BACKGROUND & AIMS: :The cytotoxic alpha-toxin (encoded by hla) of Staphylococcus aureus is regulated by three loci, agr, sarA and sae, in vitro. Here, we assess the regulation of hla in a guinea pig model of device-related infection by quantifying RNAIII (the effector molecule of agr) and hla directly in exudates accumulating in infected devices without subculturing of the bacteria. LightCycler reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify the transcripts. Strains RN6390 and Newman expressed considerably smaller amounts of RNAIII in the guinea pig than during in vitro growth. The residual RNAIII expression decreased during the course of infection and was negatively correlated with bacterial densities. As with RNAIII, the highest hla expression was detected in both strains early in infection. Even in strain Newman, a weak hla producer in vitro, a pronounced expression of hla was observed during infection. Likewise, four S. aureus isolates from cystic fibrosis (CF) patients expressed Q1hla despite an inactive agr during device-related infection as in the CF lung. Mutation of agr and sarA in strain Newman and RN6390 had no consequence for hla expression in vivo. In contrast, the mutation in sae resulted in severe downregulation of hla in vitro as well as in vivo. In conclusion, S. aureus seems to be provided with regulatory circuits different from those characterized in vitro to ensure alpha-toxin synthesis during infections.

背景与目标： 金黄色葡萄球菌的细胞毒性α-毒素（由hla编码）在体外受三个基因座agr，sarA和sae的调节。在这里，我们通过定量RNAIII（agr的效应分子）和直接在被感染设备中积聚的渗出物中的hla来评估设备相关感染的豚鼠模型中hla的调节，而无需对细菌进行传代培养。使用LightCycler逆转录-聚合酶链反应（RT-PCR）定量转录本。与体外生长期间相比，RN6390和Newman菌株在豚鼠中表达的RNAIII量要少得多。 RNAIII的残留表达在感染过程中降低，并且与细菌密度呈负相关。与RNAIII一样，在感染早期，两种菌株均检测到最高的hla表达。即使在体外弱于HLA产生者的纽曼菌株中，在感染过程中也观察到了Hla的明显表达。同样，尽管在设备相关的感染过程中，如在CF肺部感染时agr不活跃，但来自囊性纤维化（CF）患者的4株金黄色葡萄球菌分离物仍表达Q1hla。 Newman和RN6390菌株中agr和sarA的突变对体内hla表达没有影响。相反，sae的突变导致体内外hla严重下调。总之，金黄色葡萄球菌似乎具有不同于体外表征的调节回路，以确保感染期间α-毒素的合成。

BACKGROUND & AIMS: :Currently, sedation in endoscopic procedures is considered a necessary condition and a criterion of quality in digestive endoscopy. The role of SAE in conventional endoscopic procedures is clearly established in clinical guidelines, but this is not so clear in complex endoscopic procedures, such as ERCP. In recent years, numerous studies have been published, with results similar to those noticed in this article, endorsing the safety, efficacy and efficiency of SAE, when performed by properly trained staff.

背景与目标： 目前，内窥镜手术中的镇静被认为是消化内窥镜检查的必要条件和质量标准。 SAE在常规内窥镜手术中的作用已在临床指南中明确确立，但在复杂的内窥镜手术（例如ERCP）中尚不清楚。近年来，已经发表了无数研究，其结果与本文中提到的结果相似，认可了由经过适当培训的人员进行的SAE的安全性，有效性和效率。

BACKGROUND & AIMS: :Our previous studies showed that both Sae and Fur are required for the induction of eap and emp expression in low iron. In this study, we show that expression of sae is also iron-regulated, as sae expression is activated by Fur in low iron. We also demonstrate that both Fur and Sae are required for full induction of the oxidative stress response and expression of non-covalently bound surface proteins in low-iron growth conditions. In addition, Sae is required for the induced expression of the important virulence factors isdA and isdB in low iron. Our studies also indicate that Fur is required for the induced expression of the global regulators Agr and Rot in low iron and a number of extracellular virulence factors such as the haemolysins which are also Sae- and Agr-regulated. Hence, we show that Fur is central to a complex regulatory network that is required for the induced expression of a number of important S. aureus virulence determinants in low iron.

