Genes, autoimmunity and pathogenesis of rheumatic heart disease
L Guilherme1, KF K?hler1, E Postol1, J Kalil2
1 Heart Institute (InCor), School of Medicine, University of S?o Paulo, S?o Paulo;Institute for Immunology Investigation, National Institute for Science and Technology, University of S?o Paulo, S?o Paulo, Brazil
2 Heart Institute (InCor), School of Medicine, University of S?o Paulo, S?o Paulo;Institute for Immunology Investigation, National Institute for Science and Technology, University of S?o Paulo, S?o Paulo;Clinical Immunology and Allergy Division, School of Medicine, University of S?o Paulo, S?o Paulo, Brazil
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Abstract
Pathogenesis of rheumatic heart disease (RHD) remains incompletely understood. Several genes associated with RHD have been described; most of these are involved with immune responses. Single nucleotide polymorphisms in a number of genes affect patients with RHD compared to controls. Molecular mimicry between streptococcal antigens and human proteins, including cardiac myosin epitopes, vimentin and other intracellular proteins is central to the pathogenesis of RHD. Autoreactive T cells migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specific cytokines. The types of cells involved in the inflammation as well as different cytokine profiles in these patients are being investigated. High TNF alpha, interferon gamma, and low IL4 are found in the rheumatic valve suggesting an imbalance between Th1 and Th2 cytokines and probably contributing to the progressive and permanent valve damage. Animal model of ARF in the Lewis rat may further contribute towards understanding the ARF.
Keywords: Autoimmunity, rheumatic Heart disease, susceptibility genes
How to cite this URL:
Guilherme L, K?hler KF, Postol E, Kalil J. Genes, autoimmunity and pathogenesis of rheumatic heart disease. Ann Pediatr Card [serial online] 2011 [cited 2012 Nov 2];4:13-21. Available
from: https://www.doczj.com/doc/a614209843.html,/text.asp?2011/4/1/13/79617
Rheumatic heart disease (RHD) is still a major health problem in several countries due to the heart lesions that follow a rheumatic fever (RF) episode in 30-45% of patients. The incidence of acute RF (ARF) in some developing countries exceeds 50 per 100,000 children. The worldwide prevalence of RHD is at least 15.6 million cases, and this disease is responsible for around 233,000 deaths/year. [1] RHD results from autoimmune reactions triggered by an untreated S. pyogenes throat infection leading to severe valvular damage in genetically susceptible individuals. Recurrences of ARF play an important role in the worsening of valvular
lesionss. [2],[3]
In the present review, we focus on genetic susceptibility factors, their role in the development of RF and RHD, and the mechanisms that lead to autoimmune reactions and permanent valvular damage. Animal models of the disease will also be discussed, as will prospective vaccines for the prevention of RF and RHD.
Innate and Adaptive Immune Responses : A Brief Review
Protection against pathogens in the humans relies on complex interactions between innate and adaptive immunity. Most of the pathogens that enter the body are recognized initially by the innate immune system. [4]
This defense mechanism is not antigen-specific and is instead focused on the recognition of a limited number of specific patterns that are shared by groups of pathogens (pathogen-associated molecular patterns - PAMPs) by pattern recognition receptors (PRRs) in the host. These PRRs can be soluble in human serum or cell-associated. [5],[6]
The molecules that initiate the complement cascade are examples of soluble PRRs. The complement system is part of the innate immune system and consists of many proteins involved in a cascade of proteolysis and protein complex assembly that culminates in the elimination of invading pathogens. [6] Several components of the bacterial cell surface combine with PRRs such as Ficolin family of proteins, or Mannan binding lectins (MBL). These complexes, in turn combine with serine proteases and lead to complement activation via lectin pathway resulting in opsonophagocytosis of the invading pathogen, apoptosis, or modulation of inflammation. [7],[8],[9],[10]
Toll-like receptors (TLRs) are pivotal cell-associated PRRs in the innate immune system. These receptors are capable of recognizing a wide spectrum of organisms, including viruses, bacteria and other parasites, and are classified into different groups based on their localization (cell surface or intracellular) and the type of PAMPs they recognize. TLR activation leads to the production of proinflammatory cytokines that enable macrophages and dendritic cells (DC) to eliminate invading pathogens. DCs can stimulate T cell expansion and differentiation, initiating an adaptive immune response. [4] The molecules produced during the innate immune response act as signals to activate adaptive immune responses. Antigen presenting cells (APCs), such as DCs, are activated and express costimulatory (CD80 and CD86) and MHC molecules on their cell surface that enable these cells to present processed antigens to T cells through the T cell receptor (TCR). Class I MHC molecules, such as HLA-A, -B and -C, present peptides derived from intracellular pathogens to CD8 + T cells, while class II MHC molecules, such as HLA-DR, -DQ and -DP, present peptides derived from extracellular pathogens to CD4 + T cells, which secrete a wide range of cytokines and have both effector and regulatory roles. Cytokines such as TNF-a and IFN-g act at the site of infection and can affect pathogen
