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The cycle of SEC4 function in vesicular transport. SEC4循环在囊泡运输中起作用。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514450.ch14
P. Novick, P. Brennwald, N. Walworth, A. Kabcenell, M. Garrett, M. Moya, D. Roberts, H. Müller, B. Govindan, R. Bowser
Sec4 is a Ras-like GTP-binding protein required for exocytosis in yeast. Unlike Ras, it is the ability of Sec4 to cycle between the GTP- and GDP-bound forms rather than the absolute levels of the GTP-bound form that is critical for function. This cycle may be coupled to an observed cycle of Sec4 localization within the cell. Sec4 binds to secretory vesicles which then fuse with the plasma membrane in exocytosis. Sec4 can recycle from the plasma membrane through a soluble pool to rebind to a new round of vesicles. We have found an activity in yeast (Saccharomyces cerevisiae) comparable to that of the GDP dissociation inhibitor protein isolated from mammalian cells that releases GDP-bound Sec4 from membranes. DSS4-1, a dominant suppressor of the sec4-8 temperature-sensitive mutation, encodes a nucleotide exchange protein. The cycle of Sec4 may function to allow the assembly and subsequent disassembly of a set of proteins necessary for exocytosis. Candidates for members of this set of proteins are encoded by sec genes which show strong genetic interactions with sec4-8. Two of these (SEC8 and SEC15) encode large proteins which form a complex that is peripherally associated with the plasma membrane.
Sec4是酵母胞吐所需的ras样gtp结合蛋白。与Ras不同的是,对于功能至关重要的是Sec4在GTP结合形式和gdp结合形式之间循环的能力,而不是GTP结合形式的绝对水平。这个周期可能与细胞内观察到的Sec4定位周期耦合。Sec4与分泌囊泡结合,然后在胞吐过程中与质膜融合。Sec4可以通过可溶池从质膜中回收,重新结合到新一轮的囊泡上。我们已经在酵母(酿酒酵母)中发现了与从哺乳动物细胞中分离的GDP解离抑制剂蛋白相当的活性,该蛋白从膜中释放与GDP结合的Sec4。DSS4-1是sec4-8温度敏感突变的显性抑制因子,编码核苷酸交换蛋白。Sec4的循环可能起作用,允许胞吐所必需的一组蛋白质的组装和随后的拆卸。这组蛋白的候选成员由sec基因编码,与sec4-8表现出强烈的遗传相互作用。其中两种(SEC8和SEC15)编码大蛋白,形成与质膜外周相关的复合物。
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引用次数: 17
Experimental studies of ongoing conscious experience. 持续意识经验的实验研究。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514412.CH6
J. Singer
A research programme designed to find ways of applying a variety of methods in psychological science to studying the seemingly ephemeral phenomena of the human stream of consciousness and its manifestations in daydreams, interior monologues, imagery and related private experiences is described. Approaches include psychometric studies to establish normative information on daydreaming and experimental studies using signal-detection paradigms to capture the ongoing stream of thought. Recent experiments involve thought-sampling methods for identifying the determinants of the content of the stream of thought in adolescents or the ways in which self-beliefs and emotions are manifested in a group of cocaine and heroin abusers. Children's pretend play is studied as a possible forerunner of adult consciousness. It is proposed that the human condition involves a continuing tension between processing information generated from the physical and social milieu and the continuous operation of centrally generated material from long-term memory in the form of reminiscences, wishes, current concerns, expectancies and fantasies. This concept has implications for personality variation, affective arousal and adaptive behaviour.