背景与目标： ：我们以前的研究表明，Sae和Fur都需要在低铁条件下诱导eap和emp表达。在这项研究中，我们显示sae的表达也是铁调节的，因为sae的表达被低铁中的Fur激活。我们还证明，在低铁生长条件下，完全诱导氧化应激反应和表达非共价结合的表面蛋白都需要Fur和Sae。另外，在低铁条件下，重要的毒力因子isdA和isdB的诱导表达需要Sae。我们的研究还表明，在低铁和许多细胞外毒力因子（如溶血素（也受Sae和Agr调节））的诱导表达中，Fur是诱导整体调节剂Agr和Rot表达所必需的。因此，我们表明，对于低铁中许多重要的金黄色葡萄球菌毒力决定因子的诱导表达，复杂的调控网络至关重要。

BACKGROUND & AIMS: :We characterized the sae operon, a global regulator for virulence gene expression in Staphylococcus aureus. A Tn917 sae mutant was obtained by screening a Tn917 library of the agr mutant ISP479Mu for clones with altered hemolytic activity. Sequence analysis of the sae operon revealed two additional open reading frames (ORFs) (ORF3 and ORF4) upstream of the two-component regulatory genes saeR and saeS. Four overlapping sae-specific transcripts (T1 to T4) were detected by Northern blot analysis, and the transcriptional initiation points were mapped by primer extension analysis. The T1, T2, and T3 mRNAs are probably terminated at the same stem-loop sequence downstream of saeS. The T1 message (3.1 kb) initiates upstream of ORF4, T2 (2.4 kb) initiates upstream of ORF3, and T3 (2.0 kb) initiates in front of saeR. T4 (0.7 kb) represents a monocistronic mRNA encompassing ORF4 only. sae-specific transcripts were detectable in all of the 40 different clinical S. aureus isolates investigated. Transcript levels were at maximum during the post-exponential growth phase. The sae mutant showed a significantly reduced rate of invasion of human endothelial cells, consistent with diminished transcription and expression of fnbA. The expression of type 5 capsular polysaccharide is activated in the sae mutant of strain Newman, as shown by immunofluorescence and promoter-reporter fusion experiments. In summary, the sae operon constitutes a four-component regulator system which acts on virulence gene expression in S. aureus.

背景与目标： ：我们表征了sae operon，它是金黄色葡萄球菌中毒力基因表达的全球调节物。通过筛选agr突变体ISP479Mu的Tn917文库中具有改变的溶血活性的克隆来获得Tn917 sae突变体。 sae操纵子的序列分析揭示了两个成分的调控基因saeR和saeS上游的两个额外的开放阅读框（ORF）（ORF3和ORF4）。通过Northern印迹分析检测到四个重叠的sae特异性转录物（T1至T4），并且通过引物延伸分析来绘制转录起始点。 T1，T2和T3 mRNA可能在saeS下游的相同茎环序列处终止。 T1消息（3.1 kb）在ORF4的上游启动，T2（2.4 kb）在ORF3的上游启动，而T3（2.0 kb）在saeR前面启动。 T4（0.7 kb）代表仅包含ORF4的单顺反子mRNA。在所研究的40种不同临床金黄色葡萄球菌分离株中，均可检测到sae特异的转录本。在指数后的生长阶段，转录物水平最高。 sae突变体显示出人类内皮细胞的侵袭率显着降低，这与fnbA转录和表达的减少相一致。如免疫荧光和启动子-报告子融合实验所示，在纽曼菌株的sae突变体中激活了5型荚膜多糖的表达。总之，sae操纵子构成了一个四组分调节系统，该系统作用于金黄色葡萄球菌中的毒力基因表达。

