BACKGROUND & AIMS: BACKGROUND:An impairment of the intestinal barrier function is one of the major characteristics of Crohn's disease (CD). This study aimed to evaluate the impact of autophagy induction by rapamycin on the intestinal epithelial barrier function in CD model mice. METHODS:IL-10 knockout (IL-10 KO) mice were used as the human CD models in this study. All the mice were randomly assigned into four groups, (a) wild-type (WT) group; (b) IL-10 KO group; (c) IL-10 KO + rapamycin group and (d) IL-10 KO + 3-methyladenine (3-MA), containing 6 mice in each group. The disease activity index (DAI), histology, pro-inflammatory cytokines and chemotactic factors in colon tissues, intestinal and colonic permeability, distributions and expressions of tight junction (TJ) proteins, epithelial apoptosis of mice in four groups were evaluated and compared. RESULTS:Autophagy induction by rapamycin treatment ameliorated DAI and histological colitis, decreased pro-inflammatory cytokines (TNF-α, IFN-γ and IL-17) and chemotactic factors (CXCL-1 and CXCL-2), decreased intestinal and colonic permeability, improved the distribution and expression of TJ proteins in IL-10 KO mice. CONCLUSION:Autophagy induction by rapamycin significantly improved intestinal barrier function and protected IL-10 KO mice from the experimental chronic colitis.

背景与目标： 背景：肠道屏障功能的损害是克罗恩病（CD）的主要特征之一。这项研究旨在评估雷帕霉素诱导的自噬对CD模型小鼠肠上皮屏障功能的影响。
方法：以IL-10基因敲除小鼠（IL-10 KO）作为人类CD模型。将所有小鼠随机分为四组，（a）野生型（WT）组；（b）野生型（WT）组。 （b）IL-10 KO组； （c）IL-10 KO雷帕霉素组和（d）IL-10 KO 3-甲基腺嘌呤（3-MA），每组6只小鼠。评估并比较了四组小鼠的疾病活动指数（DAI），组织学，结肠组织中的促炎细胞因子和趋化因子，肠和结肠通透性，紧密连接（TJ）蛋白的分布和表达，小鼠上皮细胞凋亡。
结果：雷帕霉素诱导的自噬改善了DAI和组织性结肠炎，降低了促炎细胞因子（TNF-α，IFN-γ和IL-17）和趋化因子（CXCL-1和CXCL-2），降低了肠道和结肠的通透性，改善了IL-10 KO小鼠中TJ蛋白的分布和表达。
结论：雷帕霉素自噬诱导显着改善肠屏障功能，并保护IL-10 KO小鼠免受实验性慢性结肠炎的侵害。

BACKGROUND & AIMS: :Classically, it has been thought that high-affinity nicotinic receptors-containing beta2 subunits are the most important receptor subtypes for nicotinic involvement in cognitive function and nicotine self-administration, while low affinity alpha7-containing nicotinic receptors have not been thought to be important. In the current study, we found that knockout of either beta2 or alpha7 subunits caused significant deficits in spatial discrimination in mice. The character of the impairment in the two knockouts was different. The beta2 knockout preferentially impaired cognition in males while the alpha7 caused impairment regardless of sex. Both beta2- and alpha7-containing nicotinic receptors also are important for nicotine self-administration, also in different ways. Most animal model studies of nicotine self-administration are relatively short-term whereas the problem of tobacco addiction is considerably longer-term. To better model the impact of nicotinic receptor subtypes on nicotine self-administration over the long-term, we studied the impact of genetic knockout of low affinity alpha7 receptors vs. high-affinity beta2-containing nicotinic receptors. Mice with knockouts of either of these receptors and their wildtype counter parts were given free access to a choice of nicotine-containing and nicotine-free solution in their home cages on a continuous basis over a period of 5 months. During the first few weeks, the beta2-containing nicotinic receptor knockout mice showed a significant decrease in nicotine consumption relative to wildtype mice, whereas the alpha7 knockout mice did not significantly differ from wildtype controls at the beginning of their access to nicotine. Interestingly, in the longer-term after the first few weeks of nicotine access, the beta2 knockout mice returned to wildtype mouse levels of nicotine consumption, whereas the alpha7 knockout mice developed an emergent decrease in nicotine consumption. The alpha7 receptor knockout-induced decrease in nicotine consumption persisted for the 5-month period of the study. Both alpha7- and beta2-containing nicotinic receptors play critical roles in cognitive function and nicotine self-administration. Regarding cognitive function, beta2-containing receptors are important for maintaining normal sex differences in spatial learning and memory, whereas alpha7 receptors are important for cognitive function regardless of sex. Regarding nicotine self-administration high-affinity beta2-containing nicotinic receptors are important for consumption during the initial phase of nicotine access, but it is the alpha7 nicotinic receptors that are important for the longer-term regulation of nicotine consumption.

