BACKGROUND & AIMS: :The sensorimotor cortical system undergoes structural and functional changes across its lifespan. Some of these changes are physiological and parallel the normal aging process, while others might represent pathophysiological mechanisms underlying neurodegenerative disorders. In the last years, the study of possible age-related modifications in brain sensorimotor functional characteristics has been the focus of several research projects. Here we have used the transcranial magnetic stimulation (TMS)-electroencephalography (EEG) navigated co-registration to investigate the influence of physiological aging on the excitability and connectivity of the human sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected after stimulating the dominant primary motor cortex (M1) in healthy young subjects (mean age 24.5years) with those collected in healthy older adults (mean age 67.6years). We have shown that, after stimulation of the left motor cortex, TEPs are significantly affected by physiological aging. This phenomenon has a clear spatio-temporal specificity and we speculate that normal aging per se leads to some changes in the excitability of specific cortical neural assemblies whereas other alterations could reflect compensatory mechanisms to such changes.

背景与目标： ：感觉运动皮质系统在其整个生命周期中都会发生结构和功能的变化。这些变化中的一些是生理上的并且与正常衰老过程平行，而其他一些则可能代表了神经退行性疾病的病理生理机制。近年来，对大脑感觉运动功能特征可能与年龄有关的修饰的研究一直是数个研究项目的重点。在这里，我们已使用经颅磁刺激（TMS）-脑电图（EEG）导航的共同注册，以研究生理老化对人类感觉运动皮层系统的兴奋性和连通性的影响。为此，我们比较了健康年轻受试者（平均年龄24.5岁）和健康老年人（平均年龄67.6岁）在刺激主要运动皮层（M1）后所采集的TMS诱发的脑电势（TEP）。我们已经表明，刺激左运动皮层后，TEP受生理老化的影响很大。这种现象具有明显的时空特异性，我们推测正常衰老本身会导致特定皮层神经组件兴奋性发生某些变化，而其他变化可能反映出这种变化的补偿机制。

BACKGROUND & AIMS: :This laboratory has previously demonstrated that shortening of the cell body of a heterotrich ciliate, Blepharisma japonicum, could be induced as a step-down photophobic response. Here, we examined the structure and contractility of the myonemes in detergent-extracted cell models and in isolated cortical fragments. Ultrastructural observation showed that the myoneme was connected to the basal ends of the posterior kinetosomes and constructed a systematic network as a whole. Shortening of the cell model was induced by > 10(-4) M Ca(2+), while the rounded cell model did not re-elongate even when it was washed in a calcium-free solution either with or without addition of ATP. Fluffy fibrils, which were tentatively identified as aggregated bundles of the myonemes, were isolated with the kinetosomal complex and showed calcium-dependent and ATP-independent contraction. The minimum concentration of Ca(2+) required for inducing contraction was at the level of 10(-6) M. These results suggest that the cell body shortening in Blepharisma is caused by the Ca(2+)-dependent contraction of the myonemal network.

背景与目标： ：该实验室先前已证明杂多纤毛纤毛虫（Blepharisma japonicum）的细胞体缩短可以作为逐步降低的憎光反应而被诱导。在这里，我们检查了去污剂提取的细胞模型和分离的皮层碎片中的模因的结构和收缩性。超微结构观察表明，肌球蛋白与后运动体的基端相连，并构成了一个整体的系统网络。细胞模型的缩短是由> 10（-4）M Ca（2）引起的，而圆形细胞模型即使在无钙溶液中添加或不添加ATP洗涤也不会重新伸长。蓬松的原纤维被初步确定为肌源蛋白的聚集束，与运动体复合物分离并显示出钙依赖性和ATP依赖性收缩。诱导收缩所需的Ca（2）的最低浓度为10（-6）M。这些结果表明，在血吸虫病中细胞体的缩短是由肌层网络的Ca（2）依赖性收缩引起的。

