LRRK2

LRRK2
ساختارهای موجود
PDB	جستجوی هم‌ساخت‌شناسی: PDBe RCSB
فهرست شناسه‌های PDB
	2ZEJ, 3D6T
معین‌کننده‌ها
نام‌های دیگر	LRRK2, AURA17, DARDARIN, PARK8, RIPK7, ROCO2, leucine-rich repeat kinase 2, leucine rich repeat kinase 2
شناسه‌های بیرونی	OMIM: 609007; MGI: 1913975; HomoloGene: 18982; GeneCards: LRRK2; OMA:LRRK2 - orthologs
عدد EC	2.7.11.1,2.7.11.1
موقعیت ژن (انسان)
کروموزوم	کروموزوم ۱۲ (انسان)
پایان	40,369,285 bp
موقعیت ژن (موش)
کروموزوم	کروموزوم ۱۵ (موش)
پایان	91,700,323 bp
الگوی گسترش RNA
	بیشترین بیان در
	buccal mucosa cell; ; lower lobe of lung; ; upper lobe of lung; ; upper lobe of left lung; ; right lung; ; visceral pleura;
	بیشترین بیان در
	human kidney; ; left lung; ; left lung lobe; ; right kidney; ; superior frontal gyrus; ; lumbar spinal ganglion; ; right lung;
	داده‌های بیشتر بیان
	; ;
	داده‌های بیشتر بیان
هستی‌شناسی ژن
عملکرد ملکولی	protein homodimerization activity; signaling receptor complex adaptor activity; clathrin binding; co-receptor binding; transferase activity; GTPase activator activity; protein kinase activity; protein kinase A binding; peroxidase inhibitor activity; SNARE binding; nucleotide binding; identical protein binding; GTPase activity; syntaxin-1 binding; protein serine/threonine kinase activity; tubulin binding; transmembrane transporter binding; microtubule binding; MAP kinase kinase activity; GTP binding; ATP binding; GTP-dependent protein kinase activity; beta-catenin destruction complex binding; پیوند پروتئینی; kinase activity; actin binding; magnesium ion binding;
ترکیبات سلولی	cytoplasmic vesicle; اندوزوم; اگزوزوم; Wnt signalosome; soma; trans-Golgi network; mitochondrial membranes; سیناپس; سیتوپلاسم; mitochondrial outer membrane; synaptic vesicle membrane; پریکاریون; شبکه آندوپلاسمی; پوسته یاخته; ریزپرز; mitochondrial matrix; dendrite cytoplasm; growth cone; cell projection; دندریت; کافنده‌تن; neuron projection; Golgi-associated vesicle; میتوکندری; mitochondrial inner membrane; autolysosome; پایانه آکسون; intracellular anatomical structure; membrane; لیپید رفت; آسه; amphisome; multivesicular body, internal vesicle; synaptic vesicle; Inclusion bodies; پیوند میان‌یاخته‌ای; cytoplasmic side of mitochondrial outer membrane; سیتوزول; دستگاه گلژی; postsynapse; extracellular space; هسته سلول; intracellular membrane-bounded organelle; caveola neck; endoplasmic reticulum exit site; glutamatergic synapse; presynaptic cytosol; ribonucleoprotein complex;
فرایند زیستی	lysosome organization; پاسخ به استرس اکسیداتیو; cellular response to dopamine; regulation of autophagy; positive regulation of autophagy; positive regulation of dopamine receptor signaling pathway; regulation of neuroblast proliferation; intracellular distribution of mitochondria; negative regulation of protein processing; negative regulation of protein processing involved in protein targeting to mitochondrion; protein localization to mitochondrion; positive regulation of canonical Wnt signaling pathway; خودخواری; neuromuscular junction development; فسفرگیری; positive regulation of protein binding; regulation of branching morphogenesis of a nerve; mitochondrion localization; positive regulation of protein autoubiquitination; regulation of synaptic vesicle transport; positive regulation of protein phosphorylation; regulation of kidney size; regulation of synaptic vesicle exocytosis; positive regulation of MAP kinase activity; peptidyl-threonine phosphorylation; MAPK cascade; Wnt signalosome assembly; protein phosphorylation; regulation of synaptic transmission, glutamatergic; excitatory postsynaptic potential; negative regulation of hydrogen peroxide-induced cell death; regulation of dopamine receptor signaling pathway; regulation of membrane potential; protein autophosphorylation; regulation of mitochondrial fission; regulation of neuron maturation; reactive oxygen species metabolic process; positive regulation of programmed cell death; regulation of neuron death; regulation of mitochondrial depolarization; cellular response to oxidative stress; negative regulation of late endosome to lysosome transport; intracellular signal transduction; regulation of lysosomal lumen pH; negative regulation of GTPase activity; locomotory exploration behavior; Golgi organization; canonical Wnt signaling pathway; neuron projection morphogenesis; positive regulation of protein ubiquitination; regulation of canonical Wnt signaling pathway; exploration behavior; cellular response to organic cyclic compound; tangential migration from the subventricular zone to the olfactory bulb; regulation of protein kinase A signaling; calcium-mediated signaling; negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation; negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; negative regulation of neuron death; negative regulation of protein targeting to mitochondrion; peptidyl-serine phosphorylation; determination of adult lifespan; negative regulation of excitatory postsynaptic potential; negative regulation of protein phosphorylation; neuron death; GTP metabolic process; negative regulation of autophagosome assembly; olfactory bulb development; cellular response to starvation; regulation of dendritic spine morphogenesis; دگرگونی یاخته‌; اندوسیتوز; negative regulation of protein binding; mitochondrion organization; cellular response to manganese ion; negative regulation of macroautophagy; regulation of locomotion; positive regulation of GTPase activity; regulation of retrograde transport, endosome to Golgi; regulation of CAMKK-AMPK signaling cascade; positive regulation of histone deacetylase activity; endoplasmic reticulum organization; اسپرماتوژنز; ساماندهی بیان ژن; negative regulation of neuron projection development; striatum development; regulation of protein stability; positive regulation of nitric-oxide synthase biosynthetic process; regulation of ER to Golgi vesicle-mediated transport; protein localization to endoplasmic reticulum exit site; neuron projection arborization; regulation of synaptic vesicle endocytosis; positive regulation of synaptic vesicle endocytosis; positive regulation of microglial cell activation; protein import into nucleus;
	منابع: آمیگو / کوئیک‌گو
هم‌ساخت‌شناسی
	120892
	66725
	ENSG00000188906
	ENSMUSG00000036273
	Q5S007
	Q5S006
	NM_198578
	NM_025730
	NP_940980
	NP_080006
	ویکی‌داده
مشاهده/ویرایش انسان	مشاهده/ویرایش موش

