• 【苯巴比妥依赖性和退缩大鼠脑中谷氨酸受体,c-fos mRNA表达和激活蛋白-1 (AP-1) DNA结合活性的变化。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00134-0 复制DOI
    作者列表:Tanaka S,Kiuchi Y,Numazawa S,Oguchi K,Yoshida T,Kuroiwa Y
    BACKGROUND & AIMS: We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.

    背景与目标: 我们研究了苯巴比妥 (PB) 依赖性和退缩大鼠大脑中谷氨酸受体的变化,即刻早期基因的表达以及AP-1的DNA结合活性,以研究谷氨酸受体激活在PB戒断综合征中的可能参与。通过喂养混合药物的食物5周制备PB依赖性大鼠。放射自显影分析显示,N-甲基-d-天冬氨酸 (NMDA) 受体拮抗剂 [3H(+)-5-甲基-10,11-二氢-5H-二苯并 [a,D] cyclohepten-5,10-敏e (MK-801) 的结合,PB依赖性和24h撤回大鼠的大脑皮层显着增加。然而,[3h] MK-801在海马和 [3H]6-氰基-7-硝基喹喔啉-2结合,海马和大脑皮层中的3-二酮 (CNQX) 和 [3H] 海藻酸结合在两组中基本上没有变化。铅戒断发作后,海马和大脑皮层中c-fos mRNA的表达增加,大脑皮层中c-6月mRNA的表达增加。诱导c-MK-801可抑制fos和c-6月mRNA。此外,铅戒断增强了大脑中的AP-1 DNA结合活性。目前的发现表明,在铅戒断综合征的发展过程中,谷氨酸能神经传递的功能增强。
  • 【鸡GATA-2和GATA-3的N端指是独立的序列特异性DNA结合结构域。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.10.2874 复制DOI
    作者列表:Pedone PV,Omichinski JG,Nony P,Trainor C,Gronenborn AM,Clore GM,Felsenfeld G
    BACKGROUND & AIMS: The GATA family of vertebrate DNA binding regulatory proteins are expressed in diverse tissues and at different times of development. However, the DNA binding regions of these proteins possess considerable homology and recognize a rather similar range of DNA sequence motifs. DNA binding is mediated through two domains, each containing a zinc finger. Previous results have led to the conclusion that although in some cases the N-terminal finger can contribute to specificity and strength of binding, it does not bind independently, whereas the C-terminal finger is both necessary and sufficient for binding. Here we show that although this is true for the N-terminal finger of GATA-1, those of GATA-2 and GATA-3 are capable of strong independent binding with a preference for the motif GATC. Binding requires the presence of two basic regions located on either side of the N-terminal finger. The absence of one of these near the GATA-1 N-terminal finger probably accounts for its inability to bind. The combination of a single finger and two basic regions is a new variant of a motif that has been previously found in the binding domains of other finger proteins. Our results suggest that the DNA binding properties of the N-terminal finger may help distinguish GATA-2 and GATA-3 from GATA-1 and the other GATA family members in their selective regulatory roles in vivo.