BACKGROUND & AIMS: :Agr and sar are known regulatory loci of Staphylococcus aureus that control the production of several extracellular and cell-wall-associated proteins. A pleiotropic insertional mutation in S. aureus, designated sae, that leads to the production of drastically diminished levels of alpha- and beta-hemolysins and coagulase and slightly reduced levels of protein A has been described. The study of the expression of the genes coding for these exoproteins in the sae::Tn551 mutant (carried out in this work by Northern blot analyses) revealed that the genes for alpha- and beta-hemolysins (hla and hlb) and coagulase (coa) are not transcribed and that the gene for protein A (spa) is transcribed at a somewhat reduced level. These results indicate that the sae locus regulates these exoprotein genes at the transcriptional level. Northern blot analyses also show that the sae mutation does not affect the expression of agr or sar regulatory loci. An sae::Tn551 agr::tetM double mutant has been phenotypically characterized as producing reduced or null levels of alpha-, beta-, and delta-hemolysins, coagulase, and high levels of protein A. Northern blot analyses carried out in this work with the double mutant revealed that hla, hlb, hld, and coa genes are not transcribed, while spa is transcribed at high levels. The fact that coa is not expressed in the sae agr mutant, as in the sae parental strain, while spa is expressed at the high levels characteristic of the agr parental strain, suggests that sae and agr interact in a complex way in the control of the expression of the genes of several exoproteins.

背景与目标： ：Agr和sar是金黄色葡萄球菌的已知调节基因座，它控制几种细胞外和细胞壁相关蛋白的产生。已经描述了在金黄色葡萄球菌中的多效性插入突变，命名为sae，其导致α-和β-溶血素和凝固酶的水平急剧降低的产生以及蛋白A的水平略有降低。对sae :: Tn551突变体中编码这些外蛋白的基因表达的研究（通过Northern blot分析在这项工作中进行）显示，α-和β-溶血素（hla和hlb）和凝固酶（coa）的基因）不会被转录，并且蛋白A（spa）的基因会以某种程度的降低的水平被转录。这些结果表明，sae基因座在转录水平上调节这些外蛋白基因。 Northern印迹分析还显示，sae突变不影响agr或​​sar调控基因座的表达。一个sae :: Tn551 agr :: tetM双突变体在表型上被表征为产生降低的或无效的α-，β-和δ-溶血素，凝固酶和高水平的蛋白A。在这项工作中进行了Northern印迹分析带有双突变体的基因表明，hla，hlb，hld和coa基因不会被转录，而spa会被高水平转录。 coa在sae agr突变体中不表达，如在sae亲本菌株中表达，而spa在agr亲本菌株的高水平特征中表达，这一事实表明sae和agr在复杂的控制中相互作用。几种外蛋白基因的表达

BACKGROUND & AIMS: :In the case of an unexpected high frequency of serious adverse events (SAE), statistical methods are needed to help in the decision making process as to continuation of accrual to the trial. This paper describes an R package, named SAE that implements a method recently developed by defining stopping rules after each observed SAE. The package function control for excessive toxicity either during the trial at the observation of each SAE (function SAE) or during the planning phase of a clinical trial (function DESIGN). This description and the package documentation are complementary to help the users to apply the method. The main difficulty in the implementation of the method is the choice of a priori parameters. Data from an ongoing clinical trial are presented as an example to improve the understanding and the use of the package.

背景与目标： ：如果发生严重不良事件（SAE）的频率异常高，则需要统计方法来帮助决策过程，以继续进行试验。本文介绍了一个名为SAE的R包，该R包实现了一种新近开发的方法，该方法通过在每个观察到的SAE之后定义停止规则来实现。包装功能控制在观察每个SAE的试验期间（功能SAE）或在临床试验的规划阶段（功能设计）的过度毒性。此描述和软件包文档是互补的，以帮助用户应用该方法。该方法实施的主要困难是先验参数的选择。以正在进行的临床试验中的数据为例，以提高对包装的理解和使用。

BACKGROUND & AIMS: :Sepsis associated encephalopathy (SAE) is a poorly understood condition that is associated with severe sepsis and appears to have a negative influence on survival. The incidence of encephalopathy secondary to sepsis is unknown. Amino acid derangements, blood-brain barrier disruption, abnormal neurotransmitters, and direct CNS effect are possible causes of septic encephalopathy. Research has not defined the pathogenesis of SAE.

