Umthombo woLutsha: i-NAD + kunye neNMN njengeSongezelelo
I-AASraw ivelisa i-Cannabidiol (CBD) ipowder kunye ne-Hemp ebalulekileyo yeoyile ngobuninzi!

I-NAD + kunye neNMN

 

Ukukhutshwa kweziphumo zenzululwazi malunga nendlela i-NMN eyongeza ngayo i-NAD kwimizimba yeempuku yabetha kwiphephandaba nakwizihloko zeemagazini, ibiza ukufumanisa oku "ngumthombo wolutsha. "

Uphononongo lubike ukuba iimpuku ezindala zaba zincinci, zinamandla, kwaye zincinci xa zinikwa ikhompawundi. Ke, unokuguqula inkqubo yakho yokuguga ngokuthatha isongezelelo. Nangona kuya kufuneka uxoxe ngokuthatha naziphi na izongezo kunye nogqirha wakho.

 

HisIbali le-NMN kunye ne-NAD +

I-Nicotinamide adenine dinucleotide, okanye i-NAD ngokufutshane, yenye yezona molekyuli zibalulekileyo neziguqukayo emzimbeni. Kuba isembindini wokubonelela ngeeseli ngamandla, akukho phantse yinkqubo yebhayiloji engadingi NAD. Ngenxa yoku, i-NAD ijolise kuphando lwebhayiloji.

Ngo-1906, uArthur Harden noWilliam John Young bafumanisa into “engamanzi” eyayifunyenwe kwigwele lomenzi wokwenza iswekile ibe butywala. Le "factor", ibizwa ngokuba yi "coferment" ngelo xesha, yajika yaba yi-NAD.

U-Harden, kunye no-Hans von Euler-Chelpin, baqhubeka nokukhupha iimfihlakalo zokuvumba. Banikwa imbasa kaNobel ngo-1929 ngokuphuhlisa ulwazi olunzulu ngezi nkqubo, kubandakanya imilo yemichiza kunye neepropathi zento eza kuthiwa kungekudala njenge-NAD.

Ibali le-NAD landisiwe nge-1930's, phantsi kwesikhokelo sika-Otto Warburg, omnye ophumelele uNobel, ofumene eyona ndima iphambili ye-NAD ekuququzeleleni uninzi lwempendulo ye-biochemical. IWarburg yafumanisa ukuba i-NAD isebenza njengohlobo lokudluliselwa kwebhayoloji yee-elektronon. Ukutshintshwa kwee-elektroni ukusuka kwenye imolekyuli ukuya kwenye, kusebenza njengesiseko samandla afunekayo ukwenza zonke iimpendulo ze-biochemical.

Kwi-1937, uConrad Elvehjem kunye nabalingane kwiYunivesithi yaseWisconsin, eMadison, bafumanisa ukuba i-NAD + yokunyanga izinja ze-pellagra, okanye "uLwimi oluMnyama". Ebantwini, ipellagra ibangela uninzi lweempawu, kubandakanya urhudo, isifo sengqondo esixhalabisayo, kunye nezilonda emlonyeni. Kubangelwa kukuswela i-niacin kwaye ngoku inyangwa rhoqo nge-nicotinamide, enye ye-precursors ye-NMN.

Uphando luka-Arthur Kornberg kwi-NAD + kuyo yonke i-40 kunye ne-50 'yaba negalelo ekukhokeleni ekufumaneni imigaqo-siseko yokuphindaphindeka kwe-DNA kunye nokubhalwa kwe-RNA, iinkqubo ezimbini ezibalulekileyo ebomini. Ngo-1958, uJack Preiss noPhilip Handler babhengeza amanyathelo amathathu ezinto eziphilayo, aguqulwa yi-nicotinic acid yaba yi-NAD. Olu luhlu lwamanyathelo, abizwa ngendlela, lwaziwa namhlanje njengePreiss-Handler Pathway.

Ngo-1963, i-Chambon, i-Weill kunye ne-Mandel baxela ukuba i-nicotinamide mononucleotide (i-NMN) inike amandla afunekayo ukwenza i-enzyme yenyukliya ebalulekileyo. Oku kufunyenwe kwavulela indlela uthotho lwezinto ezimangalisayo kuhlobo lweprotein ebizwa ngokuba yiPARP. Ii-PARP zidlala indima ebalulekileyo ekulungiseni umonakalo we-DNA, ukulawula ukufa kweseli, kunye nomsebenzi wazo onxulumene notshintsho kubomi bexesha.

