Alzheimer's Disease-Associated SNP Rs708727 nyob rau hauv SLC41A1 Tej zaum yuav ua rau muaj kev pheej hmoo rau Parkinson's Disease: Tshaj Qhia Los Ntawm Kev Tshawb Fawb Txog Slovak Part 2

2.2. Genetic Analyzes

Cov kev tshuaj ntsuam genetic analyses tau ua nyob rau hauv A1 SNPs rs11240569, rs708727, thiab rs823156 nyob rau hauv lub cohort ntawm 508 PD cov neeg mob (vs. 150 cov neeg mob nyob rau hauv lub pilot txoj kev tshawb no) thiab lub cohort ntawm 472 tswj (vs. 120 tswj) nyob rau hauv lub 3 pilots. Yog li, tus naj npawb ntawm cov neeg mob PD thiab cov kev tswj hwm tau nce hauv qhov kev tshawb fawb no los ntawm 3.4-fold thiab 3.9fold, raws li kev sib piv nrog rau kev kawm tsav.

Ntau tus neeg muaj kev nco tsis nco qab thaum lawv muaj hnub nyoog, tab sis rau cov neeg uas muaj tus kab mob Parkinson, kev hloov pauv ntawm kev nco yuav qhia tau ntau dua. Txawm li cas los xij, peb yuav tsum tsis txhob xav txog cov neeg uas muaj tus kab mob Parkinson ua rau muaj kev txom nyem nco, vim tias muaj ntau yam peb tuaj yeem ua tau los pab lawv khaws lawv lub cim xeeb.

Ua ntej, tsis tu ncua ua qee yam kev cob qhia lub hlwb tuaj yeem pab cov neeg mob Parkinson txhim kho lawv lub cim xeeb. Cov dej num no yuav suav nrog: ua Sudoku, ua si board games, daws cov kev sib tw, thiab ntau dua. Los ntawm cov dej num no, lawv tuaj yeem siv lawv lub cim xeeb, txhim kho lawv lub hlwb ua haujlwm, thiab pab lawv tswj lawv lub hlwb.

Qhov thib ob, kev noj haus kuj tseem ceeb heev rau kev nco ntawm cov neeg mob Parkinson's disease. Hauv kev noj zaub mov, peb tuaj yeem ntxiv qee yam khoom noj uas muaj protein ntau thiab cov khoom noj, xws li ntses, taum, txiv ntoo, thiab lwm yam. Cov khoom noj no tuaj yeem pab peb noj qab haus huv thiab txhim kho peb lub cim xeeb.

Thaum kawg, kev tawm dag zog ib txwm tuaj yeem pab cov neeg mob Parkinson txhim kho lawv txoj kev nco. Kev tawm dag zog tsis yog tsuas yog pab peb noj qab haus huv lub cev tab sis tseem ceeb dua, txhim kho peb lub hlwb ua haujlwm. Los ntawm kev tawm dag zog tsis tu ncua, lawv tuaj yeem ua rau lawv cov kev ua haujlwm cardiopulmonary, txhim kho elasticity ntawm lawv cov leeg thiab pob txha, thiab txhim kho lawv lub cim xeeb.

Txhua yam, txawm tias cov neeg uas muaj tus kab mob Parkinson muaj kev nco poob yog nyob ntawm lawv txoj kev ua neej thiab kev noj zaub mov, nrog rau seb lawv puas xyuam xim rau tej yam xws li kev cob qhia lub hlwb thiab kev tawm dag zog. Tsuav yog peb ua tib zoo saib xyuas cov xwm txheej no, kuv ntseeg tias kev nco ntawm cov neeg mob Parkinson tuaj yeem txhim kho tau zoo. Nws pom tau tias peb yuav tsum txhim kho peb lub cim xeeb. Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm cov nqaij minced yog los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog carboxylic acid, polysaccharides, flavonoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem paub txoj hauv kev los txhim kho lub hlwb

In the sub-cohort of 96 PD patients and 100 controls, we also examined A1 SNPs rs9438393, rs56152218, and rs61822602 (first identified in the PD sub-cohort by the Sanger sequencing and afterward by RFLP analysis of the sub-cohort of controls). They were not analyzed in the pilot study (37]. The allele and genotype count and frequencies (fq) for each particular A1 SNP in the PD and the control cohorts are summarized in Table 3. The minor allele fa was, for rs11240569 (C>A) nyob rau hauv peb tag nrho cohort (PD rooj plaub + tswj probands), kwv yees piv nrog rau cov me me allele tag nrho cov pejxeem fq ntau (MATPFR) qhia los ntawm gnomAD thiab ExACdatabases, raws li nram no: fqo (saib) vs. rau (qhia) {{1 }}% ​​vs. 29-30%.

Cov me me allele fq rau rs708727 (G> A) nyob rau hauv peb tag nrho pawg yog siab dua MATPFR nyob rau hauv lub gnomAD thiab ExAC databases (fq, vs. rau=40% vs. 29-30%), tab sis yog piv nrog rs708727 me allele fq qhia rau cov neeg nyob sab Europe nyob rau hauv lub ALFA database (41%). Lub rs823156 (A> G) me me allele fq nyob rau hauv peb tag nrho pawg yog 17% thiab yog li qis dua MATPFR nyob rau hauv lub gnomAD thiab ExAC databases (23-30%) tab sis tau piv nrog rs823156 me allele fq qhia rau cov neeg nyob sab Europe hauv ALFA database (18%).

Qhov zaus ntawm me me allele ntawm rs9438393 (A> G) nyob rau hauv tag nrho pawg yog 40% thiab yog, yog li ntawd, tshwj xeeb tshaj yog siab tshaj MATPFR ntawm 26-29% qhia nyob rau hauv lub gnomAD thiab TOPMED databases, tab sis tau muab piv nrog rs9438393 me. allele zaus tshaj tawm hauv ALFA database rau cov neeg nyob sab Europe (41%). Cov me me ntawm rs56152218 (T> C) nyob rau hauv tag nrho pawg yog tam sim no nrog ib tug fq ntawm 38%, uas yog nyob rau hauv lub MATPFR ntawm 32-46% qhia los ntawm ALSPAC, TOPMED, thiab ALFA (European pejxeem) databases.

