Recent advances in understanding circular RNAs

Recent advances in understanding circular RNAs | 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/9-655" }, "headline": "Recent advances in understanding circular RNAs", "datePublished": "2020-06-29T16:52:26", "dateModified": "2020-06-29T16:52:26", "author": [ { "@type": "Person", "name": "Constanze Ebermann" }, { "@type": "Person", "name": "Theodor Schnarr" }, { "@type": "Person", "name": "Sabine Müller" } ], "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": "Exonic circular RNAs (circRNAs) have been discovered in all kingdoms of life. In many cases, the details of circRNA function and their involvement in cellular processes and diseases are not yet fully understood. However, the past few years have seen significant developments in bioinformatics and in experimental protocols that advance the ongoing research in this still-emerging field. Sophisticated methods for circRNA generation in vitro and in vivo have been developed, allowing model studies into circRNA function and application. We here review the ongoing circRNA research, giving special attention to recent progress in the field." } { "@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/9-655", "name": "Recent advances in understanding circular RNAs" } } ] } Home Browse Recent advances in understanding circular RNAs ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Ebermann C, Schnarr T and Müller S. Recent advances in understanding circular RNAs [version 1; peer review: 3 approved] . F1000Research 2020, 9 (F1000 Faculty Rev):655 ( https://doi.org/10.12688/f1000research.25060.1 ) 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 ▬ ✚ Review Recent advances in understanding circular RNAs [version 1; peer review: 3 approved] Constanze Ebermann 1 * , Theodor Schnarr 1 * , Sabine Müller https://orcid.org/0000-0002-8385-7274 1 Constanze Ebermann 1 * , Theodor Schnarr 1 * , Sabine Müller https://orcid.org/0000-0002-8385-7274 1 * Equal contributors PUBLISHED 29 Jun 2020 Author details Author details 1 Institute for Biochemistry, University Greifswald, Greifswald, Germany Constanze Ebermann Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Theodor Schnarr Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Sabine Müller Roles: Conceptualization, Data Curation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Exonic circular RNAs (circRNAs) have been discovered in all kingdoms of life. In many cases, the details of circRNA function and their involvement in cellular processes and diseases are not yet fully understood. However, the past few years have seen significant developments in bioinformatics and in experimental protocols that advance the ongoing research in this still-emerging field. Sophisticated methods for circRNA generation in vitro and in vivo have been developed, allowing model studies into circRNA function and application. We here review the ongoing circRNA research, giving special attention to recent progress in the field. READ ALL READ LESS Keywords Biogenesis, cancer, circRNA, disease, splicing Corresponding Author(s) Sabine Müller ( [email protected] ) Close Corresponding author: Sabine Müller Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2020 Ebermann C 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: Ebermann C, Schnarr T and Müller S. Recent advances in understanding circular RNAs [version 1; peer review: 3 approved] . F1000Research 2020, 9 (F1000 Faculty Rev):655 ( https://doi.org/10.12688/f1000research.25060.1 ) First published: 29 Jun 2020, 9 (F1000 Faculty Rev):655 ( https://doi.org/10.12688/f1000research.25060.1 ) Latest published: 29 Jun 2020, 9 (F1000 Faculty Rev):655 ( https://doi.org/10.12688/f1000research.25060.1 ) Introduction Exonic circular RNAs (circRNAs) constitute a large class of regulatory non-coding endogenous RNAs with variable composition. Over the past few years, research into their biogenesis and biological function has exploded. First discovered in viroids, where they appear as circular genomes 1 , circRNAs have been shown to exist in all kingdoms of life, with thousands of circRNAs identified across species from archaea to humans 2 , 3 . For decades, circRNAs were considered to be extremely rare in nature and, in particular in eukaryotes, they were seen as minor RNA structural variants attributed to transcriptional noise 4 . Owing to progress in analytical techniques and the development of specific methodologies for the discovery and identification of circRNAs (recently reviewed in 5 ), this picture has dramatically changed over the past several years. It became obvious that circRNAs are abundant, evolutionarily conserved, and stable species in all eukaryotes studied today, although some eukaryotes like Saccharomyces cerevisiae have only very few circRNAs because of their few multi-intronic genes. The biogenesis and full functional repertoire of circRNAs have not yet been fully elucidated. Here we will review recent progress in circRNA research, focussing on new data regarding their biogenesis, cellular function, and involvement in diseases. We will extend our view to strategies for controlled generation of circRNAs in vivo and in vitro and discuss putative applications. We do not include the development of tools and biochemical methods for the accurate identification and characterization of circRNAs, since this, as mentioned above, has been extensively reviewed very recently 5 . Biogenesis of circRNAs Most circRNAs are expressed from known protein-coding genes and are composed of single or multiple exons 3 . They are produced by backsplicing, a process that occurs in a reversed orientation as compared with canonical splicing. Hence, instead of joining an upstream 5'-splice site with a downstream 3'-splice site in a sequential order to produce a linear RNA, a downstream 5'-splice site is linked to an upstream 3'-splice site to yield a circRNA ( Figure 1a ) 6 – 9 . Still, the formation of circRNA was shown to be dependent on the canonical splicing machinery, making backsplicing a process that competes with canonical splicing 10 , 11 . In addition to exonic