    背景与目标: 脊椎动物DNA结合调节蛋白的GATA家族在不同的组织和发育的不同时间表达。但是,这些蛋白质的DNA结合区域具有相当大的同源性,并且可以识别相当相似范围的DNA序列基序。DNA结合通过两个结构域介导,每个结构域都包含一个锌指。先前的结果得出的结论是,尽管在某些情况下,N末端手指可以促进特异性和结合强度,但它不会独立结合,而C末端手指对于结合既必要又足够。在这里,我们表明,尽管对于GATA-1的N末端手指是正确的,但GATA-2和GATA-3的手指能够强烈独立结合,并且偏爱基序GATC。结合需要存在位于N末端手指两侧的两个基本区域。在GATA-1的N末端手指附近没有这些手指之一可能是其无法结合的原因。单个手指和两个基本区域的组合是基序的新变体,以前已在其他手指蛋白的结合域中发现。我们的结果表明,N末端手指的DNA结合特性可能有助于将GATA-2和GATA-3与GATA-1和其他GATA家族成员在体内的选择性调节作用区分开。
  • 【使用标准的匿名微阵列平台捕获DNA序列变异的基因组特征。】 复制标题 收藏 收藏
    DOI:10.1093/nar/gkl478 复制DOI
    作者列表:Cannon CH,Kua CS,Lobenhofer EK,Hurban P
    BACKGROUND & AIMS: :Comparative genomics, using the model organism approach, has provided powerful insights into the structure and evolution of whole genomes. Unfortunately, only a small fraction of Earth's biodiversity will have its genome sequenced in the foreseeable future. Most wild organisms have radically different life histories and evolutionary genomics than current model systems. A novel technique is needed to expand comparative genomics to a wider range of organisms. Here, we describe a novel approach using an anonymous DNA microarray platform that gathers genomic samples of sequence variation from any organism. Oligonucleotide probe sequences placed on a custom 44 K array were 25 bp long and designed using a simple set of criteria to maximize their complexity and dispersion in sequence probability space. Using whole genomic samples from three known genomes (mouse, rat and human) and one unknown (Gonystylus bancanus), we demonstrate and validate its power, reliability, transitivity and sensitivity. Using two separate statistical analyses, a large numbers of genomic 'indicator' probes were discovered. The construction of a genomic signature database based upon this technique would allow virtual comparisons and simple queries could generate optimal subsets of markers to be used in large-scale assays, using simple downstream techniques. Biologists from a wide range of fields, studying almost any organism, could efficiently perform genomic comparisons, at potentially any phylogenetic level after performing a small number of standardized DNA microarray hybridizations. Possibilities for refining and expanding the approach are discussed.
    背景与目标: : 使用模式生物方法的比较基因组学为整个基因组的结构和进化提供了有力的见解。不幸的是,在可预见的将来,地球生物多样性中只有一小部分将对其基因组进行测序。大多数野生生物的生活史和进化基因组学与当前的模型系统完全不同。需要一种新技术来将比较基因组学扩展到更广泛的生物体。在这里,我们描述了一种使用匿名DNA微阵列平台的新颖方法,该平台收集来自任何生物的序列变异的基因组样本。放置在定制的44 K阵列上的寡核苷酸探针序列长25 bp,并使用一组简单的标准进行设计,以最大程度地提高其在序列概率空间中的复杂性和分散性。使用来自三个已知基因组 (小鼠,大鼠和人类) 和一个未知基因组 (Gonystylus bancanus) 的全基因组样本,我们证明并验证了其功能,可靠性,传递性和敏感性。使用两个单独的统计分析,发现了大量的基因组 “指标” 探针。基于该技术的基因组签名数据库的构建将允许虚拟比较,并且简单的查询可以使用简单的下游技术生成用于大规模测定的最佳标记子集。来自广泛领域的生物学家,研究几乎任何生物,可以在进行少量标准化DNA微阵列杂交后,在潜在的任何系统发育水平上有效地进行基因组比较。讨论了改进和扩展该方法的可能性。
  • 【Tn10转座中靶位选择的因素: DDE基序在靶DNA捕获中的作用。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.10.2646 复制DOI
    作者列表:Junop MS,Haniford DB
    BACKGROUND & AIMS: Tn10, like several other transposons, exhibits a marked preference for integration into particular target sequences. Such sequences are referred to as integration hotspots and have been used to define a consensus target site in Tn10 transposition. We demonstrate that a Tn10 hotspot called HisG1, which was identified originally in vivo, also functions as an integration hotspot in vitro in a reaction where the HisG1 sequence is present on a short DNA oligomer. We use this in vitro system to define factors which are important for the capture of the HisG1 target site. We demonstrate that although divalent metal ions are not essential for HisG1 target capture, they greatly facilitate capture of a mutated HisG1 site. Analysis of catalytic transposase mutants further demonstrates that the DDE motif plays a critical role in 'divalent metal ion-dependent' target capture. Analysis of two other classes of transposase mutants, Exc+ Int- (which carry out transposon excision but not integration) and ATS (altered target specificity), demonstrates that while a particular ATS transposase binds HisG1 mutants better than wild-type transposase, Exc+ Int- mutants are defective in HisG1 capture, further defining the properties of these classes of mutants. Possible mechanisms for the above observations are considered.

