13 novembre 2024
News
Allenare muscoli aiuta i neuroni a crescere, così lo sport fa bene al cervello
Lo sport fa bene al cervello, i saggi lo sostengono da tempo immemore (il motto ‘mens sana in corpore sano’ insegna) e dalla scienza arrivano nuove prove a sostegno dei benefici mentali di uno stile di vita attivo e su un possibile risvolto ‘terapeutico’ . Uno studio ha dimostrato questi benefici a livello di singoli neuroni. A condurre gli esperimenti un team di ricercatori e ingegneri del Mit (Massachusetts Institute of Technology). Quello che è emerso è che, quando i muscoli si allenano, aiutano i neuroni a crescere . Come? Gli esperti hanno osservato che quando i muscoli si contraggono durante l’esercizio, rilasciano una ‘zuppa’ di segnali biochimici chiamati miochine. In presenza di questi segnali generati dai muscoli, i neuroni crescono 4 volte di più rispetto a quelli non esposti alle miochine. Questi esperimenti a livello cellulare suggeriscono che l’esercizio fisico può avere un effetto biochimico significativo sulla crescita dei nervi.
Muscoli, neuroni e miochine
Ma non solo: i ricercatori hanno anche scoperto che i neuroni rispondono sì ai segnali biochimici dell’esercizio, ma anche ai suoi impatti fisici. Il team ha osservato che, quando i neuroni vengono ripetutamente tirati avanti e indietro – in modo simile a come i muscoli si contraggono e si espandono durante l’esercizio – crescono tanto quanto accade quando sono esposti alle miochine di un muscolo. Mentre studi precedenti hanno indicato un potenziale collegamento biochimico tra l’attività muscolare e la crescita dei nervi, questo lavoro – affermano i ricercatori – è il primo a dimostrare che gli effetti fisici possono essere altrettanto importanti. I risultati degli esperimenti condotti, che saranno pubblicati sulla rivista ‘Advanced Healthcare Materials’, fanno luce sulla connessione tra muscoli e nervi durante l’esercizio e potrebbero guidare le terapie correlate all’esercizio per riparare i nervi danneggiati e deteriorati .
“Ora che sappiamo che esiste questa comunicazione incrociata tra muscolo e nervo, può essere utile per trattare problemi come le lesioni nervose, in cui la comunicazione tra nervo e muscolo è interrotta”, evidenzia Ritu Raman, autrice principale dello studio, professoressa associata di ingegneria meccanica al Mit. “Forse se stimoliamo il muscolo, potremmo incoraggiare il nervo a guarire e ripristinare la mobilità in chi l’ha persa per lesioni traumatiche o malattie neurodegenerative”.
Nel 2023, Raman e colleghi avevano riportato di essere riusciti a ripristinare la mobilità nei topi che avevano subito una lesione muscolare traumatica, impiantando prima tessuto muscolare nel sito della lesione, e poi esercitando il nuovo tessuto, stimolandolo ripetutamente con la luce. Nel tempo, hanno scoperto che l’innesto allenato ha aiutato i topi a riacquistare la funzione motoria, raggiungendo livelli di attività paragonabili a quelli dei topi sani. Quando i ricercatori hanno analizzato l’innesto stesso, è emerso che l’esercizio fisico regolare stimolava il muscolo innestato a produrre determinati segnali biochimici che, come noto, favoriscono la crescita dei nervi e dei vasi sanguigni. “Pensiamo sempre che i nervi controllino i muscoli, ma non pensiamo mai che i muscoli rispondano a loro volta ai nervi”, riflette Raman. “Quindi, abbiamo iniziato a pensare che stimolare i muscoli incoraggiasse la crescita dei nervi”.