circRNAs, circular RNAs containing sequences from introns (ciRNA) and circRNAs containing sequences from exons with introns retained between the exons (exon-intron circRNA or short IEciRNA) have been found. ciRNAs presumably result from intron lariats that escaped de-branching during canonical splicing and do not belong to circRNAs. They reside in the nucleus, where they may control the transcription of their parental genes 12 , 13 . However, previous work also suggests that some ciRNAs are stable in the cytoplasm 14 , 15 . Exonic circRNAs localize to the cytoplasm, where they are exported from the nucleus in a length-dependent manner 16 . In general, all exons found in linear transcripts may appear in circRNAs. However, it is also possible that circRNAs contain exons which do not appear in linearly spliced transcripts 17 . Figure 1. Biogenesis of circRNAs. ( a ) Modes of circRNA formation. ( b ) Factors supporting backsplicing: inverted repeat sequences (I), binding sites for RBPs of RNPs (II), IRE distance (III), and m 6 A-enriched sites (IV). For further explanation, see main text. ciRNA, circular RNA containing sequences from introns; circRNA, circular RNA; IEciRNA, circRNA containing sequences from exons with introns retained between the exons; IRE, inverted repeat; RBP, RNA-binding protein; snRNP, small nuclear ribonucleoprotein. Successful backsplicing requires the splice sites to be brought into proximity ( Figure 1b ). This often is supported by inverted repeats (IRE), especially Alu elements, flanking the exons to be circularized and allowing multiple circRNAs to be produced from a single gene 8 , 18 , 19 . In addition to IRE, interaction of the precursor mRNA with ribonucleoproteins (RNPs) or proteins was found to support circRNA formation 11 , 20 – 23 . Other RNA-binding proteins (RBPs) that support circularization are, for example, the heterogeneous nuclear RNP L (HNRNPL) 24 , double-stranded RNA-binding domain containing immune factors NF90/NF110 25 , or DHX9, an abundant nuclear RNA helicase 26 . Moreover, circRNA biogenesis underlies the combinatorial control of splice factors 21 and can also be suppressed by helicases 6 , 27 . Pre-mRNA structure plays an important role, as flanking sequences (e.g. IRE or RNP-binding sites) or the distance between splice sites is most important 28 . Furthermore, N6-methylation of adenosine can promote circRNA biogenesis, as it was recently shown that m 6 A-enriched sites guide backsplicing in male germ cells 29 . CircRNA levels are also modulated by the levels of core spliceosome components 30 , and it was suggested that the same spliceosome can assemble across an exon and that it either remodels to span an intron for canonical linear splicing or catalyses backsplicing to generate circRNA 31 . Backsplicing is less efficient than linear splicing 32 , and, typically, circRNAs are produced at a lower level than their linear counterparts. Yet circRNAs may be the more abundant isoform in specific cells and tissues 33 , 34 , which may be attributed to their higher stability. Owing to the covalently closed ring structure, circRNAs are resistant to degradation by exonucleases, thus undergoing slower turnover. The higher stability implies that possible functions of circRNA may be associated with their longer lifespan. Nevertheless, there is evidence of circRNA turnover, as it was shown that upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses 35 . Furthermore, m 6 A-containing circRNAs, when bound to the m 6 A reader protein YTHDF2, become rapidly degraded by the RNase P/MRP complex 36 . circRNA degradation is also mediated via a structure-related RNA decay pathway that is independent of specific single-stranded sequences but recognizes double-stranded structures in the 3' UTR of mRNAs, as well as highly structured circRNAs 37 . Biological functions of circRNAs To date, biological function has been investigated for only a minor fraction of circRNAs. Many of those have been proposed to act as miRNA sponges 38 – 42 or protein sponges 11 , 43 . In addition, circRNAs may enhance protein function 13 , 33 , assist protein target interaction 44 – 46 , or recruit proteins to specific locations 47 . An early example for a potential miRNA sponge is circRNA ciRS-7, also known as CDR1as, comprising over 70 binding sites for miR-7 40 . However, this function is still controversially discussed, in particular when looking at stoichiometric ratios of the target sequences to the number of binding sites in the circRNA 48 , 49 . Furthermore, analysis of 7,000 human circRNAs revealed that most of them are not enriched in miRNA-binding sites 3 . Some circRNAs possess binding sites for specific proteins, which upon binding lose interaction with other targets 50 . In a similar manner, circRNAs have been described to function as protein scaffolds, assisting the assembly of protein complexes 43 , 44 , 46 , 51 . For example, circFoxo3 was shown to inhibit the progression of the cell cycle by formation of a ternary complex with CDK2 and p21, thereby acting as a tumor suppressor 46 , or to specifically recruit the ubiquitinylation system, thus triggering degradation of mutated p53 by the proteasome complex 44 . CircRNA can also regulate the subcellular localization of specific proteins, as shown for circ-Amotl1 binding to Stat3, AKT1, and PDK1 45 , 52 . Because backsplicing competes with canonical splicing, the formation of circRNAs is also considered to be a mode of regulating the expression of a specific gene. The protein Muscleblind (MBL) binds to the flanking introns of circMBL derived from the muscleblind gene by backsplicing. As a result, MBL levels are modulated, which in turn strongly affects circMBL biosynthesis 43 . There has been some indication that cells can differentiate between endogenous and exogenous circRNA. Exogenously introduced circRNA was shown to have a stimulating effect on the immune system because it is recognized by the pattern recognition receptor retinoic acid inducible gene I (RIG-I), thereby eliciting a strong immune response. Apparently, this applies only to unmodified circRNA because