• 【通过预测的热应变模型进行职业热应激评估。】 复制标题 收藏 收藏
    DOI:10.2486/indhealth.44.380 复制DOI
    作者列表:Malchaire JB
    BACKGROUND & AIMS: :The work of the main European research teams in the field of thermal factors was coordinated in order to improve significantly the Required Sweat Rate model published as an international standard. Many significant modifications were brought, in particular concerning the effects of forced convection, body movements and exercise and the prediction of the skin temperature as a function of the rectal temperature and in case of severe conditions of radiation, humidity and clothing. The criteria for acceptable work durations in hot environments were updated concerning the maximum increase in core temperature and the acceptable water loss. The revised model, called Predicted Heat Strain model, was validated through a set of lab and field experiments involving stable and fluctuating conditions with high and low radiation, humidity and air velocity. It is meanwhile adopted as an ISO and CEN standard. In addition, a strategy was developed to assess the risks of heat disorders in any working situation. It is based on the three highest stages of the SOBANE strategy: an "Observation" method for improving simply the thermal conditions of work; an "Analysis" method to evaluate the magnitude of the problem and optimise the choice of solutions and an "Expert" method for in depth analysis of the working situation when needed.
    背景与目标: : 协调了欧洲主要研究小组在热因素领域的工作,以显着改善作为国际标准发布的所需汗率模型。进行了许多重大修改,特别是在强迫对流,身体运动和运动的影响以及皮肤温度随直肠温度的变化以及在辐射,湿度和衣服的严酷条件下的预测方面。更新了在高温环境中可接受的工作持续时间的标准,涉及岩心温度的最大升高和可接受的水损失。修订后的模型称为预测热应变模型,已通过一系列实验室和现场实验进行了验证,这些实验涉及高辐射和低辐射,湿度和空气速度的稳定和波动条件。同时被采用为ISO和CEN标准。此外,还制定了一项战略,以评估任何工作情况下的热病风险。它基于SOBANE策略的三个最高阶段: 一种 “观察” 方法,用于简单地改善工作的热条件; 一种 “分析” 方法,用于评估问题的严重性并优化解决方案的选择,以及一种 “专家” 方法,用于在需要时深入分析工作情况。
  • 【吸入类固醇/长效 β2激动剂组合产品可改善成人哮喘患者的24小时肺功能。】 复制标题 收藏 收藏
    DOI:10.1186/1465-9921-7-110 复制DOI
    作者列表:Lötvall J,Langley S,Woodcock A
    BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
    背景与目标:
  • 【转化生长因子-β: 血管生成、血管生成和血管壁完整性。】 复制标题 收藏 收藏
    DOI:10.1016/s1359-6101(96)00048-2 复制DOI
    作者列表:Pepper MS
    BACKGROUND & AIMS: Genetic studies have recently revealed a role for transforming growth factor-beta-1 (TGF-beta 1) and its receptors (TGF-beta Rs I and II as well as endoglin) in embryonic vascular assembly and in the establishment and maintenance of vessel wall integrity. The purpose of this review is threefoldfirst, to reassess previous studies on TGF-beta and endothelium in the light of these recent findings; second, to describe some of the well-established as well as controversial issues concerning TGF-beta and its regulatory role in angiogenesis; and third, to explore the notion of "context' with respect to TGF-beta and endothelial cell function. Although the focus of this review will be on the endothelium, other vascular wall cells are also likely to be important in the pathogenesis of the vascular lesions revealed by genetic studies.

