0,r.toDate)(e[0]):null,this.maxDate=e[1]?(0,r.toDate)(e[1]):null,this.minDate&&(this.date=new Date(this.minDate)),this.handleConfirm(!0)):(this.minDate=null,this.maxDate=null)}},methods:{handleClear:function(){this.minDate=null,this.maxDate=null,this.date=this.$options.defaultValue?f(this.$options.defaultValue):new Date,this.handleConfirm(!1)},handleDateInput:function(e,t){var n=e.target.value,i=(0,r.parseDate)(n,"yyyy-MM-dd");if(i){if("function"==typeof this.disabledDate&&this.disabledDate(new Date(i)))return;var a=new Date("min"===t?this.minDate:this.maxDate);a&&(a.setFullYear(i.getFullYear()),a.setMonth(i.getMonth(),i.getDate()))}},handleChangeRange:function(e){this.minDate=e.minDate,this.maxDate=e.maxDate,this.rangeState=e.rangeState},handleDateChange:function(e,t){var n=e.target.value,i=(0,r.parseDate)(n,"yyyy-MM-dd");if(i){var a=new Date("min"===t?this.minDate:this.maxDate);a&&(a.setFullYear(i.getFullYear()),a.setMonth(i.getMonth(),i.getDate())),"min"===t?a<this.maxDate&&(this.minDate=new Date(a.getTime())):a>this.minDate&&(this.maxDate=new Date(a.getTime()),this.minDate&&this.minDate>this.maxDate&&(this.minDate=null))}},handleTimeChange:function(e,t){var n=e.target.value,i=(0,r.parseDate)(n,"HH:mm:ss");if(i){var a=new Date("min"===t?this.minDate:this.maxDate);a&&(a.setHours(i.getHours()),a.setMinutes(i.getMinutes()),a.setSeconds(i.getSeconds())),"min"===t?a<this.maxDate&&(this.minDate=new Date(a.getTime())):a>this.minDate&&(this.maxDate=new Date(a.getTime())),this.$refs[t+"TimePicker"].value=a,this[t+"TimePickerVisible"]=!1}},handleRangePick:function(e){var t=!(arguments.length>1&&void 0!==arguments[1])||arguments[1];this.maxDate===e.maxDate&&this.minDate===e.minDate||(this.onPick&&this.onPick(e),this.maxDate=e.maxDate,this.minDate=e.minDate,t&&!this.showTime&&this.handleConfirm())},changeToToday:function(){this.date=new Date},handleShortcutClick:function(e){e.onClick&&e.onClick(this)},resetView:function(){this.minTimePickerVisible=!1,this.maxTimePickerVisible=!1},setTime:function(e,t){var n=new Date(e.getTime()),i=t.getHours(),r=t.getMinutes(),a=t.getSeconds();return n.setHours(i),n.setMinutes(r),n.setSeconds(a),new Date(n.getTime())},handleMinTimePick:function(e,t,n){this.minDate=this.minDate||new Date,e&&(this.minDate=this.setTime(this.minDate,e)),n||(this.minTimePickerVisible=t)},handleMaxTimePick:function(e,t,n){if(!this.maxDate){var i=new Date;i>=this.minDate&&(this.maxDate=new Date)}this.maxDate&&e&&(this.maxDate=this.setTime(this.maxDate,e)),n||(this.maxTimePickerVisible=t)},prevMonth:function(){this.date=(0,r.prevMonth)(this.date)},nextMonth:function(){this.date=(0,r.nextMonth)(this.date)},nextYear:function(){var e=this.date;e.setFullYear(e.getFullYear()+1),this.resetDate()},prevYear:function(){var e=this.date;e.setFullYear(e.getFullYear()-1),this.resetDate()},handleConfirm:function(){var e=arguments.length>0&&void 0!==arguments[0]&&arguments[0];this.$emit("pick",[this.minDate,this.maxDate],e)},resetDate:function(){this.date=new Date(this.date)}},components:{TimePicker:l.default,DateTable:c.default,ElInput:h.default}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-zoom-in-top"},on:{"after-leave":function(t){e.$emit("dodestroy")}}},[n("div",{directives:[{name:"show",rawName:"v-show",value:e.visible,expression:"visible"}],staticClass:"el-picker-panel el-date-range-picker",class:[{"has-sidebar":e.$slots.sidebar||e.shortcuts,"has-time":e.showTime},e.popperClass],style:{width:e.width+"px"}},[n("div",{staticClass:"el-picker-panel__body-wrapper"},[e._t("sidebar"),e.shortcuts?n("div",{staticClass:"el-picker-panel__sidebar"},e._l(e.shortcuts,function(t){return 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t=this;this.panelCreated(),this.