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《ENV 1991_钢结构设计》
&&欧标的钢结构设计要求和计算方法
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你可能喜欢Among all the coding env genes, envW and envFRD are the only two genes with a clearly identified functional property, i.e. the capacity to generate cell-cell fusion [10,12]. This property – most probably associated with its role in placentation, see the Background section – was used to characterize further the consequences of the identified SNPs on the fusogenic function of the encoded proteins. To do so, we PCR-amplified the genomic DNAs of individuals carrying the corresponding SNP alleles, with primers allowing the cloning of the env genes in appropriate expression vectors. The fusogenic function was then assayed as in [12], using two different cell lines for fusion (Figure 4). As illustrated in the figure, no difference can be observed between the four haplotypes of each of the env genes tested. This, together with the low SNP level for the two genes, is a strong indication for selection of a &function& associated with the corresponding proteins.Join ResearchGate to access over 30 million figures and 100+ million publications – all in one place.Copy referenceCopy captionEmbed figurePublished in
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However, potential hazardous HERK-K expression in hematopoietic stem cells still needs to be analyzed. Primates encode very similar endogenous retroviral genomes (SERV) and could be used as a model for safety studies28293031. Vaccination of rhesus macaques which carry SERV-K with SERV-K Gag or Env induced T cell responses without vaccinerelated pathogenicity [31]. ABSTRACT: Human endogenous retroviruses (HERVs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. However enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed inter-alia in HIV-infected individuals and tumor patients. Therefore HERV-K might serve as a tumor-specific antigen or even as a constant target for the development of an HIV vaccine.
To verify our hypothesis, we tested the immunogenicity of HERV-K Gag by using a recombinant vaccinia virus (MVA-HKcon) expressing the HERV-K Gag protein and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) and the HERV-K Gag protein (RLZ-HKGag cells). Subcutaneous application of RLZ-HKGag cells into syngenic BALB/c mice resulted in the formation of local tumors in MVA vaccinated mice. MVA-HKcon vaccination reduced the tumor growth. Furthermore, intravenous injection of RLZ-HKGag cells led to the formation of pulmonary metastases. Vaccination of tumor-bearing mice with MVA-HKcon drastically reduced the number of pulmonary RLZ-HKGag tumor nodules compared to vaccination with wild-type MVA.
The data demonstrate that HERV-K Gag is a useful target for vaccine development and might offer new treatment opportunities for cancer patients. . Full-text · Article · Mar 2014 Side effects of an HERV-K-specific vaccination can only be studied in humans. Primates encode very similar endogenous retroviral genomes and could be used as a model for safety studies[45],[46],[47],[24]. We showed proof of principle for an HERV-K cancer vaccine in a mouse tumor model. ABSTRACT: Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer. Full-text · Article · Aug 2013 +1 more author...Even more visionary, actual bioinformatics approaches will allow the identification of immunogenic core epitopes shared between different HERV copy ORFs active in different tumor entities in order to design a universal HERV-based vaccine. As a first step in that direction, we recently described two CD8 + T cell epitopes encoded by a HERV-H copy located on Xp22.3 [77] . ABSTRACT: A substantial part of the human genome is derived from t remnants of ancient retroviral infections. Conservative estimates set the percentage of human endogenous retroviruses (HERVs) in the genome at 8%. For the most part, the interplay between mutations, epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells. We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy. It has been shown that at least in some cases, tumor cells expressing HERV open reading frames (ORFs) thus gain tumor-promoting functions. However, since these proteins are not expressed in healthy tissues, they become prime target structures. Of potential pharmacological interest are the prevention of HERV transposition, the inhibition of HERV-encoded protein expression and the interference with these proteins' activities. Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries. The development of new tumor (immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects. Finally, we postulate on main future research streams in order to stimulate discussion on this hot topic. Full-text · Article · Nov 2012 Syncytin-2 is older, being conserved in the genome of all monkeys, except prosimians, for more than 40 My [11] (Fig. 3A). Compellingly, the very low rate of polymorphism of both genes within the human population argues in favor of an essential physiological function [18]. Several features of both encoded envelope proteins led to formulate the hypothesis that they contribute to the formation of an essential component of the placenta, i.e. the syncytiotrophoblast. ABSTRACT: During their replication, infectious retroviruses insert a reverse-transcribed cDNA copy of their genome, a &provirus&, into the genome of their host. If the infected cell belongs to the germline, the integrated provirus can become &fixed& within the host genome as an endogenous retrovirus and be transmitted vertically to the progeny in a Mendelian fashion. Based on the numerous proviral sequences that are recovered within the genomic DNA of vertebrates--up to ten percent in the case of mammals--such events must have occurred repeatedly during the course of millions