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马凡氏综合征和癫痫马凡氏综合征和癫痫引言马凡氏综合征（MFS）和癫痫都是神经系统疾病，对患者的身体和心理健康造成了严重的影响。
马凡氏综合征是一种罕见的先天性疾病，主要表现为四肢骨骼畸形和智力障碍。
而癫痫则是一种常见的神经系统疾病，病人会出现反复发作的癫痫发作。
本文旨在通过对马凡氏综合征和癫痫这两种疾病的描述和讨论，阐述它们的病因、症状、诊断和治疗等方面的知识，以便于大家更好地了解这两种疾病，并为患者和医务工作者提供一些相关的参考。
一、马凡氏综合征1.1 病因马凡氏综合征是由于胚胎期神经调节基因的突变而引起的一种罕见的遗传疾病。
马凡氏综合征主要与第11号染色体长臂上FBN1基因的突变有关。
FBN1基因编码纤维联结蛋白，这是一种重要的结构蛋白，参与了胶原纤维的形成和结构维持。
突变导致纤维联结蛋白的异常合成，进而影响了胶原纤维的结构和功能，导致马凡氏综合征的发生。
1.2 症状马凡氏综合征的主要症状包括四肢骨骼畸形和智力障碍。
四肢骨骼畸形表现为长而瘦的四肢，关节过度灵活，手指和脚趾长而细。
智力障碍的程度因个体而异，从轻度认知障碍到智力残疾不等。
此外，患者还可能出现其他伴随症状，如马鞍鼻、眼球突出、上颌发育不良等。
1.3 诊断和治疗马凡氏综合征的诊断主要依靠临床症状和家族史，并通过基因检测来确认疾病的遗传性。
对于马凡氏综合征患者，治疗主要是针对其症状进行辅助治疗，并提供康复服务，以改善患者的生活质量。
比如，对于智力障碍的患者，可以提供特殊教育措施，帮助他们开发和发展其潜能。
二、癫痫2.1 病因癫痫的病因很复杂，主要包括遗传因素、大脑结构异常、代谢性因素、免疫因素、感染和外伤等。
遗传因素在癫痫的发病中起着重要的作用。
家族史是癫痫的一项重要风险因素，研究表明，有癫痫家族史的人患病的风险要比一般人群高。
2.2 症状癫痫的主要特征是反复发作的癫痫发作，发作时病人会出现意识丧失、肢体抽搐、口吐白沫等症状。
癫痫的发作形式多种多样，可以是全身性的大发作，也可以是局灶性的小发作。
临床军医杂志 2020 年6 月第48 卷第6 期 Clin JMedOffic,Vol.48,IVo.6,Jun，2020• 691 ••论著-人附睾蛋白4、糖类抗原125、増强M R I单独及联合 检查对子宫内膜癌深肌层浸润诊断价值研究王安娜\兰雪玲2,龙再秋1辽宁省肿瘤医院1.妇科;2.检验科，辽宁沈阳110042[摘要]目的探讨人附睾蛋白（HE)4、糖类抗原（C A)125、增强MR1单独及联合检查对子宫内膜癌深肌层浸润的诊断价 值。
方法将辽宁省肿瘤医院自2016年6月1日至2019年12月1日收治的230例子宫内膜癌患者纳人B组，将同期健康 体检者124例纳人A组。
比较两组研究对象CA125、HE4表达水平及不同方法诊断子宫内膜癌深肌层浸润的效能，分析 CA125、HE4表达水平及肌层浸润情况与子宫内膜癌临床病理特征的关系。
结果A组CA125、HE4分别为12.7(9.0, 17.3)11/1111、38.9(31.8,44.0)?111〇1/1^均低于8组的22.7(丨3.2,39.9).11/1〇1、61.2(42.4，107.8)?111〇1/[,差异有统计学意义 (P<0. 05)。
CA125、HE4表达水平与累及卵巢、分期、肌层浸润、淋巴结转移相关（P<0. 05)。
根据深肌层浸润绘制CA125、HE4的受试者工作特征（R O C)曲线，HE4的cutoff为62.40 pm〇l/L，CA125的c u t o f f为57.55 U/ml。
深肌层浸润与淋巴结转 移、分化、H E4&62.40 p m〇l/L、C A125 3=57.55 U/m l相关（P<0.05)。
多因素L o g i s t i c回归分析中，淋巴结转移、分化、H E4身62.40 P m〇l/L、C A125>57.55 U/m l是影响深肌层浸润的独立危险因素（P<0.05)。
系统性硬化症遗传学研究进展*濮伟霖**郭士成 王久存***（复旦大学生命科学学院 上海 200438）摘 要系统性硬化症又称为硬皮病，是一种复杂的自身免疫性疾病，目前对于该疾病的病因了解尚不清晰。
多项研究显示，遗传因素在硬皮病的发病过程中起重要作用。
因此对于硬皮病遗传因素的探索有助于我们发现硬皮病发病的相关通路和分子机制。
本文介绍并综述了硬皮病截止目前的遗传学相关研究的前沿进展。
关键词 硬皮病 遗传 全基因组关联研究（GWAS）中图分类号：R593.25文献标识码：A 文章编号：1006-1533(2017)S1-0030-07The review of the advancement of SSc genetic studies*PU Weilin**, GUO Shicheng, WANG Jiucun***(Department of Life Sciences, Fudan University, Shanghai 200438, China)ABSTRACT Systemic sclerosis is a kind of complex autoimmune diseases with different manifestations. The pathogenesis of SSc is still unknown. Multiple studies have revealed the important role of genetic factors in the pathogenesis of SSc. As a result, the exploration of the genetic factors of SSc will be of great benefit to the discovery of the associated pathways and mechanisms of SSc pathogenesis. This paper summarizes the advances and leading edge of the SSc genetic studies till now.KEY WORDS Scleroderma; Genetics; genome-wide association study (GWAS)系统性硬化症（systemic sclerosis，SSc，又称硬皮病）是不明病因的复杂性自身免疫性疾病。
Why Your DNA Isn't Your Destiny DNA不是一切（中英对照）By John Cloud, TIME magazine Wednesday, Jan. 06, 2010中文翻译：Quintessence [/blog/QuintEssence/]瑞典北方，遥远而辽阔的冰天雪地中，似乎不会是顶尖遗传科学的发轫地。
瑞典国境最北的北博滕省（Norrbotten）寥无人烟，平均每平方公里只有两个人。
然而，透过这一小撮人，我们却能更加认识基因在日常生活中的作用。
The remote, snow-swept expanses of northern Sweden are an unlikely place to begin a story about cutting-edge genetic science. The kingdom's northernmost county, Norrbotten, is nearly free of human life; an average of just six people live in each square mile. And yet this tiny population can reveal a lot about how genes work in our everyday lives.十九世纪的北博滕省对外交通不便，因此若当地收成欠佳，居民只好挨饿。
由于难以事先预测荒年，使得情况更加严峻。
比如说，1800、1812、1821、1836、1856年灾情惨重；但是1801、1822、1828、1844、1863年却是五个大丰年，使得之前挨饿的居民忽然能够暴饮暴食好几个月。
Norrbotten is so isolated that in the 19th century, if the harvest was bad, people starved. The starving years were all the crueler for their unpredictability. For instance, 1800, 1812, 1821, 1836 and 1856 were years of total crop failure and extreme suffering. But in 1801, 1822, 1828, 1844 and 1863, the land spilled forth such abundance that the same people who had gone hungry in previous winters were able to gorge themselves for months.白葛恩（Lars Olov Bygren）博士是一名预防医学家，目前任职于斯德哥尔摩声望卓著的卡洛林斯卡医学研究院（Karolinska Institute）。
J Apoplexy and Nervous Diseases, July 2024, Vol 41，No. 7偏头痛发病机制及生物标志物研究进展毛西京， 朱博驰综述， 于挺敏审校摘要： 偏头痛是一种具有多种亚表型的异质性疾病，其诊断主要基于临床标准，缺乏特异性的生物标志物进行客观评估，影响了偏头痛的精确诊断、治疗选择以及预后评估。
近年来偏头痛在遗传、生化、影像等方面研究取得重大进展，为临床诊断及治疗偏头痛提供了客观的检测指标。
如能在临床工作中选择特异性、敏感性、易检测、可行性高的标志物将推动偏头痛早期诊断、精准化治疗的步伐。
关键词： 偏头痛； 生物标志物； 神经元； 胶质细胞中图分类号：R747.2 文献标识码：A Research advances in the pathogenesis and biomarkers of migraine MAO Xijing ，ZHU Bochi ，YU Tingmin. （The Sec⁃ond Hospital of Jilin University ， Changchun 130000， China ）Abstract ： Migraine is a heterogeneous disease with various subtypes ， and the diagnosis of migraine mainly relies on clinical criteria. The lack of specific biomarkers for objective assessment impacts the precise diagnosis ， treatment selec⁃tion ， and prognostic assessment of migraine. In recent years ， great progress has been made in migraine in terms of genet⁃ics ， biochemistry ，and imaging ， which provides objective indicators for the clinical diagnosis and treatment of migraine. Identifying specific ，sensitive ，easily detectable ，and highly feasible markers in clinical practice will accelerate the early di⁃agnosis and precise treatment of migraine.Key words ： Migraine ； Biomarkers ； Neurons ； Glial cells偏头痛的发病机制尚不完全明确，越来越多的研究发现神经元-神经胶质细胞-血管交互作用的炎性病理生理过程参与其中，并且从血液、脑脊液、唾液、影像检查中均发现了有意义的标志物，这些标志物成为偏头痛诊疗的潜在靶点。
世界卫生组织关于脑膜炎球菌疫苗的立场文件（2011年11月）依据为各成员国提供卫生政策方面指导意见这一职责，世界卫生组织（WHO）就预防具有全球公共卫生影响的疾病的疫苗及联合疫苗问题，发布一系列定期更新的立场文件。
这些文件着重关注疫苗在大规模免疫规划中的使用，归纳了各相关疾病与疫苗的基本背景信息，并就如何在全世界范围内使用这些疫苗表明了世卫组织目前的立场。
这些文件经外部专家和世卫组织工作人员审阅，并由世卫组织的免疫战略咨询专家组（SAGE）（http://www.who.int/immunization/sage/en/）审核和认可。
这些立场文件主要供各国的公共卫生官员和免疫规划管理人员使用。
