CCR5小分子拮抗剂结构与抗HIV活性构效关系的研究

目的本文针对51个具有CCR5拮抗剂作用的咪唑并吡啶衍生化合物进行构效关系研究,希望能够为设计此类小分子药物提供依据。方法运用比较分子力场分析(Co MFA)和比较分子相似性指数分析(Co MSIA)这2种经典的三维定量构效关系(3D-QSAR)方法,分别建立了相应的模型,进行分子结构和抗病毒活性彼此关系的分析。结果 Co MFA模型的交叉验证系数q~2和相关系数r~2分别为0.617和0.825,立体场和静电场对活性的贡献为62%和38%;Co MSIA模型的交叉验证系数q~2和相关系数r~2分别为0.599和0.810,立体场、静电场、疏水场、氢键供体场和受体场对活性的贡献分别为9.8%、12.5%、33.8%、30.8%和13.1%。结论这2种模型都显示出了较好的预测性和稳定性,其三维等势图也证实了这些化合物拮抗CCR5的构效关系。     

R基团搜索策略用于HEA类β分泌酶抑制剂的三维定量构效关系研究与分子虚拟筛选

β分泌酶是治疗阿尔茨海默病(AD)的理想作用靶点。采用以R基团技术为核心的Topomer CoMFA研究HEA类β分泌酶抑制剂的三维定量构效关系(3D-QSAR),构建了拟合与预测能力良好的3D-QSAR模型,得到拟合、交叉与外部验证的复相关系数分别为r2=0.928,q2loo=0.605和r2pred=0.626。通过3D-QSAR模型搜索ZINC化合物结构片段源,得到活性贡献提高的R基团并结合公共骨架设计得到15个新颖化合物,其预测活性值均优于训练集中的活性最高分子。用分子对接研究新设计化合物与β分泌酶的相互作用模式,结果表明,氢键和疏水性是影响亲和力的重要因素。研究表明,基于R基团的Topomer CoMFA与Topomer Search可以有效地筛选和设计HEA类β分泌酶抑制剂,所设计的分子为AD药物的研发提供了新的候选物。     

家蝇二氯苯醚菊酯抗性机理的初步研究

为了研究家蝇拟除虫菊酯抗性机理,在实验室选育了家蝇二氯苯醚菊酯抗性品系,根据P450基因CYP6D1的保守序列设计合成引物,用PCR方法从敏感品系和抗性品系个体都能扩增出一条约210bp的特异性片段,从片段大小和条带明亮程度上均未显示出二者之间有什么差异,初步表明抗性家蝇P450基因在DNA水平上没有明显的变化。RT-PCR结果多次重复显示抗性品系的扩增带明显比敏感品系的亮,揭示二者RNA的含量可能不同,抗性品系P450基因的转录活性可能升高。这些为在分子水平研究P450基因相关的拟除虫菊酯抗性机理打下基础。     

蚊虫对拟除虫菊酯的抗药性检测技术研究进展

本文针对目前拟除虫菊酯在蚊虫防治中的使用情况、蚊虫对拟除虫菊酯的抗药性和蚊虫抗药性监测过程中的检测技术进行了综述。认为生物测定方法检测蚊虫对拟除虫菊酯抗性在实际应用中简便、快捷,但是也存在一定的局限性;随机扩增多态性DNA技术、等位基因特异性PCR、实时荧光定量PCR等分子生物学技术以及解毒代谢酶系在蚊虫对拟除虫菊酯抗性检测中的研究深入,都为寻找准确有效的检测技术提供有效的理论依据。     

利用表面等离子体共振技术测定BSA-抗BSA抗体间二维反应动力学

生物大分子间二维和三维反应动力学过程之间的本构关系还没有被完全认识.表面等离子体共振技术是成熟的研究三维反应动力学的方法.通过相同的技术实时记录耦联到载体(细胞、玻璃小球或脂质体)上的抗原分子与相应的耦联在芯片上的抗体分子之间,在不同实验条件下的反应动力学过程,建立了用表面等离子体共振技术测定抗体-抗原二维反应动力学的方法,可适用于建立生物大分子间二维与三维反应动力学间的定量关系.     

