The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review

The role of therapeutic MicroRNA in... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/13-470" }, "headline": "The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review", "datePublished": "2024-05-09T17:12:54", "dateModified": "2024-11-14T15:17:25", "author": [ { "@type": "Person", "name": "Muhamad Taufik Ismail" }, { "@type": "Person", "name": "Dyah Wulan Anggrahini" }, { "@type": "Person", "name": "Sofia Mubarika Haryana" }, { "@type": "Person", "name": "Budi Yuli Setianto" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease (PAD) and has poor clinical outcomes. Recently, stimulating arteriogenesis has been proposed to improve clinical outcomes. Several studies have shown that miRNAs have beneficial effects on limb ischemia related to arteriogenesis. This study aimed to review the roles of therapeutic miRNAs in the arteriogenesis of limb ischemia. Methods A systematic search was conducted through July 2021 using the PubMed, Scopus, and ScienceDirect databases. Two authors independently assessed studies that investigated the role of miRNAs in the arteriogenesis of limb ischemia, both in vivo and in clinical studies. Results All selected studies were in vivo studies, with a total of 36 articles and 28 types of miRNAs. miRNAs potentially regulate arteriogenesis by targeting different targets. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. MiRNA-126 was the most studied miRNA, and SPRED1 was the most common target of microRNA. However, the included studies showed high heterogeneity in terms of inducing hindlimb ischemia, the timing of administration, and the method used for evaluating arteriogenesis. Moreover, most studies presented unclear or high-risk bias. Conclusion MicroRNA application in a preclinical model of hindlimb ischemia has beneficial effects on arteriogenesis. This result indicates that miRNAs might be potentially beneficial in patients with CLTI. Registration The review protocol was registered with PROSPERO under registration number CRD42024484988. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-470/v2", "name": "The role of therapeutic MicroRNA in arteriogenesis process in limb..." } } ] } Home Browse The role of therapeutic MicroRNA in arteriogenesis process in limb... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Ismail MT, Anggrahini DW, Haryana SM and Setianto BY. The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.12688/f1000research.147482.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] Muhamad Taufik Ismail https://orcid.org/0000-0002-8239-997X 1 , Dyah Wulan Anggrahini 1 , Sofia Mubarika Haryana 2 , Budi Yuli Setianto 1 Muhamad Taufik Ismail https://orcid.org/0000-0002-8239-997X 1 , Dyah Wulan Anggrahini 1 , Sofia Mubarika Haryana 2 , Budi Yuli Setianto 1 PUBLISHED 14 Nov 2024 Author details Author details 1 Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia 2 Histology and Cell Biology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia Muhamad Taufik Ismail Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Dyah Wulan Anggrahini Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Sofia Mubarika Haryana Roles: Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Budi Yuli Setianto Roles: Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease (PAD) and has poor clinical outcomes. Recently, stimulating arteriogenesis has been proposed to improve clinical outcomes. Several studies have shown that miRNAs have beneficial effects on limb ischemia related to arteriogenesis. This study aimed to review the roles of therapeutic miRNAs in the arteriogenesis of limb ischemia. Methods A systematic search was conducted through July 2021 using the PubMed, Scopus, and ScienceDirect databases. Two authors independently assessed studies that investigated the role of miRNAs in the arteriogenesis of limb ischemia, both in vivo and in clinical studies. Results All selected studies were in vivo studies, with a total of 36 articles and 28 types of miRNAs. miRNAs potentially regulate arteriogenesis by targeting different targets. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. MiRNA-126 was the most studied miRNA, and SPRED1 was the most common target of microRNA. However, the included studies showed high heterogeneity in terms of inducing hindlimb ischemia, the timing of administration, and the method used for evaluating arteriogenesis. Moreover, most studies presented unclear or high-risk bias. Conclusion MicroRNA application in a preclinical model of hindlimb ischemia has beneficial effects on arteriogenesis. This result indicates that miRNAs might be potentially beneficial in patients with CLTI. Registration The review protocol was registered with PROSPERO under registration number CRD42024484988. READ ALL READ LESS Keywords Keywords: microRNA, arteriogenesis, limb ischemia, gene target Corresponding Author(s) Muhamad Taufik Ismail ( [email protected] ) Close Corresponding author: Muhamad Taufik Ismail Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Ismail MT et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Ismail MT, Anggrahini DW, Haryana SM and Setianto BY. The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.12688/f1000research.147482.2 ) First published: 09 May 2024, 13 :470 ( https://doi.org/10.12688/f1000research.147482.1 ) Latest published: 14 Nov 2024, 13 :470 ( https://doi.org/10.12688/f1000research.147482.2 ) Revised Amendments from Version 1 We revised a sentence from introduction that explains the role of miRNA in the angiogenic signalling pathway to prevent potential misunderstanding. The original sentence was written in a way that suggested miRNA could signal independently, whereas in fact, miRNA requires interaction with proteins to exert its effect. We also added method used to reduce risk of interobserver bias, improved resolution of the figure, and made a minor revision to clarify that curcumin does not contain miRNA but rather upregulates miRNA expression. We revised a sentence from introduction that explains the role of miRNA in the angiogenic signalling pathway to prevent potential misunderstanding. The original sentence was written in a way that suggested miRNA could signal independently, whereas in fact, miRNA requires interaction with proteins to exert its effect. We also added method used to reduce risk of interobserver bias, improved resolution of the figure, and made a minor revision to clarify that curcumin does not contain miRNA but rather upregulates miRNA expression. See the authors' detailed response to the review by Brian H Annex READ REVIEWER RESPONSES Introduction Chronic limb-threatening ischemia (CLTI) is a severe form of peripheral artery disease (PAD) due to the blockage of blood vessels. 1 Its amputation and mortality rates using a conservative approach are still high at 27% and 18% at 12 months after diagnosis, respectively, 2 despite being successfully revascularized. 3 , 4 Patients who present with late-onset and severe degree of tissue damage have the highest risk of amputation. 4 Therefore, other therapeutic approaches need to be developed. Genetic or cellular-based therapeutic approaches have been developed to increase neovascularization in the form of arteriogenesis and angiogenesis. 1 Unfortunately, angiogenesis is inadequate for replacing occluded or stenotic arteries. Furthermore, the long distance between the stenotic vessel and tissue hypoperfusion makes it more relevant to arteriogenesis than angiogenesis. 