m 6 A-modified circRNA was shown to inhibit innate immunity 53 . Endogenous circRNA, on the contrary, did not show such an effect. Based on this observation, it was proposed that endogenous circRNA is recognized as self, owing to the identity of its flanking introns that led to circularization 54 . More recent findings, however, are contradictory, as they suggest that unmodified exogenous circRNA is able to bypass cellular RNA sensors and thus does not induce an immune response in RIG-I and Toll-like receptor (TLR) competent cells and in mice 55 . Endogenous circRNAs can collectively bind and suppress activation of the double-stranded RNA (dsRNA)-activated protein kinase PKR, thereby controlling innate immune responses 56 . As already mentioned above, double-stranded RNA-binding domain-containing immune factors NF90/NF110 are key regulators in circRNA biogenesis, pointing to the role of circRNAs in immunity. Upon viral infection, circRNA expression is decreased, and NF90/NF110 released from circRNP complexes bind to viral mRNAs as part of their functions in antiviral immune response 25 . Interestingly, some circRNAs containing internal ribosome entry site (IRES) elements and AUG sites may be translated into unique peptides under specific conditions, in particular upon cellular stress 52 , 57 – 61 , although the functional relevance of the majority of circRNA-derived peptides is not yet known. Earlier studies had suggested that circRNAs might be translated without the existence of an IRES sequence, following the so-called rolling circle translation mechanism 62 . In more recent studies, however, translation of circRNAs was shown to be dependent on the presence of different IRESs (either viral IRES sequences 36 , 37 or m 6 A 28 ). Yet it should be noted that even though several studies have reported cases of circRNA translation, others have completely failed to find evidence 63 . Taken together, circRNAs appear to play a regulatory role in different levels of gene expression, which also explains their association with diverse diseases, pathological conditions, and expression patterns specific for certain cell types and tissues. CircRNAs in diseases CircRNAs have been associated with the initiation and progression of several diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes 51 , 64 – 69 , and thus have also been considered as biomarkers for disease prognostics and diagnostics and as targets or tools for disease treatment 70 – 72 . There is also indication of circRNAs accumulating with aging 73 – 75 . Work in the field is currently centered around screening for and identifying disease-associated circRNAs, whereas the underlying mechanisms of action remain mostly unknown. In particular, the involvement of circRNAs in cancer development and progression is obvious, as numerous circRNAs have been discovered to upregulate or downregulate gene expression in cancer tissues and promote cancer cell reproduction 35 , 66 , 76 – 83 . Over the past two years, numerous circRNAs have been shown to affect cell proliferation, invasion, migration, and apoptosis and have been suggested to act as therapeutic targets or biomarkers for diagnosis and prognosis in various types of cancers 84 – 90 . There have been indications of circRNAs occurring in the tumor microenvironment 91 and in exosomes 92 , with their role in cell-to-cell communication and spreading of pathological processes continuing to be unveiled 92 – 94 . Recent results have shown that circRNA-loaded exosomes promote cell proliferation and invasion in colorectal 95 and prostate 96 cancer. It has been suggested that the effect of extracellular circRNAs can be reversed by the addition of siRNAs targeting those circRNAs, hence making it a promising therapeutic strategy 96 , 97 . Standing out in the majority of research of "more classical" diseases is the increasing knowledge of the roles of circRNAs in aging, where age-related changes in splicing, and thus in the level of lncRNAs and circRNAs, are discussed 98 . Furthermore, it has been found that the expression of circRNAs can be sensitive to different types of pollution (organic, heavy metal, and others) and therefore might be used as a biomarker or prevention/treatment target for pollution-induced diseases 99 . Strategies for controlled generation of circRNAs in vitro and in vivo Several methods for controlled generation of circRNAs based on chemical or enzymatic/ribozymatic strategies have been investigated 100 , 101 . Circularization can be performed either in vivo or in vitro . For direct production of circRNA in cell culture, usually the sequence of interest is cloned into an artificial exon that is flanked by complementary intronic repeats. The plasmid is then transfected into cells, transcription is induced, and the cellular splicing machinery generates the desired circRNA 19 , 102 ( Figure 2a ). Alternatively, the sequence of interest can be cloned in between a permuted self-splicing intron (permuted intron exon [PIE] strategy, see below), such that circularization occurs by the inherent ribozyme activity of the intron 103 , 104 . An expression vector comprising such self-splicing introns is also suited for circularization in vitro by linearization of the plasmid and subsequent in vitro transcription of the linearized template. The formed transcript undergoes circularization by its self-splicing activity 103 . Figure 2. Strategies for circRNA generation in vitro and in vivo . ( a ) Overexpression vector, ( b ) chemical or enzymatic ligation, ( c ) circularization via Tornado system, ( d ) permuted intron exon (PIE) strategy, ( e ) induction of backsplicing by Csy4, and ( f ) generation of circRNA using tRNA splicing mechanism. For further explanation, see main text. BHB, bulge-helix-bulge; IRES, internal ribosome entry site; TSEN, tRNA splicing endonuclease complex. Chemical ligation methods can be applied only for in vitro circularization. Linear RNA obtained from chemical synthesis or in vitro transcription and phosphorylated at the 3'- or 5'- terminus can be intramolecularly ligated with the help of condensing agents 100 . In addition, enzymatic ligation with DNA or RNA ligases is an option ( Figure 2b ) 100 , 101 . Recently, a seminal approach for circRNA production in vivo , called Tornado (twister optimized RNA for durable overexpression), was introduced ( Figure 2c ) 105 . The twister ribozyme is employed in a combined approach with the cellular RtcB ligase. The ribozymes flanking the sequence to be circularized generate by cutting themselves off the 5'-terminal OH and 3'-terminal phosphate required by the cellular RtcB ligase to perform the following ligation step. Already known for a while and newly moved into focus by recent studies is the PIE strategy, which uses a group I self-splicing intron (also a ribozyme) for the production of a circRNA either in vitro or in vivo 106 . The two intron halves (5'- and 3'- intron) flanking the exon are arranged in a permuted manner, such that during splicing a circularized exon and two linear intron halves are formed ( Figure 2d ). The PIE strategy was successfully applied for RNA sequences up to five kilobases, and a PIE-produced circRNA carrying an IRES sequence was shown to be successfully translated in cells 52 , 104 , 107 . Another possibility to selectively circularize RNA sequences is utilizing the tRNA splicing machinery 108 , 109 . A tRNA precursor is specifically recognized by the tRNA splicing endonuclease complex (TSEN) based on a bulge-helix-bulge (BHB) motif, then cleaved and ligated by a ligase, yielding the mature tRNA and a circularized intron ( Figure 2f ). A desired sequence can be introduced in such a construct between the two intron halves to become circularized upon tRNA splicing. Still another method exploiting the cell’s own splicing machinery for circularization is the system based on RNA cleavage by the CRISPR endonuclease Csy4 110 . Csy4 recognizes a 16-nucleotide hairpin in RNA and specifically cleaves off the RNA downstream of that hairpin region. The protein is utilized for RNA circularization to cleave a site in a defined intron, thereby removing a competing downstream splice site, which otherwise would interfere with backsplicing, and thus inducing formation of the desired circRNA ( Figure 2e ) 110 . Application of circRNAs After research in the field of circRNA was dominated by their identification and studies into biogenesis and function, reports on the application of circRNAs have started to emerge more recently. Because of their stability and association with diseases, endogenous circRNAs are potential candidates as biomarkers or therapeutic targets 111 – 113 . Likewise, exogenous circRNAs can be introduced into cells to fulfil a defined function. Several feasible concepts for the therapeutic application of circRNAs have already been discussed and to some extent successfully implemented. An obvious possibility for the application of circRNAs is the development of designed miRNA sponges. An artificial circRNA molecule comprising multiple binding sites for miRNA-122, which plays an essential role in the life cycle of the hepatitis C virus, was successfully used to inhibit the synthesis of viral proteins in the host cell 114 . In a similar way, the activity of specific proteins in the cellular context was controlled by circularized aptamers 105 . Moreover, circular aptamers have shown great potential as intracellularly expressed biosensors for defined metabolites 103 , 105 . Because some circRNAs play a role in alternative splicing and transcription, it is feasible to use them for the regulation of those processes within the cell, thereby driving gene expression in the direction of specific transcription and splicing products. In addition, circularization of RNA opens up the opportunity to apply RNA therapeutics that are administered as a linear construct until now (for example, mRNA vaccines) in a circular form, thereby significantly increasing their stability. If the circRNA additionally possesses an IRES sequence, translation of that RNA is possible, whereby therapeutic proteins may be expressed directly in target cells. Because of results suggesting that circRNAs can activate the immune system via the RIG-I pathway, it is also feasible to employ exogenous circRNA as an adjuvant in vaccines to elicit a more efficient immune response upon vaccination 54 . In all of the approaches described above, it has to be taken into consideration that side effects may arise as a result of the applied circRNA. For example, expression of the desired circRNA from an overexpression vector or translation of a protein encoded by the circRNA can significantly vary dependent on the respective cell type 115 . In some cases, the formation of linear RNA concatemers by rolling circle transcription was also observed 112 . Those concatemers can lead to toxic effects within the cell. The function of immune activator mentioned above can also be a drawback of circRNA if the RNA is to be applied in a context wherein an immune response is not desired. Conclusions The occurrence of circRNAs in all kingdoms of life has been demonstrated, and it is beyond doubt that these abundant stable RNA species play important biological roles. The elucidation of circRNA function has included the development of methods for circRNA identification and characterization and of strategies for circRNA generation. It has become clear that circRNAs are strongly involved in diseases, although their action is enormously multifaceted. Even with all of the effort over the past decade to shed light onto this still-emerging field, the intracellular and extracellular roles of circRNAs as well as their functional role in bigger networks with other RNAs and proteins require ongoing endeavor to gain full understanding, and with that the opportunity to use circRNAs as biomarkers or therapeutic agents and targets. Abbreviations ciRNA, circular RNA containing sequences from introns; circRNA, circular RNA; IRE, inverted repeats; IRES, internal ribosome entry site; MBL, muscleblind; PIE, permuted intron exon; RIG-I, retinoic acid inducible gene I; RNP, ribonucleoprotein. Faculty Opinions recommended References 1. Flores R, Grubb D, Elleuch A, et al. : Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: Variations on a theme. RNA Biol. 2011; 8 (2): 200–6. PubMed Abstract | Publisher Full Text 2. Danan M, Schwartz S, Edelheit S, et al. : Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res. 2012; 40 (7): 3131–42. PubMed Abstract | Publisher Full Text | Free Full Text 3. Guo JU, Agarwal V, Guo H, et al. : Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014; 15 (7): 409. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 4. Cocquerelle C, Mascrez B, Hétuin D, et al. : Mis-splicing yields circular RNA molecules. FASEB J. 1993; 7 (1): 155–60. PubMed Abstract | Publisher Full Text 5. Kristensen LS, Andersen MS, Stagsted LVW, et al. : The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019; 20 (11): 675–91. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 6. Ivanov A, Memczak S, Wyler E, et al. : Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 2015; 10 (2): 170–7. PubMed Abstract | Publisher Full Text 7. Kelly S, Greenman C, Cook PR, et al. : Exon Skipping Is Correlated with Exon Circularization. J Mol Biol. 2015; 427 (15): 2414–7. PubMed Abstract | Publisher Full Text 8. Zhang XO, Wang HB, Zhang Y, et al. : Complementary sequence-mediated exon circularization. Cell. 2014; 159 (1): 134–47. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 9. Barrett SP, Wang PL, Salzman J: Circular RNA biogenesis can proceed through an exon-containing lariat precursor. eLife. 2015; 4 : e07540. PubMed Abstract | Publisher Full Text | Free Full Text 10. Starke S, Jost I, Rossbach O, et al. : Exon circularization requires canonical splice signals. Cell Rep. 2015; 10 (1): 103–11. PubMed Abstract | Publisher Full Text 11. Ashwal-Fluss R, Meyer M, Pamudurti NR, et al. : circRNA Biogenesis Competes with Pre-mRNA Splicing. Mol Cell. 2014; 56 (1): 55–66. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 12. Li Z, Huang C, Bao C, et al. : Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015; 22 (3): 256–64. PubMed Abstract | Publisher Full Text 13. Zhang Y, Zhang XO, Chen T, et al. : Circular Intronic Long Noncoding RNAs. Mol Cell. 2013; 51 (6): 792–806. PubMed Abstract | Publisher Full Text 14. Talhouarne GJS, Gall JG: Lariat intronic RNAs in the cytoplasm of vertebrate cells. Proc Natl Acad Sci U S A. 2018; 115 (34): E7970–E7977. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 15. Talhouarne GJS, Gall JG: Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA. 2014; 20 (9): 1476–87. PubMed Abstract | Publisher Full Text | Free Full Text 16. Huang C, Liang D, Tatomer DC, et al. : A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs. Genes Dev. 2018; 32 (9–10): 639–44. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 17. Zhang XO, Dong R, Zhang Y, et al. : Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res. 2016; 26 (9): 1277–87. PubMed Abstract | Publisher Full Text | Free Full Text 18. Jeck WR, Sorrentino JA, Wang K, et al. : Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013; 19 (2): 141–57. PubMed Abstract | Publisher Full Text | Free Full Text 19. Liang D, Wilusz JE: Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 2014; 28 (20): 2233–47. PubMed Abstract | Publisher Full Text | Free Full Text 20. Conn SJ, Pillman KA, Toubia J, et al. : The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015; 160 (6): 1125–34. PubMed Abstract | Publisher Full Text 21. Kramer MC, Liang D, Tatomer DC, et al. : Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev. 2015; 29 (20): 2168–82. PubMed Abstract | Publisher Full Text | Free Full Text 22. Nasim FUH, Hutchison S, Cordeau M, et al. : High-affinity hnRNP A1 binding sites and duplex-forming inverted repeats have similar effects on 5' splice site selection in support of a common looping out and repression mechanism. RNA. 2002; 8 (8): 1078–89. PubMed Abstract | Publisher Full Text | Free Full Text 23. Lamichhane R, Daubner GM, Thomas-Crusells J, et al. : RNA looping by PTB: Evidence using FRET and NMR spectroscopy for a role in splicing repression. Proc Natl Acad Sci U S A. 2010; 107 (9): 4105–10. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 24. Fei T, Chen Y, Xiao T, et al. : Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc Natl Acad Sci U S A. 2017; 114 (26): E5207–E5215. PubMed Abstract | Publisher Full Text | Free Full Text 25. Li X, Liu CX, Xue W, et al. : Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. Mol Cell. 2017; 67 (2): 214–227.e7. PubMed Abstract | Publisher Full Text 26. Aktaş T, Avşar Ilık İ, Maticzka D, et al. : DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature. 2017; 544 (7648): 115–9. PubMed Abstract | Publisher Full Text 27. Ottesen EW, Luo D, Seo J, et al. : Human Survival Motor Neuron genes generate a vast repertoire of circular RNAs. Nucleic Acids Res. 2019; 47 (6): 2884–905. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 28. Welden JR, Stamm S: Pre-mRNA structures forming circular RNAs. Biochim Biophys Acta Gene Regul Mech. 2019; 1862 (11–12): 194410. PubMed Abstract | Publisher Full Text 29. Tang C, Xie Y, Yu T, et al. : m 6 A-dependent biogenesis of circular RNAs in male germ cells. Cell Res. 2020; 30 (3): 211–28. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 30. Liang D, Tatomer DC, Luo Z, et al. : The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting. Mol Cell. 2017; 68 (5): 940–954.e3. PubMed Abstract | Publisher Full Text | Free Full Text 31. Li X, Liu S, Zhang L, et al. : A unified mechanism for intron and exon definition and back-splicing. Nature. 2019; 573 (7774): 375–80. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 32. Zhang Y, Xue W, Li X, et al. : The Biogenesis of Nascent Circular RNAs. Cell Rep. 2016; 15 (3): 611–24. PubMed Abstract | Publisher Full Text 33. Salzman J, Gawad C, Wang PL, et al. : Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012; 7 (2): e30733. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 34. Izuogu OG, Alhasan AA, Mellough C, et al. : Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular. BMC Genomics. 2018; 19 (1): 276. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 35. Liu J, Li D, Luo H, et al. : Circular RNAs: The star molecules in cancer. Mol Aspects Med. 2019; 70 : 141–52. PubMed Abstract | Publisher Full Text 36. Park OH, Ha H, Lee Y, et al. : Endoribonucleolytic Cleavage of m 6 A-Containing RNAs by RNase P/MRP Complex. Mol Cell. 2019; 74 (3): 494–507.e8. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 37. Fischer JW, Busa VF, Shao Y, et al. : Structure-Mediated RNA Decay by UPF1 and G3BP1. Mol Cell. 2020; 78 (1): 70–84.e6. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 38. Piwecka M, Glažar P, Hernandez-Miranda LR, et al. : Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science. 2017; 357 (6357): eaam8526. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 39. Zheng Q, Bao C, Guo W, et al. : Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016; 7 : 11215. PubMed Abstract | Publisher Full Text | Free Full Text 40. Hansen TB, Jensen TI, Clausen BH, et al. : Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495 (7441): 384–8. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 41. Memczak S, Jens M, Elefsinioti A, et al. : Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 495 (7441): 333–8. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 42. Hausser J, Zavolan M: Identification and consequences of miRNA-target interactions--beyond repression of gene expression. Nat Rev Genet. 2014; 15 (9): 599–612. PubMed Abstract | Publisher Full Text 43. Abdelmohsen K, Panda AC, Munk R, et al. : Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1 . RNA Biol. 2017; 14 (3): 361–9. PubMed Abstract | Publisher Full Text | Free Full Text 44. Du WW, Fang L, Yang W, et al. : Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ. 2017; 24 (2): 357–70. PubMed Abstract | Publisher Full Text | Free Full Text 45. Zeng Y, Du WW, Wu Y, et al. : A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair. Theranostics. 2017; 7 (16): 3842–55. PubMed Abstract | Publisher Full Text | Free Full Text 46. Du WW, Yang W, Liu E, et al. : Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016; 44 (6): 2846–58. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 47. Chen N, Zhao G, Yan X, et al. : A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1. Genome Biol. 2018; 19 (1): 218. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 48. Denzler R, Agarwal V, Stefano J, et al. : Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol Cell. 2014; 54 (5): 766–76. PubMed Abstract | Publisher Full Text | Free Full Text 49. Thomson DW, Dinger ME: Endogenous microRNA sponges: Evidence and controversy. Nat Rev Genet. 2016; 17 (5): 272–83. PubMed Abstract | Publisher Full Text 50. Luo J, Liu H, Luan S, et al. : Guidance of circular RNAs to proteins’ behavior as binding partners. Cell Mol Life Sci. 2019; 76 (21): 4233–43. PubMed Abstract | Publisher Full Text 51. Holdt LM, Stahringer A, Sass K, et al. : Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016; 7 : 12429. PubMed Abstract | Publisher Full Text | Free Full Text 52. Yang Y, Fan X, Mao M, et al. : Extensive translation of circular RNAs driven by N 6 -methyladenosine. Cell Res. 2017; 27 (5): 626–41. PubMed Abstract | Publisher Full Text | Free Full Text 53. Chen YG, Chen R, Ahmad S, et al. : N6 -Methyladenosine Modification Controls Circular RNA Immunity. Mol Cell. 2019; 76 (1): 96–109.e9. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 54. Chen YG, Kim MV, Chen X, et al. : Sensing Self and Foreign Circular RNAs by Intron Identity. Mol Cell. 2017; 67 (2): 228–238.e5. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 55. Wesselhoeft RA, Kowalski PS, Parker-Hale FC, et al. : RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo . Mol Cell. 2019; 74 (3): 508–520.e4. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 56. Liu CX, Li X, Nan F, et al. : Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity. Cell. 2019; 177 (4): 865–880.e21. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 57. Zhang M, Zhao K, Xu X, et al. : A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun. 2018; 9 (1): 4475. PubMed Abstract | Publisher Full Text | Free Full Text 58. Zhang M, Huang N, Yang X, et al. : A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene. 2018; 37 (13): 1805–14. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 59. Pamudurti NR, Bartok O, Jens M, et al. : Translation of CircRNAs. Mol Cell. 2017; 66 (1): 9–21.e7. PubMed Abstract | Publisher Full Text | Free Full Text 60. Legnini I, Di Timoteo G, Rossi F, et al. : Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis. Mol Cell. 2017; 66 (1): 22–37.e9. PubMed Abstract | Publisher Full Text | Free Full Text 61. Begum S, Yiu A, Stebbing J, et al. : Novel tumour suppressive protein encoded by circular RNA, circ-SHPRH , in glioblastomas. Oncogene. 2018; 37 (30): 4055–7. PubMed Abstract | Publisher Full Text 62. Abe N, Matsumoto K, Nishihara M, et al. : Rolling Circle Translation of Circular RNA in Living Human Cells. Sci Rep. 2015; 5 : 16435. PubMed Abstract | Publisher Full Text | Free Full Text 63. Stagsted LVW, Nielsen KM, Daugaard I, et al. : Noncoding AUG circRNAs constitute an abundant and conserved subclass of circles. Life Sci Alliance. 2019; 2 (3): e201900398. PubMed Abstract | Publisher Full Text | Free Full Text 64. Fang Y, Wang X, Li W, et al. : Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus. Int J Mol Med. 2018; 42 (4): 1865–74. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 65. Hanan M, Soreq H, Kadener S: CircRNAs in the brain. RNA Biol. 2017; 14 (8): 1028–34. PubMed Abstract | Publisher Full Text | Free Full Text 66. Kristensen LS, Hansen TB, Venø MT, et al. : Circular RNAs in cancer: Opportunities and challenges in the field. Oncogene. 2018; 37 (5): 555–65. PubMed Abstract | Publisher Full Text | Free Full Text 67. Li H, Li K, Lai W, et al. : Comprehensive circular RNA profiles in plasma reveals that circular RNAs can be used as novel biomarkers for systemic lupus erythematosus. Clinica Chimica Acta. 2018; 480 : 17–25. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 68. Aufiero S, Reckman YJ, Pinto YM, et al. : Circular RNAs open a new chapter in cardiovascular biology. Nat Rev Cardiol. 