• 【神经元自噬:从发育到变性。】 复制标题 收藏 收藏
    DOI:10.1016/j.mam.2006.08.009 复制DOI
    作者列表:Boland B,Nixon RA
    BACKGROUND & AIMS: :Macroautophagy, a lysosomal pathway responsible for the turnover of organelles and long-lived proteins, has been regarded mainly as an inducible process in neurons, which is mobilized in states of stress and injury. New studies show, however, that macroautophagy is also constitutively active in healthy neurons and is vital to cell survival. Neurons in the brain, unlike cells in the periphery, are protected from large-scale autophagy induction because they can use several different energy sources optimally, receive additional nutrients and neurotrophin support from glial cells, and benefit from hypothalamic regulation of peripheral nutrient supplies. Due to its exceptional efficiency, constitutive autophagy in healthy neurons proceeds in the absence of easily detectable autophagic vacuole intermediates. These intermediates can accumulate rapidly, however, when late steps in the autophagic process are blocked. Autophagic vacuoles also accumulate abnormally in affected neurons of several major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, where they have been linked to various aspects of disease pathogenesis including neuronal cell death. The build-up of autophagic vacuoles in these neurological disorders and others may reflect either heightened autophagy induction, impairment in later digestive steps in the autophagy pathway, or both. Determining the basis for AV accumulation is critical for understanding the pathogenic significance of autophagy in a given pathologic state and for designing possible therapies based on modulating autophagy. In this review, we discuss the special features of autophagy regulation in the brain, its suspected roles in neurodevelopment and plasticity, and recent progress toward understanding how dysfunctional autophagy contributes to neurodegenerative disease.
    背景与目标: :巨噬细胞吞噬,一种负责细胞器和长寿蛋白质更新的溶酶体途径,主要被认为是神经元的诱导过程,在压力和损伤状态下被动员。然而,新研究表明,巨噬细胞自噬在健康神经元中也具有组成性活性,对细胞存活至关重要。与周围的细胞不同,大脑中的神经元可以免受大规模自噬的诱导,因为它们可以最佳地利用几种不同的能源,可以从神经胶质细胞中获得更多的营养和神经营养蛋白支持,并受益于下丘脑对周围营养供应的调节。由于其出色的效率,健康神经元中的组成型自噬在缺乏易于检测的自噬液泡中间体的情况下进行。但是,当自噬过程的后期步骤被阻滞时,这些中间体会迅速积累。自噬空泡还在几种主要的神经退行性疾病(包括阿尔茨海默氏病和帕金森氏病)的受影响神经元中异常蓄积,它们与疾病发病机制的各个方面(包括神经元细胞死亡)相关。在这些神经系统疾病和其他神经系统疾病中,自噬泡的形成可能反映了自噬诱导的增强,自噬途径中以后消化步骤的损伤或两者兼而有之。确定AV积累的基础对于理解给定病理状态下自噬的致病意义以及基于调节自噬设计可能的治疗方法至关重要。在这篇综述中,我们讨论了大脑中自噬调节的特殊功能,其在神经发育和可塑性中的可疑作用,以及在理解功能失调自噬如何导致神经退行性疾病方面的最新进展。
  • 【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: 人们认为神经活动在大脑皮层的发育过程中起着重要的作用。在这项研究中,我们研究了整体活动阻滞或增强的作用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(突触形成开始之后)存活的能力的影响。通过添加河豚毒素(TTX)和增加培养基中镁的浓度来阻止神经元活性,这会大大降低皮质细胞的存活率。通过提高外部钾离子浓度来增加神经元活性可以显着改善皮层神经元的存活率。我们推测,在发育中的神经元网络中,神经细胞的存活受到涉及细胞内钙浓度变化的突触介导事件的调节。为了进一步检查这个问题,我们通过光学记录许多神经元的细胞内钙信号同时监测了发育中网络的活动。这些记录表明,在低镁状态下,新皮层神经元表达其细胞内钙浓度的同步振荡。在培养的第二周内,网络同步多个细胞的细胞内钙变化的能力逐渐显现,同时突触密度增加和存活神经元数量减少。通过在录制会话几天后检查识别出的细胞的命运,我们发现与其他神经元共激活的神经细胞比不参与同步事件的细胞具有更高的存活机会。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。

  • 【T(2)加权的microMRI和诱发的低髓鞘转基因小鼠的发展过程中视觉系统测量的潜力。】 复制标题 收藏 收藏
    DOI:10.1007/s11064-006-9121-z 复制DOI
    作者列表:Martin M,Reyes SD,Hiltner TD,Givogri MI,Tyszka JM,Fisher R,Campagnoni AT,Fraser SE,Jacobs RE,Readhead C
    BACKGROUND & AIMS: :Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.
