BACKGROUND & AIMS: :Neuronal death associated with cerebral ischemia and hypoglycemia is related to increased release of excitatory amino acids (EAA) and energy failure. The intrahippocampal administration of the glycolysis inhibitor, iodoacetate (IOA), induces the accumulation of EAA and neuronal death. We have investigated by microdialysis the role of exocytosis, glutamate transporters and volume-sensitive organic anion channel (VSOAC) on IOA-induced EAA release. Results show that the early component of EAA release is inhibited by riluzole, a voltage-dependent sodium channel blocker, and by the VSOAC blocker, tamoxifen, while the early and late components are blocked by the glutamate transport inhibitors, L-trans-pyrrolidine 2,4-dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA); and by the VSOAC blocker 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). Riluzole, DL-TBOA and tamoxifen did not prevent IOA-induced neuronal death, while PDC and DNDS did. The VSOAC blockers 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) and phloretin had no effect either on EAA efflux or neuronal damage. Results suggest that acute inhibition of glycolytic metabolism promotes the accumulation of EAA by exocytosis, impairment or reverse action of glutamate transporters and activation of a DNDS-sensitive mechanism. The latest is substantially involved in the triggering of neuronal death. To our knowledge, this is the first study to show protection of neuronal death by DNDS in an in vivo model of neuronal damage, associated with deficient energy metabolism and EAA release, two conditions involved in some pathological states such as ischemia and hypoglycemia.

背景与目标： ：与脑缺血和低血糖有关的神经元死亡与兴奋性氨基酸（EAA）释放增加和能量衰竭有关。海马内糖酵解抑制剂碘乙酸盐（IOA）的给药可诱导EAA积累和神经元死亡。我们已经通过微透析研究了胞吐作用，谷氨酸转运蛋白和体积敏感性有机阴离子通道（VSOAC）对IOA诱导的EAA释放的作用。结果表明，EAA释放的早期组分被电压依赖性钠通道阻滞剂利鲁唑和VSOAC阻断剂他莫昔芬抑制，而谷氨酸转运抑制剂L-反式吡咯烷2则阻断了早期和晚期组分。 ，4-二羧酸盐（PDC）和DL-苏-β-苄氧基天冬氨酸（DL-TBOA）;通过VSOAC阻滞剂4,4'-二硝基二苯乙烯-2,2'-二磺酸（DNDS）。利鲁唑，DL-TBOA和他莫昔芬不能预防IOA诱导的神经元死亡，而PDC和DNDS可以预防。 VSOAC阻滞剂5-硝基-2-（3-苯基丙基-氨基）苯甲酸（NPPB）和荧光素对EAA流出或神经元损伤均无影响。结果表明，糖酵解代谢的急性抑制可通过胞吐作用，谷氨酸转运蛋白的损伤或逆向作用以及DNDS敏感机制的激活来促进EAA的积累。最新消息实质上涉及神经元死亡的触发。据我们所知，这是第一个在体内神经元损伤模型中由DNDS保护神经元死亡的研究，该模型与能量代谢不足和EAA释放有关，这是某些病理状态（例如局部缺血和低血糖）的两个条件。

BACKGROUND & AIMS: :Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MβCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications.

背景与目标： ：甲基-β-环糊精（MβCD）减少Niemann-Pick疾病C1型（NPC1）患者成纤维细胞中的溶酶体胆固醇蓄积。然而，不同实验室报道的MβCD的药理活性是不同的。为了确定这种变化的潜在原因，我们分析了三种MβCDs制剂的质谱特征，药理活性以及不同来源的MβCDs治疗后NPC1患者成纤维细胞的蛋白质表达谱。我们的数据揭示了这三种制备自不同批次和不同来源的MβCD制剂在减少NPC1成纤维细胞中溶酶体胆固醇积累方面的不同质谱曲线和药理活性。此外，蛋白质组学分析显示了这三种MβCD制剂在改善NPC1细胞中蛋白质表达失调水平方面的差异。结果证明了在用作治疗剂之前预先筛选不同的环糊精制剂的重要性。质谱分析，药理活性测量和蛋白质组学分析相结合，为表征环糊精用于治疗应用提供了有效的分析程序。

BACKGROUND & AIMS: BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy. OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients. METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