对这些立场文件感兴趣的还可能包括一些国际资助机构、疫苗制造厂家、医学界、科学媒体和公众。
本文件反映了脑膜炎球菌疫苗领域的最新进展,为各国在国家免疫接种计划中引进和使用脑膜炎球菌疫苗提供了指导意见。
本文件用于取代2002年10月《疫情周报》公布的关于脑膜炎球菌疫苗的立场文件。
SAGE在2011年4月召开会议，讨论了关于脑膜炎球菌疫苗使用的建议。
该会议提出的证据可参见：http://www.who.int/immunization/sage/previous/en/index.html。
本文件的脚注仅提供了部分核心参考文献。
参考文献清单可从以下网址获取：http://www.who.int/immunization/documents/positionpapers/en/index.html。
通过上述链接及本文的参考文献也可获取分级表，利用这些分级表可以评估支持重要建议的科学证据的质量。
引言流行病学在大多数国家，脑膜炎奈瑟菌（Neisseria meningitidis，脑膜炎双球菌）都已被确认为导致脑膜炎和爆发性败血症的首要原因，并且已构成严重的公共卫生问题。
然而，许多国家（尤其是亚洲国家）的监测数据不完整或缺乏，当前尚无关于本病的全球负担估计。
[10]Wang J,Liu ZY ,Ding HS,et al.Correlation between small and denselow density lipoprotein,lipoprotein-associated phospholipase A2and cathepsin S levels and carotid atherosclerosis in patients with coro-nary atherosclerotic heart disease [J].China Industrial Economics,2020,28(6):572-575.王娟,刘志云,丁宏胜,等.冠状动脉粥样硬化性心脏病患者小而密低密度脂蛋白、脂蛋白相关磷脂酶A2和组织蛋白酶S 水平与颈动脉粥样硬化的相关性[J].中华高血压杂志,2020,28(6):572-575.[11]Wu M,Zhong JH,Lin DH,et al.Correlation between serum cathep-sin S level and severity of coronary heart disease in elderly patients [J].Chinese Journal of Geriatrics,2019,38(6):605-608.吴淼,钟江华,林德洪,等.血清cathepsin S 与老年人冠心病严重程度的相关性[J].中华老年医学杂志,2019,38(6):605-608.[12]Li Z,Shao ML,Hu L,et al.Serum MMP -2and MMP -9levels in pa-tients with chronic heart failure and their significance [J].Chinese and Foreign Medical Research,2018,16(29):54-55.李镇,邵名亮,胡龙,等.慢性心力衰竭患者血清MMP -2、9水平及意义[J].中外医学研究,2018,16(29):54-55.[13]Yan T,Li G,Zhong L.Expression and significance of platelet-reac-tive protein -1and cathepsin S in patients with coronary atherosclerot-ic heart disease complicated with heart failure [J].Zhejiang Practical Medicine,2020,25(3):165-166,170.严婷,李刚,钟雷.血小板反应蛋白-1、组织蛋白酶S 在冠状动脉粥样硬化性心脏病并发心力衰竭患者中的表达及意义[J].浙江实用医学,2020,25(3):165-166,170.[14]Hong QC,Fang YT,Liu PX.Study on the relationship between se-rum heat shock protein and oxidative damage index and disease se-verity in patients with chronic heart failure [J].Prevention and Treat-ment of Cardiovascular Disease,2021,10(14):12-14.洪清楚,方跃亭,柳鹏翔.血清热休克蛋白及氧化损伤指标与慢性心力衰竭患者疾病严重程度的关系探究[J].心血管病防治知识,2021,10(14):12-14.[15]Xiang Y ,Zhang Z,Xie C,et al.Serum cat S,TSP -1,IL -11,BNP andsST2diagnostic and prognostic value in chronic heart failure [J].Al-tern Ther Health Med,2022,28(4):55-59.(收稿日期：2022-08-17)宫颈癌患者血清HE4、CEACAM6、AFP 表达水平及其与临床病理特征的相关性何涯丽，王玉，薛小芳，李森森，崔娟南阳南石医院妇产科，河南南阳473000【摘要】目的探究宫颈癌患者血清人附睾蛋白4(HE4)、癌胚抗原相关细胞黏附分子6(CEACAM6)、甲胎蛋白(AFP)表达水平及其与临床病理特征的相关性。
人体寄生虫学英语单词Parasitology 寄生虫学Fasiolopsis buski布氏姜片吸虫Parasite 寄生虫Paragonimus westermani卫氏并殖吸虫Parasitosis 寄生虫病Schistosomajaponicum日本血吸虫lifecycle 生活史schistosomiasis 血吸虫病host 宿主Oneomelania 钉螺definitiveorfinalhost 终宿主cestode(Class Cestoda) 绦虫intermediatehost 中间宿主Taenia solium 链状带绦虫reserviorhost 储蓄宿主Taenia saginata肥胖带绦虫paratenichost 转续宿主Cystieercus 囊尾蚴infectivestage 感染期cysticercosis 囊虫病epidemiology 流行病学Echinococcusgranulosus细粒棘球绦虫pathogenesis 致病机理hydatidcyst 棘球蚴concomitantimmunity 伴随免疫Protczca 原生动物亚界premunition 带虫免疫Entamoeba histolytica溶组织内阿米巴carrier 带虫者trophozoite 滋养体ectopicparasitism 异位寄生cyst 包囊helminth 蠕虫opportunisticprotozoan 机会致病原虫nematode(Class Nematoda) 线虫(纲) malaria 疟疾Ascaris lumbricoides似蚓蛔线虫Plasmodium vivax间日疟原虫adultworm 成虫ringform 环形滋养体ovum(p1．ova) 卵细胞sporozoite 子孢子directsmear 直接涂片法relapse 复发Trichuris trichiura毛首鞭形线虫recrudescence 再燃hookworm 钩虫flagellate 鞭毛虫．Ancylostoma duodonale十二指肠钩口线虫Leishmania donovani 杜氏利什曼原虫Necator americanus美洲板口线虫Kala-azar 黑热病larve(p1．1arvae) 幼虫leishimaniasis 利什曼病brinefloration 盐水浮集法Trichimonus vaginalis阴道毛滴虫Trichinella spiralis 旋毛形线虫Giadia lamblia蓝氏贾第鞭毛虫filariasis 丝虫病Toxoplasma gondii刚地弓形虫microfilaria 微丝蚴Pneumocystis carinii 卡氏肺孢子虫Wuchereria bancrofti 班氏吴策线虫tachymite 速殖于Brugia malayi马来布鲁线虫bradyzoite 缓殖子noctunalperiodicity 夜现周期性PhylumArthropoda 节肢动物门Enterobius vermicularis蠕形住肠线虫insect 昆虫trematodeematoda) 吸虫(钢) vector 媒介sucker 吸盘metamorphosis 变态oralsucker 口吸盘entomology 昆虫学ventralsucker 腹吸盘tick 蜱miracidum 毛蚴mosquito 蚊cercaria 尾蚴metacercaria 后尾蚴、囊蚴Clonorchis sinensis 华枝睾吸虫。
In 1948, Mandel and Métais 1 described the presence of cell-free nucleic acid (cfNA) in human blood for the first time. This attracted little attention in the scientific com-munity and it was not until 1994 that the importance of cfNA was recognized as a result of the detection of mutated RAS gene fragments in the blood of cancer patients 2,3 (TIMELINE). In 1996, microsatellite altera-tions on cell-free DNA (cfDNA) were shown in cancer patients 4, and during the past decade increasing atten-tion has been paid to cfNAs (such as DNA, mRNA and microRNAs (miRNAs)) that are present at high concentra-tions in the blood of cancer patients (FIG. 1). Indeed, their potential value as blood biomarkers was highlighted in a recent editorial in the journal Science 5.Detecting cfNA in plasma or serum could serve as a ‘liquid biopsy’, which would be useful for numer-ous diagnostic applications and would avoid the need for tumour tissue biopsies. Use of such a liquid biopsy delivers the possibility of taking repeated blood sam-ples, consequently allowing the changes in cfNA to be traced during the natural course of the disease or during cancer treatment. However, the levels of cfNA might also reflect physiological and pathological processes that are not tumour-specific 6. cfNA yields are higher in patients with malignant lesions than in patients without tumours, but increased levels have also been quantified in patients with benign lesions, inflammatory diseases and tissue trauma 7. The physi-ological events that lead to the increase of cfNA during cancer development and progression are still not well understood. However, analyses of circulating DNA allow the detection of tumour-related genetic and epi-genetic