    背景与目标: 遗传研究最近揭示了转化生长因子-beta-1 (TGF-beta 1) 及其受体 (TGF-beta Rs I和II以及endoglin) 在胚胎血管组装以及血管壁完整性的建立和维持中的作用。这篇综述的目的是三重首先,根据这些最新发现重新评估先前关于TGF-β 和内皮的研究; 第二,描述一些关于TGF-β 及其在血管生成中的调节作用的公认的和有争议的问题; 第三,探讨TGF-β 和内皮细胞功能的 “背景” 概念。尽管本综述的重点将放在内皮上,但其他血管壁细胞也可能在遗传学研究揭示的血管病变的发病机理中很重要。
  • 【人冠状动脉粥样斑块切除术中肝细胞生长因子的免疫组织化学分析: 与转化生长因子 β 亚型的比较。】 复制标题 收藏 收藏
    DOI:10.1007/s004280050050 复制DOI
    作者列表:Ueda H,Imazu M,Hayashi Y,Ono K,Yasui W,Yamakido M
    BACKGROUND & AIMS: The expression and localization of hepatocyte growth factor/scatter factor (HGF/SF) were examined immunohistochemically in 59 human coronary artery lesions retrieved by directional coronary atherectomy and compared with the localization of transforming growth factor beta isoforms (TGF-beta 1, -beta 2, and -beta 3). In 21 of the 59 specimens (35.6%) HGF-like immunoreactivity (HGF-IR) was revealed. The HGF immunopositivity rate of 45% (14/31) in thrombotic tissue was significantly (P < 0.05) higher than the rates of 7.3% (4/55), 7.1% (3/42), and 0% (0/14) in fibrous tissue, neointimal hyperplasia and atheromatous gruel, respectively. Immunoreactivity for HGF was much weaker than that for TGF-beta isoforms in these components except in thrombotic tissue. These cells exhibiting strong HGF-IR were inflammatory cells such as monocytes/macrophages in thrombotic tissue, in tissue lesions adjacent to a thrombus, and outside the capillary walls in a portion of the neovascularized lesions. Smooth muscle cells (SMCs) hardly demonstrated HGF-IR. In contrast, in control coronary arteries obtained at autopsy, the HGF-IR was strongly expressed in SMCs. These findings suggest that HGF produced by macrophages play a part in the process of coronary plaque formation attributable to thrombus in man.

    背景与目标: 通过免疫组织化学检查了通过定向冠状动脉粥样斑块切除术检索的59例人冠状动脉病变中肝细胞生长因子/散射因子 (HGF/SF) 的表达和定位,并将其与转化生长因子 β 亚型 (tgf-β1,-β2和-β3) 的定位进行了比较。在59个标本中的21个 (35.6%) 中,HGF样免疫反应性 (hgf-ir) 被揭示。血栓组织中45% (14/31) 的HGF免疫阳性率显着 (P < 0.05) 高于纤维组织,新内膜增生和动脉粥样硬化稀粥中的7.3% (4/55),7.1% (3/42) 和0% (0/14)。分别。除血栓形成组织外,这些成分中HGF的免疫反应性比TGF-β 同工型的免疫反应性弱得多。这些表现出强hgf-ir的细胞是炎性细胞,例如血栓形成组织中,与血栓相邻的组织病变以及部分新生血管病变的毛细血管壁外部的单核细胞/巨噬细胞。平滑肌细胞 (smc) 几乎不显示HGF-IR。相反,在尸检获得的对照冠状动脉中,hgf-ir在smc中强烈表达。这些发现表明,巨噬细胞产生的HGF在人类血栓形成引起的冠状动脉斑块形成过程中发挥了作用。
  • 【JTE-607是一种多种细胞因子产生抑制剂,可改善SCID小鼠异种移植急性髓细胞性白血病模型中的疾病。】 复制标题 收藏 收藏
    DOI:10.1016/j.exphem.2006.05.016 复制DOI
    作者列表:Uesato N,Fukui K,Maruhashi J,Tojo A,Tajima N
    BACKGROUND & AIMS: OBJECTIVE:Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS:SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS:The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION:Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.
    背景与目标:
  • 【Β1-和 β2-肾上腺素能受体在三环抗抑郁药的抗伤害感受作用中的意义。】 复制标题 收藏 收藏
    DOI:10.1016/s0924-977x(97)00411-2 复制DOI
    作者列表:Micó JA,Gibert-Rahola J,Casas J,Rojas O,Serrano MI,Serrano JS
    BACKGROUND & AIMS: Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulusbeta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

    背景与目标: 三环抗抑郁药已被证明可用于治疗不同病因的疼痛。单胺能系统似乎与这种现象有关。在这项研究中,使用物理和化学伤害性测试在小鼠中研究了选择性 β1- (CGP 20712A) 和 β2- (ICI 118551) 肾上腺素能阻滞剂对地昔帕明和去甲替林的抗伤害感受作用的影响,该测试涉及中枢神经系统 (CNS) 中不同水平的感觉-运动整合。进行活性测试以检测 “假阳性” 或 “假阴性” 结果。获得的结果表明,CGP 20712A和ICI 118551都能够在物理测试 (热板和甩尾) 中拮抗这些抗抑郁药的抗伤害感受作用。然而,在化学测试 (乙酸和福尔马林) 中,所使用的抗抑郁药的镇痛作用仅被CGP 20712A拮抗。这些结果表明,地昔帕明和去甲替林的镇痛作用是由 β-肾上腺素受体介导的。涉及的 β-肾上腺素能受体取决于伤害性刺激的类型,当刺激是物理刺激时,β1和 β2都涉及,但当刺激是化学刺激时,只有 β1涉及。
  • 【雄激素依赖性病理学在小鼠敲入模型中证明了肌病对肯尼迪病表型的贡献。】 复制标题 收藏 收藏
    DOI:10.1172/JCI28773 复制DOI
    作者列表:Yu Z,Dadgar N,Albertelli M,Gruis K,Jordan C,Robins DM,Lieberman AP
    BACKGROUND & AIMS: :Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.