Interestingly, nyob rau hauv Nyab Laj, Kauslim Teb, thiab Qatari cov pejxeem, tus me allele yog T thiab tsis C, raws li tau pom nyob rau hauv cov neeg nyob sab Europe [https://www.ncbi.nlm.nih.gov/snp/?term{{0} }rs56152218, nkag rau 2 Lub Yim Hli 2021)]. Qhov fq ntawm me me allele hauv rs61822602 (G> T) tau pom tias yog 12%. Qhov no yog piv nrog T allele zaus tshaj tawm los ntawm ALSPAC thiab TWINSUK databases (12% thiab 13%, feem) tab sis yog siab dua qhov fq ntawm T allele qhia hauv cov neeg nyob sab Europe hauv ALFA database (6%).

Txhua qhov kev sim A1 SNPs hauv peb PD thiab pawg tswj hwm tau nyob hauv Hardy-Weinberg equilibrium (HWE; Table 4).

Tom ntej no, peb xam qhov sib txawv ntawm qhov sib txawv (LOSSIS) ntawm cov me me allele thiab cov genotypes uas muaj cov me me allele rau txhua qhov kev sim SNP. Cov txiaj ntsig no tau sau tseg hauv Table 5. Lub GA genotype hauv rs708727 tau txuam nrog PD (OR=1.42 (1.08–1.87), p=0.01) hauv peb cov pejxeem. Tsis tas li ntawd, peb tau sim cov kev sib koom ua ke ntawm kev sib txuas ntawm genotypic rau txhua qhov kev sim SNP nrog PD hauv cov khoom siv tsis zoo, tseem ceeb, thiab ua tiav cov qauv caj ces (Table 6). Coherent nrog cov ntaub ntawv dhau los, peb tau txheeb xyuas lub koom haum ntawm rs708727 minor allele (A) nrog PD hauv qhov tseem ceeb (GG vs. GA + AA) thiab tag nrho tshaj-dominant (GG + AA vs. GA) genetic qauv (ORD=1 }.36 (1.05–1.77), p=0.02 thiab ORCOD=1.34 (1.04–1.72), p=0.02, ntsig txog). Cov SNPs uas tseem tshuav tsis pom muaj kev koom tes nrog PD hauv cov qauv kuaj caj ces (Table 6).

Peb kuj tau soj ntsuam qhov sib npaug ntawm cov pejxeem feem ntawm ib qho kev sib xyaw genotypic uas muaj xws li duplets, triplets, quadruplets, quintuplets, lossis sextuplets ntawm SNPs kuaj hauv PD cohort (N {{0}}}) thiab pawg tswj hwm ( N=100) txhawm rau tshuaj xyuas qhov loj ntawm qhov cuam tshuam ntawm kev sib cuam tshuam ntawm cov kev sim A1 SNPs mus rau qhov cuam tshuam rau kev tsim PD hauv peb cov pej xeem. Nyob rau hauv tag nrho, ib tug tag nrho ntawm 12 genotypic ua ke (ob duplets, xya triplets, thiab peb quadruplets, Table 7) nrog heev (p < 0.05, 10 genotypes; p < 0.06, ob genotypes ) Cov suav sib txawv hauv PD thiab pawg tswj hwm tau txheeb xyuas (Table 7). Ua raws li Cohen cov txheej txheem [39], uas piav qhia txog qhov sib txawv ntawm qhov sib piv, tsuas yog triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) tawm ntawm 12 genotypes qhia qhov "nruab nrab" qhov sib txawv uas txhais los ntawm Cohen's h(2arcsin √ pr. -2arcsin√ prp2) Ntau dua lossis sib npaug rau 0.5.

Tus nqi h rau qhov seem 11 genotypes ranged ntawm 0.32 thiab 0.46 thiab yog li nyob rau hauv lub sijhawm h ntawm 0.2 mus rau 0.5, uas txhais qhov sib txawv me me hauv proportions (Table 7) [39]. Yog li ntawd, triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) tej zaum yuav muaj txiaj ntsig zoo, thiab kev tshuaj ntsuam xyuas yav tom ntej ntawm no genotype txog PD susceptibility yuav tsum tau ua. Rau rs11240569, rs708727, thiab rs823156, peb tau ua tib yam kev tshuaj ntsuam nrog cov ntaub ntawv los ntawm pawg neeg ntawm 508 PD cov neeg mob thiab pawg ntawm 472 tswj. Plaub genotypes, ob duplets (GG(rs11240569) + AG(rs708727), GG(rs708727) + AG(rs823156)) thiab ob triplets (GG(rs11240569) + GG(rs708727) + 32G5(rs8), + GG(rs708727) + AG(rs823156)), nrog rau qhov sib txawv (p <0.05) sib txawv ntawm PD thiab tswj pawg, tau txheeb xyuas. thiab yog li ntawd, qhov sib txawv ntawm cov pej xeem feem ntau ntawm cov pab pawg kuaj yog, nyob rau hauv tag nrho plaub qhov teeb meem, negligible.

Kev laus, ua raws li cov txiv neej poj niam txiv neej, yog suav tias yog qhov tseem ceeb tshaj plaws ntawm kev pheej hmoo rau qhov pib ntawm idiopathic PD [37]. Hauv peb txoj kev tshawb nrhiav, lub hnub nyoog ntawm qhov pib ntawm idiopathic PD nyob rau hauv pawg ntawm 150 PD cov neeg mob tsis muaj feem cuam tshuam nrog kev muaj kev sib xyaw ua ke rau SNPs rs11240569, rs708727, thiab rs823156 [37]. Ntawm no, peb tau txheeb xyuas lub hnub nyoog ntawm qhov pib ntawm PD nrog (1) qhov muaj nyob ntawm txhua qhov kev sib txuas ntawm genotypic rau SNPs rs11240569, rs708727, thiab rs823156 hauv pawg 508 PD cov neeg mob (Daim duab 2), thiab (2) nrog rau txhua tus. genotypic kev sib xyaw ua ke rau SNPs rs11240569, rs708727, rs823156, rs9438393, rs56152218, thiab rs61822602, hauv sub-cohort ntawm PD cov neeg mob, xaiv xaiv los ntawm PD1 kev sib koom ua ke (A. Txog hnub nyoog pib, ib txoj kev ANOVA tsom xam tau qhia tias tsis muaj qhov tseem ceeb (p <0.05) qhov sib txawv ntawm cov genotypic sub-populations rau txhua qhov kev sim SNPs hauv ob pawg PD loj thiab hauv sub-cohort ntawm PD. cov neeg mob. Yog li, ib qho genotype tshwj xeeb hauv kev sim SNPs tsis cuam tshuam rau lub hnub nyoog pib ntawm daim ntawv idiopathic ntawm PD. Qhov no yog nyob rau hauv tag nrho cov kev pom zoo nrog cov lus xaus kos nyob rau hauv peb pilot kawm [37].