alterations that are relevant to cancer develop-ment and progression. In addition, circulating miRNAs have recently been shown to be potential cancer biomarkers in blood.This Review focuses on the clinical utility of cfNA, including genetic and epigenetic alterations that can be detected in cfDNA, as well as the quantification of nucleo s omes and miRNAs, and discusses the relationship between cfNA and micrometastatic cells.Biology of cfNAThe release of nucleic acids into the blood is thought to be related to the apoptosis and necrosis of cancer cells in the tumour microenvironment. Secretion has also been suggested as a potential source of cfDNA (FIG. 1). Necrotic and apoptotic cells are usually phagocytosed by macrophages or other scavenger cells 8. Macrophages that engulf necrotic cells can release digested DNA into the tissue environment. In vitro cell culture experiments indicated that macrophages can be either activated or dying during the process of DNA release 8. Fragments of cellular nucleic acids can also be actively released 9,10. It has been estimated that for a patient with a tumour that weighs 100 g, which corresponds to 3 × 1010 tumour cells, up to 3.3% of tumour DNA may enter the blood every day 11. On average, the size of this DNA varies between small fragments of 70 to 200 base pairs and large fragments of approximately 21 kilobases 12. Tumour cells that circulate in the blood, and micro-metastatic deposits that are present at distant sites, such as the bone marrow and liver, can also contribute to the release of cfNA 13,14.T umours usually represent a mixture of different cancer cell clones (which account for the genomic and epig-enomic heterogeneity of tumours) and other normal cell types, such as haematopoietic and stromal cells. Thus, during tumour progression and turnover both tumour-derived and wild-type (normal) cfNA can be released into the blood. As such, the proportion of cfNA that originates from tumour cells varies owing to the state*Institute of T umour Biology, Center of ExperimentalMedicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.‡Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.Correspondence to K.P . e-mail:pantel@uke.uni-hamburg.de doi:10.1038/nrc3066Published online 12 May 2011microRNAsSmall non-coding RNAmolecules that modulate the activity of specific mRNA molecules by binding and inhibiting their translation into polypeptides.Cell-free nucleic acids as biomarkers in cancer patientsHeidi Schwarzenbach*, Dave S. B. Hoon ‡ and Klaus Pantel*Abstract | DNA, mRNA and microRNA are released and circulate in the blood of cancerpatients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.and size of the tumour. The amount of cfNA is also influ-enced by clearance, degradation and other physiological filtering events of the blood and lymphatic circulation. Nucleic acids are cleared from the blood by the liver and kidney and they have a variable half-life in the circulation ranging from 15 minutes to several hours7. Assuming an exponential decay model and plotting the natural loga-rithm of cfDNA concentration against time, serial DNA measure m ents have shown that some forms of cfNA might survive longer than others. When purified DNA was injected into the blood of mice, double-stranded DNA remained in the circulation longer than single-stranded DNA15. Moreover, viral DNA as a closed ring may survive longer than linear DNA15. However, regardless of its size or configuration, cfDNA is cleared from the circulation rapidly and efficiently16. miRNAs seem to be highly stable, but their clearance rate from the blood has not yet been well studied in cancer patients owing to the novelty of this area of research. The nuclease activ-ity in blood may be one of the important factors for the turnover of cfNA. However, this area of cfNA physiology remains unclear and needs further examination. Circulating cfDNADNA content. In patients with tumours of different histo-pathological types, increased levels of total cfDNA, which consists of epigenomic and genomic, as well as mito-chondrial and viral DNA, have been assessed by different fluorescence-based methods (such as, PicoGreen stain-ing and ultraviolet (UV) spectrometry) or quantitative PCR (such as, SYBR Green and TaqMan). Although cancer patients have higher cfDNA levels than healthy control donors, the concentrations of overall cfDNA vary considerably in plasma or serum samples in both groups17–19. A range of between 0 and >1,000 ng per ml of blood, with an average of 180 ng per ml cfDNA, has been measured20–23. By comparison, healthy subjects have concentrations between 0 and 100 ng per ml cfDNA of blood, with an average of 30 ng per ml cfDNA7. However, it is difficult to draw conclusions from these studies, as the size of the investigated patient cohort is often small and the techniques used to quantify cfDNA vary. A large prospective study assessed the value of plasma DNA levels as indicators for the development of neoplastic or pulmonary disease. The concentration of plasma DNA varied considerably between the European Prospective Investigation into Cancer and Nutrition (EPIC) centres that were involved in the study. This variation was pro-posed to be due to the type of population recruited and/or the treatment of the samples24. However, the quantifica-tion of cfDNA concentrations alone does not seem to be useful in a diagnostic setting owing to the overlapping DNA concentrations that are found in healthy individuals with those in patients with benign and malignant disease. The assessment of cfDNA concentration might prove to be useful in combination with other blood