$nextTick(function(e){return t.ajustScrollTop()})}},methods:{panelCreated:function(){var e=h(this.value);e.minTime===this.minTime&&e.maxTime===this.maxTime||(this.handleMinChange({hours:e.minTime.getHours(),minutes:e.minTime.getMinutes(),seconds:e.minTime.getSeconds()}),this.handleMaxChange({hours:e.maxTime.getHours(),minutes:e.maxTime.getMinutes(),seconds:e.maxTime.getSeconds()}))},handleClear:function(){this.handleCancel()},handleCancel:function(){this.$emit("pick")},handleChange:function(){this.minTime>this.maxTime||(u.setFullYear(this.minTime.getFullYear()),u.setMonth(this.minTime.getMonth(),this.minTime.getDate()),c.setFullYear(this.maxTime.getFullYear()),c.setMonth(this.maxTime.getMonth(),this.maxTime.getDate()),this.$refs.minSpinner.selectableRange=u,this.maxTime,this.$refs.maxSpinner.selectableRange=this.minTime,c,this.handleConfirm(!0))},handleMaxChange:function(e){void 0!==e.hours&&(this.maxTime.setHours(e.hours), 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e=this.reference||this.$refs.reference,t=this.popper||this.$refs.popper;if(!e&&this.$slots.reference&&this.$slots.reference[0]&&(e=this.referenceElm=this.$slots.reference[0].elm),"click"===this.trigger)(0,s.on)(e,"click",this.doToggle),(0,s.on)(document,"click",this.handleDocumentClick);else if("hover"===this.trigger)(0,s.on)(e,"mouseenter",this.handleMouseEnter),(0,s.on)(t,"mouseenter",this.handleMouseEnter),(0,s.on)(e,"mouseleave",this.handleMouseLeave),(0,s.on)(t,"mouseleave",this.handleMouseLeave);else if("focus"===this.trigger){var n=!1;if([].slice.call(e.children).length)for(var 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n={success:"el-icon-circle-check",warning:"el-icon-warning",error:"el-icon-circle-cross"};t.default={name:"ElAlert",props:{title:{type:String,default:"",required:!0},description:{type:String,default:""},type:{type:String,default:"info"},closable:{type:Boolean,default:!0},closeText:{type:String,default:""},showIcon:{type:Boolean,default:!1}},data:function(){return{visible:!0}},methods:{close:function(){this.visible=!1,this.$emit("close")}},computed:{typeClass:function(){return"el-alert--"+this.type},iconClass:function(){return n[this.type]||"el-icon-information"},isBigIcon:function(){return this.description||this.$slots.default?"is-big":""},isBoldTitle:function(){return this.description||this.$slots.default?"is-bold":""}}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return 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this.onClick&&this.onClick()},close:function(){this.closed=!0,"function"==typeof this.onClose&&this.onClose()},clearTimer:function(){clearTimeout(this.timer)},startTimer:function(){var e=this;this.duration>0&&(this.timer=setTimeout(function(){e.closed||e.close()},this.duration))}},mounted:function(){var e=this;this.duration>0&&(this.timer=setTimeout(function(){e.closed||e.close()},this.duration))}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-notification-fade"}},[n("div",{directives:[{name:"show",rawName:"v-show",value:e.visible,expression:"visible"}],staticClass:"el-notification",class:e.customClass,style:{top:e.top?e.top+"px":"auto"},on:{mouseenter:function(t){e.clearTimer()},mouseleave:function(t){e.startTimer()},click:e.click}},[e.type||e.iconClass?n("i",{staticClass:"el-notification__icon",class:[e.typeClass,e.iconClass]}):e._e(),n("div",{staticClass:"el-notification__group",class:{"is-with-icon":e.typeClass||e.iconClass}},[n("h2",{staticClass:"el-notification__title",domProps:{textContent:e._s(e.title)}}),n("div",{staticClass:"el-notification__content"},[e._t("default",[e._v(e._s(e.message))])],2),n("div",{staticClass:"el-notification__closeBtn el-icon-close",on:{click:function(t){t.stopPropagation(),e.close(t)}}})])])])},staticRenderFns:[]}},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var 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e===t[n]})||this.setValues()},dragging:function(e){e||this.setValues()},firstValue:function(e){this.range?this.