Peb kuj tau ua tib yam kev tshuaj ntsuam xyuas rau txhua qhov kev sim SNPs hauv cov pej xeem ntawm cov poj niam thiab cov txiv neej uas tau muab los ntawm pawg neeg loj (N=508) thiab cov pab pawg (N=96) ) ntawm PD cov neeg mob. Raws li pom nyob rau hauv cov duab ntxiv S1–S3, tsis muaj qhov tseem ceeb (p < 0.05) kev sib koom ua ke ntawm lub hnub nyoog pib thiab muaj ib qho kev sib xyaw genotype hauv kev sim SNPs rs11240569, rs708727, rs823156, rs94383912, rs9438393, thiab rs61822602 nyob rau hauv cov poj niam txiv neej-split sub-pab pawg tau muab los ntawm pawg PD loj (NM=306, NF=202) lossis PD sub-cohort xaiv rau A1 txhawb nqa sequencing (NM {{20}) }, NF=42).

2.3. RandomForest Tshuab Kawm (RF-ML)

Tag nrho ntawm A1 SNPs tau sim rau lawv lub peev xwm los sib cais ntawm PD cov neeg mob thiab kev tswj hwm nrog RF-ML. RF-ML algorithm tau raug cob qhia siv peb cov ntaub ntawv, thiab qhov tseem ceeb ntawm kev ntxub ntxaug ntawm tus kheej SNPs los ntawm kev tsim qauv, hu ua graph qhov tob, tau soj ntsuam [37,40]. Raws li hauv peb txoj kev tshawb nrhiav [37], qhov kev kwv yees muaj peev xwm ntawm kev sim SNPs tau pom thiab pom los ntawm ROC (tus neeg txais kev ua haujlwm tus yam ntxwv) nkhaus thiab los ntawm AUC (chaw nyob hauv ROC nkhaus), feem. Lub peev xwm ntawm kev ntxub ntxaug ntawm cov neeg kwv yees tau muab nyob rau hauv lub sijhawm ntawm AUC los ntawm 100% (qhov muaj peev xwm sib cais siab tshaj plaws) mus txog 50% (muaj peev xwm cais tsawg tsawg); AUC < 50% sib raug rau tsis muaj kev ntxub ntxaug.

RF algorithm tau kawm nyob rau hauv cov qauv hauv qab no: (1) nrog peb lossis rau (Table 8) tshwj xeeb A1 SNPs (txhua SNP, peb genotypes (AMAM/AMAm/AmAm, qhov twg AM stands rau loj allele thiab Am rau me allele), Raws li kev kwv yees (peb lossis rau RF qauv, ib qho rau txhua SNP), (2) nrog genotypic duplets ntawm cov khub SNPs raws li kev kwv yees (peb RF qauv (peb SNPs) lossis 15 RF qauv (rau SNPs), ib qho rau txhua khub ntawm SNPs; Table 8), (3) nrog genotypic triplets ntawm peb SNPs raws li kev kwv yees (ib qho qauv RF (peb SNPs) lossis 20 RF qauv (rau SNPs), ib qho rau txhua triplet ntawm SNPs; Table 8), (4) nrog genotypic quadruplets ntawm rau SNPs raws li kev kwv yees (15 RF qauv, ib qho rau txhua quadruplet; Table 8), (5) nrog genotypic quintuplets ntawm rau SNPs raws li kev kwv yees (rau RF qauv, ib qho rau txhua quintuplet; Table 8), thiab ( 6) nrog genotypic sextuplet (ib qho qauv RF, Table 8).

Yog li, thaum singletons, duplets, triplets, quadruplets, quintuplets, thiab sextuplet ntawm A1 SNPs tau siv los ua tus kwv yees, lawv tsis muaj peev xwm los cais tawm ntawm cov neeg mob PD thiab kev tswj hwm (Table 8). Yog li ntawd, raws li RF-ML tsom xam, thiab nyob rau hauv kev pom zoo nrog rau txoj kev tshawb no pilot [37], A1 SNPs tsis muaj peev xwm ua hauj lwm raws li kev ntxub ntxaug ntawm kev tswj thiab PD cov neeg mob thiab, txog PD, tsis muaj kev kwv yees los yog kuaj tus nqi nyob rau hauv cov pej xeem Slovak. .

3. Kev sib tham

PARK16 locus tau txais kev saib xyuas hauv zej zog kev tshawb fawb vim tias nws koom nrog PD thiab nws lub luag haujlwm sib tham hauv kev txheeb xyuas qhov cuam tshuam rau qhov mob nyuaj no. Hauv 2019, peb tau tshaj tawm txoj kev tshawb fawb uas peb tau txheeb xyuas cov koom haum ntawm peb A1 SNPs, uas yog rs11240569, rs708727, thiab rs823156, nrog rau daim ntawv idiopathic ntawm PD hauv Slovak (Western Slavs) cov pejxeem. Lub koom haum tshaj tawm ntawm rs11240569 thiab rs823156 nrog rau kev cuam tshuam rau PD feem ntau hauv cov neeg Esxias / Oriental tsis pom nyob rau hauv peb txoj kev tshawb fawb [37]. Tsis muaj lub koom haum tuaj yeem lees paub siv cov kev txheeb cais nquag (kev tshuaj ntsuam xyuas caj ces) lossis los ntawm RF-ML tsom xam [37].

Qhov kev txwv loj ntawm peb txoj kev tshawb fawb yog, txawm li cas los xij, cov neeg mob / cov neeg mob tsawg tsawg hauv PD thiab tswj cov pab pawg (150 thiab 120, feem). Peb tau hais tias, los ntawm kev txheeb cais ntawm qhov kev pom, cov ntaub ntawv yuav tsum tau muab txhais ua tib zoo saib vim yog cov qauv me me hauv ob qho tib si ntawm pawg neeg thiab vim tias lub zog qis ntawm cov kev ntsuas tau ua [37]. Txawm li cas los xij, los ntawm kev siv ML mus kom ze, uas yuav tsum muaj cov qauv me me ntau dua li cov ntaub ntawv nquag nquag siv los yog kwv yees li kev suav Bayesian, peb tuaj yeem tshuaj xyuas nrog kev ntseeg siab txog qhov muaj peev xwm ntawm A1 SNPs tshwj xeeb rau kev ntxub ntxaug ntawm PD cov neeg mob thiab kev tswj xyuas. Hauv txhua qhov xwm txheej, ML txoj hauv kev tau qhia qhov tseem ceeb tsis muaj kev kuaj mob thiab kev kwv yees qhov tseeb ntawm SNPs rs11240569, rs708727, thiab rs823156 hauv cov pej xeem Slovak [37].