5 Therefore, patients with CLTI generally require more arteriogenesis than angiogenesis. 6 Studies on stem cell therapy for CLTI in clinical studies recently has not yet shown promising outcome. 1 It is possibly due to inability of stem cells in the ischemic condition. 6 Similar result occurred with the trials of growth factors administration in CLTI patients. 7 The expectation of increase neovascularization to compensate the ischemic limb, comes into a failure due to angiogenic signaling resistance. Therefore, miRNAs may offer a solution by alleviating impaired angiogenic signaling pathways and overcoming angiogenic resistance. 8 Several miRNAs can improve arteriogenesis through different signaling pathways, either by increasing or inhibiting their expression depending on a specific type of miRNA. 8 Arteriogenesis consists of two phases: an early inflammatory phase followed by an increase in blood vessel diameter, remodeling, and vessel maturation. Furthermore, several processes including proliferation of endothelial cells, smooth muscle cells, and remodeling of tunica adventitia are also essential for arteriogenesis. 9 MicroRNAs can interfere those processes through gene regulation, since several genes are needed, particularly involved in the proliferation of endothelial cells, smooth muscle cells, activation of adhesion molecules, regulation of extracellular matrix, and regulation of growth factors and their receptors. 10 Therefore, this study was aimed to review the role of therapeutic microRNAs in arteriogenesis process of limb ischemia. Methods The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (registration number: CRD42024484988), however the protocol has yet to be published. We performed this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Search strategy We searched for basic and clinical studies published in the PubMed, Scopus, and ScienceDirect databases on July 25, 2021. The literature is limited to English. We use the PICO strategy to answer this research question. The following terms were used for the literature search: (peripheral arterial disease OR peripheral artery disease OR chronic limb threatening Ischemia OR critical limb ischemia OR hindlimb Ischemia OR hind-limb ischemia OR femoral artery ligation OR hindlimb) AND (microRNA OR microRNAs OR miRNAs OR “micro RNA” OR miRNA OR “micro RNAs”) AND (angiogenesis OR arteriogenesis OR neovascularization OR collateral). Eligibility criteria Two authors (MT and DA) independently assessed the eligibility of the studies. The inclusion criteria were as follows: 1) Explaining the role of miRNAs in the arteriogenesis process of limb ischemia, either in vivo or clinical studies; 2) if in vivo study, inducing limb ischemia in animal models must be clearly described; 3) articles published in full-text journals; 4) Articles in English; and 5) articles assessing arteriogenesis using imaging or staining methods. The exclusion criteria were as follows: 1) the study involved only an in vitro study, 2) there was no control group in an in vivo study, and 3) the study was not conducted as primary research. Data extraction Two authors independently extracted the data from the included studies (MT and DA). The extracted data included the author’s name, publication year, animal models (type of animal, strain, age, how to induce limb ischemia, concomitant conditions, and if any animal gender was also included), type of microRNA, administration method in intervention and control groups, and techniques for evaluating arteriogenesis, including time points of assessment and outcomes. Any disagreements between the authors were resolved through discussion with senior reviewers (BY and SM) to reach a consensus. Owing to the high heterogeneity of the included studies, a meta-analysis could not be conducted. We developed ‘Characteristics of study’ tables to summarize and compare the data above. Risk of bias assessment The risk of bias was evaluated by two authors (MT and DA) using the SYRCLE’s risk of bias tool for animal studies. Disagreements were resolved through discussion. Results Search results A systematic search of several databases identified 1317 relevant papers for this study (PRISMA Flowchart for The Systematic Review). 59 A total of 130 articles remained after removing duplicate publications and screening titles and abstracts. Furthermore, 3 articles with no full text available and 91 studies were not included because there was no analysis of miRNA in arteriogenesis. Therefore, 36 articles with 28 types of miRNAs were eligible for further analysis in this systematic review. The selected articles showed substantial heterogeneity, including animal models, intervention approaches, control groups, timing of administration, and methodology used to assess arteriogenesis. Study characteristics All the selected studies in Characteristics of Study ( Table 1 ) 59 show that strain, animal models, concomitant conditions, and techniques used to induce limb ischemia varied among studies. Almost all of the studies (n=35, 97,2%) used a rodent as a model, of which 33 studies used mice and 2 studies used rats. BALB/c and C57Bl/6 were the most commonly used mouse strains. The two strains used in this study were Fischer and Adult Sprague-Dawley rats. Furthermore, only one study used New Zealand White rabbits. Regarding concomitant conditions, diabetic mice were used in five studies and immunocompromised mice were used in two studies, 2 studies used hypercholesterolemic mice model, and 1 study used aging mice. Three studies used genetically modified mice compared to wild-type mice to determine the effect of a specific type of microRNA on arteriogenesis. Moreover, the techniques used to create hindlimb ischemia vary widely varied. 59 Table 1. MicroRNAs involved in arteriogenesis. MiRNA Expression (Therapeutic Purpose) Details Target let-7g ↑ • let-7g enhanced expression of VEGF-A and VEGFR-2 through targeting HIF-3α and TP53. Moreover, let-7g influenced the splicing factor SC35, which consequently increased the alternative splicing of VEGF-A, from VEGF-A 165b (anti-angiogenic isoform) to VEGF-A 164a (pro-angiogenic isoform). 11 HIF-3α and TP53. 15a/16 ↓ • Inhibition of miR-15a/16 enhanced arteriogenesis and angiogenesis in a mouse model of limb ischemia. 12 • Overexpression of miR-15a or-16 decreased Tie2 at the protein level. 13 • VEGF-A and AKT3 • Tie2 14q32 microRNA gene cluster ↓ • Inhibition of miR-329, miR-487b, miR-494, and miR-495 led to arteriogenesis and angiogenesis. 10 - 15b/5p ↓ • Regulating arteriogenesis and angiogenesis via targeting AKT3/eNOS pathway. 14 AKT3 21 ↑ • Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) contained miR-21 which repaired neovascularization by increasing the activity of HIF-1α by targeting CHIP. 15 CHIP 29a ↓ • Downregulation of MiR29a and upregulation of ADAM12 in ischemia with hyperglycemia state was impaired. Knocking down miR29a was adequate for fixing ADAM12 upregulation in ischemia with a hyperglycemia state. Hence, improving perfusion and angiogenesis even when vascular endothelial growth factor signaling was impaired. 16 ADAM12 92a ↓ • Inhibition of miR-92a contributed to enhancing angiogenesis and arteriogenesis. 17 mRNA encoding integrin subunit alpha5 93 ↑ • miR-93 impeded interferon regulatory factor-9 to reduce the production of IRG1–itaconic acid, therefore it stimulated M2-like polarization in ischemic muscle. Consequently, it increased angiogenesis, arteriogenesis, and blood perfusion. 