背景与目标： 败血症相关性脑病（SAE）是一种鲜为人知的疾病，与严重的败血症有关，并且似乎对生存产生负面影响。败血症继发性脑病的发病率未知。氨基酸紊乱，血脑屏障破坏，异常神经递质和直接的中枢神经系统作用可能是败血性脑病的原因。研究尚未定义SAE的发病机理。

BACKGROUND & AIMS: :The two-component system SaeRS of Staphylococcus aureus is closely involved in the regulation of major virulence factors. However, little is known about the signals leading to saeRS activation. A total of four overlapping transcripts (T1 to T4) from three different transcription starting points are expressed in the sae operon. We used a beta-galactosidase reporter assay to characterize the putative promoter regions within the saeRS upstream region. The main transcript T2 is probably generated by endoribonucleolytic processing of the T1 transcript. Only two distinct promoter elements (P1 and P3) could be detected within the saeRS upstream region. The P3 promoter, upstream of saeRS, generates the T3 transcript, includes a cis-acting enhancer element and is repressed by saeRS. The most distal P1 promoter is strongly autoregulated, activated by agr, and repressed by sigma factor B. In strain Newman a mutation within the histidine kinase SaeS leads to a constitutively activated sae system. Evaluation of different external signals revealed that the P1 promoter in strain ISP479R and strain UAMS-1 is inhibited by low pH and high NaCl concentrations but activated by hydrogen peroxide. The most prominent induction of P1 was observed at subinhibitory concentrations of alpha-defensins in various S. aureus strains, with the exception of strain ISP479R and strain COL. P1 was not activated by the antimicrobial peptides LL37 and daptomycin. In summary, the results indicate that the sensor molecule SaeS is activated by alteration within the membrane allowing the pathogen to react to phagocytosis related effector molecules.

背景与目标： 金黄色葡萄球菌的两组分系统SaeRS与主要毒力因子的调节密切相关。但是，对于导致saeRS激活的信号知之甚少。来自三个不同转录起点的总共四个重叠转录物（T1至T4）在sae操纵子中表达。我们使用了β-半乳糖苷酶报告基因分析来表征saeRS上游区域内推定的启动子区域。主要成绩单T2可能是由T1成绩单的核糖核酸内切加工产生的。在saeRS上游区域内只能检测到两个不同的启动子元件（P1和P3）。在saeRS上游的P3启动子产生T3转录本，包括一个顺式作用增强子元件，并被saeRS抑制。最远端的P1启动子被强烈自动调节，被agr激活，并被sigma因子B抑制。在纽曼菌株中，组氨酸激酶SaeS内的突变导致组成性激活的sae系统。对不同外部信号的评估表明，菌株ISP479R和UAMS-1中的P1启动子受到低pH和高NaCl浓度的抑制，但被过氧化氢激活。在除金黄色葡萄球菌菌株中亚抑菌素浓度亚抑制浓度下观察到最明显的P1诱导，除了菌株ISP479R和菌株COL。 P1没有被抗菌肽LL37和达托霉素激活。总而言之，结果表明传感器分子SaeS通过膜内的改变被激活，从而使病原体对吞噬作用相关的效应子分子起反应。

BACKGROUND & AIMS: :Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology.

背景与目标： ：小泛素样修饰子（SUMO）家族蛋白通过翻译后修饰来调节靶蛋白的功能。然而，一直缺乏靶向SUMO途径的有效和选择性抑制剂。在这里，我们描述ML-792，这是一种基于机制的SUMO活化酶（SAE）抑制剂，在细胞测定中具有纳摩尔浓度。 ML-792有选择地阻断SAE酶的活性和总SUMOylation，从而减少癌细胞的增殖。此外，我们发现MYC癌基因的诱导增加了癌细胞中ML-792介导的生存能力，从而表明SAE抑制剂在治疗MYC扩增的肿瘤中的潜在应用。使用ML-792，我们进一步探索了SUMOylation在有丝分裂进程和染色体分离中的关键作用。此外，SAE催化亚基（UBA2）S95N M97T突变体的表达挽救了SUMOylation损失和ML-792诱导的有丝分裂缺陷，从而证实了ML-792的选择性。作为一种有效且选择性的SAE抑制剂，ML-792可快速损失内源性SUMO酰化的蛋白质，从而促进对SUMO生物学的新见解。