背景与目标： ：通常，人们一直认为，含有高亲和力烟碱受体的β2亚基是烟碱参与认知功能和尼古丁自我给药的最重要的受体亚型，而低亲和力的含α7烟碱受体尚未被认为是重要的。在当前的研究中，我们发现敲除beta2或alpha7亚基会导致小鼠的空间分辨力明显不足。两种基因敲除的损伤特征是不同的。 beta2基因敲除优先削弱男性的认知能力，而alpha7则不论性别如何均引起损害。含β2和α7的烟碱样受体对于尼古丁的自我给药也很重要，也有不同的用法。尼古丁自我管理的大多数动物模型研究都是相对短期的，而烟草成瘾的问题则是相当长期的。为了更好地模拟烟碱样受体亚型对尼古丁自我给药的长期影响，我们研究了基因敲除低亲和力α7受体与高亲和力的含β2烟碱样受体的影响。敲除这些受体及其野生型对应部分中的任一个的小鼠可在其笼子中连续5个月自由接触选择的含尼古丁和不含尼古丁的溶液。在最初的几周内，相对于野生型小鼠，含β2的烟碱样受体敲除小鼠的尼古丁消耗量显着减少，而α7敲除小鼠在接触尼古丁的初期与野生型对照无显着差异。有趣的是，在进入尼古丁的最初几周后，长期而言，β2敲除小鼠恢复了野生型小鼠的尼古丁消耗水平，而alpha7敲除小鼠出现了尼古丁消耗的突然下降。在研究的5个月中，α7受体基因敲除引起的尼古丁消耗减少一直持续。含α7和β2的烟碱样受体在认知功能和尼古丁自我给药中都起着关键作用。关于认知功能，含β2受体对于维持空间学习和记忆中的正常性别差异很重要，而alpha7受体对于无论性别如何的认知功能都很重要。关于尼古丁的自我给药，含高亲和力的含β2的尼古丁受体对于尼古丁进入初期的消耗很重要，但是α7尼古丁受体对于长期调节尼古丁的消耗很重要。

BACKGROUND & AIMS: :Metallo-β-lactamases (MBL) producing Pseudomonas aeruginosa isolates have been well characterized. Quinolones are commonly used in the treatment of carbapenem-resistant P. aeruginosa infections; however, data about PMQR in this species are scarce. The objective of this study was to report the simultaneous presence of qnrS and blaVIM-11 in P. aeruginosa, and to characterize the qnrS-harboring plasmid. Thirty-eight carbapenem-resistant P. aeruginosa isolates were recovered from a hospital in Buenos Aires during 2012. Screening for MBL was assessed by the double disk synergy test using EDTA and carbapenem discs. Plasmid DNA extraction was performed by a method using phenol-chloroform. PCR followed by sequencing was carried out to determine each MBL and PMQR allele. PCR-BseGI-RFLP was performed to detect aac-(6')-Ib-cr. The gyrA-QRDR was sequenced in those PMQR-harboring isolates. Plasmid incompatibility groups and addiction systems were characterized by PCR. The PMQR-carrying plasmid was sequenced using Illumina technology, annotated using RAST and manually curated. Eleven/38 isolates were VIM producers (blaVIM-2 and blaVIM-11) while 1/38 harbored blaIMP-13. One isolate harbored blaVIM-11 and the PMQR qnrS1; however, both markers were located in different plasmids. The qnrS1-harboring plasmid (pP6qnrS1) was 117945bp in size, presented 154 CDS and corresponded to the IncR group. In addition to qnrS1, it harbored several aminoglycoside resistance markers. Although pP6qnrS1 was non-conjugative, it presented an oriT which made it possible for this plasmid to be transferable. This is the first report on P. aeruginosa carrying both blaVIM-11 and qnrS1, plus the first detection of an IncR plasmid in Argentina.