本文描述了一个研究项目,旨在寻找应用心理科学中的各种方法来研究人类意识流的看似短暂的现象及其在白日梦、内心独白、意象和相关私人经历中的表现。方法包括心理测量学研究来建立关于白日梦的规范信息,以及使用信号检测范式来捕捉正在进行的思维流的实验研究。最近的实验涉及思想抽样方法,以确定青少年思想流内容的决定因素,或一群可卡因和海洛因滥用者的自我信念和情绪表现方式。儿童的假装游戏被研究为成人意识的可能先驱。有人提出,人类的状况涉及处理从物质和社会环境中产生的信息与从长期记忆中以回忆、愿望、当前关注、期望和幻想的形式集中产生的材料之间的持续紧张关系。这一概念对人格变异、情感唤醒和适应性行为都有影响。
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引用次数: 51
Programming by early nutrition in man. 人类早期营养的编程。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514047.CH4
A. Lucas
Whether early diet influences long-term health or achievement is a key question in nutrition. Such long-term consequences would invoke the concept of 'programming'--a more general process whereby a stimulus or insult at a critical period of development has lasting or lifelong significance. Data from small mammals and primates show that early nutrition may have potentially important long-term effects, for example on blood lipids, plasma insulin, obesity, atherosclerosis, behaviour and learning. Corresponding studies in man have been largely retrospective and difficult to interpret. The preterm infant is however an important model for human research because formal random assignment to early diet is practical. A large prospective randomized multicentre study has been undertaken on 926 preterm infants to test the hypothesis that early diet influences long-term outcome. Diets included human milk, standard formula and nutrient-enriched preterm formula. The diet consumed for on average the first month post partum had a major impact on subsequent developmental attainment, growth and allergic status in early childhood. That such a brief period of dietary manipulation has lasting significance implies that the neonatal period is critical for nutrition after preterm birth. These data may have broader implications for human nutrition.
早期饮食是否影响长期健康或成就是营养学的一个关键问题。这种长期的后果会引发“编程”的概念——这是一种更普遍的过程,在发展的关键时期,刺激或侮辱具有持久或终身的意义。来自小型哺乳动物和灵长类动物的数据表明,早期营养可能有潜在的重要长期影响,例如对血脂、血浆胰岛素、肥胖、动脉粥样硬化、行为和学习。对人类的相应研究在很大程度上是回顾性的,难以解释。然而,早产儿是人类研究的一个重要模型,因为对早期饮食的正式随机分配是可行的。对926名早产儿进行了一项大型前瞻性随机多中心研究,以验证早期饮食影响长期预后的假设。饮食包括母乳、标准配方奶粉和营养丰富的早产儿配方奶粉。产后第一个月的平均饮食对随后的发育成就、生长和儿童早期过敏状况有重大影响。如此短暂的饮食控制具有持久的意义,这意味着新生儿期对早产后的营养至关重要。这些数据可能对人类营养有更广泛的影响。
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引用次数: 919
The relationship between erythromycin consumption and resistance in Finland. Finnish Study Group for Antimicrobial Resistance. 芬兰红霉素消费与耐药性的关系。芬兰抗菌素耐药性研究小组。
Pub Date : 2007-09-28 DOI: 10.1002/9780470515358.CH3
P. Huovinen, H. Seppălä, J. Kataja, T. Klaukka
Because the discovery of new antimicrobial agents cannot be expected in the near future, we will have to manage with the antimicrobials currently available at least for the next decade or two. Therefore, attempts to prevent development of antimicrobial resistance are of major importance. The relationship of local antimicrobial consumption and antimicrobial resistance has been shown in many hospital studies but not in the community, even though this is where most antibiotics are used. At the beginning of 1990s, erythromycin resistance in group A streptococci increased rapidly in Finland. The geographical variations found led to a nationwide study of the possible relation between local erythromycin consumption and variations in erythromycin resistance in the community. Erythromycin resistance was found to be significantly (P = 0.006) linked to local consumption of erythromycin. In further experiments, we found that a new erythromycin resistance phenotype belonging to the T4 serotype was spread over the whole country; 83% of the erythromycin-resistant isolates were of this new phenotype in 1994. In 1991, recommendations were given to reduce use of erythromycin in Finland. Following these recommendations, macrolide consumption decreased by 40% from 1991-1994. Studies are now in progress to evaluate the effect of this reduction on erythromycin resistance of group A streptococci.