BACKGROUND & AIMS: OBJECTIVE:The study sought to quantify coordination of epilepsy care, over time, between neurologists and other health care providers using social network analysis (SNA). METHODS:The Veterans Health Administration (VA) instituted an Epilepsy Center of Excellence (ECOE) model in 2008 to enhance care coordination between neurologists and other health care providers. Provider networks in the 16 VA ECOE facilities (hub sites) were compared to a subset of 33 VA facilities formally affiliated (consortium sites) and 14 unaffiliated VA facilities. The number of connections between neurologists and each provider (node degree) was measured by shared epilepsy patients and tallied to generate estimates at the facility level separately within and across facilities. Mixed models were used to compare change of facility-level node degree over time across the three facility types, adjusted for number of providers per facility. RESULTS:Over the time period 2000-2013, epilepsy care coordination both within and across facilities significantly increased. These increases were seen in all three types of facilities namely hub, consortium, and unaffiliated site, relatively equally. The increase in connectivity was more dramatic with providers across facilities compared to providers within the same facilities. CONCLUSION:Establishment of the ECOE hub and spoke model contributed to an increase in epilepsy care coordination both within and across facilities from 2000 to 2013, but there was substantial variation across different facilities. SNA is a tool that may help measure coordination of specialty care.

背景与目标： 目的：本研究试图通过社交网络分析（SNA）量化神经科医师与其他医疗保健提供者之间随着时间的推移癫痫治疗的协调性。
方法：退伍军人卫生管理局（VA）在2008年建立了癫痫病卓越中心（ECOE）模型，以加强神经科医生与其他卫生保健提供者之间的护理协调。将16个VA ECOE设施（集线器站点）中的提供商网络与33个正式关联的VA设施（财团站点）和14个未关联的VA设施的子集进行了比较。由共享的癫痫患者测量神经科医师与每个提供者之间的联系数（节点度），并计算以在设施级别内部和设施之间分别在设施级别生成估计值。混合模型用于比较三种设施类型上设施级别节点度随时间的变化，并针对每个设施的提供者数量进行了调整。
结果：在2000年至2013年期间，设施内和设施间的癫痫护理协调性显着提高。这些增加在三种类型的设施中都可以看到，即枢纽，财团和非附属场所，相对均等。与同一设施内的提供商相比，跨设施的提供商的连接性增长更为显着。
结论：从2000年到2013年，建立ECOE枢纽和轮辐模型有助于增加设施内和设施之间的癫痫护理协调，但不同设施之间存在很大差异。 SNA是一种工具，可以帮助评估专科护理的协调性。

BACKGROUND & AIMS: BACKGROUND:Many brain areas participate to supraspinal control of nociception. In these regions, few studies have investigated the role of glial cells in supraspinal plasticity and the effect of 7-day intrathecal nerve growth factor-like (BB14®, Blueprint Biotech, Milano, Italy) treatment. METHODS:In male Sprague-Dawley rats, we evaluated by immunohistochemistry the morphological and molecular rearrangement of neuroglial network occurring in several supraspinal brain regions involved in pain processing following spared nerve injury (SNI) of the sciatic nerve. In particular, the medial prefrontal cortex, the amygdala (Amy), the nucleus accumbens (Acb), the thalamus and the periaqueductal gray were analysed. RESULTS:Despite the modifications occurring in the dorsal horn of spinal cord following SNI, no significant changes in the Iba1 and glial fibrillary acidic protein (GFAP) expression were detected in all the analysed supraspinal regions, except for the Amy, showing a remarkable GFAP increase. Interestingly, neuropathic rats also displayed a significant increase of glial transporters (GTs) in all the supraspinal regions. Finally, the analysis of vesicular glutamate transporter 1 (vGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (vGAT) expression revealed a significant enhancement of glutamatergic/GABAergic ratio in all selected brain regions of SNI animals, except for Acb. Both glial activation in the Amy and alteration of GTs and vGLUT/vGAT levels observed in neuropathic animals were largely reversed by BB14® treatment. CONCLUSIONS:All together, these data strengthen the role of supraspinal neuroglial network plasticity in the establishment of neuropathic pain syndrome. The hallmark is represented by the divergence between glial reaction confined to Amy and the widespread changes in the GT distribution and glutamate/GABA ratio detected in the other supraspinal region.

