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Unlike other antiapoptotic Bcl-2 family members, Mcl-1 also mediates resistance to cancer therapy by uniquely inhibiting chemotherapy-induced senescence (CIS). In general, Bcl-2 family members regulate apoptosis at the level of the mitochondria through a common prosurvival binding groove. Through mutagenesis, we determined that Mcl-1 can inhibit CIS even in the absence of its apoptotically important mitochondrion-localizing domains. This finding prompted us to generate a series of Mcl-1 deletion mutants from both the N and C termini of the protein, including one that contained a deletion of all of the Bcl-2 homology domains, none of which impacted anti-CIS capabilities. Through subsequent structure-function analyses of Mcl-1, we identified a previously uncharacterized loop domain responsible for the anti-CIS activity of Mcl-1. The importance of the loop domain was confirmed in multiple tumor types, two in vivo models of senescence, and by demonstrating that a peptide mimetic of the loop domain can effectively inhibit the anti-CIS function of Mcl-1. The results from our studies appear to be highly translatable because we discerned an inverse relationship between the expression of Mcl-1 and of various senescence markers in cancerous human tissues. In summary, our findings regarding the unique structural properties of Mcl-1 provide new approaches for targeted cancer therapy.  相似文献   
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Past studies have suggested that a key feature of the mechanism of heparin allosteric activation of the anticoagulant serpin, antithrombin, is the release of the reactive center loop P14 residue from a native state stabilizing interaction with the hydrophobic core. However, more recent studies have indicated that this structural change plays a secondary role in the activation mechanism. To clarify this role, we expressed and characterized 15 antithrombin P14 variants. The variants exhibited basal reactivities with factors Xa and IXa, heparin affinities and thermal stabilities that were dramatically altered from wild type, consistent with the P14 mutations perturbing native state stability and shifting an allosteric equilibrium between native and activated states. Rapid kinetic studies confirmed that limiting rate constants for heparin allosteric activation of the mutants were altered in conjunction with the observed shifts of the allosteric equilibrium. However, correlations of the P14 mutations'' effects on parameters reflecting the allosteric activation state of the serpin were inconsistent with a two-state model of allosteric activation and suggested multiple activated states. Together, these findings support a minimal three-state model of allosteric activation in which the P14 mutations perturb equilibria involving distinct native, intermediate, and fully activated states wherein the P14 residue retains an interaction with the hydrophobic core in the intermediate state but is released from the core in the fully activated state, and the bulk of allosteric activation has occurred in the intermediate.  相似文献   
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Eukaryotic protein kinases are typically strictly controlled by second messenger binding, protein/protein interactions, dephosphorylations or similar processes. None of these regulatory mechanisms is known to work for protein kinase CK2 (former name “casein kinase 2”), an acidophilic and constitutively active eukaryotic protein kinase. CK2 predominantly exists as a heterotetrameric holoenzyme composed of two catalytic subunits (CK2α) complexed to a dimer of non-catalytic subunits (CK2β). One model of CK2 regulation was proposed several times independently by theoretical docking of the first CK2 holoenzyme structure. According to this model, the CK2 holoenzyme forms autoinhibitory aggregates correlated with trans-autophosphorylation and driven by the down-regulatory affinity between an acidic loop of CK2β and the positively charged substrate binding region of CK2α from a neighboring CK2 heterotetramer. Circular trimeric aggregates in which one-half of the CK2α chains show the predicted inhibitory proximity between those regions were detected within the crystal packing of the human CK2 holoenzyme. Here, we present further in vitro support of the “regulation-by-aggregation” model by an alternative crystal form in which CK2 tetramers are arranged as approximately linear aggregates coinciding essentially with the early predictions. In this assembly, the substrate binding region of every CK2α chain is blocked by a CK2β acidic loop from a neighboring tetramer. We found these crystals with CK2Andante that contains a CK2β variant mutated in a CK2α-contact helix and described to be responsible for a prolonged circadian rhythm in Drosophila. The increased propensity of CK2Andante to form aggregates with completely blocked active sites may contribute to this phenotype.  相似文献   
