• 【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,以及了解功能失调的自噬如何导致神经退行性疾病的最新进展。
  • 【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,我们检查了全局活性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)Proteins in髓磷脂。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。
  • 【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。
  • 【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。

  • 【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,这是通过在小鼠体内出现类似的睾丸综合症而证明的。 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。

  • 【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。
  • 【来自UT-7子系UT-7 / GM的红系和巨核细胞的体外发育。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Komatsu N,Kirito K,Shimizu R,Kunitama M,Yamada M,Uchida M,Takatoku M,Eguchi M,Miura Y
    BACKGROUND & AIMS: UT-7 is a human megakaryoblastic leukemia cell line with absolute dependence on interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin (EPO) for growth and survival. We isolated a novel subline, UT-7/GM after long-term culture of UT-7 with GM-CSF. The hemoglobin concentration and gamma-globin and EPO-receptor mRNA levels were significantly higher in EPO-treated UT-7/GM cells than in untreated cells. In contrast, the platelet factor 4 and glycoprotein IIb mRNA levels were much higher in thrombopoietin (TPO)-treated UT-7/GM cells than in untreated cells. Some TPO-treated cells had morphologically mature megakaryocytic characteristics such as a developed demarcation membrane in the cytoplasm and multilobular nuclei. These findings indicate that UT-7/GM is a bipotential cell line that can be induced to differentiate into erythroid and megakaryocytic lineages by EPO and TPO, respectively. Moreover, a minority of UT-7/GM cells acquired a high hemoglobin concentration by treatment with TPO, suggesting that TPO in part induced the erythroid differentiation of the UT-7/GM cells. Interestingly, GM-CSF inhibited the EPO- or TPO-induced erythroid differentiation and the TPO-induced megakaryocytic differentiation of UT-7/GM cells. These results support the hypothesis that cytokines influence the programming of gene expression required for lineage commitment or differentiation.

    背景与目标: UT-7是一种人类巨核细胞白血病细胞系,其绝对依赖白介素3,粒细胞巨噬细胞集落刺激因子(GM-CSF)或促红细胞生成素(EPO)来生长和存活。在将UT-7与GM-CSF长期培养后,我们分离出一个新的亚系UT-7 / GM。在EPO处理的UT-7 / GM细胞中,血红蛋白浓度,γ-珠蛋白和EPO受体mRNA水平显着高于未处理的细胞。相反,血小板生成素(TPO)处理的UT-7 / GM细胞中的血小板因子4和糖蛋白IIb mRNA水平比未处理的细胞高得多。一些用TPO处理过的细胞具有形态成熟的巨核细胞特征,例如在细胞质和多叶核中形成了分界膜。这些发现表明,UT-7 / GM是一种双能细胞系,可以被EPO和TPO分别诱导分化为红系和巨核细胞谱系。此外,少数UT-7 / GM细胞通过TPO处理获得了高血红蛋白浓度,这表明TPO部分诱导了UT-7 / GM细胞的类红细胞分化。有趣的是,GM-CSF抑制了EPO或TPO诱导的红系分化以及TPO诱导的UT-7 / GM细胞的巨核细胞分化。这些结果支持以下假设:细胞因子会影响谱系定型或分化所需的基因表达程序。

  • 【通过选择性阻断CD28预防NZB / NZW小鼠狼疮性肾炎的发展。】 复制标题 收藏 收藏
    DOI:10.1002/eji.201746923 复制DOI
    作者列表:Laurent L,Le Fur A,Bloas RL,Néel M,Mary C,Moreau A,Poirier N,Vanhove B,Fakhouri F
    BACKGROUND & AIMS: :Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.
