• 【通过微孔过滤测量的外周血中性粒细胞流变学很好地反映了白塞氏病的活动。】 复制标题 收藏 收藏
    DOI:10.1016/s0923-1811(97)00599-9 复制DOI
    作者列表:Iijima S,Otsuka F
    BACKGROUND & AIMS: Activated neutrophils take a long time to pass through a narrow lumen like a micropore, and are supposed to play a deteriorating effect on microcirculation. Although the activation of neutrophils has been demonstrated in Behçet's disease, nobody analyzes the clinical activity of the disease by means of the rheological measure of neutrophils activity. Using a micropore (pore diameter 5 microns) filtration technique, we measured the filtration time of peripheral blood neutrophils, as a rheological measure of their activity, in order to determine the clinical activity of Behçet's disease. Twenty-one patients with Behçet's disease and 14 healthy control individuals were enrolled in the study. Symptoms and signs exhibited in the patients led us to distinguish the Behçet's disease into inactive and active cases. The latter were further differentiated into cases with absent symptoms and with present symptoms. Neutrophil filtration times were 11.5 +/- 4.8 s in the active cases with present symptoms, which were significantly (P < 0.05) larger than those (7.4 +/- 1.9 s) in the active cases with absent symptoms. The latter filtration times were further significantly (P < 0.001) larger than values (3.7 +/- 1.3 s) in the inactive cases and also those (4.8 +/- 1.2 s) in control subjects. Furthermore, increases in the filtration time obtained immediately after the exposure of cells to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP10 nM) were significantly (P < 0.01) larger in the active cases with present symptoms than those in the active cases with absent symptoms. The latter were also larger, but not significantly, than those in the inactive cases, and were significantly (P < 0.01) larger than those in control subjects. The present results demonstrate that the micropore filtration method reflects well the rheological activity of neutrophils as well as the clinical status of Behçet's disease. This method is much better than the measurement of O2 production to differentiate between active cases with absent symptoms and inactive patients or even control individuals. Furthermore, it is more sensitive and useful than laboratory data like the CRP value or the number of peripheral blood neutrophils.

    背景与目标: 活化的中性粒细胞需要很长时间才能通过像微孔一样的狭窄管腔,并且应该对微循环起到恶化的作用。尽管在beh ç et病中已经证明了中性粒细胞的激活,但没有人通过中性粒细胞活性的流变学测量来分析该疾病的临床活性。使用微孔 (孔径5微米) 过滤技术,我们测量了外周血中性粒细胞的过滤时间,作为其活性的流变学指标,以确定白塞氏病的临床活性。21名beh ç et病患者和14名健康对照者参加了这项研究。患者表现出的症状和体征使我们将白塞氏病区分为不活跃和活跃的病例。后者进一步分为无症状和现有症状的病例。有症状的活动病例的中性粒细胞过滤时间为11.5 +/- 4.8 s,显著 (P < 0.05) 大于无症状的活动病例的中性粒细胞过滤时间 (7.4 +/- 1.9 s)。后者的过滤时间进一步显著 (P < 0.001) 大于非活性情况下的值 (3.7 +/- 1.3 s),也大于对照受试者中的值 (4.8 +/- 1.2 s)。此外,在细胞暴露于趋化肽甲酰基-甲硫酰基-亮氨酸-苯丙氨酸 (fmlp10nm) 后立即获得的过滤时间的增加在存在症状的活动病例中比在不存在症状的活动病例中显着 (P < 0.01) 大。后者也比不活跃的情况更大,但不显著,并且显著 (P < 0.01) 大于对照组。目前的结果表明,微孔过滤方法很好地反映了嗜中性粒细胞的流变活性以及白塞病的临床状况。此方法比O2产生的测量要好得多,可以区分无症状的活跃病例和不活跃的患者甚至对照组。此外,它比CRP值或外周血中性粒细胞数量等实验室数据更敏感和有用。
  • 【体外药物活性和药代动力学在预测抗分枝杆菌治疗有效性中的价值: 一项重要综述。】 复制标题 收藏 收藏
    DOI:10.1097/00000441-199706000-00008 复制DOI
    作者列表:Burman WJ
    BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

    背景与目标: 耐药结核病和非结核分枝杆菌感染的病例率显着增加,为开发新的分枝杆菌感染治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感结核病治疗的广泛已发表的临床经验,以评估这些临床前措施在预测抗细菌治疗临床结果中的应用。药物活性的体外测量可以预测药物的效力,以防止对其他抗细菌药物的耐药性出现,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量无法可靠地预测生物体应被认为具有抗性的水平。药物在组织中的渗透和对细胞内杆菌的活性的测定适度增加了药物活性的体外测量的预测值,但仍不能预测灭菌活性。相反,结核病的动物模型已经预测了相对的药物效力 (包括灭菌活性),多药疗法的功效以及所需的治疗持续时间。尽管药代动力学参数表明每天需要多次剂量,但所有一线抗结核药物在每周两次的情况下均具有活性。很难预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是可以预测灭菌活性的模型。
  • 【神经元活动的同步促进单个大鼠新皮层神经元在早期发育中的存活。】 复制标题 收藏 收藏
    DOI:10.1111/j.1460-9568.1997.tb01449.x 复制DOI
    作者列表:Voigt T,Baier H,Dolabela de Lima A
