List of Paris MoU deficiency codesi
中国罕见病参考名录列表
名称1 苯丙酮尿症Phenylk etonuria (PKU)2 肝豆状核变性Wilson disease (WD)3 杜氏肌营养不良症Duchen ne muscula r dystroph y (DMD)4 糖原累积病Glycoge n storage disease (GSD)5 粘多糖贮积症Mucopol ysaccha ridosis (MPS)Fanconi anemia (FA)7 血友病Hemoph ilia8 戈谢病Gaucher disease (GD)9 先天性肾上腺皮质增生症Congeni tal adrenal hyperpla sia (CAH) 10 原发性肉碱缺乏症Primary carnitine deficien cy (PCD)血症Methylmalonic academia (MA)12 大疱性表皮松解症Epiderm olysisbul losa (EB)13 遗传性进行性肾炎（Alport 综合征）Alport syndrom e14 马凡综合征Marfan syndrome15 亨廷顿舞蹈症Huntingt on?dise ase (HD)缩症Spinalmuscularatrophy(SMA) 17 半乳糖血症Galactosemia 18 脊髓小脑性共济失调Spinoce rebellar ataxia (SCA) 19 先天性高胰岛素性低血糖血症Familial hyperins ulinemic hypogly cemia (HHF)（脆骨病）Osteogenesisim perfecta(OI)21 常染色体隐性多囊肾病Autoso mal recessiv e polycysti c kidney disease (ARPKD )22 软骨发育不全Achondr oplasia 23 脊髓延髓肌肉萎缩症(肯尼迪氏症) Spinal and bulbar muscula r atrophy (Kenned y disease) 24 枫糖尿症Maple syrup urine disease (MSUD) 25 尿素循环障碍 Urea cycle disorder 26 湿疹血小板减少伴免疫缺陷综合征Wiskott-Aldrich syndrom e (WAS)27 白化病Albinism 28 结节性硬化症Tuberous sclerosi s complex(TSC) 29 法布雷病Fabry disease 30 雷特综合征Rett syndrom e31 普拉德-威利综合征（小胖威利综合征）Prader-Willi syndrom e (PWS)32 威廉姆斯综合征Williams syndrome (WS)33 小儿X连锁无丙种球蛋白血症X-linked agamm aglobuli nemia (XLA) 34 神经纤维瘤Neurofib romatosi s (NF) 35 异戊酸血症Isovaleri cacidem ia (IVA) 36 β-酮硫解酶缺乏症Beta-ketothiol ase deficien cy37 阵发性睡眠性血红蛋白尿症Paroxysmal nocturn al hemoglo binuria 38 肢带型肌营养不良Limb-girdle muscula r dystroph y (LGMD) 39 尼曼-匹克氏病Nieman n-Pick disease(NPD) 40 戊二酸血症Glutaric academi a (GA)41 重症联合免疫缺陷Severecombine d immuno deficien cy(SCID) 42 酪氨酸血症Tyrosine mia43 多发性硬化Multiple Sclerosis (MS) 44 脂肪酸氧化作用缺陷 Fatty acid oxidation defect 45 家族性痉挛性截瘫Heredita ry spastic paraple gia (HSP)46 X连锁肾上腺脑白质营养不良 X-linked adrenol eukodys trophy (XLD) 47 努南综合征Noonan syndrome (NS)48 瓜氨酸血症Citrullin emia49 中链酰基辅酶A脱氢酶缺乏症Medium chain acyl-CoA dehydro genase deficien cy (MCAD脉高压Primary Pulmon ary Hyperte nsion (PPH) 51 肌萎缩侧索硬化症Amyotro phic lateral sclerosi s (ALS) 52 视网膜色素变性症Retinitis pigment osa(RP)53 佩梅病Pelizaeu s-Merzbac her disease (PMD)症Charcot-Marie-Tooth disease (CMT) 55 白塞病Beh?et disease 56 克罗恩病Crohn's disease 57 热纳综合征Asphyxi ating Thoracic Dystrop hy (Jeune syndrom e)58 淋巴管肌瘤病Lympha ngioleio myomat osis (LAM)59 肢端肥大症Acrome galy60 早发性帕金森病Early-onset Parkins on disease 61 多发性骨髓瘤Multiple myelom a62 掌跖角化症Palmopl antarker atoderm a63 生物素酶缺乏症Biotinida se deficien cy64 原发性慢性肉芽肿病Chronicprimary granulo matous disease 65 先天性角化不良Dyskera tosiscon genita 66 丙酸血症Propioni c academia67 四氢生物蝶呤缺乏症Tetrahy drobiopt erin deficien cy68 X-连锁高IgM 综合症X-linked hyper IgM syndrom e69 低碱性磷酸酯酶血症Hypoph osphata sia70 脆性X染色体综合征Fragile X syndrom e (FX) 71 Leber遗传性视神经病变 Leber heredita ry optic neuropa thy (LHON)72 地中海贫血Thalassemia 73 卡尔曼综合征Kallman n syndrom e74 天使综合征Angelm an syndrome (AS)75 视网膜母细胞瘤Retinobl astoma76 线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS 综合征) Mitochondrial encepha lopathy, lactic acidosis , and stroke-like77 先天性红细胞生成障碍性贫血Congeni tal dyseryth ropoietic anemia (CDA) 78 生长激素缺乏症Growth hormon e deficien79 婴儿严重肌阵挛性癫痫(Dravet 综合征) Dravet syndrom e80 永久性新生兒糖尿病Perman ent Neonata l Diabete s81 体质性肝功能不良性黄疸(Gilbert 综合征）Gilbert's syndrome (GS)82 季肋发育不全Hypoch ondropl83 非典型溶血性尿毒症综合征Atypical hemolyti c-uremic syndrom e (aHUS) 84 朗格汉斯细胞组织细胞增生症Pulmon ary Langerh ans cell histiocyt osis (PLCH) 85 烟雾病Moyamo ya disease 86 家族性低血钾症Familial Hypokal emia87 林岛综合征（VHL 综合征）Von Hippel–Lindau disease (VHL syndrom 88 硬皮病Sclerod erma 89 红细胞增多症Erythocy tosis90 先天性肌无力综合征Congeni tal Myasthe nic Syndro mes91 视神经脊髓炎Neurom yelitisop tica (NMO)92 遗传性血管性水肿Hereditary angioed ema (HAE) 93 全羧化酶合成酶缺乏症Holocar boxylas esynthet ase deficien cy94 低磷性佝偻病Hypoph osphate micrickets 95 侏儒综合征Laron syndrom e96 溶酶体酸性脂肪酶缺乏症Lysosomal acid lipase deficien cy97 重症先天性粒细胞缺乏症Severe congenit al neutropenia98 卟啉病Porphyri a99 Aicardi-Goutières综合症Aicardi-Goutières syndrom e （AGS发育不良综合征Alagillesyndrom e101 轴前肢端骨发育不全Nagerac rofaciald ysostosi s (Preaxia lacrodysostosis) 102 多发性骨骺发育不良Multiple epiphys eal dysplasi a103 进行性骨化性肌炎Myositis ossifica nsprogr essiva (MOP)症Incontin entiapig menti 105 遗传性果糖不耐受症Heredita ry fructose intoleran ce106 无脑回畸形Lissenc ephaly 107 竹节状毛发综合征（Nethe rton综合征）Netherto n syndrom e血性毛细血管扩张症Heriditary hemorrh agic telangiectasia 109Rubinst ein-Taybi综合征Rubinst ein-Taybi syndrom e110 隐眼-并指(趾)综合征Cryptop hthalmo s-syndact ylysyndr om综合症(Turner-Kieser综合征)Nail-patella syndrom e (Turner-Kieser syndrom 112 谷固醇血症Sitosterolemia 113 自身免疫性肠病第I型Immune dysregul ation-polyend ocrinopa thy-enterop athy-X-linked syndrom e （IPEX素E综合征（巴特综合征）Hyperprostaglan din E syndrom e (Barttersyndrom 115 先天性Cajal氏间质细胞增生合并肠道神经元发育异常Congeni tal Interstiti al Cell of Cajal Hyperpl asia with Neurona116 先天性胆酸合成障碍Inborn errors of bile acid synthesi s117 弗里曼-谢尔登氏综合征Freema n-Sheldon syndrom e (FSS) 118 躯干发育异常Campo melic dysplasi a （CD）119 Lennox-Gastaut 综合征Lennox-Gastaut syndrom e (LGS)120 神经病-共济失调-色素性视网膜炎综合征Neuropathy -ataxia, and retinitis pigment osa (NARPsyndrom 121 肌强直性营养不良Myotoni c dystroph y (MD) 122 面肩胛肱型肌营养不良症Faciosc apulohu meral muscula r dystroph123 共济失调-毛细血管扩张症Ataxia-telangie ctasia (AT) 124 低血钾型周期性麻痹Hypokal emic periodic paralysis125 线粒体肌病Nemalin e myopathy126 再生障碍性贫血Aregene rative anemia 127 高苯丙氨酸血症Hyperph enylalan inemia征Turner syndrom e129 X联锁鱼鳞病Recessi ve X-linked ichthyos is130 镰刀型细胞贫血病Sickle cell disease 131 骨髓增生异常综合征Myelody splastic syndrom es (MDS) 132 歌舞伎面谱综合征Kabuki syndrom e发育不全Pseudo achondr oplasia 134 进行性家族性肝内胆汁淤积症Progres sive familial intrahep atic cholesta 135 新生儿呼吸窘迫综合征Neonata l respirat ory distress syndrom 136 囊性纤维化Cystic fibrosis (CF)137 遗传性多发脑梗死性痴呆Heredita ry multi-infarct dementi a (Cerebr al autosom al dominan t arteriop athy 138 Gitelma n综合征Gitelma n syndrom e139 Joubert 综合征Joubert syndrom e140 McCune -Albright 综合征McCune -Albright syndrom e (MAS) 141 家族性高胆固醇血症Familial hyperch ylomicro nemia （FH）142 黑斑息肉综合征Peutz-Jeghers syndrom e (PJS) 143 黑斑息肉综合征Peutz一Jeghers syndrom e (PJS)143 庞贝氏症Pompe disease 144 腹膜假黏液瘤Pseudo myxoma ?periton e (PMP) 145 克氏综合症Klinefelt er syndrom e146 重症肌无力Myasthe nia gravis (MG) 147 猫叫综合征（5P-综合征） cri-du-chat syndrom e (5p-syndrom e)。
石家庄地区新生儿Citrin蛋白缺乏症串联质谱筛查结果分析
DOI:10.12280/gjszjk.20200585贾立云，封纪珍，王熙，马翠霞，封露露【摘要】目的：明确Citrin蛋白缺乏症在石家庄地区活产新生儿中的患病率，进一步分析其致病基因突变情况。