    背景与目标: :我们的目标是通过非侵入性高分辨率(117 x 117 x 70 microm)磁共振(microMRI)和诱发视觉系统(VEP)技术追踪转基因小鼠的运动异常,然后部分恢复。我们使用经工程改造过表达Golli-mbp基因复合物产物Golli J37(特别是在少突胶质细胞中)的JOE(用于J​​37 golli过表达)转基因小鼠。从21岁到75天大,使用11.7 T扫描仪上的非侵入性体内VEP和3D T2加权显微MRI对个体JOE转基因及其未受影响的兄弟姐妹进行跟踪研究,我们认为这是同类研究中的首次纵向研究。显微MRI数据表明,在峰值髓鞘形成期(21-42天)期间出现了明显的整体性低髓鞘形成,与对照组相比,JOE小鼠在以后的年龄(> 60天)中得到了部分纠正。这些显微MRI数据与[Campagnoni AT(1995)“髓鞘形成的分子生物学”)有很好的相关性。在:Ransom B,Kettenmann H(eds)Neuroglia-专着中。牛津大学出版社,伦敦,第555-570页]髓磷脂染色,[Campagnoni AT,Macklin WB(1988)髓磷脂蛋白基因表达的细胞和分子方面。 [Mol Neurobiol 2:41-89]在髓鞘形成高峰期发生短暂的意向性震颤,此现象在以后的年龄有所减轻,[Lees MB,Brostoff SW(1984)蛋白在髓鞘中。在:莫雷尔(编辑)髓磷脂。 [Plenum Press,纽约和伦敦,第197-224页] VEP均表明JOE小鼠的CNS髓磷脂发育显着延迟和持续性髓鞘减少。总体而言,这些非侵入性技术能够在空间上解决正常发育和发育迟缓的小鼠大脑中髓鞘形成的增加。
  • 【胎儿小脑发育的磁共振成像。】 复制标题 收藏 收藏
    DOI:10.1080/14734220600589210 复制DOI
    作者列表:Triulzi F,Parazzini C,Righini A
    BACKGROUND & AIMS: :In the last few years fetal magnetic resonance imaging (MRI) has been proposed as a second level technique in the evaluation of fetal brain anomalies. It has been demonstrated that MRI is highly accurate in illustrating the morphologic changes of developing brain and fetal brain abnormalities being a useful procedure when ultrasonography is inconclusive or doubtful. Starting from the 19-20 weeks gestational age (GA), MRI can reliably depict fetal brain anatomy and locating pathology, offering a robust and reliable tool in the assessment of fetal CNS diseases. In this review both in vivo MRI quantitative and qualitative data about fetal cerebellar development are presented and compared with ultrasonography data. Fetal cerebellar development is gradual, steady, and largely comparable to the development of the supratentorial brain. Archicerebellar (flocculo-nodular lobe) and paleocerebellar (vermis) structures develop first, whereas neocerebellum (cerebellar hemispheres) develop slowly and largely after birth.
