Design,delivery and efficacy testing of therapeutic nucleic acids used to inhibit hepatitis C virus gene expression in vitro and in vivo

Despite major achievements in the treatment ofchronic hepatitis C with the combination ofinterferons and the nucleoside analog ribavirin themajority of patients with chronic hepatitis C virus(HCV) infection cannot be treated effectively.Toimprove this response rate we used antisensetechnologies to inhibit HCV translation as possibleadditional option for experimental treatment.Antisense oligodeoxynucleotides(ODN) are

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

Causality assessment of suspected drug induced liver injury(DILI) and herb induced liver injury(HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences(CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. 2014 Baishideng Publishing Group Co., Limited. All

Catheter ablation of atrial fibrillation facilitated by preprocedural three-dimensional transesophageal echocardiography: Long-term outcome

AIM To evaluate the long-term outcome of catheter ablation of atrial fibrillation(AF) facilitated by preprocedural threedimensional(3-D) transesophageal echocardiography.METHODS In 50 patients, 3D transesophageal echocardiography(3D TEE) was performed immediately prior to an ablation procedure(paroxysmal AF: 30 patients, persistent AF: 20 patients). The images were available throughout the ablation procedure. Two different ablation strategies were used. In most of the patients with paroxysmal AF, the cryoablation technique was used(Arctic Front Balloon, Cryo Cath Technologies/Medtronic; group A2). In the other patients, a circumferential pulmonary vein ablation was performed using the CARTO system [Biosense Webster; group A1(paroxysmal AF), group B(persistent AF)]. Success rates and complication rates were analysed at 4-year follow-up.RESULTS A 3D TEE could be performed successfully in all patients prior to the ablation procedure and all four pulmonaryvein ostia could be evaluated in 84% of patients. The image quality was excellent in the majority of patients and several variations of the pulmonary vein anatomy could be visualized precisely(e.g., common pulmonary vein ostia, accessory pulmonary veins, varying diameter of the left atrial appendage and its distance to the left superior pulmonary vein). All ablation procedures could be performed as planned and almost all pulmonary veins could be isolated successfully. At 48-mo followup, 68.0% of all patients were free from an arrhythmia recurrence(group A1: 72.7%, group A2: 73.7%, group B: 60.0%). There were no major complications.CONCLUSION3 D TEE provides an excellent overview over the left atrial anatomy prior to AF ablation procedures and these procedures are associated with a favourable long-term outcome.

Catheter ablation of atrial fibrillation: Radiofrequency catheter ablation for redo procedures after cryoablation

AIM: To evaluate the effectiveness of two different strategies using radiofrequency catheter ablation for redo procedures after cryoablation of atrial fibrillation.METHODS: Thirty patients(paroxysmal atrial fibrillation: 22 patients,persistent atrial fibrillation: 8 patients) had to undergo a redo procedure after initially successful circumferential pulmonary vein(PV) isolation with the cryoballoon technique(Arctic Front Balloon,CryoCath Technologies/Medtronic).The redo ablation procedures were performed using a segmental approach or a circumferential ablation strategy(CARTO;Biosense Webster) depending on the intra-procedural findings.After discharge,patients were scheduled for repeated visits at the arrhythmia clinic.A 7-day Holter monitoring was performed at 3,12 and 24 mo after the ablation procedure.RESULTS: During the redo procedure,a mean number of 2.9 re-conducting pulmonary veins(SD ± 1.0 PVs) were detected(using a circular mapping catheter).In 20 patients,a segmental approach was sufficient to eliminate the residual pulmonary vein conduction because there were only a few recovered pulmonary vein fibres.In the remaining 10 patients,a circumferential ablation strategy was used because of a complete recovery of the PV-LA conduction.All recovered pulmonary veins could be isolated successfully again.At 2-year follow-up,73.3% of all patients were free from an arrhythmia recurrence(22/30).There were no major complications.CONCLUSION: In patients with an initial circumferential pulmonary vein isolation using the cryoballoon technique,a repeat ablation procedure can be performed safely and effectively using radiofrequency catheter ablation.