$emit("input",[this.minValue,this.maxValue]):this.$emit("input",e)},secondValue:function(){this.range&&this.$emit("input",[this.minValue,this.maxValue])},min:function(){this.setValues()},max:function(){this.setValues()}},methods:{valueChanged:function(){var e=this;return this.range?![this.minValue,this.maxValue].every(function(t,n){return t===e.oldValue[n]}):this.value!==this.oldValue},setValues:function(){var e=this.value;this.range&&Array.isArray(e)?e[1]<this.min?this.$emit("input",[this.min,this.min]):e[0]>this.max?this.$emit("input",[this.max,this.max]):e[0]<this.min?this.$emit("input",[this.min,e[1]]):e[1]>this.max?this.$emit("input",[e[0],this.max]):(this.firstValue=e[0],this.secondValue=e[1],this.valueChanged()&&(this.$emit("change",[this.minValue,this.maxValue]),this.dispatch("ElFormItem","el.form.change",[this.minValue,this.maxValue]),this.oldValue=e.slice())):this.range||"number"!=typeof e||isNaN(e)||(e<this.min?this.$emit("input",this.min):e>this.max?this.$emit("input",this.max):(this.firstValue=e,this.valueChanged()&&(this.$emit("change",e),this.dispatch("ElFormItem","el.form.change",e),this.oldValue=e)))},setPosition:function(e){var t=this.min+e*(this.max-this.min)/100;if(!this.range)return void this.$refs.button1.setPosition(e);var n=void 0;n=Math.abs(this.minValue-t)<Math.abs(this.maxValue-t)?this.firstValue<this.secondValue?"button1":"button2":this.firstValue>this.secondValue?"button1":"button2",this.$refs[n].setPosition(e)},onSliderClick:function(e){if(!this.disabled&&!this.dragging)if(this.resetSize(),this.vertical){var t=this.$refs.slider.getBoundingClientRect().bottom;this.setPosition((t-e.clientY)/this.sliderSize*100)}else{var n=this.$refs.slider.getBoundingClientRect().left;this.setPosition((e.clientX-n)/this.sliderSize*100)}},resetSize:function(){this.$refs.slider&&(this.sliderSize=this.$refs.slider["client"+(this.vertical?"Height":"Width")])}},computed:{stops:function(){var e=this;if(0===this.step)return[];for(var t=(this.max-this.min)/this.step,n=100*this.step/(this.max-this.min),i=[],r=1;r<t;r++)i.push(r*n);return this.range?i.filter(function(t){return t<100*(e.minValue-e.min)/(e.max-e.min)||t>100*(e.maxValue-e.min)/(e.max-e.min)}):i.filter(function(t){return t>100*(e.firstValue-e.min)/(e.max-e.min)})},minValue:function(){return Math.min(this.firstValue,this.secondValue)},maxValue:function(){return Math.max(this.firstValue,this.secondValue)},barSize:function(){return this.range?100*(this.maxValue-this.minValue)/(this.max-this.min)+"%":100*(this.firstValue-this.min)/(this.max-this.min)+"%"},barStart:function(){return this.range?100*(this.minValue-this.min)/(this.max-this.min)+"%":"0%"},precision:function(){var e=[this.min,this.max,this.step].map(function(e){var t=(""+e).split(".")[1];return t?t.length:0});return Math.max.apply(null,e)},runwayStyle:function(){return this.vertical?{height:this.height}:{}},barStyle:function(){return this.vertical?{height:this.barSize,bottom:this.barStart}:{width:this.barSize,left:this.barStart}}},mounted:function(){this.range?(Array.isArray(this.value)?(this.firstValue=Math.max(this.min,this.value[0]),this.secondValue=Math.min(this.max,this.value[1])):(this.firstValue=this.min,this.secondValue=this.max),this.oldValue=[this.firstValue,this.secondValue]):("number"!