18 Another study showed that curcumin improved angiogenesis and arteriogenesis by promoting the expression of miR-93. 19 • miR-93 increased arteriogenesis and angiogenesis by regulating the expression of multiple genes that coordinated the pathway of apoptosis and cell proliferation. 20 • miR-93 inhibited CDKN1A expression at the mRNA and protein expression levels. Hence, promoting arteriogenesis and angiogenesis. 21 • interferon regulatory factor-9 (IRF9) multiple genes • Cyclin dependent kinase inhibitor 1A (CDKN1A) gene 100 ↓ mTOR expression was down-regulated in endothelial cells and vascular smooth muscle cells by overexpression of miR-100, hence it decreased cellular proliferation. 22 mTOR 124-3p ↓ Overexpression of miR-124-3p reduced STAT3 protein expression levels. Hence, mir 124-3p impaired perfusion and angiogenesis. 23 STAT3 126 ↑ • CD34Exo contained high level of miR-126-3p which enhanced arteriogenesis and angiogenesis by suppressing the expression of SPRED1. Hence, modulating severals genes expression (VEGF, angiopoietin 1, angiopoietin 2, MMP9, thrombospondin 1, etc). 24 • The sustained release of miR-126 loaded with poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) enhanced perfusion and angiogenesis by suppressing the expression of SPRED1. 25 Another study showed that miR-126 loaded with Bubble liposomes had the same result. 26 • Adipose-Derived Stem Cell Therapeutic Factor Concentrate had a high level of miR-126, which increased perfusion and angiogenesis. 27 • MiR-126-3p repaired perfusion and angiogenesis by suppressing the expression of SPRED1 and PIK3R2. 28 SPRED1, PIK3R2 130a ↑ Overexpression of miR-130a decreased the expression of MEOX2 and HOXA5 (antiangiogenic genes). Those genes were up-regulated in ischemic muscles of aging mice. Hence, miR-130a improved perfusion and angiogenesis in ischemia related to aging. 29 MEOX2 and HOXA5 132/212 ↑ MiR-132/212 enhanced the Ras-Mitogen-activated protein kinase MAPK signaling pathway through direct inhibition of Rasa1 and Spred1. The miR-132/212 cluster could enhance arteriogenesis by regulating the Ras-MAPK signaling pathway via direct targeting of the inhibitors Rasa1 and Spred1. 30 RASA1, SPRY1, SPRED1 133a ↓ In models of occlusive artery disease with diabetes, overexpression of miR-133a inhibited NO- CGMP angiogenic pathway via targeting GCH1. 31 GCH1 139-5p ↓ The diabetic condition led to overexpression of miR-139-5p in endothelial cells, thereby it inhibited the c-jun pathway and downregulated the expression of VEGF and PDGF-β. Hence, contributing in the reduction of ECFC migration, proliferation, and tube formation, which consequently diminished endothelial cell survival. 32 c-jun pathway 143-3p ↑ In vivo study showed that increased expression of microRNA 143-3p in response to fluid shear stress could play a role in the reorganization of the extracellular matrix which was important in the process of vascular remodeling through inhibition of V-á2 collagen biosynthesis. 33 V-á2 collagen 146b ↑ miR-146b promoted angiogenesis and arteriogenesis through targets TRAF6 and impeded oxLDL-induced TRAF6-TNFa inflammatory pathway. Therefore, decreased miR-146b expression led to impair arteriogenesis and angiogenesis in hypercholesterolemic conditions. 34 TRAF6 146a ↓ Anti microRNA 146a in vivo with femoral artery ligation model showed a 22% increase in collateral artery diameter compared to controls. However, there was no beneficial effect in the process of angiogenesis or muscle regeneration. These effects occurred by upregulation of pro-inflammatory (i.e., NFκB) endothelial cell activation. In addition, arteriogenesis was also possibly mediated via pericollateral Ly6C hi monocyte proliferation and/or migration. 35 NFκB 150 ↑ Hypercholesterolemia and exposure to oxidized LDL were associated with increased expression of SRC kinase signaling inhibitor 1 and decreased Src activity. MiR-150 mimics could reduce the expression of SRC kinase signaling inhibitor 1 and restored Src activity and Akt (protein kinase B) activity. Hypercholesterolemia was associated with decreased miR-150 expression, impaired Src signaling pathway, and inefficient neovascularization in response to ischemia. Administration of miR-150 using miR mimics might be a new therapeutic strategy to enhance ischemia-induced neovascularization in atherosclerotic conditions. 36 SRCIN-1 155 ↑ MicroRNA 155 had the opposite effect as proarteriogenic and antiangiogenic. Its expression in endothelial cells and bone marrow–derived cells was important for arteriogenesis in response to ischemia. MiRNA-155 directly suppressed SOCS1 in monocytes or macrophages, which was a negative feedback regulator of JAK-STAT signaling. Hence, miRNA-155 enhanced monocyte/macrophage rolling, adhesion, migration, and the production of pro-arteriogenic cytokine. 37 SOCS1 199a-5p ↓ miR-199a-5p suppressed gene expression of pro-arteriogenic (IKKb, Cav1) and inhibited pericollateral macrophage recruitment. In addition, overexpression of miR-199a reduced collateral artery growth by ±25% (±2.4-fold decrease in conductance) and inhibition of miR-199a increased arteriogenesis by 36% (>3.4-fold conductance increase). 38 IKKb, Cav1 210 ↑ miR-210 diminished ROS in endothelial cells and ischemic muscle tissue through downregulated P4HB protein levels in EC under a hypoxic environment. 39 P4HB 223 ↓ miR-223 deterred endothelial cell proliferation by targeting β1 integrin. 40 β1 integrin 352 ↓ Anti miR-352 increased the expression of insulin-like growth factor II receptor (IGF2R), which may contribute in the complex pathway for arterial growth. Furthermore, infusion of antagomir miR-352 could enhance collateral vessel growth. 41 IGF2R 503 ↓ Inhibition of miR-503 in ischemic adductor muscle ameliorated post-ischemic blood flow restoration in a mouse model which involved the CDC25A target. 42 CDC25A 615-5p ↓ miR-615-5p impeded the VEGF-AKT/eNOS signaling pathway in endothelial cells by directly reduced the level of Ras-associating domain family member 2 (RASSF2) and insulin-like growth factor 2 (IGF2). 43 RASSF-2 dan IGF-2 675 ↑ Incorporating miR-675 into exosomes encapsulated in silk fibroin hydrogel promoted blood perfusion by inhibiting the TGF-β1/p21 signaling pathway. 44 TGF-β1/p21 pathway 939-5p ↓ miR-939-5p in exosomes from patients with myocardial ischemia (isc-Exo) inhibited the expression and activity of iNOS, therefore it reduced NO production in endothel. Consequently, it impaired angiogenesis and arteriogenesis. 