    背景与目标: :在最近几年中,胎儿磁共振成像(MRI)已被提出作为评估胎儿脑异常的第二级技术。已经证明,当超声检查不确定或值得怀疑时,MRI可以高度准确地说明发育中的大脑和胎儿脑部异常的形态变化,这是一种有用的方法。从19-20周胎龄(GA)开始,MRI可以可靠地描绘胎儿的大脑解剖结构和定位病理,从而为评估胎儿CNS疾病提供了强大而可靠的工具。在这篇综述中,提出了关于胎儿小脑发育的体内MRI定量和定性数据,并将其与超声检查数据进行了比较。胎儿小脑发育是渐进的,稳定的,并且在很大程度上可与上脑上脑的发育相媲美。先生小脑(结节状结节状)和小脑((状)结构,而新小脑(小脑半球)出生后缓慢且大部分发育。
  • 【体内形成SMAC的成熟免疫突触介导病毒感染的星形胶质细胞从大脑中清除。】 复制标题 收藏 收藏
    DOI:10.1084/jem.20060420 复制DOI
    作者列表:Barcia C,Thomas CE,Curtin JF,King GD,Wawrowsky K,Candolfi M,Xiong WD,Liu C,Kroeger K,Boyer O,Kupiec-Weglinski J,Klatzmann D,Castro MG,Lowenstein PR
    BACKGROUND & AIMS: :The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell-antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer-target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor-rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in vivo has cast doubts on its functional relevance. Herein, we demonstrate that the in vivo formation of SMAC at immunological synapses between effector CD8+ T cells and target cells precedes and mediates clearance of virally infected brain astrocytes.
    背景与目标: :对被感染的脑细胞免疫清除的微观解剖学知之甚少。免疫突触是必不可少的解剖结构,可在T细胞功能的启动阶段和效应阶段以及自然杀伤分子与靶细胞的相互作用期间,引导T细胞抗原呈递细胞(APC)之间的信息交换。 T细胞建立的免疫突触的标志是超分子激活簇(SMAC)的形成,其中粘附分子(如白细胞功能相关抗原1)分离到免疫突触(p-SMAC)的外围结构域,周围T细胞受体丰富或中央SMAC(c-SMAC)。迄今为止,尚无法在体内检测到SMAC的形成,对其功能相关性产生了疑问。在本文中,我们证明了在效应CD8 T细胞和靶细胞之间的免疫突触中SMAC的体内形成先于并介导了病毒感染的脑星形胶质细胞的清除。
  • 【PedsQL脑肿瘤模块:初始可靠性和有效性。】 复制标题 收藏 收藏
    DOI:10.1002/pbc.21026 复制DOI
    作者列表:Palmer SN,Meeske KA,Katz ER,Burwinkle TM,Varni JW
    BACKGROUND & AIMS: BACKGROUND:Brain tumors (BT) are second only to acute lymphoblastic leukemia as the most prevalent form of pediatric cancer, with BT 5-year survival rates approaching 70%. With increased survival, quality of life has emerged as an essential health outcome. This investigation examines the internal consistency reliability and construct validity of the Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module. METHODS:The PedsQL 4.0 Generic Core Scales, PedsQL Multidimensional Fatigue Scale, and PedsQL Brain Tumor Module were administered to 99 families. The average age of the 56 boys and 43 girls was 9.76 years (range=2-18 years). The sample included children with tumors located in the posterior fossa/brainstem (N=62, 62.6%), supratentorial (N=15, 15.2%), and midline (N=22, 22.2%). Children were on treatment (N=46, 46.5%), off treatment<12 months (N=19, 19.2%), or off treatment>12 months/long-term survivor (N=34, 34.3%). Treatment included radiation (N=61, 61.6%), surgery (N=83, 83.8%), chemotherapy (N=87, 87.9%), and bone marrow transplant (N=5, 5.1%). RESULTS:Internal consistency reliability was demonstrated for the 24-item PedsQL Brain Tumor Module (average alpha=0.78-0.92, parent proxy-report, n=99; average alpha=0.76-0.87, child self-report, n=51). Construct validity for the PedsQL Brain Tumor Module was supported through an analysis of the intercorrelations with the Generic Core Scales and Fatigue Scale. CONCLUSIONS:The findings provide support for the measurement properties of the PedsQL Brain Tumor Module.