方法：采用串联质谱技术对石家庄地区2014年1月—2019年12月出生的160061例新生儿进行血氨基酸水平检测，对疑似患儿进行基因检测。
结果：160061例新生儿中，筛查阳性患儿20例，经SLC25A13基因检测，确诊1例；另1例患儿筛查阴性，于不足1个月因皮肤黄染加重入院，查血串联质谱，显示瓜氨酸和甲硫氨酸升高，尿有机酸结果示4-羟基苯乳酸及4-羟基苯丙酮酸升高，此例患儿筛查呈现假阴性。
Citrin蛋白缺乏症在石家庄地区的患病率为2/160061。
基因确诊的1例患儿为SLC25A13基因复合杂合突变，突变位点分别为c.1021+1G>A、c.851_854delTATG，其中c.1021+1G>A在人类基因突变数据库中未见报道。
结论：串联质谱技术应用于新生儿疾病筛查可及早发现Citrin蛋白缺乏症患儿；部分患儿筛查呈现假阴性；Citrin蛋白缺乏症在石家庄地区新生儿中的患病率2/160061；发现了1种SLC25A13基因新突变位点。
【关键词】新生儿筛查；尿素循环障碍，先天性；串联质谱法；突变；Citrin蛋白缺乏症Newborn Screening for Citrin Deficiency by Tandem Mass Spectrometry in Shijiazhuang JIA Li-yun,FENG Ji-zhen,WANG Xi,MA Cui-xia,FENG Lu-lu.Newborn Disease Screening and Treatment Center,Shijiazhuang Maternity&Child Healthcare Hospital,Shijiazhuang050000,ChinaCorresponding author:FENG Ji-zhen,E-mail:****************【Abstract】Objective:To determine the prevalence of citrin protein deficiency in neonates in Shijiazhuang,and further analyze the mutations of pathogenic genes.Methods:A total of160061newborns in Shijiazhuangfrom January2014to December2019were detected for blood amino acid levels by tandem mass spectrometry(MS/MS),and the genetic testing were performed for suspected infants.Results:Among the160061newborns,20cases were screened as positive cases,including1case confirmed the diagnosis with SLC25A13gene testing;and1case that was false negative in newborn screening.The latter child patient was admitted to the hospital due toyellowish skin aggravated in less than1month.The blood tandem mass spectrometry showed that citrulline andmethionine were elevated.The results of urine organic acids showed that4-hydroxyphenyllactic acid and4-hydroxyphenylpyruvic acid were both significantly increased.The prevalence of citrin protein deficiency inShijiazhuang is2/160061.The gene testing showed that one case was a compound heterozygous mutation ofSLC25A13gene.The mutation sites were c.1021+1G>A and c.851_854delTATG.There was no report of c.1021+1G>A in the human gene mutation database.Conclusions:The application of tandem mass spectrometry inneonatal disease screening can detect the citrin protein deficiency as early as possible.Some newborn patients maybe false negative screening;the gene testing is helpful for the diagnosis of citrin protein deficiency.The prevalenceof citrin deficiency in Shijiazhuang area is2/160061.In this paper,we reported a novel mutation site ofSLC25A13gene.【Keywords】Neonatal screening；Urea cycle disorders，inborn；Tandem mass spectrometry；Mutation；Citrindeficiency（ＪＩｎｔＲｅｐｒｏｄＨｅａｌｔｈ蛐ＦａｍＰｌａｎ，2021，40：182-184）·论著·基金项目：河北省医学科学研究重点课题（20191423）作者单位：050000石家庄市妇幼保健院新生儿疾病筛查诊治中心通信作者：封纪珍，E-mail：****************Citrin蛋白缺乏症是一类常染色体隐性遗传病，由SLC25A13基因突变所致，引起肝细胞线粒体Citrin蛋白功能不足，导致机体代谢紊乱[1]。
人间传染的病原微生物目录
人间传染的病原微生物目录表1.病毒分类目录附录：朊病毒注：BSL-n/ABSL-n：不同的实验室/动物实验室生物安全防护等级。
a.病毒培养：指病毒的分离、扩增和利用活病毒培养物的相关实验操作（包括滴定、中和试验、活病毒及其蛋白纯化、核酸提取时裂解剂或灭活剂的加入、病毒冻干、利用活病毒培养物或细胞提取物进行的生化分析、血清学检测、免疫学检测等）以及产生活病毒的重组实验。
b.动物感染实验：指以活病毒感染动物以及感染动物的相关实验操作（包括感染动物的饲养、临床观察、特殊检查，动物样本采集、处理和检测，动物解剖，动物排泄物、组织、器官、尸体等废弃物处理等）。
c.未经培养的感染材料的操作：指未经培养的感染材料在采用可靠的方法灭活前进行的病毒抗原检测、血清学检测、核酸检测、生化分析等操作。
未经可靠灭活或固定的人和动物组织标本因含病毒量较高，其操作的防护级别应比照病毒培养。
d.灭活材料的操作：指感染性材料或活病毒采用可靠的方法灭活，但未经验证确认后进行的操作。
e.无感染性材料的操作：指针对确认无感染性的材料的各种操作，包括但不限于无感染性的病毒DNA或cDNA操作。
f.运输包装分类：按国际民航组织文件Doc9284《危险品航空安全运输技术细则》的分类包装要求，将相关病原和标本分为A、B两类，对应的联合国编号分别为UN2814（动物病毒为UN2900）和UN3373。
对于A类感染性物质，若表中未注明“仅限于病毒培养物”，则包括涉及该病毒的所有材料；对于注明“仅限于病毒培养物”的A类感染性物质，则病毒培养物按UN2814包装，其它标本按UN3373要求进行包装。
凡标明B类的病毒和相关样本均按UN3373的要求包装和空运。
通过其他交通工具运输的可参照以上标准进行包装。
g.猴痘病毒：未经培养的感染材料的操作在BSL-2实验室，个人防护应遵从国家卫生健康委的相关规定。
h.这里特指亚欧地区传播的蜱传脑炎、俄罗斯春夏脑炎和中欧型蜱传脑炎。
新检查机制(NIR)
附件1NEW INSPECTION REGIME新检查机制(NIR)1Ship Risk Profile2船舶风险属性2.1All ships in the information system of APCIS will be assigned either as high, standard or low risk based on generic and historic parameters.1.1依据类别和历史参数，港口国监督亚太地区计算机信息系统(以下简称APCIS)中的所有船舶可分为3类：高风险、标准风险和低风险。
1.2High Risk Ships (HRS) are ships which meet criteria to a total value of 4 or more weighting points.1.3高风险船舶是指满足对应标准，权重值之和大于或等于4的船舶。
1.4Low Risk Ships (LRS) are ships which meet all the criteria of the LRS parameters and have had at least one inspection in the previous 36 months.1.5低风险船舶是指满足所有的对应参数标准，并且在过去36个月中至少接受过一次检查的船舶。
1.6Standard Risk Ships (SRS) are ships which are neither LRS nor HRS.1.7除高风险及低风险之外的船舶为标准风险船舶。
表1船舶风险属性1) The Black, Grey and White list for flag State performance is established annually taking account of the inspection and detention history over the preceding three calendar years and is adopted by the Tokyo MOU Committee to publish in the Annual Report.1)船旗国绩效中的黑灰白名单是每年综合考虑其过去3个日历年度内检查和滞留的历史情况而得出的并将在东京备忘录委员会发布的年度报告中予以公示。
ICD-10疾病编码表
L02.412 L02.413 L02.451 L02.452 L02.453 L02.454 L02.455 L02.456 L02.801 L02.802 L02.803 L02.804 L02.851 L02.901 L02.902 L02.903 L02.904 L02.905 L02.906 L02.907 L03.001 L03.002 L03.003 L03.004 L03.005 L03.006 L03.007 L03.008 L03.051 L03.052 L03.053 L03.101 L03.102 L03.103 L03.104 L03.105 L03.106 L03.151 L03.152 L03.153 L03.154 L03.201 L03.202 L03.203 L03.301 L03.302 L03.304
足部痈 足脓肿 指脓肿 趾脓肿 踝部脓肿 髋部脓肿 肩脓肿 腋脓肿 帽状腱膜下脓肿 头部疖 头部皮肤脓肿 头部痈 头部脓肿 多发性疖肿 多发性脓肿 疖肿病(多发性疖肿病) 脓肿 皮肤疖肿 新生儿疖肿 痈 甲沟炎(瘭疽) 甲床炎 甲周炎 指蜂窝组织炎 指甲床炎 指甲沟脓肿 指甲沟炎 趾甲沟炎 瘭疽[化脓性指头炎] 指蜂窝织炎 趾蜂窝织炎 臂蜂窝织炎 髂窝脓肿 手蜂窝织炎 腿蜂窝织炎 腕蜂窝织炎 足蜂窝织炎 手掌间隙感染 膝蜂窝织炎 肩蜂窝织炎 急性臂淋巴管炎 颌部蜂窝织炎 颌下降区蜂窝织炎 面部蜂窝织炎 躯干部蜂窝组织炎 躯干部炎性肿物 臀蜂窝织炎
腹股沟感染 背蜂窝组织炎 胸壁蜂窝组织炎 颈部蜂窝组织炎 头部蜂窝织炎 蜂窝织炎 NOS 急性淋巴管炎 急性淋巴管炎伴脓肿或蜂窝织炎 急性蜂窝织炎 急性颌下淋巴结炎 急性颈淋巴结炎 急性面淋巴结炎 急性头部淋巴结炎 化脓性面部淋巴结炎 化脓性颈部淋巴结炎 急性躯干淋巴结炎 急性髋淋巴结炎 臂急性淋巴管炎 急性肩淋巴结炎 急性腋淋巴结炎 腿急性淋巴管炎 其他部位急性淋巴结炎 化脓性淋巴结炎 坏死性淋巴结炎 急性淋巴结炎 淋巴结坏死 皮肤病性淋巴结炎 亚急性坏死性淋巴结炎 急性淋巴结脓肿 急性淋巴结腺炎 急性化脓性淋巴结炎 先天性胸壁皮肤窦道伴脓肿 藏毛囊肿伴脓肿 藏毛囊肿 尾骨瘘 脓疱性细菌疹 脓疱性疹 脓皮病 化脓性皮炎 脓毒性皮炎 红癣 背部感染性窦道 腹壁感染性窦道 皮肤感染性窦道 增殖性脓皮病 脓疱疹 头面颈部皮肤感染
C.parvum全基因组序列
