Toll样受体在寄生虫感染过程中的作用

Toll样受体（TLR）是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要的作用。TLR通过识别病原相关模式分子以激活抗感染的天然免疫应答和适应性免疫应答。TLR信号通路可通过诱导炎性因子的产生在适应性免疫应答中发挥重要作用。本文就TLR在寄生虫感染中发挥的作用作一综述。     

脑缺血后TLR4作用与小胶质细胞的激活

脑缺血性损伤早期小胶质细胞即被激活。激活的小胶质细胞既有细胞毒性又有神经营养作用。小胶质细胞行使免疫功能的信号转导受体之一是TLR4（toll-like receptor 4）。TLR4在脑内主要表达在小胶质细胞，是一种模式识别受体（pattern recognition receptor，PRR）, 识别一些外源性和内源性的配体。最近的研究表明，TLR4信号通路在脑缺血再灌注损伤中起重要作用。TLR4通过激活小胶质细胞，大量表达炎症因子，加重脑缺血性损伤。     

Notch信号通路在感染过程中对免疫应答的调控作用

感染启动的先天性和适应性免疫应答依赖于巨噬细胞、树突状细胞以及T细胞等对病原体的识别与控制。Notch信号是一种高度保守的信号通路,通过相邻细胞间配受体结合被激活,进而协调细胞的重要生命过程。目前已证实Notch信号通路参与多种免疫细胞发育、分化、成熟和激活,并在感染性疾病中发挥重要作用。本文综述Notch信号通路在不同病原体感染过程中的免疫调控作用及其与其他通路的相互作用,并讨论在感染性疾病中以Notch信号为靶点的治疗方法及面临的挑战。     

Toll样受体激动剂在肿瘤治疗中的研究进展

Toll样受体是一类天然模式识别受体,在人和小鼠中均大量表达,其家族包括TLR1~TLR10等一系列受体。TLR配体的激活能够活化下游信号通路,促发多种生物活性因子的释放。近来发现,TLR配体可以作为佐剂或免疫激活剂用于肿瘤治疗,但也有配体发挥肿瘤促进作用,本文就不同配体对肿瘤的作用及其机制进行综述。     

Toll样受体4信号转导研究进展

Toll样受体（Toll-like-receptors,TLRs）是一个主要分布于炎症细胞的识别病源分子的受体超家族,其中TLR4主要识别革兰阴性细菌细胞壁成分脂多糖（lipopolysaccharide,LPS）。LPS与TLR4结合后活化髓样分化因子88 (myeloid differentiation factor 88, MyD88)依赖性和非依赖性两条信号途径;前者活化丝裂原激活的蛋白激酶（mitogen-activated protein kinase,MAPK）和核因子-κB（nuclear factor kappa B,NF-κB）信号通路,后者活化NF-κB和干扰素调节因子-3(IFN-regulated factor-3,IRF3)信号通路。通过这些信号途径TLR4诱导炎症细胞释放炎症因子介导炎症反应;同时TLR4通过活化树突状细胞促进抗原递呈,介导先天性免疫向获得性免疫的转化。此外,TLR4能诱导磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-AKT）的信号转导,LPS介导的细胞存活和增殖与TLR4活化 PI3K-AKT途径有关。     

Toll样受体7在抗感染与自身免疫疾病中的作用

Toll样受体7(TLR7)是表达在哺乳动物细胞内涵体膜表面的跨膜信号传导受体,通过识别单链RNA,激活天然免疫系统,同时通过诱导浆细胞样树突状细胞(pDC)分泌Ⅰ型干扰素(IFN-α)来调控获得性免疫反应。TLR7尤其在抗感染与自身免疫方面发挥重要作用。在深入研究TLR7及其信号通路的基础上,以其作为药物干预靶点,对治疗相关感染性疾病、自身免疫性疾病具有重要的科学意义和应用价值。     

Rab7 基因沉默对巨噬细胞中R848 激活的细胞因子及MAPK 信号通路影响

目的:本实验阐述了Rab7 对Raw264.7 巨噬细胞中R848 激活TLR7(Toll like receptor-7)所产生的细胞因子的影响,并探讨Rab7 对MAPK 信号转导的影响。方法:使用Rab7 刺激silence-Rab7-Raw264.7 细胞,检测R848 激活TLR7 后产生的TNF鄄琢、IL鄄6、IFN-α、IFN-β与IP-10,通过Western blot 检测MAPK 的磷酸化水平,分析Rab7 对MAPK 的信号转导的作用。结果:Rab7 对TLR7 激活后细胞因子的产生具有抑制作用,Rab7 对MAPK 信号通路具有抑制作用。结论:本实验结果进一步说明Rab7 是TLR7 信号转导通路的负向调控因子,并且参与到MAPK 信号通路中。     

脂多糖通过TLR4对幼年哮喘大鼠气道炎症的调节作用

以前的研究表明，TH2细胞的优势应答是导致嗜酸性粒细胞性哮喘发生发展的主要免疫学基础。近年研究发现，Toll样受体（TLR）信号通路激活诱导TH1免疫应答的作用可用来防治有害的TH2优势应答，如哮喘病的发生发展。然而在免疫激活的初始阶段TLR4刺激物脂多糖（LPS）的不同构型、不同浓度以及不同作用时间会影响适应性免疫应答的极化方向，目前对LPS在哮喘的气道炎症发生发展中的作用仍有争论。     

Toll样受体与肿瘤免疫

toll样受体（toll-like receptors,TLRs）是新近十余年发现的主要在哺乳动物细胞表面进化上高度保守的受体分子家族,主要通过识别病原相关分子模式（pathogen-associated molecular patterns,PAMPs）来迅速激活天然免疫系统,并且还能够诱导获得性免疫的产生。迄今为止,已经发现哺乳动物至少有13种toll样受体,其中人的toll样受体鉴定出11种（TLR1-TLR11）。在某些肿瘤中TLRs的表达发生量的变化,并且许多微生物组分和药物能够通过TLRs信号通路介导肿瘤的免疫治疗。     