云南勐腊地区微小按蚊钠通道序列分析

微小按蚊Anophelesminimus是云南省勐腊地区的重要传疟媒介,DDT和拟除虫菊酯类杀虫剂在该地区长期大量使用,研究微小按蚊与kdr抗性密切相关的para型钠通道基因对该地区选择合理的媒介控制方案预防和阻断疟疾的流行提供理依据。本文分别于2010和2011年9～10月在云南省勐腊县龙塘村和东方红村现场采集微小按蚊后,用分子学方法进行分型,根据GenBank发布的微小按蚊para钠通道IIS6段基因组DNA序列设计特异性引物,扩增现场采集的微小按蚊的该段基因,并测序对比。通过对415个个体的检测发现,1014位点编码的TTA氨基酸密码子没有突变,说明截止目前云南勐腊地区微小按蚊对DDT和拟除虫菊酯类杀虫剂抗性的kdr分子机制尚未出现,其击倒抗性较低,对DDT和拟除虫菊酯类杀虫剂仍然保持敏感。     

PLS方法应用于T细胞表位定量构效关系的研究

目的 研究了CTL表位与MHC分子结合的定量构效关系模型.方法 采用偏最小二乘法(PLS)对校正集进行校正,并对预测集中的样本进行预测.结果 得到比较满意的短肽-MHC分子结合亲合力与短肽氨基酸序列之间的关系式;模型的预测精确度达到66.8%.结论 偏最小二乘方法可作为CTL表位预测方法.用该模型对预测样本进行短肽-MHC分子的结合亲合力的预测,结果令人满意,说明这种模型在预测CTL表位方面是可行的.     

嘌呤环类mTOR免疫抑制剂的三维定量构效关系研究

目的通过构建嘌呤环类衍生物与哺乳动物雷帕霉素靶蛋白(m TOR)的分子对接模型,并基于分子对接建立可预测性强的三维定量构效关系(3D-QSAR)模型,探讨此类化合物免疫抑制作用的分子机理,为设计新型嘌呤环类m TOR受体拮抗剂奠定理论基础。方法本实验采用Surflex-dock研究44个嘌呤环类衍生物与m TOR的分子对接模式,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)对嘌呤环类衍生物进行3D-QSAR研究,建立具有良好预测能力的模型。结果Surflex-dock结果显示,此类分子与m TOR的ASP2195、TYR2225、VAL2240等活性功能残基具有氢键作用,嘌呤母环占据了活性口袋的连接链区形成疏水和范德华相互作用,从而发挥免疫抑制作用。Co MFA模型的q2=0.8,r2=0.976,最佳主成分为5,立体场和静电场对活性的贡献为59%和41%;Co MSIA模型的q2=0.679,r2=0.965,最佳主成分为6,立体场、静电场、疏水场、氢键供体场和受体场对活性的贡献分别为25.9%、9.5%、28.4%、24.7%和11.4%。结论基于嘌呤环类衍生物所建立的3D-QSAR模型的q2均大于0.5,证明此模型具有良好的预测能力。3D-QSAR结果分析和分子对接相一致,疏水场、立体场和氢键作用对嘌呤环类分子的免疫抑制活性影响最大,为设计新型靶向性嘌呤环类m TOR受体拮抗剂奠定了理论基础。     

拟除虫菊酯对昆虫钠通道作用的研究进展

电压依赖性钠通道 (voltage dependentsodiumchannel)是存在于脊椎动物和无脊椎动物可兴奋细胞膜上的一种糖基化大分子蛋白 ,主要调控细胞膜钠离子的瞬时通透性 ,参与形成细胞膜动作电位的上升相 ,在细胞兴奋性的传导上具有重要作用 ,是拟除虫菊酯和许多神经毒性药物作用的分子靶标。拟除虫菊酯是一类化学合成杀虫剂。由于它具有快速击倒 ,杀虫效能高 ,对人畜等非靶生物低毒 ,在环境低滞留等特点被广泛用于农、林和卫生害虫的防治。然而拟除虫菊酯的大量使用 ,已使得昆虫对拟除虫菊酯抗性问题日益显现出来。如何减少抗性的发生 ,延缓抗性的…     