Construct and correlates of basic motor competencies in primary school-aged children

Background: A central aim of physical education is the promotion of basic motor competencies(in German: Motorische Basiskompetenzen;MOBAK), which are prerequisites for children's active participation in sports culture. This article introduces the MOBAK-1 test instrument for 6-to 8-year-old children and determines the construct validity of this test instrument. In addition, the relationship between MOBAK and motor ability(i.e., strength) as well as body mass index(BMI), sex, and age is investigated.Methods: We analyzed data of 923 first and second graders(422 girls, 501 boys, age = 6.80 ±0.44 years). The children's basic motor competencies were assessed by the MOBAK-1 test instrument. Besides analyses of frequency, correlation, and variance, 3 confirmatory factor analyses with covariates were performed.Results: We found 2 MOBAK factors consisting of 4 items each. The first factor, locomotion, included the items balancing, rolling, jumping, and side stepping; the second factor, object control, included the items throwing, catching, bouncing, and dribbling. The motor ability strength had a significant influence on the factors locomotion(b = 0.60) and object control(b = 0.50). Older pupils achieved better results than younger pupils on object control(b = 0.29). Boys performed better on object control(b = -0.44), whereas girls achieved better results in locomotion(b = 0.07).Pupils with a high BMI achieved lower performance only on the factor locomotion(b =-0.28).Conclusion: The MOBAK-1 test instrument developed for this study meets psychometric validity demands and is suitable to evaluate effects of sports and physical education.

Chemotherapy of glioblastoma in rats using doxorubicin - loaded nanoparticles

Glioblastomas belong to the most aggressive human cancers with short survival times.Due to the blood-brainbarrier,they are mostly inaccessible to traditional chemotherapy.We have recently shown that doxorubicin boundto polysorbate-coated nanoparticles crossed the intact blood-brain barrier,thus reaching therapeutic concentra-tions in the brain.Here,we investigated the therapeutic potential of this formulation of doxorubicin in vivo using ananimal model created by implantation of 101/8 glioblastoma tumor in rat brains.Groups of 5-8 glioblastoma-

Score based assessment of implant-related post fusion MRI artifacts focused on different interbody disc spacers: An <i>in vitro</i>study

Interbody disc spacers for anterior spine fusion are made of different materials, such as titanium alloys or carbon fiber reinforced polymers (CFRP). Implant-related susceptibility artifacts can decrease the quality of MRI scans. This cadaveric study aimed to demonstrate the extent that implant-related MRI artifacting affects the post fusion differentiation of the spinal canal (SC) and intervertebral disc space (IDS). In 6 cadaveric porcine spines, we evaluated the post-im- plantation MRI scans of a titanium and CFRP spacer that differed in shape and surface qualities. A spacer made of human cortical bone was used as a control. A defined evaluation unit was divided into regions of interest (ROI) to characterize the SC and IDS. Considering 15 different MRI sequences read independently by an interobserver-validated team of specialists artifact-affected image quality of the median MRI slice was rated on a modified score of 0-1-2-3. A maximum score of 15 points for the SC and 9 points for the IDS (100%) was possible. Turbo spin echo sequences produced the best scores for both spacers and the control. Only the control achieved a score of 100%. For the IDS the titanium and CFRP spacer maximally scored 0% and 74%, for the SC 80% and 99%, respectively. By using favored T1 TSE sequences the CFRP-spacer represented clear advantages in post fusion spinal imaging. Independent of artifact dimensions the used scoring system allowed us to create an implant-related ranking of MRI scan quality in reference to the bone control.

Evaluation of Multiparametric MRI of the Prostate: Impact of Standardized Examination Protocols and the Endorectal Coil

Purpose: The aim of the present study was to evaluate the patient population, different MRI examination protocols and the patient’s acceptance of the endorectal coil in the diagnosis of prostate cancer regarding the current discussion in PI-RADS v2.1. Material and Methods: In our institute, 256 patients were examined with different protocols and separated into six groups. The value of the different MRI protocols was identified by analyzing sensitivity, specificity, negative predictive value and positive predictive value. The patient population was tested for statistically significant differences in their characteristics to detect a distortion of the results. The patients’ acceptance of endorectal coil was evaluated by a query. Results: In total 4.7% of the patients would not recommend a MRI examination because of subjective physical strain and 65.6% of all patients subjectively saw a benefit in the examination in regard to an optimal diagnostic process. The protocol groups reached a sensitivity from 66.7% - 100%, a specificity from 40% - 75%, a positive predictive value from 33.3% - 80% and a negative predictive value from 66.7% - 100%. Conclusion: MRI of the prostate is a safe and comfortable tool with high sensitivity and negative predictive value and the potential of ruling out a clinically significant prostate cancer. However, a general recommendation for the use of biparametric MRI could not be given, considering a higher sensitivity could be performed when using dynamic contrast-enhanced MRI or spectroscopy.