    背景与目标: 系统性红斑狼疮(SLE)是一种慢性全身性炎症性疾病。通过自身反应性B细胞和CD4 T细胞之间的相互作用,产生并维持针对狼疮的标志性双链DNA(ds DNA)的自身抗体(autoAbs)。这种相互作用是由CD28 / CD80-86 / CTLA-4轴控制的。在这里,我们研究了CD28-CD80 / 86共刺激相互作用的选择性阻断是否消除了狼疮性肾炎在SLE鼠模型中的发展。为了这个目的,将NZB / NZW F1小鼠用抗CD28 Fab'片段或对照Fab'-IgG治疗3个月。评估了CD28阻断对狼疮肾炎发作,生存,抗ds DNA抗体产生和共刺激分子的影响。 CD28阻滞剂在3个月的治疗期间和12周后预防了狼疮性肾炎的发展并延长了生存期。此外,抗ds DNA autoAb的产生减少。最后,CD28阻断的保护作用与免疫调节分子吲哚胺2、3-二加氧酶,共抑制受体编程的细胞死亡-1(PD-1)及其配体编程的死亡配体的肾内表达增加有关。 -1(PDL-1)。总之,CD28阻断可预防NZB / NZW F1小鼠的狼疮性肾炎。这种免疫调节策略是人类SLE治疗的有希望的候选者。
  • 【蛋氨酸腺苷基转移酶2A在牛植入前发育及其相关基因组区域中的作用。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-04003-1 复制DOI
    作者列表:Ikeda S,Kawahara-Miki R,Iwata H,Sugimoto M,Kume S
    BACKGROUND & AIMS: :Methionine adenosyltransferase (MAT) is involved in folate-mediated one-carbon metabolism, which is essential for preimplantation embryos in terms of both short-term periconceptional development and long-term phenotypic programming beyond the periconceptional period. Here, our immunofluorescence analysis of bovine oocytes and preimplantation embryos revealed the consistent expression of MAT2A (the catalytic subunit of the ubiquitously expressed-type of MAT isozyme) during this period. Addition of the MAT2A inhibitor FIDAS to the culture media of bovine preimplantation embryos reduced their blastocyst development, revealing the particular importance of MAT2A in successful blastocyst development. Exploration of MAT2A-associated genomic regions in bovine blastocysts using chromatin immunoprecipitation and sequencing (ChIP-seq) identified candidate MAT2A-associated genes implicated not only in short-term periconceptional embryo development, but also in long-term phenotypic programming during this period in terms of growth, metabolism, and immune functions. These results suggest the critical involvement of MAT2A in the periconceptional period in life-long programming of health and disease as well as successful preimplantation development.
    背景与目标: :蛋氨酸腺苷基转移酶(MAT)参与叶酸介导的一碳代谢,这对于植入前的胚胎而言,无论是短期的受孕发育还是经过长期的表型编程,都是必不可少的。在这里,我们对牛卵母细胞和植入前胚胎的免疫荧光分析揭示了在此期间MAT2A(MAT酶的普遍表达型的催化亚基)的一致表达。在牛植入前胚胎的培养基中添加MAT2A抑制剂FIDAS可减少其胚泡发育,从而揭示MAT2A在成功的胚泡发育中特别重要。利用染色质免疫沉淀和测序(ChIP-seq)探索牛胚泡中与MAT2A相关的基因组区域,确定了与MAT2A相关的候选基因,不仅与短期围产期胚胎发育有关,而且与这一时期的长期表型编程有关。生长,新陈代谢和免疫功能。这些结果表明,MAT2A在整个生命周期的健康和疾病规划以及成功的植入前发展过程中,都处于围孕期的关键时期。
  • 【通过马拉维社区儿童保育中心改善儿童营养和发育-NEEP-IE研究:一项随机对照试验的研究方案。】 复制标题 收藏 收藏
    DOI:10.1186/s13063-017-2003-7 复制DOI
    作者列表:Gelli A,Margolies A,Santacroce M,Sproule K,Theis S,Roschnik N,Twalibu A,Chidalengwa G,Cooper A,Moorhead T,Gladstone M,Kariger P,Kutundu M
    BACKGROUND & AIMS: BACKGROUND:The Nutrition Embedded Evaluation Programme Impact Evaluation (NEEP-IE) study is a cluster randomised controlled trial designed to evaluate the impact of a childcare centre-based integrated nutritional and agricultural intervention on the diets, nutrition and development of young children in Malawi. The intervention includes activities to improve nutritious food production and training/behaviour-change communication to improve food intake, care and hygiene practices. This paper presents the rationale and study design for this randomised control trial. METHODS:Sixty community-based childcare centres (CBCCs) in rural communities around Zomba district, Malawi, were randomised to either (1) a control group where children were attending CBCCs supported by Save the Children's Early Childhood Health and Development (ECD) programme, or (2) an intervention group where nutritional and agricultural support activities were provided alongside the routine provision of the Save the Children's ECD programme. Primary outcomes at child level include dietary intake (measured through 24-h recall), whilst secondary outcomes include child development (Malawi Development Assessment Tool (MDAT)) and nutritional status (anthropometric measurements). At household level, primary outcomes include smallholder farmer production output and crop-mix (recall of last production season). Intermediate outcomes along theorised agricultural and nutritional pathways were measured. During this trial, we will follow a mixed-methods approach and undertake child-, household-, CBCC- and market-level surveys and assessments as well as in-depth interviews and focus group discussions with project stakeholders. DISCUSSION:Assessing the simultaneous impact of preschool meals on diets, nutrition, child development and agriculture is a complex undertaking. This study is the first to explicitly examine, from a food systems perspective, the impact of a preschool meals programme on dietary choices, alongside outcomes in the nutritional, child development and agricultural domains. The findings of this evaluation will provide evidence to support policymakers in the scale-up of national programmes. TRIAL REGISTRATION:ISRCTN registry, ID: ISRCTN96497560 . Registered on 21 September 2016.