tumour bio-markers. Following surgery, the levels of cfDNA in cancer patients with localized disease can decrease to levels that are observed in healthy individuals25. However, when the cfDNA level remains high, it might indicate the presence of residual tumour cells17. Further studies are needed for the repeat assessment of quantitative cfNA in large cohorts of patients with well-defined clinical parameters. Such investigations will be crucial if we are to use cfDNA as a prognostic biomarker, as will the isolation and processingof cfNA to defined standards (discussed below).cfDNA is composed of both genomic DNA (gDNA) and mitochondrial DNA (mtDNA). Interestingly, the levels of cell-free mtDNA and gDNA do not correlate in some tumour types26,27, indicating the different nature of circulating mtDNA and gDNA. In contrast to two copies of gDNA, a single cell contains up to several hundred copies of mtDNA. Whereas gDNA usually circulates in a cell-free form, circulating mtDNA in plasma exists in both particle-associated and non-particle-associated forms28. Diverging results have been reported regarding whether cell-free mtDNA levels are increased and clinically relevant in cancer patients.The cfDNA can also include both coding and non-coding gDNA that can be used to examine microsatellite instability, loss of heterozygosity (LOH), mutations, poly-morphisms, methylation and integrity (size). In recent years, considerable attention has been paid to non-coding DNA, particularly repetitive sequences, such as ALU (which is a short interspersed nucleic element (SINE)) and as long interspersed nucleotide elements such as LINE1 (REFS 29–31) (discussed below). ALU and LINE1 are dis-tributed throughout the genome and are known to be less methylated in cancer cells compared with normal cells32. Tumour-specific LOH. Genetic alterations found in cfDNA frequently include LOH that is detected using PCR-based assays13,18,33–38(TABLE 1). Although similar plasma- and serum-based LOH detection methods have been used, a great variability in the detection of LOH in cfDNA has been reported. Despite the concordance between tumour-related LOH that is present in cfDNA in blood and LOH that is found in DNA isolated from matched primary tumours, discrepancies have also been found7. These contradictory LOH data that have been derived from blood and tumour tissue and the low incidence of LOH in cfDNA have partly been explained by technical problems and the dilution of tumour-associated cfDNA in blood by DNA released from normal cells11,39–41. Moreover, the abnormal proliferation of benign cells, owing to inflammation or tissue repair processes, for example, leads to an increase in apoptotic cell death, the accumulation of small, fragmented DNA in blood and the masking of LOH42.Alternative approaches, such as the detection of tumour-specific deletions are needed to better address the inherent problems of LOH analyses.Tumour-specific gene mutations.The analysis of cfDNA for specific gene mutations, such as those in KRAS and TP53, is desirable because these genes have a high mutation frequency in many tumour types and contribute to tumour progression43. Additionally, clini-cally relevant mutations in BRAF, epidermal growth factor receptor (EGFR) and adenomatous polyposis coli (APC) have now been studied in cfDNA. Several thera-peutic agents in clinical trials target the KRAS, BRAF, EGFR or p53 pathways44,45, and require the identifica-tion of the mutation status of the patient’s tumour to predict response to treatment. In this regard, cfDNA provides a unique opportunity to repeatedly monitor patients during treatment. In particular, in stage IV cancer patients, biopsies are not possible or repeat sam-pling of primary tumour and metastatic samples is not practical or ethical.The major problem with this approach has been assay specificity and sensitivity. Assays targeting cfDNA mutations require that the mutation in the tumour occurs frequently at a specific genomic site.A major drawback of cfDNA assays is the low frequency of some of the mutations that occur in tumours. In general, wild-type sequences often interfere with cfDNA muta-tion assays. This is due to the low level of cfDNA mutations and the dilution effect of DNA fragments and wild-type DNA in circulation. In PCR-based assays technological design can significantly limit the assay sensitivity and specificity. An example is the KRAS muta-tion tissue assay that can frequently detect mutations in tumour tissues, such as the pancreas, colon and lung;Quantitative real-time clamp PCR assayA technique that uses a peptide nucleic acid clamp and locked nucleic acid probes, which are DNA synthetic analogues that hybridize to complementary DNA and are highly sensitive and specific for recognizing single base pair mismatches.however, cfDNA mutation assays using blood sam-ples have not yet been concordantly successful46–48.New approaches are needed, such as cfDNA sequenc-ing. The BRAF mutation V600E, which is present in>70% of metastatic melanomas, can be detectedin cfDNA and has been shown to be useful in monitor-ing patients with melanoma who are receiving ther-apy49. This mutation has been detected in differentstages of melanoma (according to the American JointCommittee on Cancer (AJCC) Cancer Staging Manual)using a quantitative real-time clamp PCR assay, with thehighest levels found in the more advanced stages49. Thisis one of the first major studies to demonstrate thatcfDNA mutation assays have the sensitivity to monitorpatient responses before and after treatment. The util-ity of a cfDNA BRAF mutation assay has gained moreimportance, as new