Ngo-1976, uRechsteiner kunye nabalingane bakhe bafumana ubungqina obukholisayo be-NAD + kubonakala ngathi banakho "omnye umsebenzi omkhulu" kwiiseli zamamalia, ngaphaya kwendima yayo yeklasi ye-biochemical njenge-molecule yokudlulisa amandla.

Oku kufunyenwe kwenza ukuba uLeonard Guarente kunye noogxa bakhe bafumanise ukuba iiproteni ezibizwa ngokuba zi-sirtuins zisebenzisa i-NAD ukwandisa ixesha lokuphila ngokugcina ngokwahlukeneyo ezinye zofuzo "zithule". Ukusukela ngoko, inzala ikhulile kwi-NAD nakwizinto zayo eziphakathi, i-NMN kunye ne-NR, ukubanakho kwabo ukuphucula iimeko ezinxulumene nobudala.

I-NAD + kunye neNMN

Wumnqwazi Ukutya kuqulethe i-NMN?

I-NMN ivela ngokwendalo ekutyeni okunjengeavokhado, ibroccoli, ikhaphetshu kunye neetumato. Ngoku unokucinga: “Ukuba i-NMN ifumaneka ekutyeni, andinakonyusa amanqanaba am eNAD + ngokutya ngaphezulu koku kutya? “Lowo ngumbuzo omhle kwaye siyakukhuthaza ukuba utye ukutya okusempilweni. Kodwa, nanku umcimbi:

Nangona i-NMN isenzeka koku kutya, ugxininiso lungaphantsi kwe-1 mg ngekg nganye yokutya. Ngamanye amagama, ukufumana malunga ne-1mg ye-NMN, kuya kufuneka utye malunga ne-1kg ye-broccoli!

Kufunyenwe ukuba ukunyusa amanqanaba e-NAD + ebantwini, amanqanaba e-NMN kufuneka abe kumakhulu emiligram ngedosi. Le ndlela iphezulu kunento esinokuyifumana kwizidlo zethu, nokuba sisitya kangakanani i-broccoli.

 

Kutheni usongeza nge-NMN?

Njengoko sibonisile, i-NMN idlala indima ebalulekileyo ekwenzeni i-NAD +. Xa sinamanqanaba aphezulu e-NAD + kwimizimba yethu, ukwanda kwamandla eselfowuni okuba sisixhobo sobomi-ukunika amandla onke amalungu kunye neseli emizimbeni yethu nokusikhusela kumonakalo we-DNA. I-NAD + ikwasebenzisa ii-Sirtuins eziyimfuneko ekwandiseni ixesha lokuphila kunye nokucothisa inkqubo yokuguga.

Ukuxhaswa nge-NMN kunyusa ngokuthe ngqo amanqanaba e-NAD + kwimizimba yethu, echasene nokwehla kwendalo okwenzeka njengoko sikhula. Uphando lubonakalisile ukuba ngokuxhasa i-NMN, i Amanqanaba e-NAD + kubantu abadala banokuphakanyiselwa kulowo uneminyaka engama-20 ubudala!

 

(1) Yintoni iNicotinamide Adenine Dinucleotide (NAD +) kunye nemisebenzi yayo?

I-NAD + yi-coenzyme ebalulekileyo efunekayo ebomini nakwimisebenzi yeselula. I-Enzymes zizinto ezenza ukuba ukubakho kwe-biochemical kunokwenzeka. Ii-coenzymes “zezokunceda” iimolekyuli ezifuna ii-enzymes ukuze zisebenze.

I-NAD + yeyona molekyuli ininzi emzimbeni ngaphandle kwamanzi, kwaye ngaphandle kwayo, umzimba ungafa. I-NAD + isetyenziswa ziiproteni ezininzi kuwo wonke umzimba, njengee-sirtuins, ezilungisa iDNA eyonakeleyo. Kukwabalulekile kwi-mitochondria, eziyizindlu zamandla zeseli kunye nokuvelisa amandla emichiza asetyenziswa yimizimba yethu.

