BACKGROUND & AIMS: :Colorectal carcinoma (CRC) is the second leading cause of cancer-related death in the United States in the general population (men and women combined). Epidemiologic data obtained over the last several decades shows convincing evidence for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of risk of CRC through the inhibition of cycloxygenase (COX). Recent research has also demonstrated that prostaglandin E2 (PGE2), a predominant product of COX, plays a critical role in tumorigenesis of CRCs through its guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), EP2, and EP4. Molecular analysis of CRC and its precursor lesions have shown that mutation of Adenomatous Polyposis Coli (APC), a gene involved in the wingless type signaling pathway, is an early event during the neoplastic progression in the majority of sporadic CRCs. The fundamental questions are: why is wild type APC so important in adult colorectal tissues in preventing this tumorigenesis, and what are the mechanisms by which NSAIDs prevent colorectal tumorigenesis? We reviewed the recent literature concerning the PGE2-GPCR signaling pathway and the APC-beta-catenin (wingless type) pathway in CRC cells and propose a unifying schema regarding the tumorigenesis of CRC. Colorectal epithelia are continuously exposed to various extracellular agonists (including low levels of PGE2). The binding of these agonists to their corresponding GPCRs leads to formation of activated Galphas, which in turn activates beta-catenin. In normal colorectal epithelia, wild type APC blocks the Galphas-induced activation of beta-catenin, and therefore maintains homeostasis and prevents tumorigenesis. In contrast, in the absence of functional APC, continuous formation of activated Galphas by the binding of various extracellular agonists to their receptors leads to the activation and nuclear accumulation of beta-catenin. This elevated nuclear beta-catenin in turn increases transcription of many genes (COX-2, C-myc, Cyclin D1, vascular endothelial growth factor, T cell factor, etc.) involved in tumorigenesis. Increased transcription of COX-2 also leads to excessive production of PGE2 that in turn forms a stimulatory loop with many biologic functions (proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis), which may result in the development of CRC. Because NSAIDs inhibit COX and decrease the production of PGE2, interruption of the cycle helps prevent colorectal tumorigenesis.

背景与目标： 大肠癌（CRC）是美国普通人群（男性和女性合计）中与癌症相关的死亡的第二大主要原因。在过去的几十年中获得的流行病学数据表明，非甾体类抗炎药（NSAIDs）通过抑制环氧合酶（COX）降低CRC风险的功效令人信服。最近的研究还表明，COX的主要产物前列腺素E2（PGE2）通过鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体（GPCR），EP2和EP4在CRC的肿瘤发生中起关键作用。对CRC及其前体病变的分子分析表明，在大多数散发性CRC中，腺瘤性息肉病（APC）的突变是无翼型信号传导途径中的一个基因，是肿瘤发展过程中的早期事件。基本的问题是：为什么野生型APC在成人结直肠组织中如此重要，以防止这种肿瘤发生，以及NSAIDs预防结直肠肿瘤发生的机制是什么？我们回顾了有关CRC细胞中PGE2-GPCR信号通路和APC-β-catenin（无翼型）通路的最新文献，并提出了关于CRC肿瘤发生的统一方案。大肠上皮细胞不断暴露于各种细胞外激动剂（包括低水平的PGE2）。这些激动剂与其相应的GPCR结合会导致形成活化的Galpha，进而激活β-catenin。在正常的结直肠上皮细胞中，野生型APC阻断了Galphas诱导的β-catenin活化，因此保持体内平衡并防止了肿瘤的发生。相反，在不存在功能性APC的情况下，通过各种细胞外激动剂与其受体的结合而连续形成活化的Galpha，会导致β-catenin的活化和核蓄积。这种升高的核β-catenin反过来又增加了参与肿瘤发生的许多基因（COX-2，C-myc，Cyclin D1，血管内皮生长因子，T细胞因子等）的转录。 COX-2转录的增加还导致PGE2的过量产生，进而形成具有许多生物学功能（增殖，迁移，侵袭，血管生成和细胞凋亡抑制）的刺激环，这可能导致CRC的发展。由于NSAIDs抑制COX并减少PGE2的产生，因此周期的中断有助于预防结直肠癌的发生。