Exclusive Population of n=2 S-states in He-like Uranium by Ionization Process

K-shell ionization for Li-like uranium ions in collisions with a N2 target was performed at the ESR storage ring. We found surprisingly that in such close encounters the 2 s electron remain almost unaffected by the collisions. A dedicated experimental study was conducted by using Li-like uranium ions at an initial energy of 378 MeV/u in order to manifest the situation. In Fig.1 a typical spectrum is shown registered by a Ge(i)

石榴辉石岩的电导率及对岩浆底侵的约束

河北汉诺坝新生代玄武岩携带的石榴辉石岩为岩浆底侵于上地幔顶部40～45km形成的堆晶岩，是壳幔过渡带的典型样品。本文使用S01artron1260阻抗分析仪，测量1．2GPa和380～900℃下石榴辉石岩WD958的电阻率。样品电导率（d）与温度的关系遵守Arrhenius方程：d=exp（=AH／kT），其中T是样品的绝对温度，k是Boltzmann常数，指前因子GO为97．5S／m，活化焓AH为1．27eV。使用傅立叶红外光谱仪测定样品中单斜辉石的平均含水量为117×10-6 H2O，橄榄石无水，石榴子石的含水量凶蚀变无法测定。使用Hashin—Shtrikman平均方法计算样品WD958的电导率，发现样品可看作由含水单斜辉石、无水石榴子石和无水橄榄石组成的高阻集合体，电导率同时受小极化予导电和质子导电的影响。如果原位的石榴辉石岩的矿物含水量保持平衡，其电导率将提高1个数量级，质子导电成为主控导电机制。石榴辉石岩在高温的壳一幔过渡带（～1000℃）表现为高导层，而在正常地温梯度上，与尖晶石二辉橄榄岩的电导率近似，为高阻层。闪此，在岩浆底侵作用下，电性上的壳一幔边界将随着温度和含水量的变化而改变。

自发性低颅压的对比剂增强MR脊髓成像时类似脑脊液漏伪影的表现

在对比剂增强（CE）的MR脊髓成像中，频谱预饱和反转恢复序列（SPIR）的T1WI中硬膜内间隙外的高信号通常被认为是脑脊液漏引起的。本研究回顾性分析了原发性低颅压（n=5）、脑脊液鼻漏（n=2）、腰椎术后（n=1）病人和正常对照组（n=6）在上述序列中出现于肺尖部的高信号改变。

MRI技术在评估下肢畸形方面的可重复性、准确性和临床应用

本研究的假设前提是MRI对腿模型的长度、转矩及轴向的测量准确性高、重复性好，可应用于腿部畸形的病人。2例模型和30例病人（膝内翻15例；膝外翻15例）采用优化的MRI技术进行研究。利用测微螺距和测角器完成参数测量。病人腿的长度和轴线与包括两脚的全长X线平片对照。利用平均绝对差值（mean absolute difference，MAD）和95％的可信区间，计算观察者自己与观察者间的可重复性和准确性。病人参数之间比较采用配对Studentt检验。

脂肪细胞力学感知受体的发现

肥胖已经成为世界性的公共卫生问题。申请人团队围绕代谢疾病的力学调控,取得以下发现:(1)发现Piezo1通道是肥胖中脂肪细胞体积膨胀的力学感知受体,提出机械应力-脂肪生成偶联的新概念,开创性地揭示了肥胖发生的力学调控规律。本文发掘了脂肪细胞响应机械应力的确切上游感受器Piezo1,首次提出肥胖力学调控的新理论:脂肪生成受脂肪细胞体积膨胀产生的机械应力反馈调控。

Dietary glycine blunts liver injury after bile duct ligation in rats

AIM： To investigate the effects of （dietary） glycine against oxidant-induced injury caused by bile duct ligation （BDL）.METHODS： Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley （SD） rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid （DCA） in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase （LDH） activity was determined in the supernatant of cultivated hepatocytes.RESULTS： Serum alanine transaminase levels increased to about 600 U/L 1 d alter BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed.CONCLUSION： These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis.