45 iNOS The therapeutic and timing of administration varied among the included studies. Intramuscular injection was the most commonly used (n=21), followed by tail vein (n=5), intra-arterial (n=2), oral (n=1), retro-orbital (n=1), and not clearly explained (n=1). Meanwhile, there were 3 studies that did not use therapeutic agents (owing to genetic modification). Regarding the timing of administration, 11 studies performed repeated administration at different time points: 10 studies administered agent immediately after ligation, 2 studies administered drug one day before ligation, one study delivered agent 30 min before ligation, one study administered agent on day 1 after ligation, one study gave agent on day 7 after ligation. Unfortunately, 7 studies did not clearly state when the agent was administered. The methods used to evaluate arteriogenesis also varied among the included studies. Imaging techniques were the most commonly used among the studies, from which 31 studies used laser Doppler perfusion imaging, one study used high-resolution laser color Doppler imaging, one study used laser speckle perfusion imaging, one study used contrast-enhanced ultrasound (CEU), one study used periCam perfusion speckle imager, two studies used whole-mount vascular casting, one study used postmortem vascular casting, and one study used postmortem angiogram. Staining methods were also used, and α-smooth muscle actin (α-SMA) staining was the most commonly used method, either by immunohistochemistry or immunofluorescence (n=12). Some of the techniques were combined, of which the most common combination was laser Doppler perfusion imaging and α-smooth muscle actin (α-SMA) staining (n=11). The duration of outcome observation varied among the studies from 7 days to 48 days. The observation time points varied during the observation period. Table 1 shows that, depending on the specific type of miRNA, some miRNAs need to be upregulated or downregulated to enhance arteriogenesis and vice versa. Some of microRNAs need to be upregulated, namely, miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. In contrast, several microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. Several microRNAs were loaded when administered to hindlimb ischemia models, namely microRNA-126 was naturally contained in CD34Exo and adipose-derived stem cell therapeutic factor concentrate. MicroRNA-939-5p was abundant in exosomes from patients with myocardial ischemia (isc-Exo). Furthermore, microRNA-21 is abundant in umbilical cord blood-derived mesenchymal stem cells (UCBMSCs). Finally, curcumin modulate the expression of microRNA-93. Table 1 also shows that miR-126 and miR-93 are the most commonly assessed miRNAs in hindlimb ischemia. Regarding the therapeutic target of microRNAs, SPRED1 was the most common, namely miR-126 and -132/212. Risk of bias assessment SYRCLE’s risk of bias tool for animal studies was used to assess the risk of bias, and the outcomes are shown in Risk of Bias Assessment. 59 In most studies, the risk of bias fell into two categories: “unclear” or “high.” In particular, the majority of studies did not specify the adequacy of the generation and application of the allocation sequence, the concealment of allocation to different groups during the experiment, or the random housing or selection of animals for outcome assessment, whether investigators were blinded to the interventions received by each animal, or whether the outcome assessor was blinded. Discussion This study aimed to systematically search and review the literature on the therapeutic potential of microRNAs in limb ischemia. To date, only in vivo studies have evaluated the potential role of miRNAs in arteriogenesis. Depending on the specific type, the expression could lead to enhanced or decreased arteriogenesis. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. These miRNAs have different target sites in arteriogenesis, with miRNA-126 being the most studied ( Figure 1 ). The high heterogeneity among selected studies in terms of microRNA used, techniques for inducing limb ischemia, administration methods in intervention and control groups, and techniques for evaluating arteriogenesis as well as time-points of outcome assessment, hindered the performance of a meta-analysis. Figure 1. Proposed mechanism of several microRNAs in arteriogenesis process. In this study, mice were the most commonly used limb ischemia models because of their practical aspects and their similarity to humans in terms of neovascularization patterns and genetic aspect. 46 – 48 Moreover the availability of several transgenic mice might be the reason for preferring the use of mice, as shown in these studies. Unfortunately, only two studies were performed in immunocompromised mice, since miRNAs might stimulate immune responses, including macrophages and T cells, and thus might affect the outcome of arteriogenesis. 46 , 49 The technical approach for inducing limb ischemia was also widely varied in this study, which might affect the arteriogenesis outcome. Double ligation of the iliac and femoral arteries causes severe ischemia rather than single ligation. Moreover, the ligation approach is better than electrocoagulation since recoil will not occur. 46 Concurrent ligation and excision methods will increase the severity level of ischemia. 50 Regarding to sex animal models, most of the selected studies used male due to hinder the effects of estrogen on vascular regrowth. 51 Unfortunately, several studies did not clearly declare animal sex, and two studies in rabbits and mice used female sex. Imaging techniques can assess arteriogenesis anatomically or functionally. 52 In this study, most studies used a functional approach such as laser doppler perfusion imaging which assesses restoration of tissue perfusion, equivalent to the sign of effective arteriogenesis. 52 The anatomical approaches used in this study were whole mount vascular casting, postmortem vascular casting, and postmortem angiogram. A combination of anatomical and functional approaches can provide more insight into both the visual and quantitative extent of circulation formation and its functional effectiveness. 52 In this study, miR-199a-5p and miR-146 were assessed using both methods. In addition to imaging methods, histological staining has also been used to assess arteriogenesis. 53 Unfortunately, none of these studies used a combination of anatomical, functional imaging, and histological staining. Such a combination may yield more reliable results. In general, the arteriogenesis process requires endothelial and smooth muscle cell proliferation, in which growth factor is crucial to proliferate smooth muscle cells. In the later process, adventitia remodeling through activation and proliferation of fibroblast caused enlargement of lumen vessels. 9 Nevertheless, the exact molecular mechanisms involved in all multifactorial arteriogenesis process is still not fully understood. 54 However, recent evidence showed that microRNA is involved in signaling pathways related to arteriogenesis. 8 As shown in this study, microRNAs affect several pathways related to arteriogenesis, such as Ras-MAPK, TGF-β1/p21, AKT3/eNOS, and JAK-STAT signaling pathway. Table 1 also shows that miRNAs can lead to arteriogenesis by directly targeting several genes and proteins. VEGF-A is essential for endothelial proliferation by binding to VEGFR-2 to stimulate intracellular signaling process. 55 That evidence is supported in this study, in which promoting mir126 and letting 7 g as well as inhibiting mir 15a/16 activate VEGF, leading to arteriogenesis. Another study showed that an increase in miR-139-5p expression in diabetic mice led to downregulation of VEGF, consequently decreasing arteriogenesis. Moreover, miR-223, 100, and 93 also affect cell proliferation by binding to their respective targets, ultimately affecting arteriogenesis. Macrophage recruitment is essential for arteriogenesis. Activated macrophages produce TNF-α, growth factor, and chemokines and recruit more monocytes, thereby promoting arteriogenesis. 9 Those results were supported by the results of the present study, in which miRNAs 199a-5p, 146a, and 155 had a role in macrophage recruitment. Moreover, macrophage polarization to an anti-inflammatory macrophage type 2 in ischemic muscle, shown by miR-93, is essential during post-ischemic vascular injury and repair, since M2 macrophages are pro-angiogenic. 