背景与目标： 背景：许多大脑区域参与了脊髓上的伤害感受控制。在这些地区，很少有研究调查神经胶质细胞在棘上棘可塑性中的作用以及7天鞘内神经生长因子样治疗的作用（BB14®，Blueprint Biotech，米兰，意大利）。
方法：在雄性Sprague-Dawley大鼠中，我们通过免疫组织化学方法评估了坐骨神经备用神经损伤（SNI）后参与疼痛处理的多个棘上大脑区域中神经胶质网络的形态和分子重排。特别地，分析了内侧前额叶皮层，杏仁核（Amy），伏隔核（Acb），丘脑和导水管周围的灰色。
结果：尽管SNI后脊髓背角发生了改变，但除Amy外，在所有分析的脊髓上上区均未检测到Iba1和神经胶质纤维酸性蛋白（GFAP）表达的显着变化，显示GFAP显着增加。有趣的是，神经病变大鼠在所有棘上神经区也显示出神经胶质转运蛋白（GTs）的显着增加。最后，对囊泡谷氨酸转运蛋白1（vGLUT1）和囊泡γ-氨基丁酸（GABA）转运蛋白（vGAT）表达的分析显示，除Acb外，SNI动物所有选定大脑区域的谷氨酸能/ GABA能比均显着提高。在神经病动物中观察到的Amy中的神经胶质激活以及GTs和vGLUT / vGAT水平的改变都可以通过BB14®治疗大幅度逆转。
结论：这些数据加在一起增强了脊髓上神经胶质网络可塑性在建立神经性疼痛综合征中的作用。具有标志性的特征是仅限于Amy的神经胶质反应与在其他上棘突区域中检测到的GT分布和谷氨酸/ GABA比的广泛变化之间存在差异。

BACKGROUND & AIMS: This paper reports on the application of an artificial neural network to the clinical analysis of ophthalmological data. In particular a 2-dimensional Kohonen self-organising feature map (SOM) is used to analyse visual field data from glaucoma patients. Importantly, the paper addresses the problem of how the SOM can be utilised to accommodate the noise within the data. This is a particularly important problem within longitudinal assessment, where detecting significant change is the crux of the problem in clinical diagnosis. Data from 737 glaucomatous visual field records (Humphrey Visual Field Analyzer, program 24-2) are used to train a SOM with 25 nodes organised on a square grid. The SOM clusters the data organising the output map such that fields with early and advanced loss are at extreme positions, with a continuum of change in place and extent of loss represented by the intervening nodes. For each SOM node 100 variants, generated by a computer simulation modelling the variability that might be expected in a glaucomatous eye, are also classified by the network to establish the extent of noise upon classification. Field change is then measured with respect to classification of a subsequent field, outside the area defined by the original field and its variants. The significant contribution of this paper is that the spatial analysis of the field data, which is provided by the SOM, has been augmented with noise analysis enhancing the visual representation of longitudinal data and enabling quantification of significant class change.

背景与目标： 本文报道了人工神经网络在眼科数据临床分析中的应用。特别是，二维Kohonen自组织特征图（SOM）用于分析来自青光眼患者的视野数据。重要的是，本文解决了如何利用SOM来容纳数据中的噪声的问题。这在纵向评估中是一个特别重要的问题，在纵向评估中，检测到重大变化是临床诊断中问题的症结所在。来自737青光眼视野记录（汉弗莱视野分析仪，程序24-2）的数据用于训练SOM，并在一个正方形网格上组织25个节点。 SOM对组织输出图的数据进行聚类，以使具有早期和晚期损失的字段处于极端位置，并且中间节点代表的损失位置和程度的连续变化。对于每个SOM节点100，通过计算机模拟生成的变量也可以通过网络进行分类，以建立分类后的噪声范围，这些变量是在青光眼中可能预期的可变性建模而成的。然后根据原始字段及其变体定义的区域之外的后续字段的分类，测量字段变化。本文的重要贡献在于，由SOM提供的现场数据的空间分析已通过噪声分析得到了增强，从而增强了纵向数据的可视化表示并能够量化重大的类别变化。

BACKGROUND & AIMS: :The identification of essential proteins in protein-protein interaction (PPI) networks is of great significance for understanding cellular processes. With the increasing availability of large-scale PPI data, numerous centrality measures based on network topology have been proposed to detect essential proteins from PPI networks. However, most of the current approaches focus mainly on the topological structure of PPI networks, and largely ignore the gene ontology annotation information. In this paper, we propose a novel centrality measure, called TEO, for identifying essential proteins by combining network topology, gene expression profiles, and GO information. To evaluate the performance of the TEO method, we compare it with five other methods (degree, betweenness, NC, Pec, and CowEWC) in detecting essential proteins from two different yeast PPI datasets. The simulation results show that adding GO information can effectively improve the predicted precision and that our method outperforms the others in predicting essential proteins.