背景与目标： 背景：Th17细胞分泌的白细胞介素17（IL-17）是一种促炎细胞因子，与多发性硬化症（MS）的发病机制有关，并且在MS患者对干扰素-β（IFN-α）无反应中起作用β）疗法。
目的：本研究的目的是建立无应答者（NR）与IL-17A血清滴度和针对IFN-β的结合抗体（BAbs）之间的相关性，以及找出IL-17A血清水平与其他特征之间的相关性MS患者。
方法：我们的前瞻性研究包括72例接受IFN-β治疗至少18个月的非活动性复发缓解型多发性硬化症（RRMS）患者和15名健康受试者。我们确定了IL-17A和BAbs的血清水平。如果记录值大于1.6 pg / ml，则认为IL-17A水平升高（IL-17A）。
结果：27名患者（37.5％）为NR，与应答者组相比，血清IL-17A水平显着更高。 19名患者（26.4％）为IL-17A，在前一年中复发率明显更高，而“扩展残疾状态评分”更高。大多数IL-17A患者为NR，MS病程较短。
结论：与低IL-17A水平的患者相比，血清IL-17A水平高的RRMS患者对IFN-β治疗的反应不佳，MS病程较短。该反应不受BAbs的存在的影响。

BACKGROUND & AIMS: :Molecular dynamics simulations in explicit water were carried out for two stacks, each composed of six 10-strand antiparallel β-sheets for two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains. The first system, referred to as 10×6×MK contained the DLSFMKGE sequence from the Drosophila, while the second one, referred to as 10×6×KK, contained the human DLSFKKGE sequence. It was found that the 10×6×MK β-sheet stack is stable, but the 10×6×KK β-sheet stack is not. The stability of the 10×6×MK β-sheet stack results from the hydrophobic interactions of the methionine and phenylalanine residues and the leucine residues of the neighboring sheets. The Met, Phe, and Leu hydrophobic units make a hydrophobic core for the stack of β-sheets. During the MD run, the Met, Phe, and Leu residues of the neighboring β-sheets acted as a conformational switch moving the β-sheets so that the Phe residue interacted with the Met residue from the neighboring β-sheet. Replacement of Met by Lys destroys the hydrophobic core, which is the stability factor of the β-sheet stack. For the 10×6×KK system, individual β-sheets were preserved during simulations, but the interactions between the β-sheets were lost. The calculations of a six β-sheet stack confirm the conclusion drawn from our earlier studies of single β-sheet systems that the β-sheets must form stacks to be stabilized. These results suggest that the two conserved basic residues at the diverging turn of SH3 domains could act as gatekeepers to avoid aggregation.

背景与目标： ：在显式水中对两个堆叠进行分子动力学模拟，每个堆叠由六个肽的十链反平行β-折叠组成，对应于两个同源Abl-SH3结构域的发散转向的两个肽。第一个系统称为10×6×MK，包含来自果蝇的DLSFMKGE序列，而第二个系统称为10×6×KK，包含人的DLSFKKGE序列。发现10×6×MKβ-折叠堆叠是稳定的，但是10×6×KKβ-折叠堆叠不是稳定的。 10×6×MKβ-折叠叠层的稳定性是由蛋氨酸和苯丙氨酸残基与相邻薄片的亮氨酸残基之间的疏水性相互作用造成的。 Met，Phe和Leu疏水单元构成β-折叠堆叠的疏水核心。在MD运行期间，相邻β-折叠的Met，Phe和Leu残基充当构象开关，移动β-折叠，使Phe残基与来自相邻β-折叠的Met残基相互作用。 Lys取代Met会破坏疏水核，这是β-折叠堆叠的稳定性因素。对于10×6×KK系统，在模拟过程中保留了单独的β-折叠，但丢失了β-折叠之间的相互作用。六个β-折叠电池堆的计算证实了我们先前对单个β-折叠系统的研究得出的结论，即β-折叠必须形成要稳定的电池堆。这些结果表明，在SH3结构域的不同转弯处的两个保守的碱性残基可以充当看门人以避免聚集。

BACKGROUND & AIMS: :As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor β (TGF-β1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis.