    背景与目标: 背景:脑肿瘤(BT)仅次于急性淋巴细胞白血病,是儿童癌症的最普遍形式,其BT 5年生存率接近70%。随着生存率的提高,生活质量已成为一种必不可少的健康结果。这项研究检查了儿童生命质量量表(PedsQL)脑肿瘤模块的内部一致性可靠性和构建效度。
    方法:将PedsQL 4.0通用核心量表,PedsQL多维疲劳量表和PedsQL脑肿瘤模块应用于99个家庭。 56名男孩和43名女孩的平均年龄为9.76岁(范围= 2-18岁)。样本包括肿瘤位于后颅窝/脑干(N = 62,62.6%),幕上(N = 15,15.2%)和中线(N = 22,22.2%)的儿童。儿童接受治疗(N = 46,46.5%),不接受治疗<12个月(N = 19,19.2%)或不接受治疗> 12个月/长期幸存者(N = 34,34.3%)。治疗包括放疗(N = 61,61.6%),手术(N = 83,83.8%),化学疗法(N = 87,87.9%)和骨髓移植(N = 5,5.1%)。
    结果:24项PedsQL脑肿瘤模块具有内部一致性可靠性(平均α= 0.78-0.92,父母代理报告,n = 99;平均α= 0.76-0.87,孩子自我报告,n = 51)。通过分析通用核心量表和疲劳量表之间的相互关系,支持了PedsQL脑肿瘤模块的构建效度。
    结论:这些发现为PedsQL脑肿瘤模块的测量特性提供了支持。
  • 【口服用多糖凝胶包衣的小丸的开发1.物理机械性能。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijpharm.2006.07.004 复制DOI
    作者列表:Sriamornsak P,Burton MA,Kennedy RA
    BACKGROUND & AIMS: :Spherical pellets containing theophylline, calcium acetate and microcrystalline cellulose were extruded and spheronized, before being coated with six different pectins or alginates by interfacial complexation. The aim of this study was to discover the effect of the coatings on physico-mechanical properties that will be crucial in determining the pellets' utility as sustained release systems. An insoluble, smooth and uniformly thick coat of calcium polysaccharide was formed around the core pellets. A factorial experiment was designed to investigate the effect of pellet size and polysaccharide type and concentration on the entrapment efficiency, mechanical properties and other physical characteristics. Coated pellets were observed by scanning electron microscopy and, depending on the particular polysaccharide used, the dry coats were found to be 30-80 microm thick. The size of pellet, the type and concentration of polysaccharide influenced the yield of theophylline in the coated pellets. Although the mechanical properties of the pellets were improved by applying any of the gel coats, use of an alginate with a high content of guluronic acid or an amidated pectin coating gave the best results. This is probably because both of these have significant potential to form very stable cross-links within the gel coats.
    背景与目标: :将含有茶碱,乙酸钙和微晶纤维素的球形小球挤出并滚圆,然后通过界面络合用六种不同的果胶或藻酸盐包衣。这项研究的目的是发现包衣对物理机械性能的影响,这对于确定微丸作为缓释系统的用途至关重要。在核心药丸周围形成了不溶的,光滑且均匀厚的钙多糖涂层。设计了析因实验,以研究颗粒大小,多糖类型和浓度对包封效率,机械性能和其他物理特性的影响。通过扫描电子显微镜观察包衣的小丸,并且根据所使用的特定多糖,发现干衣的厚度为30-80微米。药丸的大小,多糖的类型和浓度影响了包衣药丸中茶碱的产量。尽管可通过使用任何凝胶包衣来改善丸粒的机械性能,但使用具有高含量古洛糖醛酸的藻酸盐或酰胺化果胶包衣的效果最佳。这可能是因为这两者都具有在凝胶涂层内形成非常稳定的交联的巨大潜力。
  • 【鲨鱼脑中一种含有羟脯氨酸的蛋白质,与髓磷脂碱性蛋白质有关。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.1990.tb04958.x 复制DOI
    作者列表:Wood DD,McLaurin J,Moscarello MA