    BACKGROUND & AIMS: Neural activity is thought to play a significant role during the development of the cerebral cortex. In this study, we examined the effects of global activity block or enhancement and the effects of patterned firing on the ability of cultured rat neocortical neurons to survive during the second week in vitro, beyond the beginning of synaptogenesis. Blockade of neuronal activity by adding tetrodotoxin (TTX) and increasing magnesium concentration in the medium strongly reduced the survival of cortical cells. Increasing neuronal activity by raising the external potassium concentration significantly improved the survival of cortical neurons. We postulated that in a developing neuronal network the survival of nerve cells is regulated by synaptically mediated events that involve changes in the intracellular calcium concentration. To examine this question further, we monitored the activity of the developing network by optically recording the intracellular calcium signals of many neurons simultaneously. These recordings show that in low magnesium neocortical neurons express synchronized oscillation of their intracellular calcium concentration. The ability of a network to synchronize the changes in intracellular calcium of multiple cells appeared gradually during the second week in culture, paralleled by both an increase in the synaptic density and a decline in the number of surviving neurons. By examining the fate of identified cells several days after a recording session, we found that those nerve cells that were co-activated with other neurons had a significantly higher chance to survive than cells that did not participate in synchronized events. These experiments demonstrate that during early cortical network development cortical neurons show synchronized firing activity and that the survival of neurons is at least partially dependent on this pattern of neuronal activity.

    背景与目标: 神经活动被认为在大脑皮层发育过程中起着重要作用。在这项研究中,我们研究了整体活动阻滞或增强的影响以及图案化放电对培养的大鼠新皮层神经元在体外第二周 (突触开始后) 存活的能力的影响。通过添加河豚毒素 (TTX) 和增加培养基中的镁浓度来阻断神经元活性,从而大大降低了皮质细胞的存活。通过提高外部钾浓度来增加神经元活性,显着改善了皮质神经元的存活。我们推测,在发育中的神经元网络中,神经细胞的存活受到突触介导的事件的调节,这些事件涉及细胞内钙浓度的变化。为了进一步研究这个问题,我们通过同时光学记录许多神经元的细胞内钙信号来监测发育网络的活动。这些记录表明,在低镁的新皮层神经元中,其细胞内钙浓度表达同步振荡。在培养的第二周,网络使多个细胞的细胞内钙的变化同步的能力逐渐出现,同时突触密度增加和存活神经元数量减少。通过在记录过程几天后检查已识别细胞的命运,我们发现与其他神经元共同激活的神经细胞比不参与同步事件的细胞存活的机会要高得多。这些实验表明,在早期皮质网络发育过程中,皮质神经元显示出同步的放电活动,并且神经元的存活至少部分取决于这种神经元活动模式。
  • 【使用皮质听觉诱发电位评估成人语音的神经编码。】 复制标题 收藏 收藏
    DOI:10.3766/jaaa.17.8.3 复制DOI
    作者列表:Agung K,Purdy SC,McMahon CM,Newall P
    BACKGROUND & AIMS: :There has been considerable recent interest in the use of cortical auditory evoked potentials (CAEPs) as an electrophysiological measure of human speech encoding in individuals with normal as well as impaired auditory systems. The development of such electrophysiological measures such as CAEPs is important because they can be used to evaluate the benefits of hearing aids and cochlear implants in infants, young children, and adults that cannot cooperate for behavioral speech discrimination testing. The current study determined whether CAEPs produced by seven different speech sounds, which together cover a broad range of frequencies across the speech spectrum, could be differentiated from each other based on response latency and amplitude measures. CAEPs were recorded from ten adults with normal hearing in response to speech stimuli presented at a conversational level (65 dB SPL) via a loudspeaker. Cortical responses were reliably elicited by each of the speech sounds in all participants. CAEPs produced by speech sounds dominated by high-frequency energy were significantly different in amplitude from CAEPs produced by sounds dominated by lower-frequency energy. Significant effects of stimulus duration were also observed, with shorter duration stimuli producing larger amplitudes and earlier latencies than longer duration stimuli. This research demonstrates that CAEPs can be reliably evoked by sounds that encompass the entire speech frequency range. Further, CAEP latencies and amplitudes may provide an objective indication that spectrally different speech sounds are encoded differently at the cortical level.