留声机唱片的形式

作为全能型的思想家,美学仅仅只是阿多诺的一个研究方向,T.W.阿多诺的研究涉及除美学之外的其他广阔学术领域。而就美学研究来说,阿多诺除了耽于哲学层面的思辨外,还有大量涉及文学、绘画、电影、电视、音乐等具体艺术类型的文艺理论研究,《留声机唱片的形式》就堪为典范。在阿多诺看来,所谓留声机唱片的形式,不是留声机本身的物理构架形式,对此,留声机唱片的形式毋宁说是无形式。留声机唱片的形式在于留声机唱片的音乐超越时间的倏逝而使生命得以持存。在此意义上,留声机唱片的音乐,与文字相仿,让即将消逝的生命在时间中存在下来。其物理基础在于克拉尼的声音图像。这使得留声机唱片的音乐形式具有文字乃至语言的特征。

In silico analysis of regulatory networks underlines the role of miR-10b-5p and its target BDNF in huntington’s disease

Non-coding RNAs(ncRNAs)play various roles during central nervous system development.MicroRNAs(miRNAs)are a class of ncRNAs that exert their function together with argonaute proteins by post-transcriptional gene silencing of messenger RNAs(mRNAs).Several studies provide evidence for alterations in miRNA expression in patients with neurodegenerative diseases.Among these is huntington‘s disease(HD),a dominantly inherited fatal disorder characterized by deregulation of neuronal-specific mRNAs as well as miRNAs.Recently,next-generation sequencing(NGS)miRNA profiles from human HD and neurologically normal control brain tissues were reported.Five consistently upregulated miRNAs affect the expression of genes involved in neuronal differentiation,neurite outgrowth,cell death and survival.We re-analyzed the NGS data publicly available in array express and detected nineteen additional differentially expressed miRNAs.Subsequently,we connected these miRNAs to genes implicated in HD development and network analysis pointed to miRNA-mediated downregulation of twenty-two genes with roles in the pathogenesis as well as treatment of the disease.In silico prediction and reporter systems prove that levels of BDNF,a central node in the miRNA-mRNA regulatory network,can be post-transcriptionally controlled by upregulated miR-10b-5p and miR-30a-5p.Reduced BDNF expression is associated with neuronal dysfunction and death in HD.Moreover,the 3’UTR of CREB1 harbors a predicted binding site for these two miRNAs.CREB1 is similarly downregulated in HD and overexpression decreased susceptibility to 3-nitropropionic-induced toxicity in a cell model.In contradiction to these observations,it is presumed that miR-10b-5p upregulation in HD exerts a neuroprotective role in response to the mutation in the huntingtin gene.Therefore,the function of miR-10b-5p and especially its effect on BDNF expression in HD requires further academic research.

Measurements of dihadron correlations relative to the event plane in Au+Au collisions at√^(S)NN=200 GeV

Dihadron azimuthal correlations containing a high transverse momentum(pr)trigger particle are sensit-ive to the properties of the nuclear medium created at RHIC through the strong interactions occurring between the traversing parton and the medium,ie.jet-quenching.Previous measurements revealed a strong modification to di-hadron azimuthal correlations in Au+Au collisions with respect to ptp and d+Au collisions.The modification in-creases with the collision centrality,suggesting a path-length or energy density dependence to the je-quenching ef-fect.This paper reports STAR measurements of dihadron azimuthal correlations in mid-central(20%-60%)Au+Au collisions at√^(S)NN=200 GeV as a function of the trigger particle's azimuthal angle relative to the event plane,Ф_(s)=|Ф_(t)-ψ_(Ep)|.The azimuthal correlation is studied as a function of both the trigger and associated particle pr.The subtractions of the combinatorial background and anisotropic flow,assuming Zero Yield At Minimum(ZYAM),are described.The correlation results are first discussed with subtraction of the even harmonic(elliptic and quadrangu-lar)flow backgrounds.The away-side correlation is strongly modifed,and the modification varies withФ_(s),with a double-peak structure for out-of-plane trigger particles.The near-side ridge(long range pseudo-rapidity△_(η)correla-tion)appears to drop with increasingФ_(s)while the jet-like component remains approximately constant.The correla-tion functions are further studied with the subtraction of odd harmonic triangular flow background arising from fluc-tuations.It is found that the triangular flow,while responsible for the majority of the amplitudes,is not sufficient to explain theφs-dependence of the ridge or the away-side double-peak structure.The dropping ridge withФ_(s)could be attributed to aФ_(s)-dependent lliptie anisotropy;however,the physics mechanism of the ridge remains an open ques-tion.Even with aФ_(s)-dependent elliptic flow,the away-side correlation structure is robust.These results,with extens-ive systematic studies of the dihadron correlations as a function ofФ_(s),trigger and associated particle pT,and the pseudo-rapidity range△_(η),should provide stringent inputs to help understand the underlying physics mechanisms of jet-medium interactions in high energy nuclear collisions.