由于不可能在不久的将来发现新的抗微生物药物,我们将不得不至少在未来十年或二十年使用目前可用的抗微生物药物。因此,努力防止抗菌素耐药性的发展是非常重要的。许多医院研究显示了当地抗菌素消费与抗菌素耐药性之间的关系,但没有在社区中显示出来,尽管社区是使用抗生素最多的地方。20世纪90年代初,芬兰A群链球菌对红霉素的耐药性迅速增加。发现的地理差异导致在全国范围内研究当地红霉素消费与社区红霉素耐药变化之间可能的关系。发现红霉素耐药性与当地红霉素消费显著相关(P = 0.006)。在进一步的实验中,我们发现一种属于T4血清型的新的红霉素耐药表型在全国范围内蔓延;1994年,83%的红霉素耐药株为这种新表型。1991年,芬兰提出了减少红霉素使用的建议。按照这些建议,大环内酯类药物的消费量从1991年到1994年下降了40%。目前正在进行研究,以评估这种减少对A群链球菌红霉素耐药性的影响。
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引用次数: 24
Antibody catalysis of carbon-carbon bond formation. 抗体催化碳-碳键形成。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514108.CH12
D. Hilvert
We have used rationally designed transition state analogues to generate antibodies that catalyse two important carbon-carbon bond forming reactions: a bimolecular Diels-Alder cycloaddition and a unimolecular Claisen rearrangement. Our tailored immunoglobulin catalysts (abzymes) exhibit all the properties of naturally occurring enzymes, including substantial rate accelerations, substrate specificity, and high regio- and stereoselectivity. As first generation abzymes are generally inferior to naturally occurring enzymes, we are also employing classical genetic selection strategies to augment their chemical efficiency. We have expressed the antibody that catalyses the Claisen rearrangement of chorismate in yeast cells that lack natural chorismate mutase activity. Improved versions of the abzyme will be identified, following random mutagenesis, by their ability to repair this metabolic defect. The development and study of highly efficient catalytic antibodies promises to advance our understanding of how enzymes work and evolve, how protein function correlates with structure, and how entirely new enzymic activities can be created for use in research, industry and medicine.
我们使用合理设计的过渡态类似物生成了催化两个重要碳-碳键形成反应的抗体:双分子Diels-Alder环加成反应和单分子Claisen重排反应。我们量身定制的免疫球蛋白催化剂(抗体酶)具有天然酶的所有特性,包括显著的速率加速、底物特异性以及高区域和立体选择性。由于第一代酶通常不如天然存在的酶,我们也采用经典的遗传选择策略来提高它们的化学效率。我们已经表达了一种抗体,在缺乏天然choris酸突变酶活性的酵母细胞中催化choris酸clisen重排。改进版本的抗酶将被识别,在随机突变之后,通过他们的能力来修复这种代谢缺陷。高效催化抗体的开发和研究有望推进我们对酶如何工作和进化,蛋白质功能如何与结构相关,以及如何创造全新的酶活性用于研究,工业和医学的理解。
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引用次数: 2
Detrusor-external sphincter dyssynergia.
Pub Date : 2007-09-28 DOI: 10.1002/9780470513941.CH11
M. Chancellor, S. Kaplan, J. Blaivas
Detrusor-external sphincter dyssynergia (DESD) is characterized by involuntary contractions of the external urethral sphincter during an involuntary detrusor contraction. It is caused by neurological lesions between the brainstem (pontine micturition centre) and the sacral spinal cord (sacral micturition centre). These include traumatic spinal cord injury, multiple sclerosis, myelodysplasia and other forms of transverse myelitis. There are three main types of DESD. In Type 1 there is a concomitant increase in both detrusor pressure and sphincter EMG activity. At the peak of the detrusor contraction the sphincter suddenly relaxes and unobstructed voiding occurs. Type 2 DESD is characterized by sporadic contractions of the external urethral sphincter throughout the detrusor contraction. In Type 3 DESD there is a crescendo-decrescendo pattern of sphincter contraction which results in urethral obstruction throughout the entire detrusor contraction. In patients with sufficient manual dexterity the most reasonable treatment option is to abolish the involuntary detrusor contractions (to ensure continence) and then to institute intermittent self-catheterization (in order to empty the bladder). The bladder may be paralysed pharmacologically or may be surgically converted to a low pressure urinary reservoir by the technique of augmentation enterocystoplasty. In quadriplegic men, transurethral external sphincterotomy may be performed and the incontinence managed with an external urinary appliance. Without proper treatment over 50% of men with DESD develop serious urological complications within about five years. In women these complications are much less common.
