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In contrast to 5'-O-carbonate 3TC derivatives (23, 24), which are clearly 3TC prodrugs, the corresponding 3TC carbamates (15-21 and 25), found to be very stable compounds with respect to enzymatic hydrolysis (cellular lysates and culture cell media) and still active on both HIV-1 and HBV infected cells, may not be 3TC prodrugs. The antiviral properties as well as the mechanism of action of 3TC analogues have been studied and evaluated.  相似文献   

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Maelstrom (MAEL) plays a crucial role in a recently-discovered piRNA pathway; however its specific function remains unknown. Here a novel MAEL-specific domain characterized by a set of conserved residues (Glu-His-His-Cys-His-Cys, EHHCHC) was identified in a broad range of species including vertebrates, sea squirts, insects, nematodes, and protists. It exhibits ancient lineage-specific expansions in several species, however, appears to be lost in all examined teleost fish species. Functional involvement of MAEL domains in DNA- and RNA-related processes was further revealed by its association with HMG, SR-25-like and HDAC_interact domains. A distant similarity to the DnaQ-H 3'–5' exonuclease family with the RNase H fold was discovered based on the evidence that all MAEL domains adopt the canonical RNase H fold; and several protist MAEL domains contain the conserved 3'–5' exonuclease active site residues (Asp-Glu-Asp-His-Asp, DEDHD). This evolutionary link together with structural examinations leads to a hypothesis that MAEL domains may have a potential nuclease activity or RNA-binding ability that may be implicated in piRNA biogenesis. The observed transition of two sets of characteristic residues between the ancestral DnaQ-H and the descendent MAEL domains may suggest a new mode for protein function evolution called "active site switch", in which the protist MAEL homologues are the likely evolutionary intermediates due to harboring the specific characteristics of both 3'–5' exonuclease and MAEL domains.  相似文献   

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用支持向量机预测人类基因5'/3'选择性剪切位点   总被引:1,自引:0,他引:1  
选择性剪切是调解基因表达的重要机制.识别选择性剪切位点是后基因组时代的一个重要工作.本文从最新的EBI人类基因选择性剪切数据库中,选取5'/3'选择性剪切位点作为正集,选取在剪切位点附近的假剪切位点作为负集,并把所有的选择性剪切位点和假剪切位点随机分成训练集和测试集.本文选用的预测选择性剪切位点的方法是基于位置权重矩阵和离散增量的支持向量机方法.此方法仅基于训练集,以不同位点的单碱基概率和序列片断的三联体频数作为信息参数,利用位置权重矩阵和离散增量算法结合支持向量机,得到了选择性供体位点和受体位点的分类器,并用此分类器对测试集中的选择性供体位点和受体位点进行预测.对独立测试集中的选择性供体位点和选择性受体位点的预测成功率分别为88.74%和90.86%,特异性分别为85.62%和81.19%.本文预测选择性剪切位点的方法成功率高于其它选择性剪切位点预测方法预测成功率,此预测方法进一步提高了对选择性剪切位点的理论预测能力.  相似文献   

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A fibre-type x-ray diffraction photograph from thymidylyl-3',5'-thymidine is interpreted in terms of a seven-residues per turn, left-handed helical structure in which the first thymine of one molecule is linked to the second thymine of the next molecule by 'wobble' type hydrogen bonds. The first thymidine is in the anti conformation, with a C2'endo - C3'exo sugar and the second is in the syn conformation with a C3'endo - C4'exo sugar. The C5' - 05' bond in the inter-nucleotide linkage is in the g- conformation and that of the P-05' is g+.  相似文献   

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利用x2分析方法,对6种古菌起始密码子上游和终止密码子下游各50位非编码区进行了分析.结果表明,Methanopyris kandleri和Aeropyrum pernix中存在一个与大肠杆菌SD序列极为相似的高保守区(φ区).但φ区的核苷酸并不能和其16sRNA3'端序列的反SD序列很好的配对;Pyrobaculum aerophilum缺乏φ区,但在其起始密码子上游20~30核苷酸处却存在另一个高度保守的区域,该区域在大肠杆菌和酵母中均缺乏;而其它3种古菌却同时存在这2个区域.6种古菌在终止密码子下游第一位的核苷酸非常保守,存在四核苷酸终止信号;在终止密码子后约20个核苷酸范围内保守性相对较高,其中某些核苷酸在翻译终止过程中可能发挥调控作用.  相似文献   