DOI: 10.1126/science.1094786, 441 (2004);304Science et al.Mitchell S. Abrahamsen,Cryptosporidium parvum Complete Genome Sequence of the Apicomplexan, (this information is current as of October 7, 2009 ):The following resources related to this article are available online at/cgi/content/full/304/5669/441version of this article at:including high-resolution figures, can be found in the online Updated information and services,/cgi/content/full/1094786/DC1 can be found at:Supporting Online Material/cgi/content/full/304/5669/441#otherarticles , 9 of which can be accessed for free: cites 25 articles This article 239 article(s) on the ISI Web of Science. cited by This article has been /cgi/content/full/304/5669/441#otherarticles 53 articles hosted by HighWire Press; see: cited by This article has been/cgi/collection/genetics Genetics: subject collections This article appears in the following/about/permissions.dtl in whole or in part can be found at: this article permission to reproduce of this article or about obtaining reprints Information about obtaining registered trademark of AAAS.is a Science 2004 by the American Association for the Advancement of Science; all rights reserved. The title Copyright American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the Science o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m3.R.Jackendoff,Foundations of Language:Brain,Gram-mar,Evolution(Oxford Univ.Press,Oxford,2003).4.Although for Frege(1),reference was established rela-tive to objects in the world,here we follow Jackendoff’s suggestion(3)that this is done relative to objects and the state of affairs as mentally represented.5.S.Zola-Morgan,L.R.Squire,in The Development andNeural Bases of Higher Cognitive Functions(New York Academy of Sciences,New York,1990),pp.434–456.6.N.Chomsky,Reflections on Language(Pantheon,New York,1975).7.J.Katz,Semantic Theory(Harper&Row,New York,1972).8.D.Sperber,D.Wilson,Relevance(Harvard Univ.Press,Cambridge,MA,1986).9.K.I.Forster,in Sentence Processing,W.E.Cooper,C.T.Walker,Eds.(Erlbaum,Hillsdale,NJ,1989),pp.27–85.10.H.H.Clark,Using Language(Cambridge Univ.Press,Cambridge,1996).11.Often word meanings can only be fully determined byinvokingworld knowledg e.For instance,the meaningof “flat”in a“flat road”implies the absence of holes.However,in the expression“aflat tire,”it indicates the presence of a hole.The meaningof“finish”in the phrase “Billfinished the book”implies that Bill completed readingthe book.However,the phrase“the g oatfin-ished the book”can only be interpreted as the goat eatingor destroyingthe book.The examples illustrate that word meaningis often underdetermined and nec-essarily intertwined with general world knowledge.In such cases,it is hard to see how the integration of lexical meaning and general world knowledge could be strictly separated(3,31).12.W.Marslen-Wilson,C.M.Brown,L.K.Tyler,Lang.Cognit.Process.3,1(1988).13.ERPs for30subjects were averaged time-locked to theonset of the critical words,with40items per condition.Sentences were presented word by word on the centerof a computer screen,with a stimulus onset asynchronyof600ms.While subjects were readingthe sentences,their EEG was recorded and amplified with a high-cut-off frequency of70Hz,a time constant of8s,and asamplingfrequency of200Hz.14.Materials and methods are available as supportingmaterial on Science Online.15.M.Kutas,S.A.Hillyard,Science207,203(1980).16.C.Brown,P.Hagoort,J.Cognit.Neurosci.5,34(1993).17.C.M.Brown,P.Hagoort,in Architectures and Mech-anisms for Language Processing,M.W.Crocker,M.Pickering,C.Clifton Jr.,Eds.(Cambridge Univ.Press,Cambridge,1999),pp.213–237.18.F.Varela et al.,Nature Rev.Neurosci.2,229(2001).19.We obtained TFRs of the single-trial EEG data by con-volvingcomplex Morlet wavelets with the EEG data andcomputingthe squared norm for the result of theconvolution.We used wavelets with a7-cycle width,with frequencies ranging from1to70Hz,in1-Hz steps.Power values thus obtained were expressed as a per-centage change relative to the power in a baselineinterval,which was taken from150to0ms before theonset of the critical word.This was done in order tonormalize for individual differences in EEG power anddifferences in baseline power between different fre-quency bands.Two relevant time-frequency compo-nents were identified:(i)a theta component,rangingfrom4to7Hz and from300to800ms after wordonset,and(ii)a gamma component,ranging from35to45Hz and from400to600ms after word onset.20.C.Tallon-Baudry,O.Bertrand,Trends Cognit.Sci.3,151(1999).tner et al.,Nature397,434(1999).22.M.Bastiaansen,P.Hagoort,Cortex39(2003).23.O.Jensen,C.D.Tesche,Eur.J.Neurosci.15,1395(2002).24.Whole brain T2*-weighted echo planar imaging bloodoxygen level–dependent(EPI-BOLD)fMRI data wereacquired with a Siemens Sonata1.5-T magnetic reso-nance scanner with interleaved slice ordering,a volumerepetition time of2.48s,an echo time of40ms,a90°flip angle,31horizontal slices,a64ϫ64slice matrix,and isotropic voxel size of3.5ϫ3.5ϫ3.5mm.For thestructural magnetic resonance image,we used a high-resolution(isotropic voxels of1mm3)T1-weightedmagnetization-prepared rapid gradient-echo pulse se-quence.The fMRI data were preprocessed and analyzedby statistical parametric mappingwith SPM99software(http://www.fi/spm99).25.S.E.Petersen et al.,Nature331,585(1988).26.B.T.Gold,R.L.Buckner,Neuron35,803(2002).27.E.Halgren et al.,J.Psychophysiol.88,1(1994).28.E.Halgren et al.,Neuroimage17,1101(2002).29.M.K.Tanenhaus et al.,Science268,1632(1995).30.J.J.A.van Berkum et al.,J.Cognit.Neurosci.11,657(1999).31.P.A.M.Seuren,Discourse Semantics(Basil Blackwell,Oxford,1985).32.We thank P.Indefrey,P.Fries,P.A.M.Seuren,and M.van Turennout for helpful discussions.Supported bythe Netherlands Organization for Scientific Research,grant no.400-56-384(P.H.).Supporting Online Material/cgi/content/full/1095455/DC1Materials and MethodsFig.S1References and Notes8January2004;accepted9March2004Published online18March2004;10.1126/science.1095455Include this information when citingthis paper.Complete Genome Sequence ofthe Apicomplexan,Cryptosporidium parvumMitchell S.Abrahamsen,1,2*†Thomas J.Templeton,3†Shinichiro Enomoto,1Juan E.Abrahante,1Guan Zhu,4 Cheryl ncto,1Mingqi Deng,1Chang Liu,1‡Giovanni Widmer,5Saul Tzipori,5GregoryA.Buck,6Ping Xu,6 Alan T.Bankier,7Paul H.Dear,7Bernard A.Konfortov,7 Helen F.Spriggs,7Lakshminarayan Iyer,8Vivek Anantharaman,8L.Aravind,8Vivek Kapur2,9The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals,and causes an unrelenting infection in immuno-compromised individuals such as AIDS patients.We report the complete ge-nome sequence of C.parvum,type II isolate.Genome analysis identifies ex-tremely streamlined metabolic pathways and a reliance on the host for nu-trients.In contrast to Plasmodium and Toxoplasma,the parasite lacks an api-coplast and its genome,and possesses a degenerate mitochondrion that has lost its genome.Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected.Elu-cidation of the core metabolism,including enzymes with high similarities to bacterial and plant counterparts,opens new avenues for drug development.Cryptosporidium parvum is a globally impor-tant intracellular pathogen of humans and animals.The duration of infection and patho-genesis of cryptosporidiosis depends on host immune status,ranging from a severe but self-limiting diarrhea in immunocompetent individuals to a life-threatening,prolonged infection in immunocompromised patients.Asubstantial degree of morbidity and mortalityis associated with infections in AIDS pa-tients.Despite intensive efforts over the past20years,there is currently no effective ther-apy for treating or preventing C.parvuminfection in humans.Cryptosporidium belongs to the phylumApicomplexa,whose members share a com-mon apical secretory apparatus mediating lo-comotion and tissue or cellular invasion.Many apicomplexans are of medical or vet-erinary importance,including Plasmodium,Babesia,Toxoplasma,Neosprora,Sarcocys-tis,Cyclospora,and Eimeria.The life cycle ofC.parvum is similar to that of other cyst-forming apicomplexans(e.g.,Eimeria and Tox-oplasma),resulting in the formation of oocysts1Department of Veterinary and Biomedical Science,College of Veterinary Medicine,2Biomedical Genom-ics Center,University of Minnesota,St.Paul,MN55108,USA.3Department of Microbiology and Immu-nology,Weill Medical College and Program in Immu-nology,Weill Graduate School of Medical Sciences ofCornell University,New York,NY10021,USA.4De-partment of Veterinary Pathobiology,College of Vet-erinary Medicine,Texas A&M University,College Sta-tion,TX77843,USA.5Division of Infectious Diseases,Tufts University School of Veterinary Medicine,NorthGrafton,MA01536,USA.6Center for the Study ofBiological Complexity and Department of Microbiol-ogy and Immunology,Virginia Commonwealth Uni-versity,Richmond,VA23198,USA.7MRC Laboratoryof Molecular Biology,Hills Road,Cambridge CB22QH,UK.8National Center for Biotechnology Infor-mation,National Library of Medicine,National Insti-tutes of Health,Bethesda,MD20894,USA.9Depart-ment of Microbiology,University of Minnesota,Min-neapolis,MN55455,USA.*To whom correspondence should be addressed.E-mail:abe@†These authors contributed equally to this work.‡Present address:Bioinformatics Division,Genetic Re-search,GlaxoSmithKline Pharmaceuticals,5MooreDrive,Research Triangle Park,NC27009,USA.R E P O R T S SCIENCE VOL30416APRIL2004441o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mthat are shed in the feces of infected hosts.C.parvum oocysts are highly resistant to environ-mental stresses,including chlorine treatment of community water supplies;hence,the parasite is an important water-and food-borne pathogen (1).The obligate intracellular nature of the par-asite ’s life cycle and the inability to culture the parasite continuously in vitro greatly impair researchers ’ability to obtain purified samples of the different developmental stages.The par-asite cannot be genetically manipulated,and transformation methodologies are currently un-available.To begin to address these limitations,we have obtained the complete C.parvum ge-nome sequence and its predicted protein com-plement.(This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the project accession AAEE00000000.The version described in this paper is the first version,AAEE01000000.)The random shotgun approach was used to obtain the complete DNA sequence (2)of the Iowa “type II ”isolate of C.parvum .This isolate readily transmits disease among numerous mammals,including humans.The resulting ge-nome sequence has roughly 13ϫgenome cov-erage containing five gaps and 9.1Mb of totalDNA sequence within eight chromosomes.The C.parvum genome is thus quite compact rela-tive to the 23-Mb,14-chromosome genome of Plasmodium falciparum (3);this size difference is predominantly the result of shorter intergenic regions,fewer introns,and a smaller number of genes (Table 1).Comparison of the assembled sequence of chromosome VI to that of the recently published sequence of chromosome VI (4)revealed that our assembly contains an ad-ditional 160kb of sequence and a single gap versus two,with the common sequences dis-playing a 99.993%sequence identity (2).The relative paucity of introns greatly simplified gene predictions and facilitated an-notation (2)of predicted open reading frames (ORFs).These analyses provided an estimate of 3807protein-encoding genes for the C.parvum genome,far fewer than the estimated 5300genes predicted for the Plasmodium genome (3).This difference is primarily due to the absence of an apicoplast and mitochondrial genome,as well as the pres-ence of fewer genes encoding metabolic functions and variant surface proteins,such as the P.falciparum var and rifin molecules (Table 2).An analysis of the encoded pro-tein sequences with the program SEG (5)shows that these protein-encoding genes are not enriched in low-complexity se-quences (34%)to the extent observed in the proteins from Plasmodium (70%).Our sequence analysis indicates that Cryptosporidium ,unlike Plasmodium and Toxoplasma ,lacks both mitochondrion and apicoplast genomes.The overall complete-ness of the genome sequence,together with the fact that similar DNA extraction proce-dures used to isolate total genomic DNA from C.parvum efficiently yielded mito-chondrion and apicoplast genomes from Ei-meria sp.and Toxoplasma (6,7),indicates that the absence of organellar genomes was unlikely to have been the result of method-ological error.These conclusions are con-sistent with the absence of nuclear genes for the DNA replication and translation machinery characteristic of mitochondria and apicoplasts,and with the lack of mito-chondrial or apicoplast targeting signals for tRNA synthetases.A number of putative mitochondrial pro-teins were identified,including components of a mitochondrial protein import apparatus,chaperones,uncoupling proteins,and solute translocators (table S1).However,the ge-nome does not encode any Krebs cycle en-zymes,nor the components constituting the mitochondrial complexes I to IV;this finding indicates that the parasite does not rely on complete oxidation and respiratory chains for synthesizing adenosine triphosphate (ATP).Similar to Plasmodium ,no