BACKGROUND & AIMS: :The steadily increasing availability of human embryonic stem (hES) cell lines has created strong interest in applying available tools for gene transfer in murine cells to human systems. Here we present a method for the transduction of hES cells with ecotropic retroviral vectors. hES cells were transiently transfected with a construct carrying the murine retrovirus receptor mCAT1. Subsequently, the cells were exposed to replication-deficient Moloney murine leukemia virus (MoMuLV) derivatives or pseudotyped lentiviral vectors. With oncoretroviral vectors, this procedure yields overall transduction efficiencies of up to 20% and permits selection of permanently transduced clones with high frequency. Selected clones maintained expression of pluripotency-associated markers and exhibited multi-germ layer differentiation both in vitro and in vivo. HES cell-derived somatic cells including neural progeny maintained high levels of transgene expression. Lentiviral vectors pseudotyped with the MoMuLV envelope could be introduced in the same manner with efficiencies of up to 33%. Transgene expression of lentivirally transduced hES cells remained permanent after differentiation even without selection pressure. Bypassing the regulatory issues associated with the use of amphotropic retroviral systems and exploiting the large pool of existing murine vectors, this method provides a safe and versatile tool for gene transfer and lineage analysis in hES cells and their progeny.

背景与目标： ：人类胚胎干（hES）细胞系的可用性不断提高，引起了人们的广泛兴趣，他们希望将可利用的工具将鼠细胞中的基因转移至人类系统。在这里，我们介绍了一种用嗜性逆转录病毒载体转导hES细胞的方法。用携带鼠逆转录病毒受体mCAT1的构建体瞬时转染hES细胞。随后，将细胞暴露于复制缺陷型莫洛尼鼠白血病病毒（MoMuLV）衍生物或假型慢病毒载体。使用核转录病毒载体，此过程可产生高达20％的总体转导效率，并允许选择高频率的永久转导克隆。选定的克隆在体外和体内维持多能性相关标志物的表达，并表现出多胚层分化。 HES细胞来源的体细胞（包括神经后代）保持高水平的转基因表达。用MoMuLV包膜假型化的慢病毒载体可以以相同的方式导入，效率高达33％。慢病毒转导的hES细胞的转基因表达在分化后仍保持永久不变，即使没有选择压力也是如此。绕过与使用两性逆转录病毒系统相关的监管问题并利用现有的大量鼠载体，该方法为hES细胞及其后代的基因转移和谱系分析提供了一种安全且通用的工具。

BACKGROUND & AIMS: :Pathways that control aging act via regulated biochemical processes, among which metabolism of xenobiotics (potentially harmful chemical agents encountered as environmental toxicants, for example, drugs, or produced internally) is one possible candidate. A new study of long-lived Ghrhr mutant mice reports that increased bile acid levels activate xenobiotic metabolism via the nuclear receptor, farnesoid X receptor. This increases resistance to xenobiotic stress, possibly contributing to longevity.

背景与目标： ：控制衰老的途径是通过受控的生化过程起作用的，其中异生素（作为环境毒物遇到的潜在有害化学剂，例如药物或内部产生）的代谢是一种可能的选择。一项针对长寿Ghrhr突变小鼠的新研究报告，胆汁酸水平升高会通过核受体，法呢素X受体激活异种生物代谢。这增加了对异种生物胁迫的抵抗力，可能有助于延长寿命。

BACKGROUND & AIMS: :The transcription factor SOX9 (Sry-type high-mobility-group box 9) is expressed in all chondrocytes and is essential for the expression of aggrecan, which during biosynthesis is substituted with more than 10 times its weight of CS (chondroitin sulfate) and is secreted by chondrocytes to form the characteristic GAG (glycosaminoglycan)-rich ECM (extracellular matrix) of cartilage. SOX9 expression rapidly falls during monolayer culture of isolated chondrocytes and this turns off aggrecan and associated CS synthesis. We therefore investigated whether SOX9 transduction of cultured human articular chondrocytes had any effect on the gene expression of the glycosyltransferases and sulfotransferases necessary for GAG biosynthesis. Retroviral SOX9 transduction of passaged chondrocytes increased the endogenous rate of GAG synthesis and the total capacity for GAG synthesis assessed in monolayer culture with beta-xyloside. Both the endogenous rate and the total capacity of GAG biosynthesis were increased further in chondrogenic cell aggregate cultures. The GAG synthesized was predominantly CS and the hydrodynamic size of the newly synthesized chains was unchanged by SOX9 transduction. Aggrecan gene expression was increased in the SOX9-transduced chondrocytes and increased further in chondrogenic culture, but no comparable effects were found in SOX9 transduced dermal fibroblasts. However, the expression of CS glycosyltransferase and sulfotransferase genes in chondrocytes was unaffected by SOX9 transduction. Therefore SOX9 transduction in chondrocytes increased their CS synthetic capacity, but this was not accompanied by changes in the transcription of the CS biosynthetic enzymes and must occur by indirect regulation of enzyme activity through control of enzyme protein translation or enzyme organization.