    背景与目标: Tn10与其他几个转座子一样,表现出对整合到特定靶序列的明显偏好。此类序列被称为整合热点,并已用于定义Tn10转座中的共有靶位点。我们证明了最初在体内鉴定的称为HisG1的Tn10热点在HisG1序列存在于短DNA寡聚物上的反应中也起着体外整合热点的作用。我们使用此体外系统来定义对于捕获HisG1靶位点很重要的因素。我们证明,尽管二价金属离子对于HisG1靶捕获不是必需的,但它们极大地促进了突变HisG1位点的捕获。催化转座酶突变体的分析进一步表明,DDE基序在 “二价金属离子依赖性” 靶捕获中起关键作用。对另外两类转座酶突变体Exc Int- (进行转座子切除但不整合) 和ATS (改变靶特异性) 的分析表明,尽管特定的ATS转座酶比野生型转座酶更好地结合HisG1突变体,但Exc Int-突变体在HisG1捕获中存在缺陷,进一步定义这些类别的突变体的属性。考虑了上述观察的可能机制。
  • 【Exogean: 在真核基因组DNA中注释蛋白质编码基因的框架。】 复制标题 收藏 收藏
    DOI:10.1186/gb-2006-7-s1-s7 复制DOI
    作者列表:Djebali S,Delaplace F,Roest Crollius H
    BACKGROUND & AIMS: BACKGROUND:Accurate and automatic gene identification in eukaryotic genomic DNA is more than ever of crucial importance to efficiently exploit the large volume of assembled genome sequences available to the community. Automatic methods have always been considered less reliable than human expertise. This is illustrated in the EGASP project, where reference annotations against which all automatic methods are measured are generated by human annotators and experimentally verified. We hypothesized that replicating the accuracy of human annotators in an automatic method could be achieved by formalizing the rules and decisions that they use, in a mathematical formalism. RESULTS:We have developed Exogean, a flexible framework based on directed acyclic colored multigraphs (DACMs) that can represent biological objects (for example, mRNA, ESTs, protein alignments, exons) and relationships between them. Graphs are analyzed to process the information according to rules that replicate those used by human annotators. Simple individual starting objects given as input to Exogean are thus combined and synthesized into complex objects such as protein coding transcripts. CONCLUSION:We show here, in the context of the EGASP project, that Exogean is currently the method that best reproduces protein coding gene annotations from human experts, in terms of identifying at least one exact coding sequence per gene. We discuss current limitations of the method and several avenues for improvement.
    背景与目标:
  • 【靶向抗龋DNA疫苗的免疫原性和持久性。】 复制标题 收藏 收藏
    DOI:10.1177/154405910608501008 复制DOI
    作者列表:Xu QA,Yu F,Fan MW,Bian Z,Chen Z,Fan B,Jia R,Guo JH
    BACKGROUND & AIMS: :We have previously reported that a targeted anti-caries DNA vaccine, pGJA-P, induced accelerated and increased antibody responses compared with a non-targeted anti-caries DNA vaccine. Recently, pGJA-P/VAX, a new targeted anti-caries DNA vaccine for human trials, was constructed by replacing the pCI vector used in the construction of pGJA-P with pVAX1, the only vector authorized by the US Food and Drug Administration in clinical trials. Here, we report on our exploration of the kinetics of the antibody responses generated following pGJA-P/VAX immunization and the persistence of pGJA-P/VAX at both the inoculation site and the draining lymph nodes. Intranasal vaccination of mice with pGJA-P/VAX induced strong antibody responses that lasted for more than 6 months. Furthermore, pGJA-P/VAX could still be detected at both the inoculation site and the draining cervical lymph nodes 6 months after immunization. Thus, the persistent immune responses are likely due to the DNA depot in the host, which acts as a booster immunization.