56 In this study, the delivery approach varied; however, most of them used intramuscular injections. However, all delivery approaches, including tail vein, intravenous injection, oral, retro-orbital, and intra-arterial, showed positive results related to arteriogenesis. These results suggested that miRNAs have systemic effects. Depending on the specific type of microRNA, all studies that used concomitant conditions such as diabetic and hypercholesterolemic mice showed positive results in arteriogenesis. These results might suitably explain the use of microRNAs in humans, since CLTI is strongly associated with cardiovascular risk factors, such as diabetes mellitus and dyslipidemia. 57 Aging mice might also be analogous to patients with CLTI due to the increasing number of CLTI in the older population. 58 The application of SYRCLE’s risk of bias tool to assess animal studies revealed a prevalent “unclear” or “high” risk of bias across the majority of cases. These studies exhibited deficiencies in essential aspects, such as the generation and application of allocation sequences, allocation concealment, randomization of housing, selection for outcome assessment, and blinding of investigators and outcome assessors. Therefore, these results should be cautiously interpreted. Our systematic review had several limitations. First, we reviewed only studies published in English. Second, all research conducted in animal models had high heterogeneity related to inducing hindlimb ischemia, intervention, and outcome assessment methods. Therefore, clinical studies in humans are required to verify the effect of miRNA modulation using mimic and/or inhibitor miRNAs in patients with chronic limb-threatening ischemia. Conclusion Taken together, our review identifies several miRNAs in preclinical models that show potential for therapeutic purposes to enhance arteriogenesis in patients with chronic limb-threatening ischemia. Hence, a study involving patients with chronic limb-threatening ischemia is required. Data availability Underlying data All data underlying the results are available as part of the article and no additional source data are required. Extended data Figshare: The Role of Therapeutic MicroRNA in Arteriogenesis Process in Limb Ischemia: A Systematic Review. DOI: https://doi.org/10.6084/m9.figshare.25036163.v3 . 59 This project contains the following extended data: • PRISMA Flowchart for The Systematic Review • Table 1. Characteristics of Study • Risk of Bias Assessment • Completed PRISMA checklist Data are available under the terms of the Creative Commons Zero CC0. Acknowledgements We thank Hariadi, Yohanes William, Tinanda Tarigan, Afif Ramadhan, and Jessica Eve from Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health and Nursing Gadjah Mada University, Sleman, Indonesia for their technical support, all of whom approved their inclusion. References 1. Conte MS, Bradbury AW, Kolh P, et al. : Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur. J. Vasc. Endovasc. Surg. 2019; 58 (1): S1–S109.e33. PubMed Abstract | Publisher Full Text | Free Full Text 2. van Reijen NS , Hensing T, Santema TKB, et al. : Outcomes of conservative treatment in patients with chronic limb threatening ischaemia: A systematic review and meta-analysis. Eur. J. Vasc. Endovasc. Surg. 2021; 62 (2): 214–224. PubMed Abstract | Publisher Full Text 3. Fridh EB, Andersson M, Thuresson M, et al. : Amputation rates, mortality, and pre-operative comorbidities in patients revascularised for intermittent claudication or critical limb ischaemia: A population based study. Eur. J. Vasc. Endovasc. Surg. 2017; 54 (4): 480–486. Publisher Full Text 4. Reinecke H, Unrath M, Freisinger E, et al. : Peripheral arterial disease and critical limb ischaemia: Still poor outcomes and lack of guideline adherence. Eur. Heart J. 2015; 36 (15): 932–938. PubMed Abstract | Publisher Full Text 5. Scholz D, Cai WJ, Schaper W: Arteriogenesis, a new concept of vascular adaptation in occlusive disease. Angiogenesis. 2001; 4 (4): 247–257. PubMed Abstract | Publisher Full Text 6. Caicedo D, Devesa P, Arce VM, et al. : Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage. Ther. Adv. Cardiovasc. Dis. 2018; 12 (2): 53–72. PubMed Abstract | Publisher Full Text | Free Full Text 7. Iyer SR, Annex BH: Therapeutic angiogenesis for peripheral artery disease: Lessons learned in translational science. JACC Basic Transl. Sci. 2017; 2 (5): 503–512. PubMed Abstract | Publisher Full Text | Free Full Text 8. Pérez-Cremades D, Cheng HS, Feinberg MW: Noncoding RNAs in critical limb ischemia. Arterioscler. Thromb. Vasc. Biol. 2019; 40 : 523–533. PubMed Abstract | Publisher Full Text | Free Full Text 9. Hutchings G, Kruszyna Ł, Nawrocki MJ, et al. : Molecular mechanisms associated with ros-dependent angiogenesis in lower extremity artery disease. Antioxidants. 2021; 10 (5). PubMed Abstract | Publisher Full Text | Free Full Text 10. Welten SMJ, Bastiaansen AJNM, de Jong RCM , et al. : Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 increases neovascularization and blood flow recovery after ischemia. Circ. Res. 2014; 115 (8): 696–708. PubMed Abstract | Publisher Full Text 11. Hsu PY, Hsi E, Wang TM, et al. : MicroRNA let-7g possesses a therapeutic potential for peripheral artery disease. J. Cell. Mol. Med. 2017; 21 (3): 519–529. PubMed Abstract | Publisher Full Text | Free Full Text 12. Spinetti G, Fortunato O, Caporali A, et al. : MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia. Circ. Res. 2013; 112 (2): 335–346. PubMed Abstract | Publisher Full Text | Free Full Text 13. Besnier M, Shantikumar S, Anwar M, et al. : miR-15a/-16 inhibit angiogenesis by targeting the tie2 coding sequence: Therapeutic potential of a miR-15a/16 decoy system in limb ischemia. Mol. Ther. Nucleic Acids. 2019; 17 : 49–62. PubMed Abstract | Publisher Full Text | Free Full Text 14. Zhu LP, Zhou JP, Zhang JX, et al. : MiR-15b-5p regulates collateral artery formation by targeting AKT3 (Protein Kinase B-3). Arterioscler. Thromb. Vasc. Biol. 2017; 37 (5): 957–968. PubMed Abstract | Publisher Full Text 15. Zhou Y, Zhu Y, Zhang L, et al. : Human stem cells overexpressing MIR-21 promote angiogenesis in critical limb ischemia by targeting CHIP to enhance HIF-1α activity. Stem Cells. 2016; 34 (4): 924–934. PubMed Abstract | Publisher Full Text 16. Chen L, Okeke E, Ayalew D, et al. : Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia. Exp. Biol. Med. 2017; 242 (14): 1432–1443. PubMed Abstract | Publisher Full Text | Free Full Text 17. Bonauer A, Carmona G, Iwasaki M, et al. : MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009; 324 (5935): 1710–1713. PubMed Abstract | Publisher Full Text 18. Ganta VC, Choi MH, Kutateladze A, et al. : A microRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation. 2017; 135 (24): 2403–2425. PubMed Abstract | Publisher Full Text | Free Full Text 19. Zhang J, Wang Q, Rao G, et al. : Curcumin improves perfusion recovery in experimental peripheral arterial disease by upregulating microRNA-93 expression. Exp. Ther. Med. 2019; 17 (1): 798–802. PubMed Abstract | Publisher Full Text | Free Full Text 20. Hazarika S, Farber CR, Dokun AO, et al. : MicroRNA-93 controls perfusion recovery after hindlimb ischemia by modulating expression of multiple genes in the cell cycle pathway. Circulation. 