    背景与目标: 背景:营养嵌入式评估计划影响评估(NEEP-IE)研究是一项集群随机对照试验,旨在评估基于托儿所的营养和农业综合干预对马拉维幼儿饮食,营养和发育的影响。干预措施包括改善营养食品生产的活动和培训/行为改变交流,以改善食物摄入,护理和卫生习惯。本文介绍了这项随机对照试验的原理和研究设计。
    方法:将马拉维Zomba地区周边农村社区的60个社区托儿中心(CBCC)随机分为(1)对照组,在该组中,儿童参加了由Save the Children's Early Childhood Health and Development(ECD)计划支持的CBCC,或(2)一个干预小组,在该小组的日常服务之外,还提供了营养和农业支持活动。儿童一级的主要结局包括饮食摄入量(通过24小时召回来衡量),而次级一级的结局包括儿童发育(马拉维发育评估工具(MDAT))和营养状况(人体测量)。在家庭一级,主要成果包括小农户的农产品产量和作物结构(回顾上个生产季节)。测量了沿理论化的农业和营养途径的中间结果。在此试验期间,我们将采用混合方法,并进行儿童,家庭,CBCC和市场级别的调查和评估,以及与项目利益相关者的深入访谈和焦点小组讨论。
    讨论:评估学龄前膳食对饮食,营养,儿童发育和农业的同时影响是一项复杂的工作。这项研究是第一个从食品系统的角度明确检查学龄前儿童饮食计划对饮食选择以及营养,儿童发育和农业领域的成果的影响的研究。评估的结果将为支持决策者扩大国家计划提供证据。
    试用注册:ISRCTN注册,ID:ISRCTN96497560。 2016年9月21日注册。
  • 【俄斯特拉发大学附属医院血液中心的粒细胞采集程序。】 复制标题 收藏 收藏
    DOI:10.5507/bp.2012.071 复制DOI
    作者列表:Cermakova Z,Blahutova S,Papajik T,Galuszkova D,Hubacek J,Sommerova M
    BACKGROUND & AIMS: BACKGROUND:Granulocyte apheresis is a safe and effective method for granulocyte collection. We present a five year experience (2006-2010) of the Blood Center, Faculty Hospital Ostrava, Czech Republic. Donor granulocyte transfusion is one treatment option for haemato-oncology patients with severe neutropenia complicated by bacterial/fungal infections unresponsive to standard antibiotic/antifungal treatment. In this study, we describe the experiences of the Blood Centre at the Faculty Hospital in Ostrava of granulocyte apheresis. METHODS AND RESULTS:A total of 149 granulocyte units were collected for 33 patients from the Department of Haemato-oncology, University Hospital Olomouc, over a 5-year period (2006-2010). Information on donor selection, laboratory screening, mobilization regimen and granulocyte yield was obtained and analyzed. All mandatory screening tests for infection markers, AB0 and Rh and abnormal erythrocyte antibodies were performed. The cytomegalovirus status of the donors was not investigated. Steroids were the only mobilization regimen used, and were generally well accepted. The mean granulocyte yield was 12.6×10(9)/per transfusion unit (range 5.4-30.3). All granulocyte concentrates were irradiated and transfused according to AB0 Rh compatibility within 24 h after collection. CONCLUSION:Based on our experience, granulocytapheresis is a safe and effective method for obtaining granulocytes but the yield can be significantly influenced by other variables. From the recipients' perspective, the use of donor granulocytes supports an effective therapeutic modality.