背景与目标： ：由于在大多数工业化国家中，结直肠癌仍然是与癌症相关的死亡的第二大原因，因此，确定预防结直肠肿瘤发展的新策略仍然是一项重要的挑战。 BAG-1是一种多功能蛋白，其表达在大肠肿瘤发生的相对早期阶段就被上调。重要的是，BAG-1被认为通过促进肿瘤细胞的存活来增强结直肠肿瘤的进展。在这里，我们首次报道了BAG-1的新作用，确立了它作为大肠肿瘤细胞中转化生长因子β（TGF-β1）表达的抑制剂。微阵列分析首先凸显了BAG-1可能调节TGF-β1表达的可能性，TGF-β1是正常结肠组织稳态中的关键细胞因子。 Q-RT-PCR和ELISA结果表明，当小干扰RNA降低BAG1水平时，TGFB1 mRNA和蛋白表达显着增加。另外，BAG-1L的诱导导致结直肠肿瘤细胞中TGFB1 mRNA的抑制。使用报道分子和染色质免疫沉淀测定法，鉴定了BAG-1与TGFB1基因调控区的直接关联。免疫组织化学和Weiser分数数据表明，体内正常结肠上皮中BAG-1和TGF-β1的含量呈负相关，这与BAG-1介导的抑制TGF-β1产生的作用一致。体外研究表明，操纵BAG-1后TGF-β1产生的变化在功能上是相关的。通过诱导TGF-β1依赖的正常大鼠肾成纤维细胞中不依赖贴壁的生长以及调节TGF-β1敏感的腺瘤细胞中SMAD2磷酸化。综上所述，这项研究确定了抗凋亡蛋白BAG-1是抑制生长因子TGF-β1的抑制剂，这表明BAG-1的高表达可以影响多种癌症，对促进癌症的发展具有潜在的重要意义。大肠癌发生的早期阶段。建立BAG-1作为TGF-β1的阻遏物具有重要的生物学意义，并突出了BAG-1在结直肠肿瘤发生中的新作用。

BACKGROUND & AIMS: :Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial-mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.

背景与目标： 人冠状动脉内皮细胞（HCAEC）有可能经历纤维化内皮-间质转化（EndMT），从而导致产生基质的成纤维细胞，从而有助于心脏纤维化的发病机理。最近，已证明原纤维化细胞因子转化生长因子-β（TGF-β）是关键的致病性驱动因子，已被证实可诱导EndMT。 C-Ski是TGF-β信号传导的重要调节剂。然而，在很大程度上没有阐明c-Ski的详细作用以及c-Ski影响HCAECs中TGF-β诱导的EndMT的分子机制。在本研究中，我们用不同浓度的TGF-β处理HCAEC，以诱导EndMT。我们发现，无论是否使用TGF-β处理，HCAEC中c-Ski的过表达要么通过阻碍波形蛋白，蜗牛，Slug和Twist的表达而阻断EndMT，同时增强CD31的表达。相反，抑制c-Ski进一步增强了EndMT。当前，miRNA表达障碍经常被报道与心脏纤维化有关。通过使用在线工具，我们将miR-155视为可以靶向c-Ski的候选miRNA，这已通过荧光素酶测定法进行了验证。 C-Ski表达受到miR-155的负调控。 TGF-β诱导的EndMT被miR-155沉默抑制； TGF-β对波形蛋白，CD31，蜗牛，Slug和Twist的作用可以被miR-155部分恢复。总之，这些发现将阐明miR-155通过c-Ski调节TGF-β诱导的HCAECs EndMT的作用和机制，从而影响心脏纤维化，而miR-155 / c-Ski可能代表了新型的生物标志物和治疗靶点。心脏纤维化的治疗。

BACKGROUND & AIMS: PURPOSE:The purpose of this study was to assess demographic characteristics of women prescribed beta-blocker (beta-blocker) medication and compare to those not using beta-blocker medication, and to determine if there are differences in depression and fatigue among women who used beta-blockers compared to nonusers 6-12 months after myocardial infarction (MI). DATA SOURCES:This was a descriptive cross-sectional study of 84 women (61 using beta-blockers and 23 not using beta-blockers) aged 65 and older who were 6-12 months post-MI. Women had their height and weight measured and completed a Demographic Health Form, the Geriatric Depression Scale, and the Revised Piper Fatigue Scale (RPFS). CONCLUSIONS:While most of the women were taking beta-blockers after MI (74%), significantly fewer Black women were taking beta-blockers (chi(2) = 5.086, p = 0.032). Most of the beta-blocker users were overweight or obese. There were no significant differences in age, t(82) = 0.7, p = 0.486; body mass index, t(82) = 0.76, p = 0.445; income, chi(2)(df = 2) = 3.219, p = 0.075; mean depression, t(82) = 1.648, p = 0.103; or fatigue scores, t(82) = 0.993, p = 0.324, between beta-blocker users and nonusers. More of those not taking beta-blockers reported fatigue with significantly higher fatigue in the affective meaning dimension of the RPFS, t(82) = 2.272, p = 0.03. IMPLICATIONS FOR PRACTICE:beta-Blocker medication continues to be underutilized in older women. Because no difference was noted in fatigue and depression in the two groups, these may mean that these side effects are not barriers in prescribing this medication post-MI. Nurse practitioners are in pivotal positions to monitor the ongoing physiological and psychological sequelae post-MI and implement interventions to improve their outcomes.