Toll样受体在机体抗病毒免疫反应中的作用

哺乳动物的Toll样受体(TLR)家族具有模式识别受体的功能,其可以识别微生物的保守分子成分,启动机体的固有免疫系统,从而帮助机体清除病原体.利用TLR敲除的动物或细胞模型进行的研究使人们认识到TLR在机体抗病毒免疫反应中发挥着重要作用.病毒与宿主细胞的TLR结合后,通过NF-κB或IRF-3的信号路径激活细胞因子的表达,从而激发免疫应答.研究TLR如何与病原体结合及如何激活下游基因对深入认识病原体所致相关疾病的发病机制、免疫应答及病理生理具有重要的意义,并为病毒性疾病的临床治疗或免疫预防提供新的思路.     

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.     

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.     

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.     

'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.     

Guidelines for the Validation and Use of Immunoassays for Determination of Introduced Proteins in Biotechnology Enhanced Crops and Derived Food Ingredients

Recent advancements in agricultural biotechnology have created a need for analytical techniques to determine introduced proteins in crops enhanced through modern biotechnology techniques. These proteins are expressed in plant tissues and may be present in food ingredients. Immunoassays are ideally suited for protein detection and may be used as both quantitative and threshold methods. Microplate ELISA and lateral flow devices are two of the most commonly used immunoassay formats for agricultural biotechnology applications. This paper provides general background information and a discussion of criteria for the validation and application of immunochemical methods to the analysis of proteins introduced into plants and food ingredients using biotechnology methods. It is the result of a collaborative effort of members of the Analytical Environmental Immunochemical Consortium. This collaborative effort represents the combined expertise of several organizations to reach consensus on establishing guidelines for the validation and use of immunoassays. Further, the paper offers developers and users a consistent approach to adopting the technology as well as aid in producing accurate and meaningful results.     

HLA in North Colombia Chimila Amerindians

HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.     

Ultracryotomy: development and application (with examples from the yeast cytology) (author's transl)

The preparation steps usually necessary for obtaining ultrathin frozen sections of biological material (chemical prefixation, enclosing, cryoprotective treatment, freezing, sectioning, and post-staining the sections for transmission electron microscopy) are submitted to a critical analysis. The application of cryo-ultramicrotomy, in particularly for cytochemical purposes, is reviewed. Fundamental considerations of chemical prefixation and poststaining are supported by examples from yeast cytology. Furthermore, the efficiency of the cryo-ultramicrotomy (electron optical resolution of ultrastructural details) is demonstrated on yeast cells and protoplasts.     

The universal muscular chamber. A basic unit of the genitourinary, cardiovascular, gastro-intestinal, skeletal, cutaneous, respiratory and other systems, endocameral hypertension; and spasm, the key to their idiopathic diseases and arthropathies

Starting with the integument, we see many organs are contractile sacs or multiples thereof, which tubes or bags constitute the major part of the entire body. Recognition of this basic unit and its characteristics sheds new light, individually and collectively, on many disorders previously considered unrelated. Muscular tears and perforations develop in the walls of these chambers, being no way peculiar to those organs, wherein, hydrochloric acid occurs. So, it is not necessary to explain the absence of excessive acid from patients who exhibit holes in the gastric, uterine, aortic, duodenal, rectal, pulmonary, retina, and other walls. Muscle, not acid is the great common factor relating idiopathic disorders in the gastrointestinal tract to each other and to similar diseases in other systems. When the units are linked together, the lesions tend to appear as arthropathies, i.e. at the joints. Rephrasing common-place observations, frees us from conventional, conceptual cul-de-sacs. An observation is only as good as its interpretation, so all possibilities must be considered, otherwise, we will remain blinded by our misconceptions.     

Der Einfluß von Nahrungsmitteln und Rauchen auf die klinisch-chemische Diagnostik von Phäochromozytom,Neuroblastom und Karzinoid-Syndrom

Zusammenfassung Der Einfluß von verschiedenen Nahrungsmitteln auf Methoden zur Bestimmung von Adrenalin (AD), Noradrenalin (NA), Vanillinmandelsäure (VMS), Metanephrinen (MN), Homovanillinsäure (HVS) und 5-Hydroxyindolessigsäure (5-HIE) im 24 h-Harn zur Diagnose des Phäochromozytoms bzw. Karzinoid-Syndroms wurde untersucht. Die in die Untersuchung einbezogenen Nahrungsmittel waren: Tee, Kaffee, Mandeln, Ananas, Käse, Walnüsse, Vanillepudding, Bananen, Tomaten und Milchschokolade. Außerdem wurde der Einfluß des Zigarettenrauchens auf die Bestimmung von AD, NA, VMS und MN untersucht.Walnüsse führten zu einer starken Erhöhung der 5-HIE-Ausscheidung. Bananen erhöhten die Ausscheidung von AD, NA, VMS, MN und 5-HIE. Kaffee und Ananas bewirkten eine geringe Zunahme der MN-Werte. Rauchen von 20–30 Zigaretten/Tag beeinflußte keine der vier Variablen.Wenn die beschriebenen Methoden benutzt werden, sollte lediglich auf den Verzehr von Bananen und Walnüssen vor und während der Harnsammelperioden verzichtet werden, da die oberen Normgrenzen im Harn überschritten werden könnten. Ein Verzicht auf Kaffee und Ananas in normalen Mengen ist nicht erforderlich. Es besteht kein Anlaß, weiterhin die bisherigen umfangreichen Restriktionen der übrigen Nahrungsmittel beizubehalten.