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Abstract

A simple procedure is described for the preparation of the title compounds 1, 8 and 9. 3′-3′ or 3′-5′ or 5′-5′ TpT was reacted with a twofold molar excess of TPS in anhydrous DMF, at room temperature, for 5 min, followed by a 1 min in situ treatment of the reaction mixture with excess 7.0 N NH4OH, at 0°C. The alkaline hydrolysis of 1, 8 and 9 proceeds without the assistance of 3′- and 5′-hydroxyl groups resulting in equimolar mixtures of thymidine (4) and thymidine 3′-phosphoramidate (6) (for the 3′-3′ isomer) or thymidine 5′-phosphoramidate (7) (for the 5′-5′ isomer) or 6 and 7 in equal quantities (for the 3′-5′ isomer).  相似文献   

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The change in the content of cyclic GMP, cyclic AMP, ATP, ADP, AMP and fructose-2,6-bisphosphate that occurred in the mantle of the mussel Mytilus galloprovincialis Lmk when specimens of this mollusk were subjected to a hypoxia/anoxia situation were assessed. After the early 24 h in anaerobiosis, a clear decrease was observed in the ATP content, which remained close to that value for the rest of the time. AMP content doubled during the early 24 h in anaerobiosis and, from that time on, it remained close to that value. Fructose-2,6-bisphoshate and cyclic GMP showed a similar behavior. The levels of these compounds rose significantly during the early hours in anaerobiosis, and then fell to values similar to those of aerobiosis, remaining constant for the rest of the time. Neither ADP nor cAMP showed significant variations.  相似文献   

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In the screening for inhibitors of cyclic adenosine-3′,5′-monophosphate phosphodiesterase, two compounds, PDE-I (C13H13N3O5) and PDE-II (C14H14N2O5), were isolated from culture filtrates of a Streptomyces. Concentrations for 50% inhibitions of PDE-I and PDE-II against the high Km enzyme were 15 µm and 13 µm, and those against the low Km enzyme were 65 µm and 130 µm, respectively. Production, isolation and characterization of these compounds are described.  相似文献   

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黄病毒是一些世界范围内都很重要的疾病的致病因子 ,充分了解病毒的复制机制 ,可筛选阻止病毒复制的抗病毒因子 ,为疫苗的研制提供理论依据。黄病毒基因组RNA的 5 和 3 非编码区末端核苷酸都可形成高度保守的二级结构 ,与病毒的复制和病毒的神经毒力有关。本文对 5 和 3 非编码区的结构和功能研究进展进行综述。  相似文献   

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Conclusion By manipulating the rat's calcium balance, we have discovered that the calcium homeostatic system is a main regulator of cell proliferation in the bone marrow and thymus gland. Although the limits of the system's sphere of influence have yet to be completely defined, it is already known to include such diverse elements as chicken fibroblasts, liver parenchymal cells, and circulating small lymphocytes. Of even greater significance is the possibility that the ubiquitous cyclic AMP is calcium's partner and may even be the ion's intracellular agent for the control of cell proliferation. Thus, we now have a wide variety of possible explanations for diseases involving uncontrolled cell proliferation. Issued as NRCC No. 12996. Supported by a grant from the American Cancer Society.  相似文献   

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The 5’ non-translated region (NTR) is an important molecular determinant that controls replication and virulence of coxsackievirus B (CVB)3. Previous studies have reported many nucleotide (nt) sequence differences in the Nancy strain of the virus, including changes in the 5’ NTR with varying degrees of disease severity. In our studies of CVB3-induced myocarditis, we sought to generate an infectious clone of the virus for routine in vivo experimentation. By determining the viral nt sequence, we identified three new nt substitutions in the clone that differed from the parental virus strain: C97U in the 5’ NTR; a silent mutation, A4327G, in non-structural protein 2C; and C5088U (resulting in P1449L amino acid change) in non-structural protein 3A of the virus leading us to evaluate the role of these changes in the virulence properties of the virus. We noted that the disease-inducing ability of the infectious clone-derived virus in three mouse strains was restricted to pancreatitis alone, and the incidence and severity of myocarditis were significantly reduced. We then reversed the mutations by creating three new clones, representing 1) U97C; 2) G4327A and U5088C; and 3) their combination together in the third clone. The viral titers obtained from all the clones were comparable, but the virions derived from the third clone induced myocarditis comparable to that induced by wild type virus; however, the pancreatitis-inducing ability remained unaltered, suggesting that the mutations described above selectively influence myocarditogenicity. Because the accumulation of mutations during passages is a continuous process in RNA viruses, it is possible that CVB3 viruses containing such altered nts may evolve naturally, thus favoring their survival in the environment.  相似文献   