=typeof this.value||isNaN(this.value)?this.firstValue=this.min:this.firstValue=Math.min(this.max,Math.max(this.min,this.value)),this.oldValue=this.firstValue),this.resetSize(),window.addEventListener("resize",this.resetSize)},beforeDestroy:function(){window.removeEventListener("resize",this.resetSize)}}},function(e,t){e.exports=n(256)},function(e,t,n){var i=n(5)(n(257),n(258),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var 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e=[],t=0,n=this.currentValue;for(this.allowHalf&&this.currentValue!==Math.floor(this.currentValue)&&n--;t<n;t++)e.push(this.activeClass);for(;t<this.max;t++)e.push(this.voidClass);return e}},watch:{value:function(e){this.$emit("change",e),this.currentValue=e,this.pointerAtLeftHalf=this.value!==Math.floor(this.value)}},methods:{getValueFromMap:function(e,t){var n="";return n=e<=this.lowThreshold?t.lowColor||t.lowClass:e>=this.highThreshold?t.highColor||t.highClass:t.mediumColor||t.mediumClass},showDecimalIcon:function(e){var t=this.disabled&&this.valueDecimal>0&&e-1<this.value&&e>this.value,n=this.allowHalf&&this.pointerAtLeftHalf&&e-.5<=this.currentValue&&e>this.currentValue;return t||n},getIconStyle:function(e){var 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n("div",{staticClass:"el-step",class:["is-"+e.$parent.direction],style:[e.style,e.isLast?"":{marginRight:-e.$parent.stepOffset+"px"}]},[n("div",{staticClass:"el-step__head",class:["is-"+e.currentStatus,{"is-text":!e.icon}]},[n("div",{staticClass:"el-step__line",class:["is-"+e.$parent.direction,{"is-icon":e.icon}],style:e.isLast?"":{marginRight:e.$parent.stepOffset+"px"}},[n("i",{staticClass:"el-step__line-inner",style:e.lineStyle})]),n("span",{staticClass:"el-step__icon"},["success"!==e.currentStatus&&"error"!==e.currentStatus?e._t("icon",[e.icon?n("i",{class:["el-icon-"+e.icon]}):n("div",[e._v(e._s(e.index+1))])]):n("i",{class:["el-icon-"+("success"===e.currentStatus?"check":"close")]})],2)]),n("div",{staticClass:"el-step__main",style:{marginLeft:e.mainOffset}},[n("div",{ref:"title",staticClass:"el-step__title",class:["is-"+e.currentStatus]},[e._t("title",[e._v(e._s(e.title))])],2),n("div",{staticClass:"el-step__description",class:["is-"+e.currentStatus]},[e._t("description",[e._v(e._s(e.description))])],2)])])},staticRenderFns:[]}},function(e,t,n){"use 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e.label.toString().length>0})}},watch:{items:function(e){e.length>0&&this.setActiveItem(this.initialIndex)},activeIndex:function(e,t){this.resetItemPosition(t),this.$emit("change",e,t)},autoplay:function(e){e?this.startTimer():this.pauseTimer()}},methods:{handleMouseEnter:function(){this.hover=!0,this.pauseTimer()},handleMouseLeave:function(){this.hover=!1,this.startTimer()},itemInStage:function(e,t){var n=this.items.length;return t===n-1&&e.inStage&&this.items[0].active||e.inStage&&this.items[t+1]&&this.items[t+1].active?"left":!!(0===t&&e.inStage&&this.items[n-1].active||e.inStage&&this.items[t-1]&&this.items[t-1].active)&&"right"},handleButtonEnter:function(e){var t=this;this.items.forEach(function(n,i){e===t.itemInStage(n,i)&&(n.hover=!0)})},handleButtonLeave:function(){this.items.forEach(function(e){e.hover=!1})},updateItems:function(){this.items=this.$children.filter(function(e){return"ElCarouselItem"===e.