2019; 16 (8): 503–14. PubMed Abstract | Publisher Full Text 69. Vo JN, Cieslik M, Zhang Y, et al. : The Landscape of Circular RNA in Cancer. Cell. 2019; 176 (4): 869–881.e13. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 70. Li P, Chen S, Chen H, et al. : Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta. 2015; 444 : 132–6. PubMed Abstract | Publisher Full Text 71. Bahn JH, Zhang Q, Li F, et al. : The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva. Clin Chem. 2015; 61 (1): 221–30. PubMed Abstract | Publisher Full Text | Free Full Text 72. Fang Y: Circular RNAs as novel biomarkers with regulatory potency in human diseases. Future Science OA. 2018; 4 (7): FSO314. PubMed Abstract | Publisher Full Text | Free Full Text 73. Cortés-López M, Gruner MR, Cooper DA, et al. : Global accumulation of circRNAs during aging in Caenorhabditis elegans . BMC Genomics. 2018; 19 (1): 8. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 74. Gruner H, Cortés-López M, Cooper DA, et al. : CircRNA accumulation in the aging mouse brain. Sci Rep. 2016; 6 : 38907. PubMed Abstract | Publisher Full Text | Free Full Text 75. Westholm JO, Miura P, Olson S, et al. : Genome-wide Analysis of Drosophila Circular RNAs Reveals Their Structural and Sequence Properties and Age-Dependent Neural Accumulation. Cell Rep. 2014; 9 (5): 1966–80. PubMed Abstract | Publisher Full Text | Free Full Text 76. Jamal M, Song T, Chen B, et al. : Recent Progress on Circular RNA Research in Acute Myeloid Leukemia. Front Oncol. 2019; 9 : 1108. PubMed Abstract | Publisher Full Text | Free Full Text 77. Handschuh L: Not Only Mutations Matter: Molecular Picture of Acute Myeloid Leukemia Emerging from Transcriptome Studies. J Oncol. 2019; 2019 : 7239206. PubMed Abstract | Publisher Full Text | Free Full Text 78. Liu Y, Cheng Z, Pang Y, et al. : Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia. J Hematol Oncol. 2019; 12 (1): 51. PubMed Abstract | Publisher Full Text | Free Full Text 79. Mei M, Wang Y, Li Z, et al. : Role of circular RNA in hematological malignancies. Oncol Lett. 2019; 18 (5): 4385–92. PubMed Abstract | Publisher Full Text | Free Full Text 80. Guo S-S, Li B-X, Zou D-B, et al. : Tip of the iceberg: Roles of circRNAs in hematological malignancies. Am J Cancer Res. 2020; 10 (2): 367–82. PubMed Abstract | Free Full Text 81. Naeli P, Pourhanifeh MH, Karimzadeh MR, et al. : Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role. Crit Rev Oncol Hematol. 2020; 145 : 102854. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 82. Sun J, Li B, Shu C, et al. : Functions and clinical significance of circular RNAs in glioma. Mol Cancer. 2020; 19 (1): 34. PubMed Abstract | Publisher Full Text | Free Full Text 83. Hao Z, Hu S, Liu Z, et al. : Circular RNAs: Functions and Prospects in Glioma. J Mol Neurosci. 2019; 67 (1): 72–81. PubMed Abstract | Publisher Full Text 84. Sheng R, Li X, Wang Z, et al. : Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Lett. 2020; 473 : 139–47. PubMed Abstract | Publisher Full Text 85. Zhang C, Ma L, Niu Y, et al. : Circular RNA in Lung Cancer Research: Biogenesis, Functions, and Roles. Int J Biol Sci. 2020; 16 (5): 803–14. PubMed Abstract | Publisher Full Text | Free Full Text 86. Jahani S, Nazeri E, Majidzadeh-A K, et al. : Circular RNA; a new biomarker for breast cancer: A systematic review. J Cell Physiol. 2020; 235 (7–8): 5501–10. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 87. Chaichian S, Shafabakhsh R, Mirhashemi SM, et al. : Circular RNAs: A novel biomarker for cervical cancer. J Cell Physiol. 2019; 235 (2): 718–24. PubMed Abstract | Publisher Full Text 88. Jiang P-C, Bu S-R: Clinical value of circular RNAs and autophagy-related miRNAs in the diagnosis and treatment of pancreatic cancer. Hepatobiliary Pancreat Dis Int. 2019; 18 (6): 511–6. PubMed Abstract | Publisher Full Text 89. Hua JT, Chen S, He HH: Landscape of Noncoding RNA in Prostate Cancer. Trends Genet. 2019; 35 (11): 840–51. PubMed Abstract | Publisher Full Text 90. Hao Q, Han Y, Xia W, et al. : Systematic Review and Meta-Analysis of the Utility of Circular RNAs as Biomarkers of Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2019; 2019 : 684039. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 91. Zhang Q, Wang W, Zhou Q, et al. : Roles of circRNAs in the tumour microenvironment. Mol Cancer. 2020; 19 (1): 14. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 92. Wang Y, Liu J, Ma J, et al. : Exosomal circRNAs: Biogenesis, effect and application in human diseases. Mol Cancer. 2019; 18 (1): 116. PubMed Abstract | Publisher Full Text | Free Full Text 93. Hosaka T, Yamashita T, Tamaoka A, et al. : Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases. Int J Mol Sci. 2019; 20 (13): 3148. PubMed Abstract | Publisher Full Text | Free Full Text 94. Di Liegro CM, Schiera G, Di Liegro I: Extracellular Vesicle-Associated RNA as a Carrier of Epigenetic Information. Genes (Basel). 2017; 8 (10): 240. PubMed Abstract | Publisher Full Text | Free Full Text 95. Zhao H, Chen S, Fu Q: Exosomes from CD133 + cells carrying circ-ABCC1 mediate cell stemness and metastasis in colorectal cancer. J Cell Biochem. 2020; 121 (5–6): 3286–97. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 96. Zheng Y, Li JX, Chen CJ, et al. : Extracellular vesicle-derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR-497/septin 2 pathway. Cell Biol Int. 2020; 44 (4): 1037–45. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 97. Wang X, Zhang H, Yang H, et al. : Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer. Mol Oncol. 2020; 14 (3): 539–55. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 98. Lai RW, Lu R, Danthi PS, et al. : Multi-level remodeling of transcriptional landscapes in aging and longevity. BMB Rep. 2019; 52 (1): 86–108. PubMed Abstract | Publisher Full Text | Free Full Text 99. Li D, Li Z, Yang Y, et al. : Circular RNAs as biomarkers and therapeutic targets in environmental chemical exposure-related diseases. Environ Res. 2020; 180 : 108825. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 100. Müller S, Appel B: In vitro circularization of RNA. RNA Biol. 2016; 14 (8): 1018–27. PubMed Abstract | Publisher Full Text | Free Full Text 101. Li J, Mohammed-Elsabagh M, Paczkowski F, et al. : Circular Nucleic Acids: Discovery, Functions and Applications. Chembiochem. 2020; 21 (11): 1547–66. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 102. Tatomer DC, Liang D, Wilusz JE: Inducible Expression of Eukaryotic Circular RNAs from Plasmids. Methods Mol Biol. 2017; 1648 : 143–54. PubMed Abstract | Publisher Full Text 103. Umekage S, Kikuchi Y: In vitro and in vivo production and purification of circular RNA aptamer. J Biotechnol. 2009; 139 (4): 265–72. PubMed Abstract | Publisher Full Text 104. Wesselhoeft RA, Kowalski PS, Anderson DG: Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat Commun. 2018; 9 (1): 2629. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 105. Litke JL, Jaffrey SR: Highly efficient expression of circular RNA aptamers in cells using autocatalytic transcripts. Nat Biotechnol. 2019; 37 (6): 667–75. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 106. Umekage S, Tomoe U, Fujita Y, et al. : In Vivo Circular RNA Expression by the Permuted Intron-Exon Method. INTECH Open Access Publisher: 2012. Publisher Full Text 107. Wang Y, Wang Z: Efficient backsplicing produces translatable circular mRNAs. RNA. 2015; 21 (2): 172–9. PubMed Abstract | Publisher Full Text | Free Full Text 108. Noto JJ, Schmidt CA, Matera AG: Engineering and expressing circular RNAs via tRNA splicing. RNA Biol. 2016; 14 (8): 978–84. PubMed Abstract | Publisher Full Text | Free Full Text 109. Schmidt CA, Noto JJ, Filonov GS, et al. : A Method for Expressing and Imaging Abundant, Stable, Circular RNAs In Vivo Using tRNA Splicing. Meth Enzymol. 2016; 572 : 215–36. PubMed Abstract | Publisher Full Text 110. Borchardt EK, Meganck RM, Vincent HA, et al. : Inducing circular RNA formation using the CRISPR endoribonuclease Csy4. RNA. 2017; 23 (5): 619–27. PubMed Abstract | Publisher Full Text | Free Full Text 111. Franz A, Rabien A, Stephan C, et al. : Circular RNAs: A new class of biomarkers as a rising interest in laboratory medicine. Clin Chem Lab Med. 2018; 56 (12): 1992–2003. PubMed Abstract | Publisher Full Text 112. Holdt LM, Kohlmaier A, Teupser D: Circular RNAs as Therapeutic Agents and Targets. Front Physiol. 2018; 9 : 1262. PubMed Abstract | Publisher Full Text | Free Full Text 113. Li Z, Ruan Y, Zhang H, et al. : Tumor-suppressive circular RNAs: Mechanisms underlying their suppression of tumor occurrence and use as therapeutic targets. Cancer Sci. 2019; 110 (12): 3630–8. PubMed Abstract | Publisher Full Text | Free Full Text 114. Jost I, Shalamova LA, Gerresheim GK, et al. : Functional sequestration of microRNA-122 from Hepatitis C Virus by circular RNA sponges. RNA Biol. 2018; 15 (8): 1032–9. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 115. Meganck RM, Borchardt EK, Castellanos Rivera RM, et al. : Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo . Mol Ther Nucleic Acids. 2018; 13 : 89–98. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 29 Jun 2020 ADD YOUR COMMENT Comment Author details Author details 1 Institute for Biochemistry, University Greifswald, Greifswald, Germany Constanze Ebermann Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Theodor Schnarr Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Sabine Müller Roles: Conceptualization, Data Curation, Methodology, Project Administration, Resources, Supervision, 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 (1) version 1 Published: 29 Jun 2020, 9:655 https://doi.org/10.12688/f1000research.25060.1 Copyright © 2020 Ebermann C 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 Ebermann C, Schnarr T and Müller S. Recent advances in understanding circular RNAs [version 1; peer review: 3 approved] . F1000Research 2020, 9 (F1000 Faculty Rev):655 ( https://doi.org/10.12688/f1000research.25060.1 ) 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 Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Ling-Ling Chen , State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China Competing interests: No competing interests were declared. (for version 1) Jeremy E. Wilusz , Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, USA Competing interests: No competing interests were declared. (for version 1) Amaresh Chandra Panda , Institute of Life Sciences, India Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 29 Jun 2020 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 2 3 Version 1 29 Jun 20 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Ling-Ling Chen , State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China Competing interests: No competing interests were declared. View more View less Jeremy E. Wilusz , Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, USA Competing interests: No competing interests were declared. View more View less Amaresh Chandra Panda , Institute of Life Sciences, India Competing interests: No competing interests were declared. View more View less 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 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 = "Recent advances in understanding circular...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/9-655/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/9-655/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/9-655/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Ebermann C 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/9-655/v1/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/9-655", templates : { twitter : "Recent advances in understanding circular RNAs. Ebermann C et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/9-655/v1" } }; 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/25060/27648") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "27648"); $(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 = { "65729": 0, "65731": 1, "65730": 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 = "3d950d22-0f26-4e76-8d9e-727b8d100102"; 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(",","/")); } }); });