NLRP3炎性小体研究进展

炎性小体是一种多蛋白复合体,它能够识别多种病原微生物及应激相关内源性信号分子,在固有免疫中发挥重要作用。炎性小体可通过活化半胱氨酸天冬氨酸酶-1(caspase-1)诱导促炎因子IL-1β和IL-18的成熟、释放,引起炎性反应,参与多种疾病如家族性周期性自身炎性反应、缺血再灌注损伤和动脉粥样硬化等的发生发展过程。     

NLRP 3炎性小体激活调控机制及抑制剂研究新进展

含NLR家族PYRIN域蛋白3(NLRP3)炎性小体是一类细胞内多蛋白复合物,可被多种病原微生物或内源性危险分子激活,释放细胞因子IL-1β和IL-18以及引起细胞焦亡,是机体固有免疫的重要组成部分。然而其过度活化可导致慢性炎性反应,与多种重大疾病的发生发展密切相关。因此,深入探究NLRP3炎性小体激活机制对于发展其特异性抑制剂以及相关疾病的治疗具有重要意义。     

NLRP3炎性小体在中枢神经系统疾病中的作用研究进展

炎症是具有血管系统的活体组织对损伤因子所发生的防御反应。神经炎症是神经系统疾病发病机制的重要组成部分,过度的神经炎症会导致神经元死亡、加剧神经系统疾病的发展,抑制神经炎症有助于神经元的存活,改善神经系统疾病的症状和预后。大量研究证实,促炎因子白介素-1β(IL-1β)、白介素-18(IL-18)和肿瘤坏死因子TNF-α在炎症反应中起关键作用。最近研究发现NLRP 3炎性小体可介导IL-1β和IL-18释放,对引发炎性反应部位的细胞焦亡至关重要。目前对神经系统疾病与炎性因子的研究较多,但对神经系统疾病与NLRP 3炎性小体之间关系的研究还在起步阶段,探明它们间的具体关系和作用将对阐明中枢神经系统疾病的发病机制和提高治疗效果具有重要意义。本文对NLRP 3炎性小体在常见神经系统疾病中的作用进行综述。     

NLRP3炎性小体在中枢神经系统疾病中的作用研究进展

炎症是具有血管系统的活体组织对损伤因子所发生的防御反应。神经炎症是神经系统疾病发病机制的重要组成部分,过度的神经炎症会导致神经元死亡、加剧神经系统疾病的发展,抑制神经炎症有助于神经元的存活,改善神经系统疾病的症状和预后。大量研究证实,促炎因子白介素-1β(IL-1β)、白介素-18(IL-18)和肿瘤坏死因子TNF-α在炎症反应中起关键作用。最近研究发现NLRP 3炎性小体可介导IL-1β和IL-18释放,对引发炎性反应部位的细胞焦亡至关重要。目前对神经系统疾病与炎性因子的研究较多,但对神经系统疾病与NLRP 3炎性小体之间关系的研究还在起步阶段,探明它们间的具体关系和作用将对阐明中枢神经系统疾病的发病机制和提高治疗效果具有重要意义。本文对NLRP 3炎性小体在常见神经系统疾病中的作用进行综述。     

髓源性抑制细胞在慢性骨髓炎中的作用研究北大核心CSCD

目的 研究髓系来源的抑制性细胞（myeloid-derived suppressor cells,MDSCs）在大鼠慢性骨髓炎疾病中的免疫作用，为骨髓炎的治疗探索新方法。方法 首先建立大鼠慢性骨髓炎模型，并使用吉西他滨抑制MDSCs增长，通过流式细胞术及免疫荧光检测大鼠骨髓及脾脏中的MDSCs比例，ELISA检测外周血中炎性因子变化，分析正常大鼠、骨髓炎大鼠以及吉西他滨抑制后的大鼠外周血中炎性因子水平（TNF-α、PCT、IL-4、IL-10、IL-17、IFN-γ、TGF-β）与骨髓中MDSCs的相关性，分析MDSCs在慢性骨髓炎疾病中的免疫作用。结果 骨髓炎模型大鼠骨髓及脾脏中的MDSCs细胞比例增高，使用吉西他滨组MDSCs细胞比例明显降低（P<0.05），炎性因子水平（TNF-α、PCT、IL-4、IL-10、IL-17、IFN-γ、TGF-β）与MDSCs的细胞比例变化呈正相关（P<0.05）。结论 大鼠骨髓炎中MDSCs细胞比例变化与炎性因子水平呈正相关，吉西他滨抑制MDSCs可能通过抑制MDSCs而降低炎性反应，促进机体修复。     