背景与目标： 产生铜绿假单胞菌的金属β-内酰胺酶（MBL）已被很好地鉴定。喹诺酮类药物通常用于治疗对碳青霉烯耐药的铜绿假单胞菌感染。但是，有关该物种PMQR的数据很少。这项研究的目的是报告铜绿假单胞菌同时存在qnrS和blaVIM-11，并表征携带qnrS的质粒。 2012年期间，从布宜诺斯艾利斯的一家医院中回收了38株对碳青霉烯类耐药的铜绿假单胞菌分离株。通过双盘协同试验，使用EDTA和碳青霉烯圆片对MBL的筛选进行了评估。质粒DNA的提取通过使用苯酚-氯仿的方法进行。进行PCR，然后测序以确定每个MBL和PMQR等位基因。进行PCR-BseGI-RFLP以检测aac-（6'）-Ib-cr。在携带PMQR的分离物中对gyrA-QRDR进行了测序。通过PCR表征质粒不相容性组和成瘾系统。使用Illumina技术对携带PMQR的质粒进行测序，使用RAST进行注释，然后手动进行固化。 11/38个隔离株是VIM生产者（blaVIM-2和blaVIM-11），而1/38则带有blaIMP-13。一个隔离株带有blaVIM-11和PMQR qnrS1；但是，两种标记都位于不同的质粒中。携带qnrS1的质粒（pP6qnrS1）大小为117945bp，呈递154个CDS，与IncR组相对应。除qnrS1外，它还包含一些氨基糖苷抗性标记。尽管pP6qnrS1是非结合性的，但它提供了一个oriT，使得该质粒可以转移。这是关于携带blaVIM-11和qnrS1的铜绿假单胞菌的首次报道，也是阿根廷首次检测到IncR质粒的报道。

BACKGROUND & AIMS: :The fadBA operon in the fatty acid beta-oxidation pathway of P. putida KCTC1639 was blocked to induce a metabolic flux of the intermediates to the biosynthesis of medium chain-length PHA (mcl-PHA). Succinate at 150 mg l(-1) stimulated cell growth and also the biosynthesis of medium chain-length-polyhydroxyalkanoate. pH-stat fed-batch cultivation of the fadA knockout mutant P. putida KCTC1639 was carried out for 60 h, in which mcl-PHA reached 8 g l(-1) with a cell dry weight of 10.3 g l(-1).

背景与目标： ：恶臭假单胞菌KCTC1639的脂肪酸β-氧化途径中的fadBA操纵子被阻断，以诱导中间体的代谢通量，以合成中等链长的PHA（mcl-PHA）。 150 mg l（-1）的琥珀酸酯刺激细胞生长，也刺激中等链长的聚羟基链烷酸酯的生物合成。对fadA敲除突变体恶臭假单胞菌KCTC1639进行pH固定补料培养60 h，其中mcl-PHA达到8 g l（-1），细胞干重为10.3 g l（-1）。

BACKGROUND & AIMS: :Segmental duplication is a major structural variation that occurs in chromosomes. Duplication leads to the production of gene copies with increased numbers of related repeat segments, causing the global genome to be in a state of imbalance. In addition, if the added segment contains a centromeric specific DNA, the duplicated chromosome will have structural multiple centromeres. We identified a segmental duplication containing structurally tricentric regions derived from the short arm of chromosome 11 (11L∙ + 11L∙ + 11S∙11S∙11S∙11S, "∙" represents the centromeric DNA repeat loci), and analyzed its implications for cell division and genome-wide expression. In the variant, only the middle centromere of 11S∙11S∙11S∙11S is functionally active. As a result, the structurally tricentric chromosome was stable in mitosis, because it is actually a functional monocentric chromosome. However, the structurally tricentric chromosome, which usually formed a bivalent, was either arranged on the equatorial plane or was lagging, which affected its separation during meiosis. Furthermore, RNA-seq and RT-qPCR analysis showed that the segmental duplication affected genome-wide expression patterns. 34.60% of genes in repeat region showed positive dosage effect. Thus, the genes on chromosome arm 11S-2 didn't exhibit obviously dosage compensation, as illustrated by no peak around a ratio of 1.00. However, the gene dosage effect will reduce after sexual reproduction of a generation.

