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| 1 | Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection显示文摘Missense mutations in Leucine-Rich Repeat Kinase 2(LRRK2)cause the majority of familial and some sporadic forms of Parkinson’s disease(PD).The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity,promoting the development of LRRK2 kinase inhibitors as therapeutics.Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise.However,nearly all inhibitors are ATP competitive—some with unwanted side effects and unclear clinical outcome—alternative types of LRRK2 inhibitors are lacking.Herein we identify 5′-deoxyadenosylcobalamin(AdoCbl),a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity.Multiple assays show that AdoCbl directly binds LRRK2,leading to the alterations of protein conformation and ATP binding in LRRK2.STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain.Furthermore,we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization.Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue,and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C.elegans and D.melanogaster expressing LRRK2 disease variants.Finally,AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models.Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism,which can be harnessed to develop new LRRK2-based PD therapeutics in the future. | Adam Schaffner Xianting Li Yacob Gomez-Llorente Emmanouela Leandrou Anna Memou Nicolina Clemente Chen Yao Farinaz Afsari Lianteng Zhi Nina Pan Keita Morohashi Xiaoluan Hua Ming-Ming Zhou Chunyu Wang Hui Zhang Shu G.Chen Christopher J.Elliott Hardy Rideout Iban Ubarretxena-Belandia Zhenyu Yue | 2019 | Cell Research2019，29，4： | 7 |
| 2 | Standardisation and Benchmarking for Improving Translator Training显示文摘过去十年,在高等院校尤其是研究生层次,译员培训课程数量增长巨大。这些课程面临的挑战是,要确保毕业生在瞬息万变的市场中能胜任各行各业翻译的需要。本文主要谈到下列问题:这些高校如何使译员培训课程适应快速变化的行业以及随之而来的行规的改变?一方面,行业要求毕业生要具有实际的职业技能,另一方面,高校要求毕业生要具有一定深度的学术修养和知识技能,如何将二者协调?有哪些合适的标准和尺度来确保译员培训的质量?本文最后讨论了EMT(欧洲翻译硕士)译员能力行规对高校译员培训课程带来哪些挑战。 | Christina Schaffner | 2012 | 中国翻译2012，33，6： | 3 |
| 3 | 被激光损伤软骨释放的凋亡因子诱导软骨细胞凋亡的研究显示文摘目的探讨组织损伤后凋亡信号怎样促进细胞的死亡进程。方法在激光照射后猪软骨块置培液中,在不同时间(3、6、9、12、24 h)收集的培液,即实验条件培养液(TCM),从未经激光照射的软骨块培液取得的为对照条件培养液(CCM)。软骨块继续培养28 d,用聚焦显微镜评价其受损区的进展。分离的软骨细胞单层放于 TCM、CCM 或正常培养液(NM)培养,阳性对照组单层细胞经紫外线照射10 min 后继续用正常培养液培养,培养24 h 后,收集细胞并用荧光标记物染色,经流式细胞仪分析。结果所有经 TCM 培养的细胞显现半胱氨酸蛋白水解酶(caspase)-3阳性、CMXRos 和一氧化氮信号减少或失去;经 CCM 或 NM 培养的细胞显现 caspase-3阴性、CMXRos 和一氧化氮信号完好;阳性对照组细胞显现 Caspase-3和 CMXRos 均阳性、一氧化氮信号减少或失去,代表处于凋亡早期的细胞。不同 TCM 浓度(100%、50%、25%、12.5%)和时间(0.5、1、3、9、12 h)对细胞作用后,所有细胞均呈现 caspase-3阳性、CMXRos 和一氧化氮信号减少或失去。结论激光照射受损软骨释放凋亡因子,可诱导单层细胞死亡。 | 郑敏 Grogan SP Schaffner T Mainil-Varlet P | 2007 | 中华医学杂志2007，87，21： | 3 |
| 4 | Comprehensive lifestyle intervention vs soy protein-based meal regimen in non-alcoholic steatohepatitis显示文摘BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content.AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein.METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group(MR-G)with soy-yogurt-honey preparation or to guided lifestyle change group(LC-G)with endurance activity and nutrition counselling. Serum alanine transaminase(ALT), aspartate transaminase(AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod? device. Pre-and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median(interquartile range).RESULTS Twenty-two subjects(MR-G, n = 11 and LC-G, n = 11) completed the study(9 women, 13 men; age 52.1(15.0) years, body mass index(BMI) 32.3(3.3) kg/m^2).In both groups a significant weight loss was achieved(MR-G:-6.4(3.6) kg, P <0.01; LC-G:-9.1(10.4) kg, P < 0.01). BMI dropped in both groups(MR-G:-2.3(1.5)kg/m^2, P = 0.003; LC-G:-3.0(3.4) kg/m^2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT.Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes.CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients. | Peter Deibert Adhara Lazaro Denise Schaffner Aloys Berg Daniel Koenig Wolfgang Kreisel Manfred W Baumstark Daniel Steinmann Martin Buechert Thomas Lange | 2019 | World Journal of Gastroenterology2019，25，9： | 3 |
| 5 | Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension显示文摘AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension. | Denise Schaffner Adhara Lazaro Peter Deibert Peter Hasselblatt Patrick Stoll Lisa Fauth Manfred W Baumstark Irmgard Merfort Annette Schmitt-Graeff Wolfgang Kreisel | 2018 | World Journal of Gastroenterology2018，24，38： | 2 |
| 6 | Microbial risk assessment of Staphylococcal food poisoning in Korean kimbab 显示文摘 | RHO M J SCHAFFNER D W | 2007 | Int J Food Microbiol2007，116，3： | 1 |
| 7 | Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial显示文摘 | Frei-Kleiner S Schaffner W Rahlfs VW | 2005 | Maturitas2005，51，4： | 1 |
| 8 | Diurnal variations in hydraulic conductivity and root pressure can be correlated with the expression of putative aquaporlns in the roots of Lotus japonicus显示文摘 | HENZLER T WATERHOUSE R N SMYTH A J CARVAJAL M COOKE D T SCHAFFNER A R STEUDLE E CLARKSOND T | 1999 | Planta1999，210，： | 1 |
| 9 | Rail rectification specifications and modern grinding stone technology显示文摘 | Jim Cooper Jean Claude Schaffner | 1993 | Rail Engineering International Edition1993，，1： | 1 |
| 10 | Extended preservation of rat liver graft by induction of heme oxygenase-1显示文摘 | REDAELI CA TIAN YH SCHAFFNER | 2002 | Hepatology2002，35，5： | 1 |
| 11 | Survival of Salmonella in processed chicken products during frozen storage显示文摘 | DOMINGUEZ S A SCHAFFNER D W | | 0，，10： | 1 |
| 12 | Early and late outcome of operated and non-operated acute dissection of the descending aorta显示文摘 | Gysi J Schaffner T Mohaesi P | 1997 | Eur J Cardiothorac Surg1997，11，6： | 1 |
| 13 | Inhibition of tissue factor signaling suppresses tumor growth显示文摘 | Versteeg HH Schaffner F Kerver M | 2008 | Blood2008，111，1： | 1 |
| 14 | The taste of heavy metals: gene regulation by MTF-I 显示文摘 | Gunther V Lindert U Schaffner W | 2012 | Biochim Biophys Acta2012，1823，9： | 1 |
| 15 | Inhibition of tissue factor signaling suppresses tumor growth显示文摘 | Versteeg HH Schaffner F Kerver M | | 0，，01： | 1 |
| 16 | Glove barriers to bacterial cross-contamination between hands to food 显示文摘 | Montville R CHEN Y Schaffner D W | 2001 | Journal of Food Protection2001，64，6： | 1 |
| 17 | Tissue factor and PAR2 signaling in the tumor microenvironment显示文摘 | Schaffner F Ruf W | | 0，，12： | 1 |
| 18 | Donor-site morbidity and patient satisfaction using a composite nipple graft for unilateral nipple reconstruction in the radiated and nonradiated breast 显示文摘 | Spear SL Schaffner AD Jespersen MR | 2011 | Plast Reconstr Surg2011，127，4： | 1 |
| 19 | Effect of hyperlipemic serum and irradiation on wound healing in primary quiescent cultures of vascular cells显示文摘 | Dimitrievich GS schaffner T | 1989 | Exp Mol Pathol1989，52，： | 1 |
| 20 | Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis显示文摘 | Nickowitz RE Wozniak RW Schaffner F | 1994 | Gasteoenterology1994，106，1： | 1 |
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