2013; 127 (17): 1818–1828. PubMed Abstract | Publisher Full Text | Free Full Text 21. Shu X, Mao Y, Li Z, et al. : MicroRNA-93 regulates angiogenesis in peripheral arterial disease by targeting CDKN1A. Mol. Med. Rep. 2019; 19 (6): 5195–5202. PubMed Abstract | Publisher Full Text | Free Full Text 22. Grundmann S, Hans FP, Kinniry S, et al. : MicroRNA-100 regulates neovascularization by suppression of mammalian target of rapamycin in endothelial and vascular smooth muscle cells. Circulation. 2011; 123 (9): 999–1009. PubMed Abstract | Publisher Full Text 23. Shi Y, Xu X, Luan P, et al. : miR-124-3p regulates angiogenesis in peripheral arterial disease by targeting STAT3. Mol. Med. Rep. 2020; 22 (6): 4890–4898. PubMed Abstract | Publisher Full Text | Free Full Text 24. Mathiyalagan P, Liang Y, Kim D, et al. : Angiogenic mechanisms of human CD34+ stem cell exosomes in the repair of ischemic hindlimb. Circ. Res. 2017; 120 (9): 1466–1476. PubMed Abstract | Publisher Full Text | Free Full Text 25. Tsumaru S, Masumoto H, Minakata K, et al. : Therapeutic angiogenesis by local sustained release of microRNA-126 using poly lactic-co-glycolic acid nanoparticles in murine hindlimb ischemia. J. Vasc. Surg. 2018; 68 (4): 1209–1215. PubMed Abstract | Publisher Full Text 26. Endo-Takahashi Y, Negishi Y, Nakamura A, et al. : Systemic delivery of miR-126 by miRNA-loaded Bubble liposomes for the treatment of hindlimb ischemia. Sci. Rep. 2014; 4 : 3883. PubMed Abstract | Publisher Full Text | Free Full Text 27. Procházka V, Jurčíková J, Vítková K, et al. : The role of miR-126 in critical limb ischemia treatment using adipose-derived stem cell therapeutic factor concentrate and extracellular matrix microparticles. Med. Sci. Monit. 2018; 24 : 511–522. PubMed Abstract | Publisher Full Text | Free Full Text 28. Cao WJ, Rosenblat JD, Roth NC, et al. : Therapeutic angiogenesis by ultrasound-mediated microRNA-126-3p delivery. Arterioscler. Thromb. Vasc. Biol. 2015; 35 (11): 2401–2411. PubMed Abstract | Publisher Full Text 29. Dhahri W, Dussault S, Légaré É, et al. : Reduced expression of microRNA-130a promotes endothelial cell senescence and age-dependent impairment of neovascularization. Aging (Albany NY). 2020; 12 (11): 10180–10193. PubMed Abstract | Publisher Full Text | Free Full Text 30. Lei Z, van Mil A , Brandt MM, et al. : MicroRNA-132/212 family enhances arteriogenesis after hindlimb ischaemia through modulation of the Ras-MAPK pathway. J. Cell. Mol. Med. 2015; 19 (8): 1994–2005. PubMed Abstract | Publisher Full Text | Free Full Text 31. Chen L, Liu C, Sun D, et al. : MicroRNA-133a impairs perfusion recovery after hindlimb ischemia in diabetic mice. Biosci. Rep. 2018; 38 (4). PubMed Abstract | Publisher Full Text | Free Full Text 32. Luo YF, Wan XX, Zhao LL, et al. : MicroRNA-139-5p upregulation is associated with diabetic endothelial cell dysfunction by targeting c-jun. Aging (Albany NY). 2021; 13 (1): 1186–1211. PubMed Abstract | Publisher Full Text | Free Full Text 33. Troidl K, Hammerschick T, Albarran-Juarez J, et al. : Shear stress-induced miR-143-3p in collateral arteries contributes to outward vessel growth by targeting collagen V-α2. Arterioscler. Thromb. Vasc. Biol. 2020; 40 (5): e126–e137. PubMed Abstract | Publisher Full Text 34. Desjarlais M, Dussault S, Rivard F, et al. : Forced expression of microRNA-146b reduces TRAF6-dependent inflammation and improves ischemia-induced neovascularization in hypercholesterolemic conditions. Atherosclerosis. 2019; 289 : 73–84. PubMed Abstract | Publisher Full Text 35. Heuslein JL, McDonnell SP, Song J, et al. : MicroRNA-146a regulates perfusion recovery in response to arterial occlusion via arteriogenesis. Front. Bioeng. Biotechnol. 2018; 6 : 1. PubMed Abstract | Publisher Full Text | Free Full Text 36. Desjarlais M, Dussault S, Dhahri W, et al. : MicroRNA-150 modulates ischemia-induced neovascularization in atherosclerotic conditions. Arterioscler. Thromb. Vasc. Biol. 2017; 37 (5): 900–908. PubMed Abstract | Publisher Full Text 37. Pankratz F, Bemtgen X, Zeiser R, et al. : MicroRNA-155 exerts cell-specific antiangiogenic but proarteriogenic effects during adaptive neovascularization. Circulation. 2015; 131 (18): 1575–1589. PubMed Abstract | Publisher Full Text 38. Heuslein JL, Gorick CM, McDonnell SP, et al. : Exposure of endothelium to biomimetic flow waveforms yields identification of miR-199a-5p as a potent regulator of arteriogenesis. Mol. Ther. Nucleic Acids. 2018; 12 : 829–844. PubMed Abstract | Publisher Full Text | Free Full Text 39. Zhang J, Rao G, Qiu J, et al. : MicroRNA-210 improves perfusion recovery following hindlimb ischemia via suppressing reactive oxygen species. Exp. Ther. Med. 2020; 20 (6): 231–236. PubMed Abstract | Publisher Full Text | Free Full Text 40. Shi L, Fisslthaler B, Zippel N, et al. : MicroRNA-223 antagonizes angiogenesis by targeting β1 integrin and preventing growth factor signaling in endothelial cells. Circ. Res. 2013; 113 (12): 1320–1330. PubMed Abstract | Publisher Full Text 41. Guan Y, Cai B, Wu X, et al. : MicroRNA-352 regulates collateral vessel growth induced by elevated fluid shear stress in the rat hind limb. Sci. Rep. 2017; 7 (1): 6643. PubMed Abstract | Publisher Full Text | Free Full Text 42. Caporali A, Meloni M, Völlenkle C, et al. : Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. 2011 January 25; 123 (3): 282–291. PubMed Abstract | Publisher Full Text 43. Icli B, Wu W, Ozdemir D, et al. : MicroRNA-615-5p regulates angiogenesis and tissue repair by targeting Akt/eNOS (protein kinase B/endothelial nitric oxide synthase) signaling in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2019; 39 (7): 1458–1474. PubMed Abstract | Publisher Full Text | Free Full Text 44. Han C, Zhou J, Liu B, et al. : Delivery of miR-675 by stem cell-derived exosomes encapsulated in silk fibroin hydrogel prevents aging-induced vascular dysfunction in mouse hindlimb. Mater. Sci. Eng. C. 2019; 99 : 322–332. PubMed Abstract | Publisher Full Text 45. Li H, Liao Y, Gao L, et al. : Coronary serum exosomes derived from patients with myocardial ischemia regulate angiogenesis through the miR-939-mediated nitric oxide signaling pathway. Theranostics. 2018; 8 (8): 2079–2093. PubMed Abstract | Publisher Full Text | Free Full Text 46. Aref Z, de Vries MR , Quax PHA: Variations in surgical procedures for inducing hind limb ischemia in mice and the impact of these variations on neovascularization assessment. Int. J. Mol. Sci. 2019; 20 (15): 3704. PubMed Abstract | Publisher Full Text | Free Full Text 47. van Weel V , Deckers MML, Grimbergen JM, et al. : Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo. Circ. Res. 2004; 95 (1): 58–66. PubMed Abstract | Publisher Full Text 48. Vandamme TF: Use of rodents as models of human diseases. J. Pharm. Bioallied Sci. 2014; 6 (1): 2–9. PubMed Abstract | Publisher Full Text | Free Full Text 49. Lee SWL, Paoletti C, Campisi M, et al. : MicroRNA delivery through nanoparticles. J. Control. Release. 2019; 313 : 80–95. PubMed Abstract | Publisher Full Text | Free Full Text 50. Lotfi S, Patel AS, Mattock K, et al. : Towards a more relevant hind limb model of muscle ischaemia. Atherosclerosis. 2013; 227 (1): 1–8. PubMed Abstract | Publisher Full Text 51. Barnabas O, Wang H, Gao XM: Role of estrogen in angiogenesis in cardiovascular diseases. J. Geriatr. Cardiol. 