    BACKGROUND & AIMS: :Myelin basic protein (MBP) from shark (Chondricthyes) consists of a simpler mixture of charge isomers than human MBP. About two-thirds of the total amount applied to a CM-52 cellulose cation-exchange column was recovered in the unbound fraction of the column; the remaining one-third bound to column and was eluted as a single OD280 peak. This bound material did not sow the usual pattern of charge microheterogeneity found with human or bovine MBP. The unbound fraction was composed of a high molecular weight protein (55-60 kDa), which constituted most of this protein fraction and a low molecular weight protein (approximately 18 kDa). The amino acid composition of our unbound fraction was similar to that reported earlier. The Glx (glutamic acid + glutamine) was increased about threefold whereas the Arg content was only about 25% of that of the 18.5 kDa variant of bovine or human origin. The presence of hydroxyproline (1.2 residues/100) in this protein was noteworthy, identification of which was achieved by amino acid analysis in two different systems and by mass spectrometry. In the precolumn derivatization method, hydroxyproline eluted at 2.7 min; in the postcolumn derivatization method it eluted at 12.2 min. Identification of hydroxyproline was completed by fast atom bombardment-mass spectral analysis. The effect of hydroxyproline on the secondary structure of this protein is being studied. Verification that this high molecular weight protein contained MBP sequences within its primary structure was confirmed by immunological methods.(ABSTRACT TRUNCATED AT 250 WORDS)
    背景与目标: :鲨鱼(Chondricthyes)的髓磷脂碱性蛋白(MBP)由电荷异构体组成的混合物比人MBP更简单。应用于CM-52纤维素阳离子交换柱的总量的约三分之二是在该柱的未结合馏分中回收的;剩余的三分之一与色谱柱结合,并以一个OD280峰洗脱。这种结合的材料并未播种人或牛MBP常见的电荷微异质性模式。未结合的部分由高分子量蛋白质(55-60 kDa)和低分子量蛋白质(约18 kDa)组成,其中高分子量蛋白质占该蛋白质部分的大部分。我们未结合部分的氨基酸组成与先前报道的相似。 Glx(谷氨酸谷氨酰胺)增加了约三倍,而Arg含量仅为牛或人来源的18.5 kDa变体的Arg含量的约25%。值得注意的是,该蛋白质中存在羟脯氨酸(1.2个残基/ 100个),通过在两个不同系统中进行氨基酸分析并通过质谱法进行鉴定。在柱前衍生化方法中,羟脯氨酸在2.7分钟洗脱;在柱后衍生化方法中,它在12.2分钟时洗脱。通过快速原子轰击质谱分析完成了羟脯氨酸的鉴定。羟脯氨酸对该蛋白二级结构的影响正在研究中。通过免疫学方法证实了这种高分子量蛋白质在其一级结构中包含MBP序列。(摘要截短为250字)
  • 【注意缺陷多动障碍可能与中枢性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: 注意缺陷多动障碍(ADHD)是儿童期常见的精神病。尽管进行了深入的研究,但多动症的病因仍然未知。当前证据表明,ADHD的病因是异质的,由多种因素组成。最近,已经提出,脑源性神经营养因子(BDNF),神经营养因子家族的成员,可能与ADHD的发病有关。这一假说得到了多动症最近的遗传学研究的支持。根据对ADHD药物的研究发现,该药物与中枢BDNF表达,BDNF基因敲除小鼠的过度活跃,BDNF对中脑多巴胺能功能的影响以及BDNF与多巴胺转运蛋白(ADHD发病机理的重要分子)之间的紧密联系有关,因此提出了这一建议。在这里,中央BDNF的降低,特别是在中脑区域,可能在ADHD的发病中起重要作用。该假设可能对ADHD的临床发现有一定的影响(例如,ADHD与严重抑郁症的合并症),并为ADHD治疗药物的开发提供了新的方向。
  • 【大鼠脑缺血后泛素和hsp70的基因表达】 复制标题 收藏 收藏
    DOI:10.1097/00001756-199703240-00036 复制DOI
    作者列表:Noga M,Hayashi T,Tanaka J
    BACKGROUND & AIMS: Expression of genes coding for ubiquitin and heatshock protein (hsp) 70 were examined by in situ hybridization using a rat model with permanent occlusion of the distal middle cerebral artery (MCA). Only polyubiquitin (UbC) mRNA increased markedly following ischaemia in the central zone of the MCA territory of the neocortex. UbC gene expression reached the maximum level 4 h post-occlusion and remained elevated at 24 h. UbC expression was retarded slightly compared with that of the hsp70 gene. UbB and Ub-S30 were expressed at almost similar levels in both the ischaemic and non-ischaemic hemispheres. These results indicated that UbC probably has the most stress-inducible characteristics among the three ubiquitin genes.