survival and control the immune response. Activation of CD4 + T cells not only leads to the expansion of CD4 + effector cells, but also can promote the expansion and differentiation of antigen-specific CD8 + T cells and B cells. [4]
Cytokines
Cytokines seem to play a pivotal role in the activation of immunological and inflammatory responses in RF. It has been shown that peripheral blood mononuclear cells (PBMC) from children with RF produce more TNF-α than heal thy controls. [20] Moreover, interleukin-6 (IL-6) and TNF-α are considered inducers of the acute phase of RF and are strongly correlated with C-reactive protein. [21],[22]
TNF-α is a proinflammatory cytokine that has been associated with the severity of different autoimmune and inflammatory diseases. The gene that encodes this cytokine is located within the MHC region on chromosome 6p21.3. This region is highly polymorphic, and the TNF-alpha gene also contains a large number of polymorphisms. [23] Some of these were investigated in RF/RHD patients in different countries. An SNP in the promoter region of TNF-alpha (-308A) was associated with susceptibility to RHD in Mexico, Turkey, Brazil, and Egypt. [21],[22],[23],[24],[25],[26] The TNF-alpha -238G allele was also associated with RHD in Mexican and Brazilian patients. [24],[25] The TNF-alpha gene has a proinflammatory effect and is probably associated with the exacerbation of the inflammatory response in RF/RHD patients who present with high serum TNF-α levels[20],[22],[27],[28] and large numbers of TNF-α-producing cells in the throat and valves. [29]
Polymorphisms in other cytokine genes have also been investigated and seem to be involved with the disease. These include TGF beta1, [30],[31] interleukin-1 receptor antagonist (IL1Ra), [32] interleukin 10, [21] amongst others. In Taiwanese RHD patients, both the -509T and 869T alleles of TGF beta 1 were found to be risk factors for the development of valvular RHD lesions. [30] Similar results were found in Egyptian patients. [31] RHD patients from Egypt and Brazil with severe carditis showed low frequencies of allele 1 for IL1Ra, suggesting the absence of control of the inflammatory process. [21],[32]
Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines, together with TGF-β and IL-35. It is produced by activated immune cells, especially monocytes/macrophages and T cell subsets, including regulatory T cells (Tr1 and Treg) and Th1 cells. IL-10 acts through a transmembrane receptor complex, and regulates the functions of many different immune cells. [33]The gene encoding human IL-10 is located on chromosome 1. A large number of polymorphisms have been identified in the IL-10 gene promoter. The genotype IL-10 -1082G/A that is overrepresented in RHD Egyptian patients is associated with the development of multiple valvular lesions (MVL) and with the severity of RHD. [21] More recently, polymorphism in cytotoxic T cell Lymphocyte antigen 4 (CTLA-4), which is a negative regulator of T cell proliferation has also been shown in Turkish RHD patients.[34]
Human Leucocyte Antigen
Human leucocyte antigen (HLA) molecules are encoded by the HLA genes (-A, -B, -C, -DR, -DQ and -DP), which are located on the short arm of human chromosome 6. Early studies of susceptibility for RF/RHD pointed out the association of the disease with several HLA class II alleles, mainly those encoded by the DR and DQ genes.
Several HLA class II alleles were described in locations around the world [Figure 2]. [35],[36]
Figure 2: RF/RHD associated HLA class II alleles:
distribution around the world Several identified
alleles by serology in the 80`s and/or molecular
biology after the 90`s were shown. Americas: (USA,
Mexico, Martinique, South of Brazil); Asia:
(Paquistan-Kashmir, North India, Latvia, Japan,
South China), United Arab Emirates: (Saudi Arabia)
Europe-Asia: (Turkey), Africa: (South Africa and
Egypt)
Click here to view
The HLA-DR7 allele that was found in Brazilian, Turkish, Egyptian, and Latvian patients could be considered the HLA class II gene that is most consistently associated with RF/RHD. HLA-DR4 and -DR7 are associated with HLA-DR53 [Figure 2]. In addition, the association of HLA-DR7 with some HLA-DQB or -DQA alleles may be related to the development of multiple valvular lesions (MVL) in RHD patients in Egypt and in Latvia. [37],[38],[39]
The molecular mechanism by which HLA class II molecules confer susceptibility to autoimmune diseases is not clear. As mentioned above, the role of HLA class II molecules is to present antigens to the TCR, leading to the recruitment of large numbers of CD4 + T cells that specifically recognize antigenic peptides from extracellular pathogens and the activation of adaptive immune responses. Therefore, the associated alleles probably encode molecules that facilitate the presentation of some streptococcal peptides to T cells that later trigger autoimmune reactions mediated by molecular mimicry.
In summary, several alleles of the HLA class II genes appear to be the dominant contributors to the development of RF and RHD. Polymorphisms (SNPs and variable number of tandem repeat sequences of nucleotides) in genes involved with inflammatory responses and host defenses against pathogens that are associated with disease probably contribute to the development of valvular lesions and can determine the type of rheumatic valvular lesions
(stenosis, regurgitation, or both) that occur in RHD patients.