炎性细胞因子在肌萎缩侧索硬化诊断治疗中的研究进展

肌萎缩侧索硬化(ALS)是一种多个基因参与的复杂疾病,涉及多种机制。神经炎性反应是其中机制之一,有许多炎性细胞因子参与,其有可能作为生物标志物及治疗靶点应用于临床。突变基因编码的许多蛋白质可损害免疫系统功能,导致免疫功能失调,驱动中枢神经系统和外周免疫系统的炎性反应。炎性细胞因子种类较多,水平变化较大,受疾病阶段、类型及共病影响,目前在ALS中的结果尚不一致,无单一炎性细胞因子可做为特异标志物。炎性细胞因子做为治疗监测标志物及靶点有一定前景。     

IL-37在肿瘤炎性微环境中的作用

炎症在肿瘤的发生发展过程中起关键性作用,慢性炎症持续存在形成炎性微环境可促进肿瘤的发生发展。IL-37通过抑制免疫细胞、降低细胞因子的表达和阻断相关信号通路的激活等抑制炎症反应。在抑制肿瘤的增殖、侵袭、迁移、血管生成和相关信号通路的激活过程中,IL-37发挥重要作用。本文主要综述IL-37在肿瘤炎性微环境中的抗肿瘤作用,为肿瘤治疗提供新的思路。     

IL-1家族新成员IL-36、IL-37和IL-38在炎症性疾病中的作用

IL-1参与多种炎症和自身免疫性疾病过程。IL-1家族新成员IL-36、IL-37和IL-38在炎症性疾病中发挥不同的调节作用。它们参与银屑病、类风湿关节炎、痛风、系统性红斑狼疮和克罗恩病等炎症性疾病的发病过程。IL-36作为促炎细胞因子能促进更多炎症介质的活化;相反,IL-37和IL-38是抑炎细胞因子,能抑制炎症反应。因此,研究IL-1家族成员的失衡对未来相关疾病的治疗十分重要。本文综述了IL-1家族新成员IL-36、IL-37和IL-38的表达及在相关炎症性疾病中作用的研究进展。     

NLRP3炎性小体在缺血再灌注损伤治疗中作用的研究进展

NLRP3 (NLRP3)炎性小体作为组成先天免疫系统的蛋白复合体，可通过调节IL-1β和IL-18的成熟释放介导炎性反应，是机体发生多种病理损伤的基础。缺血/再灌注损伤(I/RI)时产生的多种损伤因子均可激活NLRP3炎性小体，导致IL-1β和IL-18的过度释放，进而引起炎性级联反应使各组织器官的损伤加重。而抑制NLRP3炎性小体活化已成为减轻器官I/RI的有效方法。因此，探究NLRP3炎性小体介导I/RI的详细作用机制，可以为器官I/RI的防治提供理论依据。     

组蛋白去乙酰化酶2在烟雾致COPD大鼠肺组织中表达下降

慢性阻塞性肺疾病(chronic obstructive pneumonia disease,COPD)是一种有多种炎性因子、炎性介子参与的气道慢性炎性反应疾病,其炎性反应过程复杂使病情反复迁延[1]。组蛋白乙酰化酶(histone acetylase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)在各种炎性反应基因的表达中起重要作用。因此,COPD气道炎性反应可能与之变化所致的炎性反应基因表达增加有关。本实验使用烟熏制备     

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.     

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.     

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.     

The case for allele‐specific recognition by the TCR

There is a sharp difference in how one views TCR structure–function–behaviour dependent on whether its recognition of major histocompatibility complex‐encoded restriction elements (R) is germline selected or somatically generated. The generally accepted or Standard model is built on the assumption that recognition of R is by the V regions of the αβ TCR, which is not driven by allele specificity, whereas the competing model posits that recognition of R is allele‐specific. The establishing of allele‐specific recognition of R by the TCR would rule out the Standard model and clear the road to a consideration of a competing construct, the Tritope model. Here, the case for allele‐specific recognition (germline selected) is detailed making it obvious that the Standard model is untenable.     

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.