 

(2) Iindlela zokunyusa amanqanaba e-NAD +

Ukuzila ukutya okanye ukunciphisa ukutya ikhalori, eyaziwa ngokuba kukuthintela ikhalori, kubonisiwe kukonyusa amanqanaba e-NAD + kunye nomsebenzi we-sirtuin. Kwiimpuku, ukwanda kwe-NAD + kunye nomsebenzi we-sirtuin ukusuka kuthintelo lweekhalori kubonisiwe ukuthoba inkqubo yokuguga. Nangona i-NAD + ikhona kwezinye ukutya, ugxininiso luphantsi kakhulu ukuba lungachaphazela ukugxila kwangaphakathi. Ukuthatha izongezo ezithile, ezinje nge-NMN, kubonisiwe kukonyusa amanqanaba e-NAD +.

 

(3) NAD+ Yongeza njenge-NMN

Ukugxilwa kwe-Intracellular ye-NAD + kuncipha ekugugeni njengesiqhelo imisebenzi yeselfowuni ichitha i-NAD + yokuhambisa ixesha. Amanqanaba aphilileyo e-NAD + acingelwa ukuba abuyiselwe ngokuxhaswa nge-NAD + yangaphambili. Ngokophando, abaphambili njenge-NMN kunye I-nicotinamide riboside (NR) zijongwa njengezongezo zemveliso ye-NAD, ukonyusa ukugxila kwe-NAD +. UDavid Sinclair, umphandi we-NAD + waseHarvard, uthi, "Ukondla okanye ukusebenzisa i-NAD + ngqo kwizinto eziphilayo ayisiyonto ilungileyo. Imolekyuli ye-NAD + ayinakuwela ngokulula inwebu yeseli ukungena kwiiseli, kwaye ke ngenxa yoko ayinakufumaneka ngokuchaphazela ngokuqinisekileyo imetabolism. Endaweni yoko, iimolekyuli ezingaphambili kwi-NAD + kufuneka zisetyenziselwe ukunyusa amanqanaba e-bioava ezikhoyo e-NAD +. ” Oku kuthetha ukuba i-NAD + ayinakusetyenziswa ngokuthe ngqo zongeza, kuba ayifunxwa lula. I-NAD + zangaphambili zifunxeka ngokulula kune-NAD + kwaye zisebenza ngokufanelekileyo.

 

Yintoni iNicotinamide Mononucleotide (NMN)?

INicotinamide Mononucleotide (CAS:1094-61-7), ekwabizwa ngokuba yi-NMN, eyindalo eyenzeka ngokwendalo ekwimali encinci emzimbeni womntu kunye nokutya okuthile. I-NMN ayifumaneki ngomlomo, kwaye xa ithathwa ngomlomo inokuxhasa amanqanaba e-NAD + ngaphakathi kwesibindi kunye nezicubu zomzimba.

Uphando lwamva nje lucebise ukuba i-NMN inokuxhasa impilo yentliziyo, imveliso yamandla, impilo yokuqonda, kunye ne-retinal kunye nethambo. Enye into enomdla ngakumbi kuphando lwe-NMN kukuba inokukhuthaza ukulungiswa kwe-DNA kunye nokuxhasa ukwenziwa kohlobo lwe-SIRTUIN ekucingelwa ukuba ludlala indima ekugugeni okusempilweni.

 

 I-NMN idityaniswa njani eMzimbeni?

I-NMN iveliswa kwiivithamini B emzimbeni. I-enzyme ejongene nokwenza i-NMN emzimbeni ibizwa ngokuba yi-nicotinamide phosphoribosyltransferase (NAMPT). I-NAMPT incamathisela i-nicotinamide (ivithamini B3) kwi-phosphate yeswekile ebizwa ngokuba yi-PRPP (5'-phosphoribosyl-1-pyrophosphate). I-NMN inokwenziwa kwakhona 'nicotinamide riboside' (NR) ngokongezwa kweqela le-phosphate.

'I-NAMPT' yithamo lokunciphisa umda kwimveliso ye-NAD +. Oku kuthetha ukuba amanqanaba asezantsi e-NAMPT abangele ukwehla kwemveliso ye-NMN, kukhokelela ekunciphiseni amanqanaba e-NAD +. Ukongeza iimolekyuli zangaphambi kwe-NMN kunokukhawulezisa imveliso ye-NAD +.