背景与目标： ：蛋白质-蛋白质相互作用（PPI）网络中必需蛋白质的鉴定对理解细胞过程具有重要意义。随着大规模PPI数据可用性的提高，已经提出了许多基于网络拓扑的集中度检测方法来检测PPI网络中的必需蛋白。但是，当前大多数方法主要集中在PPI网络的拓扑结构上，而在很大程度上忽略了基因本体注释信息。在本文中，我们提出了一种新的集中度度量，称为TEO，它通过结合网络拓扑，基因表达谱和GO信息来鉴定必需蛋白质。为了评估TEO方法的性能，我们将其与其他五种方法（度，中间性，NC，Pec和CowEWC）进行比较，以检测来自两个不同酵母PPI数据集的必需蛋白质。仿真结果表明，添加GO信息可以有效地提高预测精度，并且我们的方法在预测必需蛋白质方面优于其他方法。

BACKGROUND & AIMS: :Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options.

背景与目标： ：20世纪系统毒理学方法使人们能够发现响应活性物质而受到影响的生物途径。在这里，我们简要概述了当前的网络方法，这些方法有助于对给定刺激对生物系统的影响进行详细的机械理解。我们还将介绍基于网络的方法以及两个用例，并说明因果生物学网络模型与计算方法的结合如何提供定量的机理见解。我们的方法提供了不同实验系统中转录反应的可靠比较，并能够鉴定响应暴露而调制的基于网络的生物标记。这些进展也可以应用于药理学，在这种药理学中，对于疾病机理和药物不良作用的了解对于开发有效和安全的治疗方法至关重要。

BACKGROUND & AIMS: :Gene network (GN) inference from temporal gene expression data is a crucial and challenging problem in systems biology. Expression data sets usually consist of dozens of temporal samples, while networks consist of thousands of genes, thus rendering many inference methods unfeasible in practice. To improve the scalability of GN inference methods, we propose a novel framework called GeNICE, based on probabilistic GNs; the main novelty is the introduction of a clustering procedure to group genes with related expression profiles and to provide an approximate solution with reduced computational complexity. We use the defined clusters to perform an exhaustive search to retrieve the best predictor gene subsets for each target gene, according to multivariate criterion functions. GeNICE greatly reduces the search space because predictor candidates are restricted to one gene per cluster. Finally, a multivariate analysis is performed for each defined predictor subset to retrieve minimal subsets and to simplify the network. In our experiments with in silico generated data sets, GeNICE achieved substantial computational time reduction when compared to solutions without the clustering step, while preserving the gene expression prediction accuracy even when the number of clusters is small (about 50) relative to the number of genes (order of thousands). For a Plasmodium falciparum microarray data set, the prediction accuracy achieved by GeNICE was roughly 97%, while the respective topologies involving glycolytic and apicoplast seed genes had a very large intramodularity, very small interconnection between modules, and some module hub genes, reflecting small-world and scale-free topological properties, as expected.

背景与目标： ：从时间基因表达数据推断基因网络（GN）是系统生物学中一个至关重要且具有挑战性的问题。表达数据集通常由数十个时间样本组成，而网络由数千个基因组成，因此使许多推理方法在实践中不可行。为了提高GN推论方法的可扩展性，我们提出了一个基于概率GN的新颖框架GeNICE。主要的新颖之处在于引入了聚类程序，可对具有相关表达谱的基因进行分组，并提供具有降低的计算复杂度的近似解决方案。我们使用定义的聚类来执行详尽的搜索，以根据多变量标准函数为每个目标基因检索最佳的预测基因子集。 GeNICE极大地减少了搜索空间，因为预测变量的候选对象仅限于每个簇一个基因。最后，对每个定义的预测变量子集执行多元分析，以检索最小子集并简化网络。在我们使用计算机生成的数据集进行的实验中，与没有聚类步骤的解决方案相比，GeNICE大大减少了计算时间，同时即使相对于基因数量而言，聚类数量很小（约50个），也能保持基因表达预测的准确性（数千个订单）。对于恶性疟原虫微阵列数据集，GeNICE达到的预测准确性约为97％，而涉及糖酵解和apicoplast种子基因的各个拓扑具有非常大的内模量，模块之间的互连非常小，以及一些模块中枢基因，反映了小-符合预期的世界和无标度的拓扑特性。