背景与目标： ：节段重复是发生在染色体上的主要结构变异。复制导致产生具有相关重复片段数量增加的基因拷贝，从而导致全球基因组处于失衡状态。另外，如果添加的片段包含着丝粒特异性DNA，则复制的染色体将具有多个结构着丝粒。我们鉴定出一个片段重复，该片段包含源自11号染色体短臂的结构性三中心区域（11L∙11L∙11S∙11S∙11S∙11S，“∙”代表着丝粒DNA重复基因座），并分析了其对细胞分裂和基因组的影响范围内的表达式。在变体中，只有11S∙11S∙11S∙11S的中间着丝粒起作用。结果，结构上的三中心染色体在有丝分裂中是稳定的，因为它实际上是功能性的单中心染色体。但是，通常形成二价的结构性三中心染色体要么排列在赤道平面上，要么滞后，影响了减数分裂过程中的分离。此外，RNA-seq和RT-qPCR分析表明，节段重复会影响全基因组表达模式。重复区域中34.60％的基因显示出积极的剂量效应。因此，第11S-2号染色体上的基因没有明显的剂量补偿，如1.00左右的峰没有显示。但是，一代有性繁殖后，基因剂量效应将降低。

BACKGROUND & AIMS: :The authors wish to make a correction to Section 2 [...].

背景与目标： ：作者希望对第2节[...]进行更正。

BACKGROUND & AIMS: :Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain-derived neurotrophic factor (BDNF) levels, but non-specific overexpression of BDNF only partially improves the phenotype of Mecp2-deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho-mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice-even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.

背景与目标： ：X连锁的MECP2基因突变导致Rett综合征（RTT），这是一种严重的神经系统疾病，目前尚无治疗方法。几项研究已将MeCP2功能的丧失与脑源性神经营养因子（BDNF）水平的改变联系起来，但是BDNF的非特异性过表达仅部分改善了Mecp2缺陷型小鼠的表型。我们和其他人以前已经表明，亨廷顿（HTT）支架分子运动复合物，运输包含BDNF的囊泡，并在Mecp2基因敲除的大脑中表达不足。在这里，我们证明通过模仿磷酸酯酶的磷酸化突变或抑制磷酸钙调神经磷酸酶来促进Ser421处的HTT磷酸化，可在皮质口途径中体外恢复内源性BDNF轴突运输，增加纹状体BDNF的可用性和体内突触连接性，并改善表型和Mecp2基因敲除小鼠的存活-即使仅在小鼠已经出现症状后才开始治疗。因此，刺激内源性细胞途径可能是治疗RTT患者的一种有前途的方法。

BACKGROUND & AIMS: :Although the benefits of moderate intake of red wine in decreasing incidence of cardiovascular diseases associated to hypercholesterolemia are well recognized, there are still widespread misconceptions about its effects on the hypercholesterolemia-related cognitive impairments. Herein we investigated the putative benefits of regular red wine consumption on cognitive performance of low-density lipoprotein receptor knockout (LDLr-/-) mice, an animal model of familial hypercholesterolemia, which display cognitive impairments since early ages. The red wine was diluted into the drinking water to a final concentration of 6% ethanol and was available for 60 days for LDLr-/- mice fed a normal or high-cholesterol diet. The results indicated that moderate red wine consumption did not alter locomotor parameters and liver toxicity. Across multiple cognitive tasks evaluating spatial learning/reference memory and recognition/identification memory, hypercholesterolemic mice drinking red wine performed significantly better than water group, regardless of diet. Additionally, immunofluorescence assays indicated a reduction of astrocyte activation and lectin stain in the hippocampus of LDLr-/- mice under consumption of red wine. These findings demonstrate that the moderate consumption of red wine attenuates short- and long-term memory decline associated with hypercholesterolemia in mice and suggest that it could be through a neurovascular action.