I-NAD + kunye neNMN

Izibonelelo ezinokubakho zeNMN

Nje ukuba ungene ngaphakathi kwiiseli zezilwanyana, i-NMN ityisa imveliso ye-NAD +, ebonelela ngeeseli ngamandla afunekayo kwaye kucingelwa ukuba ibalulekile ekugugeni okusempilweni. I-NAD + ikwadlala indima ephambili ekusebenzeni kweeproteni ezigcina ukuthembeka kwe-DNA yethu. Ngenxa yendima yayo ephambili kwiinkqubo ezininzi zeselula, izibonelelo ezinokubakho zeNMN zanda phantse kuzo zonke iinkqubo zomzimba. Apha ngezantsi kukho eminye imizekelo eyaziwa ngcono.

 

 Ukukhuthaza impilo yeVascular kunye nokuHamba kweGazi

Sithembele kwimisipha yethu yokuhamba, ukuzinza kunye namandla. Ukuze zihlale zomelele kwaye zikwimeko entle, ezi zihlunu kufuneka zisebenzise izixa ezikhulu zeemolekyuli zamandla, njengeglucose kunye namafutha acid. Ngenxa yokuba i-NAD + iyacelwa ukuba idibanise ezi molekyuli, izihlunu zethu zifuna unikezelo oluzinzileyo lweebhloko zokwakha, ezinjengeNMN.

Izifundo kwiimpuku zibonise ukuba i-NMN ikhusela ekunciphiseni okuninzi kokuguga kwezempilo, njengokuqina kwemithambo yegazi, uxinzelelo lwe-oxidative, amandla eeseli zethu okuqhubeka ukwahlula, kunye notshintsho kwindlela esebenza ngayo imfuza intetho.

 

 Ukuphucula ukunyamezela kweMisipha kunye namandla

Izifundo zibonise ukuba iimpuku ezondla i-NMN ixesha elide zinamandla okuphucula imetabolism ngaphandle kweziphumo ebezingalindelekanga. Impilo yemisipha yethu ikhula ibaluleke ngakumbi njengoko sikhula kunye nokubonelelwa kwethu kwe-NAD + kuyehla.

 

 Ikhusela kwizifo zentliziyo

Ubuncinci izihlunu zakho zamathambo kufuneka uthathe ikhefu. Ayisiyiyo kuphela intliziyo yakho engakwaziyo ukuphumla, ayinakucothisa isantya sayo ngaphandle kokubangela iingxaki ezinzulu. Imfuneko yamandla entliziyo, ke ngoko, inkulu kakhulu. Kwaye ukuyigcina ikhathaza, kufuneka yenze yonke i-NAD + ibe nakho. Yiyo loo nto iiseli zentliziyo zifuna unikezelo oluzinzileyo lweNMN.

 

 Ukunciphisa umngcipheko wokuTyeba kakhulu

Ukutyeba kakhulu kunxulunyaniswa noluhlu olubanzi lweemeko ezingenampilo kwaye kunokuba ngumceli mngeni omkhulu kunyango. Akukho sisombululo silula sokutyeba kakhulu kunye neemeko ezinxulumene nesifo seswekile kunye nesifo se-metabolic syndrome. Ngelixa uhlengahlengiso lwendlela yokuphila njengokuzilolonga rhoqo kunye nokutya okusempilweni kubaluleke kakhulu, yonke into inceda.

Kwizifundo zeempuku, i-NMN ibonisa umphumo olingisa imiba yothintelo lwekhalori (CR). Nangona i-CR ibonakalisiwe ukuba ibonelela ngezibonelelo ezininzi ekugugeni nakwimpilo, ngumgaqo onzima ukugcina ixesha elide. Ukulinganisa izibonelelo zayo ngaphandle kokunamathela kukutya okugabadeleyo kuya kuba yingenelo ngokungathandabuzekiyo.