BACKGROUND & AIMS: BACKGROUND:Protein remote homology detection and fold recognition are central problems in computational biology. Supervised learning algorithms based on support vector machines are currently one of the most effective methods for solving these problems. These methods are primarily used to solve binary classification problems and they have not been extensively used to solve the more general multiclass remote homology prediction and fold recognition problems. RESULTS:We present a comprehensive evaluation of a number of methods for building SVM-based multiclass classification schemes in the context of the SCOP protein classification. These methods include schemes that directly build an SVM-based multiclass model, schemes that employ a second-level learning approach to combine the predictions generated by a set of binary SVM-based classifiers, and schemes that build and combine binary classifiers for various levels of the SCOP hierarchy beyond those defining the target classes. CONCLUSION:Analyzing the performance achieved by the different approaches on four different datasets we show that most of the proposed multiclass SVM-based classification approaches are quite effective in solving the remote homology prediction and fold recognition problems and that the schemes that use predictions from binary models constructed for ancestral categories within the SCOP hierarchy tend to not only lead to lower error rates but also reduce the number of errors in which a superfamily is assigned to an entirely different fold and a fold is predicted as being from a different SCOP class. Our results also show that the limited size of the training data makes it hard to learn complex second-level models, and that models of moderate complexity lead to consistently better results.

背景与目标： 背景：蛋白质远程同源性检测和折叠识别是计算生物学中的核心问题。目前，基于支持向量机的监督学习算法是解决这些问题的最有效方法之一。这些方法主要用于解决二进制分类问题，尚未广泛用于解决更一般的多类远程同源性预测和折叠识别问题。
结果：我们目前对在SCOP蛋白质分类的背景下建立基于SVM的多类别分类方案的许多方法进行了全面评估。这些方法包括直接构建基于SVM的多类模型的方案，采用第二级学习方法来组合由一组基于二进制SVM的分类器生成的预测的方案以及为各个级别的SVM构建和组合二进制分类器的方案。 SCOP层次结构超出了定义目标类的层次结构。
结论：分析不同方法在四个不同数据集上获得的性能，我们发现大多数提议的基于多类SVM的分类方法在解决远程同源性预测和折叠识别问题方面非常有效，并且使用来自二进制模型的预测的方案为SCOP层次结构内的祖先类别构建的结构不仅会导致较低的错误率，而且还会减少将超家族分配给完全不同的折叠并预测来自不同SCOP类的折叠的错误数量。我们的结果还表明，训练数据的数量有限，很难学习复杂的第二级模型，而中等复杂性的模型则可以始终如一地获得更好的结果。

BACKGROUND & AIMS: AIMS AND OBJECTIVES:To explore suicide predictors in rural outpatients with schizophrenia. Background.  Suicide is a major cause of mortality in patients with schizophrenia. Evidence indicates that patients in rural areas are at high risk for inadequate health care services. However, information is limited on suicide risk in outpatients with schizophrenia in rural areas. DESIGN:Cross-sectional survey. METHODS:Data were collected on individuals enrolled in the 2007 Taiwan National Health Insurance program as diagnosed with schizophrenia, ≥ 18 years, and living in a rural county. Eligible individuals (n=1655) were assessed by 12 community-based nurses at 12 public health centres. Participants' personal information was retrieved from National Health Insurance records using a personal data sheet, and treatment experiences were obtained by interviewing patients with a 10-item risk-assessment inventory. Data were collected over 18 months (2007-2008) and analysed by descriptive statistics and regression analyses. RESULTS:Risk of suicide attempt in the previous year had four significant predictors: number of self-harm incidents during the previous year, violent incidents towards others during the previous year, number of follow-ups by mental health clinics and number of involuntary hospitalisations during the previous year (R(2) = 0.337, adjusted R(2) = 0.334, F=133.19, p=0.000). CONCLUSION:Health care providers should assess rural outpatients with schizophrenia for suicidal thoughts by asking simple questions to evaluate for a history of self-harm and violence and by comparing this information with health system data on follow-ups by mental health clinics and involuntary hospitalisations. RELEVANCE TO CLINICAL PRACTICE:Community-based health providers may use these results to prioritise assessments when they have a high case load of patients with schizophrenia. Community-based nurses need to be trained to recognise these four predictors to increase their sensitivity to suicidality among patients with schizophrenia.