BACKGROUND & AIMS: AIMS:To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM). METHODS AND MATERIALS:We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link. RESULTS:The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9 mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses. LIMITATIONS:Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results. CONCLUSIONS:Our research suggests that liraglutide 0.9 mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.

背景与目标： 目的：确定利拉鲁肽和二肽基肽酶-4（DPP-4）抑制剂作为抗糖尿病药物对日本2型糖尿病（T2DM）患者的比较疗效和安全性。
方法和材料：我们搜寻了截至2016年8月截止的未控制T2DM并包括利拉鲁肽或DPP-4抑制剂的日本成年人的结局评估的随机对照试验（RCT）。我们提取了有关试验和患者特征的数据，以及以下结果：HbA1c，体重，满足HbA1c <7％的患者，发生降血糖事件，微量白蛋白尿，估计的肾小球滤过率（eGFR）和肌酐的患者。我们使用贝叶斯框架，使用网络荟萃分析（NMA）对数据进行了合成。使用正常可能性和同一性联系对连续结果进行建模，而使用二项式可能性和对数联系对二分结果进行建模。
结果：系统的文献综述产生了涉及38个试验的39种出版物。共有27项试验（5032例患者）报告了12周和24周时HbA1c的变化9项试验（2091例患者）。在12周和24周时，所有治疗均显示HbA1c相对于安慰剂有统计学意义的降低。在报告的第12周和第24周，0.9 mg利拉鲁肽优于所有DPP-4干预措施（维格列汀，西他列汀，利那列汀，阿格列汀，替利格列汀，海拉格列汀和奥格列汀）。就体重变化和低血糖风险而言，治疗无统计学差异。最后，没有进行eGFR和微量白蛋白尿的比较，因为该数据报道的试验太少而无法进行分析。
局限性：一些重要的结果受限于报告不佳（eGFR和微量白蛋白尿）或事件发生率低（低血糖）。随访时间相对较短。临床上，24周时间点更为重要，因为它显示了更持久的结果。
结论：我们的研究表明，在日本成年患者中，比起DPP-4抑制剂，0.9mg利拉鲁肽为T2DM提供了更有效的治疗选择，并且对于这一人群是可行的选择。

BACKGROUND & AIMS: :Chemotherapy-induced alopecia is a major problem in clinical oncology. Doxorubicin, a widely used cancer chemotherapy drug, induces disruption of the hair cycle and subsequent alopecia. We show in this report that doxorubicin causes disruption of the hair-follicle-associated blood vessel network resulting in a greatly reduced density of these blood vessels. Dystrophic hair follicles were also observed with abnormal melanogenesis in the mice treated with doxorubicin. Visualization of the effect of doxorubicin on hair-follicle angiogenesis was made possible by the use of transgenic mice in which green fluorescent protein was driven by regulatory elements of the nestin gene (ND-GFP). In these transgenic mice, the hair-follicle stem cells and the follicle structure as well as the blood vessels associated with the hair follicles express ND-GFP. The hair-follicle stem cells did not appear to be affected by doxorubicin, which may explain why hair regrows after chemotherapy. These results suggest that inhibition of hair-follicle-associated angiogenesis by doxorubicin may be an important factor in hair-follicle dystrophy associated with chemotherapy-induced alopecia. The ND-GFP mouse model is thus useful for the study of the role of angiogenesis in the hair-follicle cycle and the effect of drugs on processes associated with chemotherapy-induced alopecia.