背景与目标： ：尽管众所周知，适量摄入红酒可以降低与高胆固醇血症相关的心血管疾病的发生率，但人们仍对其对高胆固醇血症相关认知障碍的影响存在广泛的误解。在这里，我们调查了经常喝红酒对低密度脂蛋白受体敲除（LDLr-/-）小鼠（家族性高胆固醇血症的动物模型，自幼就表现出认知功能障碍）的认知性能的推定益处。将该红酒稀释到饮用水中，使乙醇的最终浓度达到6％，并且对于喂食正常或高胆固醇饮食的LDLr-/-小鼠而言，可使用60天。结果表明，适量的红酒消费不会改变运动参数和肝毒性。在评估空间学习/参考记忆和识别/识别记忆的多个认知任务中，无论饮食如何，喝红酒的高胆固醇血症小鼠的表现均明显优于水组。另外，免疫荧光测定法表明，在喝红酒的情况下，LDLr-/-小鼠海马中的星形胶质细胞活化和凝集素染色减少。这些发现表明，适量饮用红酒可减轻小鼠高胆固醇血症相关的短期和长期记忆衰退，并表明这可能是通过神经血管作用引起的。

BACKGROUND & AIMS: OBJECTIVE:To investigate the functions of Fibroblast Growth Factor Receptor-2 (FGFR2) at different stages of cell differentiation. The engineered murine embryonic stem (ES) cells with conditional knockout of FGFR2 were developed depending on Cre-loxP. METHODS:Cre-loxP system was used in a conditional targeting vector. The competent AM-1 bacteria, which expressed Cre-recombinase, was used to confirm the Cre-mediated deletion of the floxed exons 7 and 8 of FGFR2. The targeting vector was electroporated into the ES cells, and the transfected ES cells were screened with G418 and Ganciclovir. Finally, the ES clones with correct targeting events were identified by Southern Blot and PCR. RESULTS:The targeting vector with conditional knockout of murine FGFR2 was successfully constructed and confirmed by PCR and digestion analysis in bacteria. 86 ES clones were collected by selective culture with G418 and Ganciclovir. Four of the 86 ES clones were found containing the targeting gene sequence in genomic DNA proved by Southern Blot with a 5'-end flank probe. Two of the four ES clones had the correct targeting events that included the insertion of the targeting gene sequence in genomic DNA and were checked by Southern Blot with a 3'-end flanking probe. Finally, the insertion of loxP (loxP3) between exons 8 and 9 in genomic DNA was identified in one of the two ES clones by Southern Blot and PCR. CONCLUSION:FGFR2 conditional knockout depending on Cre-loxP can be successfully used in ES cells.

背景与目标： 目的：探讨成纤维细胞生长因子受体2（FGFR2）在不同分化阶段的功能。根据Cre-loxP，开发了具有条件敲除FGFR2的工程鼠胚胎干（ES）细胞。
方法：将Cre-loxP系统用于条件靶向载体。表达Cre重组酶的感受态AM-1细菌用于确认Cre介导的FGFR2外显子7和8的缺失。将靶向载体电穿孔到ES细胞中，并用G418和更昔洛韦筛选转染的ES细胞。最后，通过Southern印迹和PCR鉴定具有正确靶向事件的ES克隆。
结果：成功构建了有条件敲除鼠FGFR2的靶向载体，并通过PCR和酶切分析鉴定。通过用G418和更昔洛韦选择性培养收集了86个ES克隆。发现86个ES克隆中有四个在基因组DNA中包含靶向基因序列，该DNA由Southern Blot用5'端侧翼探针证实。四个ES克隆中的两个具有正确的靶向事件，包括在基因组DNA中插入了靶向基因序列，并使用3'端侧翼探针通过Southern Blot检测。最后，通过Southern印迹和PCR在两个ES克隆之一中鉴定出loxP（loxP3）在基因组DNA的外显子8和9之间的插入。
结论：依赖于Cre-loxP的FGFR2条件敲除可成功用于ES细胞。