anti-BRAF drugs, such as PLX4032(Roche)50 and GSK2118436 (GlaxoSmithKline)51, haveshown substantial responses in patients in early clinicaltrials. EGFR mutations that occur in a specific subset ofpatients with lung cancers52–54 make these tumours sen-sitive to EGFR-targeted therapies; however, the detec-tion of EGFR mutations in cfDNA has not been welldeveloped owing to issues with sensitivity and specifi-city. Patients whose tumours have a specific gene muta-tion would be strong candidates for monitoring of theircfDNA in blood for the respective specific mutation.However, sensitivity, specificity and validation needto be carried out in multicentre settings to determinetrue clinical utility. Alternatively, cfDNA assays mightbe more appropriate when used with other biomarkerassays, and this might be applicable to personalizedmedicine, rather than diagnostic screens that can beused across a wide group of cancer patients.DNA integrity. Another assay that is applicable to cfDNAthat has gained interest in recent years is the integrityof non-coding gDNA, such as the repeat sequences ofALU and LINE1. The ALU and LINE1 sequences havebeen referred to as ‘junk DNA’; however, in recentyears evidence has indicated their importance invarious physiological events, such as DNA repair,transcription, epigenetics and transposon-based activ-ity55,56. Approximately 17–18% of the human genomeconsists of LINE1. In normal cells LINE1 sequencesare heavily methylated, restricting the activities ofthese retrotransposon elements and thus preventinggenomic instability. LINE1 sequences are moderatelyCpG-rich, and most methylated CpGs are locatedin the 5′ region of the sequence that can function asan internal promoter23. These forms of DNA can bedetected as cfDNA of different sizes, but also as methyl-ated and unmethylated DNA. Studies on these types ofcfDNA are still in their infancy; however, recent studieshave shown potential prognostic and diagnostic util-ity23,29–31. The assays are based on the observation thatcommon DNA repeat sequences are preferentiallyreleased by tumour cells that are undergoing non-apoptotic or necrotic cell death, and these fragmentscan be between 200 bp and 400 bp in size. The ALU andLINE1 sequences are well interspersed throughout thegenome on all chromosomes, so although specificity understood; tumour burden and tumour cell proliferation rate may have a substantial role in these events. Individual tumour types can release more than one form of cfDNA.for an individual cancer type is lost in these assays, sen-sitivity is enhanced. Using a PCR assay, the integrity of cfDNA ALU sequences in blood has been shown to be sensitive for the assessment of the early stages of breast cancer progression, including micro m etastasis30. DNA integrity cfDNA assays have also been used in testicular, prostate, nasopharyngeal and ovarian cancer31,57–59. These assays are still in their infancy and address an important challenge of whether a ‘universal’ blood biomarker for multiple cancers can be of clinical utility. Further validation of these assays will also determine their clinical utility in specific cancers.Table 1 |Detection of cfDNA and its alterations in patients with different tumour types*cancers in both males and females182. This table is not meant to be comprehensive and is based on our own view of studies that offer substantial clinical insight. cfDNA, cell-free DNA.Epigenetic alterations. Epigenetic alterations can have a substantial effect on tumorigenesis and progression (BOX 1). Several studies have revealed the presence of methylated DNA in the serum or plasma of patients with various types of malignancy (TABLE 1). The detection of methylated cfDNA represents one of the most promising approaches for risk assessment in cancer patients. Assays for the detection of promoter hypermethylation may have a higher sensitivity than microsatellite analyses, and can have advantages over mutation analyses. In gen-eral, aberrant DNA methylation, which seems to be com-mon in cancer, occurs at specific CpG dinucleotides60. The acquired hypermethylation of a specific gene can be detected by sodium bisulphite treatment of DNA, which converts unmethylated (but not methylated) cytosines to uracil. The modified DNA is analysed using either methylation-specific PCR, with primers that are specific for methylated and unmethylated DNA, or DNA sequenc-ing61. Nevertheless, to improve the assay conditions and the clinical relevance, the selection of appropriate tumour-related genes from a long list of candidate genes that are known to be methylated in neoplasia is essential. Although epigenetic alterations are not unique for a single tumour entity, there are particular tumour suppressor genes that are frequently methylated and downregulated in certain tumours62,63. For example, important epigenetic events in carcinogenesis include the hypermethylation of the promoter region of the genes pi-class glutathione S-transferase P1 (GSTP1) and APC, which are the most common somatic genome abnormalities in prostate and colorectal cancer, respectively62,63. Other important methylated genes that have shown prognostic utility using cfDNA assays in significant numbers of patients include RAS association domain family 1A (RASSF1A), retinoic acid receptor-b (RARB), septin 9 (SEPT9), oestrogen receptor-a (ESR1)and cyclin-dependent kinase inhibitor 2A (CDKN2A) (TABLE 1). The first commercial real-time PCR plasma test for the detection of early colorectal cancer (developed by Epigenomics AG and Abbott Molecular) is for the detection of SEPT9. This biomarker is still under-going validation, but it demonstrates