کیناز ۲ با تکرارهای غنی از لوسین (انگلیسی: Leucine-rich repeat kinase 2) یا به اختصار «LRRK2» که با نام «داردارین» (برگرفته از واژهٔ dardara در زبان باسکی به معنای لرزش) هم شناخته می‌شود، یک آنزیم کیناز بزرگ و چندمنظوره است که یک در انسان توسط ژن «LRRK2» کُدگذاری می‌شود.^[۵]^[۶] این آنزیم متعلق به خانواده‌ای از کینازهاست که در ساختمان خود دارای تکرار غنی از لوسین هستند. واریانت‌هایی از این ژن با افزایش ابتلا به بیماری پارکینسون و بیماری کرون مرتبط است.^[۵]^[۶]

این ژن نوعی پروتئین را کد می‌کند که دارای ناحیه‌ای از توالی آرمادیلو (ARM)، یک تکرار آنکرین (ANK)، دومِـین تکرار غنی از لوسین (LRR)، دومِـین کیناز، دومِـین RAS، دومِـین جی‌تی‌پی‌آز و دومِـین تکرار WD40 است. پروتئین تا حد زیادی در سیتوپلاسم وجود دارد اما با غشای خارجی میتوکندری نیز مرتبط است.

این پروتئین با پایانه-C دومین انگشت رینگ از مولکول پارکین تعامل دارد. در ژن یاد شده سبب آپوپتوز در سلول‌های نوروبلاستوما و در نورون‌های قشر مغز موش‌ها می‌شود.^[۷]

بیان ژن‌های جهش یافتهٔ LRRK2 دخیل در بیماری پارکینسون اتوزومال غالب، باعث کوتاه شدن و ساده‌سازی شاخه‌های دندریت نورون‌ها در داخل بدن و همچنین در نورون‌های کشت‌شده آزمایشگاهی می‌شود.^[۸] این تا حدی با تغییرات در ماکرو-اُتوفاژی^[۹]^[۱۰]^[۱۱]^[۱۲]^[۱۳] انجام می‌شود و می‌توان با تنظیم پروتئین کیناز آ در پروتئین اتوفاژی LC3 از آن جلوگیری کرد.^[۱۴]

اهمیت بالینی

جهش در ژن «LRRK2» با بروز بیماری پارکینسون؛ نوع ۸^[۱۵]^[۱۶] و بیماری کرون^[۱۷]^[۱۸] در ارتباط است.