    背景与目标: : 我们以前曾报道过,与非靶向抗龋DNA疫苗相比,靶向抗龋DNA疫苗pGJA-P诱导了加速和增加的抗体反应。最近,pGJA-P/VAX是一种用于人体试验的新型靶向抗龋齿DNA疫苗,通过用pVAX1代替用于构建pGJA-P的pCI载体,这是美国食品药品监督管理局在临床试验中唯一授权的载体。在这里,我们报告了我们对pGJA-P/VAX预防接种后产生的抗体反应的动力学以及pGJA-P/VAX在接种部位和引流淋巴结的持久性的探索。用pGJA-P/VAX对小鼠进行鼻内疫苗接种可诱导持续6个月以上的强烈抗体反应。此外预防接种后6个月,在接种部位和引流颈淋巴结中仍可检测到pGJA-P/VAX。因此,持续的免疫反应可能是由于宿主中的DNA储存库而起加强预防接种作用。
  • 【CpG寡脱氧核苷酸作为脊椎动物的DNA佐剂及其在免疫治疗中的应用。】 复制标题 收藏 收藏
    DOI:10.1016/j.intimp.2006.06.001 复制DOI
    作者列表:Chaung HC
    BACKGROUND & AIMS: :The genomes of bacterial and viral DNA contain a much higher frequency of unmethylated CpG dinucleotides than those of vertebrates. This difference in genome structure allows the innate immune system of vertebrates to distinguish bacterial or viral DNA from self-DNA, and consequently to perceive a 'danger signal' when bacterial or viral DNA is encountered. Multiple sources of evidence suggest that CpG motifs, including bacterial DNA and CpG ODNs (synthetic oligodeoxynucleotides containing unmethylated CpG), are capable of evoking a range of immunostimulatory effects in vertebrates and have a tremendous potential to be used as therapeutic agents and adjuvants. CpG motifs with different sequences have been shown to induce various types or levels of immunostimulatory responses whereas the immunostimulatory effects of CpG motifs are species-specific. A better understanding of CpG recognition at the molecular level is fundamental to the identification of those motifs that have desired immunostimulatory responses. It is hoped that this would allow the optimization and application of CpG motifs as therapeutic agents and adjuvants, for numerous diseases in various species.
    背景与目标: : 细菌和病毒DNA的基因组含有比脊椎动物更高的未甲基化CpG二核苷酸的频率。基因组结构的这种差异使脊椎动物的先天免疫系统能够将细菌或病毒DNA与自身DNA区分开,从而在遇到细菌或病毒DNA时感知到 “危险信号”。多种证据表明,CpG基序,包括细菌DNA和CpG odn (含有未甲基化CpG的合成寡脱氧核苷酸),能够在脊椎动物中引起一系列免疫刺激作用,并具有用作治疗剂和佐剂的巨大潜力。已显示具有不同序列的CpG基序可诱导各种类型或水平的免疫刺激反应,而CpG基序的免疫刺激作用是物种特异性的。在分子水平上更好地理解CpG识别对于鉴定具有所需免疫刺激反应的基序至关重要。希望这将允许CpG基序作为治疗剂和佐剂的优化和应用,以治疗各种物种中的许多疾病。
  • 8 Activation volume of DNA duplex formation. 复制标题 收藏 收藏

    【DNA双链体形成的活化体积。】 复制标题 收藏 收藏
    DOI:10.1021/bi963175n 复制DOI
    作者列表:Lin MC,Macgregor RB Jr
    BACKGROUND & AIMS: The denaturation-renaturation thermal hysteresis was used to investigate the kinetics of the helix-coil equilibrium of four 22-base pair homopurine-homopyrimidine duplex oligonucleotides with fractional G x C base pair content (f(G x C)) between 0.14 and 0.5. In 20 mM NaCl and 20 mM Tris-HCl at pH 7.0 and at hydrostatic pressures up to 200 MPa, a two-state bimolecular reaction mechanism adequately described the observed kinetics. At 1 MPa and 47 degrees C, the rate constant for helix formation, k1, increased by a factor of 210, and the reverse rate constant, k(-1), decreased by a factor of 420 upon increasing f(G x C) from 0.14 to 0.5. The activation energies for formation of the duplexes were negative and relatively insensitive to f(G x C). The pressure-induced change in the rate constants is related to the activation volume of the reaction step. Pressure causes k1 to become larger, and the magnitude of the change in k1 with pressure increases the lower the f(G x C) value. Thus, when f(G x C) = 0.14, the activation volume for forward reaction, delta V++(1), equals -20 mL/mol, while when f(G x C) = 0.5, delta V++(1) = -6.7 mL/mol. The rate constant for strand separation, k(-1), decreases at high pressure. The activation volume for this step, delta V++(1), varies from 17 to 1.6 mL/mol when f(G x C) = 0.14 and 0.5, respectively. The delta V for helix formation calculated from the activation parameters changed from -23 mL/mol when f(G x C) = 0.14 to -5.8 mL/mol when f(G x C) = 0.5. From extrapolation, it is estimated that the molar volume change for formation of G x C base pairs in homopurine-homopyrimidine sequences is approximately 0 mL/mol. Parameters calculated from kinetics of other two duplex molecules, when f(G x C) = 0.23 and 0.32, lie between these extremes.