    背景与目标: : 肯尼迪病是一种以雄激素依赖性神经肌肉无力为特征的退行性疾病,是由雄激素受体 (Ar) 基因中的CAG/谷氨酰胺道扩增引起的。我们开发了肯尼迪病的小鼠模型,使用基因靶向将小鼠雄激素受体 (AR) 转化为人类序列,同时引入113谷氨酸。AR113Q小鼠出现激素和谷氨酰胺长度依赖性神经肌肉无力,其特征是肌病和神经源性骨骼肌病理的早期发生以及脊髓神经元核内包涵体的晚期发展。AR113Q男性在2-4个月时意外死亡。我们显示这种雄激素依赖性死亡反映了骨骼肌氯化物通道1 (CLCN1) 和骨骼肌钠通道 α 亚基的表达降低,导致下尿路骨骼肌中的肌强肌放电。AR113Q肢体肌肉显示出相似的肌病特征,并表达编码neurotrophin-4和神经胶质细胞系衍生的神经营养因子的mrna水平降低。这些数据定义了对肯尼迪病表型的重要肌病贡献,并暗示了肌肉在较低运动神经元的非细胞自主毒性中的作用。
  • 【在CLP免疫抑制后的小鼠模型中,IL-10中和和IFN-γ 给药的组合不能改善细菌清除率和死亡率。】 复制标题 收藏 收藏
    DOI:10.1097/01.shk.0000226343.70904.4f 复制DOI
    作者列表:Murphey ED,Sherwood ER
    BACKGROUND & AIMS: :Immunocompromise after a major injury is presumed to be a predisposing factor for sepsis. Mice subjected to sublethal cecal ligation and puncture (CLP) and challenged 5 days later with Pseudomonas aeruginosa had more bacterial growth in lung tissue, lower serum interferon gamma (IFN-gamma) and interleukin (IL) 12,and higher serum IL-10 when compared with sham CLP mice challenged with Pseudomonas. To test the functional significance of these alterations in cytokine production in the immune response to bacteria, we administered IFN-gamma and anti-IL-10 to post-CLP mice before the Pseudomonas challenge. Administration of IFN-gamma and anti-IL-10 did not improve bacterial clearance or mortality in post-CLP mice. In further studies, we administered IFN-gamma to IL-10 knockout mice before a challenge with P. aeruginosa. Our results showed no significant differences in bacterial clearance or mortality in IL-10 knockout mice with or without IFN-gamma treatment compared with wild-type controls. Finally, because most mortality occurred within 2 to 3 days of the Pseudomonas challenge in the aforementioned studies and was likely associated with a marked proinflammatory response, we investigated the effect of IFN-gamma and anti-IL-10 on clearance of Pseudomonas in C3H/HeJ mice, which do not mount an exaggerated proinflammatory response to endotoxin or Gram-negative bacteria. Neither clearance of the Pseudomonas bacteria nor mortality was improved in C3H/HeJ mice receiving anti-IL-10 and IFN-gamma. These results suggest that the suppressed IFN-gamma and IL-12 responses, in combination with an exaggerated IL-10 response to P. aeruginosa challenge after injury, do not correlate with bacterial clearance or survival.