منابع

1 2 3 GRCh38: Ensembl release 89: ENSG00000188906 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036273 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
1 2 Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB (November 2004). "Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease". Neuron. 44 (4): 595–600. doi:10.1016/j.neuron.2004.10.023. PMID 15541308. S2CID 16688488.
1 2 Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (November 2004). "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology". Neuron. 44 (4): 601–7. doi:10.1016/j.neuron.2004.11.005. PMID 15541309. S2CID 8642468.
↑ Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (December 2005). "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18676–81. Bibcode:2005PNAS..10218676S. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.
↑ MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (November 2006). "The familial Parkinsonism gene LRRK2 regulates neurite process morphology". Neuron. 52 (4): 587–93. doi:10.1016/j.neuron.2006.10.008. PMID 17114044. S2CID 16966163.
↑ Plowey ED, Cherra SJ, Liu YJ, Chu CT (May 2008). "Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells". Journal of Neurochemistry. 105 (3): 1048–56. doi:10.1111/j.1471-4159.2008.05217.x. PMC 2361385. PMID 18182054.
↑ Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (May 2012). "Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain". The Journal of Neuroscience. 32 (22): 7585–93. doi:10.1523/JNEUROSCI.5809-11.2012. PMC 3382107. PMID 22649237.
↑ Gómez-Suaga P, Luzón-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S (February 2012). "Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP". Human Molecular Genetics. 21 (3): 511–25. doi:10.1093/hmg/ddr481. PMC 3259011. PMID 22012985.
↑ Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (April 2011). Cai H (ed.). "Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2". PLOS ONE. 6 (4): e18568. Bibcode:2011PLoSO...618568R. doi:10.1371/journal.pone.0018568. PMC 3071839. PMID 21494637.{{cite journal}}: نگهداری یادکرد:شماره مقاله به‌جای شماره صفحه (رده)
↑ Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (November 2009). "LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model". Human Molecular Genetics. 18 (21): 4022–34. doi:10.1093/hmg/ddp346. PMC 2758136. PMID 19640926.
↑ Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (August 2010). "Regulation of the autophagy protein LC3 by phosphorylation". The Journal of Cell Biology. 190 (4): 533–9. doi:10.1083/jcb.201002108. PMC 2928022. PMID 20713600.
↑ "Entrez Gene: LRRK2 leucine-rich repeat kinase 2". Archived from the original on 6 مارس 2010. Retrieved 21 اكتبر 2024. {{cite web}}: تاریخ وارد شده در |access-date= را بررسی کنید (کمک)
↑ PhD, Lindsey Shapiro (2023-09-18). "Researchers win Breakthrough Prize for Parkinson's genetics discoveries | Parkinson's News Today". parkinsonsnewstoday.com (in American English). Retrieved 2023-09-20.
↑ Manolio TA (July 2010). "Genomewide association studies and assessment of the risk of disease". The New England Journal of Medicine. 363 (2): 166–76. doi:10.1056/NEJMra0905980. PMID 20647212.
↑ Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW (February 2011). "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies". Lancet. 377 (9766): 641–9. doi:10.1016/S0140-6736(10)62345-8. PMC 3696507. PMID 21292315.

برای مطالعهٔ بیشتر

Singleton AB (August 2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin". Trends in Neurosciences. 28 (8): 416–21. doi:10.1016/j.tins.2005.05.009. PMID 15955578. S2CID 53204736.
Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (May 2006). "LRRK2 in Parkinson's disease: protein domains and functional insights". Trends in Neurosciences. 29 (5): 286–93. doi:10.1016/j.tins.2006.03.006. PMID 16616379. S2CID 11458231.
Haugarvoll K, Wszolek ZK (July 2006). "PARK8 LRRK2 parkinsonism". Current Neurology and Neuroscience Reports. 6 (4): 287–94. doi:10.1007/s11910-006-0020-0. PMID 16822348. S2CID 25252449.
Bonifati V (September 2006). "The pleomorphic pathology of inherited Parkinson's disease: lessons from LRRK2". Current Neurology and Neuroscience Reports. 6 (5): 355–7. doi:10.1007/s11910-996-0013-z. PMID 16928343. S2CID 41352829.
Schapira AH (September 2006). "The importance of LRRK2 mutations in Parkinson disease". Archives of Neurology. 63 (9): 1225–8. doi:10.1001/archneur.63.9.1225. PMID 16966498.
Whaley NR, Uitti RJ, Dickson DW, Farrer MJ, Wszolek ZK (2006). "Clinical and pathologic features of families with LRRK2-associated Parkinson's disease". Parkinson's Disease and Related Disorders. pp. 221–229. doi:10.1007/978-3-211-45295-0_34. ISBN 978-3-211-28927-3. PMID 17017533. {{cite book}}: از |journal= صرف‌نظر شد (کمک)
Gasser, T. (2006). "Molecular genetic findings in LRRK2 American, Canadian and German families". Parkinson's Disease and Related Disorders. pp. 231–234. doi:10.1007/978-3-211-45295-0_35. ISBN 978-3-211-28927-3. PMID 17017534. {{cite book}}: از |journal= صرف‌نظر شد (کمک)
Tan EK (November 2006). "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease". Annals of the Academy of Medicine, Singapore. 35 (11): 840–2. doi:10.47102/annals-acadmedsg.V35N11p840. PMID 17160203.