    背景与目标: : 最近,人们对使用皮质听觉诱发电位 (CAEPs) 作为听觉系统正常和受损个体的人类语音编码的电生理测量方法引起了极大的兴趣。开发此类电生理措施 (例如caep) 很重要,因为它们可用于评估无法合作进行行为言语辨别测试的婴儿,幼儿和成人的助听器和人工耳蜗的益处。当前的研究确定了是否可以根据响应延迟和幅度度量来区分由七个不同的语音声音产生的caep,这些声音共同覆盖了整个语音频谱中的广泛频率范围。记录了十名听力正常的成年人的caep,以响应通过扬声器以对话水平 (65 dB SPL) 呈现的语音刺激。在所有参与者中,每种语音都可靠地引起了皮质反应。由高频能量主导的语音产生的caep与由低频能量主导的声音产生的caep的振幅显着不同。还观察到刺激持续时间的显着影响,较短的持续时间刺激比较长的持续时间刺激产生更大的幅度和更早的延迟。这项研究表明,涵盖整个语音频率范围的声音可以可靠地诱发caep。此外,CAEP延迟和幅度可以提供客观指示,表明在皮层水平上不同的语音在频谱上被不同地编码。
  • 【内源性BDNF和NT-3在调节皮质树突生长中的相反作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0896-6273(00)80316-5 复制DOI
    作者列表:McAllister AK,Katz LC,Lo DC
    BACKGROUND & AIMS: :Neurons within each layer of cerebral cortex express multiple members of the neurotrophin family and their corresponding receptors. This multiplicity could provide functional redundancy; alternatively, different neurotrophins may direct distinct aspects of cortical neuronal growth and differentiation. By neutralizing endogenous neurotrophins in organotypic slices of developing cortex with Trk receptor bodies (Trk-IgGs), we found that BDNF and NT-3 oppose one another in regulating the dendritic growth of pyramidal neurons. In layer 4, both endogenous and exogenous NT-3 inhibited the dendritic growth stimulated by BDNF. In contrast, in layer 6 both endogenous and exogenous BDNF inhibited dendritic growth stimulated by NT-3. These antagonistic actions of endogenous BDNF and NT-3 provide a mechanism by which dendritic growth and retraction can be dynamically regulated during cortical development, and suggest that the multiple neurotrophins expressed in developing cortex represent distinct components of an extracellular signaling system for regulating dendritic growth.