$options.name})},resetItemPosition:function(e){var t=this;this.items.forEach(function(n,i){n.translateItem(i,t.activeIndex,e)})},playSlides:function(){this.activeIndex<this.items.length-1?this.activeIndex++:this.activeIndex=0},pauseTimer:function(){clearInterval(this.timer)},startTimer:function(){this.interval<=0||!this.autoplay||(this.timer=setInterval(this.playSlides,this.interval))},setActiveItem:function(e){if("string"==typeof e){var t=this.items.filter(function(t){return t.name===e});t.length>0&&(e=this.items.indexOf(t[0]))}if(e=Number(e),!isNaN(e)&&e===Math.floor(e)){var n=this.items.length;e<0?this.activeIndex=n-1:e>=n?this.activeIndex=0:this.activeIndex=e}},prev:function(){this.setActiveItem(this.activeIndex-1)},next:function(){this.setActiveItem(this.activeIndex+1)},handleIndicatorClick:function(e){this.activeIndex=e},handleIndicatorHover:function(e){"hover"===this.trigger&&e!==this.activeIndex&&(this.activeIndex=e)}},created:function(){var e=this;this.throttledArrowClick=(0,a.default)(300,!0,function(t){e.setActiveItem(t)}),this.throttledIndicatorHover=(0,a.default)(300,function(t){e.handleIndicatorHover(t)})},mounted:function(){var e=this;this.updateItems(),this.$nextTick(function(){(0,s.addResizeListener)(e.$el,e.resetItemPosition),e.initialIndex<e.items.length&&e.initialIndex>=0&&(e.activeIndex=e.initialIndex),e.startTimer()})},beforeDestroy:function(){this.$el&&(0,s.removeResizeListener)(this.$el,this.resetItemPosition)}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return 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r=e.clientY-t.top;r=Math.min(r,t.height-n.offsetHeight/2),r=Math.max(n.offsetHeight/2,r),i=Math.round((r-n.offsetHeight/2)/(t.height-n.offsetHeight)*360)}else{var a=e.clientX-t.left;a=Math.min(a,t.width-n.offsetWidth/2),a=Math.max(n.offsetWidth/2,a),i=Math.round((a-n.offsetWidth/2)/(t.width-n.offsetWidth)*360)}this.color.set("hue",i)},getThumbLeft:function(){if(this.vertical)return 0;var e=this.$el,t=this.color.get("hue");if(!e)return 0;var n=this.$refs.thumb;return Math.round(t*(e.offsetWidth-n.offsetWidth/2)/360)},getThumbTop:function(){if(!this.vertical)return 0;var e=this.$el,t=this.color.get("hue");if(!e)return 0;var n=this.$refs.thumb;return Math.round(t*(e.offsetHeight-n.offsetHeight/2)/360)},update:function(){this.thumbLeft=this.getThumbLeft(),this.thumbTop=this.getThumbTop()}},mounted:function(){var 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t=this.$refs.thumb,n=e.target;n!==t&&this.handleDrag(e)},handleDrag:function(e){var t=this.$el.getBoundingClientRect(),n=this.$refs.thumb;if(this.vertical){var i=e.clientY-t.top;i=Math.max(n.offsetHeight/2,i),i=Math.min(i,t.height-n.offsetHeight/2),this.color.set("alpha",Math.round((i-n.offsetHeight/2)/(t.height-n.offsetHeight)*100))}else{var r=e.clientX-t.left;r=Math.max(n.offsetWidth/2,r),r=Math.min(r,t.width-n.offsetWidth/2),this.color.set("alpha",Math.round((r-n.offsetWidth/2)/(t.width-n.offsetWidth)*100))}},getThumbLeft:function(){if(this.vertical)return 0;var e=this.$el,t=this.color._alpha;if(!e)return 0;var n=this.$refs.thumb;return Math.round(t*(e.offsetWidth-n.offsetWidth/2)/100)},getThumbTop:function(){if(!this.vertical)return 0;var e=this.$el,t=this.color._alpha;if(!e)return 0;var n=this.$refs.thumb;return Math.round(t*(e.offsetHeight-n.offsetHeight/2)/100)},getBackground:function(){if(this.color&&this.color.value){var e=this.color.toRgb(),t=e.r,n=e.g,i=e.b;return"linear-gradient(to right, rgba("+t+", "+n+", "+i+", 0) 0%, rgba("+t+", "+n+", "+i+", 1) 100%)"}return null},update:function(){this.thumbLeft=this.getThumbLeft(),this.thumbTop=this.getThumbTop(),this.background=this.getBackground()}},data:function(){return{thumbLeft:0,thumbTop:0,background:null}},mounted:function(){var e=this,t=this.