BACKGROUND & AIMS: OBJECTIVE:Orthorexia is a pathological fixation about the consumption of healthy food. The present study aimed to reveal the psychometric properties of the Turkish version of ORTO-15, which was developed to evaluate orthorexia, and to investigate the relationship betweenorthorexia, and eating attitude, obsessive-compulsive symptoms, and some demographic variables. METHOD:The study included 994 participants aged between 19 and 66 years. ORTO-15, the Maudsley Obsessive-Compulsive Inventory, and the Eating Attitude Test-40 were administered to the participants. RESULTS:A 3-factor solution with varimax rotation explained 40.62% of the variance. When 4 items with factor loadings below+/- 0.50 were eliminated from ORTO-15, the Cronbach's alpha coefficient was 0.62. The remaining 11 items were thought to have statistically satisfactory properties for the Turkish version of ORTO and were collectively referred to as ORTO-11. This version was used to investigate the relationship between orthorexia, and eating attitude and obsessive-compulsive symptoms. Pathological eating attitude and obsessive-compulsive symptoms were related to orthorexia. Women exhibited more orthorexic symptoms then men. In the present study high a body mass index was an important variable for orthorexia, but only together with gender (female), pathological eating attitude, and increased obsessive-compulsive symptoms. The results, implications, and limitations of the study are discussed. CONCLUSION:ORTO-11 demonstrated statistically satisfactory properties. Orthorexia was related to pathological eating attitude and obsessive-compulsive symptoms; however, caution should be used when generalizing the reported results.

背景与目标： 目的：骨质疏松症是一种关于食用健康食品的病理学方法。本研究旨在揭示土耳其版ORTO-15的心理测量特性，该版被开发用于评估矫正症，并研究矫正症与进食态度，强迫症和某些人口统计学变量之间的关系。
方法：该研究包括994名年龄在19至66岁之间的参与者。对参与者进行ORTO-15，Maudsley强迫症量表和饮食态度测验40。
结果：3变量解的方差极大值旋转解释了40.62％的方差。当从ORTO-15中删除4个因子负载低于/-0.50的项目时，Cronbach的alpha系数为0.62。其余11项被认为具有土耳其版ORTO的统计上令人满意的性能，被统称为ORTO-11。该版本用于研究骨质疏松症与进食态度和强迫症之间的关系。病理性饮食态度和强迫症与骨质减少有关。女性比男性表现出更多的正畸症状。在本研究中，高体重指数是骨质疏松的重要变量，但仅与性别（女性），病理性饮食态度和强迫症症状增加有关。讨论了研究的结果，意义和局限性。
结论：ORTO-11具有统计学上令人满意的性能。食欲减退与病理性进食态度和强迫症有关。但是，在归纳报告结果时应格外小心。

BACKGROUND & AIMS: :A comparative mapping approach was applied in order to refine the extent and the distribution of conserved segments between human chromosome 11 (HSA11) and cattle chromosomes 15 and 29 (BTA15 and BTA29 respectively). Eight genes from HSA11 were mapped using a bovine-hamster somatic cell hybrid panel and seven represent new assignments. Adding these assignments to those present in human, mouse and cattle databases, a new conserved segment was identified between the telomeric region of HSA11 and BTA29. This brings to seven the number of conserved segments identified between HSA11 and BTA15 and 29, and our study refines their boundaries to the level of the human cytogenetic band.

背景与目标： ：为了比较人类11号染色体（HSA11）与15号和29号牛染色体（分别为BTA15和BTA29）保守区段的范围和分布，采用了比较作图法。使用牛-仓鼠体细胞杂种杂交组对来自HSA11的八个基因进行了定位，其中七个代表了新的任务。将这些分配添加到人，小鼠和牛数据库中的分配中，在HSA11和BTA29的端粒区域之间鉴定了一个新的保守区段。这使HSA11与BTA15和29之间鉴定的保守区段的数目增加到了七个，我们的研究将它们的边界改进到了人类细胞遗传学带的水平。

