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Insights from an academic endeavor into central nervous system drug discovery

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Neural Regeneration Research 2025年第6期20卷 1717-1718页

作者： Lieve van Veggel An m.Voets tim Vanmierlo Rudy Schreiber BIOmED Biomedical Research Institute Faculty of Medicine and Life SciencesHasselt UniversityHasseltBelgium Department of Psychiatry and Neuropsychology Division of Translational NeuroscienceEuropean Graduate School of NeuroscienceSchool for Mental Health and NeuroscienceMaastricht UniversityMaastrichtThe Netherlands Section of Psychopharmacology Neuropsychology and PsychopharmacologyFaculty of Psychology and NeuroscienceMaastricht UniversityMaastrichtThe Netherlands University mS Center(UmSC) Hasselt-PeltBelgium

Historically,"big pharma"did most central nervous system drug discovery R&D ***,in modern times their"management reductionism"resulted in disappointing pipelines and pharma resided to(late)development,regulatory approval,and marketing(Thong,2015).This had significant consequences for financing and executing research,resulting in a larger role for funding by governments and patient-organizations and a shift of research to academia(mazzucato,2013).

关键词： academic approval consequences

Intraoperative application of three-dimensional printed guides in total hip arthroplasty: A systematic review

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World Journal of Orthopedics 2024年第7期15卷 660-667页

作者： tim P Crone Bart m W Cornelissen Jakob Van Oldenrijk Pieter Koen Bos Ewout S Veltman Department of Orthopedic Surgery and Sports medicine Erasmus Medical CenterRotterdam 3015 GDNetherlands Department of Oral and maxillofacial Surgery Erasmus Medical CenterRotterdam 3015 GDNetherlands

BACKGROUND Acetabular component positioning in total hip arthroplasty(THA)is of key importance to ensure satisfactory post-operative outcomes and to minimize the risk of *** majority of acetabular components are aligned freehand,without the use of navigation *** specific instruments(PSI)and three-dimensional(3D)printing of THA placement guides are increasingly used in primary THA to ensure optimal *** To summarize the literature on 3D printing in THA and how they improve acetabular component *** Pubmed was used to identify and access scientific studies reporting on different 3D printing methods used in *** studies with 236 hips in 228 patients were *** studies could be divided into two main categories;3D printed models and 3D printed *** 3D printing in THA helped improve preoperative cup size planning and post-operative Harris hip scores between intervention and control groups(P=0.019,P=0.009).Otherwise,outcome measures were heterogeneous and thus difficult to *** overarching consensus between the studies is that the use of 3D guidance tools can assist in improving THA cup positioning and reduce the need for revision THA and the associated *** The implementation of 3D printing and PSI for primary THA can significantly improve the positioning accuracy of the acetabular cup component and reduce the number of complications caused by malpositioning.

关键词： Total hip arthroplasty Three-dimensional printing Hip replacement surgery Three-dimensional planning Surgical guides

LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

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Genes & Diseases 2024年第3期11卷 417-426页

作者： Zijian Xu Elizabeth R.Davies Liudi Yao Yilu Zhou Juanjuan Li Aiman Alzetani Ben G.marshall David Hancock tim Wallis Julian Downward Rob m.Ewing Donna E.Davies mark G.Jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK clinical and Experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK Institute for Life Sciences University of SouthamptonSouthampton SO171BJUK NIHR Southampton Biomedical Research Centre University Hospital SouthamptonSouthampton SO166YDUK University Hospital Southampton Southampton SO166YDUK Oncogene Biology The Francis Crick InstituteLondon NW11ATUK

The factors that determine fibrosis progression or normal tissue repair are largely *** previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EmT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine ***,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces EmT as a *** IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and mRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast ***,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EmT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

关键词： CAB39L Crosstalk EmT LKB1 Pulmonary fibrosis

Variability and trends of near-surface wind speed over the Tibetan Plateau:The role played by the westerly and Asian monsoon

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Advances in Climate Change Research 2024年第3期15卷 525-536页

作者： Gang-Feng ZHANG Cesar AZORIN-mOLINA Deliang CHEN tim RmCVICAR Jose AGUIJARRO Kai-Qiang DENG Lorenzo mINOLA Jaeyeon LEE Seok-Woo SON Heng mA Pei-Jun SHI State Key Laboratory of Earth Surface Processes and Resource Ecology Beijing Normal UniversityBeijing 100875China Engineering Center of Desertification and Blown-Sand Control of ministry of Education Faculty of Geographical ScienceBeijing Normal UniversityBeijing 100875China Key Laboratory of Environmental Change and Natural Disaster of ministry of Education Beijing Normal UniversityBeijing 100875China Centro de Investigaciones Sobre Desertificaci'on Consejo Superior de Investigaciones Cientı'ficas(CIDECSIC-UV-Generalitat alenciana)ClimateAtmosphere and Ocean Laboratory(Climatoc-Lab)Moncada 46113Spain Regional Climate Group Department of Earth SciencesUniversity of GothenburgGothenburg 40530Sweden CSIRO Environment CanberraACT 2600Australia Australian Research Council Centre of Excellence for Climate Extremes CanberraACT 2600Australia State meteorological Agency Balearic Islands OfficePalma de Mallorca 07015Spain School of Atmospheric Sciences Sun Yat-sen UniversityZhuhai 519082China Interuniversity Department of Regional and Urban Studies and Planning(DIST) Politecnico and University of TurinTurin 10125Italy School of Earth and Environmental Sciences Seoul National UniversitySeoul 08826South Korea Atmospheric and Oceanic Sciences Program Princeton UniversityPrinceton NJ 08544USA Geophysical Fluid Dynamics Laboratory NOAAPrinceton NJ 08544USA