$refs,n=t.bar,i=t.thumb,r={drag:function(t){e.handleDrag(t)},end:function(t){e.handleDrag(t)}};(0,a.default)(n,r),(0,a.default)(i,r),this.update()}}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{staticClass:"el-color-alpha-slider",class:{"is-vertical":e.vertical}},[n("div",{ref:"bar",staticClass:"el-color-alpha-slider__bar",style:{background:e.background},on:{click:e.handleClick}}),n("div",{ref:"thumb",staticClass:"el-color-alpha-slider__thumb",style:{left:e.thumbLeft+"px",top:e.thumbTop+"px"}})])},staticRenderFns:[]}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("transition",{attrs:{name:"el-zoom-in-top"},on:{"after-leave":e.doDestroy}},[n("div",{directives:[{name:"show",rawName:"v-show",value:e.showPopper,expression:"showPopper"}],staticClass:"el-color-dropdown"},[n("div",{staticClass:"el-color-dropdown__main-wrapper"},[n("hue-slider",{ref:"hue",staticStyle:{float:"right"},attrs:{color:e.color,vertical:""}}),n("sv-panel",{ref:"sl",attrs:{color:e.color}})],1),e.showAlpha?n("alpha-slider",{ref:"alpha",attrs:{color:e.color}}):e._e(),n("div",{staticClass:"el-color-dropdown__btns"},[n("span",{staticClass:"el-color-dropdown__value"},[e._v(e._s(e.currentColor))]),n("a",{staticClass:"el-color-dropdown__link-btn",attrs:{href:"JavaScript:"},on:{click:function(t){e.$emit("clear")}}},[e._v(e._s(e.t("el.colorpicker.clear")))]),n("button",{staticClass:"el-color-dropdown__btn",on:{click:e.confirmValue}},[e._v(e._s(e.t("el.colorpicker.confirm")))])])],1)])},staticRenderFns:[]}},function(e,t){e.exports={render:function(){var e=this,t=e.$createElement,n=e._self._c||t;return n("div",{directives:[{name:"clickoutside",rawName:"v-clickoutside",value:e.hide,expression:"hide"}],staticClass:"el-color-picker"},[n("div",{staticClass:"el-color-picker__trigger",on:{click:function(t){e.showPicker=!e.showPicker}}},[n("span",{staticClass:"el-color-picker__color",class:{"is-alpha":e.showAlpha}},[n("span",{staticClass:"el-color-picker__color-inner",style:{backgroundColor:e.displayedColor}}),e.value||e.showPanelColor?e._e():n("span",{staticClass:"el-color-picker__empty el-icon-close"})]),n("span",{staticClass:"el-color-picker__icon el-icon-caret-bottom"})]),n("picker-dropdown",{ref:"dropdown",staticClass:"el-color-picker__panel",attrs:{color:e.color,"show-alpha":e.showAlpha},on:{pick:e.confirmValue,clear:e.clearValue},model:{value:e.showPicker,callback:function(t){e.showPicker=t},expression:"showPicker"}})],1)},staticRenderFns:[]}},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(375),a=i(r);a.default.install=function(e){e.component(a.default.name,a.default)},t.default=a.default},function(e,t,n){var i=n(5)(n(376),n(380),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var r=n(31),a=i(r),s=n(15),o=i(s),l=n(10),u=i(l),c=n(377),d=i(c);t.default={name:"ElTransfer",mixins:[o.default,u.default],components:{TransferPanel:d.default,ElButton:a.default},props:{data:{type:Array,default:function(){return[]}},titles:{type:Array,default:function(){return[]}},buttonTexts:{type:Array,default:function(){return[]}},filterPlaceholder:{type:String,default:""},filterMethod:Function,leftDefaultChecked:{type:Array,default:function(){return[]}},rightDefaultChecked:{type:Array,default:function(){return[]}},renderContent:Function,value:{type:Array,default:function(){return[]}},footerFormat:{type:Object,default:function(){return{}}},filterable:Boolean,props:{type:Object,default:function(){return{label:"label",key:"key",disabled:"disabled"}}}},data:function(){return{leftChecked:[],rightChecked:[]}},computed:{sourceData:function(){var e=this;return this.data.filter(function(t){return e.value.indexOf(t[e.props.key])===-1})},targetData:function(){var e=this;return this.data.filter(function(t){return e.value.indexOf(t[e.props.key])>-1})}},watch:{value:function(e){this.dispatch("ElFormItem","el.form.change",e)}},methods:{onSourceCheckedChange:function(e){this.leftChecked=e},onTargetCheckedChange:function(e){this.rightChecked=e},addToLeft:function(){var e=this.value.slice();this.rightChecked.forEach(function(t){var n=e.indexOf(t);n>-1&&e.splice(n,1)}),this.