背景与目标： 目的：本研究的目的是评估处方使用β-受体阻滞剂（β-blocker）药物的女性的人口统计学特征，并将其与未使用β-受体阻滞剂的女性进行比较，并确定使用这种药物的女性在抑郁和疲劳方面是否存在差异心肌梗塞（MI）后6至12个月与非使用者相比，β受体阻滞剂的使用率更高。
数据来源：这是一项描述性横断面研究，涉及MI后6-12个月的84位65岁及以上的女性（61位使用β受体阻滞剂，23位未使用β阻滞剂）。对妇女的身高和体重进行测量，并填写人口健康表格，老年抑郁量表和修订的派珀疲劳量表（RPFS）。
结论：虽然大多数女性在心梗后服用β受体阻滞剂（74％），但黑人妇女服用β阻滞剂的比例却明显减少（chi（2）= 5.086，p = 0.032）。大多数的β受体阻滞剂使用者超重或肥胖。年龄无显着差异，t（82）= 0.7，p = 0.486；体重指数，t（82）= 0.76，p = 0.445；收入，chi（2）（df = 2）= 3.219，p = 0.075;平均抑郁，t（82）= 1.648，p = 0.103; β受体阻滞剂使用者与非使用者之间的疲劳评分，t（82）= 0.993，p = 0.324。在没有服用β受体阻滞剂的人中，有更多人报告说疲劳感在RPFS的情感意义维度上明显更高，t（82）= 2.272，p = 0.03。
实践的意义：老年妇女使用β受体阻滞剂的药物仍未得到充分利用。由于两组在疲劳和抑郁方面均未见差异，这可能意味着这些副作用并非在心梗后开这种药的障碍。护士执业医师处于关键地位，以监测心梗后持续的生理和心理后遗症，并实施干预措施以改善其结局。

BACKGROUND & AIMS: :A novel lectin was purified from the fruiting bodies of king bolete mushrooms (Boletus edulis, also called porcino, cep or penny bun). The lectin was structurally characterized i.e its amino acid sequence and three-dimensional structure were determined. The new protein is a homodimer and each protomer folds as β-trefoil domain and therefore we propose the name Boletus edulis lectin (BEL) β-trefoil to distinguish it from the other lectin that has been described in these mushrooms. The lectin has potent anti-proliferative effects on human cancer cells, which confers to it an interesting therapeutic potential as an antineoplastic agent. Several crystal forms of the apoprotein and of complexes with different carbohydrates were studied by X-ray diffraction. The structure of the apoprotein was solved at 1.12 Å resolution. The interaction of the lectin with lactose, galactose, N-acetylgalactosamine and T-antigen disaccharide, Galβ1-3GalNAc, was examined in detail. All the three potential binding sites present in the β-trefoil fold are occupied in at least one crystal form and are described in detail in this paper. No important conformational changes are observed in the lectin when comparing its co-crystals with carbohydrates with those of the ligand-free protein.

背景与目标： ：从牛肝菌王菇（Boletus edulis，也称为牛肝菌，cep或便士面包）的子实体中纯化出一种新型凝集素。对凝集素进行结构表征，即确定其氨基酸序列和三维结构。新蛋白是同源二聚体，每个前体折叠成β-三叶结构域，因此我们提出了牛肝菌凝集素（BEL）β-三叶的名称，以将其与这些蘑菇中描述的其他凝集素区分开。所述凝集素对人癌细胞具有有效的抗增殖作用，使其具有作为抗肿瘤剂的令人感兴趣的治疗潜力。通过X射线衍射研究了载脂蛋白的几种晶体形式以及与不同碳水化合物的复合物。载脂蛋白的结构以1.12Å的分辨率解析。详细检查了凝集素与乳糖，半乳糖，N-乙酰半乳糖胺和T抗原二糖Galβ1-3GalNAc的相互作用。 β-三叶折叠中存在的所有三个潜在结合位点均以至少一种晶体形式占据，并在本文中进行了详细描述。当将其与碳水化合物的共晶体与不含配体的蛋白质的共晶体进行比较时，在凝集素中未观察到重要的构象变化。