    背景与目标: 变性-复性热滞后用于研究0.14和0.5之间具有分数G x C碱基对含量 (f(G x C)) 的四种22碱基对高嘌呤-高嘧啶双链体寡核苷酸的螺旋-螺旋平衡动力学。在pH 7.0和高达200 MPa的静水压力下,在20 mM NaCl和20 mM Tris-HCl中,两态双分子反应机理充分描述了观察到的动力学。在1 mpa和47 ℃ 下,当f(G x C) 从0.14增加到0.5时,螺旋形成的速率常数k1增加了210倍,反向速率常数k(-1) 降低了420倍。形成双链体的活化能为负,并且对f(G x C) 相对不敏感。压力引起的速率常数变化与反应步骤的活化体积有关。压力导致k1变大,并且k1随压力变化的幅度增加,f(G x C) 值越低。因此,当f(G x C) = 0.14时,正向反应的活化体积 δ V ++(1) 等于-20 mL/mol,而当f(G x C) = 0.5时,δ V ++(1) = -6.7 mL/mol。在高压下,链分离的速率常数k(-1) 降低。当f(G x C) = 0.14和0.5时,该步骤的活化体积 Δ V ++(1) 分别从17至1.6 mL/mol变化。由活化参数计算的螺旋形成的 δ V从f (gxc) = 0.14时的-23 mL/mol变化到f (gxc) = 0.5时的-5.8 mL/mol。根据外推法,估计在均嘌呤-高嘧啶序列中形成G x C碱基对的摩尔体积变化约为0毫升/mol。当f(G x C) = 0.23和0.32时,根据其他两个双链体分子的动力学计算出的参数介于这些极端之间。
  • 【使用聚合酶链反应检测Lindow Man古代遗骸中的大肠杆菌DNA。】 复制标题 收藏 收藏
    DOI:10.1046/j.1472-765x.1997.00066.x 复制DOI
    作者列表:Fricker EJ,Spigelman M,Fricker CR
    BACKGROUND & AIMS: The polymerase chain reaction has been applied to the detection of Escherichia coli DNA in the upper gut contents of Lindow Man, an Iron Age bog body dated to ca 300 BC. With sets of primers from the uidA and lacZ genes, E. coli DNA could be detected reproducibly. Initial attempts at detecting DNA from freshly voided faeces from a healthy volunteer were unsuccessful due to inhibition of the reaction. Development of a method, based on guanidine thiocyanate and silica extraction and purification of the DNA fragments, facilitated the detection of the E. coli DNA in both freshly voided faeces and the upper gut contents of Lindow Man. These findings indicate that it may be possible to study the existence of infectious diseases in ancient civilizations and to learn more about the evolution of microbes.

    背景与目标: 聚合酶链反应已用于检测Lindow Man的上肠内容物中的大肠杆菌DNA,Lindow Man是铁器时代的沼泽体,可追溯至公元前300年。使用uidA和lacZ基因的引物组,可以重复检测大肠杆菌DNA。由于抑制反应,最初尝试从健康志愿者的新鲜排空粪便中检测DNA的尝试均未成功。基于硫氰酸胍和二氧化硅提取和纯化DNA片段的方法的开发,有助于检测新鲜排空的粪便和Lindow Man的上肠内容物中的大肠杆菌DNA。这些发现表明,可能有可能研究古代文明中传染病的存在,并更多地了解微生物的进化。
  • 【小家鼠 β 珠蛋白单倍型Hbbs和Hbbd的DNA片段。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.76.3.1385 复制DOI
    作者列表:Weaver S,Haigwood NL,Hutchison CA 3rd,Edgell MH
    BACKGROUND & AIMS: :Two alternative haplotypes at the complex locus controlling hemoglobin beta chain synthesis in Mus musculus were compared at the DNA level. As expected, Hbbd homozygotes--which as adults synthesize two species of beta chain--have two genes for beta globin. Adult mice homozygous for the Hbbs haplotype make only a single type of beta polypeptide, yet they also have two beta globin genes. Apparently the two Hbbs genes encode identical proteins, or one of the two genes is not detectably expressed. The Hbbs and Hbbd haplotypes are thus more similar at the DNA level than studies of their polypeptide products have indicated.