the potential diag-nostic screening utility of methylated tumour-related cfDNA to differentiate cancer patients from healthy individuals and to identify the tumour type.It is also possible to detect tumour-related alterations in histone modifications in the blood. By monitoring changes in the circulating histones and DNA methylation pattern, the antitumour effects of histone deacetylase and histone methyltransferase inhibitors may be evalu-ated and consequently allow a better screening of cancer patients64,65.Circulating nucleosomes.Circulating gDNA that is derived from tumours seems to predominantly exist as mononucleosomes and oligonucleosomes, or it is bound to the surface of blood cells by proteins that harbour specific nucleic acid-binding properties66. A nucleosome consists of a histone octamer core wrapped twice by a 200 bp-long DNA strand. Under physiological condi-tions these complexes are packed in apoptotic particles and engulfed by macrophages67. However, an excess of apoptotic cell death, as occurs in large and rapidly pro-liferating tumours or after chemotherapy treatment, can lead to a saturation of apoptotic cell engulfment and thus increased nucleosome levels in the blood68. The detection of circulating nucleosomes that are associ-ated with cfDNA suggests that DNA in blood retains at least some features of the nuclear chromatin during the process of release.Enzyme-linked immunosorbent assays (ELISAs) have been developed to quantify circulating nucleosomes. As increased concentrations are found in both benign and malignant tumours, high nucleosome levels in blood are not indicators of malignant disease69. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the increased serum levels of nucleosomes have been linked to breast cancer progression70. As typical cell-death products, the quan-tification of circulating nucleosomes seems to be valu-able for monitoring the efficacy of cytotoxic cancer therapies71. For example, platinum-based chemotherapy induces caspase-dependent apoptosis of tumour cells and an increase in circulating nucleosomes in the blood of patients with ovarian cancer17. Moreover, the outcome of therapy can be indicated by nucleosome levels during the first week of chemotherapy and radiotherapy in patients with lung, pancreatic and colorectal cancer, as well as in patients with haematological malignancies71.Viral DNA. Viral cfDNA can also be detected in some tumour types. Viruses, such as human papillomavirus (HPV), hepatitis B virus (HBV) and Epstein–Barr virus (EBV), are aetiological factors in various malignancies, such as nasopharyngeal, cervical, head and neck, and hepatocellular cancer and lymphoma72–75. Their specific DNA may have the potential to be used as molecular biomarkers for neoplastic disease. Associations between circulating viral DNA and disease have been reported for EBV with Hodgkin’s disease, Burkitt’s lymphoma and nasopharyngeal carcinoma; for HBV with some forms of hepatic cell carcinoma; and for HPV with head and neck, cervical and hepatocellular cancers (TABLE 1). The clinical utility of EBV cfDNA in diagnosis and prognosis of nasopharyngeal carcinoma has been demonstrated in multiple studies with large cohorts of patients76–80, and the use of this cfDNA has became one of the leading cfDNA blood tests for the assessment of nasopharyngeal carci-noma progression in Hong Kong, Taiwan and China, where this cancer is highly prevalent77,78,81. The limitationof most viral cfNA assays is that benign viral infections that are caused by the same viruses can complicate the interpretation of results, particularly in diagnostic screen-ing. Establishing clinically meaningful cut-off levels is important to move these screens into the clinic. Genometastasis.The genometastasis hypothesis describes the horizontal transfer of cell-free tumour DNA to other cells that results in transformation. If true, metastases could develop in distant organs as a result of a transfection-like uptake of dominant oncogenes that are released from the primary tumour82. García-Olmo et al.83 showed that plasma isolated from patients with colon cancer is able to transform NIH-3T3 cells and that these cells can form carcinomas when injected into non-obese diabetic-severe combined immunodeficient mice83. Whether this biological function of circulating DNA has relevance in human blood is an aspect to be considered in the future.cfDNA assay issuesOne of the problems in evaluating cfNA is the standard-ization of assays, such as isolation technologies, standards, assay conditions, and specificity and sensitivity7. It remains controversial whether plasma or serum is the optimal sampling specimen. The diversity of protocols and reagents currently in use impedes the comparison of data from different laboratories.The pre-analytical phases of cfDNA analysis such as blood collection, processing (plasma and serum), storage, baseline of patients, diurnal variations and accurate clinical conditions need to be better defined before comparisons and clinical utility can be validated84.A major technical issue that hampers consistency in all the cfDNA assays is the efficacy of the extraction pro-cedures, with only small amounts of DNA obtained from plasma and serum. Another key issue is quanti-fication before assessment on specific assay platforms. Improvement is needed in these aspects for cfDNA analysis to be more robust, consistent, comparative and informative. Extraction of cfDNA can be carried out in accordance with many methods; for example, commer-cial kits, company in-house procedures or individual laboratory protocols. To date no approach has been