    背景与目标: : 大脑皮层各层内的神经元表达神经营养蛋白家族的多个成员及其相应的受体。这种多样性可以提供功能冗余; 或者,不同的神经营养蛋白可能会指导皮质神经元生长和分化的不同方面。通过用Trk受体体 (Trk-igg) 中和发育中的皮层器官型切片中的内源性神经营养蛋白,我们发现BDNF和NT-3在调节锥体神经元的树突状生长方面相互对抗。在第4层中,内源性和外源性NT-3均抑制BDNF刺激的树突状生长。相反,在第6层中,内源性和外源性BDNF均抑制NT-3刺激的树突生长。内源性BDNF和NT-3的这些拮抗作用提供了一种机制,通过该机制可以在皮质发育过程中动态调节树突生长和收缩,并表明在发育中的皮质中表达的多种神经营养蛋白代表了调节树突生长的细胞外信号系统的不同成分。
  • 【山羊 α-乳白蛋白中单个Trp残基的荧光贡献。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbapap.2006.07.011 复制DOI
    作者列表:Vanhooren A,Illyes E,Majer Z,Hanssens I
    BACKGROUND & AIMS: :Goat alpha-lactalbumin (GLA) contains four tryptophan (Trp) residues. In order to obtain information on the fluorescence contribution of the individual Trp residues in native GLA, we recorded the fluorescence spectra of four GLA mutants, W26F, W60F, W104F, and W118F, in each of which a single Trp residue was replaced with phenylalanine (Phe). Comparison of the fluorescence spectra of the four mutants with that of wild-type GLA indicated that, in native GLA, three Trp residues (Trp60, Trp104, and Trp118) are strongly quenched and account for the partial indirect quenching of Trp26. As a consequence, the fluorescence of wild-type GLA and of the mutants W60F, W104F, and W118F mainly results from Trp26. An inspection of the crystal structure indicated that, in addition to the disulfide bonds that are in direct contact with the indole groups of Trp60 and Trp118, backbone peptide bonds that are in direct contact with the indole groups of Trp60, Trp104, and Trp118, contribute to the direct quenching effects. Interestingly, the lack of direct quenching of Trp26 explains why the cleavage of disulfide bonds by UV light is mediated more by the highly fluorescent Trp26 than by the less fluorescent Trp104 and Trp118.
    背景与目标: : 山羊 α-乳白蛋白 (GLA) 含有四个色氨酸 (Trp) 残基。为了获得有关天然GLA中单个Trp残基的荧光贡献的信息,我们记录了四个GLA突变体W26F,W60F,W104F和W118F的荧光光谱,其中每个单个Trp残基被替换为苯丙氨酸 (Phe)。将四个突变体的荧光光谱与野生型GLA的荧光光谱进行比较表明,在天然GLA中,三个Trp残基 (Trp60,Trp104和Trp118) 被强烈淬灭,并解释了trp26的部分间接猝灭。因此,野生型GLA和突变体W60F,W104F和W118F的荧光主要来自trp26。对晶体结构的检查表明,除了与Trp60和Trp118的吲哚基团直接接触的二硫键外,与Trp60,Trp104和Trp118的吲哚基团直接接触的骨架肽键有助于直接猝灭作用。有趣的是,缺乏Trp26的直接猝灭解释了为什么高荧光的Trp26比低荧光的Trp104和trp118更多地介导紫外光对二硫键的裂解。
  • 【根据哌唑嗪的亲和力,人类良性前列腺肥大组织中的 α-1肾上腺素受体亚型 (高,低)。】 复制标题 收藏 收藏
    DOI:10.1002/(sici)1097-0045(19970601)31:4<216::aid-pro 复制DOI
    作者列表:Takeda M,Hatano A,Komeyama T,Koizumi T,Mizusawa T,Kanai T,Tomita Y,Maruyama K,Nagatomo T
    BACKGROUND & AIMS: BACKGROUND:A novel classification of alpha-1 adrenoceptor subtypes (High, Low) was applied to human benign prostatic hypertrophy (BPH) tissue. METHODS:Human BPH specimens were examined by a radioligand binding assay method using 3H-prazosin, and those data were compared with preoperative therapies. RESULTS:(1) Scatchard analysis showed a high-affinity site (Kd:27.18 +/- 6.41 pM; Bmax:9.29 +/- 0.98 fM/mg protein; mean +/- SE) as alpha 1H, and a low-affinity site (Kd: 4088.0 +/- 744.34 pM, Bmax: 140.81 +/- 19.98 fM/mg protein) as alpha 1L subtype, for prazosin. (2) The Kd and Bmax were not different in the nontreated group (n = 5), alpha 1 blocker group (n = 5), and antiandrogen group (n = 5), in either alpha 1-high affinity or alpha 1-low affinity subtype. (3) Phenoxybenzamine had different pKi values for the above two adrenoceptor subtypes. Scatchard analysis showed that alpha 1-high affinity binding site disappeared in the presence of 1 microM of phenoxybenzamine, and the Kd and Bmax values in the presence of 1 microM of phenoxybenzamine were almost identical to the alpha 1-low affinity site of the two subtypes. CONCLUSIONS:Human BPH tissue possesses both alpha 1H- and alpha 1L-adrenoceptor subtypes according to the affinities for prazosin, and only the alpha 1H subtype can be completely inhibited by some concentration of phenoxybenzamine. Treatment by alpha 1 blocker may not change the conditions of alpha 1-adrenoceptors in prostatic tissue.