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目的:探讨经阴道超声与宫腔镜检查诊断子宫内膜病变的临床价值,为临床诊断子宫内膜病变提供理论依据。方法:选取2011年3月-2014年3月间我院收治的158例疑似子宫内膜病变患者,分别采用经阴道超声和宫腔镜进行检查,并以病理诊断结果为"金标准",比较两种检查方法的诊断价值。结果:病理检查结果中,143例患者被确诊为子宫内膜病变,其中子宫内膜增生23例(16.08%),子宫内膜息肉31例(21.68%),子宫粘膜下肌瘤24例(16.78%),子宫内膜癌19例(13.29%),慢性非特异性子宫内膜炎46例(32.17%)。宫腔镜对子宫内膜病变诊断的准确率为94.41%,高于阴道超声的81.12%,差异有统计学意义(P0.05),其中阴道超声和宫腔镜对子宫粘膜下肌瘤、子宫内膜癌诊断的准确率比较差异无统计学意义(P0.05),阴道超声对子宫内膜增生、子宫内膜息肉及慢性非特异性子宫内膜炎的诊断准确率均较宫腔镜降低,差异有统计学意义(P0.05)。阴道超声对子宫内膜病变诊断的特异度较宫腔镜更低(P0.05),但两者灵敏度、AUC比较差异无统计学意义(P0.05)。结论:经阴道超声诊断子宫内膜病变简单、有效,而宫腔镜诊断子宫内膜病变具有准确率以及特异度较高的特点。  相似文献   
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目的:探讨孟鲁司特联合信必可治疗支气管哮喘的疗效及对患者肺功能和血嗜酸细胞(EOS)、C反应蛋白(CRP)水平的影响。方法:选取我院2016年1月~2017年4月收治的136例支气管哮喘患者,按照随机数字表法均分为两组。对照组(68例)采取信必可治疗,观察组(68例)在此基础上加用孟鲁司特治疗。治疗12周后,评价两组的临床疗效,对比两组治疗前后哮喘症状评分、肺功能、外周血EOS计数及血清CRP水平变化的情况。结果:经12周治疗后,观察组总有效率为95.59%(65/68),与对照组[79.41%(54/68)]相比显著上升(P0.01)。与治疗前对比,两组治疗12周后日间与夜间哮喘评分、外周血EOS计数、血清CRP水平均显著下降(P0.01),且观察组以上指标均显著低于对照组(P0.01)。与治疗前相比,两组治疗12周后肺功能指标FVC、FEV1、PEF值均有明显升高(P0.01);且观察组以上指标均显著高于对照组(P0.01)。结论:孟鲁司特联合信必可治疗支气管哮喘可有效改善患者的肺功能,减轻气道炎症反应,促进哮喘症状缓解,疗效确切。  相似文献   
8.
目的:探讨有氧康复运动对慢性心力衰竭(chronic cardiac failure,CHF)患者心室重构及血管内皮功能的影响。方法:78例CHF患者随机分为运动组(n=39)、对照组(n=39)。对照组给予常规内科药物治疗、日常活动能力训练,运动组在此基础上根据美国心脏病学会(American Heart Association,AHA)的《三阶段康复运动方案》进行有氧康复运动,共持续12周。比较两组治疗前后心脏结构和功能、血管内皮功能及生活质量的改善情况。结果:干预后,两组左室收缩末期内径(left ventricular end systolic diameter,LVESD)、左室舒张末期内径(left ventricular end-diastolic diameter,LVEDD)、明尼苏达心衰生活质量(Minnesota Living With Heart Failure,MLHF)评分、血清内皮素-1(Endothelin-1,ET-1)、血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)水平均明显减小,左室射血分数(left ventricular ejection fraction,LVEF)、6分钟步行试验(6 minute walking test,6MWT)、血清一氧化氮(nitric oxide,NO)、降钙素基因相关肽(calcitonin gene-related peptide,CGRP)水平均明显升高,且运动组LVESD、LVEDD、MLHF评分、血清ET-1、Ang Ⅱ水平明显低于对照组,LVEF、6MWT、血清NO、CGRP水平明显高于对照组,差异均有统计学意义(P0.05)。运动组干预期间心衰再入院率显著低于对照组,差异均有统计学意义(P0.05)。结论:有氧运动康复训练有助于改善CHF患者的血管内皮功能,延缓或逆转心室重构,提高生活质量,改善预后。  相似文献   
9.
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.  相似文献   
10.
Epigenetic complexes play an essential role in regulating chromatin structure, but information about their assembly stoichiometry on chromatin within cells is poorly understood. The cellular assembly stoichiometry is critical for appreciating the initiation, propagation, and maintenance of epigenetic inheritance during normal development and in cancer. By combining genetic engineering, chromatin biochemistry, and single-molecule fluorescence imaging, we developed a novel and sensitive approach termed single-molecule chromatin immunoprecipitation imaging (Sm-ChIPi) to enable investigation of the cellular assembly stoichiometry of epigenetic complexes on chromatin. Sm-ChIPi was validated by using chromatin complexes with known stoichiometry. The stoichiometry of subunits within a polycomb complex and the assembly stoichiometry of polycomb complexes on chromatin have been extensively studied but reached divergent views. Moreover, the cellular assembly stoichiometry of polycomb complexes on chromatin remains unexplored. Using Sm-ChIPi, we demonstrated that within mouse embryonic stem cells, one polycomb repressive complex (PRC) 1 associates with multiple nucleosomes, whereas two PRC2s can bind to a single nucleosome. Furthermore, we obtained direct physical evidence that the nucleoplasmic PRC1 is monomeric, whereas PRC2 can dimerize in the nucleoplasm. We showed that ES cell differentiation induces selective alteration of the assembly stoichiometry of Cbx2 on chromatin but not other PRC1 components. We additionally showed that the PRC2-mediated trimethylation of H3K27 is not required for the assembly stoichiometry of PRC1 on chromatin. Thus, these findings uncover that PRC1 and PRC2 employ distinct mechanisms to assemble on chromatin, and the novel Sm-ChIPi technique could provide single-molecule insight into other epigenetic complexes.  相似文献   
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