La ‘zuppa’ biochimica
Nel nuovo studio, il team si è prefissato di determinare se l’esercizio dei muscoli abbia un effetto diretto proprio su questo, sul modo in cui i nervi crescono, concentrandosi esclusivamente sui muscoli e sul tessuto nervoso. I ricercatori hanno fatto crescere cellule muscolari dei topi in lunghe fibre che si sono fuse per formare un piccolo foglio di tessuto muscolare maturo delle dimensioni di circa un quarto di dollaro. Hanno poi modificato geneticamente il muscolo per farlo contrarre in risposta alla luce, in modo da imitare l’atto dell’esercizio. Raman aveva precedentemente sviluppato un tappetino di gel su cui far crescere ed esercitare il tessuto muscolare. Il team ha quindi raccolto campioni della soluzione circostante in cui era stato allenato il tessuto muscolare, pensando che dovesse contenere miochine, incluso fattori di crescita, Rna e un mix di altre proteine. In altre parole, “una zuppa biochimica di cose che i muscoli secernono, alcune delle quali potrebbero essere buone per i nervi “, racconta Raman. “I muscoli secernono praticamente sempre miochine, ma quando li alleni ne producono di più”.
Il team ha trasferito la soluzione di miochina in una capsula separata contenente neuroni motori, nervi presenti nel midollo spinale che controllano i muscoli coinvolti nel movimento volontario. Come per il tessuto muscolare, i neuroni sono stati coltivati su un tappetino di gel simile. Dopo che i neuroni sono stati esposti alla miscela di miochina, il team ha osservato che hanno iniziato a crescere rapidamente, 4 volte più velocemente dei neuroni che non hanno ricevuto la soluzione biochimica. “Crescono molto più lontano e più velocemente e l’effetto è piuttosto immediato”, osserva Raman. Dall’analisi genetica “abbiamo visto che molti dei geni sovraregolati nei neuroni stimolati dall’esercizio non erano solo correlati alla crescita dei neuroni, ma anche alla loro maturazione, a quanto bene comunicano con i muscoli e altri nervi e a quanto sono maturi gli assoni. L’esercizio sembra dunque avere un impatto non solo sulla crescita dei neuroni, ma anche su quanto sono maturi e ben funzionanti”.
Questo succede a livello biochimico. Ma l’impatto fisico dell’esercizio sui nervi? “I neuroni sono fisicamente attaccati ai muscoli, quindi si allungano e si muovono con il muscolo”, dice Raman. “Volevamo vedere, anche in assenza di segnali biochimici dal muscolo, se potevamo allungare i neuroni avanti e indietro, imitando le forze meccaniche (dell’esercizio), e se questo potesse avere un impatto anche sulla crescita”. Così i ricercatori hanno fatto crescere un diverso set di neuroni motori su un tappetino di gel con incorporati piccoli magneti. Con un magnete esterno hanno fatto muovere il tappetino (e i neuroni) avanti e indietro. In questo modo, hanno ‘esercitato’ i neuroni, per 30 minuti al giorno. A sorpresa, hanno scoperto che questo esercizio meccanico stimolava i neuroni a crescere tanto quanto le miochine. “Questo è un buon segno, perché ci dice che sia gli effetti biochimici che quelli fisici dell’esercizio sono ugualmente importanti”, conclude Raman. Prossima sfida? Capire come la stimolazione muscolare mirata possa essere utilizzata per far crescere e guarire i nervi danneggiati e ripristinare la mobilità nelle persone affette da una malattia neurodegenerativa come la Sla. “Questo è solo il nostro primo passo verso la comprensione e il controllo dell’esercizio fisico come medicina”, chiosa la scienziata.