背景与目标： 化学疗法引起的脱发是临床肿瘤学中的主要问题。阿霉素是一种广泛使用的癌症化学治疗药物，可引起毛发周期破坏和随后的脱发。我们在这份报告中表明，阿霉素会导致毛囊相关血管网络的破坏，从而导致这些血管的密度大大降低。在用阿霉素治疗的小鼠中还观察到营养不良的毛囊黑色素生成异常。通过使用其中巢蛋白基因（ND-GFP）调控元件驱动绿色荧光蛋白的转基因小鼠，可以看到阿霉素对毛囊血管生成的作用。在这些转基因小鼠中，毛囊干细胞，毛囊结构以及与毛囊相关的血管均表达ND-GFP。毛囊干细胞似乎没有受到阿霉素的影响，这可以解释为什么化疗后头发会长大。这些结果表明，阿霉素抑制与毛囊相关的血管生成可能是与化学疗法引起的脱发有关的毛囊营养不良的重要因素。因此，ND-GFP小鼠模型可用于研究血管生成在毛囊周期中的作用以及药物对与化学疗法引起的脱发相关的过程的作用。

BACKGROUND & AIMS: :We used functional MRI (fMRI) to study the aging influence on functional connectivity of the motor network in the resting state. A network model based on graph theory was used to measure functional connectivity. The total connectivity degree of each region within the motor network was calculated and compared between aged and young groups. We found that the pattern of functional connectivity was changed in aged subjects, including a significant decrease in the functional connectivity degree of the right cingulate motor area and left premotor area compared to young subjects. Our study demonstrates that normal aging modulates the functional connectivity of motor network in the resting state. We postulate that this abnormal functional connectivity of motor network in the baseline state is an important reason contributing to the deteriorated motor ability in aged subjects.

背景与目标： ：我们使用功能性MRI（fMRI）来研究衰老对静止状态下运动网络功能连接的影响。使用基于图论的网络模型来测量功能连通性。计算了电动机网络内每个区域的总连接度，并比较了老年和青年组。我们发现，在老年受试者中，功能连接的模式发生了变化，包括与年轻受试者相比，右侧扣带回运动区和左侧运动前区的功能连接度显着降低。我们的研究表明，正常老化会在静止状态下调节电机网络的功能连通性。我们假设在基线状态下这种运动网络的异常功能连通性是导致老年受试者运动能力下降的重要原因。

BACKGROUND & AIMS: BACKGROUND:Multiple sclerosis (MS) impairs signal transmission along cortico-cortical and cortico-subcortical connections, affecting functional integration within the motor network. Functional magnetic resonance imaging (fMRI) during motor tasks has revealed altered functional connectivity in MS, but it is unclear how much motor disability contributed to these abnormal functional interaction patterns. OBJECTIVE:To avoid any influence of impaired task performance, we examined disease-related changes in functional motor connectivity in MS at rest. METHODS:A total of 42 patients with MS and 30 matched controls underwent a 20-minute resting-state fMRI session at 3 Tesla. Independent component analysis was applied to the fMRI data to identify disease-related changes in motor resting-state connectivity. RESULTS:Patients with MS showed a spatial expansion of motor resting-state connectivity in deep subcortical nuclei but not at the cortical level. The anterior and middle parts of the putamen, adjacent globus pallidus, anterior and posterior thalamus and the subthalamic region showed stronger functional connectivity with the motor network in the MS group compared with controls. CONCLUSION:MS is characterised by more widespread motor connectivity in the basal ganglia while cortical motor resting-state connectivity is preserved. The expansion of subcortical motor resting-state connectivity in MS indicates less efficient funnelling of neural processing in the executive motor cortico-basal ganglia-thalamo-cortical loops.