Rheumatic Fever and Rheumatic Heart Disease are
Mediated by Molecular Mimicry Between S.Pyogenes and
Human Proteins
Molecular mimicry between components of B hemolyticus streptococci and human heart tissues is the central problem in the pathogenesis of ARF and RHD. The precise mechanisms are being investigated for many years, and some real progress in the understanding of the pathogenesis is occurring slowly. [40],[41],[42],[43]
Both T and B lymphocytes can recognize pathogenic and self antigens via four different types of molecular mimicry: (1) identical amino acid sequences, (2) homologous but non-identical sequences, (3) common or similar amino acid sequences of different molecules (proteins, carbohydrates) and (4) structural similarities between the microbe or environmental agent and its host.[43],[44] Autoimmune diseases from molecular mimicry may be facilitated because of the phenomena of epitope spreading and TCR degeneracy. Epitope spreading is the mechanism by which an ongoing immune response leads to reactivity against epitopes that are distinct from the original disease-inducing epitope [43],[45] and degeneracy of TCRs, which allows the recognition of a broad spectrum of antigens (self and microbial antigens) by the same T lymphocyte through it`s receptor. [41],[42],[46]
The M protein is the most important antigenic structure of the S. pyogenes and shares structural homology with a-helical coiled-coil human proteins such as cardiac myosin, tropomyosin, keratin, laminin, vimentin and several valvular proteins. [40],[41],[42],[47]
Several studies done in the last 50 years described the presence of cross-reactivity between human proteins and streptococcal antigens recognized by antibodies. [40] Among these human proteins, cardiac myosin and vimentin seem to be the major targets of cross-reactive reactions, along with other intracellular valvular proteins. N-acetyl ?-D-glucosamine, a polysaccharide present in streptococcal cell wall, induces cross-reactivity against laminin, an extracellular matrix alpha helical coiled-coil protein present in the valves. [40] By using affinity purified anti-myosin antibodies, Cunningham?s group identified a five amino acid (Gln-Lys-Ser-Lys-Gln) epitope of the N-terminal M proteins of serotypes 5 and 6 (M5, M6) as being cross-reactive with cardiac myosin. [40]
The interplay of humoral and cellular immune responses in RHD was recently demonstrated by Cunningham?s group through two elegant studies. They showed that, in rheumatic carditis, antibodies that cross-react with streptococcal and human proteins bind to the endothelial surface and upregulate the adhesion molecule VCAM-1 [48] , leading to inflammation, cellular infiltration and valve scarring. [49] These data suggest that ARF may result from initial antibody mediated damage that later may be perpetuated by cell mediated inflammation. [50]
Although antibodies in the sera of RF/RHD patients cross-react with several human proteins, we demonstrated that rheumatic heart disease lesions are mediated mainly by inflammatory cells and CD4 + T lymphocytes. [51]
Studies performed in the last 25 years showed that CD4 + T cells are the major effectors of autoimmune reactions in the heart tissue in RHD patients. [51],[52],[53] The in vitro reactivity of peripheral T cells from RHD patients was evaluated in an early study that showed that these cells were able to recognize a 50- to 54-kDa myocardial protein fraction indicating autoreactivity to heart antigens, which was probably caused by streptococcal infection. [54] The role of T cells in the pathogenesis of RF and RHD was demonstrated through the analysis of heart-tissue infiltrating T cell clones. We demonstrated for the first time that M5 protein peptides (residues 81-96 and 83-103) displayed cross-reactivity with valvular proteins by molecular mimicry. [51] We also showed that valve-infiltrating T cells recognized cardiac myosin peptides by molecular mimicry and epitope spreading mechanisms. [55]These immunodominant M5 epitopes were preferentially recognized by peripheral T lymphocytes from RHD patients, when compared with normal individuals, mainly in the context of HLA-DR7. [56] These results suggested that autoreactive T cells migrate from the periphery to the site of heart lesions. Similarly, Yoshinaga et al. [57] reported that T cell lines derived from heart valve specimens and PBMC from RF and RHD patients react with cell wall and membrane streptococcal antigens. These lymphocytes, however, did not cross-react with the M protein or mammalian cytoskeletal proteins. [57]
Recently, two studies demonstrated mimicry between cardiac myosin and the streptococcal M protein and pointed out different patterns of T cell antigen cross-recognition. One of them focused on peripheral T cell clones from one patient with RHD, which recognized different alpha helical coiled-coil proteins, such as the streptococcal M protein, myosin, laminin and tropomyosin. [58]The other study focused on the reactivity of intralesional T cell clones derived from myocardium and valvular tissue of six RHD patients against cardiac myosin, the streptococcal M5 protein and valve-derived proteins. A high frequency of reactive T cell clones was found (63%). These T cells displayed three patterns of cross-reactivity: (1) cardiac myosin and valve-derived proteins; (2) cardiac myosin and streptococcal M5 peptides; and (3) cardiac myosin, streptococcal M5 peptides and valve-derived proteins.[55]
Using a proteomics approach, we showed that T cells recognize vimentin, further supporting the role of this protein as a putative autoantigen involved in rheumatic lesions. In addition, we identified myocardial and valvular autoantigens that were recognized by heart-infiltrating and peripheral T cells from RF/RHD patients. Novel heart tissue proteins were identified, including disulfide isomerase ER-60 precursor (PDIA3) protein and a 78-kDa glucose-regulated protein precursor (HSPA5). [59] However, their role in RHD pathogenesis and other autoimmune diseases is not clear.