    背景与目标: : 重大损伤后的免疫损害被认为是败血症的诱发因素。与假单胞菌相比,接受亚致死性盲肠结扎和穿刺 (CLP) 并在5天后用铜绿假单胞菌攻击的小鼠肺组织中细菌生长更多,血清干扰素 γ (IFN-γ) 和白介素 (IL) 12降低,血清IL-10更高。为了测试这些细胞因子产生变化在对细菌的免疫反应中的功能意义,我们在假单胞菌攻击之前对CLP后小鼠施用IFN-γ 和anti-IL-10。施用IFN-γ 和anti-IL-10不会改善CLP后小鼠的细菌清除率或死亡率。在进一步的研究中,我们在用铜绿假单胞菌攻击之前对IL-10基因敲除小鼠施用IFN-γ。我们的结果表明,与野生型对照相比,有或没有IFN-γ 处理的IL-10基因敲除小鼠的细菌清除率或死亡率没有显着差异。最后,由于大多数死亡率发生在上述研究中假单胞菌攻击的2至3天内,并且可能与明显的促炎反应有关,因此我们研究了IFN-γ 和anti-IL-10对C3H/HeJ小鼠中假单胞菌清除的影响,它们不会对内毒素或革兰氏阴性细菌产生夸张的促炎反应。在接受anti-IL-10和IFN-γ 的C3H/HeJ小鼠中,假单胞菌的清除率和死亡率均未改善。这些结果表明,受抑制的IFN-γ 和IL-12反应,再加上损伤后对铜绿假单胞菌攻击的过度IL-10反应,与细菌清除或存活无关。
  • 【序数性状分析的多变量模型。】 复制标题 收藏 收藏
    DOI:10.1038/sj.hdy.6800885 复制DOI
    作者列表:Xu S,Xu C
    BACKGROUND & AIMS: :Many economically important characteristics of agricultural crops are measured as ordinal traits. Statistical analysis of the genetic basis of ordinal traits appears to be quite different from regular quantitative traits. The generalized linear model methodology implemented via the Newton-Raphson algorithm offers improved efficiency in the analysis of such data, but does not take full advantage of the extensive theory developed in the linear model arena. Instead, we develop a multivariate model for ordinal trait analysis and implement an EM algorithm for parameter estimation. We also propose a method for calculating the variance-covariance matrix of the estimated parameters. The EM equations turn out to be extremely similar to formulae seen in standard linear model analysis. Computer simulations are performed to validate the EM algorithm. A real data set is analyzed to demonstrate the application of the method. The advantages of the EM algorithm over other methods are addressed. Application of the method to QTL mapping for ordinal traits is demonstrated using a simulated baclcross (BC) population.
    背景与目标: : 农业作物的许多经济上重要的特征被衡量为序数性状。序数性状的遗传基础的统计分析似乎与常规数量性状有很大不同。通过Newton-Raphson算法实现的广义线性模型方法在分析此类数据时提供了更高的效率,但并未充分利用线性模型领域中开发的广泛理论。相反,我们开发了用于顺序特征分析的多变量模型,并实现了用于参数估计的EM算法。我们还提出了一种计算估计参数的方差-协方差矩阵的方法。事实证明,EM方程与标准线性模型分析中的公式极为相似。进行计算机仿真以验证EM算法。分析了实际数据集以证明该方法的应用。讨论了EM算法相对于其他方法的优势。使用模拟的baclcross (BC) 种群证明了该方法在顺序性状的QTL映射中的应用。
  • 【VEGF亚型与体内VEGFR-1,VEGFR-2和神经纤毛蛋白的相互作用: 人类骨骼肌的计算模型。】 复制标题 收藏 收藏
    DOI:10.1152/ajpheart.00637.2006 复制DOI
    作者列表:Mac Gabhann F,Popel AS
    BACKGROUND & AIMS: :The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the proangiogenic activation of VEGF receptors (VEGFRs) by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF(121), VEGF(165)), their cell surface receptors, and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR-1 and VEGFR-2) and nonsignaling neuropilin-1 coreceptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (nonexercising) muscle and the activation of VEGFR signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF(165) does not affect steady-state receptor binding. In the absence of neuropilin, VEGF(121) and VEGF(165) behave similarly, but neuropilin enhances the binding of VEGF(165) to VEGFR-2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and it provides a platform for the design and evaluation of therapeutic approaches.