    背景与目标:
  • 【产气荚膜梭菌的 α 毒素不是鸡坏死性肠炎的必需毒力因子。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.00806-06 复制DOI
    作者列表:Keyburn AL,Sheedy SA,Ford ME,Williamson MM,Awad MM,Rood JI,Moore RJ
    BACKGROUND & AIMS: :The Clostridium perfringens alpha-toxin has previously been implicated as the major virulence factor in necrotic enteritis in chickens, although definitive proof has not been reported. In this study an alpha-toxin mutant was constructed in a virulent chicken isolate and shown to retain full virulence in a chicken disease model. These results demonstrated that alpha-toxin is not an essential virulence factor in the pathogenesis of necrotic enteritis in chickens.
    背景与目标: : 尽管尚未报道明确的证据,但以前曾将产气荚膜梭菌 α 毒素作为鸡坏死性肠炎的主要毒力因子。在这项研究中,在强毒鸡分离株中构建了一个 α 毒素突变体,并显示在鸡疾病模型中保留了完全的毒力。这些结果表明,在鸡坏死性肠炎的发病机理中,α-毒素不是必需的毒力因子。
  • 【一系列赛庚胺类似物的合成,对5-HT2A,5-HT2B和5-HT2C 5-羟色胺受体的亲和力和结构-活性关系。】 复制标题 收藏 收藏
    DOI:10.1248/cpb.45.842 复制DOI
    作者列表:Honrubia MA,Rodriguez J,Dominguez R,Lozoya E,Manaut F,Seijas JA,Villaverde MC,Calleja JM,Cadavid MI,Maayani S,Sanz F,Loza MI
    BACKGROUND & AIMS: :Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
    背景与目标: : 赛庚胺是一种对2型 (5-HT2) 受体显示高亲和力的药物。我们研究了通过修饰Cyp (二苯并环庚二烯) 的三环体系获得的一系列化合物: 2f (噻吩),2g (xanthene),2h (二氢二苯并环庚二烯),2j (二苯基),2i (芴) 和3b (苯基甲基)。它们在大鼠大脑皮层5-HT2A受体上的活性为 (pKi +/-s.e.M.): 8.80 +/- 0.11 (Cyp),8.60 +/- 0.07 (2f),8.40 +/- 0.02 (2g),8.05 +/- 0.03 (2h),7.87 +/- 0.12 (2j),6.70 +/- 0.02 (2i) 和6.45 +/- 0.02 (3b); 大鼠胃底5-HT2B受体 (pA2 +/-s.e.M.) 为: 9.14 +/- 0.25 (Cyp),8.49 +/- 0.07 (2f),7.58 +/- 0.58 (2g),7.02 +/- 0.14 (2h),6.07 +/- 0.20 (2j) 和不可检测 (2i,3b): 猪脉络丛5-HT2C受体 (pKi +/-s.e.M.) 为: 8.71 +/- 0.08 (Cyp),8.68 +/- 0.01 (2f),8.58 +/- 0.20 (2g),7.95 +/- 0.05 (2h) 、7.57 +/- 0.04 (2j) 、6.98 +/- 0.04 (2i) 和6.63 +/- 0.20 (3b)。坡度与统一没有显着差异。这些化合物在每种类型的受体上都表现出相同的活性顺序,并且最具活性的分子呈现某些空间 (三环系统的蝴蝶构象) 和静电 (中心环顶部的质子亲和力) 模式。结论是,赛庚胺衍生物在5-HT2受体上的活性与这些分子特征有关,这使得与所有三种5-HT2亚型相互作用的共同处置是可行的。
  • 【鸽子中两个 α-珠蛋白基因 α (A) 和 α (D) 隔离和测序以及 α (D)-珠蛋白基因胚胎特异性表达的证据。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6667 复制DOI
    作者列表:Ikehara T,Eguchi Y,Kayo S,Takei H
    BACKGROUND & AIMS: :By screening a pigeon genomic DNA library, we isolated a recombinant phage clone containing the alpha(A)-globin gene. The DNA sequence of the approximately 6kbp-long insert fragment of the phage clone was determined. The sequence suggested the existence of pigeon alpha(D)-globin gene located 3.1 kbp upstream from the alpha(A)-globin gene. The expression of the alpha(D)-globin in late embryo was also shown by the N-terminal amino-acid sequence of the intact globin chain. These results show that two adult alpha-globin genes, alpha(A) and alpha(D), exist in the pigeon genome, and the alpha(D)-globin is expressed at the late embryo stage. The stage-specific expression suggests the existence of regulatory elements and factors interacting to inhibit transcription at the adult stage.
