Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

Molecular mimicry of viral antigens with self determinants has been proposed as one of the pathogenic mechanisms in autoimmune disease. Evidence of viral mimicry in animal models of autoimmunity is accumulating. Murine adenovirus, Semliki forest virus, lactate dehydrogenase-elevating virus, herpes simplex virus type-1, hepatitis B virus, encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, Coxsackievirus and cytomegalovirus have been found to mimic physiologically important host proteins. However, epitope homology of a viral and self determinant is not in itself strong evidence for mimicry as a pathogenic mechanism. The mimicking determinant must also be capable of inducing disease in the absence of replicative virus. Animal models provide evaluation of the viral trigger, and development and therapy for autoimmune diseases. Identification of host proteins that can induce disease together with the knowledge of immune system dysregulation, genetic association and environmental factors may lead to improved immunotherapeutic strategies for human autoimmune diseases.     

Experimental economics' inconsistent ban on deception

According to what I call the ‘argument from public bads’, if a researcher deceived subjects in the past, there is a chance that subjects will discount the information that a subsequent researcher provides, thus compromising the validity of the subsequent researcher's experiment. While this argument is taken to justify an existing informal ban on explicit deception in experimental economics, it can also apply to implicit deception, yet implicit deception is not banned and is sometimes used in experimental economics. Thus, experimental economists are being inconsistent when they appeal to the argument from public bads to justify banning explicit deception but not implicit deception.     

Molecular mimicry: a critical look at exemplary instances in human diseases

Molecular mimicry, the concept that antigenic determinants of microorganisms resemble antigenic determinants of the host, is frequently cited as a plausible mechanism to account for the association of infection and autoimmune disease. Based on analogous sequences of amino acids or on cross-reactions of monoclonal antibodies, numerous examples of such mimicry have been reported. There are, however, no clear examples of a human disease caused by molecular mimicry.     

Apoptosis and apoptotic mimicry: the Leishmania connection

Different death-styles have been described in unicellular organisms. In most cases they evolve with phenotypic features similar to apoptotic death of animal cells, such as phosphatidylserine (PS) exposure, oligonucleosomal DNA fragmentation, and loss of mitochondrial transmembrane potential, hinting that similar mechanisms operate in both situations. However, the biochemical pathways underlying death in unicellular organisms are still unclear. Host recognition of PS exposed on the surface of unicellular parasites is an important feature of the process of infection and progression of the disease. Here, we discuss data showing that entirely different mechanisms of PS exposure co-exist during the life-cycle of Leishmania amazonensis: in the case of promastigotes, a sub-population dies by apoptosis; in the case of amastigotes, the entire population exposes PS, not necessarily followed by apoptotic death. This phenomenon has been called apoptotic mimicry. The elusive caspase-like activities described in protozoa are also discussed.     

Molecular mimicry in neurological disease: what is the evidence?

Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans. Received 9 July 2007; received after revision 15 November 2007; accepted 27 November 2007     

Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes

Autoimmune diseases result from a combination of genetic, immunologic, hormonal, and environmental factors. Infectious agents may induce the breakdown of immunological tolerance and the appearance of autoreactivity. However, the specific relationship between infection and autoimmunity is still unclear. One of the mechanisms responsible could be molecular mimicry between the infectious agent and self. The concept of molecular mimicry is a viable hypothesis in the investigation of the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Immune-mediated (type 1) diabetes in humans and in non-obese diabetic (NOD) mice is polygenic and characterized by autoimmune destruction of insulin-producing pancreatic beta cells in islets of Langerhans. In NOD mice, a T-helper 1 (Th1)-based autoimmune response arises spontaneously against glutamate decarboxylase (GAD) concurrently with the onset of insulitis. Subsequently. this Th1-type autoreactivity spreads intra- and intermolecularly to other beta cell autoantigens, suggesting that a Th1-type response is responsible for the progression of the disease, whereas Th2 responses when experimentally induced are protective. In humans, a homology between GAD and the P2-C protein of Coxsackie B make a cause-and-effect molecular mimicry an attractive hypothesis. Evidence to support the concept of molecular mimicry in diabetes is reviewed.     

Presence of hsp65 in bacterial extracts (OM-89): A possible mediator of orally-induced tolerance?

Heat shock proteins (HSP) have been implicated in rodent models of autoimmunity, particularly arthritis, and there is suggestive though inconclusive evidence that they may also play a role in human autoimmune disease. The simplest hypothesis is based on molecular mimicry due to the amino-acid sequence homology between mammalian and microbial HSP. Recently OM-89, an extract of several strains ofEscherichia coli, has shown some efficacy in the treatment of rheumatoid arthritis (RA) when taken orally. Using species-specific antibodies, we show here that OM-89 contains the 65 kDa HSP (hsp65), while hsp65 was not detected in another bacterial extract containing other microorganisms, includingStaphylococcus aureus (OM-85). We suggest that if the human homologue of hsp65 is a relevant target antigen in the human disease, the efficacy of the preparation could be due to induction of oral tolerance or to switching the Th1 response towards Th2. Alternatively, even if the human hsp65 is not a target molecule in RA joints, OM-89 may evoke bystander suppression of joint inflammation via induction of TGF-secreting effector cells. These hypotheses should be tested in further studies.     