背景与目标： ：转录因子SOX9（Sry型高迁移率族框9）在所有软骨细胞中表达，对于表达聚集蛋白聚糖至关重要，聚集蛋白聚糖在生物合成过程中被其重量的十倍以上的CS（硫酸软骨素）和软骨细胞分泌的软骨素形成软骨的特征性富含GAG（糖胺聚糖）的ECM（细胞外基质）。在分离的软骨细胞单层培养过程中，SOX9的表达迅速下降，从而关闭了聚集蛋白聚糖和相关CS合成。因此，我们研究了培养的人关节软骨细胞的SOX9转导是否对GAG生物合成所必需的糖基转移酶和磺基转移酶的基因表达有任何影响。传代软骨细胞的逆转录病毒SOX9转导提高了GAG合成的内源性速率，并提高了用β-木糖苷单层培养评估的GAG合成总容量。在软骨细胞聚集体培养中，GAG生物合成的内源速率和总容量都进一步增加。合成的GAG主要为CS，而新合成的链的流体动力学大小通过SOX9转导而没有改变。 Aggrecan基因表达在SOX9转导的软骨细胞中增加，并在软骨培养物中进一步增加，但是在SOX9转导的真皮成纤维细胞中未发现可比的效果。然而，CS糖基转移酶和磺基转移酶基因在软骨细胞中的表达不受SOX9转导的影响。因此，软骨细胞中SOX9的转导增加了CS的合成能力，但这并没有伴随CS生物合成酶的转录变化，必须通过控制酶蛋白翻译或酶组织间接调节酶活性来发生。

BACKGROUND & AIMS: :Heart development begins with the induction of cardiogenic cells from the embryonic mesoderm, followed by the coalescing of these cells into a linear heart tube. Subsequent looping of the heart tube brings the rudimentary atria and ventricles into alignment for further development into the four-chambered heart. Underlying these morphologic events is a complex program of signaling between cells and tissues that orchestrates their participation in heart development. Among these signals are bone morphogenetic proteins, fibroblast growth factors, Wnts, Hedgehog, and members of the transforming growth factor-beta family of signaling molecules. We review here the various properties of these signaling molecules and their signal transduction pathways in hopes of providing a greater appreciation of the molecular events driving heart development.

背景与目标： ：心脏的发育始于从胚胎中胚层诱导心源性细胞，然后将这些细胞聚集成线性心管。随后的心管环回使基本的心房和心室对齐，以进一步发展为四腔心脏。这些形态学事件的基础是细胞和组织之间发信号的复杂程序，可以协调它们参与心脏发育。这些信号包括骨形态发生蛋白，成纤维细胞生长因子，Wnt，刺猬和信号分子的转化生长因子-β家族成员。我们在这里回顾这些信号分子的各种特性及其信号转导途径，以期对驱动心脏发育的分子事件提供更多的了解。

BACKGROUND & AIMS: :PRRSV (porcine reproductive and respiratory syndrome virus) nucleocapsid (N) protein is the most abundant structural protein of the virus. During infection, the N protein is specifically localized to the nucleus and nucleolus in addition to its normal cytoplasmic distribution. Previously, a nuclear localization signal (NLS, 41-PGKK(N/S)KKKN)-null mutant virus (41-PGGGNKKKN) showed reduced viremia and increased production of neutralizing antibodies in infected pigs. However, the mutagenized NLS underwent strong selection pressure in the pig that resulted in partial or complete reversion and reacquisition of NLS function, and thus the biological effect of the NLS-null mutation needed further investigation. In the present study, a total of 9 "reversion resistant" mutants were generated by amino acid deletions and substitutions using an infectious cDNA clone. Two mutant clones (PG--SKKKS and PG--S-KKS) that produced progeny viruses were genetically stable for at least 20 passages in cell culture. Infection of pigs with those mutants induced neutralizing antibodies to higher titers than with wild-type virus. Both mutant viruses induced viremia of lower titer and of shorter duration than wild-type virus. RT-PCR from tonsils showed that both mutants persisted at a reduced level. Virus transmission to contact pigs was also lower in the mutant virus infected groups. No reversion to functional NLS was detected in either mutant from any pig. These data demonstrate that N protein nuclear localization is indeed associated with viral pathogenesis and host response to PRRS.