    背景与目标: : 通过筛选鸽子基因组DNA文库,我们分离出含有 α (a)-珠蛋白基因的重组噬菌体克隆。确定了噬菌体克隆的约6kbp长的插入片段的DNA序列。该序列表明存在位于 α (A)-珠蛋白基因上游3.1 kbp的鸽子 α (D)-珠蛋白基因。完整珠蛋白链的N端氨基酸序列也显示了 α (D)-珠蛋白在晚期胚胎中的表达。这些结果表明,鸽子基因组中存在两个成年的 α-珠蛋白基因 α (A) 和 α (D),并且 α (D)-珠蛋白在胚胎晚期表达。阶段特异性表达表明存在调节元件和因子相互作用以抑制成年阶段的转录。
  • 【注意缺陷多动障碍可能与中枢脑源性神经营养因子活性降低有关: 临床和治疗意义。】 复制标题 收藏 收藏
    DOI:10.1016/j.mehy.2006.06.025 复制DOI
    作者列表:Tsai SJ
    BACKGROUND & AIMS: :Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.
    背景与目标: : 注意力缺陷多动障碍 (ADHD) 是一种常见的儿童精神疾病。尽管进行了大量研究,但ADHD的病因仍然未知。目前的证据表明,ADHD的病因是异质的,由多种因素组成。最近,有人提出,神经营养因子家族的成员脑源性神经营养因子 (BDNF) 可能与ADHD的发病机理有关。该假设得到了ADHD最近的遗传研究的支持。根据对ADHD药物的研究结果,该药物与中枢BDNF表达,BDNF基因敲除小鼠的活动过度,BDNF在中脑多巴胺能功能中的作用以及BDNF与多巴胺转运蛋白 (ADHD发病机理的重要分子) 之间的密切联系有关,在这里提出降低中枢BDNF,特别是在中脑区域,可能在ADHD的发病机理中起重要作用。该假设可能对ADHD的临床发现 (例如,ADHD与重度抑郁症之间的合并症) 具有一定的意义,并为ADHD治疗药物的发展提供了新的方向。
  • 【具有NMDA拮抗剂活性的天然衍生肽抑制神经病理性疼痛。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00183-2 复制DOI
    作者列表:Siegan JB,Hama AT,Sagen J
    BACKGROUND & AIMS: :Chronic pain may result from hyperexcitability following activation of spinal NMDA receptors. A naturally-derived mammalian peptide, histogranin, may possess NMDA antagonist activity. This study explored the possibility that stable analog [Ser1]Histogranin (SHG) could reduce chronic pain. Neuropathic pain was induced using the chronic constriction injury model (CCI). Intrathecal injection of SHG markedly attenuated the hyperalgesia and allodynia resulting from CCI, nearly normalizing responses. These results suggest that the natural peptide histogranin may be a novel adjunct in neuropathic pain management.