As mentioned above, both epitope spreading and the degeneracy of T cell receptors contributed to the amplification of cross-reactivity that leads to tissue damage.
By using a molecular approach, we evaluated Vb chain usage by TCRs and the degree of clonality of heart-tissue infiltrating T cells. In RHD, the autoreactive T lymphocytes that infiltrate both the myocardium and the valves were identified in oligoclonal expansions by analyzing their TCRs. A high number of T cell oligoclonal expansions were found in the valvular tissue, indicating that specific and cross-reactive T cells migrate to the valves. [49]
An effective immune response depends on cytokine production. CD4 + T helper cells are crucial regulators of the adaptive immune response. Antigen-activated CD4 + T cells become polarized toward a Th1 or Th2 phenotype based on the cytokines they secrete. Th1 cells are involved with cellular immune response and produce IL-2, IFN-γ and TNF-α. Th2 cells mediate humoral and allergic immune responses and produce IL-4, IL-5 and IL-13. A new lineage of CD4 + T cells (Th17) was recently described and is characterized by the production of IL-17. In vitro studies indicated a proinflammatory function for IL-17, and its expression was found to be associated with some inflammatory and autoimmune diseases. [60],[61]
The role of cytokines in RF/RHD was first evaluated by examining the sera of patients and peripheral mononuclear cells stimulated by streptococcal antigens. These samples showed increased amounts of proinflammatory cytokines (IL-1, IL-6, TNF-a and IFN-g). [62] Immunohistochemistry on heart tissue (myocardium and valves) from acute and chronic RHD patients, showed a large number of mononuclear cells able to secrete TNF-a, IFN-g and the regulatory cytokine IL-10. Importantly, while a significant number of IL-4 + cells were found in the myocardium, these cells were very scarce in valve lesions in RHD patients. It is important to remember that valve damage and not myocarditis is the main problem in ARF. These observations indicated a role for balanced Th1/Th2 cytokines in healing myocarditis and in the induction of progressive and permanent valve damage. [29] IL-17 and Il-23 (Th17 cytokines) were recently analyzed by immunohistochemistry in both myocardium and valvular tissue from RHD patients. We observed a large number of IL-17 + and IL-23 + heart-tissue infiltrating cells (unpublished results), showing that these cytokines also play an important role in the development of heart lesions.
Animal Models of RF/RHD
Humans are unique hosts for S. pyogenes infections.Several studies (in mice, rats, hamsters, rabbits and primates) have been done to find a suitable animal model in which to examine the autoimmune process leading to RF/RHD with little success. [63] In the last decade, a model in Lewis rats has been developed that appears to be useful for the study of RF/RHD. These rats have already been used to induce experimental autoimmune myocarditis and study the pathogenesis of RF/RHD. [64],[65],[66]
Immunization of Lewis rats with recombinant M6 protein induced focal myocarditis, myocyte necrosis and valvular heart lesions in three out of six animals. The disease in these animals
included verruca-like nodules and the presence of Anitschkow cells, which are large macrophages (also known as caterpillar cells), in mitral valves. Lymph node cells from these animals showed a proliferative response against cardiac myosin, but not skeletal myosin or actin. A CD4 + T cell line responsive to both the M protein and cardiac myosin was also obtained. Taken together, these results confirm the cross-reactivity between the M protein and cardiac myosin triggered by molecular mimicry, as observed in humans, possibly causing a break in tolerance leading to autoimmunity. [67],[68]
Similarly, immunizing the Lewis rats with synthetic peptides from the conserved regions of M5 protein, or from B and C regions , or a recombinant M5 proteins have yielded focal myocarditis, infiltration with CD4+T cells, CD68 + macrophage but no typical aschoff`s nodule. [69],[70],[71],[72]
Thus the Lewis Rat model could be considered a model of autoimmune valvulitis akin to ARF.