Hauv txoj kev tshawb no, peb tau tshuaj xyuas tsis yog peb qhov SNPs tau hais los saum no xwb, tab sis kuj yog peb SNPs (rs9438393, rs56152218, thiab rs61822602) nyob hauv cheeb tsam txhawb nqa ntawm A1. Cov SNPs no tau raug txheeb xyuas los ntawm kev ua tiav ntawm 96 PD cov qauv ua raws li RFLP kev soj ntsuam ntawm cov qauv tswj thiab RFLP kev txheeb xyuas ntawm cov qauv PD sib txuas. Peb qhov kev ntsuam xyuas caj ces tau nthuav tawm qhov tseem ceeb tsis muaj kev koom tes ntawm ib qho ntawm peb qhov kev kawm tshiab SNPs nrog PD. Qhov zoo ib yam yog qhov tseeb rau rs11240569 thiab rs823156, uas tau txheeb xyuas hauv PD thiab tswj cov pawg sib koom ua ke (96/100) thiab tseem nyob hauv pawg ntawm 508 PD cov neeg mob thiab 472 tswj. Cov txiaj ntsig no tau pom zoo tag nrho nrog cov txiaj ntsig ntawm kev sim ua haujlwm [37]. Txawm li cas los xij, hauv pawg loj, rs708727 yog txuam nrog kev pheej hmoo ntawm PD hauv cov pej xeem Slovak.

Rau peb qhov kev paub zoo tshaj plaws, tsis muaj kev tshawb fawb tseem muaj feem cuam tshuam ncaj qha A1 SNP rs708727 nrog kev hloov pauv kev pheej hmoo rau kev tsim PD [19,37]. Hauv peb txoj kev tshawb fawb loj (thaum piv nrog cov kev tshawb fawb sim [37]), qhov me me allele A hauv rs708727 yog txuam nrog kev pheej hmoo ntawm PD pib thaum kuaj hauv dominant [40] (ORD=1.36 (1.05– 1.77), p=0.02) los yog overdominant [41] (ORCOD=1.34 (1.04–1.72), p=0.02) qauv (Table 5). Yog li, lub xub ntiag ntawm cov me me allele (A) hauv rs708727 tej zaum yuav cuam tshuam nrog kev pheej hmoo ntawm kev tsim PD. Thaum Sanchez-Mut et al. [27] and Wang et al. [42] tau qhia meej meej tias qhov muaj me me allele A hauv rs708727 hloov cov methylation ntawm PM20D1 tus txhawb nqa (thiab, yog li, nws cov lus qhia) nyob rau hauv koob tshuaj (quantitative), qhov zoo tshaj plaws-fitting genetic qauv hauv peb txoj kev tshawb fawb. qhia tau hais tias muaj ib qho rs708727 A allele txaus los hloov qhov cuam tshuam rau qhov pib ntawm PD. PD-susceptibility (phenotype), txog seb ib lossis ob daim ntawv luam ntawm cov me me allele muaj nyob rau hauv rs708727 (genotype), tseem yuav tau piav qhia ntxiv.
Sanchez-Mut et al. tau txheeb xyuas PM20D1 (localized nyob rau hauv PARK16 locus thiab encoding rau peptidase M20-domain muaj protein ib enzyme nrog ob qho tib si hydrolase thiab peptidase kev ua ub no; N-fatty acyl amino acid synthase/hydrolase) raws li ib tug methylation thiab qhia kom muaj nuj nqis. locus (mQTL) ua ke rau AD-risk txuam haplotype, uas qhia txog cov yam ntxwv zoo li kev txhawb nqa thiab hu rau PM20D1 tus txhawb nqa los ntawm haplotype-dependent, CTCF (CCCTC-binding-) transcription-factor-mediated chromatin voj [27]. Los ntawm kev sib piv cov qauv los ntawm kev tswj hwm kev noj qab haus huv thiab cov neeg mob uas muaj theem siab AD, lawv tau pom tias PM20D1 tsis tu ncua qhia txog kev txhawb nqa hypermethylation hauv cov neeg mob AD [27]. A1 SNP rs708727 cuam tshuam nrog cov theem ntawm PM20D1 DNA methylation hauv tib neeg frontal cortex thiab hippocampus [27], zoo li SNP rs960603 [27]. Wang thiab cov npoj yaig, hauv lawv txoj haujlwm ntawm cov ntshav peripheral, tau txais cov ntaub ntawv lees paub tias PM20D1 yog ib qho mQTL kho feem ntau los ntawm AD-risk-sociated A1 SNP rs708727 [42].

Tsis tas li ntawd, lawv cov ntaub ntawv ntev qhia tau hais tias hypomethylation tshwm sim ua ntej cov tsos mob ntawm AD, conceivably los pab txhawb kev nthuav qhia ntawm PM20D1 kom qhib nws txoj haujlwm tiv thaiv [42]. AD kev nce qib yog pom los ntawm kev nce qib ntawm methylation hauv CpG Islands tuaj hauv DMR (qhov sib txawv ntawm thaj chaw methylated) ntawm PM20D1 txhawb nqa hauv cov neeg mob AD, thaum kawg ua rau inhibition ntawm cov noob transcription thiab kev qhia [27,42,43]. PM20D1 kuj tau cuam tshuam nrog ntshav qab zib [44], rog rog [45], thiab ntau yam sclerosis [46], thiab txij li nws tau nyob hauv thaj chaw PARK16, nws muaj peev xwm koom nrog / koom nrog PD yog xav tau [47].