    背景与目标: : 细胞因子的血管内皮生长因子 (VEGF) 家族参与现有成人血管的维持以及血管生成,新血管的萌发。为了研究骨骼肌中VEGF家族成员对VEGF受体 (VEGFRs) 的促血管生成激活,我们建立了VEGF同工型 (VEGF(121),VEGF(165)),它们的细胞表面受体和细胞外基质的计算模型。体内组织。我们建立在我们验证的VEGF同工型与受体酪氨酸激酶 (VEGFR-1和VEGFR-2) 之间的生化相互作用的模型,以及体外非信号neuropilin-1共受体。该模型是通用的,可以应用于任何组织; 在这里,我们应用该模型来模拟人外侧肌中VEGF同工型的运输,这在生理实验中得到了广泛的研究。模拟预测了静息 (非运动) 肌肉中VEGF亚型的分布以及VEGFR信号传导的激活。肌肉中几乎没有VEGF蛋白以游离的,未结合的细胞外细胞因子的形式存在; 大多数与细胞表面受体或细胞外基质结合。然而,VEGF(165) 的间质隔离不影响稳态受体结合。在不存在神经菌毛蛋白的情况下,VEGF(121) 和VEGF(165) 表现相似,但是神经菌毛蛋白增强VEGF(165) 与VEGFR-2的结合。该模型是第一个研究人肌肉中VEGF组织分布和受体激活的模型,它为治疗方法的设计和评估提供了平台。
  • 【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。
  • 【光遗传刺激对人癫痫果蝇模型的癫痫发作易感性研究。】 复制标题 收藏 收藏
    DOI:10.1534/genetics.116.194779 复制DOI
    作者列表:Saras A,Wu VV,Brawer HJ,Tanouye MA
    BACKGROUND & AIMS: :We examined seizure-susceptibility in a Drosophila model of human epilepsy using optogenetic stimulation of ReaChR (red-activatable channelrhodopsin). Photostimulation of the seizure-sensitive mutant parabss1 causes behavioral paralysis that resembles paralysis caused by mechanical stimulation, in many aspects. Electrophysiology shows that photostimulation evokes abnormal seizure-like neuronal firing in parabss1 followed by a quiescent period resembling synaptic failure and apparently responsible for paralysis. The pattern of neuronal activity concludes with seizure-like activity just prior to recovery. We tentatively identify the mushroom body as one apparent locus of optogenetic seizure initiation. The α/β lobes may be primarily responsible for mushroom body seizure induction.
    背景与目标: : 我们使用ReaChR (红色激活的通道视紫红质) 的光遗传学刺激检查了果蝇癫痫模型中的癫痫发作敏感性。在许多方面,对癫痫敏感的突变体parabss1的光刺激会导致行为麻痹,类似于机械刺激引起的麻痹。电生理学表明,光刺激会在parabss1中引起异常的癫痫样神经元放电,随后是类似于突触衰竭的静止期,显然是造成瘫痪的原因。神经元活动的模式在恢复之前以癫痫样活动结束。我们初步确定蘑菇体是光遗传发作开始的一个明显基因座。Α/β 裂片可能是引起蘑菇体癫痫发作的主要原因。
  • 【猪心肌梗死模型心室去极化和复极化变化的特征。】 复制标题 收藏 收藏
    DOI:10.1088/0967-3334/33/12/1975 复制DOI
    作者列表:Romero D,Ringborn M,Demidova M,Koul S,Laguna P,Platonov PG,Pueyo E
    BACKGROUND & AIMS: :In this study, several electrocardiogram (ECG)-derived indices corresponding to both ventricular depolarization and repolarization were evaluated during acute myocardial ischemia in an experimental model of myocardial infarction produced by 40 min coronary balloon inflation in 13 pigs. Significant changes were rapidly observed from minute 4 after the start of coronary occlusion, achieving their maximum values between 11 and 22 min for depolarization and between 9 and 12 min for repolarization indices, respectively. Subsequently, these maximum changes started to decrease during the latter part of the occlusion. Depolarization changes associated with the second half of the QRS complex showed a significant but inverse correlation with the myocardium at risk (MaR) estimated by scintigraphic images. The correlation between MaR and changes of the downward slope of the QRS complex, [Formula: see text], evaluated at the two more relevant peaks observed during the occlusion, was r = -0.75, p < 0.01 and r = -0.79, p < 0.01 for the positive and negative deflections observed in [Formula: see text], temporal evolution, respectively. Repolarization changes, analyzed by evaluation of ST segment elevation at the main observed positive peak, also showed negative, however non-significant correlation with MaR: r = -0.34, p = 0.28. Our results suggest that changes evaluated in the latter part of the depolarization, such as those described by [Formula: see text], which are influenced by R-wave amplitude, QRS width and ST level variations simultaneously, correlate better with the amount of ischemia than other indices evaluated in the earlier part of depolarization or during the ST segment.