背景与目标： ：PRRSV（猪生殖和呼吸综合征病毒）核衣壳（N）蛋白是该病毒中最丰富的结构蛋白。在感染过程中，N蛋白除了其正常的细胞质分布外，还特异地位于细胞核和核仁中。以前，核定位信号（NLS，41-PGKK（N / S）KKKN）-无效突变病毒（41-PGGGNKKKN）显示出降低的病毒血症，并增加了感染猪中和抗体的产生。但是，诱变的NLS在猪中受到强大的选择压力，导致NLS功能部分或完全回复和重新获得，因此NLS-null突变的生物学效应需要进一步研究。在本研究中，使用感染性cDNA克隆通过氨基酸缺失和置换产生了总共9个“抗逆转”突变体。产生后代病毒的两个突变体克隆（PG--SKKKS和PG--S-KKS）在细胞培养中至少20代具有遗传稳定性。用那些突变体感染猪所诱导的中和抗体的滴度要高于野生型病毒。与野生型病毒相比，两种突变病毒均能引起较低的滴度和持续时间较短的病毒血症。扁桃体的RT-PCR显示两个突变体均以降低的水平持续存在。在突变病毒感染组中，接触猪的病毒传播率也较低。在任何猪的任一突变体中均未检测到功能性NLS的逆转。这些数据表明，N蛋白核定位确实与病毒发病机制和宿主对PRRS的反应有关。

BACKGROUND & AIMS: :Prescription-event monitoring (PEM) is a non-interventional intensive method for post-marketing drug safety monitoring of newly licensed medicines. PEM studies are cohort studies where exposure is obtained from a centralised service and outcomes from simple questionnaires completed by general practitioners. Follow-up forms are sent for selected events. Because PEM captures all events and not only the suspected adverse drug reactions, PEM cohorts potentially differ in respect to the distribution of number of events per person depending on the nature of the drug under study. This variance can be related either with the condition for which the drug is prescribed (e.g. a condition causing high morbidity will have, in average, a higher number of events per person compared with a condition with lower morbidity) or with the drug effect itself. This paper describes an exploratory investigation of the distortion caused by product-related variations of the number of events to the interpretation of the proportional reporting ratio (PRR) values ("the higher the PRR, the greater the strength of the signal") computed using drug-cohort data. We studied this effect by assessing the agreement between the PRR based on events (event of interest vs all other events) and PRR based on cases (cases with the event of interest vs cases with any other events). PRR were calculated for all combinations reported to ten selected drugs against a comparator of 81 other drugs. Three of the ten drugs had a cohort with an apparent higher proportion of patients with lower number of events. The PRRs based on events were systematically higher than the PRR based on cases for the combinations reported to these three drugs. Additionally, when applying the threshold criteria for signal screening (n > or =3, PRR > or =1.5 and Chi-squared > or =4), the binary agreement was generally high but apparently lower for these three drugs. In conclusion, the distribution of events per patient in drug cohorts shall be examined when comparing the 'strength of the signals' across drugs using PRR values. Further research will be required to address the sensitivity and specificity of the two ways of calculating PRR using data derived from drug cohorts.

背景与目标： ：处方事件监测（PEM）是一种非干预性密集型方法，用于对新许可药品的上市后药物安全性进行监测。 PEM研究是一项队列研究，其中从集中服务获得暴露，并从全科医生完成的简单问卷中得出结果。针对所选事件发送后续表格。由于PEM不仅捕获所有事件，而且不仅捕获可疑的药物不良反应，因此PEM队列在每个人的事件数分布方面可能存在差异，具体取决于所研究药物的性质。这种差异可以与开药的条件有关（例如，与发病率较低的疾病相比，引起高发病率的疾病平均每人发生的事件数更高）或与药物作用本身有关。本文描述了对由事件数量的乘积相关变化引起的失真的探索性研究，以解释使用以下方法计算出的比例报告比率（PRR）值（“ PRR越高，信号强度越大”）。药物队列数据。我们通过评估基于事件的PRR（关注事件与所有其他事件）和基于案例的PRR（涉及事件的案例与任何其他事件的案例）之间的一致性来研究这种影响。针对报告给十种选定药物的所有组合与其他81种药物的比较者的PRR进行了计算。十种药物中的三种具有较高的队列率，而事件数较少的患者比例明显较高。基于事件的PRR在系统上高于针对这三种药物报告的组合病例的PRR。此外，当应用信号筛选的阈值标准（n>或= 3，PRR>或= 1.5以及卡方>或= 4）时，这三种药物的二元协议通常较高，但明显较低。总之，在使用PRR值比较不同药物之间的“信号强度”时，应检查药物组中每个患者事件的分布。将需要进行进一步的研究，以解决使用药物组数据得出的两种计算PRR的敏感性和特异性。