2013; 10 (4): 377–382. PubMed Abstract | Publisher Full Text | Free Full Text 52. Simons M: Chapter 14. Assessment of arteriogenesis. Methods Enzymol. 2008; 445 (08): 331–342. PubMed Abstract | Publisher Full Text 53. Limbourg A, Korff T, Napp LC, et al. : Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat. Protoc. 2009; 4 (12): 1737–1748. PubMed Abstract | Publisher Full Text 54. Deindl E, Quax PHA: Arteriogenesis and therapeutic angiogenesis in its multiple aspects. Cells. 2020; 9 (6). PubMed Abstract | Publisher Full Text | Free Full Text 55. Simons M, Eichmann A: Molecular controls of arterial morphogenesis. Circ. Res. 2015; 116 (10): 1712–1724. PubMed Abstract | Publisher Full Text | Free Full Text 56. Tidball JG: Regulation of muscle growth and regeneration by the immune system. Nat. Rev. Immunol. 2017 March; 17 (3): 165–178. PubMed Abstract | Publisher Full Text | Free Full Text 57. Davies MG: Criticial limb ischemia: epidemiology. Methodist Debakey Cardiovasc. J. 2012; 8 (4): 10–14. PubMed Abstract | Publisher Full Text | Free Full Text 58. Hiatt WR, Fowkes FGR, Heizer G, et al. : Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N. Engl. J. Med. 2017; 376 (1): 32–40. PubMed Abstract | Publisher Full Text 59. Ismail MT, Anggrahini DA Haryana SM, Setianto BY: Data from: The role of therapeutic microRNA in arteriogenesis process in limb ischemia: A systematic review. figshare. 2024. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 09 May 2024 ADD YOUR COMMENT Comment Author details Author details 1 Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia 2 Histology and Cell Biology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia Muhamad Taufik Ismail Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Dyah Wulan Anggrahini Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Sofia Mubarika Haryana Roles: Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Budi Yuli Setianto Roles: Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 14 Nov 2024, 13:470 https://doi.org/10.12688/f1000research.147482.2 version 1 Published: 09 May 2024, 13:470 https://doi.org/10.12688/f1000research.147482.1 Copyright © 2024 Ismail MT et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Ismail MT, Anggrahini DW, Haryana SM and Setianto BY. The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.12688/f1000research.147482.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 14 Nov 2024 Revised Views 0 Cite How to cite this report: Annex BH. Reviewer Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.174708.r340588 ) The direct URL for this report is: https://f1000research.com/articles/13-470/v2#referee-response-340588 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 26 Nov 2024 Brian H Annex , Medical College of Georgia at Augusta University, Augusta, Georgia, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.174708.r340588 the response was adequate. ... Continue reading READ ALL the response was adequate. I have no further comments. Competing Interests: I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Annex BH. Reviewer Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.174708.r340588 ) The direct URL for this report is: https://f1000research.com/articles/13-470/v2#referee-response-340588 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 09 May 2024 Views 0 Cite How to cite this report: Annex BH. Reviewer Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.161682.r326630 ) The direct URL for this report is: https://f1000research.com/articles/13-470/v1#referee-response-326630 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 Oct 2024 Brian H Annex , Medical College of Georgia at Augusta University, Augusta, Georgia, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.161682.r326630 The manuscript by Asmail et al. is a systematic/literature review of micro-RNA reported to be related to peripheral arterial disease. In general, the limitations of such reviews are well known but the benefits are in providing a single go-to source ... Continue reading READ ALL The manuscript by Asmail et al. is a systematic/literature review of micro-RNA reported to be related to peripheral arterial disease. In general, the limitations of such reviews are well known but the benefits are in providing a single go-to source of information. Before this reviewer lists a series of relatively minor comments/areas that require clarification, one request for additional (new) data will be listed. 1) Often in a study that focuses on a microRNA, other microRNAs are also examined. If a publication focused on miR-A (letter intentionally used to avoid confusion) were other miRs that ultimately ended in this report also studied? For example, if in the study of miR-A, miR-B and miR-C (where miR-B and miR-C ultimately made this report) were also found to differentially regulated, that would provide a validation. If several reports of course even better. It of course could turn out that study of the regulation miR-B in teh report on miR-A could be different. That would be valuable as well. Likely, in many, this may not be possible but this could expand the value of the review. More minor comments: 1) Introduction, paragraph 2, last sentence. Given that no agent has definitely driven angiogiogenesis in CLTI, this sentence may not be completely accurate. To make the statement one would need an agent that promoted angiogenesis, not arteriogenesis, and had no therapeuitc effect. 2) Introduction, paragraph 3, miRs do not signal unless the authors are referring to miR-protein interactions. 3) Methods, when the two "selectors" disagreed initially on inclusion -- how often was the agreement for and how often against inclusion. 4) Curcumin was mentioned. Was this referring to the dietary supplement? Would a miR be stable through the GI track? Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests: I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company. Reviewer Expertise: Human and experimental peripheral arterial disease including but not limited to non-coding RNAs. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Annex BH. Reviewer Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.161682.r326630 ) The direct URL for this report is: https://f1000research.com/articles/13-470/v1#referee-response-326630 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 14 Nov 2024 Muhamad Taufik Ismail , Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia 14 Nov 2024 Author Response Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific ... Continue reading Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings. Here is the response for addressing minor comments: 1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context. 2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling. 3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers. 4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases. Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings. Here is the response for addressing minor comments: 1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context. 2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling. 3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers. 4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases. Competing Interests: We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 14 Nov 2024 Muhamad Taufik Ismail , Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia 14 Nov 2024 Author Response Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific ... Continue reading Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings. Here is the response for addressing minor comments: 1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context. 