Near-surface wind speed exerts profound impacts on many environmental issues,while the long-term(≥60 years)trend and multidecadal variability in the wind speed and its underlying causes in global high-elevation and mountainous areas(e.g.,Tibetan Plateau)remain largely ***,by examining homogenized wind speed data from 104 meteorological stations over the Tibetan Plateau for 1961-2020 and ERA5 reanalysis datasets,we investigated the variability and long-term trend in the near-surface wind speed and revealed the role played by the westerly and Asian *** results show that the homogenized annual wind speed displays a decreasing trend(-0.091 m s^(−1)per decade,pm s^(−1)per decade,pmn(-0.071 m s^(−1)per decade,pmultidecadal variability of wind speed,which manifested in an prominent increase in 1961-1970,a sustained decrease in 1970-2002,and a consistent increase in *** observed decadal variations are likely linked to large-scale atmospheric circulation,and the correlation analysis unveiled a more important role of westerly and East Asian winter monsoon in modulating near-surface wind changes over the Tibetan *** potential physical processes associated with westerly and Asian monsoon changes are in concordance with wind speed change,in terms of overall weakened horizontal air flow(i.e.,geostrophic wind speed),declined vertical thermal and dynamic momentum transfer(i.e.,atmospheric stratification thermal instability and vertical wind shear),and varied Tibetan Plateau *** indicates that to varying degrees these processes may have contributed to the changes in near-surface wind speed over the Tibetan *** study has implications for wind power production and soil wind erosion prevention in the Tibetan Plateau.

关键词： Tibetan Plateau Wind speed Decadal change Atmospheric circulation Physical processes

Subpopulations of regulatory T cells are associated with subclinical atherosclerotic plaques,levels of LDL,and cardiorespiratory fitness in the elderly

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Journal of Sport and Health Science 2024年第3期13卷 288-296,I0002页

作者： tim Böttrich Pascal Bauer Vincent Gröβer magdalena Huber Hartmann Raifer Torsten Frech Svenja Nolte Theresa Dombrowski Franz Cemic Natascha Sommer Robert Ringseis Klaus Eder Karsten Krüger Christopher Weyh Department of Exercise Physiology and Sports Therapy Institute of Sports ScienceJustus-Liebig-UniversityGiessen 35394Germany Department of Cardiology and Angiology Justus-Liebig-University GiessenGiessen 35392Germany Institute for Systems Immunology Center for Tumor und ImmunologyMarburg 35032Germany TH mittelhessen Department of Computer ScienceUniversity of Applied Sciences GiessenGiessen 35390Germany Department of Internal medicine Universities of Giessen and Marburg Lung Center(UGMLC)Member of the German Center for Lung Research(DZL)Giessen 35394Germany Excellence Cluster Cardio-Pulmonary Institute(CPI) Justus-Liebig UniversityGiessen 35394Germany Institute of Animal Nutrition and Nutrition Physiology Justus-Liebig-University GiessenGiessen 35390Germany

Background:Atherosclerosis forms the pathological basis for the development of cardiovascular *** pathological processes initially develop without clinically relevant symptoms,the identification of early markers in the subclinical stage plays an important role for initiating early *** is evidence that regulatory T cells(Tregs)are involved in the development of ***,the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques(SAP).In addition,various lifestyle and risk factors,such as cardiorespiratory fitness,were investigated as associated ***:A cross-sectional study was performed in 79 participants(male:n=50;age=63.6±3.7 years;body mass index=24.9±3.1 kg/m2;mean±SD)who had no previous diagnosis of chronic disease and were not taking *** of the carotids to identify SAP,cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were ***,tests were conducted to assess blood lipids and determine glucose *** of Tregs and their subtypes(resting(rTregs)and effector/memory(mTregs))was performed by 8-chanel flow *** were categorized according to atherosclerotic plaque *** and logistic regression models were used to analyze associations between ***:SAP was detected in a total of 29 *** participants with plaque were older(64.8±3.6 years vs.62.9±3.5 years)and had higher peripheral systolic blood pressure(133.8±14.7 mmHg vs.125.8±10.9 mmHg).The participants with SAP were characterized by a lower percentage of rTregs(28.8%±10.7%vs.34.6%±10.7%)and a higher percentage of mTregs(40.3%±14.7%vs.30.0%±11.9%).multiple logistic regression identified age(odds ratio(OR)=1.20(95%confidence interval(95%CI):1.011.42))and

关键词： Cardiorespiratory fitness Elderly Regulatory T cells Subclinical atherosclerosis

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura J.Brylka Assil-Ramin Alimy miriam E.A.Tschaffon-müller Shan Jiang Tobias malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa melanie Haffner-Luntzer David J.Beech Frank timo Beil michael Amling Johannes Keller Anita Ignatius timur A.Yorgan tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and metabolic medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell *** we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in *** we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)*** with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate ***,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth *** skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of ***,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage ***,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) *** further observed increased Piezo1 protein abundance in cartilaginous zones of human ***,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in ***,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

东亚大槽和西伯利亚高压的季节内变率对冬季东亚气温的影响

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大气科学学报 2024年第2期47卷 184-200页

作者：李天明丁柳丹南京信息工程大学气象灾害教育部重点实验室/气候与环境变化国际联合实验室/气象灾害预报预警与评估协同创新中心江苏南京210044 夏威夷大学马诺阿分校大气科学系夏威夷檀香山96822

基于气候态定义了西伯利亚高压指数(SH index)、东亚大槽指数(ET index)和高低压系统间的东亚经向风指数(V index),使用回归分析探究西伯利亚高压和东亚大槽在季节内尺度上对东亚地区冬季温度的影响机理,构建线性模型对冬季华南地区季... 详细信息

基于气候态定义了西伯利亚高压指数(SH index)、东亚大槽指数(ET index)和高低压系统间的东亚经向风指数(V index),使用回归分析探究西伯利亚高压和东亚大槽在季节内尺度上对东亚地区冬季温度的影响机理,构建线性模型对冬季华南地区季节内尺度温度进行延伸期预报。结果表明:西伯利亚高压和东亚大槽系统变化中最显著的是季节内尺度信号;季节内尺度SH index和ET index对V index的贡献分别为82.6%和42.2%;3个指数的回归模态在对流层中层对应西北-东南向低频罗斯贝波列缓慢东南传播,低层水汽、近地面层环流、降水及2 m温度场配置良好,当西伯利亚高压深厚或东亚大槽发展时,经向风关键区北风强盛,有利于冬季高纬度地区干冷空气向东亚输送;V index对华南地区冬季季节内尺度2 m气温的有效预报时效达25 d。

关键词：西伯利亚高压东亚大槽季节内尺度变率冬季东亚气温延伸期预报

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RFLP Tagging of a Gene Pm12 for Powdery mildew Resistance in Wheat (Triticum aestivum L. )

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Science China Chemistry 1994年第5期37卷 531-537页

作者：贾继增 T.E.miller S.m.Reader m.D.gale Institute of Crop Germplasm Resources CAAS Beijing 100081 PRC Cambridge Laboratory Norwich NR4 7UJUK

A dominant gene, Pml2, conferring the resistance to powdery mildew (Erysiphe graminis) has been transferred to wheat from Aegilops speltoides. Sixteen RFLP probes were used to test Line 31 and its parents, showing that Line 31 is a 6B/6S translocation lines. The linkage analysis by five probes indicates that Pm12 is located on the chromosome 6B/6S, and tightly flanked by an RFLP marker α-Amy-1 (1.1 cm), identified by RFLP and isozyme analysis. This approach is equally applicable to the identification of other transferred alien genes and the segments of alien chromosome introgressed into wheat.

关键词： wheat powdery mildew resistance RFLP linkage.

Frog community responses to recent American bullfrog invasions

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Current Zoology 2011年第1期57卷 83-92页

作者： Yiming LI Zhunwei KE Yihua WANG tim m. BLACKBURN Key Laboratory of Animal Ecology and Conservation Biology Institute of Zoology The Chinese Academy of Sciences Chao yang District Beijing 100101 China Graduate University of the Chinese Academy of Sciences 19 Yuquan Road Beijing 100039 China Institute of Zoology ZSL Regent's Park London NW1 4RY United Kingdom

Native species may decline quickly when confronted with an exotic species to which they are not adapted. The extent of decline may depend on the abundance of an invader and the length of time since it first arrived in the community （residence time）, and the interaction between these two variables. We tested these effects using data on the effects of American bullfrog Lithobates catesbeianus invasion on native frog communities in 65 permanent lentic waters on islands in the Zhoushan Archipel- ago, China. We examined variation in native frog abundance and species richness in relation to features of the American bullfrog invasion, habitat disturbance, characteristics of the water body and fish communities and the presence of red swamp crayfish. Bullfrog invaded sites had lower native frog density and species richness, higher submerged vegetation cover and greater fre- quency of repairs to the water body than did non-invaded sites. The minimum adequate general linear mixed models showed that both native frog density and species richness were negatively related to post-metamorphosis bullfrog density, and that native frog species richness was also positively related to the vegetation cover. There was no effect on either native frog density or species richness of residence time or its interaction with bullfrog density, or of the abundance of bullfrog tadpoles. The results suggested that post-metamorphosis bullfrogs had impacts on native frog communities in the islands, and that the extents of these impacts are proportional to post-metamorphosis bullfrog density

关键词： Invader abundance Residence time Impact .American bullfrog Native frog decline