BACKGROUND & AIMS: :Olig2 protein, a member of the basic helix-loop-helix transcription factor family, was introduced into the mouse embryonic carcinoma cell line P19 for induction of motor neuron differentiation. We show that Olig2 protein has the ability to permeate the cell membrane without the addition of a protein transduction domain (PTD), similar to other basic helix-loop-helix transcription factors such as MyoD and NeuroD2. Motor neuron differentiation was evaluated for the elongation of neurites and the expression of choline acetyltransferase (ChAT) mRNA, a differentiation marker of motor neurons. By addition of Olig2 protein, motor neuron differentiation was induced in P19 cells.

背景与目标： ：Olig2蛋白是基本螺旋-环-螺旋转录因子家族的成员，已被引入小鼠胚胎癌细胞系P19中以诱导运动神经元分化。我们显示，Olig2蛋白具有渗透细胞膜的能力，而无需添加蛋白转导域（PTD），类似于其他基本的螺旋-环-螺旋转录因子，如MyoD和NeuroD2。评估运动神经元分化的神经突伸长和胆碱乙酰转移酶（ChAT）mRNA（运动神经元的分化标志物）的表达。通过添加Olig2蛋白，可以在P19细胞中诱导运动神经元分化。

BACKGROUND & AIMS: :Local field potentials (LFPs) and spiking activity reflect different types of information procssing. For example, neurophysiological studies indicate that signal novelty in the ventrolateral prefrontal cortex is differentially represented by LFPs and spiking activity: LFPs habituate to repeated stimulus presentations, whereas spiking activity does not. The neural mechanisms that allow for this differential representation between LFPs and spiking activity are not clear. Here, we model and simulate LFPs and spiking activity of neurons in the ventrolateral prefrontal cortex in order to elucidate potential mechanisms underlying this differential representation. We demonstrate that dynamic negative-feedback loops cause LFPs to habituate in response to repeated presentations of the same stimulus while spiking activity is maintained. This disassociation between LFPs and spiking activity may be a mechanism by which LFPs code stimulus novelty, whereas spiking activity carries abstract information, such as category membership and decision-related activity.

背景与目标： ：局部场电势（LFP）和尖峰活动反映了不同类型的信息处理。例如，神经生理学研究表明，腹侧前额叶皮层的信号新颖性由LFP和加标活动差异表示：LFP习惯于重复刺激，而加标活动则没有。 LFP和加标活性之间存在差异的神经机制尚不清楚。在这里，我们建模和模拟腹侧前额叶皮层的LFP和神经元的突波活动，以阐明这种差异表示的潜在机制。我们证明动态负反馈循环导致LFP习惯于响应相同刺激的重复呈现，同时维持尖峰活动。 LFP和加标活动之间的这种分离可能是LFP编码刺激新颖性的机制，而加标活动携带抽象信息，例如类别成员资格和与决策相关的活动。

BACKGROUND & AIMS: :Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21(CIP1) transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21(CIP1) expression in B-Raf(V600E)-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-Raf(V600E)- or ΔRaf-1:ER-induced MEK/ERK activation, p21(CIP1) expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21(CIP1) regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21(CIP1) regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21(CIP1) has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death.

背景与目标： ：Raf / MEK /细胞外信号调节激酶（ERK）信号失调，是肿瘤发生的常见标志，可以触发固有的肿瘤抑制机制，必须将其抑制才能发生癌变。这种先天性的肿瘤抑制信号传导可能会提供潜在的治疗靶点。在这里我们报告，mortalin（HSPA9 / GRP75 / PBP74）是Raf / MEK / ERK的新型负调节剂，可能为癌症通路中抑癌信号的重新激活提供目标。我们发现，mortalin存在于MEK1 / MEK2蛋白质组中，并在人类黑素瘤活检标本中上调。在不同的MEK / ERK激活的癌细胞系中，凡尔林耗竭诱导细胞死亡和生长停滞，并伴随着p21（CIP1）转录和MEK / ERK活性的增加。值得注意的是，MEK / ERK活性对于在B-Raf（V600E）转化的癌细胞中诱导p21（CIP1）表达的人乳清蛋白耗尽是必需的，而与p53的状态无关。相反，在表现出正常MEK / ERK状态的细胞类型中，mortalin过表达抑制了B-Raf（V600E）-或ΔRaf-1：ER诱导的MEK / ERK活化，p21（CIP1）表达和细胞周期停滞。其他HSP70家族分子伴侣不能有效替代p21（CIP1）调节中的mortalin，这提示了mortalin的独特作用。这些发现揭示了MEK / ERK激活的癌症中p21（CIP1）调节的基础的新机制，并确定了mortalin作为介导Raf / MEK / ERK信号失调的肿瘤抑制和致癌结果的分子开关。我们的研究还表明，p21（CIP1）在耗尽凡尔林的条件下具有双重作用，即在限制细胞死亡的同时介导细胞周期停滞。