    背景与目标: : 在DNA水平上比较了控制小家鼠血红蛋白 β 链合成的复杂位点的两种替代单倍型。正如预期的那样,Hbbd纯合子-成年后合成了两个 β 链物种-具有两个 β 球蛋白基因。Hbbs单倍型纯合的成年小鼠仅产生一种 β 多肽,但它们也有两个 β 球蛋白基因。显然,这两个Hbbs基因编码相同的蛋白质,或者这两个基因中的一个无法检测到表达。因此,hbb和Hbbd单倍型在DNA水平上比其多肽产物的研究更相似。
  • 【免疫治疗反应的DNA损伤和修复生物标志物。】 复制标题 收藏 收藏
    DOI:10.1158/2159-8290.CD-17-0226 复制DOI
    作者列表:Mouw KW,Goldberg MS,Konstantinopoulos PA,D'Andrea AD
    BACKGROUND & AIMS: :DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675-93. ©2017 AACR.
    背景与目标: : DNA损伤剂广泛用于临床肿瘤学,并利用肿瘤DNA修复中的缺陷。鉴于免疫检查点阻断作为一种治疗策略的作用不断扩大,肿瘤DNA损伤与免疫系统的相互作用最近成为人们关注的焦点,现在很明显,肿瘤DNA修复景观在驱动免疫检查点阻断的反应中具有重要作用。在这里,我们总结了DNA损伤和基因组不稳定性被发现形成抗肿瘤免疫反应的机制,并描述了使用DNA修复生物标志物指导免疫导向疗法的临床努力。意义: 只有一部分患者对免疫检查点阻断有反应,需要可靠的预测反应生物标志物来指导治疗决策。DNA修复缺陷在肿瘤中很常见,新出现的实验和临床证据表明,基因组不稳定性的特征与对免疫导向疗法的反应有关。癌症椎间盘; 7(7); 675-93。©2017 AACR.
  • 【“生物碱harmalol与DNA的结合: 光物理和量热方法” 的勘误 [J. Photochem. Photobiol. B: Biol. 130 (2014) 272-280]。】 复制标题 收藏 收藏
    DOI:10.1016/j.jphotobiol.2015.03.003 复制DOI
    作者列表:Sarkar S,Bhadra K
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【用重组亚单位或DNA疫苗递送的猪肺炎支原体抗原P37,P42,P46和P95免疫小鼠。】 复制标题 收藏 收藏
    DOI:10.1016/j.vaccine.2012.10.088 复制DOI
    作者列表:Galli V,Simionatto S,Marchioro SB,Fisch A,Gomes CK,Conceição FR,Dellagostin OA
    BACKGROUND & AIMS: :Porcine enzootic pneumonia (PEP), which is caused by the fastidious bacterium Mycoplasma hyopneumoniae, is one of the most economically important diseases in the pig industry worldwide. Commercial bacterins provide only partial protection; therefore, the development of more efficient vaccines against PEP is necessary. In this study, the cellular and humoral immune responses elicited by DNA and recombinant subunit vaccines based on the P37, P42, P46 and P95 antigens of M. hyopneumoniae were evaluated after the intramuscular inoculation of BALB/c mice. The expression of the cytokines INFγ, TNFα and IL1 was evaluated by real-time RT-PCR in splenocytes from vaccinated mice. All antigens delivered as subunit vaccines, especially P42 and P95, and the pcDNA3/P46 DNA vaccine were able to elicit strong immune responses. These vaccines induced cellular immune responses and the production of antibodies able to react with native M. hyopneumoniae proteins. Because both cellular and humoral immune responses were induced, P42 and P95 are promising candidates for a recombinant subunit vaccine and P46 is a promising candidate for a DNA vaccine against PEP.