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Editore: Associazione Reportage - Direttore responsabile: Annamaria Persico
Reportage è una testata iscritta al n.18 Registro Stampa Tribunale di Lamezia Terme il 27-11-1962. © 2020 - reportage
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e,t,n,i,s;const{screen:{width:a,height:o},self:r,top:d,matchMedia:c,opener:l}=window,{documentElement:{clientWidth:h,clientHeight:u}}=document;let p;try{p=(new Date).getTimezoneOffset()/60*-1}catch(e){p=null}return{popup:!(!l||l===window),timezone_offset:p,user_preference:null===(e=null===Intl||void 0===Intl?void 0:Intl.DateTimeFormat())||void 0===e?void 0:e.resolvedOptions(),user_using_darkmode:Boolean(c&&c("(prefers-color-scheme: dark)").matches),user_supports_darkmode:Boolean(c),window_resolution:{width:null!=h?h:0,height:null!=u?u:0},screen_resolution:{width:null!=a?a:0,height:null!=o?o:0},frame:d===r?null:{innerWidth:null!==(t=null==r?void 0:r.innerWidth)&&void 0!==t?t:0,innerHeight:null!==(n=null==r?void 0:r.innerHeight)&&void 0!==n?n:0,outerWidth:null!==(i=null==r?void 0:r.outerWidth)&&void 0!==i?i:0,outerHeight:null!==(s=null==r?void 0:r.outerHeight)&&void 0!==s?s:0}}},TRACKING_URL="_tr",buildSignature=({callbacks:e,context:t},n)=>{var i,s,a,o;return Object.assign({ad_loaded_callback:null==e?void 0:e.adLoadedCallback,app_version:version,caf_client_id:null===(i=null==t?void 0:t.pageOptions)||void 0===i?void 0:i.pubId,caf_timed_out:null==e?void 0:e.cafTimedOut,caf_loaded_ms:null==e?void 0:e.cafLoadedMs,channel:null===(s=null==t?void 0:t.pageOptions)||void 0===s?void 0:s.channel,desktop:t.desktop,terms:null===(a=null==t?void 0:t.pageOptions)||void 0===a?void 0:a.terms,fd_server_datetime:t.fd_server_datetime,fd_server:t.fd_server,flex_rule:t.flex_rule,host:t.host,ip:t.ip,ivt:null===(o=null==t?void 0:t.pageOptions)||void 0===o?void 0:o.ivt,js_error:t.js_error,mobile:t.mobile,no_ads_redirect:t.noAdsRedirect,page_headers:t.page_headers,page_loaded_callback:null==e?void 0:e.pageLoadedCallback,page_method:t.page_method,page_request:t.page_request,page_time:t.page_time,page_url:t.page_url,reportable_channel:t.reportableChannel,reportable_style_id:t.reportableStyleId,tablet:t.tablet,template_id:t.templateId,type:n,user_has_ad_blocker:t.user_has_ad_blocker,uuid:t.uuid,zeroclick:t.zeroClick},browserState())},trackVisit=({callbacks:e,context:t},n,i="")=>{const s=`${i}/${TRACKING_URL}`,a=i?"include":"same-origin",o=buildSignature({callbacks:e,context:t},n);let r={};"click"===n&&(r={click:"true",session:t.uuid,nc:Date.now().toString()}),fetch(s,{method:"POST",headers:{Accept:"application/json","Content-Type":"application/json"},credentials:a,body:JSON.stringify(Object.assign({signature:encode(o)},r))})};var State$1;!function(){if(!window.CustomEvent){function e(e,t){t=t||{bubbles:!1,cancelable:!1,detail:void 0};const n=document.createEvent("CustomEvent");return n.initCustomEvent(e,t.bubbles,t.cancelable,t.detail),n}e.prototype=window.Event.prototype,window.CustomEvent=e}}(),function(e){e[e.Pending=0]="Pending",e[e.Loaded=1]="Loaded",e[e.Failed=2]="Failed"}(State$1||(State$1={}));class Provider{constructor(e){this.timeoutSeconds=5,this.handlePixelEvent=e=>{switch(this.state){case State$1.Failed:break;case State$1.Pending:setTimeout((()=>this.handlePixelEvent(e)),100);break;case State$1.Loaded:this.onPixelEvent(e)}},this.watch=()=>{switch(this.state){case State$1.Loaded:case State$1.Failed:break;case State$1.Pending:this.isLoaded()?this.state=State$1.Loaded:this.isTimedOut()?this.state=State$1.Failed:setTimeout(this.watch,50)}},this.config=e,this.identifier&&this.identifier.length>0?