Txawm hais tias tsis muaj kev tshuaj ntsuam xyuas molecular, peb kwv yees, nyob rau hauv lub teeb ntawm peb cov ntaub ntawv tam sim no, tias AD thiab PD (thiab lwm yam kab mob tsis tshua muaj cov kab mob neurodegenerative) tsis tsuas yog "paub zoo" cov txheej txheem pathophysiological (xws li, cuam tshuam mitophagy, retromer, thiab proteasome. functions), tab sis kuj epigenetic mechanisms, xws li A1 rs 708727- raws li kev cai ntawm PM20D1 qhia [27,42]. Peb txoj haujlwm tsis ncaj qha ntxiv rau qhov xav tau kom ntxaws ntxaws ntawm lub luag haujlwm ntawm endogenous N-acyl amino acids (NAAs) uas tau metabolized los ntawm PM20D1 hauv pathobiology ntawm PD thiab lwm yam kab mob neurodegenerative. NAAs thiab N-acyl conjugates ntawm neurotransmitters (NAANs) tam sim no paub tias ua lub luag haujlwm tseem ceeb hauv neuromodulation [48,49]. Cov ntaub ntawv pov thawj txuas PM20D1 qhia nrog N-acyl dopamine (NADA) tau muab los ntawm kev ua haujlwm tsis ntev los no ntawm Song li al. Cov kws sau ntawv no tau pom tias qhov kev tshem tawm ntawm kir6.2 (ib qho pore-forming subunit ntawm ATP-sensitive K + channels) ua rau txo qis ntawm mitochondria thiab txo qis ATP ntau lawm los ntawm kev nce qib ntawm PM20D1 thiab ntawm cov neeg ua haujlwm uncoupling mitochondrial ua pa. , suav nrog NADA, hauv murine midbrain [49].

NADA yog ib tug muaj zog inhibitor ntawm 5-lipoxygenase (5-LOX) thiab muaj ib tug faib txwv rau lub hlwb nrog theem siab tshaj plaws nyob rau hauv lub striatum thiab tsawg heev lwm qhov [48,50,51]. 5-LOX catalyzes cov synthesis ntawm leukotriene los yog 5-HpETE (5-hydroperoxy eicosatetraenoic acid) los ntawm arachidonic acid thiab tau txuam nrog neurodegeneration (AD thiab PD) los ntawm nws txoj kev koom tes hauv neuroinflammation [51, 52] ib. Peb thiaj li hais tias qhov txo qis PM20D1 qhia, tom qab qis dua ntawm NADA, thiab nce kev ua haujlwm ntawm 5-LOX ua rau muaj txiaj ntsig zoo rau cov kab mob ntawm PD (thiab lwm yam kab mob neurodegenerative).

Sanchez-Mut thiab cov neeg ua hauj lwm tau pom tias qhov overexpression ntawm PM20D1 nyob rau hauv murine AD hippocampus ua rau kev txhim kho kev kawm, whereas nws knock-down nce lub amyloid plaque load [27]. Ob leeg Lewy-type thiab Alzheimer-type pathologies yog qhov tseem ceeb hauv PD-txog dementia [53]. Ib lub pas dej loj ntawm PD cov neeg mob raug kev txom nyem los ntawm kev dementia zuj zus thaum muaj tus kab mob [54]. Ua raws li cov kev soj ntsuam no rau hauv kev txiav txim siab peb kwv yees, seb rs 708727-txuas kev ua haujlwm uas ntsiag to PM20D1 pab txhawb rau PD-dementia pib thiab seb qhov kev saib xyuas ntawm PM20D1 kev ua ub no tuaj yeem ua qhov ntsuas ntsuas rau qhov pib ntawm PD-dementia.

Cov ntawv tshaj tawm yav dhau los tau qhia txog kev koom tes ntawm Mg2+ cov neeg thauj khoom hauv cov kab mob pathobiology ntawm PD [18–22,55]. A1, ua tus tseem ceeb hauv Mg homeostasis ntawm somatic hlwb, tau txuas rau PD ncaj qha [20–22]. Kev hloov pauv hauv cov ntsiab lus hauv A1 ua rau hloov pauv p.A350V, p.R244H, thiab p.R285Q tau ua rau muaj kev cuam tshuam nrog PD, thiab ob qho tib si tsis muaj kev ua haujlwm thiab kev poob ntawm kev hloov pauv hauv A1 yog xav tias muaj kev cuam tshuam rau cov neurons, yog li pab txhawb rau PD phenotype [20–22]. Qhov no ua haujlwm tsis ncaj qha mus rau qhov muaj peev xwm tsis tsuas yog cuam tshuam ntawm A1 cov haujlwm tseem ceeb (Na+/Mg2+ pauv) tab sis kuj A1-txuas (rs708727) epigenetic regulation ntawm PM20D1 qhia (thiab kev ua), pab txhawb rau pathobiology ntawm PD.

Hauv txoj kev tshawb no, peb tau txheeb xyuas cov genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) raws li qhov muaj txiaj ntsig zoo hauv kev kho mob (h Ntau dua lossis sib npaug rau 0.5). Interestingly, rs708727 nrog genotype GG yog ib feem ntawm triplet. Txawm li cas los xij, nyob rau hauv lub teeb ntawm kev tshawb fawb yav dhau los, cov genotype uas muaj cov me me allele A hauv rs708727 yuav tsum tau txuas mus rau qhov muaj peev xwm PD muaj feem cuam tshuam nrog qhov triplet no. Tam sim no, peb tsis tuaj yeem tawm tswv yim txog kev sib cuam tshuam ntawm molecular / genetic / epigenetic cuam tshuam nrog SNPs hauv triplet GG(rs708727) + AG(rs823156) + CC(rs61822602), thiab yog li, ntawm txhua qhov kev koom tes ntawm qhov triplet no rau ib qho nyiaj. ntawm kev pheej hmoo ntawm PD pib.

Hauv peb txoj kev tshawb nrhiav, peb tau siv RF-ML los ntsuas thiab txhais peb cov ntaub ntawv [37]. Qhov txiaj ntsig loj ntawm RF-ML cov ntaub ntawv txheeb xyuas yog ob npaug, raws li hauv qab no: (1) nws tso cai rau kev ntxub ntxaug ntawm SNPs ntawm PD cov neeg mob thiab kev tswj kom muaj nuj nqis [37], thiab (2) nws yuav tsum muaj cov qauv qis dua rau kev ntsuam xyuas ntawm qhov tseem ceeb ntawm kev ntxub ntxaug ntawm tus kheej SNPs lossis lawv cov kev sib txuas [37]. Tsis tas li ntawd, RF-ML hla dhau qhov teeb meem p-value feem ntau cuam tshuam nrog cov qauv loj, txawm tias lawv muaj [56]. Raws li nyob rau hauv peb tsab ntawv tshaj tawm dhau los, tsis muaj ib qho ntawm A1 SNPs uas tau kuaj pom tias muaj lub zog rau kev ntxub ntxaug ntawm PD cov neeg mob thiab cov tsis-PD probands hauv peb pawg (Table 8). Yog li, peb tuaj yeem xav tias tsis muaj qhov kuaj A1 SNPs tsim nyog rau kev ua haujlwm raws li PD / tsis yog PD kev ntxub ntxaug hauv cov pej xeem Slovak.