    背景与目标: : 猪传染性肺炎 (PEP) 是由挑剔的细菌支原体肺炎e引起的,是全球养猪业最重要的经济疾病之一。商业细菌仅提供部分保护; 因此,必须开发针对PEP的更有效疫苗。在这项研究中,在肌内接种BALB/c小鼠后,评估了基于猪肺炎支原体P37,P42,P46和P95抗原的DNA和重组亚基疫苗引起的细胞和体液免疫反应。通过实时rt-pcr评估了免疫小鼠脾细胞中细胞因子inf γ,tnf α 和IL1的表达。作为亚单位疫苗递送的所有抗原,尤其是P42和P95,以及pcDNA3/P46 DNA疫苗能够引发强烈的免疫反应。这些疫苗可诱导细胞免疫反应,并产生能够与天然猪肺炎支原体蛋白反应的抗体。由于诱导了细胞和体液免疫反应,因此P42和P95是重组亚单位疫苗的有希望的候选者,而P46是针对PEP的DNA疫苗的有希望的候选者。
  • 【组蛋白泛素化在DNA损伤反应中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.dnarep.2017.06.011 复制DOI
    作者列表:Uckelmann M,Sixma TK
    BACKGROUND & AIMS: :DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio-temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining.
    背景与目标: : DNA双链断裂需要有组织地修复,以保持基因组完整性。在组织忠实修复中,组蛋白泛素化起着至关重要的作用。最近的发现表明,通过位点特异性组蛋白泛素化和与其他翻译后修饰的串扰,建立了DNA修复调控的综合模型。在这里,我们讨论了如何在分子水平上实现位点特异性组蛋白泛素化,以及不同的多蛋白复合物如何协同工作以整合不同的组蛋白泛素化状态。我们提出了一个模型,其中位点特异性H2A泛素化组织DNA修复因子的时空募集,这最终将有助于同源重组和非同源末端连接之间的DNA修复途径选择。
  • 【对G-四链体DNA表现出高保真度的卤化五甲胺花青染料。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.008 复制DOI
    作者列表:Nanjunda R,Owens EA,Mickelson L,Alyabyev S,Kilpatrick N,Wang S,Henary M,Wilson WD
    BACKGROUND & AIMS: :Design and optimization of quadruplex-specific small molecules is developing into an attractive strategy for anti-cancer therapeutics with some promising candidates in clinical trials. A number of therapeutically favorable features of cyanine molecules can be effectively exploited to develop them as promising quadruplex-targeting agents. Herein, the design, synthesis and evaluation of a series of dimethylindolenine cyanine dyes with varying halogen substitutions are reported. Their interactions with telomeric and c-myc quadruplexes as well as a reference duplex sequence have been evaluated using thermal melting, biosensor-surface plasmon resonance, circular dichroism, isothermal titration calorimetry and mass spectrometry. Thermal melting analysis indicates that these ligands exhibit significant quadruplex stabilization and a very low duplex binding, with the dimethyl incorporation of paramount importance for decreased duplex affinity. Circular dichroism studies showed that the interaction of cyanines with quadruplex structures are primarily through stacking at one or both ends of the terminal tetrads with the two (trimethylammonium)propyl groups interacting in the accessible quadruplex grooves. Surface plasmon resonance and mass spectral studies shows the formation of an initial strong 1:1 complex followed by a significantly weaker secondary binding. Isothermal calorimetry studies show that the interaction of cyanines is predominantly entropy driven. In line with the design principles, this work provides new insights for further developing potent, highly selective cyanines as promising quadruplex-specific agents.
    背景与目标: : 四链特异性小分子的设计和优化正在发展成为一种有吸引力的抗癌治疗策略,在临床试验中有一些有前途的候选药物。可以有效地利用花青分子的许多治疗上有利的特征来开发它们作为有希望的四链靶向剂。本文报道了一系列具有不同卤素取代的二甲基吲哚烯花青染料的设计,合成和评估。已使用热熔,生物传感器-表面等离子体共振,圆二色性,等温滴定量热法和质谱法评估了它们与端粒和c-myc四链体以及参考双链体序列的相互作用。热熔分析表明,这些配体表现出显着的四链稳定性和非常低的双链体结合,其中二甲基掺入对于降低双链体亲和力至关重要。圆二色性研究表明,花青与四重结构的相互作用主要是通过在末端四重的一端或两端堆叠,其中两个 (三甲基铵) 丙基基团在可及的四重沟槽中相互作用。表面等离子体共振和质谱研究表明,形成了初始的强1:1络合物,随后显着较弱的二级结合。等温量热法研究表明,花青的相互作用主要是熵驱动的。符合设计原则,这项工作为进一步开发有效的,高选择性的花青作为有希望的四链特异性试剂提供了新的见解。

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