BACKGROUND & AIMS: :Much evidence indicates that various naturally occurring compounds have an anti-cancer effect, but the detailed mechanisms are not well understood. In this study, we selected anti-cancer phytochemicals such as epigallocatechin-3-gallate (EGCG), resveratrol (RES) and α-mangostin (α-M), all of which are well-characterized chemopreventive agents. We sought to elucidate the mechanism of their anti-cancer effects and the synergistic effects obtained by combined treatment with the anti-cancer drug 5-fluorouracil (5-FU) in three human colon cancer cell lines. The numbers of viable cells were consistently decreased by the treatment with EGCG, RES or α-M at more than 10 μM in all three cell lines tested. All compounds mainly induced apoptosis and suppressed the PI3K/Akt signaling pathway. Additionally, α-M, which had the greatest PI3K/Akt-suppressing activity, also suppressed MAP kinase (MAPK)/Erk1/2 signaling. Importantly, the combination treatment with RES and 5-FU induced a remarkably synergistic enhancement of growth inhibition and apoptosis through the additional suppression of the MAPK/Erk1/2 signaling pathway in colon cancer DLD-1 cells. Interestingly, RES increased the intracellular expression level of miR-34a, which down-regulated the target gene E2F3 and its downstream Sirt1, resulting in growth inhibition. These findings indicate that these compounds functioned as chemosensitizers when combined with anti-cancer drugs through the modulation of apoptotic and growth-related signaling pathways. Also, RES exerted its anti-cancer activity in part through a newly defined mechanism, i.e., the miR-34a/E2F3/Sirt1 cascade.

背景与目标： ：许多证据表明，各种天然存在的化合物均具有抗癌作用，但其详细机理尚不清楚。在这项研究中，我们选择了抗癌植物化学物质，例如表没食子儿茶素-3-没食子酸酯（EGCG），白藜芦醇（RES）和α-芒果（α-M），它们都是特征明确的化学预防剂。我们试图阐明它们的抗癌作用机理以及通过与抗癌药5-氟尿嘧啶（5-FU）联合治疗在三种人结肠癌细胞系中获得的协同作用。在所有测试的所有三个细胞系中，通过以大于10μM的EGCG，RES或α-M处理，存活细胞的数量持续减少。所有化合物主要诱导细胞凋亡并抑制PI3K / Akt信号传导途径。此外，具有最大的PI3K / Akt抑制活性的α-M也抑制了MAP激酶（MAPK）/ Erk1 / 2信号传导。重要的是，通过RES和5-FU的联合治疗，通过额外抑制结肠癌DLD-1细胞中的MAPK / Erk1 / 2信号传导途径，可显着协同增强生长抑制和凋亡。有趣的是，RES增加了miR-34a的细胞内表达水平，从而下调了靶基因E2F3及其下游Sirt1，从而抑制了生长。这些发现表明，当这些化合物与抗癌药物通过调节细胞凋亡和与生长相关的信号通路结合在一起时，它们起化学增敏剂的作用。此外，RES部分通过新定义的机制即miR-34a / E2F3 / Sirt1级联发挥其抗癌活性。

BACKGROUND & AIMS: :A hypercolumn of monkey striate cortex was studied with an array of 30 closely spaced microelectrodes. Prominent broad peaks appearing in spike train correlograms are considered here. These were not due to shared stimulation, were mostly 30 to 100 ms wide, and were presumably the consequence of intraretinal lateral interactions. The correlogram peak areas were found to be predictable from the products of the spike rates, to which they were proportional. One can conclude that the correlation occurs before the overall reduction of spike rates from retina to cortex takes place. Furthermore, when a neurone dominated by one eye was stimulated via that eye, the correlogram formed with a neurone dominated by the other eye showed a displaced peak, indicating that excitation traveled from the well-responding to the unresponsive neurone in about 10 ms. When a left-eye stimulus was delivered, the same pair of neurones had a correlogram with a reversed peak displacement. This effect was only observed in layers IVb and c, indicating that in these layers the paths from the two eyes to a given cell are of unequal length, whereas in other layers, cells receive input from both eyes via similar connections differing only in strength.