2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling. 3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers. 4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases. Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings. Here is the response for addressing minor comments: 1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context. 2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling. 3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers. 4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases. Competing Interests: We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 09 May 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 2 (revision) 14 Nov 24 read Version 1 09 May 24 read Brian H Annex , Medical College of Georgia at Augusta University, Augusta, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Annex B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 26 Nov 2024 | for Version 2 Brian H Annex , Medical College of Georgia at Augusta University, Augusta, Georgia, USA 0 Views copyright © 2024 Annex B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions the response was adequate. I have no further comments. Competing Interests I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Annex BH. Peer Review Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.174708.r340588) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-470/v2#referee-response-340588 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Annex B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 Oct 2024 | for Version 1 Brian H Annex , Medical College of Georgia at Augusta University, Augusta, Georgia, USA 0 Views copyright © 2024 Annex B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript by Asmail et al. is a systematic/literature review of micro-RNA reported to be related to peripheral arterial disease. In general, the limitations of such reviews are well known but the benefits are in providing a single go-to source of information. Before this reviewer lists a series of relatively minor comments/areas that require clarification, one request for additional (new) data will be listed. 1) Often in a study that focuses on a microRNA, other microRNAs are also examined. If a publication focused on miR-A (letter intentionally used to avoid confusion) were other miRs that ultimately ended in this report also studied? For example, if in the study of miR-A, miR-B and miR-C (where miR-B and miR-C ultimately made this report) were also found to differentially regulated, that would provide a validation. If several reports of course even better. It of course could turn out that study of the regulation miR-B in teh report on miR-A could be different. That would be valuable as well. Likely, in many, this may not be possible but this could expand the value of the review. More minor comments: 1) Introduction, paragraph 2, last sentence. Given that no agent has definitely driven angiogiogenesis in CLTI, this sentence may not be completely accurate. To make the statement one would need an agent that promoted angiogenesis, not arteriogenesis, and had no therapeuitc effect. 2) Introduction, paragraph 3, miRs do not signal unless the authors are referring to miR-protein interactions. 3) Methods, when the two "selectors" disagreed initially on inclusion -- how often was the agreement for and how often against inclusion. 4) Curcumin was mentioned. Was this referring to the dietary supplement? Would a miR be stable through the GI track? Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company. Reviewer Expertise Human and experimental peripheral arterial disease including but not limited to non-coding RNAs. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 14 Nov 2024 Muhamad Taufik Ismail, Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings. Here is the response for addressing minor comments: 1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context. 2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling. 3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers. 4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases. View more View less Competing Interests We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance. reply Respond Report a concern Annex BH. Peer Review Report For: The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved] . F1000Research 2024, 13 :470 ( https://doi.org/10.5256/f1000research.161682.r326630) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-470/v1#referee-response-326630 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "The role of therapeutic MicroRNA in arteriogenesis...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/13-470/v2" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/13-470/v2&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/13-470/v2" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Ismail MT et al.'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/13-470/v2/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/13-470", templates : { twitter : "The role of therapeutic MicroRNA in arteriogenesis process in.... Ismail MT et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/13-470/v2" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/147482/174708") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("articles", "article", "174708"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "369949": 0, "369948": 0, "369951": 0, "369950": 0, "369944": 0, "369947": 0, "369946": 0, "355365": 0, "355364": 0, "355367": 0, "355366": 0, "355361": 0, "369953": 0, "355360": 0, "369952": 0, "355363": 0, "355362": 0, "369954": 0, "341039": 0, "341038": 0, "355369": 0, "355368": 0, "341045": 0, "341044": 0, "341046": 0, "341041": 0, "341040": 0, "341043": 0, "341042": 0, "330557": 0, "361021": 0, "330556": 0, "361020": 0, "330559": 0, "361023": 0, "330558": 0, "361022": 0, "330555": 0, "361019": 0, "361018": 0, "330564": 0, "330561": 0, "361025": 0, "330560": 0, "361024": 0, "330563": 0, "361027": 0, "330562": 0, "361026": 0, "420942": 0, "420943": 0, "420940": 0, "420941": 0, "322388": 0, "322389": 0, "322390": 0, "420948": 0, "322391": 0, "420949": 0, "322384": 0, "420946": 0, "322385": 0, "420947": 0, "322386": 0, "420944": 0, "322387": 0, "420945": 0, "339293": 0, "339292": 0, "339295": 0, "339294": 0, "322392": 0, "322393": 0, "339300": 0, "339297": 0, "339296": 0, "339299": 0, "339298": 0, "340588": 13, "443764": 0, "443765": 0, "352125": 0, "365181": 0, "352124": 0, "365180": 0, "352127": 0, "352126": 0, "365177": 0, "365179": 0, "365178": 0, "352133": 0, "352132": 0, "352129": 0, "352128": 0, "352131": 0, "352130": 0, "347791": 0, "347790": 0, "347793": 0, "347792": 0, "347794": 0, "359103": 0, "359104": 0, "344781": 0, "344780": 0, "344783": 0, "344782": 0, "344777": 0, "344776": 0, "344779": 0, "344778": 0, "344785": 0, "344784": 0, "326623": 0, "326628": 0, "326629": 0, "326630": 33, "435428": 0, "326631": 0, "435429": 0, "326624": 0, "326625": 0, "326626": 0, "326627": 0, "326632": 0, "335349": 0, "335348": 0, "335351": 0, "335350": 0, "335347": 0, "335346": 0, "335353": 0, "335352": 0, "335355": 0, "335354": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "acce89eb-3868-407c-ad12-603ae1377fea"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });