abstract：:Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are perf...

journal_title：American journal of human genetics

authors： Hu YJ,Berndt SI,Gustafsson S,Ganna A,Genetic Investigation of ANthropometric Traits (GIANT) Consortium.,Hirschhorn J,North KE,Ingelsson E,Lin DY

更新日期：2013-08-08 00:00:00

abstract：:Huntington disease (HD) is a dominantly inherited neurodegenerative disorder characterized by dysregulation of various genes. Recently, microRNAs (miRNAs) have been reported to be involved in this dysregulation, suggesting that manipulation of appropriate miRNA regulation may have a therapeutic benefit. Here, we repor...

journal_title：American journal of human genetics

authors： Cheng PH,Li CL,Chang YF,Tsai SJ,Lai YY,Chan AW,Chen CM,Yang SH

更新日期：2013-08-08 00:00:00

abstract：:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo m...

journal_title：American journal of human genetics

authors： Gregor A,Oti M,Kouwenhoven EN,Hoyer J,Sticht H,Ekici AB,Kjaergaard S,Rauch A,Stunnenberg HG,Uebe S,Vasileiou G,Reis A,Zhou H,Zweier C

更新日期：2013-07-11 00:00:00

abstract：:Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss...

journal_title：American journal of human genetics

authors： Li M,Cheng R,Liang J,Yan H,Zhang H,Yang L,Li C,Jiao Q,Lu Z,He J,Ji J,Shen Z,Li C,Hao F,Yu H,Yao Z

更新日期：2013-06-06 00:00:00

abstract：:Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog ...

journal_title：American journal of human genetics

authors： Oates EC,Rossor AM,Hafezparast M,Gonzalez M,Speziani F,MacArthur DG,Lek M,Cottenie E,Scoto M,Foley AR,Hurles M,Houlden H,Greensmith L,Auer-Grumbach M,Pieber TR,Strom TM,Schule R,Herrmann DN,Sowden JE,Acsadi G,Mene

更新日期：2013-06-06 00:00:00

abstract：:Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that ther...

journal_title：American journal of human genetics

authors： Liu X,Ong RT,Pillai EN,Elzein AM,Small KS,Clark TG,Kwiatkowski DP,Teo YY

更新日期：2013-06-06 00:00:00

abstract：:Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci perturb gene expression in trans. The information in trans variants...

journal_title：American journal of human genetics

authors： He X,Fuller CK,Song Y,Meng Q,Zhang B,Yang X,Li H

更新日期：2013-05-02 00:00:00

abstract：:Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this ...

journal_title：American journal of human genetics

authors： Jenkinson EM,Rehman AU,Walsh T,Clayton-Smith J,Lee K,Morell RJ,Drummond MC,Khan SN,Naeem MA,Rauf B,Billington N,Schultz JM,Urquhart JE,Lee MK,Berry A,Hanley NA,Mehta S,Cilliers D,Clayton PE,Kingston H,Smith MJ,W

更新日期：2013-04-04 00:00:00

abstract：:Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recess...

journal_title：American journal of human genetics

authors： Pyott SM,Tran TT,Leistritz DF,Pepin MG,Mendelsohn NJ,Temme RT,Fernandez BA,Elsayed SM,Elsobky E,Verma I,Nair S,Turner EH,Smith JD,Jarvik GP,Byers PH

更新日期：2013-04-04 00:00:00

abstract：:Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly p...

journal_title：American journal of human genetics

authors： Böhm J,Chevessier F,Maues De Paula A,Koch C,Attarian S,Feger C,Hantaï D,Laforêt P,Ghorab K,Vallat JM,Fardeau M,Figarella-Branger D,Pouget J,Romero NB,Koch M,Ebel C,Levy N,Krahn M,Eymard B,Bartoli M,Laporte J

更新日期：2013-02-07 00:00:00

abstract：:Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, w...

journal_title：American journal of human genetics

authors： Pasternack SM,Refke M,Paknia E,Hennies HC,Franz T,Schäfer N,Fryer A,van Steensel M,Sweeney E,Just M,Grimm C,Kruse R,Ferrándiz C,Nöthen MM,Fischer U,Betz RC

更新日期：2013-01-10 00:00:00

abstract：:Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clini...

journal_title：American journal of human genetics

authors： Flanagan SE,Xie W,Caswell R,Damhuis A,Vianey-Saban C,Akcay T,Darendeliler F,Bas F,Guven A,Siklar Z,Ocal G,Berberoglu M,Murphy N,O'Sullivan M,Green A,Clayton PE,Banerjee I,Clayton PT,Hussain K,Weedon MN,Ellard S

更新日期：2013-01-10 00:00:00

abstract：:The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association s...

journal_title：American journal of human genetics

authors： Diogo D,Kurreeman F,Stahl EA,Liao KP,Gupta N,Greenberg JD,Rivas MA,Hickey B,Flannick J,Thomson B,Guiducci C,Ripke S,Adzhubey I,Barton A,Kremer JM,Alfredsson L,Consortium of Rheumatology Researchers of North America.,Rhe

更新日期：2013-01-10 00:00:00

abstract：:We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched con...

journal_title：American journal of human genetics

authors： Sanna-Cherchi S,Kiryluk K,Burgess KE,Bodria M,Sampson MG,Hadley D,Nees SN,Verbitsky M,Perry BJ,Sterken R,Lozanovski VJ,Materna-Kiryluk A,Barlassina C,Kini A,Corbani V,Carrea A,Somenzi D,Murtas C,Ristoska-Bojkovska N,

更新日期：2012-12-07 00:00:00

abstract：:Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctiv...

journal_title：American journal of human genetics

authors： Haack TB,Hogarth P,Kruer MC,Gregory A,Wieland T,Schwarzmayr T,Graf E,Sanford L,Meyer E,Kara E,Cuno SM,Harik SI,Dandu VH,Nardocci N,Zorzi G,Dunaway T,Tarnopolsky M,Skinner S,Frucht S,Hanspal E,Schrander-Stumpel C,

更新日期：2012-12-07 00:00:00

abstract：:Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI ...

journal_title：American journal of human genetics

authors： Carmignac V,Thevenon J,Adès L,Callewaert B,Julia S,Thauvin-Robinet C,Gueneau L,Courcet JB,Lopez E,Holman K,Renard M,Plauchu H,Plessis G,De Backer J,Child A,Arno G,Duplomb L,Callier P,Aral B,Vabres P,Gigot N,Arbu

更新日期：2012-11-02 00:00:00

abstract：:A subset of nuclear-encoded RNAs has to be imported into mitochondria for the proper replication and transcription of the mitochondrial genome and, hence, for proper mitochondrial function. Polynucleotide phosphorylase (PNPase or PNPT1) is one of the very few components known to be involved in this poorly characterize...

journal_title：American journal of human genetics

authors： von Ameln S,Wang G,Boulouiz R,Rutherford MA,Smith GM,Li Y,Pogoda HM,Nürnberg G,Stiller B,Volk AE,Borck G,Hong JS,Goodyear RJ,Abidi O,Nürnberg P,Hofmann K,Richardson GP,Hammerschmidt M,Moser T,Wollnik B,Koehler CM

更新日期：2012-11-02 00:00:00

abstract：:Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutat...

journal_title：American journal of human genetics

authors： Twigg SR,Lloyd D,Jenkins D,Elçioglu NE,Cooper CD,Al-Sannaa N,Annagür A,Gillessen-Kaesbach G,Hüning I,Knight SJ,Goodship JA,Keavney BD,Beales PL,Gileadi O,McGowan SJ,Wilkie AO

更新日期：2012-11-02 00:00:00

abstract：:Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-an...

journal_title：American journal of human genetics

authors： Franceschini N,van Rooij FJ,Prins BP,Feitosa MF,Karakas M,Eckfeldt JH,Folsom AR,Kopp J,Vaez A,Andrews JS,Baumert J,Boraska V,Broer L,Hayward C,Ngwa JS,Okada Y,Polasek O,Westra HJ,Wang YA,Del Greco M F,Glazer NL,

更新日期：2012-10-05 00:00:00

abstract：:The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal...

journal_title：American journal of human genetics

authors： Chong JX,Ouwenga R,Anderson RL,Waggoner DJ,Ober C

更新日期：2012-10-05 00:00:00

abstract：:The extended Simes' test (known as GATES) and scaled chi-square test were proposed to combine a set of dependent genome-wide association signals at multiple single-nucleotide polymorphisms (SNPs) for assessing the overall significance of association at the gene or pathway levels. The two tests use different strategies...