人源抗梭曼过渡态类似物(P6)的抗体筛选

目的:从大容量天然噬菌体抗体库中筛选抗梭曼过渡态类似物的人源单链抗体(scFv)并进行鉴定。方法:以膦酸梭曼水解过渡态类似物五配位-羟基膦酸酯,3-羟基-1-对硝基苯基甲膦酸单频哪基醇酯,为半抗原,通过吸附-洗脱-扩增过程从大容量天然噬菌体抗体库中筛选特异性抗体,对其抗原结合活性进行鉴定。结果:经过4轮的筛选,分别获得14个抗梭曼类似物的阳性克隆。经DNA指纹分析,判断所获克隆分别包含4个不同的抗梭曼类似物的scFv基因。结论:利用噬菌体抗体库技术获得了特异性的人源抗梭曼类似物抗体。     

Renal dysplasia and asplenia in two sibs

A family is reported in which two sibs, one male and the other female, both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second child showed gross renal dysplasia. In both children the pancreas was enlarged, nodular and cystic but the liver appeared macroscopically normal. In the second child, histological examination confirmed pancreatic fibrosis with cystic dilation of ducts, but showed portal fibrosis with bile duct proliferation in the liver.
This combination of findings is very reminiscent of those in a girl and her brother reported by Ivemark et al. (1959). The children reported here also showed absence or hypoplasia of the spleen, cardiac anomalies and other features of the Ivemark syndrome (Ivemark 1955), a quite different, usually sporadic, congenital disorder. It is suggested that the children described here have a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.     

Schizophrenia in a North Swedish geographical isolate, 1900–1977. Epidemiology, genetics and biochemistry

Over 200 schizophrenic patients belonging to three major and interrelated pedigree complexes have been investigated over the past 30 years in a North Swedish geographically isolated population, presently numbering about 6,000. An intensive investigation of a number of biochemical correlates and genetic markers in a few selected families belonging to one of the major pedigrees has indicated new strategies for the current research program.
Schizophrenia, as defined operationally, is significantly associated with decreased activities of two enzymes (1) blood platelet monoamine oxidase, (2) plasma dopamine-β-hydroxylase, and (3) with the genetic marker Gc² (group specific antigen). Both enzymes are subject to genetic variation. A positive score for linkage between schizophrenia and low plasma DBH activity has been calculated, but, so far, available data are insufficient for discrimination between linkage and partial contribution of genetically controlled low plasma DBH to the pathogenesis of the disease. Alternatively, both mechanisms could be involved.
As a model for continued research, schizophrenia is explained as based on a double dominant-recessive genotype (Aabb), representing a vulnerability which in about 50 % of cases develops into clinical schizophrenia. It is suggested that the dominant mutation (A) operates on or affects MAO activity, and that the recessive genotype (bb) is instrumental in low variates of DBH activity and very likely such variates within the normal range of physiological variation. Moreover, it is suggested that the combined effects of MAO- and DBH-reduced efficiency on the metabolism of e.g. dopamine could be an essential pathogenic mechanism for the schizophrenic illness which is segregating in this population.     

What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.     

The universal muscular chain reaction,muscle spasm,Torsions, ruptures and extravasations. Chameleons of pathology and some manifestations of simple muscular disorders

Most bodily functions require the coordinated actions of complementary and supplementary paired muscle groups. Where this essential muscular cooperation is lacking, hollow organs may burst and others become literally screwed up, giving rise to many similar spastic diseases such as Torticollis, Twisted ovarian cyst, Torsion of the Testis, Volvulus of the intestines, Varicose Veins, Megacolon, Aortamegaly, Scoliosis, Erb's Palsy, Peyronie's Disease, Main-en-Griffe, Undescended Foot (Pes Cavus), Talipes, Strabismus. Spasm is “panenepidemic” and unclassified examples of Torsion Dystonia and Dyskinesia really are as common as debt and taxes.     