Prospective Vaccines against S.Pyogenes
Many studies have focused on developing a vaccine against S. pyogenes in order to prevent infection and its complications. There are four anti-group A streptococci (GAS) vaccine candidates based on the M protein and eight more candidates based on other streptococci antigens, including group A CHO, C5a peptidase (SCPA), cysteine protease (Spe B), binding proteins similar to fibronectin, opacity factor, lipoproteins, Spes (super antigens) and streptococcal pili. [73]
A multivalent vaccine, currently under phase II clinical trials, combines the amino acid sequences of the N-terminal portion of the M protein from the 26 most common strains of GAS in the US as a recombinant protein. [74],[75],[76]
Because the C-terminal portion of the M protein is conserved among the 200 strains identified by their emm-types, vaccines based on this region are expected to provide broad coverage. The first attempt to develop a vaccine based on the C-terminal portion of the M protein was performed by Fischetti et al. [77] This vaccine was able to induce protection against S. pyogenes containing homologous (M6) and heterologous (M14) M protein, demonstrating that the use of conserved region-derived peptides could induce protection against different serotypes. [78]
Conserved epitopes from the M protein have been also studied by a group from Australia, where the incidence of streptococcal infections in aboriginal communities is very high. Two synthetic peptides from the M5 protein (J8 and J14) were selected, and several formulations presented promising results. [79],[80],[81],[82] A combination of J8 and the fibronectin-binding repeats region (FNBR) of fibronectin I (SfbI) provided enhanced protection against S. pyogenes in mice. [83]
We developed a vaccine epitope (StreptInCor) composed of 55 amino acid residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. [84]
The structural, chemical and biological properties of this peptide were evaluated and have shown that StreptInCor is a very stable molecule, an important property for a vaccine candidate. [85] Furthermore, experiments with mice showed that this construct is immunogenic and safe. [86]
The greatest challenge for the development of a GAS vaccine resides in the promotion of immunity without generating cross-reactivity with human tissue. An effective and safe vaccine is still needed, most of all in developing countries.
Conclusion
Several genes involved in the control of infection and the immune response play a role in the development of RF and RHD. Some genes are associated with the innate immune response, and others with the adaptive immune response. Many of these genes are responsible for the inflammatory process and autoimmune reactions.
In rheumatic carditis, antibodies that cross-react with streptococcal and human proteins upregulate adhesion molecules, leading to inflammation and increased cellular infiltration. CD4 + T cells that cross-react with heart tissue and streptococcal antigens are the major effectors of heart lesions.
Large numbers of mononuclear cells that infiltrate rheumatic heart lesions produce inflammatory cytokines (TNF-a and IFN-g) and the imbalance between these cells and the IL-4-producing Th2 cells in the valve tissue might contribute to the progression and maintenance of rheumatic valvular lesions. Th17 cells also play a role in the development of autoimmunity.
Several pathogenic M protein epitopes were identified that can induce cross-reactive responses against human proteins. Both epitope spreading and TCR degeneracy increase the possibility of cross-reactivity between infectious agents and self antigens.
An animal model of Lewis rat displays similar heart lesions to RHD and is considered a good model of the disease.
The development of a vaccine against S. pyogenes is an important goal and, given the number of ongoing studies, will probably be a reality in the near future.
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原创性声明 （黑体、小2号、加粗、居中）（段前为0.5行、段后为0.5行） □□本人呈交的毕业论文，是在导师的指导下，独立进行研究工作所取得的成果，所有数据、图片资料真实可靠。尽我所知，除文中已经注明引用的内容外，本毕业论文的研究成果不包含他人享有著作权的内容。对本论文所涉及的研究工作做出贡献的其他个人和集体，均已在文中以明确的方式标明。本毕业论文的知识产权归属于培养单位。 （宋体小4号） 本人签名：（手签）日期：