truly developed that is consistent, robust, reproduc-ible, accurate, and validated on a large-scale patient and normal donor population. If these issues were solved a better universal standardization for the comparison of results would be provided and the clinical utility of the assays could be addressed. The development of a direct DNA assay without extraction would override many of these problems30. As new approaches in the assessment of cfDNA, such as next-generation sequencing, are being developed, the issue of extraction of DNA will continue to complicate cfDNA biomarker assay development and regulatory group approval.The other major issue for cfDNA assessment is that after DNA extraction, different platform assays are used for analysis. This can vary owing to the type of cfDNA being analysed, assay sensitivity and specificity, and ana-lytical approach. These variables are important and need to be standardized for consensus analysis and reporting. The development of PCR-based assay standardization is needed in order to report clinical and prognostic biomarker results that are similar to those outlined in the recent minimal information for the publication of quantitative real-time PCR guidelines85. However, this may take time to reach an international consensus, as has been apparent with the standardization of other cancer blood biomarkers. Unfortunately, the rate of approval of new cancer blood biomarkers over the past decade has been very slow. New regulatory guidelines, such as those listed for tumour biomarkers in clinical practice by the National Academy of Clinical Biochemistry (NACB USA)84, should help to resolve some of these issues. The NACB website provides up-to-date informative detailed guidelines with references of pre-analytical and post- analytical phases, assay validation, internal quality controls, proficiency and requirements for minimiz-ing the risk of method-related errors for biomarkers. Nevertheless, as with other types of biomarkers, new reg-ulatory guidelines mean that developing cfNA biomarkers will be more time-consuming and costly. Circulating cfRNAmRNA content. Besides the quantification of cfDNA, cir-culating gene transcripts are also detectable in the serum and plasma of cancer patients. It is known that RNA released into the circulation is surprisingly stable in spite of the fact that increased amounts of RNases circulate in the blood of cancer patients. This implies that RNA may be protected from degradation by its packaging into exosomes86, such as microparticles, microvesicles or multivesicles, which are shed from cellular surfaces into the bloodstream87. The detection and identification of RNA can be carried out using microarray technologies or reverse transcription quantitative real-time PCR88. Serum thyroglobulin levels are a specific and sensi-tive tumour marker for the detection of persistent or recurrent thyroid cancer. Levels of thyroglobulin change during thyroid hormone-suppressive therapy, as well as after stimulation with thyroid-stimulating hormone, and the levels correlate well with disease progression. The measurement of mRNA levels of thyroid-specific tran-scripts might be useful in the early detection of tumour relapse89. However, another study has shown that the detection of circulating thyroglobulin mRNA one year after thyroidectomy might be of no use in the prediction of early and midterm local and distant recurrences of this disease90.In patients with breast cancer, levels of CCND1 mRNA (encoding cyclin D1) identified patients with poor overall survival in good-prognosis groups and patients who were non-responsive to tamoxifen91. Nasopharyngeal carcinoma has been associated with disturbances in the integrity of cell-free circulating RNA, suggesting that the measurement of plasma RNA integrity may be a useful biomarker for the diagnosis and monitoring of malignant diseases92. Several groups have tried to detect human telo-merase reverse transcriptase (TERT) mRNA in plasma, and have not found any association between the pres-ence of this mRNA and clinicopathological parameters7.。
•综述・变应性鼻炎表观遗传学朱栋，何翔，李国平作者单位：999078澳门，澳门科技大学中药质量研究国家重点实验室(朱栋、李国平)；610031成都，过敏与精准医学实验室，国家呼吸系统临床研究中心成都市第三人民医院分中心，成都市呼吸健康研究所，重庆医科大学附属成都市第三人民医院(何翔、李国平)通信作者：李国平，E-mail:lzlgp@DOI：10.3969/j.issn.1673-8705.2021.01.012【摘要】变应性鼻炎是常见的变态反应性疾病，近年来发病率呈上升趋势。
其发病与外界环境关系密切，表观遗传学修饰在本病的发生中扮演重要角色。
本文就近年来表观遗传学在变应性鼻炎研究的DNA甲基化、组蛋白修饰、miRNAs表达等进行综述。
【关键词】变应性鼻炎；表观遗传学；进展基金项目：国家自然科学基金(8197010598、82000029)；四川省应用基础研究基金(2018JY0380)；四川省卫生健康委员会科研基金(19ZD002)Epigenetics of allergic rhinitis ZHU Dong,HE Xiang,LI Guo-pingState Key Laboratory of Quality Research in Chinese Medicine,Macau University of Science and Technology,Macau,999078,China(ZHU Dong,LI Guo-ping)；Chengdu Institute of Respiratory Health,Branch of National Clinical Research Center for Respiratory Disease,The Third People,s Hospital of Chengdu,ChongqiMedical university,Chengdu610031,China(HE Xiang,LI Guo-ping)Corresponding author:LI Guo-ping E-mail:lzlgp@[Abstract]Allergic rhinitis(AR)is one kind of common allergic diseases.The incidence of AR hasbeen on the rise in recent years.The onset of AR has been closely related with external environment and epigenetic modification plays an important role in the pathogenesis of AR.The progress on epigenetics of AR，such asDNA methylation，histone modification，and miRNAs expression are reviewed in this article.[Key words]allergic rhinitis；epigenetics；progressFund program:National Natural Science Foundation of China(8197010598,82000029)；AppliedBasic Research Fund of Sichuan Province(2018JY0380)；Scientific Research Fund of Sichuan Health Department(19ZD002)变应性鼻炎(allergic rhinitis,AR)俗称过敏性鼻炎，是某些个体接触过敏原后，由IgE介导的I型变态反应，通过释放炎性介质、免疫活性细胞以及细胞因子等参与的鼻部变态反应性疾病。