The dominant diseases of modernized societies as omega-3 essential fatty acid deficiency syndrome: Substrate beriberi

About 1900, modern food selection and processing caused widespread $\text{epidemics}$ of the B vitamin deficiency diseases of beriberi and pellagra which, for genetic reasons, often expressed as different diseases ranging from bowel and heart disease to dermatoses and psychoses. But the B vitamins merely help convert essential fatty acids (EFA) into the prostaglandin (PG) tissue regulators and it now turns out that, through hydrogenation, milling and selection of w3-poor southern foods, we have also been systematically depleting, by as much as 90%, a newly discovered trace Nordic EFA (w3) of special importance to primates and sole precursor of the PG3(4) series, even as a concurrent fiber deficiency increases body demand for EFA. Since substrate EFA is processed by many B vitamin catalysts, an EFA deficiency will mimic a $\text{panh}$ypovitaminosis B, i.e., a mixture of $\text{substrate}$ beriberi and $\text{substrate}$ pellagra resembling vitamin beriberi and pellagra but exhibiting as even more diverse $\text{endemic}$ disease. This would consitute a second stage of the Modern Malnutrition and explain why some workers now hold the dominant diseases of modermized societies to be new, nutritionally based, pellagraform yet lipid-related and to range, once again, from heart disease to psychosis. It is an assumption that our dominant diseases are unrelated to each other or are merely revealed by our diagnostic acumen and therapeutic success; and that hydrogenating millions of tons of food oils annually, to destroy the rancidity producing w3-EFA, is safe for $\text{primates}$. Extensive beriberiform disease is reported here in 32 typical cases taken from medical practice which responds strikingly to linseed oil supplements (60% w3-EFA) in confirmation of identical results in Capuchins.     

Hypo- und Hypermagnesämie aus kardiologischer Sicht

Zusammenfassung Eine Reihe pathologischer Zustände bedingen Magnesiummangel. Zustände mit Hypermagnesämie sind ebenfalls bekannt, doch wesentlich seltener. Für den Kardiologen beachtenswert ist, daß unter Therapie mit bestimmten Diuretica bei Herzinsuffizienz, bei Herzinfarkt, Kardiomyopathie, Digitalisintoxikation und bestimmten Herzrhythmusstörungen Hypomagnesämie beobachtet wurde. Leider kann in der klinischen Routine nur ein extracelluläres Magnesiumdefizit durch Serumbestimmungen gemessen werden; über Magnesiummangel einzelner Organe kann nichts ausgesagt werden. Hinweise für Magnesiummangel geben aber neben der Messung des Serumspiegels Anamnese, klinischer Befund, bestimmte EKG-Veränderungen wie auch evtl. Hypokalämie, ein Zustand, bei dem sich oft — besonders bei Aldosteronismus — parallele Veränderungen zeigten.Tierexperimente deuten darauf hin, daß infarktähnliche Läsionen unter Magnesiummangel entstehen, doch ob Herzinfarkt beim Menschen durch Magnesiummangel ausgelöst werden kann, ist noch ungeklärt. In Leichenherzen zeigte sich im Infarktgebiet neben Calciumakkumulation signifikanter Magnesiumverlust, wobei unklar blieb, ob sich Ursache oder Folge des Infarktes widerspiegelten. Falls ein ursächlicher Zusammenhang besteht, ist er im Myokardstoffwechsel selbst zu suchen, wie bei der Alkoholkardiomyopathie, wo myokardialer Magnesiummangel zumindest als pathogenetischer Teilfaktor anerkannt wird. Andererseits versucht man aber auch Beziehungen zwischen Atherosklerose, Blutgerinnung und Hypomagnesämie herzustellen, in der Meinung, daß Magnesiummangel auch über den coronaren Pathomechanismus des Herzinfarktes wirken könnte. Sicher scheint, daß gewisse EKG-Veränderungen und Herzrhythmusstörungen durch einen irritierten Magnesiumhaushalt bedingt sein können, da sie bei Gabe bzw. Entzug von Magnesium verschwinden. Daß Magnesiummangel die Glykosidtoleranz verringert, wird tierexperimentell bestätigt. Unter Hypomagnesämie bewirkt Acetylstrophanthidin eher und länger Rhythmusstörungen als ohne, außerdem lassen diese sich durch Magnesiumgaben eliminieren. Da in gewissen Fällen spontane und digitalisinduzierte Herzrythmusstörungen durch Magnesiuminjektionen beseitigt wurden, scheint Magnesium als Therapeuticum angebracht. Einsatz verschiedener Magnesiumsalze bei Angina pectoris, degenerativen Herzerkrankungen und Herzinsuffizienz ohne geprüften und offensichtlich gestörten Magnesiumhaushalt ist fragwürdig, weil keine eindeutigen klinischen Erfolgsbeweise vorliegen. Immerhin mag es aber larvierte, durch Serumbestimmungen nicht erfaßbare Mangelzustände geben. Allgemein erscheint es aus kardiologischer Sicht ratsam, den Magnesiumhaushalt zu überwachen und in entsprechenden Fällen auszugleichen, um möglichen Myokardläsionen oder fatalen Herzrhythmusstörungen entgegenzuwirken.     