BACKGROUND & AIMS: :A series of twenty-five derivatives of tetrahydro-β-carbolines 1-3 was synthesized and assayed on FAAH and TRPV1 and TRPA1 channels. Four carbamates, that is, 5a,c,e, and 9b inhibited FAAH with significant potency and interacted also effectively with TRPV1 and TRPA1 nociceptive receptors, while ureas 7b,d,f, and 8a,b were endowed with specific submicromolar TRPV1 modulating activities.

背景与目标： ：合成了一系列的二十五个四氢-β-咔啉1-3衍生物，并在FAAH和TRPV1和TRPA1通道上进行了测定。四种氨基甲酸酯5a，c，e和9b显着抑制FAAH，并且还与TRPV1和TRPA1伤害感受器有效相互作用，而尿素7b，d，f和8a，b具有特定的亚微摩尔TRPV1调节活性。 。

BACKGROUND & AIMS: :Propolis is a glue, prepared by honeybees from plant materials to stick their hives on the beehive wall. It has gained popularity in Japan as a healthy drink and people believe that propolis can cure inflammation, heart diseases and even diabetes and cancer. We have evaluated the β-cell protective effect of propolis against the toxicity of streptozotocin (STZ) in rats. The water extract of propolis (PWE) completely protected β-cell destruction against STZ toxicity. The protective effect of PWE was found to be almost equal to that of nicotinamide. PWE also inhibited the interleukin-1 β (IL-1 β) generation from human leukocytes. The free radical scavenging activity together with IL-1 β and nitric oxide (NO) synthase inhibitory activities are thought to be the prime factors for the protective effect of PWE against STZ toxicity.

背景与目标： ：蜂胶是一种胶水，是由蜜蜂从植物材料中制备的，用以将其蜂巢粘贴在蜂巢壁上。它在日本作为一种健康的饮料而受到欢迎，人们相信蜂胶可以治愈炎症，心脏病甚至糖尿病和癌症。我们评估了蜂胶对大鼠链脲佐菌素（STZ）毒性的β-细胞保护作用。蜂胶（PWE）的水提取物完全保护β细胞不受STZ毒性的破坏。发现PWE的保护作用几乎等于烟酰胺的保护作用。 PWE还抑制了人类白细胞产生的白介素-1β（IL-1β）。自由基清除活性以及IL-1β和一氧化氮（NO）合酶抑制活性被认为是PWE对抗STZ毒性的保护作用的主要因素。

BACKGROUND & AIMS: :Extended-spectrum β-lactamase (ESBL)-producing-Enterobacteriaceae strains were detected in 12% (6 out of 50) of fecal samples collected from the inpatients of a Japanese pediatric hospital. All the ESBLs belonged to the CTX-M-1 group. The proportion of carriage of ESBL producers was higher among patients who had received antibiotics within the past 3 months and among those who had cardiologic diseases.

背景与目标： ：从日本儿科医院住院患者收集的粪便样本中，有12％（50份中有6份）检测到产生超广谱β-内酰胺酶（ESBL）的肠杆菌科菌株。所有ESBL都属于CTX-M-1组。在过去3个月内接受过抗生素治疗的患者和患有心脏病的患者中，携带ESBL生产者的比例更高。

BACKGROUND & AIMS: OBJECTIVE:To evaluate the predictive value of gestational age and maternal serum β-hCG concentration for the determination of the depth of trophoblastic invasion into the tubal wall. METHODS:This is a retrospective trial conducted on women with a diagnosis of ampullary pregnancy (71) who were submitted to salpingectomy. Serum β-hCG measurements were obtained at the initial admission of hospital. Histological investigation was performed by a single well-experienced pathologist who was blind to the clinical and laboratory characteristics of the patients. Ampullary pregnancy was classified histologically according to the depth of trophoblastic infiltration into tubal wall: trophoblast limited to the tubal mucosa (stage I), extended to muscularis layer (stage II) and complete tubal wall infiltration up to serosal layer (stage III). RESULTS:There was a significant difference in maternal serum β-hCG concentrations regarding the histological stages of trophoblastic invasion. The serum β-hCG concentrations that the best predicted for stage III trophoblastic invasion was 6,475 mIU/ml, with a sensitivity of 100 %, a specificity of 92 %. CONCLUSION:The depth of trophoblastic tissue infiltration into tubal wall is correlated with serum β-hCG levels, but not with gestational age. These findings may explain the reason for conservative management failure of EP in women with high β-hCG concentrations.