orthologs for the ␥,␦,or εsubunits or the c subunit of the F 0proton channel were detected (whereas all subunits were found for a V-type ATPase).Cryptosporidium ,like Eimeria (8)and Plas-modium ,possesses a pyridine nucleotide tran-shydrogenase integral membrane protein that may couple reduced nicotinamide adenine dinucleotide (NADH)and reduced nico-tinamide adenine dinucleotide phosphate (NADPH)redox to proton translocation across the inner mitochondrial membrane.Unlike Plasmodium ,the parasite has two copies of the pyridine nucleotide transhydrogenase gene.Also present is a likely mitochondrial membrane –associated,cyanide-resistant alter-native oxidase (AOX )that catalyzes the reduction of molecular oxygen by ubiquinol to produce H 2O,but not superoxide or H 2O 2.Several genes were identified as involved in biogenesis of iron-sulfur [Fe-S]complexes with potential mitochondrial targeting signals (e.g.,nifS,nifU,frataxin,and ferredoxin),supporting the presence of a limited electron flux in the mitochondrial remnant (table S2).Our sequence analysis confirms the absence of a plastid genome (7)and,additionally,the loss of plastid-associated metabolic pathways including the type II fatty acid synthases (FASs)and isoprenoid synthetic enzymes thatTable 1.General features of the C.parvum genome and comparison with other single-celled eukaryotes.Values are derived from respective genome project summaries (3,26–28).ND,not determined.FeatureC.parvum P.falciparum S.pombe S.cerevisiae E.cuniculiSize (Mbp)9.122.912.512.5 2.5(G ϩC)content (%)3019.43638.347No.of genes 38075268492957701997Mean gene length (bp)excluding introns 1795228314261424ND Gene density (bp per gene)23824338252820881256Percent coding75.352.657.570.590Genes with introns (%)553.9435ND Intergenic regions (G ϩC)content %23.913.632.435.145Mean length (bp)5661694952515129RNAsNo.of tRNA genes 454317429944No.of 5S rRNA genes 6330100–2003No.of 5.8S ,18S ,and 28S rRNA units 57200–400100–20022Table parison between predicted C.parvum and P.falciparum proteins.FeatureC.parvum P.falciparum *Common †Total predicted proteins380752681883Mitochondrial targeted/encoded 17(0.45%)246(4.7%)15Apicoplast targeted/encoded 0581(11.0%)0var/rif/stevor ‡0236(4.5%)0Annotated as protease §50(1.3%)31(0.59%)27Annotated as transporter 69(1.8%)34(0.65%)34Assigned EC function ¶167(4.4%)389(7.4%)113Hypothetical proteins925(24.3%)3208(60.9%)126*Values indicated for P.falciparum are as reported (3)with the exception of those for proteins annotated as protease or transporter.†TBLASTN hits (e Ͻ–5)between C.parvum and P.falciparum .‡As reported in (3).§Pre-dicted proteins annotated as “protease or peptidase”for C.parvum (CryptoGenome database,)and P.falciparum (PlasmoDB database,).Predicted proteins annotated as “trans-porter,permease of P-type ATPase”for C.parvum (CryptoGenome)and P.falciparum (PlasmoDB).¶Bidirectional BLAST hit (e Ͻ–15)to orthologs with assigned Enzyme Commission (EC)numbers.Does not include EC assignment numbers for protein kinases or protein phosphatases (due to inconsistent annotation across genomes),or DNA polymerases or RNA polymerases,as a result of issues related to subunit inclusion.(For consistency,46proteins were excluded from the reported P.falciparum values.)R E P O R T S16APRIL 2004VOL 304SCIENCE 442 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o mare otherwise localized to the plastid in other apicomplexans.C.parvum fatty acid biosynthe-sis appears to be cytoplasmic,conducted by a large(8252amino acids)modular type I FAS (9)and possibly by another large enzyme that is related to the multidomain bacterial polyketide synthase(10).Comprehensive screening of the C.parvum genome sequence also did not detect orthologs of Plasmodium nuclear-encoded genes that contain apicoplast-targeting and transit sequences(11).C.parvum metabolism is greatly stream-lined relative to that of Plasmodium,and in certain ways it is reminiscent of that of another obligate eukaryotic parasite,the microsporidian Encephalitozoon.The degeneration of the mi-tochondrion and associated metabolic capabili-ties suggests that the parasite largely relies on glycolysis for energy production.The parasite is capable of uptake and catabolism of mono-sugars(e.g.,glucose and fructose)as well as synthesis,storage,and catabolism of polysac-charides such as trehalose and amylopectin. Like many anaerobic organisms,it economizes ATP through the use of pyrophosphate-dependent phosphofructokinases.The conver-sion of pyruvate to acetyl–coenzyme A(CoA) is catalyzed by an atypical pyruvate-NADPH oxidoreductase(Cp PNO)that contains an N-terminal pyruvate–ferredoxin oxidoreductase (PFO)domain fused with a C-terminal NADPH–cytochrome P450reductase domain (CPR).Such a PFO-CPR fusion has previously been observed only in the euglenozoan protist Euglena gracilis(12).Acetyl-CoA can be con-verted to malonyl-CoA,an important precursor for fatty acid and polyketide biosynthesis.Gly-colysis leads to several possible organic end products,including lactate,acetate,and ethanol. The production of acetate from acetyl-CoA may be economically beneficial to the parasite via coupling with ATP production.Ethanol is potentially produced via two in-dependent pathways:(i)from the combination of pyruvate decarboxylase and alcohol dehy-drogenase,or(ii)from acetyl-CoA by means of a bifunctional dehydrogenase(adhE)with ac-etaldehyde and alcohol dehydrogenase activi-ties;adhE first converts acetyl-CoA to acetal-dehyde and then reduces the latter to ethanol. AdhE predominantly occurs in bacteria but has recently been identified in several protozoans, including vertebrate gut parasites such as Enta-moeba and Giardia(13,14).Adjacent to the adhE gene resides a second gene encoding only the AdhE C-terminal Fe-dependent alcohol de-hydrogenase domain.This gene product may form a multisubunit complex with AdhE,or it may function as an alternative alcohol dehydro-genase that is specific to certain growth condi-tions.C.parvum has a glycerol3-phosphate dehydrogenase similar to those of plants,fungi, and the kinetoplastid Trypanosoma,but(unlike trypanosomes)the parasite lacks an ortholog of glycerol kinase and thus this pathway does not yield glycerol production.In addition to themodular fatty acid synthase(Cp