背景与目标： ：研究了猴纹状皮质的一个超柱，该阵列由30个紧密排列的微电极组成。这里考虑了在尖峰列相关图中出现的突出的宽峰。这些不是由于共同的刺激，主要是30到100毫秒宽，大概是视网膜内侧向相互作用的结果。发现关联图的峰面积可以从峰值速率的乘积中预测出来，它们与峰值速率成正比。可以得出这样的结论：相关性发生在从视网膜到皮层的刺突率总体降低之前。此外，当通过一只眼睛支配一只眼睛的神经元受到刺激时，与另一只眼睛支配的神经元形成的相关图显示了一个位移峰，表明激发在大约10毫秒内从响应良好的神经元传播到了无反应的神经元。传递左眼刺激时，同一对神经元的相关图具有相反的峰值位移。仅在第IVb和c层中观察到了这种影响，表明在这些层中，从两只眼睛到给定单元格的路径长度不等，而在其他层中，单元格则通过强度仅不同的相似连接来接收来自两只眼睛的输入。

BACKGROUND & AIMS: The signal recognition particle (SRP) controls the transport of secretory proteins into and across lipid bilayers. SRP-like ribonucleoprotein complexes exist in all organisms, including plants. We characterized the rice SRP RNA and its primary RNA binding protein, SRP19. The secondary structure of the rice SRP RNA was similar to that found in other eukaryotes; however, as in other plant SRP RNAs, a GUUUCA hexamer sequence replaced the highly conserved GNRA-tetranucleotide loop motif at the apex of helix 8. The small domain of the rice SRP RNA was reduced considerably. Structurally, rice SRP19 lacked two small region that can be present in other SRP19 homologues. Conservative structure prediction and site-directed mutagenesis of rice and human SRP19 polypeptides indicated that binding to the SRP RNAs occurred via a loop that is present in the N-domain of both proteins. Rice SRP19 protein was able to form a stable complex with the rice SRP RNA in vitro. Furthermore, heterologous ribonucleoprotein complexes with components of the human SRP were assembled, thus confirming a high degree of structural and functional conservation between plant and mammalian SRP components.

背景与目标： 信号识别颗粒（SRP）控制分泌性蛋白质进入和穿过脂质双层的转运。 SRP样核糖核蛋白复合物存在于所有生物体中，包括植物。我们表征了水稻SRP RNA及其主要RNA结合蛋白SRP19。水稻SRP RNA的二级结构与其他真核生物相似。但是，与其他植物SRP RNA一样，GUUUCA六聚体序列取代了螺旋8顶点的高度保守的GNRA-四核苷酸环基序。水稻SRP RNA的小结构域大大减少了。在结构上，水稻SRP19缺少两个可以在其他SRP19同源物中存在的小区域。水稻和人SRP19多肽的保守结构预测和定点诱变表明与SRP RNA的结合是通过两个蛋白质N结构域中存在的环发生的。水稻SRP19蛋白能够在体外与水稻SRP RNA形成稳定的复合物。此外，组装了具有人类SRP成分的异源核糖核蛋白复合物，从而确认了植物和哺乳动物SRP成分之间的高度结构和功能保守性。

BACKGROUND & AIMS: :CD45 is the most prominent membrane protein on lymphocytes. The function and regulation of this protein tyrosine phosphatase remain largely obscure, mainly because of the lack of a known ligand, and it still remains unknown whether such tyrosine phosphatases are subject to extracellular control at all. We report that an anti-CD45RB antibody (Ab) that prevents rejection and induces tolerance activates CD45RB tyrosine phosphatase enzymatic activity in T lymphocytes, allowing us to directly monitor the effects of increased CD45RB activity on signal transduction. Using both kinase substrate peptide arrays as well as conventional biochemistry, we also provide evidence of the various kinases involved in bringing about the inhibitory effect of this Ab on CD3-induced T-cell receptor signaling. Furthermore, we report that activated CD45RB translocates to lipid rafts and interferes with lipid raft localization and activation state of CD45 substrate Lck. Thus, these findings indeed prove that CD45 is subject to extracellular control and also define a novel mechanism by which receptor tyrosine phosphatases control lymphocyte biology and provide further insight into the intracellular signaling pathways effected by anti-CD45RB monoclonal Ab treatment.