背景与目标： 目的：评价孕龄和孕产妇血清β-hCG浓度对确定滋养细胞浸润输卵管壁的深度的预测价值。
方法：这是一项回顾性试验，针对接受壶腹部切除术的诊断为壶腹妊娠的妇女（71名）。初次入院时获得血清β-hCG测量值。组织学调查由一位经验丰富的病理学家进行，该病理学家对患者的临床和实验室特征视而不见。根据滋养细胞向输卵管壁的浸润深度在组织学上对壶腹妊娠进行分类：滋养细胞仅限于输卵管粘膜（I期），延伸至肌层（II期），完全输卵管壁浸润至浆膜层（III期）。
结果：就滋养细胞侵袭的组织学阶段而言，母体血清β-hCG浓度存在显着差异。对于第三阶段滋养细胞浸润最好的预测血清β-hCG浓度为6,475 mIU / ml，敏感性为100％，特异性为92％。
结论：滋养细胞组织渗入输卵管壁的深度与血清β-hCG水平有关，与胎龄无关。这些发现可能解释了高β-hCG浓度女性EP保守治疗失败的原因。

BACKGROUND & AIMS: BACKGROUND:There is a lack of information on stiffness parameter β, an index of arterial stiffness, in hemodialysis (HD) patients. The aim of the present study was to investigate whether stiffness parameter β is predictive of the long-term mortality of chronic HD patients. METHODS:We measured biochemical parameters and the stiffness parameter β of 80 patients on maintenance HD therapy and followed their course for 4 years, and we enrolled 70 of these 80 patients in the study. We divided the 70 patients into tertiles according to their stiffness parameter β values, and conducted multivariate analyses to examine the impact of the tertiles on 4-year mortality. RESULTS:Older age and the presence of diabetes mellitus were found to be independently associated with higher stiffness parameter β values. Fifteen patients (21.4 %) died and 16 (22.9 %) experienced a new cardiovascular event during the follow-up period. The results of a Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality in the HD patients with highest stiffness parameter β values (p = 0.0106). According to the ROC curve, the cut-off level that yielded maximal sensitivity and specificity for predicting all-cause mortality was 10.1, and the sensitivity and specificity using the cut-off value were 69.2 and 70.2 %, respectively. CONCLUSION:The results of this study suggest that stiffness parameter β is a predictor of all-cause mortality in chronic HD patients.

背景与目标： 背景：在血液透析（HD）患者中，缺乏关于刚度参数β（动脉刚度指标）的信息。本研究的目的是研究刚度参数β是否可预测慢性HD患者的长期死亡率。
方法：我们测量了维持HD治疗的80例患者的生化参数和刚度参数β，并对其病程进行了为期4年的研究，我们在这80名患者中招募了70名患者。我们根据其刚度参数β值将70例患者分为三分位数，并进行多变量分析以检查三分位数对4年死亡率的影响。
结果：老年人年龄和糖尿病的存在与高刚性参数β值独立相关。在随访期间，有15例患者（21.4％）死亡，而16例（22.9％）发生了新的心血管事件。 Kaplan-Meier分析的结果表明，刚度参数β值最高的HD患者全因死亡的风险显着更高（p = 0.0106）。根据ROC曲线，可产生最大预测全因死亡率的敏感性和特异性的临界值为10.1，使用该临界值的敏感性和特异性分别为69.2％和70.2％。
结论：这项研究的结果表明，刚度参数β是慢性HD患者全因死亡率的预测指标。