Hais txog lub koom haum ntawm A1 rs708727 nrog kev hloov pauv kev pheej hmoo rau PD, qhov tshwm sim ntawm peb RF-ML tsom xam zoo li, thaum xub thawj pom, tsis sib xws (Tables 5 thiab 6 vs. Table 8). Jakobsdottir et al. nyob rau hauv lawv cov logistic regression thiab ROC nkhaus tsom xam pom tias txawm tias muaj zog genetic koom haum tsis tau txais kev lees paub muaj txiaj ntsig kev ntxub ntxaug ntawm cov xwm txheej thiab kev tswj hwm [57]. Txawm hais tias yog cov neeg ua haujlwm tsis zoo, SNPs nrog qhov tseem ceeb LOS SIS tej zaum yuav muaj txiaj ntsig zoo rau kev tsim cov etiological hypotheses [57]. Hauv peb cov ntaub ntawv, A1 SNP rs708727 tsis muaj kev faib tawm lub zog hais txog PD, yog li, nws tsis muaj qhov tseem ceeb hauv kev kho mob. Txawm li cas los xij, nws tsis muaj zog, tab sis tseem ceeb koom nrog kev hloov pauv kev pheej hmoo rau PD tau tso cai rau peb xav txog kev koom tes ntawm rs708727 hauv pathobiology ntawm PD nyob rau hauv ib qho zoo sib xws los yog tib yam li nws koom nrog hauv AD [27].

4. Cov ntaub ntawv thiab cov txheej txheem

4.1. Cov neeg koom nrog kev kawm (Cov yam ntxwv yooj yim)

Nyob rau hauv tag nrho, 980 probands tau suav nrog hauv txoj kev tshawb no (508 PD cov neeg mob thiab 472 kev tswj hwm, ua tiav cov txheej txheem suav nrog). Daim ntawv idiopathic ntawm PD tau kuaj pom los ntawm neurologists hauv tsib lub chaw kuaj mob PD (hauv Martin, Bratislava, Trencin, Zvolen, thiab Kosice) raws li PD diagnostic cov txheej txheem ntawm MDS (Movement Disorder Society). Txhua tus neeg mob tau kho nrog tus qauv tshuaj tiv thaiv PD. Qhov nruab nrab hnub nyoog ntawm cov neeg mob PD yog 68.4 ± 9.6 xyoo. Qhov nruab nrab hnub nyoog ntawm tus kab mob pib yog 61.7 ± 10.7 xyoo. Cov neeg yau tshaj plaws tau kuaj pom thaum muaj hnub nyoog 34 xyoos thiab cov laus tshaj plaws ntawm 89 xyoo. Pawg PD muaj 202 tus poj niam (F) thiab 306 txiv neej (M) cov neeg mob, thiab yog li, F: M piv yog 1: 1.5.

Cov kev tswj hwm ntawm cov neeg siv khoom muaj xws li cov neeg mob sab nraud thiab sab hauv los ntawm Lub Tsev Kho Mob ntawm Kev Ua Haujlwm Tshuaj thiab Toxicology (University Hospital Martin (UHM)) thiab Lub Tsev Kho Mob Neurology (UHM). Tsuas yog cov neeg mob uas tsis tau kuaj pom yav dhau los nrog ib tus kab mob neurodegenerative thiab neuropsychiatric, xws li ntshav qab zib mellitus, lossis osteoporosis (tag nrho cov maladies putatively txuam nrog hloov A1 qhia thiab deregulation ntawm A1 muaj nuj nqi), tau cuv npe rau hauv pawg tswj kev kawm. Qhov nruab nrab hnub nyoog ntawm kev tswj cov khoom lag luam yog 68.3 ± 11.6 xyoo. Pawg tswj hwm muaj 208 tus poj niam thiab 264 tus txiv neej, thiab yog li, F: M piv yog 1: 1.3 hauv pawg tswj hwm.

Lub sub-cohort ntawm PD cov neeg mob, uas thaj tsam A1 txhawb nqa tau ua tiav, muaj 96 qhov kev xaiv xaiv. F: M piv yog 1: 1.3 (42 poj niam thiab 54 txiv neej). Qhov nruab nrab hnub nyoog ntawm cov neeg mob hauv PD sub-cohort yog 67.{{10}} ± 9.5 xyoo. Tus tswj subcohort muaj 41 tus poj niam thiab 59 txiv neej, yog li F: M piv yog 1: 1.4. Qhov nruab nrab hnub nyoog ntawm probands nyob rau hauv kev tswj sub-cohort yog 59.8 ± 5.0 xyoo.

Txoj kev tshawb no tau pom zoo los ntawm Pawg Saib Xyuas Kev Ncaj Ncees ntawm Jessenius Kws Qhia Ntawv ntawm Tshuaj, Comenius University (JFM CU). Kev pom zoo raug kaw hauv ID: EK 66/2019. Txhua tus neeg koom nrog kev kawm tau kos npe rau daim ntawv tso cai pom zoo.

4.2. Qauv ua

Cov ntshav kuaj tau sau rau hauv EDTA-kho BD Vacutainer® hlab (Becton, Dickinson thiab Company, Franklin Lakes, NJ USA). Genomic DNA raug cais tawm ntawm cov tshiab (UHM) los yog cov ntshav khov (lwm cov chaw PD) los ntawm kev siv Wizard® Genomic DNA Purification Kit (Promega Corporation, Maddison, WI, USA) raws li cov chaw tsim khoom raws tu qauv. Cov qauv DNA cais tau khaws cia ntawm −80 ◦C.

4.3. Genotyping

Genotyping tau ua tiav ntawm 358 PD cov qauv thiab 352 cov qauv tswj. Cov txiaj ntsig tau los ntawm cov kev sim no tau txheeb xyuas ua ke nrog cov txiaj ntsig yav dhau los tau tshaj tawm los ntawm Cibulka li al. [37]. SNPs rs11240569, rs708727, thiab rs823156 tau txheeb xyuas los ntawm kev siv TaqMan® genotyping probes C_34251_20/rs11240569, C_375742_10/rs823156, thiab C_9238453_10/rs7087rfic, MA USA) ib yam li qhia yav dhau los [37].