摘□□要 （黑体小2 居中）（段前为0.5行、段后为0.5行） 《德伯家的苔丝》是19世纪英国批判现实主义小说家托马斯·哈代的代表作。哈代将其与其他几部作品一并归类于“性格与环境的小说”。以前对他的文学批评多以人物本身以及当时社会的人物构建为中心，采用马克思主义、消费主义和女性这一理论基础进行分析，本文将采用生态批评理论分析苔丝的悲剧成因。哈代认为社会转型期内的历史性的巨变不是进步，反而代表着失望和遗憾。工业革命和现代化的生活方式都导致女性逐步的脱离自然。在哈代的写作生涯中,他对人与自然、男性和女性的关系一直给予高度关注，他认为自然和人类是紧密相连的,自然是女性生存的沃土而女性则是自然的化身,女性和自然在经验与体验上都是相统一的,她们的命运也是相辅相成的,所以生态批评主义者倡导建构生态和谐的社会。不仅使大自然摆脱被剥削的命运,也激发人们对于日益严重的环境危机的生态保护意识。本文利用生态批评主义文学理论, 并通过文献综述法，从男性与女性关系和人类与自然关系两方面来揭示哈代《德伯家的苔丝》中苔丝的悲剧根源。通过揭示苔丝悲剧的根本所在不仅能够警示读者认识到人类文明进步是以对自然环境的破坏为代价的，而且使人类意识到保护自然环境，与自然和谐相处的重要性。 (宋体小4，1.5倍行距 ) 中间无标点符号 关键词：生态批评主义□苔丝悲剧根源□女性和自然□和谐 （黑体4）（宋体小4） （所有文本页边距：上边距为25mm，下边距为20mm，左边距为25mm，右边距为20mm） 顺序为:中英文摘要、中英文目录、这四页页码为罗马数字
语言学方向论文选题 1.浅谈英汉句子结构差异 2.诗意的美和喜剧性幽默 3.英汉禁忌语、委婉语的对比研究 4.英汉数字习语的对比研究 5.词义演变的原因与方式 6.名词化的语篇功能 7.诺曼时期法语对英语词汇的影响 8.浅谈英语虚拟语气及其语用功能 9.隐喻与一词多义的关系 10.英汉被动句对比研究 11.英汉宾语类型差异的认知原因 12.英汉动词非谓语用法比较研究 13.英汉否定问句的答句对比研究 14.英汉合成词构词对比研究 15.英汉名词短语修饰模式比较 16.英汉拟声词异同探讨 17.英汉人称代词运用对比研究 18.英语复合词的语义分析及其类型 19.英语委婉语的使用原则与策略 20.语境对词义的制约作用 21.汉英色彩词汇的对比研究及其象征意义 22.中英恭维语对比研究 23.委婉语的礼貌原则研究及策略 24.汉英“山丘”对比研究 25.英汉颜色词跨域对比分析—以RED和红为例 26.英语道歉方式的策略及研究 27.英语拒绝言语行为研究 28.英语委婉语的寒暄功能 29.英语请求言语的策略研究
30.英语课堂教师提问的策略研究 31.会话得体：会话者的立场语境运用研究 32.英语课堂学生提问的策略研究 33.英语课堂的焦虑现象及策略研究 34.广告口号语的语言特点 35.从礼貌原则看短信语言 36.从合作原则看课堂师生互动 37.浅析中英言语行为中的礼貌原则 38.中英政治新闻报道中的模糊语言研究 39.言语错误分析理论在教学中的应用 40.英汉颜色词的引申义的文化差别 41.外语学习中应该重视中介语的作用 42.浅谈英汉句子结构差异 43.副词EVER的句法环境和语义特征 44.论文化差异与英语教学中的文化导入 45.学习者的动机因素对外语学习的影响 46.浅谈词汇搭配错误分析及其应对策略 47.浅析英语语言中的性别歧视现象 48.礼貌原则在商务英语写作中的应用 49.中英文性别歧视习语的对比研究 50.称谓语使用中的性别差异 51.从认知角度看隐喻在经济语篇中的应用 52.浅析广告语言的特点 53.浅谈英语新词的产生、构成及翻译 54.浅谈网络英语中的缩略语。 55.论中英文化对隐喻的影响 56.礼貌原则在商务谈判中的作用 57.浅析英汉语言中的性别歧视现象及其根源 58.英诗中的常用修辞研究 59.英语词汇中的外来语单词
扉页（英文） CulturalFactorsinChinese&EnglishProverbs Translation （TimesNewRoman二号加粗居中） by LiHairong WangZhiyun,Tutor （TimesNewRoman小二居中） RegisteredNo.09 FacultyofForeignLanguages Shanghai Business School December,2011 （TimesNewRoman小二） 论文摘要（英文）及关键词 Abstract （TimesNewRoman二号，加粗，居中） Proverbsreflectcolorfulnationalculturein（TimesNewRoman四号）…………………………………………………………………………………….…………………………………………………………………………………………………………………………………………………………........................... .....………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
………………………………………………………………………………………………………………………………………………………………………………………………………………………………………… （空一行） Keywords:proverbs;translation;culture;differences（TimesNewRoman四号） 说明： 1．关键词3-5个，词与词之间用分号隔开，除专有名词外，其他单词首字母不大写，最后一个词后面无标点符号。 2．“摘要”下空一行写摘要内容，摘要内容与关键词之间空一行。
The full-length novel Gone With The Wind, has been translated into more than thirty languages, and the bestseller for a long time in the world. Why could it’s charm last in such a long time? The reason mostly relied on it’s distinctive female characters---Scarlett, Melanie, Mammy and Belle Watling. 一．Scarlett O’Hara <一> Personality changes 1.Pre-war A. adolescent romantic B. simple capricious 2. Post-war A. strong persistent B. reality rational 3. Revelations to moderns A. in terms of workplace a. abreast of the times b. self-confidence B. in terms of interpersonal a. self-image b. unique personality <二> Views on marriage 1.Material view of marriage A. purpose B. just to be obtained not with pay 2.Revelations to moderns A. marriage is not a transaction B. balance in marriage <三> character full of contradictory and complexity 1.selfish---responsible 2.blind pursuit of love---casually take advantage of marriage 3.feminist consciousness---effect of Patriarchal society 一．Melanie Hamilton Wilkes <一> personality traits（the ordinary perfect） 1.ordinary---outside 2.perfect---intrinsic A. fraternity B. tolerant
华 中 师 范 大 学 本 科 生 课 程 论 文 论文题目 The Study of Speech Sound in Language 完成时间 2012.12 课程名称 现代语言学概论 专 业 辅修第二学位英语专业 年 级 2010英语第二学位辅修本科生 成 绩 评卷人 姓 名 学 号
The Study of Speech Sounds in Language I. Introduction Knowledge of a language includes that of the different components of the language: the morphemes,words,phrases,and sentences. It also includes knowing what sounds are in the language and how these sounds are put together to form meaningful units. Different terms can be found in describing the sound system of language. Traditional terminology puts phonetics and phonology at a paralleled level. In this terminology, phonetics is the study of separate speech sounds, while phonology is concerned with the system of combination of sounds. According to the terminology in some books, however, the study of speech sounds in a general way is termed as phonology. It is concerned with all the aspects of the speech sounds and sound systems of a language. Its subdivisions are phonemics. Phonetics deals with speech sounds in isolation, and phonemics studies the systems of speech sounds. To avoid confusion, the