背景与目标： 背景：多发性硬化症（MS）会损害沿皮质-皮质和皮质-皮质下连接的信号传输，影响运动网络内的功能集成。运动任务期间的功能磁共振成像（fMRI）已揭示MS中功能连接的改变，但尚不清楚多少运动障碍导致了这些异常的功能相互作用方式。
目的：为了避免影响任务表现的任何影响，我们研究了静止状态下MS中疾病相关的功能性运动连接改变。
方法：总共42例MS患者和30名相匹配的对照组在3特斯拉接受了20分钟的静息状态fMRI检查。将独立成分分析应用于fMRI数据，以识别运动静止状态连通性中与疾病相关的变化。
结果：患有MS的患者在深层皮层下核中显示出运动静息状态连通性的空间扩展，但在皮质水平上没有。与对照组相比，MS组的壳前部和中部，邻近的苍白球，丘脑前部和后部以及丘脑下区域显示出与运动网络的更强功能连接。
结论：MS的特点是基底神经节的运动连接更加广泛，而皮质运动的静息状态连接得以保留。 MS中皮层下运动静止状态连通性的扩展表明在执行性运动皮层-基底神经节-丘脑-皮层环路中神经处理的漏斗效率较低。

BACKGROUND & AIMS: :This study used resting-state functional magnetic resonance imaging (fMRI) to investigate whether functional connectivity is altered in people developing post-traumatic stress disorder (PTSD) following recent trauma. Sixty-two participants who had experienced recent acute traumatic events underwent a 7.3 min resting fMRI scan within 2 days post accident. Of these, 22 participants were diagnosed with PTSD within 1 to 6 months. Nineteen age- and sex-matched subjects without PTSD were selected as the trauma-exposed control group. Posterior cingulate cortex connectivity was determined from 17 PTSD patients and 15 control subjects by investigating synchronic low-frequency fMRI signal fluctuations using a temporal correlation method. To assess the relationship between PTSD symptom severity and PCC connectivity, the contrast image representing areas correlated with the PCC was correlated with the 17 PTSD subjects' Clinician Administered PTSD Scale (CAPS) scores at diagnosis. Compared with the control group, PTSD patients exhibited decreased functional connectivity in the right lingual and right middle temporal gyri, and left lingual/posterior cingulate cortex. The left inferior temporal gyrus, right middle temporal gyrus, left middle temporal gyrus/insula, left medial frontal lobe/anterior cingulate cortex, and right medial frontal gyrus also showed increased connectivity within two days post accident. A negative correlation was found between PCC connectivity and CAPS scores in the left medial prefrontal cortex (mPFC). These results suggest that patients who develop PTSD exhibit different resting-state patterns of neuronal activity following recent trauma. Abnormal FC of mPFC may be a major risk factor predisposing patients to the development of PTSD.

背景与目标： ：这项研究使用静止状态功能磁共振成像（fMRI）来研究在最近的创伤后发展为创伤后应激障碍（PTSD）的人们的功能连接性是否发生了改变。事故发生后两天内，最近经历过急性创伤事件的62名参与者进行了7.3分钟的静息功能磁共振成像扫描。其中，有22名参与者在1-6个月内被诊断为PTSD。选择十九名没有PTSD的年龄和性别匹配的受试者作为暴露于创伤的对照组。通过使用时间相关性方法研究同步低频fMRI信号波动，从17例PTSD患者和15例对照受试者中确定了扣带后部皮层的连通性。为了评估PTSD症状严重程度与PCC连通性之间的关系，将代表与PCC相关的区域的对比图像与17 PTSD受试者在诊断时由临床医生管理的PTSD量表（CAPS）评分相关联。与对照组相比，PTSD患者的右舌和右颞中回以及左舌/后扣带皮层的功能连接性降低。左下颞回，右中颞回，左中颞回/孤立，左内侧额叶/前扣带回皮层以及右内侧额回在事故发生后两天内也显示出增强的连通性。左内侧前额叶皮层（mPFC）中的PCC连接性和CAPS得分之间呈负相关。这些结果表明，发生创伤后应激障碍的患者在最近的创伤后表现出不同的神经元活动静止状态模式。 mPFC的FC异常可能是使患者易患PTSD的主要危险因素。

BACKGROUND & AIMS: :Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.