逼尿肌-外括约肌协同障碍(DESD)的特征是在不自主逼尿肌收缩时外尿道括约肌的不自主收缩。它是由脑干(脑桥排尿中心)和骶脊髓(骶排尿中心)之间的神经病变引起的。这些包括创伤性脊髓损伤、多发性硬化症、骨髓发育不良和其他形式的横贯性脊髓炎。DESD主要有三种类型。在1型中,逼尿肌压力和括约肌肌电图活动同时增加。在逼尿肌收缩的高峰期,括约肌突然放松,排尿通畅。2型DESD的特征是尿道外括约肌在整个逼尿肌收缩过程中散发收缩。在3型DESD中,括约肌收缩呈渐强-渐弱模式,导致整个逼尿肌收缩过程中尿道梗阻。对于手足够灵巧的患者,最合理的治疗选择是取消不自主逼尿肌收缩(以确保尿失禁),然后进行间歇性自我导尿(以排空膀胱)。膀胱可以通过药物麻痹,也可以通过手术通过增大膀胱成形术转化为低压尿库。四肢瘫痪的男性可经尿道外括约肌切开术,并用外尿器治疗失禁。如果没有适当的治疗,超过50%的男性DESD患者会在5年内出现严重的泌尿系统并发症。在女性中,这些并发症要少见得多。
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引用次数: 12
Intercellular calcium waves mediated by inositol trisphosphate. 三磷酸肌醇介导的细胞间钙波。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514696.CH10
Michael J. Sanderson
Intercellular calcium waves occur in diverse cells. Those that are induced by mechanical stimulation have been extensively investigated in epithelial and glial cells. Mechanical stimulation of an individual cell initiates an increase in the intracellular free calcium concentration, [Ca2+]i, that spreads across the cell. At the cell border this intracellular Ca2+ wave is arrested but, after a brief delay, similar Ca2+ waves occur in adjacent cells. The repetition of this process results in the propagation of an intercellular Ca2+ wave through a limited number of cells. The propagation of intercellular Ca2+ waves correlates with the presence of functional gap junctions and occurs in the absence of extracellular Ca2+ or following the microinjection of inositol 1,4,5-trisphosphate (InsP3). The propagation of intercellular Ca2+ waves is inhibited by heparin (an InsP3 receptor antagonist) and by U73122 (a phospholipase C inhibitor) or when intracellular Ca2+ stores are depleted with thapsigargin. These characteristics suggest that mechanical stimulation initiates InsP3 production and that intercellular Ca2+ waves are propagated through the movement of InsP3 through gap junctions. Mathematical modelling supports the idea that diffusion of InsP3 is a viable hypothesis for the generation of intercellular Ca2+ waves. The ability of cells to display changes in [Ca2+]i that are independent of neighbouring cells (i.e., asynchronous Ca2+ oscillations) and the low diffusion constant of Ca2+ suggest that Ca2+ itself is not a major messenger moving between cells to propagate Ca2+ waves.