背景与目标： ：CD45是淋巴细胞上最突出的膜蛋白。该蛋白酪氨酸磷酸酶的功能和调节仍然很大程度上不清楚，这主要是由于缺乏已知的配体，并且仍然不清楚这种酪氨酸磷酸酶是否完全受到细胞外控制。我们报告说，一种抗CD45RB抗体（Ab）可以防止排斥并诱导耐受，从而激活T淋巴细胞中的CD45RB酪氨酸磷酸酶的酶促活性，从而使我们能够直接监测信号传导中CD45RB活性增加的影响。使用激酶底物肽阵列以及常规的生物化学，我们还提供了与导致这种Ab对CD3诱导的T细胞受体信号转导的抑制作用有关的各种激酶的证据。此外，我们报告激活的CD45RB易位到脂质筏，并干扰脂质筏的本地化和CD45底物Lck的激活状态。因此，这些发现确实证明了CD45受到细胞外控制，并且还定义了一种新的机制，受体酪氨酸磷酸酶通过该机制控制淋巴细胞生物学，并进一步揭示了抗CD45RB单克隆抗体治疗影响的细胞内信号传导途径。

BACKGROUND & AIMS: BACKGROUND:Pyogenic liver abscesses in liver transplant recipients (PLA-LTR) are a rare disease whose specificities compared with PLA in non-transplanted patients (PLA-C) are unknown. METHODS:A retrospective case-control study was conducted in a French academic hospital from January 1, 2010, to December 31, 2014. RESULTS:Among 176 patients diagnosed with PLA, 14 were LTR; each case was matched with 3 PLA-C controls by date of PLA diagnosis and pathophysiological mechanism of PLA. Median time from liver transplantation to PLA diagnosis was 34.5 months. Among 14 PLA-LTR, 8/14 (57.1%) had bacteremia and 10/14 (71.4%) had positive PLA cultures. Most commonly isolated bacteria were Enterobacteriaceae (9/14; 64.3%), Enterococcus spp. (4/14; 28.6%), and anaerobic bacteria (3/14; 21.4%). Clinical, radiological, and microbiological characteristics did not significantly differ between PLA-LTR and PLA-C but there was a tendency toward more diabetic patients and a less acute presentation. All but one PLA-LTR were associated with ischemic cholangitis, whereas this was a rare cause among PLA-C (13/14 vs 3/42, respectively, P < .001) among patients with PLA-LTR. In contrast, hepatobiliary neoplasia was rare in PLA-LTR but frequent in PLA-C (1/14 vs 24/42, P = .001). No significant difference was found between PLA-LTR and PLA-C in terms of duration of antibiotic therapy (6.5 and 6 weeks, respectively), PLA drainage rates (10/14 and 26/42, respectively), or mortality at 12 months after PLA diagnosis (2/14 and 5/42, respectively). Recurrence rates within the first year were observed in 6/14 patients (42.9%), and retransplantation was needed in 5/14 (35.7%). CONCLUSIONS:Occurrence of PLA in LTR is a severe event leading to high risk of recurrence and retransplantation.

背景与目标： 背景：肝移植受者的化脓性肝脓肿（PLA-LTR）是一种罕见疾病，与非移植患者（PLA-C）相比，PLA的特异性尚不清楚。
方法：回顾性病例对照研究于2010年1月1日至2014年12月31日在法国一家学术医院进行。
结果：在诊断为PLA的176例患者中，有14例为LTR。截至PLA诊断日期和PLA的病理生理机制，每例均与3例PLA-C对照相匹配。从肝移植到PLA诊断的中位时间为34.5个月。在14个PLA-LTR中，有8/14（57.1％）的菌血症和10/14（71.4％）的PLA培养呈阳性。最常见的细菌是肠杆菌科（9/14; 64.3％），肠球菌。 （4/14; 28.6％）和厌氧菌（3/14; 21.4％）。 PLA-LTR和PLA-C之间的临床，放射学和微生物学特征无显着差异，但存在糖尿病患者增多，急性症状减少的趋势。除了一个PLA-LTR以外，所有患者均与缺血性胆管炎有关，而这是PLA-LTR患者中PLA-C罕见的原因（分别为13/14 vs 3/42，P <.001）。相比之下，PLA-LTR中肝胆肿瘤很少见，而PLA-C中则很常见（1/14 vs 24/42，P = .001）。在抗生素治疗的持续时间（分别为6.5和6周），PLA引流率（分别为10/14和26/42）或术后12个月的死亡率方面，PLA-LTR和PLA-C之间没有发现显着差异。 PLA诊断（分别为2/14和5/42）。在第一年内，有6/14例患者（42.9％）出现复发率，而在5/14例中需要再移植（35.7％）。
结论：LTR中PLA的发生是严重事件，导致复发和再移植的高风险。