    背景与目标: 编码泛素和热休克蛋白(hsp)70的基因的表达通过使用大鼠模型进行了原位杂交,该模型永久性阻塞了大脑中部远端动脉(MCA)。在新皮层MCA区域的中央区域缺血后,只有多聚泛素(UbC)mRNA显着增加。 UbC基因表达在阻塞后4 h达到最高水平,并在24 h保持升高。与hsp70基因相比,UbC表达略有延迟。在缺血半球和非缺血半球中,UbB和Ub-S30的表达水平几乎相似。这些结果表明,UbC可能在三个泛素基因​​中具有最强的应激诱导特性。

  • 【兔DQ52和DH基因在早期B细胞发育中的表达。】 复制标题 收藏 收藏
    DOI:10.1016/s0161-5890(96)00107-1 复制DOI
    作者列表:Chen HT,Alexander CB,Chen FF,Mage RG
    BACKGROUND & AIMS: Rabbits predominantly rearrange the most 3'VH gene (VH1); thus combinatorial diversity is very limited. In man and mouse, the most 3'DH gene, DQ52, is preferentially rearranged early in B-cell development. To test whether this preference for rearranging a DH gene segment based on 3' end proximity exists in rabbit, we cloned and sequenced the rabbit DQ52 gene. The 11 base pair coding region sequence is identical to a published mouse DQ52, and 81.8% similar to the human sequence. It is localized approximately 805 bp upstream of the JH1 gene. However, the 3' recombination signal sequence has an atypical nonamer. We prepared mRNA from 15- to 28-day fetal rabbits and amplified expressed VDJ sequences of mu mRNA by RT-PCR. The PCR products with VDJ rearrangements were cloned and sequenced. As expected, 44 of 45 VDJ sequences reflected use of the 3' VH1a2 gene, but the DQ52 gene was utilized very infrequently, if at all. We found only one VDJ sequence from 28-day fetal liver B-cells with 8 bp that matched the germline DQ52 sequence. Instead of expressing DQ52, another DH gene, Df was frequently expressed. We cloned the genomic Df gene and localized it about 32 kb upstream of the JH region. Thus, in contrast to man and mouse, rabbits preferentially express a DH gene located in the middle of the DH region early in B cell ontogeny. This may correlate with more frequent initial rearrangement of VH to DH in rabbit B cells.

    背景与目标: 兔子主要重新排列最3'VH基因(VH1);因此组合多样性非常有限。在人和小鼠中,最3'DH基因DQ52在B细胞发育早期被优先重排。为了测试在兔子中是否存在基于3'末端邻近性重新排列DH基因片段的偏好,我们克隆并测序了兔子DQ52基因。 11个碱基对的编码区序列与已发布的小鼠DQ52相同,而与人类序列相似的为81.8%。它位于JH1基因上游约805 bp。然而,3'重组信号序列具有非典型的九聚体。我们制备了15至28天胎兔的mRNA,并通过RT-PCR扩增了mu mRNA的表达VDJ序列。具有VDJ重排的PCR产物被克隆并测序。不出所料,在45个VDJ序列中有44个反映了3'VH1a2基因的使用,但DQ52基因很少被使用,如果有的话。我们从28天胎儿肝B细胞中发现只有一个VDJ序列,其8 bp与种系DQ52序列匹配。 Df经常表达而不是表达另一个DH基因DQ52。我们克隆了基因组Df基因,并将其定位在JH区上游约32 kb处。因此,与人和小鼠相反,兔子在B细胞个体发育中优先表达位于DH区中部的DH基因。这可能与兔B细胞中VH到DH更频繁的初始重排有关。

  • 【神经放射学专业专家对脑CT成像研究进行重新解释的质量结果。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Jordan MJ,Lightfoote JB,Jordan JE
    BACKGROUND & AIMS: PURPOSE:To determine the clinical importance and relative value of reinterpreting brain CT imaging studies by subspecialty experts regarding changes in clinical management. METHODS:Computerized records were queried at two institutions during the years 2002-2003 for both primary interpretation by board-certified nonneuroradiologists and secondary interpretation by three neuroradiologists. A total of 1,081 cases were reviewed. Each case was initially interpreted as an emergent or urgent study. The reinterpreted studies were scored as concordant or discordant by the subspecialty experts. The discordant studies were then categorized as a "major discordance" if there was a change in clinical management, or as a "minor discordance" if there was no impact or change in clinical management. RESULTS:Of the 1,081 studies reviewed, 14 studies were identified as discordant (1.3%). Of those discordant studies, four were categorized as major discrepancies necessitating a change in clinical management (0.4 %). Ten were categorized as minor discrepancies (0.9%). There were no permanent adverse outcomes with respect to morbidity and mortality as a result of any discrepancy. CONCLUSION:The vast majority of interpreted head CT cases read by board-certified general radiologists do not result in discordant interpretations as verified by subspecialty experts. Discordant interpretations did not result in changes in clinical management in most cases. Double reading of head CTs by subspecialty experts appears to be an inefficient method of substantially improving imaging health quality outcomes.