细胞间钙波存在于多种细胞中。在上皮细胞和神经胶质细胞中已经广泛研究了由机械刺激诱导的这些细胞。单个细胞的机械刺激引发细胞内游离钙浓度的增加,[Ca2+]i,扩散到整个细胞。在细胞边界,这种细胞内Ca2+波被阻止,但经过短暂的延迟,类似的Ca2+波在邻近细胞中发生。这个过程的重复导致细胞间Ca2+波通过有限数量的细胞传播。细胞间Ca2+波的传播与功能性间隙连接的存在相关,并且发生在缺乏细胞外Ca2+或微量注射肌醇1,4,5-三磷酸(InsP3)之后。细胞间Ca2+波的传播受到肝素(一种InsP3受体拮抗剂)和U73122(一种磷脂酶C抑制剂)的抑制,或者当细胞内Ca2+储存被thapsigarin耗尽时。这些特征表明,机械刺激启动了InsP3的产生,细胞间Ca2+波通过间隙连接的InsP3运动传播。数学模型支持这样的观点,即InsP3的扩散是细胞间Ca2+波产生的可行假设。细胞显示独立于邻近细胞的[Ca2+]i变化的能力(即,异步Ca2+振荡)和Ca2+的低扩散常数表明,Ca2+本身不是在细胞之间传播Ca2+波的主要信使。
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引用次数: 76
Religious aspects of human genetic information. 人类遗传信息的宗教方面。
Pub Date : 2007-09-28 DOI: 10.1002/9780470513903.CH11
Rihito Kimura, Rihito Kimura
To obtain human genetic information with the intention of treating and curing severe genetic disease would be considered to be a positive personal decision of a moral agent in various religious contexts. According to some religious teachings human suffering should not be regarded merely as a negative element of life; however, the scientific achievement of obtaining genetic information should surely increase the possibility of hope for the eventual cure of genetically determined diseases. The elimination of human suffering and tragedy in severe genetically determined illness, on the criterion of the benefit of the patient, is permitted by various contemporary religious teachings, according to an analysis of publications by the World Council of Churches and the Vatican and sources from Jewish, Islamic and Buddhist teachings.
在各种宗教背景下,以治疗和治愈严重遗传疾病为目的获取人类遗传信息将被视为道德主体的积极个人决定。根据一些宗教教义,人类的苦难不应仅仅被视为生活的消极因素;然而,获得遗传信息的科学成就肯定会增加最终治愈由遗传决定的疾病的希望的可能性。根据对世界教会理事会和梵蒂冈出版物的分析以及来自犹太教、伊斯兰教和佛教教义的资料,当代各种宗教教义都允许以病人的利益为标准,消除人类在严重的基因决定疾病中的痛苦和悲剧。
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引用次数: 4
Experimental myopia in tree shrews. 树鼩的实验性近视。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514023.CH11
T. Norton
When deprived of form vision during postnatal development, tree shrews reliably develop an axial myopia characterized by elongation of the vitreous chamber, zonular dysplasia and a slight reduction in lens weight and thickness. Corneal flattening has been observed in animals visually deprived by eyelid suture but is absent in animals visually deprived with an opaque goggle. The sensitive period for myopia development starts about 15 days after the eyes open and sensitivity remains high for about 3-4 weeks thereafter. Recovery from experimental myopia can occur in tree shrews that are visually deprived using goggles for a short period. Blockade of action potentials from ganglion cells in deprived eyes by intravitreal injections of tetrodotoxin (TTX) does not prevent the development of myopia, suggesting that local retinoscleral mechanisms can contribute to experimental myopia in this species. Open eyes receiving intravitreal injections of either saline or TTX have shorter vitreous chambers than control eyes, suggesting that puncturing the globe reduces forces within the eye that contribute to its expansion. Animals treated intraperitoneally with lathyritic agents to block collagen cross-linking for three weeks during a 75-day period of monocular visual deprivation develop a very large myopia in the visually deprived eye that is accompanied by a large vitreous chamber elongation and marked thinning of the posterior sclera. The results from studies in tree shrews are consistent with the suggestion that an internally driven expansion acts in concert with ocular growth to increase the axial length of the eye, helping to move the eye from hyperopia toward emmetropia. The resistance of the sclera and/or choroid to this expansion may be affected by activity within the retina. Increased retinal activity associated with achieving a clear image on the retina may result in increased resistance to expansion, helping to hold the retina at the focal plane. Recovery may occur by a slowing of axial expansion while the optical surfaces proceed toward adult values.