BACKGROUND & AIMS: :Mammalian sirtuin 6 (SIRT6) is involved in the regulation of many essential processes, especially metabolic homeostasis. SIRT6 knockout mice undergo premature aging and die at age ~4 weeks. Severe glycometabolic disorders have been found in SIRT6 knockout mice, and whether a dietary intervention can rescue SIRT6 knockout mice remains unknown. In our study, we found that at the same calorie intake, a high-fat diet dramatically increased the lifespan of SIRT6 knockout mice to 26 weeks (males) and 37 weeks (females), reversed multi-organ atrophy, and reduced body weight, hypoglycemia, and premature aging. Furthermore, the high-fat diet partially but significantly normalized the global gene expression profile in SIRT6 knockout mice. Regarding the mechanism, excessive glucose uptake and glycolysis induced by the SIRT6 deficiency were attenuated in skeletal muscle through inhibition of insulin and IGF1 signaling by the high-fat diet. Similarly, fatty acids but not ketone bodies inhibited glucose uptake, glycolysis, and senescence in SIRT6 knockout fibroblasts, whereas PI3K inhibition antagonized the effects of a high-fatty-acid medium in vitro. Overall, the high-fat diet dramatically reverses numerous consequences of SIRT6 deficiency through modulation of insulin and IGF1 signaling, providing a new basis for elucidation of SIRT6 and fatty-acid functions and supporting novel therapeutic approaches against metabolic disorders and aging-related diseases.

背景与目标： ：哺乳动物Sirtuin 6（SIRT6）参与许多基本过程的调节，尤其是代谢稳态。 SIRT6基因敲除小鼠会过早衰老，并在〜4周龄时死亡。在SIRT6基因敲除小鼠中发现了严重的糖代谢紊乱，饮食干预能否挽救SIRT6基因敲除小鼠仍是未知的。在我们的研究中，我们发现在摄入相同卡路里的情况下，高脂饮食可将SIRT6基因敲除小鼠的寿命显着延长至26周（雄性）和37周（雌性），逆转多器官萎缩并减轻体重，低血糖和过早衰老。此外，高脂饮食部分但显着地使SIRT6基因敲除小鼠的总体基因表达谱正常化。关于机制，通过高脂饮食抑制胰岛素和IGF1信号传导，减轻了SIRT6缺乏引起的过量葡萄糖摄取和糖酵解。类似地，脂肪酸而不是酮体抑制了SIRT6敲除成纤维细胞中的葡萄糖摄取，糖酵解和衰老，而PI3K的抑制作用则在体外拮抗了高脂肪酸培养基的作用。总体而言，高脂饮食可通过调节胰岛素和IGF1信号传导显着逆转SIRT6缺乏症的许多后果，为阐明SIRT6和脂肪酸功能提供了新的基础，并支持针对代谢性疾病和衰老相关疾病的新型治疗方法。

BACKGROUND & AIMS: :We report a case of familial frontotemporal dementia and parkinsonism characterized by early onset with mental retardation. The patient died at the age of 54; neuronal loss was severe in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus and dentate nucleus. Anti-tau-positive fibrillary changes were observed in neurons and glia in these regions. Although the patient had 2 novel point mutations of the tau gene, P301P (CCG to CCA) and an intron 10+11-splice site (T to C), exon trapping analysis indicated that the latter was pathogenic.

背景与目标： ：我们报告了一例家族性额颞叶痴呆和帕金森氏症，其特征是早发并伴有智力低下。患者死亡，享年54岁。额叶和颞皮质，苍白球，黑质，红色核和齿状核的神经元丧失严重。在这些区域的神经元和神经胶质中观察到抗tau阳性的原纤维变化。尽管该患者有2个tau基因新点突变P301P（CCG至CCA）和一个内含子10 11剪接位点（T至C），但外显子诱捕分析表明后者具有致病性。

