缺氧状态下细胞自噬变化及其对心血管疾病的改善

自噬是细胞维持内环境稳态的重要方式之一,它是一种细胞缺血及代谢应激时与缺氧相关联的幸存机制。在某些心血管疾病中,缺血（缺氧）微环境会通过多种途径激活自噬,适当的自噬能够降解自身受损蛋白等来维持细胞生存,但当自噬过度时,则会损伤细胞,甚至使细胞发生II型程序性死亡。目前,治疗这类心血管疾病的方式主要有药物疗法和干细胞移植法,而白噬在这其中扮演着重要角色。对于不同类型和不同程度的心血管疾病,自噬可作为促存活机制,也可作为促死亡机制。因此,如何利用自噬有效改善某些心血管疾病是难点所在。     

自噬与肿瘤关系的研究进展

自噬是细胞适应环境变化、防御病原微生物侵袭、维持内环境稳定的重要机制.在多种人类肿瘤中存在有自噬活性的改变,自噬在肿瘤的发生发展过程中起到了促进和抑制的双重作用.对自噬研究的不断深入,不仅进一步揭示了真核生物自身调控的复杂性和多样性,更为肿瘤的基因治疗及克服肿瘤耐药性提供了新的思路.现将自噬与肿瘤的发生、发展的研究进展做一综述.     

细胞自噬与幽门螺杆菌感染

幽门螺杆菌是一种广泛定植于人胃黏膜的革兰阴性菌,它通过逃逸机体局部免疫杀灭而持续感染,最终导致胃上皮损伤,与多种胃部疾病相关.自噬是进化过程中保留的细胞机制,既能清除胞质内容物,又不影响细胞的生存.幽门螺杆菌能够入侵胃上皮细胞和某些免疫细胞,诱导自噬的发生,并在自噬体中自我复制后被清除,推测自噬可能在幽门螺杆菌感染中扮...     

细胞自噬机制开启疾病治疗新途径

自噬是指细胞内细胞器和蛋白质等在溶酶体被降解及其降解产物被重新利用的过程。日本科学家大隅良典(Yoshinori Ohsumi)发现了15个自噬相关基因并阐述了自噬机制,获得2016年诺贝尔生理学与医学奖。他的开创性研究成果为探讨细胞自噬的生理和病理作用奠定了重要基础,并为通过调节细胞自噬治疗疾病开辟了新途径。自噬是一种普遍性细胞反应,正常情况下细胞自噬水平很低,受生理或病理性刺激后自噬水平显著升高。自噬相关基因缺失或自噬功能障碍时可导致某些疾病的发生。近来,人们试图通过激活或抑制细胞自噬预防和治疗自噬障碍相关性疾病。     

细胞自噬在病毒感染与免疫过程中的作用

自噬是细胞维持内环境稳态的一种保护机制,不仅调节细胞代谢,在应激条件下,自噬通过降解并回收利用细胞成分促进细胞存活。在病毒感染过程中,自噬作为监督机制将病毒抗原传递给富含免疫感应器的内体/溶酶体,激活固有免疫反应,自噬还可加工提呈病毒抗原激活适应性免疫反应,此外,自噬体本身就可降解病毒。然而,病毒为了逃避自噬,也进化出许多阻止自噬的方式。由于自噬的抗病毒作用,人们期望利用自噬对微生物感染进行治疗。本文对自噬在抗病毒免疫中的作用及其潜在应用价值的研究进展进行综述。     

植物凝集素诱导肿瘤细胞凋亡和自噬的研究进展

植物凝集素是一种非免疫原性的蛋白质,在植物界广泛分布。它可以专一性地识别并结合单糖或寡糖,这种结合具有可逆性。植物凝集素与细胞表面表达的糖分子结合后能够引发细胞内一系列的生物化学反应,使细胞或机体代谢发生改变,例如诱导细胞凋亡和自噬。现就植物凝集素诱导肿瘤细胞凋亡和自噬可能的分子机制作一综述。     

自噬的免疫调节作用和机制

自噬是细胞内降解细胞成分的主要通道,对生物体的生存、分化、发育和维持其动态平衡具有关键作用。自噬机制既可作为免疫系统清除细胞内病原物质的效应器,也可作为模式识别受体或细胞因子的效应器,帮助免疫系统确认病原侵入和细胞转化。更为重要的是,自噬过程还可通过将细胞内物质转移到溶酶体降解并呈递给Ⅱ型MHC分子,与细胞应激和炎症反应耦联,参与调节固有免疫和适应性免疫反应。对自噬参与免疫反应分子机制的研究将加深对免疫反应分子机制的全面了解,为自噬相关疾病防治提供新的机会和途径。     

线粒体自噬在器官纤维化疾病中作用的研究进展

线粒体自噬是一种选择性降解细胞中损伤或多余线粒体的特异性自噬现象,使细胞在应激损伤时能够维持线粒体数量和质量的稳定,从而维持细胞的正常表型和功能。其分子机制途径较为复杂,主要涉及PINK1/Parkin途径、NIX和BNIP3、FUNDC1等。线粒体自噬的异常与多种疾病密切相关,而调节不同阶段线粒体自噬分子机制在疾病发展中的作用已被重视。现就近年线粒体自噬在多种器官纤维化病变中的研究进展综述如下。     

细胞自噬的调控与自噬程序性死亡的研究进展

自噬(autophagy)是一种溶酶体依赖性降解途径,涉及细胞内长寿蛋白和受损伤细胞器的降解,其既是细胞保守的自我防御机制,又是一种程序性细胞死亡机制(PCD),与机体的多种疾病有密切关系.自噬具有独特的形态改变和特有的调控通路,自噬的调控涉及到多种机制、如翻译后修饰等.凋亡是研究最清楚的程序性细胞死亡机制,凋亡与细胞自噬程序性死亡之间存在着复杂的关系.对哺乳动物细胞自噬的分子调控机制,自噬程序性细胞死亡过程及其与凋亡的关系等方面进行探讨很有意义.     

肥胖状态下不同组织细胞与自噬关系的研究进展

近年来越来越多的关注投向肥胖与自噬之间关系的研究,肥胖状态下机体不同组织细胞中的自噬发挥不同的作用.脂肪细胞特异性自噬基因Atg7和Atg5被敲除后脂滴积累减少,胰岛素抵抗得到改善;肝细胞中增加自噬可以提高其代谢功能:胰岛β-细胞中自噬缺陷可损伤细胞功能:适宜的自噬水平对维持骨骼肌内环境的稳态至关重要.     

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.     

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.     

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.     

'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 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.