在出生后的发育过程中,当被剥夺视觉时,树鼩必然会发展为轴向近视,其特征是玻璃体腔延长,带状发育不良和晶状体重量和厚度轻微减少。在眼睑缝合剥夺视力的动物中观察到角膜变平,但在使用不透明护目镜剥夺视力的动物中没有角膜变平。近视发展的敏感期开始于睁眼后约15天,此后约3-4周内敏感性保持高水平。在短时间内使用护目镜剥夺视觉的树鼩可以从实验性近视中恢复过来。通过玻璃体内注射河豚毒素(TTX)阻断被剥夺眼睛的神经节细胞的动作电位并不能阻止近视的发展,这表明局部视网膜巩膜机制可能有助于该物种的实验性近视。接受玻璃体内生理盐水或TTX注射的裸眼玻璃体腔比对照组的眼睛短,这表明刺穿眼球会减少眼内促进其扩张的力量。在75天的单眼视力剥夺期间,腹腔注射溶石剂阻断胶原交联三周的动物会在视力剥夺的眼睛中出现非常大的近视,并伴有玻璃体腔的大延伸和后巩膜的明显变薄。对树鼩的研究结果与内部驱动的扩张与眼部生长相一致,以增加眼睛的轴向长度,帮助眼睛从远视转向远视。巩膜和/或脉络膜对这种扩张的抵抗力可能受到视网膜内活动的影响。在视网膜上获得清晰图像的视网膜活动增加可能导致对扩张的阻力增加,有助于将视网膜保持在焦平面上。当光学表面向成体值方向发展时,轴向扩张的减慢可能会导致恢复。
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引用次数: 105
Rules for the production of sensory cells. 感觉细胞产生的规律。
Pub Date : 2007-09-28 DOI: 10.1002/9780470514122.CH3
J. Lewis
During development and regeneration, cells divide, move, change their internal state, respond to environmental signals and die according to rules specified by their genome. These rules of cell behaviour are fundamental to any explanation of how sensory tissues are generated or repaired. An attempt is made to summarize and compare the rules underlying the development of four different sensory tissues: mammalian retina, avian auditory epithelium, mechanosensory bristle fields in Drosophila and, very briefly, Drosophila retina. There are parallels in cell lineage, in the timing of developmental decisions, in the postponement of the choice of differentiated state until the final cell division cycle, in the role of short-range lateral inhibition, and in the involvement of genes such as Notch and achaete/scute. These similarities may reflect the conservation of some basic mechanisms of sensory development that originated early in the evolution of multicellular animals. If so, studies in Drosophila, with its advantages for molecular genetics, may give important clues to the mechanisms of sensory development and regeneration in vertebrates.
在发育和再生过程中,细胞分裂、移动、改变其内部状态、对环境信号作出反应并根据基因组指定的规则死亡。这些细胞行为规则是解释感觉组织如何产生或修复的基础。本文试图总结和比较四种不同感觉组织的发展规律:哺乳动物视网膜、鸟类听觉上皮、果蝇机械感觉刚毛场和果蝇视网膜。在细胞谱系、发育决定的时间、分化状态的选择推迟到最后的细胞分裂周期、短距离横向抑制的作用以及Notch和achaete/ sccute等基因的参与等方面都有相似之处。这些相似之处可能反映了在多细胞动物进化早期产生的感觉发育的一些基本机制的保存。如果是这样的话,对具有分子遗传学优势的果蝇的研究,可能为研究脊椎动物感觉发育和再生的机制提供重要线索。
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引用次数: 70
期刊
Ciba Foundation symposium
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