4.4. Sanger Sequencing

Cov cheeb tsam txhawb nqa tau muab faib ua plaub ntu sib tshooj / amplicons, vim nws ntev dhau rau ib qho kev sib txuas ua ke. Ua ntej yuav ua kom tiav, lub hom phiaj cheeb tsam tau nthuav dav. Primers tau tsim los ntawm kev siv cov cuab yeej online Primer3Plus [https:// primer3plus.com/cgi--bin/dev/primer3plus.cgi (mus txog 3 Tsib Hlis 2018)]. Txhua khub ntawm primers raug kuaj xyuas kom pom muaj ntau yam khoom lag luam los ntawm PCR cov cuab yeej online UCSC [http://www.genome.ucsc.edu/cgi--bin/hgPcr (mus txog 3 Tsib Hlis 2018)].

Cov primers thiab PCR cov kev pab cuam siv rau kev nthuav dav ntawm plaub ntu tau sau tseg hauv cov lus ntxiv S1 thiab S2. Kev sib xyaw ntawm cov tswv sib xyaw rau txhua qhov ntu tau sau tseg hauv SA3. Fragments 3 thiab 4 muaj cov ntsiab lus siab ntawm G thiab C nucleotides (67.4% thiab 71.9%, feem). Cov tshuaj tiv thaiv tau nce ntxiv los ntawm qhov sib ntxiv ntawm 10 × GC Rich Enhancer (Solis Biodyne, Tartu, Estonia). Cov khoom PCR raug ntxuav los ntawm kev siv NucleoSpinTM Gel thiab PCR Clean-up kit (Macherey-Nagel GmbH&Co. KG, Düren, Lub teb chaws Yelemees). Hauv cov kauj ruam tom ntej, cov khoom siv PCR purified tau diluted mus rau qhov tsim nyog concentration rau pre-sequencing PCR (SA4, SA5). Tsuas yog pem hauv ntej (fw) primers tau siv nyob rau hauv pre-sequencing PCR. Cov tshuaj tiv thaiv sib xyaw kuj suav nrog BigDye Terminator v3.1 (Applied Biosystems, Waltham, MA, USA) thiab dideoxynucleotides.

Yog li ntawd, peb tau txais cov khoom sib xyaw ntawm ntau qhov ntau thiab tsawg los ntawm fluorescence-cim dideoxynucleotides. Cov khoom lag luam tau raug ntxuav tom qab siv SigmaSpin Sequencing Reaction Clean-Up cov khoom siv (Sigma-Aldrich, St. Louis, MO, USA) raws li cov chaw tsim khoom raws tu qauv. Ib lub ntim ntawm 3 µL ntawm cov khoom lim dej tau raug xa mus rau hauv 96- zoo phaj ua ke nrog 12 µL qib siab de-ionized formamide (Applied Biosystems, Waltham, MA, USA). Qhov sib tov yog denatured rau 5 feeb ntawm 95 ◦C hauv lub thermocycler. Fragments tau muab cais rau ntawm 8-microcapillary device ABI 3500 (Applied Biosystems, Waltham, MA, USA). Sequences raug xa tawm thiab pom los ntawm Chromas software (Technelysium Pty Ltd., South Brisbane, Australia). FASTA cov ntaub ntawv raug xa mus rau BLAST (Basic Local Alignment Search Tool) thiab ua raws li cov neeg siv genome (version GRCh38.p12).

Kev twv ua ntej ntawm qhov chaw sib txuas lus sib txuas thiab lawv cov kev hloov pauv tau ua los ntawm cov cuab yeej online ConSite [muaj nyob ntawm: http://consite.genereg.net/ ( nkag mus rau 3 Cuaj Hlis 2020)] [38]. Sequences nrog cov loj allele thiab cov me me allele tau uploaded, thiab spectra ntawm transcription yam (TF) raug generated. Qhov kev tshuaj ntsuam tau khiav yam tsis tau teeb tsa yam tsawg kawg nkaus. Cov kev hloov pauv hauv TF-binding profiles raws li qhov muaj qhov sib txawv tau sau tseg hauv Table 2.

4.5. RFLP (Kev Txwv Fragment Length Polymorphism) Kev Ntsuam Xyuas

Cov tshuaj tiv thaiv sib xyaw ua ke thiab PCR cov xwm txheej ntawm PCR amplified yog cov ntsiab lus hauv SA6 thiab SA7. Cov cuab yeej online hauv silico NEBCutter 2.0 [http://nc2.neb.com/NEBcutter2 / ( nkag mus rau 14 Lub Ob Hlis 2020)] tau siv los tsim cov kev txwv ntawm cov amplicons. Cov kev txwv enzymes hauv qab no tau raug xaiv rau kev soj ntsuam RFLP: Hpy166II (nrhiav rs9438393), NIaIII (nrhiav ntawm rs56152218), thiab BmrI (nrhiav rs61822602). Tag nrho cov enzymes tau yuav los ntawm New England Biolabs. Rau qhov sib txawv rs144056491, peb tsis tuaj yeem tsim qhov kev sim RFLP, vim tsis muaj enzyme tsim nyog. Tom qab kev txwv, peb cia siab tias cov khoom tawg tau sau tseg hauv SA8 los tsim cov txiaj ntsig. Tom qab kev txwv, cov khoom raug cais los ntawm agarose gel electrophoresis (NIaIII thiab Hpy166II 1% gel; BmrI 2% gel) thiab tom qab ntawd pom ntawm PharosFX ntsuas (Bio-Rad Laboratories). Genotypes rau txhua SNV raug txiav txim.

4.6. Kev txheeb xyuas cov ntaub ntawv

Cov ntaub ntawv tau tshawb xyuas thiab tshuaj xyuas siv R [R Core Team (2021); R: hom lus thiab ib puag ncig rau kev suav suav. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/, ver. 4. 0.5 (2021-03-31)]. Ib txoj kev tshawb fawb txog kev sib txuas caj ces (GAS) thiab kev tshuaj xyuas lub zog tau ua los ntawm R cov tsev qiv ntawv HardyWeinberg [Jan Graffelman (2015); Tshawb nrhiav Diallelic Genetic Markers: HardyWeinberg Pob. Phau ntawv Journal of Statistical Software, 64(3), 1-23. URL https://www.jstatsoft.org/v64/i03/], DescTools [Andri Signorelli et al. (2021); DescTools: Cov cuab yeej rau kev piav qhia txheeb cais. R pob version 0.99.41.], epitools [Tomas J. Aragon (2020); Epidemiology Cov cuab yeej. R pob version 0.5-10.1. URL https://CRAN.R-project.org/package=epitools], pwr [Stephane Champely (2020); pwr: Basic Functions for Power Analysis. R pob version 1.3-0. URL https://CRAN.R-project.org/package=pwr] thiab tus lej tsim hauv tsev. RandomForest kev kwv yees ua qauv tau ua nrog R lub tsev qiv ntawv randomForestSRC [Ishwaran H. thiab Kogalur UB (2021); Fast Unified RandomForests for Survival, Regression, thiab Classification (RF-SRC), R pob version 2.11.0.]. Cov ntaub ntawv tau pom los ntawm R lub tsev qiv ntawv beeswarm [Aron Eklund (2021); Beeswarm: Bee Swarm Plot, ib qho kev xaiv rau Stripchart. R pob version 0.3.1. URL https://CRAN.R-project.org/package=beeswarm]. Ib txoj kev ANOVA tau siv los ntsuas qhov kev xav tsis zoo ntawm kev sib npaug ntawm cov pejxeem txhais tau tias muaj hnub nyoog pib rau peb cov genotypes sub-populations rau txhua tus SNP. Cov kev tshawb pom nrog p-tus nqi qis dua 0.05 tau suav tias yog qhov tseem ceeb.