(this.state=State$1.Pending,this.timeoutAt=new Date,this.timeoutAt.setSeconds(this.timeoutAt.getSeconds()+this.timeoutAfter()),this.injectPixel()):this.state=State$1.Failed}get identifier(){var e;return null===(e=this.config)||void 0===e?void 0:e.key}get pixelEvents(){var e;return null===(e=this.config)||void 0===e?void 0:e.pixel_events}injectPixel(){this.injectedAt||(this.injectedAt=new Date,this.inject(),this.watch())}inject(){const e=document.createElement("script");e.text=this.script,document.head.appendChild(e)}isTimedOut(){return+new Date>=+this.timeoutAt}timeoutAfter(){return this.timeoutSeconds}selectPixelEvents(e){if(Array.isArray(this.pixelEvents))return this.pixelEvents.filter((t=>"term-view"===t.trigger&&"visit"===e||(!(!["term-click","ad-view"].includes(t.trigger)||"ctr"!==e)||"ad-click"===t.trigger&&"click"===e)))}}class Facebook extends Provider{get script(){return`!function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function(){n.callMethod?n.callMethod.apply(n,arguments):n.queue.push(arguments)};if(!f._fbq)f._fbq=n;n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0;t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js');fbq('init', '${this.identifier}');`}onPixelEvent(e){this.selectPixelEvents(e).forEach((e=>{e&&(e.custom?window.fbq("trackCustom",e.event):window.fbq("track",e.event))}))}isLoaded(){return!!window.fbq}}class Outbrain extends Provider{get script(){return`!function(_window, _document) {var OB_ADV_ID = '${this.identifier}';if (_window.obApi) {var toArray = function(object) {return Object.prototype.toString.call(object) === '[object Array]' ? object : [object];};_window.obApi.marketerId = toArray(_window.obApi.marketerId).concat(toArray(OB_ADV_ID));return;}var api = _window.obApi = function() {api.dispatch ? api.dispatch.apply(api, arguments) : api.queue.push(arguments);};api.version = '1.1';api.loaded = true;api.marketerId = OB_ADV_ID;api.queue = [];var tag = _document.createElement('script');tag.async = true;tag.src = '//amplify.outbrain.com/cp/obtp.js';tag.type = 'text/javascript';var script = _document.getElementsByTagName('script')[0];script.parentNode.insertBefore(tag, script);}(window, document);`}onPixelEvent(e){this.selectPixelEvents(e).forEach((e=>{e&&window.obApi("track",e.event)}))}isLoaded(){return!!window.obApi}}class Revcontent extends Provider{get script(){return""}inject(){const e=document.createElement("script");e.src="https://assets.revcontent.com/master/rev.js",document.head.appendChild(e)}onPixelEvent(e){this.selectPixelEvents(e).forEach((e=>{e&&window.rev("event",e.event)}))}isLoaded(){return!!window.rev}}class Taboola extends Provider{get script(){return"window._tfa = window._tfa || [];!function (t, f, a, x) {if (!document.getElementById(x)) {t.async = 1;t.src = a;t.id=x;f.parentNode.insertBefore(t, f);}}(document.createElement('script'),document.getElementsByTagName('script')[0],'//cdn.taboola.com/libtrc/unip/1451879/tfa.js','tb_tfa_script');"}onPixelEvent(e){this.selectPixelEvents(e).forEach((e=>{e&&window._tfa.push({notify:"event",name:e.event,id:e.pixel_id})}))}isLoaded(){return