Class II HLA in Georgia Caucasus Tbilisi Georgians and their Mediterranean ancestry: The Usko Mediterranean languages

Georgia (or Sakartvelo in its own language) is a South Caucasus Mts. country with its easternmost part is enigmatically named Iberia, like the Iberian Peninsula, which may refer to rivers “Kura” and “Ebro” or their valleys respectively. Most of their inhabitants speak Georgian which is included within Dene-Caucasian group and Usko-Mediterranean subgroup of languages. The latter includes Basque, Berber, ancient Iberian-Tartessian, Etruscan, Hittite, Minoan Lineal A and others. In the present paper, HLA class II -DRB1 and -DQB1 alleles has been studied and extended haplotypes calculated. Most frequent haplotypes are also of Mediterranean origin (i. e.: (A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*51)-DRB1*13:01-DQB1*06:03, or (A*24-B*35)-DRB1*01:01-DQB1*05:01) and DA genetic distances show that closest world populations to Georgians are Mediterraneans. Georgians also show common extended haplotypes ((A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*13)-DRB1*07:01-DQB1*02:01 and (A*03-B*35)-DRB1*11:01-DQB1*03:01) with Svan people, a secluded population in North Georgia mountains. We can conclude that Georgians belong to a very old Mediterranean substratum according to both linguistics (Usko Mediterranean languages) and HLA genetics.     

Environmental risk factors and their role in the management of atopic dermatitis

Introduction: The etiology of atopic dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors.

Areas covered: We review the role of prenatal exposures, irritants and pruritogens, pathogens, climate factors, including temperature, humidity, ultraviolet radiation, outdoor and indoor air pollutants, tobacco smoke exposure, water hardness, urban vs. rural living, diet, breastfeeding, probiotics and prebiotics on AD.

Expert commentary: The increased global prevalence of AD cannot be attributed to genetics alone, suggesting that evolving environmental exposures may trigger and/or flare disease in predisposed individuals. There is a complex interplay between different environmental factors, including individual use of personal care products and exposure to climate, pollution, food and other exogenous factors. Understanding these complex risk factors is crucial to developing targeted interventions to prevent the disease in millions. Moreover, patients require counseling on optimal regimens for minimization of exposure to irritants and pruritogens and other harmful exposures.     

'Very sore nights and days': the child's experience of illness in early modern England, c.1580-1720

Sick children were ubiquitous in early modern England, and yet they have received very little attention from historians. Taking the elusive perspective of the child, this article explores the physical, emotional, and spiritual experience of illness in England between approximately 1580 and 1720. What was it like being ill and suffering pain? How did the young respond emotionally to the anticipation of death? It is argued that children’s experiences were characterised by profound ambivalence: illness could be terrifying and distressing, but also a source of emotional and spiritual fulfilment and joy. This interpretation challenges the common assumption amongst medical historians that the experiences of early modern patients were utterly miserable. It also sheds light on children’s emotional feelings for their parents, a subject often overlooked in the historiography of childhood. The primary sources used in this article include diaries, autobiographies, letters, the biographies of pious children, printed possession cases, doctors’ casebooks, and theological treatises concerning the afterlife.