Current cases in which epitope mimicry is considered a component cause of autoimmune disease: Guillain-Barré syndrome

Some patients develop Guillain-Barré syndrome (GBS) after the administration of bovine gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody to GM1 ganglioside. Miller Fisher syndrome (MFS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. Molecular mimicry between GM1 and lipopolysaccharide of C. jejuni isolated from patients with GBS, and between GQ1b and C. jejuni lipopolysaccharides from patients with MFS have been demonstrated. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies. This sugar mimicry is one possible cause of the Guillain-Barré and Miller Fisher syndromes; however, unidentified host factors may contribute to the development of these syndromes.     

Über ein Chromoplastin aus reifenden Tomaten

Summary (1) By precipitation with ammonium sulfate, streptomycin, or calcium salts, we obtained from the pulp of tomatoes a substance containing carotinoids. The behaviour of this substance was analogous to that of chloroplst-substance and to that of animal cytoplasmatic nucleoproteins. Like these it contains proteins, lipids, and very probably nucleic acids. We regard this substance as achromoplastine.(2) Experiments with slices of green tomatoes show that the changing over of the chlorophyll content into the carotinoid content is inhibited by the presence of streptomycin.(3) Streptomycin inhibits the formation of chlorophyll in etiolated separated cabbage leafs, just as this drug inhibits the formation of chlorophyll in growing seeds.(4) The development of anthocyanides is not influenced by streptomycin.     

Transplantation of human cortex with Alzheimer's disease into rat occipital cortex; a model for the study of Alzheimer disease

Summary Senile dementia of the Alzheimer type (SDAT) is a major problem in the human senescent population. As this pathology cannot be reproduced in animals, research into its development is greatly impeded. The technique of implantation of the nervous tissue has been utilized in order to establish an animal model and to test the possible existence of a transmissible agent. When human temporal cortex with Alzheimer's disease is implanted in the occipital cortex of 7-week-old rats, human cerebral tissue containing abundant tangles induces in the receiver cortex a reactive fibrous gliosis. In the processes of the astrocytes, twisted filaments are evident among bundles of normal filaments. These alterations could be induced by the metabolising of abnormal filament subunits or by some infectious agent introduced by the implant.This study is supported by grant No. 2.4517.82 of Fonds de la Recherche Fondamentale Collective of Belgium.     

高中频CPM数字接收机设计

本文给出了一种适用于软件无线电的突发模式非相干二进制CPM接收机。该接收机采用前馈结构,利用FFT算法对前导进行捕获和分析,可以快速实现载波频偏和符号定时误差的联合估计,采用多符号检测算法来对CPM信号实现解调。通过仿真和对硬件的需求分析验证了本接收机可以有效检测信号的到来,快速实现载波和符号的联合同步,且比传统接收机具有更低的误码率。相对较低的硬件复杂度也使得接收机容易在FPGA上实现。     

Transplantation of human cortex with Alzheimer's disease into rat occipital cortex; a model for the study of Alzheimer disease

Senile dementia of the Alzheimer type (SDAT) is a major problem in the human senescent population. As this pathology cannot be reproduced in animals, research into its development is greatly impeded. The technique of implantation of the nervous tissue has been utilized in order to establish an animal model and to test the possible existence of a transmissible agent. When human temporal cortex with Alzheimer's disease is implanted in the occipital cortex of 7-week-old rats, human cerebral tissue containing abundant tangles induces in the receiver cortex a reactive fibrous gliosis. In the processes of the astrocytes, twisted filaments are evident among bundles of normal filaments. These alterations could be induced by the metabolising of abnormal filament subunits or by some infectious agent introduced by the implant.     

Scientific patronage in the age of Darwin: The curious case of William Boyd Dawkins

This essay examines the curious relationship between Charles Darwin and the palaeontologist William Boyd Dawkins (1837–1929). Dawkins was a beneficiary of Darwin's patronage and styled himself as a Darwinian to Darwin and the public, yet viciously attacked Darwin and his theory in anonymous reviews. This has confused historians who have misunderstood the exact nature of Dawkins's attitude towards evolution and his relationship to Darwin. The present study explains both the reasons for Dawkins's contradictory statements and his relationship with Darwin. I introduce Batesian mimicry as a conceptual framework to make sense of Dawkins's actions, suggesting that Dawkins mimicked a Darwinian persona in order to secure advancement in the world of Victorian science. Dawkins's pro-Darwinian stance, therefore, was a façade, an act of mimicry. I argue that Dawkins exploited Darwin for his patronage – which took the form of advice, support from Darwin's well-placed friends, and monetary assistance – while safely expressing his dissent from Darwinian orthodoxy in the form of anonymous reviews. This is, therefore, a case study in how scientific authority and power could be gained and maintained in Victorian science by professing allegiance to Darwin and Darwinism.     