5. Cov lus xaus

Hauv cov ntsiab lus, peb cov ntaub ntawv qhia txog qhov tsis muaj zog, tab sis lub koom haum tseem ceeb ntawm A1 SNP rs708727 nrog PD nyob rau hauv cov qauv tseem ceeb thiab ntau tshaj ntawm cov noob caj noob ces hauv cov pej xeem Slovak. Tsis muaj lwm yam kev kuaj A1 SNPs (rs11240569, rs823156, rs9438393, rs56152218, thiab rs61822602) tau cuam tshuam nrog tus kab mob hauv ib qho ntawm cov qauv kuaj caj ces. RF-ML kev tshuaj ntsuam xyuas tau txheeb xyuas tag nrho cov kev sim A1 SNPs uas yog cov neeg tsis zoo / cov neeg twv ua ntej ntawm PD, yog li lawv siv hauv kev kho mob praxis raws li kev kuaj mob lossis cov cim cim tseem ceeb tseem ceeb. Txawm li cas los xij, lub koom haum ntawm rs708727 nrog PD tau tso cai rau peb xav tias PD-kev pheej hmoo cuam tshuam nrog me me allele (G> A) hauv rs708727 pab txhawb rau tus kab mob pib thiab kev loj hlob los ntawm kev cuam tshuam ntawm epigenetic tswj ntawm PM20D1 qhia, lub tswv yim paub ua lub luag haujlwm. hauv pathobiology ntawm AD. Qhov kev xav no yuav tsum tau tshuaj xyuas ntxiv kom ua tiav cov lus qhia tseeb. Tsis tas li ntawd, ib qho kev sib koom ua ke ntawm PD-koom nrog dementia thiab rs708727 yuav tsum tau piav qhia.

Tus sau kev koom tes:

Kev xav, MK; methodology, MK, MC, MG (Marian Grendar) thiab MB; software, MG (Marian Grendar); validation, MC, MB, thiab MK; kev txheeb xyuas, MK, MG (Marian Grendar), MC, AS, ZL, ZP, TS, SS thiab MG (Milan Grofik); kev tshawb nrhiav, MC, thiab MB; data curation, MC, MB, MG (Marian Grendar), MG (Milan Grofik), JN, VN, thiab EK; kev sau ntawv—kev npaj ua ntej, MK; sau ntawv- tshuaj xyuas thiab kho, MC, MG (Marian Grendar) thiab ZP; visualization, MK, MC thiab MG (Marian Grendar); kev saib xyuas, MK; MC, MK, MG (Milan Grofik), JN, JB, VH, VN, EK, MS, thiab BV; Kev nrhiav nyiaj txiag, MK Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Nyiaj txiag:

Txoj haujlwm no tau txais kev txhawb nqa los ntawm Lub Chaw Haujlwm Saib Xyuas Kev Tshawb Fawb thiab Kev Txhim Kho Slovak, tus lej nyiaj APVV-19-0222, thiab Lub Chaw Haujlwm Saib Xyuas Kev Tshawb Fawb ntawm Lub Tsev Haujlwm Saib Xyuas Kev Kawm, Kev Tshawb Fawb, Kev Tshawb Fawb thiab Kev Ua Si ntawm Slovak Republic thiab Slovak Academy of Sciences, muab tus lej VEGA 1/0554/19, ob MK

Institutional Review Board Statement:

Txoj kev tshawb no tau pom zoo los ntawm Pawg Saib Xyuas Kev Ncaj Ncees ntawm Jessenius Kws Qhia Ntawv ntawm Tshuaj, Comenius University (JFM CU). Kev pom zoo tau sau tseg hauv ID: EK 66/2019.

Cov Lus Qhia Txog Kev Pom Zoo:

Cov ntaub ntawv tso cai tau txais los ntawm txhua yam kev koom tes hauv txoj kev tshawb fawb.

Cov ntaub ntawv muaj nyob:

Cov ntaub ntawv tiav yog muaj nyob rau hauv tsab xov xwm. Qhov xwm thiab qhov twg ntawm cov ntaub ntawv suav nrog tso cai rau kev tshuaj ntsuam meta ntxiv. Txhua yam ntaub ntawv hais txog txoj kev tshawb fawb no muaj nyob rau ntawm kev thov los ntawm tus kws sau ntawv.

Kev lees paub:

Peb ua tsaug rau txhua tus neeg koom nrog kev kawm thiab lawv tsev neeg. Peb txuas ntxiv ua tsaug rau Martin Marak (JFM CU) rau nws cov peev txheej kev txhawb nqa ntawm qhov project, rau Jan Radvanszky thiab Rastislav Hekel (ob leeg GENETON sro) rau cov lus qhia muaj txiaj ntsig ntawm A1 txhawb kev txheeb xyuas, thiab rau Theresa Jones rau kev kho lus ntawm lub phau ntawv.

Kev tsis sib haum xeeb ntawm kev txaus siab:

Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.

Cov ntaub ntawv

1. Tatarkova, Z.; de Baaij, JHF; Grendar, M.; Aschenbach, JR; Racay, P.; Bos, C.; Sponder, G.; Hoenderop, JGJ; Röntgen, M.; Turcanova Koprusakova, M.; ua al. Kev noj haus Mg2+ Kev noj haus thiab Na+/Mg2+ Exchanger SLC41A1 Influence Components ntawm Mitochondrial Energetics hauv Murine Cardiomyocytes. Int. J. Mol. Sci. 2020, 21, 8221. [CrossRef] [PubMed]

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