背景与目标： 目的和目的：探讨农村精神分裂症门诊患者自杀的预测因素。背景。自杀是精神分裂症患者死亡的主要原因。有证据表明，农村地区的患者面临医疗保健服务不足的高风险。但是，有关农村地区精神分裂症门诊患者自杀风险的信息有限。
设计：横断面调查。
方法：收集2007年台湾国民健康保险计划中被诊断患有精神分裂症，≥18岁并居住在农村县的个人的数据。由12个公共卫生中心的12位社区护士对合格的个体（n = 1655）进行了评估。使用个人数据表从国民健康保险记录中检索参与者的个人信息，并通过与10个项目的风险评估清单进行访谈来获得治疗经验。收集了18个月（2007-2008年）的数据，并通过描述性统计和回归分析进行了分析。
结果：上一年自杀未遂的风险有四个重要的预测因素：上一年自我伤害事件的数量，上一年他人暴力事件的数量，精神卫生诊所的跟进次数以及2005年期间非自愿住院的次数前一年（R（2）= 0.337，调整后的R（2）= 0.334，F = 133.19，p = 0.000）。
结论：医疗保健提供者应通过询问简单问题以评估自我伤害和暴力的历史，并将此信息与精神卫生诊所和非自愿住院随访的卫生系统数据进行比较，以评估农村精神分裂症患者的自杀意念。
与临床实践的相关性：当社区中的精神分裂症患者的工作量很高时，基于社区的医疗服务提供者可以使用这些结果来确定评估的优先级。需要对社区护士进行培训，以识别这四个预测因素，以提高他们对精神分裂症患者自杀倾向的敏感性。

BACKGROUND & AIMS: :This research was initiated to assess the turnover rates (TORs) of dopamine (DA), norepinephrine (NA), serotonin (5-HT), aspartate, glutamate, and GABA in brain regions during rodent ethanol/sucrose (EtOH) and sucrose (SUC) drinking and in animals with a history of EtOH or SUC drinking to further characterize the neuronal systems that underlie compulsive consumption. Groups of five male rats were used, with two trained to drink EtOH solutions, two to drink SUC and one to serve as a non-drinking control. When stable drinking patterns were obtained, rats were pulse labeled intravenously and killed 60 or 90 min later and the TORs of DA, norepinephrine, 5-HT, aspartate, glutamate, and GABA determined in brain regions. Changes in the TOR of 5-HT, DA, and NA were detected specific to EtOH drinking, SUC drinking or a history of EtOH or SUC drinking. An acute EtOH deprivation effect was detected that was mostly reversed with EtOH drinking. These results suggest that binge-like drinking of moderate amounts of EtOH produces a deficit in neuronal function that could set the stage for the alleviation of anhedonic stimuli with further EtOH intake that strengthen EtOH seeking behaviors which may contribute to increased EtOH use in at risk individuals.

背景与目标： ：本研究旨在评估啮齿动物乙醇/蔗糖（EtOH）和蔗糖在大脑区域中多巴胺（DA），去甲肾上腺素（NA），5-羟色胺（5-HT），天冬氨酸，谷氨酸和GABA的转化率（TORs） （SUC）饮酒和具有EtOH或SUC饮酒史的动物，以进一步表征强迫性饮酒的神经系统。使用五只雄性大鼠的组，其中两只受过训练可以喝EtOH溶液，两只可以喝SUC，另一只可以作为非饮酒对照。当获得稳定的饮酒方式时，对大鼠进行静脉脉冲标记并在60或90分钟后处死，并在大脑区域确定DA，去甲肾上腺素，5-HT，天冬氨酸，谷氨酸和GABA的TOR。检测到5-HT，DA和NA的TOR的变化特定于EtOH饮用，SUC饮用或EtOH或SUC饮用的历史。检测到急性的EtOH剥夺作用，多数情况下通过饮用EtOH可以逆转。这些结果表明，像暴饮般饮适量的EtOH会导致神经元功能的缺陷，这可能为进一步减少EtOH摄入而减轻麻痹性刺激提供了条件，从而加强了EtOH的寻求行为，这可能会增加高危人群中EtOH的使用。