Array.isArray(window._tfa)}}class Tiktok extends Provider{constructor(e,t){super(e),this.useAltTikTokEventsForAdsPlatformUser=t}get script(){return`!function (w, d, t) {w.TiktokAnalyticsObject=t;var ttq=w[t]=w[t]||[];ttq.methods=["page","track","identify","instances","debug","on","off","once","ready","alias","group","enableCookie","disableCookie"],ttq.setAndDefer=function(t,e){t[e]=function(){t.push([e].concat(Array.prototype.slice.call(arguments,0)))}};for(var i=0;i
{e&&window.ttq.instance(this.identifier).track(e.event)}))}isLoaded(){return!!window.ttq}}const ADS_PARAM$1="?caf",MESSAGE_PREFIX="FSXDC,.aCS:",ALLOWED_ORIGINS=["https://www.google.com","https://www.adsensecustomsearchads.com","https://syndicatedsearch.goog","https://googleadservices.com"];class Pixels{static build(e){const t=unpackPHPArrayObject(e,"pixel_tracking_data");if(t)return t.useAltTikTokEventsForAdsPlatformUser=e.is_ads,new Pixels(t)}constructor(e){this.onPixelEvent=e=>{const{detail:{type:t}}=e;switch(t){case"visit":case"ctr":case"click":this.providers.forEach((e=>e.handlePixelEvent(t)))}},this.providers=[new Facebook(e.facebook),new Tiktok(e.tiktok,e.useAltTikTokEventsForAdsPlatformUser),new Taboola(e.taboola),new Revcontent(e.revcontent),new Outbrain(e.outbrain)]}listenForEvents(){document.addEventListener("pixel",(e=>{this.onPixelEvent(e)}));window.onmessage=e=>{const{origin:t,data:n}=e;ALLOWED_ORIGINS.includes(t)&&(null==n?void 0:n.startsWith(MESSAGE_PREFIX))&&window.location.search.startsWith(ADS_PARAM$1)&&document.dispatchEvent(new CustomEvent("pixel",{detail:{type:"click"}}))}}dispatchEvent(e){document.dispatchEvent(new CustomEvent("pixel",{detail:e}))}}var State;!function(e){e[e.Pending=0]="Pending",e[e.Loaded=1]="Loaded",e[e.Failure=2]="Failure",e[e.TimedOut=3]="TimedOut",e[e.Errored=4]="Errored"}(State||(State={}));const CAF_SCRIPT_SRC=`https://www.google.com/adsense/domains/caf.js?${GOOGLE_MV3_URL_PARAMS}`,TIMEOUT_SCRIPTS=Number(GOOGLE_CAF_TIMEOUT_SCRIPTS),TIMEOUT_CALLBACKS=Number(GOOGLE_CAF_TIMEOUT_CALLBACKS);class StateMachine{constructor(){this.state=State.Pending}transitionTo(e){this.state=e}transitionFromPendingTo(e){this.done||(this.state=e)}get loaded(){return this.state===State.Loaded}get timedOut(){return this.state===State.TimedOut}get done(){return this.state!==State.Pending}}class Ads{constructor(e,t){this.state={script:new StateMachine,blocks:new StateMachine},this.blocksLoaded=[],this.injectScriptTags=()=>__awaiter(this,void 0,void 0,(function*(){return new Promise((e=>{const t=document.createElement("script");t.type="text/javascript",t.src=CAF_SCRIPT_SRC,t.addEventListener("load",(()=>e(!0))),t.addEventListener("error",(()=>e(!1))),document.body.appendChild(t),TIMEOUT_SCRIPTS>0&&setTimeout((()=>e(!1)),TIMEOUT_SCRIPTS)}))})),this.onPageLoaded=(e,t)=>{if(this.pageLoaded={requestAccepted:e,status:t},this.state.script.done)return;const n=null==t?void 0:t.error_code;n?