FAS1)andpolyketide synthase homolog(Cp PKS1), C.parvum possesses several fatty acyl–CoA syn-thases and a fatty acyl elongase that may partici-pate in fatty acid metabolism.Further,enzymesfor the metabolism of complex lipids(e.g.,glyc-erolipid and inositol phosphate)were identified inthe genome.Fatty acids are apparently not anenergy source,because enzymes of the fatty acidoxidative pathway are absent,with the exceptionof a3-hydroxyacyl-CoA dehydrogenase.C.parvum purine metabolism is greatlysimplified,retaining only an adenosine ki-nase and enzymes catalyzing conversionsof adenosine5Ј-monophosphate(AMP)toinosine,xanthosine,and guanosine5Ј-monophosphates(IMP,XMP,and GMP).Among these enzymes,IMP dehydrogenase(IMPDH)is phylogenetically related toε-proteobacterial IMPDH and is strikinglydifferent from its counterparts in both thehost and other apicomplexans(15).In con-trast to other apicomplexans such as Toxo-plasma gondii and P.falciparum,no geneencoding hypoxanthine-xanthineguaninephosphoribosyltransferase(HXGPRT)is de-tected,in contrast to a previous report on theactivity of this enzyme in C.parvum sporo-zoites(16).The absence of HXGPRT sug-gests that the parasite may rely solely on asingle enzyme system including IMPDH toproduce GMP from AMP.In contrast to otherapicomplexans,the parasite appears to relyon adenosine for purine salvage,a modelsupported by the identification of an adeno-sine transporter.Unlike other apicomplexansand many parasitic protists that can synthe-size pyrimidines de novo,C.parvum relies onpyrimidine salvage and retains the ability forinterconversions among uridine and cytidine5Ј-monophosphates(UMP and CMP),theirdeoxy forms(dUMP and dCMP),and dAMP,as well as their corresponding di-and triphos-phonucleotides.The parasite has also largelyshed the ability to synthesize amino acids denovo,although it retains the ability to convertselect amino acids,and instead appears torely on amino acid uptake from the host bymeans of a set of at least11amino acidtransporters(table S2).Most of the Cryptosporidium core pro-cesses involved in DNA replication,repair,transcription,and translation conform to thebasic eukaryotic blueprint(2).The transcrip-tional apparatus resembles Plasmodium interms of basal transcription machinery.How-ever,a striking numerical difference is seenin the complements of two RNA bindingdomains,Sm and RRM,between P.falcipa-rum(17and71domains,respectively)and C.parvum(9and51domains).This reductionresults in part from the loss of conservedproteins belonging to the spliceosomal ma-chinery,including all genes encoding Smdomain proteins belonging to the U6spliceo-somal particle,which suggests that this par-ticle activity is degenerate or entirely lost.This reduction in spliceosomal machinery isconsistent with the reduced number of pre-dicted introns in Cryptosporidium(5%)rela-tive to Plasmodium(Ͼ50%).In addition,keycomponents of the small RNA–mediatedposttranscriptional gene silencing system aremissing,such as the RNA-dependent RNApolymerase,Argonaute,and Dicer orthologs;hence,RNA interference–related technolo-gies are unlikely to be of much value intargeted disruption of genes in C.parvum.Cryptosporidium invasion of columnarbrush border epithelial cells has been de-scribed as“intracellular,but extracytoplas-mic,”as the parasite resides on the surface ofthe intestinal epithelium but lies underneaththe host cell membrane.This niche may al-low the parasite to evade immune surveil-lance but take advantage of solute transportacross the host microvillus membrane or theextensively convoluted parasitophorous vac-uole.Indeed,Cryptosporidium has numerousgenes(table S2)encoding families of putativesugar transporters(up to9genes)and aminoacid transporters(11genes).This is in starkcontrast to Plasmodium,which has fewersugar transporters and only one putative ami-no acid transporter(GenBank identificationnumber23612372).As a first step toward identification ofmulti–drug-resistant pumps,the genome se-quence was analyzed for all occurrences ofgenes encoding multitransmembrane proteins.Notable are a set of four paralogous proteinsthat belong to the sbmA family(table S2)thatare involved in the transport of peptide antibi-otics in bacteria.A putative ortholog of thePlasmodium chloroquine resistance–linkedgene Pf CRT(17)was also identified,althoughthe parasite does not possess a food vacuole likethe one seen in Plasmodium.Unlike Plasmodium,C.parvum does notpossess extensive subtelomeric clusters of anti-genically variant proteins(exemplified by thelarge families of var and rif/stevor genes)thatare involved in immune evasion.In contrast,more than20genes were identified that encodemucin-like proteins(18,19)having hallmarksof extensive Thr or Ser stretches suggestive ofglycosylation and signal peptide sequences sug-gesting secretion(table S2).One notable exam-ple is an11,700–amino acid protein with anuninterrupted stretch of308Thr residues(cgd3_720).Although large families of secretedproteins analogous to the Plasmodium multi-gene families were not found,several smallermultigene clusters were observed that encodepredicted secreted proteins,with no detectablesimilarity to proteins from other organisms(Fig.1,A and B).Within this group,at leastfour distinct families appear to have emergedthrough gene expansions specific to the Cryp-R E P O R T S SCIENCE VOL30416APRIL2004443o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mtosporidium clade.These families —SKSR,MEDLE,WYLE,FGLN,and GGC —were named after well-conserved sequence motifs (table S2).Reverse transcription polymerase chain reaction (RT-PCR)expression analysis (20)of one cluster,a locus of seven adjacent CpLSP genes (Fig.1B),shows coexpression during the course of in vitro development (Fig.1C).An additional eight genes were identified that encode proteins having a periodic cysteine structure similar to the Cryptosporidium oocyst wall protein;these eight genes are similarly expressed during the onset of oocyst formation and likely participate in the formation of the coccidian rigid oocyst wall in both Cryptospo-ridium and Toxoplasma (21).Whereas the extracellular proteins described above are of apparent apicomplexan or lineage-specific in-vention,Cryptosporidium possesses many