$emit("input",e),this.$emit("change",e,"left",this.rightChecked)},addToRight:function(){var e=this,t=this.value.slice();this.leftChecked.forEach(function(n){e.value.indexOf(n)===-1&&(t=t.concat(n))}),this.$emit("input",t),this.$emit("change",t,"right",this.leftChecked)}}}},function(e,t,n){var i=n(5)(n(378),n(379),null,null,null);e.exports=i.exports},function(e,t,n){"use strict";function i(e){return e&&e.__esModule?e:{default:e}}t.__esModule=!0;var 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r="";["width","height","top","right","bottom","left"].indexOf(i)!==-1&&n(t[i])&&(r="px"),e.style[i]=t[i]+r})}function c(e){var t={};return e&&"[object Function]"===t.toString.call(e)}function d(e){var t={width:e.offsetWidth,height:e.offsetHeight,left:e.offsetLeft,top:e.offsetTop};return t.right=t.left+t.width,t.bottom=t.top+t.height,t}function h(e){var t=e.getBoundingClientRect(),n=navigator.userAgent.indexOf("MSIE")!=-1,i=n&&"HTML"===e.tagName?-e.scrollTop:t.top;return{left:t.left,top:i,right:t.right,bottom:t.bottom,width:t.right-t.left,height:t.bottom-i}}function f(e,t,n){var i=h(e),r=h(t);if(n){var a=o(t);r.top+=a.scrollTop,r.bottom+=a.scrollTop,r.left+=a.scrollLeft,r.right+=a.scrollLeft}var s={top:i.top-r.top,left:i.left-r.left,bottom:i.top-r.top+i.height,right:i.left-r.left+i.width,width:i.width,height:i.height};return s}function p(e){for(var t=["","ms","webkit","moz","o"],n=0;n<t.length;n++){var i=t[n]?t[n]+e.charAt(0).toUpperCase()+e.slice(1):e;if("undefined"!=typeof m.document.body.style[i])return i}return null}var m=window,v={placement:"bottom",gpuAcceleration:!0,offset:0,boundariesElement:"viewport",boundariesPadding:5,preventOverflowOrder:["left","right","top","bottom"],flipBehavior:"flip",arrowElement:"[x-arrow]",modifiers:["shift","offset","preventOverflow","keepTogether","arrow","flip","applyStyle"],modifiersIgnored:[],forceAbsolute:!1};return e.prototype.destroy=function(){return this._popper.removeAttribute("x-placement"),this._popper.style.left="",this._popper.style.position="",this._popper.style.top="",this._popper.style[p("transform")]="",this._removeEventListeners(),this._options.removeOnDestroy&&this._popper.remove(),this},e.prototype.update=function(){var e={instance:this,styles:{}};e.placement=this._options.placement,e._originalPlacement=this._options.placement,e.offsets=this._getOffsets(this._popper,this._reference,e.placement),e.boundaries=this._getBoundaries(e,this._options.boundariesPadding,this._options.boundariesElement),e=this.runModifiers(e,this._options.modifiers),"function"==typeof this.state.updateCallback&&this.state.updateCallback(e)},e.prototype.onCreate=function(e){return e(this),this},e.prototype.onUpdate=function(e){return this.state.updateCallback=e,this},e.prototype.parse=function(e){function t(e,t){t.forEach(function(t){e.classList.add(t)})}function n(e,t){t.forEach(function(t){e.setAttribute(t.split(":")[0],t.split(":")[1]||"")})}var i={tagName:"div",classNames:["popper"],attributes:[],parent:m.document.body,content:"",contentType:"text",arrowTagName:"div",arrowClassNames:["popper__arrow"],arrowAttributes:["x-arrow"]};e=Object.assign({},i,e);var r=m.document,a=r.createElement(e.tagName);if(t(a,e.classNames),n(a,e.attributes),"node"===e.contentType?a.appendChild(e.content.jquery?e.content[0]:e.content):"html"===e.contentType?a.innerHTML=e.content:a.textContent=e.content,e.arrowTagName){var s=r.createElement(e.arrowTagName);t(s,e.arrowClassNames),n(s,e.arrowAttributes),a.appendChild(s)}var