BACKGROUND & AIMS: :To search for new biological activities of the chromeno[2,3-b]indoles, the 5-oxa analog of the indolo[2,3-b]quinolines that are known to have a potent antitumor activity, a series of 11-amino derivatives with various substituents at the C-2 position were prepared. The synthesis of the chromeno[2,3-b]indole structure involves the cyclization of 2-phenoxy-3-indolecarboxylates 3, accessible from the indole-3-carboxylate 1 and phenols 2, producing the chromeno[2,3-b]indol-11(6H)-ones 4, which is followed by dehydroxychlorination with phosphorus oxychloride to afford the 11-chlorochromeno[2,3-b]indoles 5. The treatment of 5 with various amines produced the corresponding 11-aminated chromeno[2,3-b]indoles 6, while some of the 11-ω-aminoalkylamino derivatives 6 were transformed into the 11-ω-sulfonylaminoalkylamino derivatives 8. The antiproliferative activity of these 11-aminochromeno[2,3-b]indoles 6 and 8 in vitro were tested using MV4-11 (human leukemia), A549 (lung cancer), HCT116 (colon cancer), and the normal mice fibroblast (BALB/3T3) and their potencies were described.

背景与目标： ：为了寻找新的色素沉着[2,3-b]吲哚的生物活性，吲哚[2,3-b]喹啉的5-氧杂类似物已知具有强大的抗肿瘤活性，一系列的11-制备在C-2位具有各种取代基的氨基衍生物。 chromeno [2,3-b]吲哚结构的合成涉及2-苯氧基-3-吲哚羧酸酯3（可从吲哚-3-羧酸酯1和酚2进入）的环化，从而生成chromeno [2,3-b] indol-11（6H）-ones 4，然后用三氯氧化磷进行脱羟基氯化，得到11-氯铬色[2,3-b]吲哚5。用各种胺处理5产生相应的11-胺化铬色[2] ，3-b]吲哚6，而一些11-ω-氨基烷基氨基吲哚6被转化为11-ω-磺酰基氨基烷基氨基衍生物8。这些11-氨基色酚[2,3-b]吲哚6和8的抗增殖活性在体外使用MV4-11（人类白血病），A549（肺癌），HCT116（结肠癌）和正常小鼠成纤维细胞（BALB / 3T3）进行了测试，并对其效力进行了描述。

BACKGROUND & AIMS: :Mesenchymal stem cells (MSCs) can differentiate into a variety of cell types. MSCs exist in several tissues such as the bone marrow, adipose, muscle, cartilage, and tendon. This differentiation potential makes MSCs candidates for cell-based therapeutic strategies for mesenchymal tissue injuries. MSCs can be prepared from bone marrow (BM-MSCs) and adipose (AD-MSCs); however, these MSCs exhibit senescence-associated growth arrest and display inevitable heterogeneity. We established several AD-MSC cell lines from a p53-knockout (KO) mouse. These cell lines were immortalized, but no cell lines grew anchorage-independently, suggesting that they are not cancerous. They differentiated into adipocytes, osteoblasts, and chondrocytes by treatment with certain stimuli. Moreover, following injection into the tail vein, the cells migrated into the wounded region of the liver and differentiated into hepatocytes. We succeeded in establishing several AD-MSC clonal cell lines that maintain the tissue-specific markers and characteristics of the developmental phase. These clonal cell lines will serve as important tools to study the mechanism of differentiation of MSCs.

背景与目标： 间充质干细胞（MSC）可以分化为多种细胞类型。 MSC存在于多种组织中，例如骨髓，脂肪，肌肉，软骨和肌腱。这种分化潜能使MSCs成为间充质组织损伤基于细胞的治疗策略的候选者。 MSCs可以从骨髓（BM-MSCs）和脂肪（AD-MSCs）制备。然而，这些MSC显示出与衰老相关的生长停滞并显示出不可避免的异质性。我们从p53基因敲除（KO）小鼠建立了几种AD-MSC细胞系。这些细胞系被永生化，但是没有细胞系独立地生长锚定，表明它们没有癌变。通过某些刺激的处理，它们分化为脂肪细胞，成骨细胞和软骨细胞。此外，在注入尾静脉后，细胞迁移到肝脏的受伤区域并分化为肝细胞。我们成功建立了几种维持组织特异性标志物和发育期特征的AD-MSC克隆细胞系。这些克隆细胞系将作为研究MSCs分化机制的重要工具。