    背景与目标: : 脊髓NMDA受体激活后过度兴奋可能导致慢性疼痛。天然衍生的哺乳动物肽组织蛋白可能具有NMDA拮抗剂活性。这项研究探讨了稳定的类似物 [Ser1] 组织蛋白 (SHG) 可以减轻慢性疼痛的可能性。使用慢性收缩损伤模型 (CCI) 诱发神经病理性疼痛。鞘内注射SHG可显着减轻由CCI引起的痛觉过敏和异常性疼痛,几乎使反应正常化。这些结果表明,天然肽组织粒蛋白可能是神经性疼痛管理的新型辅助手段。
  • 【EMX2的潜在靶基因包括Odz/Ten-M和其他对皮质模式有影响的基因家族。】 复制标题 收藏 收藏
    DOI:10.1016/j.mcn.2006.06.012 复制DOI
    作者列表:Li H,Bishop KM,O'Leary DD
    BACKGROUND & AIMS: :EMX2 and PAX6 are expressed by cortical progenitors and specify area patterning. We used representational difference analysis (RDA) to compare expressed RNAs from wild type and Emx2-/- cortex and identified 41 unique clones. Using secondary screening by in situ hybridization, we selected five genes for further analysis, Cdk4, Cofilin1, Crmp1, ME2, and Odz4, involved in neuronal proliferation, differentiation, migration, and axon guidance. Each exhibits differential expression in wild type cortex. Odz4 is one of four members of a vertebrate gene family homologous to the Drosophila pair-rule patterning gene, Odd Oz (Odz), a transmembrane receptor. We show that Odz genes are expressed in complementary patterns in cortex, as well as in nuclei-specific patterns in thalamus that relates to their area-unique cortical expression. In addition, each of the genes analyzed shows different expression patterns in wild type cortex, Emx2, and Pax6 mutant cortex, consistent with potential roles in area patterning. These findings identify potential targets of EMX2 that might account for its function and the defects in Emx2-/- cortex, and suggest that the Odz family of transmembrane proteins influences cortical area patterning downstream to EMX2 and PAX6.
    背景与目标: : EMX2和PAX6由皮质祖细胞表示并指定区域图案。我们使用代表性差异分析 (RDA) 来比较野生型和Emx2-/-皮质的表达rna,并鉴定出41个独特的克隆。使用原位杂交的二次筛选,我们选择了五个基因进行进一步分析,Cdk4,Cofilin1,Crmp1,ME2和Odz4,涉及神经元增殖,分化,迁移和轴突指导。每个在野生型皮层中表现出不同的表达。Odz4是与果蝇对规则模式基因Odd Oz (Odz) (跨膜受体) 同源的脊椎动物基因家族的四个成员之一。我们显示Odz基因在皮层的互补模式中表达,以及在丘脑的核特异性模式中表达,这与其区域独特的皮层表达有关。此外,所分析的每个基因在野生型皮层,Emx2和Pax6突变皮层中显示出不同的表达模式,与区域模式中的潜在作用一致。这些发现确定了可能解释其功能和EMX2-/-皮质缺陷的Emx2的潜在靶标,并表明跨膜蛋白的Odz家族会影响EMX2和pax6下游的皮质区域模式。
  • 【牙龈卟啉单胞菌主动调节 β2整合素粘附活性并促进与巨噬细胞的结合和内化。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.00784-06 复制DOI
    作者列表:Hajishengallis G,Wang M,Harokopakis E,Triantafilou M,Triantafilou K
    BACKGROUND & AIMS: :In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the beta2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this "inside-out" proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-beta-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates beta2 integrin adhesive activity for intracellular uptake.