traditional terminology is adopted in this book. II. Analysis on ---- 2.1. Analysis of speech sounds The study of phonic medium of language in isolation is the level of phonetics, attempting to describes all the sounds that occur in human language. It’s mainly concerned with the production, transmission, and perception of the speech sounds. Analysis of speech sounds can be approached from the following 4 levels Level 1: anatomy and physiology----refers to speech organs and their functions Level 2: articulatory phonetics----studies how to produce speech sounds. Level 3: auditory phonetics---studies how the sounds are perceived by the hearer. Level4: acoustic phonetics----studies the way speech sounds are transmitted in the air(using spectrographs, analyze sound waves). 2. 2. Process of speech production and perception 2.2.1. Articulatory phonetics studies the sounds from the speaker’s point of view,how a speaker manipulates his speech organs to produce speech sounds. This branch is the longest established and the most highly developed. 2.2.2. Auditory phonetics studies the way listeners perceive the speech
成绩 Root and Affixation of Lexicology Abstract: It’s important and permanent to master the vocabulary in the English learning. Everyone who has ever set foot on English realizes that it’s somewhat incredible for us to reciting numerous and difficult words. Nevertheless, there are some skills we should acquire to make word-recitation easier and more effective. This paper mainly discusses the using of vocabulary root and affix. Only by having a good knowledge of the roots and affixes, can we prosper our English vocabulary and further our English study. Key words: root; affixation; detailed analysis; difficult words 1Introduction: Blindly reciting numerous and difficult words is a total waste of time and energy. Especially, situation becomes worse for the college students with little words storage and non-interest. However, most of the English words are comprised with roots and affixes, which are limited, stable and short. If we acquire them, it will be much simpler and rapider for us to recognize the unfamiliar and difficult words through the analysis on roots and affixes. If we can master and know how to use them properly, it will be a big step for the further study of this foreign language. A road of a thousand miles begins with each single step, so does the English words. Now we are going to learn the root and affixation respectively. Definition is the basic form of a word which cannot be further analyzed without total loss of identity and it carries the main component of meaning in a word. By learning the roots, we will find it not complicated for us to understand the long and difficult words which we often encounter in the tough reading test. However long and tough the word is, we can divide it into several parts, the fundamental part is the root and then we can understand what it means and fluently blurt it out without repeating it. Here are some detail analyses of the examples: Internationalist: nation is the root which means country or state, inter- is prefix meaning between or interactive, -al is the suffix and the –ist is the suffix meaning the person. So you will quite simply find its meaning. Invigorate: the root is vigor similar to power and energy, in- means making sth have the function of verb, here is make sth vigor, -ate is the verb suffix. So invigorate is to make sth vigorous. Antecedent: -ced- is the root referring to motion or going forward, ante- is before, and –ent means somebody. So antecedent is somebody who moves ahead of us, the same as forefather or ancestor. Protract: -tract is the root like pulling sth or extending sth make it wider or longer, pro- is the prefix meaning “ahead”. After analyzing this word, we know that “protract” is similar to prolong meaning make sth longer or longer to live. A lot of words contain this root, such as detract, extract, subtract, attract, tractable, intractable, etc. Arbitrariness: arbitrary is the root indicating to randomness or out of order, -ness is the noun suffix. The profound meaning of learning roots is that you will find it much easy to memorize words because there are so many word share the same root. No matter how long and hoe difficult the word is, the basic meaning of the word is stable and unchangeable. If we recite words according the