GNSS接收机伪距测量对定位的影响

伪距测量是全球卫星导航系统（GNSS）与其它无线通信系统一大显著区别之一。在卫星导航定位系统中,必须通过PRN码测出用户接收机到各颗卫星的距离,才能定位。卫星钟差、用户钟差、多普勒效应、电离层延迟、对流层延迟等,都使测距产生一定的误差,所以称为伪距。伪距测量的精度,直接影响到定位的精度。为定量分析伪距测量对定位结果的影响,本文给出选择不同星的伪距和同一伪距不同误差情况下对最终定位结果的影响,为接收机的研发提供重要的参考。     

Edge cases in animal research law: Constituting the regulatory borderlands of the UK's Animals (Scientific Procedures) Act

This paper explores how the boundaries of the UK's Animals (Scientific Procedures) Act (A(SP)A) are constituted, as illustrative of the rising importance of legal procedures around animal research and how these are continuously being challenged and questioned. Drawing on empirical work in animal research communities, we consider how it is decided whether activities are undertaken for an “experimental or other scientific purpose”. We do this by focusing on “edge cases”, where debates occur about whether to include an activity within A(SP)A's remit. We demonstrate that the boundaries of animal research regulation in the UK are products of past and present decisions, dependencies, and social relationships. Boundaries are therefore not clear-cut and fixed, but rather flexible and changing borderlands. We particularly highlight the roles of: historical precedent; the management of risk, workload, and cost; institutional and professional identities; and research design in constituting A(SP)A's edges. In doing so, we demonstrate the importance of paying attention to how, in practice, animal law requires a careful balance between adhering to legal paragraphs and allowing for discretion. This in turn has real-world implications for what and how science is done, who does it, and how animals are used in its service.     

Estimation and forecasting in first‐order vector autoregressions with near to unit roots and conditional heteroscedasticity

This paper investigates the effects of imposing invalid cointegration restrictions or ignoring valid ones on the estimation, testing and forecasting properties of the bivariate, first‐order, vector autoregressive (VAR(1)) model. We first consider nearly cointegrated VARs, that is, stable systems whose largest root, l_max, lies in the neighborhood of unity, while the other root, l_min, is safely smaller than unity. In this context, we define the ‘forecast cost of type I’ to be the deterioration in the forecasting accuracy of the VAR model due to the imposition of invalid cointegration restrictions. However, there are cases where misspecification arises for the opposite reasons, namely from ignoring cointegration when the true process is, in fact, cointegrated. Such cases can arise when l_max equals unity and l_min is less than but near to unity. The effects of this type of misspecification on forecasting will be referred to as ‘forecast cost of type II’. By means of Monte Carlo simulations, we measure both types of forecast cost in actual situations, where the researcher is led (or misled) by the usual unit root tests in choosing the unit root structure of the system. We consider VAR(1) processes driven by i.i.d. Gaussian or GARCH innovations. To distinguish between the effects of nonlinear dependence and those of leptokurtosis, we also consider processes driven by i.i.d. t(2) innovations. The simulation results reveal that the forecast cost of imposing invalid cointegration restrictions is substantial, especially for small samples. On the other hand, the forecast cost of ignoring valid cointegration restrictions is small but not negligible. In all the cases considered, both types of forecast cost increase with the intensity of GARCH effects. Copyright © 2009 John Wiley & Sons, Ltd.     

Mechanisms underlying celiac disease and its neurologic manifestations

The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.Received 11 March 2004; received after revision 29 October 2004; accepted 12 November 2004     

Fetal and animal research in Sweden: The construction of viable lives in regulatory policy debates, 1970–1980

Following demands to regulate biomedicine in the post-war period, Sweden saw several political debates about research ethics in the 1970s. Many of the debates centered on fetal research and animal experiments. At stake were questions of moral permissibility, public transparency, and scientific freedom. However, these debates did not only reveal ethical disagreement—they also contributed to constructing new boundaries between life-forms. Taking a post-Marxist approach to discursive policy analysis, we argue that the meaning of both the “human” and the “animal” in these debates was shaped by a need to manage a legitimacy crisis for medical science. By analyzing Swedish government bills, motions, parliamentary debates, and committee memorials from the 1970s, we map out how fetal and animal research were constituted as policy problems. We place particular emphasis on the problematization of fetal and animal vulnerability. By comparing the debates, we trace out how a particular vision of the ideal life defined the human-animal distinction.     

Modes of A�� toxicity in Alzheimer��s disease

Alzheimer's disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide.     

一种有线无线混合网络下减少TCP重复应答的跨层机制

针对有线无线混合网络中TCP ACK与MAC ACK重复应答问题,提出一种跨层设计机制。通过AP代理回复移动接收端的TCP ACK,避免了移动接收端同时发送MAC ACK和TCP ACK（移动接收端只发送MAC ACK）。该机制实现简单,只需少量修改IEEE802．11帧格式,在帧控制域中添加必要的TCP ACK类型指示和传递接收端建议窗口大小,就能有效地解决MAC到TCP包收发错误和发送端不能获取接收端接收TCP数据报文能力的问题;并且很容易在现有设备上进行升级。仿真结果表明,该机稍比传统TCP重复应答机制提高约30％的吞吐量。