journal_title：American journal of human genetics

authors： Li MX,Kwan JS,Sham PC

更新日期：2012-09-07 00:00:00

abstract：:Osteogenesis imperfecta (OI) is a heterogenous group of genetic disorders of bone fragility. OI type V is an autosomal-dominant disease characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation; the causativ...

journal_title：American journal of human genetics

authors： Cho TJ,Lee KE,Lee SK,Song SJ,Kim KJ,Jeon D,Lee G,Kim HN,Lee HR,Eom HH,Lee ZH,Kim OH,Park WY,Park SS,Ikegawa S,Yoo WJ,Choi IH,Kim JW

更新日期：2012-08-10 00:00:00

abstract：:Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive con...

journal_title：American journal of human genetics

authors： Zhou J,Tawk M,Tiziano FD,Veillet J,Bayes M,Nolent F,Garcia V,Servidei S,Bertini E,Castro-Giner F,Renda Y,Carpentier S,Andrieu-Abadie N,Gut I,Levade T,Topaloglu H,Melki J

更新日期：2012-07-13 00:00:00

abstract：:Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for mul...

journal_title：American journal of human genetics

authors： Kim HG,Kim HT,Leach NT,Lan F,Ullmann R,Silahtaroglu A,Kurth I,Nowka A,Seong IS,Shen Y,Talkowski ME,Ruderfer D,Lee JH,Glotzbach C,Ha K,Kjaergaard S,Levin AV,Romeike BF,Kleefstra T,Bartsch O,Elsea SH,Jabs EW,Mac

更新日期：2012-07-13 00:00:00

abstract：:Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to ...

journal_title：American journal of human genetics

authors： Thornton T,Tang H,Hoffmann TJ,Ochs-Balcom HM,Caan BJ,Risch N

更新日期：2012-07-13 00:00:00

abstract：:Both sequence variation and copy-number variation (CNV) of the genes encoding receptors for immunoglobulin G (Fcγ receptors) have been genetically and functionally associated with a number of autoimmune diseases. However, the molecular nature and evolutionary context of this variation is unknown. Here, we describe the...

journal_title：American journal of human genetics

authors： Machado LR,Hardwick RJ,Bowdrey J,Bogle H,Knowles TJ,Sironi M,Hollox EJ

更新日期：2012-06-08 00:00:00

abstract：:Despite the fact that hundreds of genes are known to affect fertility in animal models, relatively little is known about genes that influence natural fertility in humans. To broadly survey genes contributing to variation in male fertility, we conducted a genome-wide association study (GWAS) of two fertility traits (fa...

journal_title：American journal of human genetics

authors： Kosova G,Scott NM,Niederberger C,Prins GS,Ober C

更新日期：2012-06-08 00:00:00

abstract：:Aplastic anemia (AA) and myelodysplasia (MDS) are forms of bone marrow failure that are often part of the same progressive underlying disorder. While most cases are simplex and idiopathic, some show a clear pattern of inheritance; therefore, elucidating the underlying genetic cause could lead to a greater understandin...

journal_title：American journal of human genetics

authors： Kirwan M,Walne AJ,Plagnol V,Velangi M,Ho A,Hossain U,Vulliamy T,Dokal I

更新日期：2012-05-04 00:00:00

abstract：:Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical a...

journal_title：American journal of human genetics

authors： Bhattacharjee S,Rajaraman P,Jacobs KB,Wheeler WA,Melin BS,Hartge P,GliomaScan Consortium.,Yeager M,Chung CC,Chanock SJ,Chatterjee N

更新日期：2012-05-04 00:00:00

abstract：:Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this...

journal_title：American journal of human genetics

authors： Fabre A,Charroux B,Martinez-Vinson C,Roquelaure B,Odul E,Sayar E,Smith H,Colomb V,Andre N,Hugot JP,Goulet O,Lacoste C,Sarles J,Royet J,Levy N,Badens C

更新日期：2012-04-06 00:00:00

abstract：:Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping an...

journal_title：American journal of human genetics

authors： Schossig A,Wolf NI,Fischer C,Fischer M,Stocker G,Pabinger S,Dander A,Steiner B,Tönz O,Kotzot D,Haberlandt E,Amberger A,Burwinkel B,Wimmer K,Fauth C,Grond-Ginsbach C,Koch MJ,Deichmann A,von Kalle C,Bartram CR,Kohls