o=e.parent.jquery?e.parent[0]:e.parent;if("string"==typeof o){if(o=r.querySelectorAll(e.parent),o.length>1&&console.warn("WARNING: the given `parent` query("+e.parent+") matched more than one element, the first one will be used"),0===o.length)throw"ERROR: the given `parent` doesn't exists!";o=o[0]}return o.length>1&&o instanceof Element==!1&&(console.warn("WARNING: you have passed as parent a list of elements, the first one will be used"),o=o[0]),o.appendChild(a),a},e.prototype._getPosition=function(e,t){var n=s(t);if(this._options.forceAbsolute)return"absolute";var i=l(t,n);return 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e==document.body?Math.max(document.documentElement.scrollLeft,document.body.scrollLeft):e.scrollLeft},g="fixed"===e.offsets.popper.position?0:p(h),y="fixed"===e.offsets.popper.position?0:v(h);a={top:0-(f.top-g),right:m.document.documentElement.clientWidth-(f.left-y),bottom:m.document.documentElement.clientHeight-(f.top-g),left:0-(f.left-y)}}else a=s(this._popper)===n?{top:0,left:0,right:n.clientWidth,bottom:n.clientHeight}:d(n);return a.left+=t,a.right-=t,a.top=a.top+t,a.bottom=a.bottom-t,a},e.prototype.runModifiers=function(e,t,n){var i=t.slice();return void 0!==n&&(i=this._options.modifiers.slice(0,r(this._options.modifiers,n))),i.forEach(function(t){c(t)&&(e=t.call(this,e))}.bind(this)),e},e.prototype.isModifierRequired=function(e,t){var n=r(this._options.modifiers,e);return!!this._options.modifiers.slice(0,n).filter(function(e){return e===t}).length},e.prototype.modifiers={},e.prototype.modifiers.applyStyle=function(e){var t,n={position:e.offsets.popper.position},i=Math.round(e.offsets.popper.left),r=Math.round(e.offsets.popper.top);return this._options.gpuAcceleration&&(t=p("transform"))?(n[t]="translate3d("+i+"px, "+r+"px, 0)",n.top=0,n.left=0):(n.left=i,n.top=r),Object.assign(n,e.styles),u(this._popper,n),this._popper.setAttribute("x-placement",e.placement),this.isModifierRequired(this.modifiers.applyStyle,this.modifiers.arrow)&&e.offsets.arrow&&u(e.arrowElement,e.offsets.arrow),e},e.prototype.modifiers.shift=function(e){var t=e.placement,n=t.split("-")[0],r=t.split("-")[1];if(r){var a=e.offsets.reference,s=i(e.offsets.popper),o={y:{start:{top:a.top},end:{top:a.top+a.height-s.height}},x:{start:{left:a.left},end:{left:a.left+a.width-s.width}}},l=["bottom","top"].indexOf(n)!==-1?"x":"y";e.offsets.popper=Object.assign(s,o[l][r])}return e},e.prototype.modifiers.preventOverflow=function(e){var t=this._options.preventOverflowOrder,n=i(e.offsets.popper),r={left:function t(){var t=n.left;return n.left<e.boundaries.left&&(t=Math.max(n.left,e.boundaries.left)),{left:t}},right:function(){var t=n.left;return n.right>e.boundaries.right&&(t=Math.min(n.left,e.boundaries.right-n.width)),{left:t}},top:function t(){var t=n.top;return n.top<e.boundaries.top&&(t=Math.max(n.top,e.boundaries.top)),{top:t}},bottom:function(){var t=n.top;return n.bottom>e.boundaries.bottom&&(t=Math.min(n.top,e.boundaries.bottom-n.height)),{top:t}}};return t.forEach(function(t){e.offsets.popper=Object.assign(n,r[t]())}),e},e.prototype.modifiers.keepTogether=function(e){var t=i(e.offsets.popper),n=e.offsets.reference,r=Math.floor;return t.right<r(n.left)&&(e.offsets.popper.left=r(n.left)-t.width),t.left>r(n.right)&&(e.offsets.popper.left=r(n.right)),t.bottom<r(n.top)&&(e.offsets.popper.top=r(n.top)-t.height),t.top>r(n.bottom)&&(e.offsets.popper.top=r(n.bottom)),e},e.prototype.modifiers.flip=function(e){if(!this.isModifierRequired(this.modifiers.flip,this.modifiers.preventOverflow))return console.warn("WARNING: 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