    背景与目标: : 在单核细胞中,口腔病原体牙龈卟啉单胞菌的菌毛激活从Toll样受体2 (TLR2) 到 β2整合素CD11b/CD18的串扰信号,导致诱导后者受体的高亲和力状态。CD14通过结合菌毛并促进TLR2和磷脂酰肌醇3-激酶信号的激活,在这种 “由内而外” 的前粘附途径中起重要作用。在其高亲和力状态下,CD11b/CD18介导单核细胞与内皮细胞的粘附并转移到感染部位。我们现在已经证明,牙龈卟啉单胞菌菌毛既是CD11b/CD18的激活剂又是配体。因此,菌毛会主动促进其自身与单核细胞的结合。实际上,干扰菌毛诱导的CD11b/CD18激活 (即CD14,TLR2或磷脂酰肌醇3-激酶信号传导的阻断) 的治疗也抑制了菌毛的细胞结合活性,这在很大程度上是可诱导的并且CD11b/CD18依赖性。在中国仓鼠卵巢细胞中开发了重组的由内而外信号系统,证实了菌毛激活CD14/TLR2信号并诱导其自身CD11b/CD18-dependent结合的能力。牙龈卟啉单胞菌诱导这种前粘附途径似乎发生在脂质筏中。实际上,发现甲基-β-环糊精是一种破坏脂质筏组织的胆固醇螯合剂,可抑制菌毛诱导的CD14/TLR2信号复合物的组装以及CD11b/cd18高亲和力状态的激活。使用缺乏各种模式识别受体的小鼠的巨噬细胞进行的实验表明,参与由内而外的前粘附途径 (CD14,TLR2和CD11b/CD18) 的受体对于介导巨噬细胞内牙龈卟啉单胞菌内化很重要。因此,似乎牙龈卟啉单胞菌主动调节 β2整合素粘附活性以促进细胞内摄取。
  • 【用黄色荧光蛋白变体YFP-H148Q/I152L对碘化钠同向转运体活性的细胞成像。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00291.2006 复制DOI
    作者列表:Rhoden KJ,Cianchetta S,Stivani V,Portulano C,Galietta LJ,Romeo G
    BACKGROUND & AIMS: :The sodium iodide symporter (NIS) mediates iodide (I(-)) transport in the thyroid gland and other tissues and is of increasing importance as a therapeutic target and nuclear imaging reporter. NIS activity in vitro is currently measured with radiotracers and electrophysiological techniques. We report on the development of a novel live cell imaging assay of NIS activity using the I(-)-sensitive and genetically encodable yellow fluorescent protein (YFP) variant YFP-H148Q/I152L. In FRTL-5 thyrocytes stably expressing YFP-H148Q/I152L, I(-) induced a rapid and reversible decrease in cellular fluorescence characterized by 1) high affinity for extracellular I(-) (35 muM), 2) inhibition by the NIS inhibitor perchlorate, 3) extracellular Na(+) dependence, and 4) TSH dependence, suggesting that fluorescence changes are due to I(-) influx via NIS. Individual cells within a population of FRTL-5 cells exhibited a 3.5-fold variation in the rate of NIS-mediated I(-) influx, illustrating the utility of YFP-H148Q/I152L to detect cell-to-cell difference in NIS activity. I(-) also caused a perchlorate-sensitive decrease in YFP-H148Q/I152L fluorescence in COS-7 cells expressing NIS but not in cells lacking NIS. These results demonstrate that YFP-H148Q/I152L is a sensitive biosensor of NIS-mediated I(-) uptake in thyroid cells and in nonthyroidal cells following gene transfer and suggest that fluorescence detection of cellular I(-) may be a useful tool by which to study the pathophysiology and pharmacology of NIS.
    背景与目标: : 碘化钠同向转运体 (NIS) 介导碘 (I(-)) 在甲状腺和其他组织中的转运,作为治疗靶标和核成像报告基因的重要性日益提高。目前使用放射性示踪剂和电生理技术测量体外的NIS活性。我们报告了使用I(-) 敏感且可遗传编码的黄色荧光蛋白 (YFP) 变体YFP-H148Q/I152L对NIS活性进行新型活细胞成像测定的开发。在稳定表达YFP-H148Q/I152L的FRTL-5甲状腺细胞中,I(-) 诱导细胞荧光的快速和可逆降低,其特征是1) 对细胞外I(-) (35 muM) 的高亲和力,2) NIS抑制剂高氯酸盐的抑制,3) 细胞外Na(+) 依赖性,和4) TSH依赖性,表明荧光变化是由于I(-) 通过NIS流入所致。FRTL-5细胞群内的单个细胞表现出NIS介导的I(-) 流入速率的3.5倍变化,说明YFP-H148Q/I152L用于检测NIS活性的细胞间差异。I(-) 还导致表达NIS的COS-7细胞中YFP-H148Q/I152L荧光的高氯酸盐敏感降低,但在缺乏NIS的细胞中不引起。这些结果表明,YFP-H148Q/I152L是基因转移后甲状腺细胞和非甲状腺细胞中NIS介导的I(-) 摄取的敏感生物传感器,并表明细胞I(-) 的荧光检测可能是研究的有用工具。NIS的病理生理学和药理学。

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