更新日期：2012-04-06 00:00:00

abstract：:Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have no...

journal_title：American journal of human genetics

authors： Srour M,Schwartzentruber J,Hamdan FF,Ospina LH,Patry L,Labuda D,Massicotte C,Dobrzeniecka S,Capo-Chichi JM,Papillon-Cavanagh S,Samuels ME,Boycott KM,Shevell MI,Laframboise R,Désilets V,FORGE Canada Consortium.,Maranda B,

更新日期：2012-04-06 00:00:00

abstract：:Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has...

journal_title：American journal of human genetics

authors： Michot C,Le Goff C,Goldenberg A,Abhyankar A,Klein C,Kinning E,Guerrot AM,Flahaut P,Duncombe A,Baujat G,Lyonnet S,Thalassinos C,Nitschke P,Casanova JL,Le Merrer M,Munnich A,Cormier-Daire V

更新日期：2012-04-06 00:00:00

abstract：:We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our ...

journal_title：American journal of human genetics

authors： Kurreeman FA,Stahl EA,Okada Y,Liao K,Diogo D,Raychaudhuri S,Freudenberg J,Kochi Y,Patsopoulos NA,Gupta N,CLEAR investigators.,Sandor C,Bang SY,Lee HS,Padyukov L,Suzuki A,Siminovitch K,Worthington J,Gregersen PK,Hugh

更新日期：2012-03-09 00:00:00

abstract：:Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a mult...

journal_title：American journal of human genetics

authors： Jongmans MC,Verwiel ET,Heijdra Y,Vulliamy T,Kamping EJ,Hehir-Kwa JY,Bongers EM,Pfundt R,van Emst L,van Leeuwen FN,van Gassen KL,Geurts van Kessel A,Dokal I,Hoogerbrugge N,Ligtenberg MJ,Kuiper RP

更新日期：2012-03-09 00:00:00

abstract：:To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases an...

journal_title：American journal of human genetics

authors： Saxena R,Elbers CC,Guo Y,Peter I,Gaunt TR,Mega JL,Lanktree MB,Tare A,Castillo BA,Li YR,Johnson T,Bruinenberg M,Gilbert-Diamond D,Rajagopalan R,Voight BF,Balasubramanyam A,Barnard J,Bauer F,Baumert J,Bhangale T,Böh

更新日期：2012-03-09 00:00:00

abstract：:Common variation in over 100 genes has been implicated in the risk of developing asthma, but the contribution of rare variants to asthma susceptibility remains largely unexplored. We selected nine genes that showed the strongest signatures of weak purifying selection from among 53 candidate asthma-associated genes, an...

journal_title：American journal of human genetics

authors： Torgerson DG,Capurso D,Mathias RA,Graves PE,Hernandez RD,Beaty TH,Bleecker ER,Raby BA,Meyers DA,Barnes KC,Weiss ST,Martinez FD,Nicolae DL,Ober C

更新日期：2012-02-10 00:00:00

abstract：:Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we desc...

journal_title：American journal of human genetics

authors： Forsberg LA,Rasi C,Razzaghian HR,Pakalapati G,Waite L,Thilbeault KS,Ronowicz A,Wineinger NE,Tiwari HK,Boomsma D,Westerman MP,Harris JR,Lyle R,Essand M,Eriksson F,Assimes TL,Iribarren C,Strachan E,O'Hanlon TP,Rider L

更新日期：2012-02-10 00:00:00

abstract：:Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb...

journal_title：American journal of human genetics

authors： Estrada-Cuzcano A,Neveling K,Kohl S,Banin E,Rotenstreich Y,Sharon D,Falik-Zaccai TC,Hipp S,Roepman R,Wissinger B,Letteboer SJ,Mans DA,Blokland EA,Kwint MP,Gijsen SJ,van Huet RA,Collin RW,Scheffer H,Veltman JA,Zrenne

更新日期：2012-01-13 00:00:00

abstract：:Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, α-ketoglutarate, and branched chain amino acids and in the glycine cleavage. Lipoic acid is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. ...

journal_title：American journal of human genetics

authors： Mayr JA,Zimmermann FA,Fauth C,Bergheim C,Meierhofer D,Radmayr D,Zschocke J,Koch J,Sperl W

更新日期：2011-12-09 00:00:00