BACKGROUND & AIMS: :β-Lapachone is a naturally occurring quinine, originally isolated from the bark of the lapacho tree (Tabebuia avellanedae) which is currently being evaluated in clinical trials for the treatment of cancer. In addition, recent investigations suggest its potential application for treatment of inflammatory diseases. Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation and demyelination. Reactive T cells including IL-17 and IFN-γ-secreting T cells are believed to initiate MS and the associated animal model system experimental autoimmune encephalomyelitis (EAE). IL-12 family cytokines secreted by peripheral dendritic cells (DCs) and CNS microglia are capable of modulating T-cell phenotypes. The present studies demonstrated that β-lapachone selectively inhibited the expression of IL-12 family cytokines including IL-12 and IL-23 by DCs and microglia, and reduced IL-17 production by CD4(+) T-cells indirectly through suppressing IL-23 expression by microglia. Importantly, our studies also demonstrated that β-lapachone ameliorated the development on EAE. β-Lapachone suppression of EAE was associated with decreased expression of mRNAs encoding IL-12 family cytokines, IL-23R and IL-17RA, and molecules important in Toll-like receptor signaling. Collectively, these studies suggest mechanisms by which β-lapachone suppresses EAE and suggest that β-lapachone may be effective in the treatment of inflammatory diseases such as MS.

背景与目标： ：-Lapachone是一种天然存在的奎宁，最初从lapacho树（Tabebuia avellanedae）的树皮中分离出来，目前正在临床试验中评估其治疗癌症的能力。另外，最近的研究表明其在治疗炎性疾病中的潜在应用。多发性硬化症（MS）是一种以CNS炎症和脱髓鞘为特征的自身免疫性疾病。据信包括IL-17和分泌IFN-γ的T细胞在内的反应性T细胞可引发MS和相关的动物模型系统实验性自身免疫性脑脊髓炎（EAE）。外周树突状细胞（DC）和中枢神经系统小胶质细胞分泌的IL-12家族细胞因子能够调节T细胞表型。本研究表明，β-拉帕酮可选择性抑制DC和小胶质细胞的IL-12家族细胞因子（包括IL-12和IL-23）的表达，并通过抑制IL-23间接降低CD4（）T细胞的IL-17产生。小胶质细胞表达。重要的是，我们的研究还表明，β-拉帕酮可改善EAE的发展。 β-拉帕酮对EAE的抑制作用与编码IL-12家族细胞因子，IL-23R和IL-17RA以及在Toll样受体信号转导中重要的分子的mRNA表达降低有关。这些研究共同提出了β-拉帕酮抑制EAE的机制，并提出了β-拉帕酮可能有效治疗诸如MS的炎性疾病。

BACKGROUND & AIMS: :The synaptic toxicity of soluble amyloid-β (Aβ) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed α1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Aβ-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. α1-Takusan interacts with tau either directly or indirectly, and prevents Aβ-induced tau hyperphosphorylation and mitochondrial fragmentation. Deletion analysis identified the second domain (D2) within the takusan protein that is required for PSD-95 clustering and synaptic protection from Aβ. A 51 aa sequence linking D2 to the PDZ-binding C terminus was found to be as effective as full-length takusan in protecting synapses from Aβ-induced damage. Moreover, a sequence containing the D2 from the human protein discs large homolog 5, when linked to a C-terminal PDZ-binding motif, can also increase the clustering of PSD-95 in cortical dendrites. In summary, α1-takusan protects synapses from Aβ-induced insult via interaction with PSD-95 and tau. Thus, takusan-based protein sequences from either mouse or human may be of potential therapeutic benefit in AD.

背景与目标： ：可溶性淀粉样蛋白-β（Aβ）低聚物的突触毒性在阿尔茨海默氏病（AD）的病理生理中起关键作用。在这里，我们报道过表达的α1-takusan（我们先前鉴定为通过与PSD-95相互作用增强突触活性的蛋白）减轻了寡聚Aβ诱导的突触损失。相反，takusan敲低导致突触损伤增强。 α1-Takusan直接或间接与tau相互作用，并防止Aβ诱导的tau过度磷酸化和线粒体断裂。缺失分析鉴定了takusan蛋白内的第二个结构域（D2），这是PSD-95聚集和突触保护Aβ所必需的。发现将D2连接至PDZ结合C末端的51氨基酸序列与全长takusan一样有效，可保护突触免受Aβ诱导的损伤。此外，包含来自人类蛋白质的D2序列的大同系物5，当与C端PDZ结合基序连接时，也可以增加PSD-95在皮质树突中的簇集。总之，α1-takusan通过与PSD-95和tau的相互作用保护突触免受Aβ诱导的侵害。因此，来自小鼠或人的基于takusan的蛋白质序列可能在AD中具有潜在的治疗益处。