genesencodingsecretedproteinshavinglineage-specific multidomain architectures composed of animal-and bacterial-like extracellular adhe-sive domains (fig.S1).Lineage-specific expansions were ob-served for several proteases (table S2),in-cluding an aspartyl protease (six genes),a subtilisin-like protease,a cryptopain-like cys-teine protease (five genes),and a Plas-modium falcilysin-like (insulin degrading enzyme –like)protease (19genes).Nine of the Cryptosporidium falcilysin genes lack the Zn-chelating “HXXEH ”active site motif and are likely to be catalytically inactive copies that may have been reused for specific protein-protein interactions on the cell sur-face.In contrast to the Plasmodium falcilysin,the Cryptosporidium genes possess signal peptide sequences and are likely trafficked to a secretory pathway.The expansion of this family suggests either that the proteins have distinct cleavage specificities or that their diversity may be related to evasion of a host immune response.Completion of the C.parvum genome se-quence has highlighted the lack of conven-tional drug targets currently pursued for the control and treatment of other parasitic protists.On the basis of molecular and bio-chemical studies and drug screening of other apicomplexans,several putative Cryptospo-ridium metabolic pathways or enzymes have been erroneously proposed to be potential drug targets (22),including the apicoplast and its associated metabolic pathways,the shikimate pathway,the mannitol cycle,the electron transport chain,and HXGPRT.Nonetheless,complete genome sequence analysis identifies a number of classic and novel molecular candidates for drug explora-tion,including numerous plant-like and bacterial-like enzymes (tables S3and S4).Although the C.parvum genome lacks HXGPRT,a potent drug target in other api-complexans,it has only the single pathway dependent on IMPDH to convert AMP to GMP.The bacterial-type IMPDH may be a promising target because it differs substan-tially from that of eukaryotic enzymes (15).Because of the lack of de novo biosynthetic capacity for purines,pyrimidines,and amino acids,C.parvum relies solely on scavenge from the host via a series of transporters,which may be exploited for chemotherapy.C.parvum possesses a bacterial-type thymidine kinase,and the role of this enzyme in pyrim-idine metabolism and its drug target candida-cy should be pursued.The presence of an alternative oxidase,likely targeted to the remnant mitochondrion,gives promise to the study of salicylhydroxamic acid (SHAM),as-cofuranone,and their analogs as inhibitors of energy metabolism in the parasite (23).Cryptosporidium possesses at least 15“plant-like ”enzymes that are either absent in or highly divergent from those typically found in mammals (table S3).Within the glycolytic pathway,the plant-like PPi-PFK has been shown to be a potential target in other parasites including T.gondii ,and PEPCL and PGI ap-pear to be plant-type enzymes in C.parvum .Another example is a trehalose-6-phosphate synthase/phosphatase catalyzing trehalose bio-synthesis from glucose-6-phosphate and uridine diphosphate –glucose.Trehalose may serve as a sugar storage source or may function as an antidesiccant,antioxidant,or protein stability agent in oocysts,playing a role similar to that of mannitol in Eimeria oocysts (24).Orthologs of putative Eimeria mannitol synthesis enzymes were not found.However,two oxidoreductases (table S2)were identified in C.parvum ,one of which belongs to the same families as the plant mannose dehydrogenases (25)and the other to the plant cinnamyl alcohol dehydrogenases.In principle,these enzymes could synthesize protective polyol compounds,and the former enzyme could use host-derived mannose to syn-thesize mannitol.References and Notes1.D.G.Korich et al .,Appl.Environ.Microbiol.56,1423(1990).2.See supportingdata on Science Online.3.M.J.Gardner et al .,Nature 419,498(2002).4.A.T.Bankier et al .,Genome Res.13,1787(2003).5.J.C.Wootton,Comput.Chem.18,269(1994).Fig.1.(A )Schematic showing the chromosomal locations of clusters of potentially secreted proteins.Numbers of adjacent genes are indicated in paren-theses.Arrows indicate direc-tion of clusters containinguni-directional genes (encoded on the same strand);squares indi-cate clusters containingg enes encoded on both strands.Non-paralogous genes are indicated by solid gray squares or direc-tional triangles;SKSR (green triangles),FGLN (red trian-gles),and MEDLE (blue trian-gles)indicate three C.parvum –specific families of paralogous genes predominantly located at telomeres.Insl (yellow tri-angles)indicates an insulinase/falcilysin-like paralogous gene family.Cp LSP (white square)indicates the location of a clus-ter of adjacent large secreted proteins (table S2)that are cotranscriptionally regulated.Identified anchored telomeric repeat sequences are indicated by circles.(B )Schematic show-inga select locus containinga cluster of coexpressed large secreted proteins (Cp LSP).Genes and intergenic regions (regions between identified genes)are drawn to scale at the nucleotide level.The length of the intergenic re-gions is indicated above or be-low the locus.(C )Relative ex-pression levels of CpLSP (red lines)and,as a control,C.parvum Hedgehog-type HINT domain gene (blue line)duringin vitro development,as determined by semiquantitative RT-PCR usingg ene-specific primers correspondingto the seven adjacent g enes within the CpLSP locus as shown in (B).Expression levels from three independent time-course experiments are represented as the ratio of the expression of each gene to that of C.parvum 18S rRNA present in each of the infected samples (20).R E P O R T S16APRIL 2004VOL 304SCIENCE 444 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m。
原发性免疫缺陷病概述
(primary immunodeficiency disease，PIDD)
1. 原发性体液免疫缺陷病
1）先天性低（无）丙种球蛋白血症 2）选择性IgA缺陷病 3）高 IgM综合征
2. 原发性T细胞缺陷病：先天性胸腺发育不良 3. 原发性联合免疫缺陷病
1）性联严重联合免疫缺陷病 2）MHC-Ⅱ类分子表达缺陷病 3）伴有酶缺陷的联合免疫缺陷病
治疗：骨髓移植
有酶缺陷的重症联合免疫缺陷
病因：1）腺苷脱氨酶（ADA）基因（20号染色体q13）突变或缺 失。ADA活性缺陷，2，－脱氧腺苷、S－腺苷同型半胱 氨酸和脱氧ATP在细胞中堆积，对淋巴细胞产生毒性作 用
2）嘌呤核苷磷酸化酶（PNP）基因（14号染色体q13-1）突 变或缺失，PNP活性缺陷，导致脱氧鸟苷增多，对淋巴 细胞产生毒性作用 遗传特点：常染色体隐性遗传
低或正常。但抗体产生水平降低。T细胞增殖反应、 混合淋巴细胞反应低下或缺如淋巴结T细胞区细胞 稀少，生发中心不发育，O.T.试验阴性 临床表现：反复发生病毒、真菌、胞内寄生菌感染，常伴出生 后24小时内手足抽搐，心血管及面部器官畸形。不 慎接种减毒活疫苗可造成播散性感染而死亡。 预后：严重者一般在5岁前死亡；较轻的发育不良者可逐步发育 改善，或出现胸腺组织在异位发育而改善 治疗：完全缺如者需试行胸腺或骨髓移植治疗。