 

 Ukuphucula ukuLungiswa kweDNA

I-NAD + eyenziwe nge-NMN isebenzisa iqela leeproteni ezibizwa ngokuba zii-sirtuins. Ii-Sirtuins, ngamanye amaxesha ezicingelwa njengabagcini bempilo yethu, zidlala indima ebalulekileyo ekugcineni ingqibelelo ye-DNA. Ngalo lonke ixesha iiseli zethu zahlula-hlula, i-DNA kwiiphelo zeekromosomes zethu ikhula kancinci ifutshane. Ngexesha elithile, oku kuqala ukonakalisa iigene zethu. I-Sirtuins iyicothisa le nkqubo ngokuzinzisa ezo ziphelo, zaziwa ngokwenzululwazi njengee-telomeres. Ukuze usebenze, nangona kunjalo, i-sirtuins ixhomekeke kwi-NAD +. Izifundo zamva nje zibonisile ukuba ukondla iimpuku ze-NMN ezenziwe nge-sirtuins kwaye kukhokelele kwii-telomeres ezizinzileyo.

 

 Yandisa iMitochondrial Function

Ukubeka ngokulula, asinakuphila ngaphandle kwemitochondria yethu. Ezi zakhiwo zikhethekileyo zeselula zaziwa njengezindlu zamandla zeseli. Baguqula iimolekyuli ukusuka ekutyeni esikutyayo zikuse kumandla asetyenziswa ziiseli zethu. I-NAD + isembindini wale nkqubo. Ngapha koko, iimpazamo ze-mitochondrial ezibangelwa kukuphulukana ne-NAD + zinokuchaphazela nokuphazamiseka kwemithambo-luvo njenge-Alzheimer's. Izifundo ezenziwa kwiimpuku zibonise ukuba ukuxhaswa kwe-NMN kusindise ukungasebenzi kakuhle kwemitochondrial.

 

How Ltuong Does It Tzakhe To See Eiimpembelelo Of I-NMN?

AASrawI-NMN powder inyusa inqanaba le-NMN emzimbeni wakho ngaphakathi kwemizuzu, ngelixa amanqanaba e-NAD + enyuswe ngaphakathi kwemizuzu engama-60. Nangona kunjalo, ukuze i-NAD + iqale ukuvuselela iiseli zakho, kuthatha iiveki ezimbalwa.

Uninzi lwabasebenzisi baxela ukuba baziva bebancinci kwaye besempilweni kwiiveki ezi-2 ukuya kwezi-3. Izibonelelo ezipheleleyo ze-NMN zinokuvakala emva kweenyanga ezimbalwa zokusebenzisa-kodwa sele uza kuwuva umahluko kwiiveki nje ezimbalwa!

Ke ukuba ufuna ukufumana iziphumo eziguqulwayo ze-NMN ye-AASraw, ngoku unethuba elikhethekileyo lokwenza njalo. Kwaye elona candelo lilungileyo? Awunyanzelekanga ukuba uthathe umngcipheko. I-NMN ye-AASraw igutyungelwe sisiqinisekiso sokwaneliseka. Oku kuthetha ukuba kuba baqinisekile ukuba uya kuyithanda i-NMN yabo, bazimisele ukukunika isiqinisekiso.

I-NAD + kunye neNMN

Iziphumo ebezingalindelekanga zeNMN Supplement

Ngayo nayiphi na into entsha zongeza, Kukho iinkxalabo malunga neziphumo ebezingalindelekanga. Ukuza kuthi ga ngoku, izifundo zesayensi azikhange zibonise naziphi na iziphumo ezothusayo okanye eziqinisekileyo ezinxulumene nokusebenzisa oku kongezwa.

Esona sikhalazo sinamandla malunga ne-nicotinamide mononucleotide kukungangqinelani ekusebenzeni, kodwa oko kwenzeka kumanqanaba asakhulayo esongezelelo esitsha. Ewe kunjalo, kuya kufuneka ubonane nogqirha wakho malunga nokuthatha olu ncediso, ngakumbi ukuba ukhulelwe okanye uncelisa.

 

Is I-NMN Benziwe Than NAD +?

Kwiminyaka emininzi, bekucingelwa ukuba iimolekyuli ze-NAD + zikhulu kakhulu ukuba zingathathwa ngokuthe ngqo kwaye kufuneka ziphakanyiswe kusetyenziswa isandulela esifana neNMN. Kutshanje, kufunyenwe ukuba i-NAD + inokuwela isithintelo segazi-nengqondo kwaye ifike kwi-hypothalamus ukuba ithathwe ngokungaphantsi. Inokunyusa amanqanaba e-NAD + kule ndlala eya kuthi izuze umzimba wonke kuba ilawula imetabolism. Inokuba nakho ukubakho zongeza ukunceda abo baneengxaki zemetabolism ngenxa yokuhla kwamanqanaba e-NAD + kwi-hypothalamus.