of years of evolution. Although most of the ancient proviral sequences have been disrupted, a few &endogenized& retroviral genes are conserved and still encode functional proteins. In this review, we focus on the recent discovery of genes derived from the envelope glycoprotein-encoding (env) genes of endogenous retroviruses that have been domesticated by mammals to carry out an essential function in placental development. They were called syncytins based on the membrane fusogenic capacity that they have kept from their parental env gene and which contributes to the formation of the placental fused cell layer called the syncytiotrophoblast, at the materno-fetal interface. Remarkably, the capture of syncytin or syncytin-like genes, sometimes as pairs, was found to have occurred independently from different endogenous retroviruses in diverse mammalian lineages such as primates--including humans--, muroids, leporids, carnivores, caviids, and ovis, between around 10 and 85 million years ago. Knocking out one or both mouse syncytin-A and -B genes provided evidence that they indeed play a critical role in placentation. We discuss the possibility that the immunosuppressive domain embedded within retroviral envelope glycoproteins and conserved in syncytin proteins, may be involved in the tolerance of the fetus by the maternal immune system. Finally, we speculate that the capture of a founding syncytin-like gene could have been instrumental in the dramatic transition from egg-laying to placental mammals. Full-text · Article · Jun 2012 All three are candidates for having a beneficial function because they are evolutionarily conserved and have undergone purifying selection during primate evolution [17,19,20] . Furthermore all single nucleotide polymorphisms (SNPs) within the three envelope genes are either synonymous or they do not influence fusiogenicity [20,21]. Syncytin 1 and syncytin 2 show placenta-specific expres- sion [10,15,22,23], which may be an implication of a physiological role of HERV envelope proteins in mediating cell-cell fusion in placenta forming the syncytiotrophoblast . ABSTRACT: Most human endogenous retroviruses (HERVs) invaded our genome at least 25 million years ago. The majority of the viral genes are degenerated, since no selection preserves them within the genome. However, a few intact and very old HERV genes exist, and likely are beneficial for the host. We here address evolutionary aspects of two HERV-V envelope genes, ENVV1 and ENVV2, located in tandem and containing a long open reading frame.
The ENVV2 gene is preserved with an intact reading frame during simian evolution, but none of the ENVV genes are found in the prosimian species tested. While we observe many transposon insertions in the gag and pol regions of the ERV-V2 provirus, the ENVV2 genes have escaped transposon crossfire in all species tested. Additional analysis of nucleotide substitutions provides further strong evidence of purifying selection on the ENVV2 gene during primate evolution. The other copy, ENVV1, seems to be involved in gene conversion of the major part of the envelope. Furthermore, ENVV1 and ENVV2 show placenta-specific expression in human and a baboon species.
Our analyses show that ERV-V entered our genome after the split between simian and prosimian primates. Subsequent purifying selection and gene conversion have preserved two copies of the ENVV envelope gene in most species. This is the first case of gene conversion involving long open reading frames in HERVs. Together with the placenta-specific expression of the human and baboon ENVV1 and ENVV2 envelope genes, these data provide strong evidence of a beneficial role for the host. Full-text · Article · Oct 2008 Also, SNPs within HML-2 sequences may introduce differences when compared to the human reference sequence. Previous work already indicated SNPs within HML-2 coding regions [28,59]. However, the best cDNA-provirus sequence match is still expected to be the correct one if matches to other proviruses display clearly more differences . ABSTRACT: A significant proportion of the human genome is comprised of human endogenous retroviruses (HERVs). HERV transcripts are found in every human tissue. Expression of proviruses of the HERV-K(HML-2) family has been associated with development of human tumors, in particular germ cell tumors (GCT). Very little is known about transcriptional activity of individual HML-2 loci in human tissues, though.
By employing private nucleotide differences between loci, we assigned approximately 1500 HML-2 cDNAs to individual HML-2 loci, identifying, in total, 23 transcriptionally active HML-2 proviruses. Several loci are active in various human tissue types. Transcription levels of some HML-2 loci appear higher than those of other loci. Several HML-2 Rec-encoding loci are expressed in GCT and non-GCT tissues. A provirus on chromosome 22q11.21 appears strongly upregulated in pathologic GCT tissues and may explain high HML-2 Gag protein levels in GCTs. Presence of Gag and Env antibodies in GCT patients is not correlated with activation of individual loci. HML-2 proviruses previously reported capable of forming an infectious HML-2 variant are transcriptionally active in germ cell tissue. Our study furthermore shows that Expressed Sequence Tag (EST) data are insufficient to describe transcriptional activity of HML-2 and other HERV loci in tissues of interest.
Our, to date, largest-scale study reveals in greater detail expression patterns of individual HML-2 loci in human tissues of clinical interest. Moreover, large-scale, specialized studies are indicated to better comprehend transcriptional activity and regulation of HERVs. We thus emphasize the need for a specialized HERV Transcriptome Project. Full-text · Article · Feb 2008 +1 more author...