记忆根据持续时间的长短分为长时记忆和短时记忆。
许多研究聚焦于学习和记忆如何进行的。
但是学习和记忆作为一种复杂的行为，仍然有许多问题需要去探索研究。
而在脊椎动物中发现学习和记忆的突变基因，对其机制的研究会有一定的贡献。
本实验中以斑马鱼为模式动物，经ＥＮＵ诱变及大规模遗传筛选，利用抑制逃避反应的行为学方法获得一例学习记忆的斑马鱼突变体触。
这种ｆｇｔ斑马鱼突变体的训练后２４小时的长时记忆显著的低于野生型。
触突变体表现出正常的运动活性和正常的对黑色的倾向性。
该突变体的Ｆ２代在训练后的２４小时的长时记忆中有将近一半（１３／３０）显著的低于野生型，而另一半则相对正常。
同时，在对一个新的环境的探索后，与学习记忆相关的即刻早期基因ＩＥＧｓｃ－ｆｏｓ在该突变体将近一半Ｆ２代中的表达与野生型的对照有显著性的差异（１３／３０），另外一半相对正常，与行为学结果一致。
这些结果表明，该突变体触是一个学习和记忆缺陷的显性突变。
而该ｆｇｔ突变体的发现对未来进一步学习和记忆相关的机制和信号通路提供了一种可能。
关键词：松果体，视觉敏感性，生物钟，学习和记忆，ｆｇｔ突变体，ｃ－ｌｏｓ缩略词ＬＬＬＤＤＤＳＣＮＧＦＰＥＲＧｄｐｆｈｐｆｋＫ鼠§忒ＵＡＳＮＴＲＭｔｚＭＯＥＮＵＩＥＧｓＲＴＦｓＰＶＮＦＲＡＳ符号说明英文名称Ｌｉｇｈｔ－ＬｉｇｈｔＬｉｇｈｔ－ＤａｒｋＤａｒｋ—ＤａｒｋＳｕｐｒａＣｈｉａｓｍａｔｉｃＮｕｃｌｅｕｓＧｒｅｅｎＦｌｕｏｒｅｓｃｅｎｔＰｒｏｔｅｉｎＥｌｅｃｔｒｏｒｅｔｉｎｏｇｒａｍｓＤａｙｓＰｏｓｔ－ＦｅｒｔｉｌｉｚａｔｉｏｎＨｏｕｒｓＰｏｓｔ．ＦｅｒｔｉｌｉｚａｔｉｏｎＡｒｙｌａｌｋｙｌａｍｉｎｅＮ—ａｃｅｔｙｌｔｒａｎｓｆｅｒａｓｅＵｐｓｔｒｅａｍＡｃｔｉｖａｔｉｎｇＳｅｑｕｅｎｃｅｓＮｉｔｒｏｒｅｄｕｃｔａｓｅＭｅｔｒｏｎｉｄａｚｏｔｅＭｏｒｐｈｏ·ｌｉｎｏＮ．－ｅｔｈｙｌ－－Ｎ·－ｎｉｔｒｏｓｏｕｒｅａＩｍｍｅｄｉａｔｅ－ＥａｒｌｙＧｅｎｅｓＲｅｇｕｌａｔｏｒｙＴｒａｎｓｃｒｉｐｔｉｏｎＦａｃｔｏｒｓＰａｒａｖｅｎｔｒｉｃｕｌａｒＮｕｃｌｅｕｓＦｏｓ－ｒｅｌａｔｅｄａｎｔｉｇｅｎｓＶ中文名称光照一光照光照一黑暗黑暗一黑暗视交叉上核绿色荧光蛋白视网膜电流图受精后Ｎ天受精后Ｎ小时芳烷基胺Ｎ一乙酰转移酶上游激活序列硝基还原酶甲硝唑吗啉代Ｎ．乙基一Ｎ一亚硝基脲即刻早期基因调节转录因子下丘脑室旁核Ｆｏｓ相关抗原目录帚一草闩Ｕ舌……………………………………………………………．１第一章前言……………………………………………………………．１第一节斑马鱼～脊椎动物模型………………………………………………一１第二节斑马鱼是研究昼夜节律的理想动物模型……………………………一３１．２．１生物节律概述……………………………………………………………………３１．２．２哺乳动物生物节律的分子机理…………………………………………………４１．２．３斑马鱼的松果体…………………………………………………………………６１．２．４斑马鱼是良好生物节律研究模型……………………………………………．．Ｉ１１．２．５生物节律在斑马鱼上的研究进展……………………………………………一１２第三节转基因斑马鱼的研究与应用…………………………………………２３１．３．１Ｔ０１２转座技术…………………………………………………………………一２４１．３．２ＧＡＩＡ／ＵＡＳ在斑马鱼中的应用…………………………………………………２６１．３．３ＮＴＲ／Ｍｔｚ系统在斑马鱼中的应用………………………………………………２９第四节斑马鱼的ＥＮＵ诱变…………………………………………………．．３１第五节学习和记忆相关的基因………………………………………………３５１．５．１即刻早期基因ＩＥＧｓ（ｉｍｍｅｄｉａｔｅ．ｅａｒｌｙｇｅｎｅｓ）的概述………………………．３５１．５．２ＩＥＧ的细胞功能…………………………………………………………………３８１．５．３一个特别的ＩＥＧ：ｃ－ｆｏｓ…………………………………………………………３８第二章斑马鱼松果体对维持视觉敏感性生物钟的作用……………４３第一节材料和方法……………………………………………………………４３２．１．１实验动物………………………………………………………………………一４３２．１．２主要试剂………………………………………………………………………一４３２．１．３主要仪器……………………………………………．．：…………………………４４２．１．４转基因载体ｐＴ２ＫＸＩＧ．ｇｎａｔ２一Ｇａｌ４／ＶＰｌ６的构建……………………………．．４４２．１．５ｐＣＳＴＺ２．８转座酶ｍＲＮＡ的体外转录…………………………………………４６２．１．６显微注射………………………………………………………………………一４８２．１．７转基因斑马鱼的筛选和养殖…………………………………………………．．４９ＶＩ３．１．８诱导ｃ－ｆｏｓ基因表达的行为学…………………………………………………７９３．１．９ＲＥＡＬ—ＴＩＭＥＰＣＲ……………………………………………………………………………………．７９３．１．１０统计学分析……………………………………………………………………８３第二节实验结果与分析………………………………………………………８３３．２．１野生型斑马鱼的黑色倾向性…………………………………………………．．８３３．２．２斑马鱼在抑制逃避电击后形成稳定长时记忆………………………………．．８４３．２．３学习和记忆突变体的筛选……………………………………………………一８５３．２．４基因表达水平鉴定突变体……………………………………………………一８７第三节实验讨论与总结………………………………………………………８９第四节实验结论与展望………………………………………………………９４参考文献………………………………………………………………．．９５致谢………………………………………………………………………………………．１０７个人简历、在学期问发表的学术论文与研究成果…………………１０８个人简历………………………………………………………………………１０８在学期间发表的学术论文……………………………………………………１０８ＶＩＩ工第一章前言第一节斑马鱼一脊椎动物模型斑马鱼作为一种新的可以用于研究神经发育、功能和疾病的脊椎动物模型，已经吸引全世界大批实验室和科学家围绕其展丌了广泛的研究。
TGF-β-induced epithelial to mesenchymal transition Jian Xu;Samy Lamouille;Rik Derynck【期刊名称】《细胞研究（英文版）》【年(卷),期】2009(019)002【摘要】During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation (EMT). In this process, the cells lose their epithelial characteristics, including their polarity and specialized cell-cell contacts, and acquire a migratory behavior, allowing them to move away from their epithelial cell community and to integrate into surrounding tissue, even at remote locations. EMT illustrates the differentiation plasticity during development and is complemented by another process,called mesenchymal to epithelial transition (MET). While being an integral process during development, EMT is also recapitulated under pathological conditions, prominently in fibrosis and in invasion and metastasis of carcinomas.Accordingly, EMT is considered as an important step in tumor progression. TGF-β sig naling has been shown to play an important role in EMT. In fact, adding TGF-β to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. Although much less characterized, epithelial plasticity can also be regulated by TGF-β-related bone morphogenetic proteins (BMPs), and BMPs have been shown to induce EMT or MET depending on the developmental context. In thisreview, we will discuss the induction of EMT in response to TGF-β, and focus on the underlying signaling and transcription mechanisms.【总页数】17页(P156-172)【作者】Jian Xu;Samy Lamouille;Rik Derynck【作者单位】Department of Cell and 7issue Biology, Programs in Cell Biology and Developmental Biology, University of California-San Francisco, San Francisco, CA USA;Department of Cell and 7issue Biology, Programs in Cell Biology and Developmental Biology, University of California-San Francisco, San Francisco, CA USA;Department of Cell and 7issue Biology, Programs in Cell Biology and Developmental Biology, University of California-San Francisco, San Francisco, CA USA【正文语种】中文【中图分类】Q2因版权原因，仅展示原文概要，查看原文内容请购买。
细胞焦亡2001年，cookson等首次使用pyroptosis来形容在巨噬细胞中发现caspase-1依赖的细胞死亡方式。
细胞焦亡（pyroptosis）的发现并证实是一种新的程序性细胞死亡方式，其特征为依赖于半胱天冬酶-1(caspase-1)，并伴有大量促炎症因子的释放。
细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式。
迄今为止，已经证实弗氏志贺氏杆菌、沙门氏杆菌、李斯特杆菌、绿脓杆菌、弗朗西斯氏菌属、嗜肺性军团杆菌以及叶尔森杆菌均可诱导巨噬细胞产生caspase-1依赖的细胞死亡方式。
研究发现，caspase-1依赖的细胞死亡方式不仅存在于单核巨噬细胞系，还存在于树突状细胞等其他细胞中。
诱导细胞产生caspase-1依赖细胞死亡的刺激原也不仅局限于病原体，一些非生物性的刺激源，如损伤相关模式分子(danger／damage associated molecularpattern，DAMP)、缺血坏死的产物等也可诱导细胞caspase-1依赖的细胞死亡。
此后，科学家们发现细胞焦亡本质上是由GSDMD（gasdermin D）蛋白介导的细胞炎性坏死，与多种病理生理过程紧密相关。
一旦发生，GSDMD 蛋白的N - 端高聚并与脂类结合，在细胞膜上形成孔洞，细胞逐渐膨胀至细胞破裂，最终大量细胞内含物如IL-1β释放，激活强烈的炎症反应。
研究表明，细胞焦亡广泛参与感染性疾病、神经系统相关疾病和动脉粥样硬化性疾病等的发生发展，并发挥重要作用。
对细胞焦亡的深入研究有助于认识其在相关疾病发生发展和转归中的作用,为临床防治提供新思路。
1.Nature：细胞焦亡在肿瘤化疗中发挥重要作用doi:10.1038/nature22393近日，一篇发表在国际杂志nature上的研究报告中，来自北京生命科学研究所的邵峰院士课题组报道发现细胞焦亡的重要蛋白GSDME(DFNA5)。
该蛋白在肿瘤化疗药物的作用下，通过caspase-3的切割作用获得活性，诱导肿瘤细胞的细胞焦亡，并在化疗药物对正常组织的毒副作用中扮演重要角色。