I-NMN, kwelinye icala, inyusa amanqanaba e-NAD + kwiiseli kuwo wonke umzimba kwaye iluncedo olungcono onokuyithatha ukukhulisa amanqanaba akho e-NAD + kunye nokuguga.

 

Shwankathela

I-Nicotinamide mononucleotide (i-NMN) yinto yendalo emzimbeni wakho evuselela imveliso yelinye icandelo elibizwa ngokuba yi-nicotinamide adenine dinucleotide. Zombini i-NMN kunye ne-NAD zidlala indima ebalulekileyo ekuthinteleni inkqubo yokuguga. Ubukhulu becala i-NAD, okoko umdala, ubuncinci bomzimba wakho kufuneka uvelise i-NAD. Kulapho isongezelelo seNMN sinokunceda ukusukela, xa sityiwa ziimpuku, sikhuthaza i-NAD kumathumbu asezantsi kwangoko.

Ngenxa yoko, isongezelelo sidityaniswe "ngumthombo wobutsha", kwaye inkqubo yokwaluphala komzimba iyacotha kwaye ibuye umva. Izifundo azibonisi ukuba semthethweni kwenkqubo yokuguga, kodwa isongezelelo seNMN sinokukunceda ukuthintela okanye ukunyanga ezinye izifo ezinje ngomhlaza, intliziyo nesifo seswekile. Kwi-2016, iqela lezenzululwazi laqala isifundo sokuqala seklinikhi nabantu kwiziphumo ezilungileyo ze ukuthatha izongezo ze-NMN. Nangona ukusebenza kwe-NMN kusekumanqanaba okuqala, ngakumbi nangakumbi iingxelo ziqinisekisa ukusebenza kwesongezelelo.

Xa uthatha isigqibo sokuthenga isongezelelo seNMN kwi-Intanethi, nceda ufunde amanqaku amaninzi malunga neNMN kunye neNAD +. Kuya kufuneka uyazi ukuba ilungile na emzimbeni wakho, isebenza njani emzimbeni wakho, xa uyithatha kunye nedosi ye-NMN, nayiphi na ingozi kuwe. I-Weclome ukusilandela ukuze sihlaziye ngakumbi malunga neNMN kwixesha elizayo.

 

isingqiniso Kwinqaku

[1] ULautrup S, uSinclair D okqhubekayo. I-NAD + kwi-Brain ukuguga kunye ne-Neurodegenerative Disorders. Iseli yeMetabolism 2019-30,630.

[2] UZhang, H., 2016. Ukuphinda kwakhona kwe-NAD + kuphucula ukusebenza kwe-mitochondrial kunye ne-stem cell kunye nokunyusa ixesha lokuphila kwiimpuku. Inzululwazi 352, 1436-1443.

[3] “I-NMN vs NR: Umahluko phakathi kwezi 2 ze-NAD + Precursors”. www.nmn.com. Ukufunyanwa kwe-2021-01-11.

[4] Imai, S., & Guarente, L. 2014. I-NAD kunye ne-sirtuins ekwaluphaleni nakwizifo. Iindlela eziqhubekayo kwi-Cell Biology, 24 (8), 464-471.

[5] Braidy, CK Lim, R. Grant, BJ Brew, kunye no-GJ Guillemin. 2013. ISerum Nicotinamide Adenine Dinucleotide Levels Ngezifo Zesifo kwi-Multiple Sclerosis. Ubungqina beBrain Res 1537: 267-272.

[6] Stipp D (Matshi 11, 2015). "Ngaphandle kweResveratrol: Inkqubo yokulwa nokuguga yeNAD". Inethiwekhi yeNzululwazi yaseMelika.

[7] Prolla, T., Denu, J. 2014. Ukusilela kwe-NAD kukungasebenzi kakuhle kweMitochondrial Age. Iseli Metabolism, 19 (2), 178-180.

[8] UFletcher RS, uLavery GG (Okthobha 2018). "Ukuvela kwe-nicotinamide riboside kinases kulawulo lwe-NAD + metabolism". Ijenali ye-Molecular Endocrinology. 61 (3): R107 – R121. ikhonkco: 10.1530 / JME-18-0085. I-PMC 6145238. PMID 30307159.

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