背景与目标： ：Musashi1（Msi1）是神经系统发育过程中所需的高度保守的RNA结合蛋白。 Msi1已被表征为干细胞标志物，控制着自我更新和分化之间的平衡，并且还与肿瘤发生有关，在多种肿瘤类型中高表达。我们分析了一大批髓母细胞瘤样本中的Msi1表达，发现与正常小脑相比，Msi1在肿瘤组织中高表达。值得注意的是，高Msi1表达水平证明是不良预后的迹象。已确定在髓母细胞瘤的分子亚组3和4中Msi1表达特别高。我们确定Msi1是肿瘤发生所必需的，因为通过小干扰RNA抑制Msi1表达可减少异种移植物中Daoy髓母细胞瘤细胞的生长。为了表征Msi1在髓母细胞瘤中的参与，我们进行了不同的高通量分析。核糖蛋白免疫沉淀后再进行微阵列分析（RIP芯片）用于鉴定优先与Daoy细胞中Msi1蛋白相关的mRNA种类。我们还使用聚类分析来鉴定与我们的髓母细胞瘤队列中的Msi1表达模式相似或相反的基因。网络研究确定RAC1，CTGF，SDCBP，SRC，PRL和SHC1是与Msi1相关的网络的主要节点。我们的结果表明，Msi1在髓母细胞瘤形成过程中起多个过程的调节作用，并可能成为重要的治疗靶点。

BACKGROUND & AIMS: The distal His in peroxidases forms a hydrogen bond with the adjacent Asn, which is highly conserved among many plant and fungal peroxidases. Our previous work [Nagano, S., Tanaka, M., Ishimori, K., Watanabe, Y., & Morishima, I. (1996) Biochemistry 35, 14251-14258] has revealed that the replacement of Asn70 in horseradish peroxidase C (HRP) by Val (N70V) and Asp (N70D) discourages the oxidation activity for guaiacol, and the elementary reaction rate constants for the mutants was decreased by 10-15-fold. In order to delineate the structure-function relationship of the His-Asn couple in peroxidase activity, heme environmental structures of the HRP mutant, N70D, were investigated by CD, 1H NMR, and IR spectroscopies as well as Fe2+/Fe3+ redox potential measurements. While N70D mutant exhibited quite similar CD spectra and redox potential to those of native enzyme, the paramagnetic NMR spectrum clearly showed that the hydrogen bond between the distal His and Asp70 is not formed in the mutant. The disappearance of the splitting in the 1H NMR signal of heme peripheral 8-methyl group observed in 50% H2O/50% D2O solution of N70D-CN suggests that the hydrogen bond between the distal His and heme-bound cyanide is also disrupted by the mutation, which was supported by the low C-N vibration frequency and large dissociation constant of the heme-bound cyanide in the mutant. Together with the results from various spectroscopies and redox potentials, we can conclude that the improper positioning of the distal His induced the cleavages of the hydrogen bonds around the distal His, resulting in the substantial decrease of the catalytic activity without large structural alterations of the enzyme. The His-Asn hydrogen bond in the distal site of peroxidases, therefore, is essential for the catalytic activity by controlling the precise location of the distal His.

背景与目标： 过氧化物酶的远端His与相邻的Asn形成氢键，在许多植物和真菌的过氧化物酶中高度保守。我们以前的工作[Nagano，S.，Tanaka，M.，Ishimori，K.，Watanabe，Y.＆Morishima，I.（1996）Biochemistry 35，14251-14258]揭示了辣根过氧化物酶C中Asn70的替代。 Val（N70V）和Asp（N70D）（HRP）抑制了愈创木酚的氧化活性，并且突变体的基本反应速率常数降低了10-15倍。为了描述过氧化物酶活性中His-Asn对的结构-功能关系，通过CD，1H NMR和IR光谱以及Fe2 / Fe3氧化还原电位测量研究了HRP突变体N70D的血红素环境结构。尽管N70D突变体显示出与天然酶非常相似的CD光谱和氧化还原电位，但顺磁NMR光谱清楚地表明，在该突变体中未形成远端His和Asp70之间的氢键。在N70D-CN的50％H2O / 50％D2O溶液中观察到的血红素外围8-甲基的1H NMR信号分裂的消失表明，His末端和与血红素结合的氰化物之间的氢键也被N70破坏。较低的CN振动频率和突变体中血红素结合氰化物的较大解离常数为突变提供了支持。结合各种光谱学和氧化还原电势的结果，我们可以得出结论，His末端的不正确定位导致了His末端周围氢键的裂解，导致催化活性显着下降，而酶的结构没有很大变化。 。因此，过氧化物酶远端的His-Asn氢键通过控制远端His的精确位置，对于催化活性至关重要。