    背景与目标: 目的:确定亚专业专家对临床管理变化进行重新解释脑CT成像研究的临床重要性和相对价值。
    方法:在2002年至2003年期间,在两家机构中查询了计算机记录,以获取由董事会认证的非神经放射科医生进行的主要解释,以及由三位神经放射科医生进行的次要解释。总共审查了1,081例。最初,每个案例都被解释为紧急研究。重新解释的研究被专业专家评定为一致或不一致。如果临床管理发生变化,则将不一致的研究分类为“重大不一致”,如果临床管理没有影响或发生变化,则将其分类为“轻微不一致”。
    结果:在所审查的1,081项研究中,有14项研究被确定为不一致(1.3%)。在这些不一致的研究中,有四项被归类为需要改变临床管理的主要差异(0.4%)。十个分类为轻微差异(0.9%)。任何差异都不会在发病率和死亡率方面带来永久性的不良后果。
    结论:经董事会认证的一般放射科医生阅读的绝大多数解释性头部CT病例,经专科专家验证,并不会导致不一致的解释。在大多数情况下,不一致的解释并不会导致临床管理的改变。专科专家对头颅CT进行双重读取似乎是一种实质上改善影像健康质量结果的无效方法。
  • 【功能性精子发生的发展需要生殖细胞凋亡的早期和大规模。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.9.2262 复制DOI
    作者列表:Rodriguez I,Ody C,Araki K,Garcia I,Vassalli P
    BACKGROUND & AIMS: Transgenic mice expressing high levels of the BclxL or Bcl2 proteins in the male germinal cells show a highly abnormal adult spermatogenesis accompanied by sterility. This appears to result from the prevention of an early and massive wave of apoptosis in the testis, which occurs among germinal cells during the first round of spermatogenesis. In contrast, sporadic apoptosis among spermatogonia, which occurs in normal adult testis, is not prevented in adult transgenic mice. The physiological early apoptotic wave in the testis is coincident, in timing and localization, with a temporary high expression of the apoptosis-promoting protein Bax, which disappears at sexual maturity. The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal mouse testis) in this early apoptotic wave is shown by the occurrence of a comparable testicular syndrome in mice defective in the bax gene. The apoptotic wave appears necessary for normal mature spermatogenesis to develop, probably because it maintains a critical cell number ratio between some germinal cell stages and Sertoli cells, whose normal functions and differentiation involve an elaborate network of communication.