این یک مقالهٔ خرد زیست‌شناسی مولکولی است. می‌توانید با گسترش آن به ویکی‌پدیا کمک کنید.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000188906 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036273 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid15541308-5] 1 2 Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB (November 2004). "Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease". Neuron. 44 (4): 595–600. doi:10.1016/j.neuron.2004.10.023. PMID 15541308. S2CID 16688488.

[pmid15541309-6] 1 2 Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (November 2004). "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology". Neuron. 44 (4): 601–7. doi:10.1016/j.neuron.2004.11.005. PMID 15541309. S2CID 8642468.

[pmid16352719-7] Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (December 2005). "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18676–81. Bibcode:2005PNAS..10218676S. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.

[pmid17114044-8] MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (November 2006). "The familial Parkinsonism gene LRRK2 regulates neurite process morphology". Neuron. 52 (4): 587–93. doi:10.1016/j.neuron.2006.10.008. PMID 17114044. S2CID 16966163.

[pmid18182054-9] Plowey ED, Cherra SJ, Liu YJ, Chu CT (May 2008). "Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells". Journal of Neurochemistry. 105 (3): 1048–56. doi:10.1111/j.1471-4159.2008.05217.x. PMC 2361385. PMID 18182054.

[pmid22649237-10] Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (May 2012). "Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain". The Journal of Neuroscience. 32 (22): 7585–93. doi:10.1523/JNEUROSCI.5809-11.2012. PMC 3382107. PMID 22649237.

[pmid22012985-11] Gómez-Suaga P, Luzón-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S (February 2012). "Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP". Human Molecular Genetics. 21 (3): 511–25. doi:10.1093/hmg/ddr481. PMC 3259011. PMID 22012985.

[pmid21494637-12] Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (April 2011). Cai H (ed.). "Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2". PLOS ONE. 6 (4): e18568. Bibcode:2011PLoSO...618568R. doi:10.1371/journal.pone.0018568. PMC 3071839. PMID 21494637.{{cite journal}}: نگهداری یادکرد:شماره مقاله به‌جای شماره صفحه (رده)

[pmid19640926-13] Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (November 2009). "LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model". Human Molecular Genetics. 18 (21): 4022–34. doi:10.1093/hmg/ddp346. PMC 2758136. PMID 19640926.

[pmid20713600-14] Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (August 2010). "Regulation of the autophagy protein LC3 by phosphorylation". The Journal of Cell Biology. 190 (4): 533–9. doi:10.1083/jcb.201002108. PMC 2928022. PMID 20713600.

[15] "Entrez Gene: LRRK2 leucine-rich repeat kinase 2". Archived from the original on 6 مارس 2010. Retrieved 21 اكتبر 2024. {{cite web}}: تاریخ وارد شده در |access-date= را بررسی کنید (کمک)

[16] PhD, Lindsey Shapiro (2023-09-18). "Researchers win Breakthrough Prize for Parkinson's genetics discoveries | Parkinson's News Today". parkinsonsnewstoday.com (in American English). Retrieved 2023-09-20.

[Manolio_2010-17] Manolio TA (July 2010). "Genomewide association studies and assessment of the risk of disease". The New England Journal of Medicine. 363 (2): 166–76. doi:10.1056/NEJMra0905980. PMID 20647212.

[IPDGC_2010-18] Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW (February 2011). "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies". Lancet. 377 (9766): 641–9. doi:10.1016/S0140-6736(10)62345-8. PMC 3696507. PMID 21292315.

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