    背景与目标: : 在这项研究中,在13头猪的40分钟冠状动脉球囊充气产生的心肌梗死实验模型中,评估了急性心肌缺血期间对应于心室去极化和复极化的几种心电图 (ECG) 衍生指标。从冠状动脉闭塞开始后的第4分钟开始迅速观察到显着变化,分别在去极化11至22分钟和复极化指数9至12分钟之间达到最大值。随后,在闭塞的后期,这些最大变化开始减少。与QRS复合物的后半部分相关的去极化变化与闪烁显像估计的危险心肌 (MaR) 呈显着但呈负相关。在闭塞期间观察到的两个更相关的峰处评估的MaR与QRS复合体向下斜率的变化之间的相关性为r = -0.75,p <0.01和r = -0.79,对于在 [公式: 参见文本] 中观察到的正偏转和负偏转,分别为p <0.01。通过评估主要观察到的正峰处的ST段抬高来分析复极化变化,也显示出负的,但与MaR无关: r = -0.34,p = 0.28。我们的结果表明,在去极化的后半部分评估的变化,例如 [公式: 参见文本] 所描述的变化,同时受到R波振幅,QRS宽度和ST电平变化的影响,与在去极化早期或ST段期间评估的其他指标相比,与缺血量的相关性更好。
  • 【基因疗法可减少色素失禁模型的癫痫发作。】 复制标题 收藏 收藏
    DOI:10.1002/ana.24981 复制DOI
    作者列表:Dogbevia GK,Töllner K,Körbelin J,Bröer S,Ridder DA,Grasshoff H,Brandt C,Wenzel J,Straub BK,Trepel M,Löscher W,Schwaninger M
    BACKGROUND & AIMS: OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.
    背景与目标:
  • 【食用褐藻Eisenia bicyclis对淀粉样 β 肽诱导的PC12细胞毒性的神经保护作用。】 复制标题 收藏 收藏
    DOI:10.1007/s12272-012-1116-5 复制DOI
    作者列表:Ahn BR,Moon HE,Kim HR,Jung HA,Choi JS
    BACKGROUND & AIMS: :Amyloid beta peptide (Aβ) oligomers increase intracellular reactive oxygen species (ROS) and calcium cation (Ca(2+)) concentrations, which causes neuronal cell death in Alzheimer's disease (AD). Thus, the use of neuroprotective agents with antioxidative activity might be effective in the treatment of AD. In the present study, the neuroprotective effects of the methanol extract from edible brown alga Eisenia bicyclis (Laminariaceae) and its solvent soluble fractions together with the isolated phlorotannins on Aβ-induced toxicity were assessed by cell viability, intracellular ROS, and Ca(2+) levels in PC12 cells. The addition of the methanol extract as well as its ethyl acetate and n-butanol fractions of E. bicyclis markedly reversed the Aβ-induced toxicity. Among six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5), and 7-phloroeckol (6), isolated from the most active ethyl acetate fraction, 3-6 significantly decreased Aβ-induced cell death. Furthermore, these compounds also inhibited intracellular ROS generation and Ca(2+) generation, indicating the neuroprotective effects may be mediated through reduced intracellular ROS and Ca(2+) generation. Thus, the results of the present study imply that E. bicyclis and its active components attenuated the oxidative stress and reduced neuronal cell death, suggesting that it may be used as a dietary neuroprotective agent in AD.
    背景与目标: : 淀粉样 β 肽 (a β) 低聚物会增加细胞内活性氧 (ROS) 和钙阳离子 (Ca(2)) 的浓度,从而导致阿尔茨海默氏病 (AD) 中的神经元细胞死亡。因此,使用具有抗氧化活性的神经保护剂可能有效治疗AD。在本研究中,通过细胞活力,细胞内ROS和Ca(2) 评估了食用褐藻Eisenia bicyclis (Laminariaceae) 及其溶剂可溶性级分以及分离的phlorotannins对a β 诱导的毒性的神经保护作用。) 在PC12细胞中。添加甲醇提取物及其双环E的乙酸乙酯和正丁醇馏分可显着逆转a β 诱导的毒性。从最活跃的乙酸乙酯级分中分离出的六种木酚素,包括间苯三酚 (1),间苯二酚脱氢 (2),艾可 (3),间苯三酚A (4),间苯三酚 (5) 和7-phloroeckol (6),3-6显着降低了A β 诱导的细胞死亡。此外,这些化合物还抑制细胞内ROS的产生和Ca(2) 的产生,表明神经保护作用可能是通过减少细胞内ROS和Ca(2) 的产生来介导的。因此,本研究的结果表明,双环杆菌及其活性成分减轻了氧化应激并减少了神经元细胞死亡,这表明它可以用作AD的饮食神经保护剂。

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