    背景与目标: 背景:粒细胞单采是一种安全有效的收集粒细胞的方法。我们介绍了捷克共和国俄斯特拉发学院医院血液中心的五年经验(2006-2010)。供体粒细胞输注是严重中性粒细胞减少症并发细菌/真菌感染而对标准抗生素/抗真菌治疗无反应的血液肿瘤患者的一种治疗选择。在这项研究中,我们描述了粒细胞单采的俄斯特拉发大学医院血液中心的经验。
    方法与结果:在5年期间(2006-2010年),从Olomouc大学医院血液肿瘤科收集了149粒粒细胞单位,用于33例患者。获得并分析了有关供体选择,实验室筛查,动员方案和粒细胞产量的信息。进行了所有感染标志物,AB0和Rh和异常红细胞抗体的强制性筛查测试。没有研究捐赠者的巨细胞病毒状况。类固醇是唯一使用的动员方案,并且普遍被接受。平均粒细胞产量为12.6×10(9)/每输血单位(范围5.4-30.3)。收集后24小时内,按照AB0 Rh相容性对所有粒细胞浓缩物进行辐照和输血。
    结论:根据我们的经验,粒细胞穿刺术是一种安全有效的获取粒细胞的方法,但产量会受到其他变量的显着影响。从接受者的角度来看,使用供体粒细胞支持有效的治疗方式。
  • 【肝移植后原发性硬化性胆管炎与溃疡性结肠炎相关的结肠癌的发展。】 复制标题 收藏 收藏
    DOI:10.1002/hep.1840110320 复制DOI
    作者列表:Higashi H,Yanaga K,Marsh JW,Tzakis A,Kakizoe S,Starzl TE
    BACKGROUND & AIMS: :Between February 26, 1981, and July 30, 1987, 36 patients underwent orthotopic liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Three of the 36 recipients died within 3 mo because of graft nonfunction or surgical complications. The other 33 (92%) lived for at least 1 yr. Two of the 33 died after 12 and 14 mo, respectively, of recurrent cholangiocarcinoma that was not diagnosed before transplantation. Four other patients died of recurrent liver failure (three cases) or immunoblastic sarcoma (one case) after 14, 21, 36 and 44 mo. Twenty-seven (75%) of the patients are still alive 23 to 81 mo after transplantation. Two patients have been diagnosed as having colorectal cancer 11 and 21 mo respectively, after transplantation, for an overall incidence of 5.6% (2 of 36) and a corrected incidence of 6.5% (2 of 31) if the three early deaths and two later deaths caused by cholangiocarcinomas are excluded. It is not known whether colorectal malignancies were present but undetected at the time of transplantation or whether they developed afterward. It is clear that patients who undergo liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis should have careful follow-up of the colon, including colonoscopy and multiple biopsies of the colorectal mucosa. Whether proctocolectomy should be considered prophylactically after liver transplantation is an unresolved issue.
    背景与目标: :1981年2月26日至1987年7月30日之间,因原发性硬化性胆管炎伴溃疡性结肠炎,对36例患者进行了原位肝移植。 36位接受者中有3位在3个月内死于移植物无功能或手术并发症。其余33名(92%)居住至少1年。 33例中有2例分别在移植前12个月和14个月后死于复发性胆管癌。在14、21、36和44个月后,另外四名患者死于复发性肝衰竭(三例)或免疫母细胞肉瘤(一例)。二十七(75%)位患者在移植后23到81 mo还活着。两名患者在移植后分别被诊断出患有大肠癌,分别为11和21 mo,总发病率为5.6%(36分之2),如果3例早期死亡和2例较晚死亡,则校正后的发病率为6.5%(31分2例)。胆管癌引起的死亡不包括在内。尚不知道是否存在大肠恶性肿瘤但在移植时未发现大肠恶性肿瘤或它们随后是否发展。显然,因原发性硬化性胆管炎与溃疡性结肠炎而进行肝移植的患者应仔细检查结肠,包括结肠镜检查和大肠黏膜多次活检。肝移植后是否应预防性考虑进行结肠直肠切除术尚未解决。
  • 【在晚期前列腺癌的早期药物开发中测试生物学假设的新策略。】 复制标题 收藏 收藏
    DOI:10.1373/clinchem.2012.185157 复制DOI
    作者列表:Ferraldeschi R,Attard G,de Bono JS
    BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.
    背景与目标: 背景:我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌(CRPC)治疗的新时代,最近5年中有5种新药显示出生存优势,并且数量惊人的有希望的新型药物进入临床。
    内容:我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略,不仅着眼于预测性和中间终点生物标志物的开发,还着重于新的假设检验,生物标志物驱动的临床试验设计。
    简介:随着一些有前途的药物进入临床,对CRPC进行药物开发的重新思考的压力越来越大,以确保对新型药物进行适当评估,并适当分配患者和资源。我们设想,通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试,生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。

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