    背景与目标: 在雄性生殖细胞中表达高水平BclxL或Bcl2蛋白的转基因小鼠表现出高度异常的成年精子发生并伴有不育。这似乎是由于防止了睾丸早期大量凋亡的结果,这种情况发生在第一轮精子发生过程中的生发细胞之间。相反,在成年转基因小鼠中,不能阻止正常成年人睾丸中发生的精原细胞中的偶发性细胞凋亡。睾丸中的生理性早期凋亡波在时间和位置上是一致的,具有促凋亡的蛋白Bax的临时高表达,该蛋白在性成熟时消失。 BclxL和Bax蛋白的细胞内平衡(可能是激素控制的)(在正常小鼠的睾丸中显然不表达Bcl2)在细胞内平衡中起着至关重要的作用,这是由于在小鼠中出现了类似的睾丸综合征所致。 bax基因。凋亡波似乎是正常成熟精子发生发展所必需的,这可能是因为它在某些生细胞阶段和支持细胞之间维持了关键的细胞数比,其正常功能和分化牵涉到复杂的交流网络。

  • 【新的胆囊收缩素类似物(JMV 236)对大鼠食物摄入和脑单胺的影响。】 复制标题 收藏 收藏
    DOI:10.1016/0143-4179(90)90158-u 复制DOI
    作者列表:Gourch A,Orosco M,Rodriguez M,Martinez J,Cohen Y,Jacquot C
    BACKGROUND & AIMS: :JMV 236, a new cholecystokinin-octapeptide-sulfate (CCK 8 S) derivative (Boc-Tyr (SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2) has been synthesized in the Centre de Pharmacologie-Endocrinologie (Montpellier). This peptide has been shown to present the same activity as CCK 8 S on pancreatic amylase secretion and has the advantage of a better chemical stability. With a view to further characterization, the effect of JMV 236 on food intake and brain monoamine and metabolite variations was assayed in the rat after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations. JMV 236 decreased food intake 2 and 3 hours after i.p. administration of 12.5 and 50 micrograms/kg but was inactive after i.c.v. injection. Its global action was similar to that of CCK 8 S, but was less marked with delayed onset of response. As in our previous work with CCK 8 S, JMV 236 was more potent in inducing monoaminergic variations after i.p. than after i.c.v. administration. The main effects were decreases in striatal dopamine metabolite levels and increases in hypothalamic and striatal serotonin metabolite (5-HIAA) levels. These effects are classically observed with CCK 8 S and are described in our previous reports. The interesting peptide will require further characterization and may serve as a possible reference compound for studies on CCK derivatives.
    背景与目标: :JMV 236是一种新的胆囊收缩素-八肽硫酸盐(CCK 8 S)衍生物(Boc-Tyr(SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2),已在药理学-内分泌中心(蒙彼利埃)。已显示该肽在胰腺淀粉酶分泌方面具有与CCK 8 S相同的活性,并且具有更好的化学稳定性的优点。为了进一步表征,在大鼠腹膜内(i.p.)和脑室内(i.c.v.)给药后,在大鼠中测定了JMV 236对食物摄入以及脑单胺和代谢产物变化的影响。腹腔注射后2和3小时,JMV 236的食物摄入量减少。静脉注射12.5和50微克/公斤,但在静脉内注射后无效。注射。它的整体作用与CCK 8 S相似,但反应迟缓的症状较少。就像我们以前使用CCK 8 S所做的一样,JMV 236腹腔内注射后在诱导单胺能变化方面更有效。比在i.c.v.之后行政。主要影响是纹状体多巴胺代谢物水平降低,下丘脑和纹状体5-羟色胺代谢物(5-HIAA)水平升高。这些效应在CCK 8 S上得到了经典观察,并在我们以前的报告中进行了描述。令人感兴趣的肽将需要进一步表征,并可能用作研究CCK衍生物的可能参考化合物。
  • 【N1-苄基-N2- [1-(1-萘基)乙基]-反式1,2-二氨基环己烷:4-氯苯基羧酰胺(calhex 231)的开发作为一种新型的钙感应受体配体,具有强大的钙分解活性。】 复制标题 收藏 收藏
    DOI:10.1021/jm051233+ 复制DOI
    作者列表:Kessler A,Faure H,Petrel C,Rognan D,Césario M,Ruat M,Dauban P,Dodd RH
    BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.
    背景与目标: :结构-活性关系(SAR)研究主要在N1-芳基磺酰基-N2- [1-(1-(萘基)乙基]-反式-1,2-二氨基环己烷的N1位置进行,钙敏感受体(CaSR)。该系列中活性最高的化合物是4-(三氟甲氧基)苯磺酰基衍生物7e,在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯([3H] IP)积累方面,其IC50为5.4 /-0.5 microM。表达CaSR的卵巢(CHO)细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍(7m,IC50 = 0.9 /-0.2 microM)。在合成的羧酰胺中,活性最高的化合物之一是4-氯苯基羧酰胺(1S,2S,1'R)-7n(Calhex 231,IC50 = 0.33 /-0.02 microM)。 (1S,2S,1'R)-7n的绝对构型是由化合物7d的一种非对映异构体的X射线晶体学研究得出的。 (1S,2S,1'R)异构体的立体化学偏好可以根据CaSR钙解结合口袋的三维模型来合理化。除去C-1'甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e,7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。

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