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Recently we have revealed a high content of autonomous 3"5" exonucleases (AE), i.e., those not bound covalently with DNA polymerases, in cells of vertebrates, from fish to human [1]. In the present work, using gel filtration method, cell-free extracts were studied from 15 objects located at different positions on the phylogenetic tree, such as archaebacteria, eubacteria, fungi, infusorians, coelenterates, annelids, and arthropods. It is shown that enzymatic activity of AE accounts for from 30 to 88% of the total 3"5" exonuclease activity of the extracts. A part of AE is revealed in zone of high-molecular DNA polymerases and can be separated by change of the chromatography conditions. It indicates a probable formation of complexes of AE with DNA polymerases. The high AE activity in cells of different organisms, from archae- and eubacteria to human, allows suggesting these enzymes to play a significant role in correction of polymerase errors in the processes of DNA replication and reparation, as well as in postreplicative correction of heteroduplexes in DNA.  相似文献   

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This study has identified the polar metabolites of 5α-androstane-3β, 17β-diol(3β-diol) produced by the canine prostate. The major metabolite is 5α-androstane-3β, 7α, 17β-triol (7α-triol) accounting for approximately 80% of the total polar metabolites of 3β-diol. The remaining 20% is accounted for exclusively by another triol, 5α-androstane-3β, 6α, 17β-triol(6α-triol). This study has also characterized two enzymatic hydroxylases responsible for respective triol formation: 5α-androstane-3β, 17β-diol 6α-hydroxylase (6α-hydroxylase) and 5α-androstane-3β, 17β-diol 7α-hydroxylase (7α-hydroxylase). Both of these irreversible hydroxylases are located in the particulate fraction of the prostate and can utilize either NADH or NADPH as cofactor. Several in vitro steroid inhibitors of these hydroxylases were identified including cholesterol, estradiol and diethylstilbestrol. Neither of the hydroxylases were found to be decreased by castration (3 months) when expressed as activity/DNA. Using a variety of C19 androstane substrates, 6α- and 7α-triol were found to be major components of the total 3β-hydroxy-5α-androstane metabolites produced by the canine prostate.  相似文献   

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以高分子表面活性剂HM-EO为主成相剂,金属螯合表面活性剂Triton X-114-IDA-Cu(Ⅱ)(TX-Cu(Ⅱ))为辅成相剂,构建新型亲和双水相胶束系统(ATPMS)以提高目标产物的萃取选择性,并考察重组蛋白3',5'-二磷酸核苷酸酶(YND)在系统中分配行为。结果表明,系统中不含亲和配基时YND主要分配于胶束缺失相;随着亲和配基含量的增加,YND与TX-Cu(Ⅱ)亲和结合而逐渐分配到胶束富集相并且在系统中显示出优异的稳定性;调节溶液p H能够影响YND亲和分配,最适萃取条件为pH 9.0;增大无机盐浓度,导致更多杂蛋白分配到胶束缺失相,然而对YND分配影响较小。在2.5%HM-EO、0.125%TX-Cu(Ⅱ)、p H 9.0、50 mmol/L Na Cl条件下,实验获得65.8%的酶活回收率。因此亲和ATPMS可以有效用于对富组氨酸蛋白YND的分离纯化,为该体系在重组蛋白的分离纯化试验提供相应的基础依据。  相似文献   

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A single thin layer chromatography and three antibodies were used for the specific radioimmunoassay of four androgens in pooled rat plasma (Sprague-Dawley adult males). The following values were found (pg/ml ± SD). Testosterone : 3, 138 ± 173; dihydrotestosterone : 374 ± 20; 5α-androstane-3α 17β-diol : 284 ± 24; 5α-androstane-3β, 17β-diol : 223 ± 11.  相似文献   

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The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).  相似文献   

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