The Modernity of the Ancient-Style Verse

This article explores the stylistic innovations in the Ancient-Style Verse （gutishi 古体诗）, and particularly in the subgenre ofgexing 歌行, from the Late Qing to the 1930s and 1940s. It argues that the relative free prosody of the Ancient-Style allowed innovation disguised as restoration. Yet, instead of being the prelude to modem vernacular poetry, the innovations in this genre may have found an end in themselves--namely, creating a style of verse which showed a unique combination of modern elements and deliberate stylistic archaism. Its lyric archaism and innovation were formulated in dialectical terms, which have been frequently evoked in the reformative moments of the Chinese tradition. This paper examines the evolution of the new gexing style through the close reading of a few gexing poems by Huang Zunxian 黄道宪 （1848-1905）, Liang Qichao 梁启超 （1873-1929）, Lin Gengbai 林庚白 （1896-1941）, and Liu Yazi 柳亚子 （1887-1958）. Given the rise of vernacular poetry since 1917, the poems of Lin and Liu may be called the Classicist Verse, which represents the author＇s conscious choice to elaborate on the subject matter using a particular classical genre, when other modern genres are available. In the end, I will also discuss the gexing style verses by Li Sichun 李思纯 in the translation of multi-stanza European poetry, as a practice in accord to the indigenization agenda of the Critical Review magazine.

Classicism 2.0： The Vitality of Classicist Poetry Online in Contemporary China

In this paper, we examine the various approaches toward literary classicism among contemporary Chinese poets. If ＂poetry of the establishment＂ features ideological conservatism and aesthetic populism, then its opposite is the online scene of classicist poetry which represents an innovative continuation of the poetic tradition. Here such innovations are discussed in terms of theme, language, and form. Thematic innovations include further that of ideology, worldview, and urbanity. In particular, we argue that a major distinction between contemporary online classicist poets and their premodern predecessors is in their cultural identity. Unlike a traditional literatus who is a poet, scholar, and bureaucrat, contemporary poets often endure economic, intellectual, or political marginalization; or at the very least, writing in the marginalized genre of classicist poetry is a skill that can no longer be readily translated into career success. This new type of poetic identity, in addition to their modern education, has given rise to fresh interpretations of our living world unseen in premodern poetry. Despite their broad spectrum of intellectual persuasions and aesthetic preferences, most of the poets have demonstrated an audacity to experiment, which, coupled with full versatility and virtuosity in the classical poetry tradition, creates outstanding poems. The highly original works of a few leading classicist poets like Lizilizilizi （Zeng Shaoli）, Xutang （Duan Xiaosong）, and Dugu Shiroushou （Zeng Zheng） will be examined in depth.

Frankfurt Consensus

For too long the specter of Darwinism has haunted the narrative of Chinese literary history. It is told as a story of ＂evolution,＂ a triumphant confluence of folk and vernacular literature, along a chain of genre development from dynasty to dynasty. The 1917 New Culture Movement is seen as the teleological end of this evolution. Accordingly, vernacular literature has been taken to represent literary modernity, hence enjoying a monopoly in academic research. Classical-style poetry that continued to be written in the twentieth-century has been almost entirely neglected. Generations of writers produced verse in various classical-styles and genres over the last century. Many poets, known for their vernacular verses, turned to traditional forms and expressions, especially in moments of hardship or distress, to reinvent a voice or to find an emotional outlet. Little of their endeavor, however, has been honored by literary historiography. It is true that the winner writes history. But it is a scholar＇s obligation to address selective cultural amnesia.