英语语言学论文题目 13论国际商务谈判中的语言交际技巧 33成人世界的童话——从文体学角度解析现今童话再度流行的现象49论文化差异与英汉商标互译 55浅谈英汉句子结构差异 59诗意的美和喜剧性幽默 62试论广告英语的语言特点 65统觉团对英语初学者词汇学习的影响 67外语学习中应该重视中介语的作用 69新闻报道中的转述动词研究 73英汉禁忌语、委婉语的对比研究 74英汉数字习语的对比研究 76英译汉中词序的变动 78英语广告的语言特征 80英语双关语汉译的可译性限度 101词义演变的原因与方式 137从汉语中英语借词的翻译看文化交流 138从价值观转换看斯佳丽的角色特征 142从礼貌准则看中英文化的异同 146从习语看英汉民族的文化差异 149从英语人名中看性别歧视
157动词过程类型的选择和话语隐性态度的表达161对母语在英语写作中词汇负迁移现象的思考162对严复译作中“信”的质疑 167法律英语用词特征分析 168法律语言翻译与法律文体 177副词EVER的句法环境和语义特征 180功能语法视角下的英语报纸新闻标题的功能183广告口号语的语言特点 189国际商务文化之对比研究 204汉语中双关语的翻译 213基于概念隐喻的诗歌解读 228论广告英语中的幽默 265论广告英语的语言特点 268论汉英谚语的语言特征 280论清教理念与美国西进运动 282论莎士比亚十四行诗中的时间 300论英语广告中几种常用修辞格及其汉译310论尤金?奥尼尔的表现主义手法 324名词化的语篇功能 330诺曼时期法语对英语词汇的影响 339浅谈英语虚拟语气的语用功能
340浅谈英语虚拟语气及其语用功能 345浅析二十世纪计算机英语词汇的构成特点346浅析汉英动物谚语中的文化 348浅析英汉语言中的性别歧视现象及其根源349浅析英语禁忌语及其发展 352浅析英语无标志被动句 356浅议译者能力 359认知语言学角度下“within” 的空间隐喻意义365商标英语汉译的原则和方法 384体育新闻英语文体研究 375社会语言学视野中的网络语言 418新闻英语中的语法特点研究 423颜色词在英汉互译中的不对应性 425移就的审美价值和生成基础 426以认知为基础的颜色隐喻研究 428隐喻认知功能研究的新视角 429隐喻与一词多义的关系 438英汉被动句对比研究 439英汉宾语类型差异的认知原因 440英汉动词非谓语用法之比较研究 442英汉否定问句的答句对比研究
Hello, everyone. Today, I will introduce one interesting paper: Human Behavior Prediction for Smart Homes Using Deep Learning. Before the presentation , let’s see who our group consists of. Then, it’s the outline of our presentation: motivation, purpose, basic idea, experiment, summary. Firstly, it ’s the motivation. As we can see from the picture, the fertility rate(生育率) all over the world tends to decrease by year and the average life continues to rise in future. As the result, the ratio of the number of persons aged over 65 to the number of persons aged between 15 to 64 will rise significantly. Because of this tendency, the need for smart homes which can help the old maintain independent lifestyles and increase the quality of life is emphasized. Therefore, an ability to provide a service to the users when it is needed without the user intervention is crucial for the success of smart homes. Next, it’s the purpose of the paper. Although humans can be able to understand other people ’s intention from their actions, it is difficult to extract relationship between actions and intentions in a structured way. The present paper attempts to extract the relationship between past actions and the future action using deep learning. Next, it’s the basic idea. The paper tries to improve learning method of an RBM model to solve the complex problems. Besides, they also want to explore new behavior prediction algorithms using the deep learning. Now, we briefly review deep belief network (DBN). DBN consists of multiple restricted Boltzmann machines (RBM), which are energy-based unsupervised learning models. The RBM model just looks like the right figure. Then I will make simple explanations to the RBM. One layer of an RBM consists of visible input units, which are connected to the other layer of hidden units. The distribution of state {v, h} of an RBM is specified by the following energy function: E v ,? θ =? w ij v i ?j F j =1D i =1? b i v i D i =1? a j ?j F j =1 Hinton, the man researched deep learning, proposed the contrastive divergence (CD) learning method. The method approximates the model distribution using Gibbs sampling with the probability distribution of input samples as follows: v i ?j data ? v i ?j model ≈ v i ?j data ? v i ?j G c v i ?j data =1n v i t n t =1P ?j (t )|v t ,θ v i ?j G c =1n v i t n t =1P ?j (t )|v t ,θ In fact, the conventional CD learning has some disadvantages such as an inaccurate approximation of the model distribution. Here, the paper proposes a new learning algorithm to improve the existing CD learning method. The overall
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Index（ARIAL 14号，加粗，居中） Chapter I Introduction（作为正文第1章chapter I，ARIAL 12号字体，下同 (1) ChapterII××××××（正文第2章）……………………page. 2.1××××××（C h a p t e r I I,P a r t I)…………………p 2.2 ××××××（Chapter II, Part II ）…………………………………… 2.3 ××××××（Chapter II, Part X）………………………………………p Chapter III×××××（Chapter III）………………………………………………p ………………………………（略） X ×××××（Chapter X）……………………………………………………p Conclusion………………………………………………………………………p Bibliography…………………………………………………………………p Acknowledgement………………………………………………………………p Appendix I ××××（if needed）…………………………………………p AppendixB ××××（if needed）……………………………………………p Picture 1 ×××××（if needed）…………………………………………p Picture 2 ×××××（if needed）………………………………………………p Chart1 ×××××（if needed）……………………………………………p Chart 2 ×××××（if needed）……………………………………………p 注：1. 目次中的内容一般列出“章”、“条”二级标题即可； 2．X、p表示具体的数字。