BACKGROUND & AIMS: :Antibiotic resistance is a growing problem worldwide. Of particular importance is the resistance of Mycobacterium tuberculosis (Mtb) to currently available antibiotics used in the treatment of infected patients. Up-regulation of an aminoglycoside (AG) acetyltransferase, the enhanced intracellular survival (Eis) protein of Mtb (Eis_Mtb), is responsible for resistance to the second-line injectable drug kanamycin A in a number of Mtb clinical isolates. This acetyltransferase is known to modify AGs, not at a single position, as usual for this type of enzyme, but at multiple amine sites. We identified, using in silico techniques, 22 homologues from a wide variety of bacteria, that we then cloned, purified, and biochemically studied. From the selected Eis homologues, 7 showed the ability to modify AGs to various degrees and displayed both similarities and differences when compared to Eis_Mtb. In addition, an inhibitor proved to be active against all homologues tested. Our findings show that this family of acetyltransferase enzymes exists in both mycobacteria and non-mycobacteria and in both pathogenic and nonpathogenic species. The bacterial strains described herein should be monitored for rising resistance rates to AGs.

背景与目标： ：抗生素耐药性在世界范围内正在成为一个日益严重的问题。特别重要的是结核分枝杆菌（Mtb）对目前可用于治疗感染患者的抗生素的耐药性。氨基糖苷（AG）乙酰转移酶（Mtb的增强的细胞内存活（Eis）蛋白（Eis_Mtb）的上调）对许多Mtb临床分离株中的二线可注射药物卡那霉素A产生抗性。已知这种乙酰基转移酶修饰AGs，而不是像这种酶通常那样在单个位置修饰AGs，而是在多个胺位点修饰AGs。我们使用计算机技术鉴定了来自多种细菌的22个同源物，然后对其进行了克隆，纯化和生物化学研究。从选定的Eis同源物中，与Eis_Mtb相比，有7种显示了对AG进行不同程度修饰的能力，并且显示了相似性和差异性。此外，一种抑制剂被证明对所有测试的同系物均具有活性。我们的发现表明，这种乙酰基转移酶家族存在于分枝杆菌和非分枝杆菌以及致病性和非致病性物种中。应该监测本文所述的细菌菌株对AG的抵抗率的上升。

BACKGROUND & AIMS: :Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits.

背景与目标： ：海马神经干/祖细胞（NSC）在整个成年生活中都会产生新的神经元。 NSC维持在可逆的静止状态，不能维持静止状态可能导致干细胞池过早耗尽。尚未确定维持这种静止状态的表观遗传机制。使用诱导型基因敲除小鼠模型，我们表明染色质重塑因子染色体结构域-解旋酶-DNA结合蛋白7（CHD7）对于维持NSC静止至关重要。成年NSC中的CHD7失活导致海马干细胞静止性丧失，细胞分裂短暂增加，随后神经发生显着下降。 NSC静止性的这种丧失与中年小鼠中NSC的过早丧失有关。我们发现，CHD7抑制细胞周期进程的几个积极监管机构的转录，是在静止的NSC中完全诱导Notch目标基因Hes5所必需的。这些发现直接将CHD7与NSC静止所涉及的途径联系起来，并确定了第一个染色质重塑因子与NSC静止和维持有关。由于CHD7单倍功能不全与CHARGE综合征中的一系列认知障碍有关，因此我们的观察结果可能对理解这些缺陷的基础有影响。

BACKGROUND & AIMS:

背景与目标：