赤裸淋巴综合症（BLS）――MHC-Ⅱ类分子表达缺
陷病
病因：编码MHC-Ⅱ类基因转录因子的亚单位的RFX5基因突变 MHC-Ⅱ类基因反式激活因子（CⅡTA）基因突变导致
MHC-Ⅱ类基因表达调控异常，转录障碍，无MHC-Ⅱ类 基因的mRNA表达，细胞上不表达MHC-Ⅱ类分子但MHC-Ⅱ
类基因完好 遗传特点：常染色体隐性遗传 临床表现： 对各种病原体易感，如无有效治疗常在1岁内死亡
ICD编码——免疫、血液
D76.052 D76.051 D76.007 D76.006 D76.005 D76.004 D76.003 D76.002 D76.001 D75.903 D75.902 D75.901 D75.851 D75.808 D75.807 D75.806 D75.805 D75.804 D75.803 D75.802 D75.801 D75.251 D75.201 D75.160 D75.159 D75.158 D75.157 D75.156 D75.155 D75.154 D75.153 D75.152 D75.151 D75.102 D75.101 D75.051 D75.001 D74.901 D74.852 D74.851 D74.053 D74.052 D74.051 D74.001 D73.951
疾病名称 性别限制 疗效限制 免疫疾病 NOS 无 无 POEMS综合征 无 无 其他特指的免疫机制疾患，NEC 无 无 高丙球蛋白血症 NOS 无 无 高丙种球蛋白血症 无 无 继发性冷球蛋白血症 无 无 原发性冷球蛋白血症 无 无 混合性冷球蛋白血症 无 无 特发性冷球蛋白血症 无 无 自发性冷球蛋白血症 无 无 冷球蛋白血症血管炎 无 无 冷球蛋白血症性紫癜 无 无 冷球蛋白血症 无 无 高丙球蛋白血症性(良性)紫癜[瓦尔登斯特 伦] 无 无 多克隆丙球蛋白病 无 无 高球蛋白血症性紫癜 无 无 多克隆高丙种球蛋白血症 无 无 伯克结节病 无 无 结节病 NOS 无 无 结节病中的肌炎 无 无 结节病中的关节病 无 无 结节病中的心肌炎 无 无 结节病中的虹膜睫状体炎 无 无 结节病中的多发性颅神经麻痹 无 无 眼色素层腮腺炎[黑福特病] 无 无 皮肤结节病 无 无 达里耶－鲁西结节病 无 无 肺结核病伴淋巴结结节病 无 无 淋巴结结节病 无 无 良性淋巴肉芽肿 无 无 肺结节病 无 无 免疫缺陷病 NOS 无 无 其他特指的免疫缺陷 无 无 补体1酯酶抑制剂缺乏[C-INH] 无 无 遗传性血管神经性水肿 无 无 补体成分缺乏 无 无 淋巴细胞机能抗原-1[LFA-1]缺陷 无 无 普通易变型免疫缺陷 NOS 无 无 其他普通易变型免疫缺陷 无 无 普通易变型免疫缺陷，伴有对Ｂ或Ｔ细胞 的自身抗体 无 无 普通易变型免疫缺陷，伴有显著的免疫调 节和T细胞疾患 无 无 普通易变型免疫缺陷，伴有显著的Ｂ细胞 数量和功能异常 无 无 严重缺陷有关的免疫缺陷 NOS 无 无
WHO药品不良反应术语集累及的系统_器官代码检索 9
2019年国家医保谈判准入药品名单-西药部分
甲
48 联苯双酯
口服常释剂型
甲 ★（48） 联苯双酯
滴丸剂
乙
49 促肝细胞生长素
注射剂
乙
50 多烯磷脂酰胆碱
口服常释剂型
乙 ★（50） 多烯磷脂酰胆碱
注射剂
乙
51 复方甘草甜素（复方甘草酸苷） 口服常释剂型
乙 ★（51） 复方甘草甜素（复方甘草酸苷） 注射剂
乙
52 甘草酸二铵
口服常释剂型
乙 ★（52） 甘草酸二铵
口服常释剂型 口服常释剂型 注射剂 口服常释剂型 注射剂 口服常释剂型
备注
限有说明书标明的疾病诊断且有禁食医嘱或吞咽困难的患者 限有十二指肠溃疡、反流性食管炎诊断患者的二线用药 限有说明书标明的疾病诊断且有禁食医嘱或吞咽困难的患者
8
药品分类代码 XA02BX XA03 XA03A
XA03B
XA03F
注射剂 注射剂 注射剂 注射剂
注射剂 注射剂 注射剂
注射剂
甲
110 精蛋白生物合成人胰岛素(预混 注射剂
50R)
精蛋白重组人胰岛素(预混
甲
111 30/70)
注射剂
精蛋白重组人胰岛素混合
甲
112
注射剂
(30/70)
备注
限1型糖尿病患者；限其他短效胰岛素或口服药难以控制的2 型糖尿病患者 限1型糖尿病患者；限其他短效胰岛素或口服药难以控制的2 型糖尿病患者 限1型糖尿病患者；限其他短效胰岛素或口服药难以控制的2 型糖尿病患者 限1型糖尿病患者；限其他短效胰岛素或口服药难以控制的2 型糖尿病患者
药品分类
编号
药品名称
乙 ★（18） 兰索拉唑
乙
19 雷贝拉唑
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1 List of Paris MoU deficiency 01 Certificates & Documentation、02 - Structural condition、03 - Water/Weathertight condition 、04 - Emergency Systems 、05 - Radio communication、06 - Cargo operations including equipment 、07 - Fire safety 、08 – Alarms 、09 - Working and Living Conditions、10 - Safety of Navigation 、11 - Life saving appliances 、12 - Dangerous Goods 、13 - Propulsion and auxiliary machinery、14 - Pollution Prevention 、15 – ISM 、16 - ISPS 、17 – Other、18 - MLC, 2006 Minimum requirements to work on a ship 、
THETIS Code Defective item 01 Certificates & Documentation 011 - Certificates & Documentation - Ship Certificate 01101 Cargo ship safety equipment (including exemption) 01102 Cargo ship safety construction (including exempt.) 01103 Passenger ship safety (including exemption) 01104 Cargo ship safety radio (including exemption) 01105 Cargo ship safety (including exemption) 01106 Document of compliance (DoC/ ISM) 01107 Safety management certificate (SMC/ ISM) 01108 Load lines (including Exemption) 01109 Decision-support system for masters on pass. ships 01110 Authorization for grain carriage 01111 Liquefied gases in bulk (CoF/GC Code) 01112 Liquefied gases in bulk (ICoF/IGC Code) 01113 Minimum safe manning document 01114 Dangerous chemicals in bulk (CoF/BCH Code) 01115 Dangerous chemicals in bulk (ICoF/IBC Code) 01116 Operational limitations for passenger ships 01117 Internation Oil Pollution Prevention (IOPP) 01118 Pollution prevention by noxious liquid sub in bulk 01119 International sewage pollution prevention Cert. 01120 Statement of Compliance CAS 01121 Interim Statement of Compliance CAS 01122 International ship security certificate 01123 Continuous synopsis record 01124 International Air Pollution Prevention Cert 01125 Engine International Air Pollution Prevention Cert 01126 Document of compliance dangerous goods 01127 Special purpose ship safety 01128 High speed craft safety and permit to operate 01129 Mobile offshore drilling unit safety 01130 INF certificate of fitness 01131 International AFS certificate *) 01132 Tonnage certificate 01133 Civil liability for oil pollution damage cert. 01134 Other (certificates) 01135 Document for carriage of dangerous goods 01136 Ballast Water Management Certificate 01137 Civil liability for Bunker oil pollution damage cert 01138 International Energy Efficiency Cert 2
01139 Maritime Labour Certificate 01140 Declaration of Maritime Labour Compliance (Part I and II)
012 - Certificates & Documentation - Crew Certificate 01201 Certificates for master and officers 01202 Certificate for rating for watchkeeping 01203 Certificates for radio personnel 01204 Certificate for personnel on tankers 01205 Certificate for personnel on fast rescue boats 01206 Certificate for advanced fire-fighting 01209 Manning specified by the minimum safe manning doc 01210 Certificate for medical first aid 01211 Cert for personnel on survival craft & rescue boat 01212 Certificate for medical care 01213 Evidence of basic training 01214 Endorsement by flagstate 01215 Application for Endorsement by flagstate 01217 Ship Security Officer certificate 01218 Medical certificate 01219 Training and qualification MLC - Personnel safety training 01220 Seafarer’ employment agreement SEA 01221 Record of employment 01222 Doc evidence for personnel on passenger ships 01223 Security awareness training
013 - Certificates and Documentation – Document 01301 Cargo gear record book 01302 SAR co-operation plan for pass.ships trad on fixe 01303 Unattended machinery spaces (UMS) evidence 01304 Declaration of AFS compliance 01305 Log-books/compulsory entries 01306 Shipboard working arrangements 01307 Maximum hours of work or the minimum hours of rest 01308 Records of seafarers' daily hours of work or rest 01309 Fire control plan – all 01310 Signs, indications 01311 Survey report file 01312 Thickness measurement report 01313 Booklet for bulk cargo loading/unloading/stowage 01314 Shipboard oil pollution emergency plan (SOPEP) 01315 Oil record book 01316 Cargo information 01317 Cargo record book 01318 P & A manual 01319 Shipbpard mar. poll. Emercency plan (MPEP) for NLS 01320 Garbage record book 01322 Conformance Test Report 01323 Fire safety operational booklet