(this.state.script.transitionTo(State.Failure),this.failureReason=`caf_pageloaderror_${n}`):this.state.script.transitionTo(State.Loaded)},this.onBlockLoaded=(e,t,n,i)=>{this.blocksLoaded.push({containerName:e,adsLoaded:t,isExperimentVariant:n,callbackOptions:i}),this.state.blocks.done||(t?this.state.blocks.transitionTo(State.Loaded):this.blocksLoaded.length>=this.blocks.length&&(this.state.blocks.transitionTo(State.Failure),this.failureReason=`caf_adloadfail_${e}`))},this.onTimeout=()=>{this.state.script.transitionFromPendingTo(State.TimedOut),this.state.blocks.transitionFromPendingTo(State.TimedOut)},this.blocks=e,this.options=t}get loaded(){return this.state.script.loaded&&!this.blocksLoaded.map((e=>e.adsLoaded)).includes(!1)}waitForBlocks(){return __awaiter(this,void 0,void 0,(function*(){return new Promise((e=>{const t=()=>{const n=performance.now();if(this.state.blocks.done)return this.cafLoadTime=Math.round(n-this.cafStartTime),void e();const i=this.blocksLoaded.map((e=>e.adsLoaded));i.includes(!1)||i.length>=this.blocks.length?e():setTimeout(t,50)};t()}))}))}inject(){return __awaiter(this,void 0,void 0,(function*(){try{const e=yield this.injectScriptTags();return this.cafStartTime=performance.now(),e&&void 0!==window.google?(new window.google.ads.domains.Caf(Object.assign(Object.assign({},this.options),{pageLoadedCallback:this.onPageLoaded,adLoadedCallback:this.onBlockLoaded}),...this.blocks),TIMEOUT_CALLBACKS>0&&setTimeout(this.onTimeout,TIMEOUT_CALLBACKS),yield new Promise((e=>{const t=()=>{this.state.script.done?e():setTimeout(t,10)};t()}))):void this.state.script.transitionTo(State.Failure)}catch(e){return void(this.error=e.toString())}}))}toCallbacks(){return{adLoadedCallback:this.blocksLoaded.slice(-1)[0],pageLoadedCallback:this.pageLoaded,cafTimedOut:this.state.script.timedOut||this.state.blocks.timedOut,cafLoadedMs:this.cafLoadTime,googleAdsFailure:!!this.failureReason}}toContext(){const e={cafScriptWasLoaded:this.state.script.loaded,cafScriptLoadTime:this.cafLoadTime,callbacks:this.toCallbacks};return this.error&&(e.js_error={message:this.error}),this.state.script.loaded||(e.zeroclick={reason:"googleAdsFailure"}),e}mockFailedState(){this.state.blocks.transitionTo(State.Failure),this.state.script.transitionTo(State.Failure)}}class TagManager{constructor(e){this.injected=!1,this.identifier=e}inject(){if(this.injected)return;if(!this.identifier)return;if("TEST"===this.identifier)return;const e=document.createElement("script");e.setAttribute("src",`https://www.googletagmanager.com/gtag/js?id=${this.identifier}`),document.head.appendChild(e),this.track(),this.injected=!0}track(){this.push("js",new Date),this.push("config",this.identifier)}push(e,t){window.dataLayer||(window.dataLayer=[]),window.dataLayer.push(arguments)}}const ADS_PARAM="caf",ADS_TRACKING_URL="_tr",BLOCKS_TYPE="ads",BLOCKS_CONTAINER="rs",KNOWN_CAF_PARAMS=["caf","query","afdToken","pcsa","nb","nm","nx","ny","is","clkt"];class Google{static build({pageOptions:e,preferredLanguage:t,blocks:n,googleAnalytics:i},s,a,o){let r={};e&&(r=Object.assign({},e),r.hl||(r.hl=t));let d=null==e?void 0:e.resultsPageBaseUrl;d||(d=window.location.origin);return new Google(s.uuid,n,r,i,d,o)}constructor(e,t,n,i,s,a){this._blocks=t,this._pageOptions=n,this.uuid=e,this._baseURL=new URL(s),this._signature=a,this.ads=new Ads(this.blocks,this.pageOptions),this.tagManager=new TagManager(i)}injectTagManager(){this.tagManager.inject()}injectAds(){return __awaiter(this,void 0,void 0,(function*(){yield this.ads.inject()}))}waitForBlocks(){return __awaiter(this,void 0,void 0,(function*(){return this.ads.waitForBlocks()}))}get blocks(){return(this._blocks||[]).filter((e=>this.wantsToServeAds?e.type===BLOCKS_TYPE:e.container===BLOCKS_CONTAINER)).map((e=>{const t=this.baseURL;new URLSearchParams(window.location.search).forEach(((e,n)=>{t.searchParams.has(n)||t.searchParams.append(n,e)}));const n=Object.assign({},e);if(n.resultsPageBaseUrl=t.toString(),this.wantsToServeAds){const e=new URLSearchParams;e.append("click","true"),e.append("session",this.uuid);const t=Object.assign({},this._signature);delete t.ad_loaded_callback,delete t.caf_loaded_ms,delete t.caf_timed_out,delete t.flex_rule,delete t.frame,delete t.js_error,delete t.no_ads_redirect,delete t.page_headers,delete t.page_request,delete t.page_loaded_callback,delete t.popup,delete t.screen_resolution,delete t.user_has_ad_blocker,delete t.user_preference,delete t.user_supports_darkmode,delete t.user_using_darkmode,delete t.zeroclick,e.append("signature",encode(t)),n.clicktrackUrl=`${TRACKING_DOMAIN}${ADS_TRACKING_URL}?${e.toString()}`}return n}))}get baseURL(){const e=new URL(this._baseURL.origin);return e.searchParams.append(ADS_PARAM,"1"),this._baseURL.searchParams.forEach(((t,n)=>{e.searchParams.append(n,t)})),e}get pageOptions(){const e=Object.assign({},this._pageOptions);return Object.keys(this._pageOptions).forEach((t=>{t.startsWith("bodis")&&delete e[t]})),e}get cannotLoadAds(){return!this.ads.loaded}get wantsToServeAds(){return new URLSearchParams(window.location.search).has(ADS_PARAM)}get adsMode(){return this.ads.loaded&&this.wantsToServeAds}get adsReady(){return this.wantsToServeAds&&!this.cannotLoadAds}get noAdsRedirectUrl(){const e=new URLSearchParams(window.location.search);return KNOWN_CAF_PARAMS.forEach((t=>e.delete(t))),`${window.location.origin}?${e.toString()}`}get callbacks(){return this.ads.toCallbacks()}toContext(){return Object.assign({blocks:this.blocks,pageOptions:this.pageOptions},this.ads.toContext())}}class CookieConsentManager{constructor(){this.injectScriptTag=()=>__awaiter(this,void 0,void 0,(function*(){return new Promise((e=>{const t=document.createElement("script");t.setAttribute("src",COOKIE_CONSENT_JS_URL),t.addEventListener("load",(()=>this.awaitConsent(e))),t.addEventListener("error",(()=>e(!1))),document.head.appendChild(t)}))}))}inject(){return __awaiter(this,void 0,void 0,(function*(){this.injected||!COOKIE_CONSENT_JS_URL||isLocal()||(this.injected=yield this.injectScriptTag())}))}awaitConsent(e){let t=0;const n=setInterval((()=>{t+=1,20===t&&(clearInterval(n),e(!0)),void 0!==window.__tcfapi&&(window.addEventListener("ConsentActivity",(t=>{const{detail:{status:n}}=t;n&&e(!0)})),clearInterval(n))}),50)}}class App{main(){var e,t;return __awaiter(this,void 0,void 0,(function*(){if(this.parkResponse=decode(),this.findDomainResponse=yield getFindDomain(),!this.findDomainResponse)throw new Error("Domain failed to load.");this.pixels=Pixels.build(this.findDomainResponse),null===(e=this.pixels)||void 0===e||e.listenForEvents(),this.adblock=new Adblock,yield this.adblock.inject(),this.google=Google.build(this.findDomainResponse,this.parkResponse,this.adblock,buildSignature({context:this.context,callbacks:null===(t=this.google)||void 0===t?void 0:t.callbacks},"click")),this.google.injectTagManager();const n=Parking.build(this.findDomainResponse,this.google);Render.prerender(n),this.cookieConsentManager=new CookieConsentManager,yield this.cookieConsentManager.inject();let i=Failed.cannotPark(this.findDomainResponse);if(i)return void(yield this.transitionToFailed(i));yield this.google.injectAds();let s=Disabled.build(this.findDomainResponse,this.adblock.state);if(s)return void(yield this.transitionToDisabled(s));const a=this.adblock.hasAdblocker();a&&this.adblock.handleAdblocked();const o=Sales.build(this.findDomainResponse);if(o)return void(yield this.transitionToSales(o));this.eligibleForZeroClick&&(this.zeroClickResponse=yield getZeroClick(this.context));const r=Redirect.build(this.findDomainResponse,this.zeroClickResponse,this.google);if(r)yield this.transitionToRedirect(r);else{if(a)return s=Disabled.build(this.findDomainResponse,this.adblock.state),void(yield this.transitionToDisabled(s));i=Failed.noSponsors(this.google),i?yield this.transitionToFailed(i):yield this.transitionToParking(n)}}))}transitionToParking(e){return __awaiter(this,void 0,void 0,(function*(){this.state=e,Render.template(e),Render.revealPage(),yield this.google.waitForBlocks(),yield this.track()}))}transitionToRedirect(e){return __awaiter(this,void 0,void 0,(function*(){this.state=e;const t=this.track();Render.revealPage(),yield waiter(e.delay,(e=>Render.loading(e))),yield t,window.location.href=e.url,log(`➡ Redirecting [${e.url}]`)}))}transitionToFailed(e){return __awaiter(this,void 0,void 0,(function*(){this.state=e,Render.message(e.message),Render.revealPage(),yield this.track()}))}transitionToSales(e){return __awaiter(this,void 0,void 0,(function*(){this.state=e,e.init(this.context),yield this.track()}))}transitionToDisabled(e){return __awaiter(this,void 0,void 0,(function*(){this.state=e,Render.message(e.message),Render.revealPage(),yield this.track()}))}track(){var e;return __awaiter(this,void 0,void 0,(function*(){if(!this.state.track)return Promise.resolve();try{const t=this.state.trackingType;return null===(e=this.pixels)||void 0===e||e.dispatchEvent({type:t}),trackVisit({context:this.context,callbacks:this.google.callbacks},t)}catch(e){return}}))}get eligibleForZeroClick(){const{cannotPark:e,canZeroClick:t,zeroClick:n}=this.findDomainResponse,{cannotLoadAds:i,wantsToServeAds:s}=this.google;return this.adblock.state!==Blocking.BLOCKED&&(!!t&&(!!e||(!(!i||s)||!!(null==n?void 0:n.reason))))}get context(){var e,t,n,i;const s=this.findDomainResponse,a=this.parkResponse,o=null===(e=this.state)||void 0===e?void 0:e.toContext(),r=null===(t=this.adblock)||void 0===t?void 0:t.toContext(),d=null===(n=this.google)||void 0===n?void 0:n.toContext(),c=browserState(),l=Object.assign(Object.assign({},null===(i=this.findDomainResponse)||void 0===i?void 0:i.zeroClick),this.zeroClickResponse);return Object.assign(Object.assign(Object.assign(Object.assign(Object.assign(Object.assign(Object.assign({app_version:APP_VERSION},s),a),r),d),o),c),{zeroClick:l})}init(){return __awaiter(this,void 0,void 0,(function*(){try{window.__parkour=this,yield this.main()}catch(e){console.error("app",e);const t=Failed.fromError(e);this.state=t,Render.message(t.message),Render.revealPage()}}))}}(new App).init(),exports.App=App}));