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  • 1
    Publication Date: 2018-10-18
    Description: Epilepsy is a common neurological disease, and approximately 30% of patients do not respond adequately to antiepileptic drug treatment. Recent studies suggest that G protein–coupled receptor 40 (GPR40) is expressed in the central nervous system and is involved in the regulation of neurological function. However, the impact of GPR40 on epileptic seizures remains unclear. In this study, we first reported that GPR40 expression was increased in epileptic brains. In the kainic acid–induced epilepsy model, GPR40 activation after status epilepticus alleviated epileptic activity, whereas GPR40 inhibition showed the opposite effect. In the pentylenetetrazole-induced kindling model, susceptibility to epilepsy was reduced with GPR40 activation and increased with GPR40 inhibition. Whole-cell patch-clamp recordings demonstrated that GPR40 affected N -methyl- d -aspartate (NMDA) receptor–mediated synaptic transmission. Moreover, GPR40 regulated NR2A and NR2B expression on the surface of neurons. In addition, endocytosis of NMDA receptors and binding of GPR40 with NR2A and NR2B can be regulated by GPR40. Together, our findings indicate that GPR40 modulates epileptic seizures, providing a novel antiepileptic target.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 2
    Publication Date: 2018-06-20
    Description: Objectives We aimed to evaluate the relation of total homocysteine (tHcy) concentrations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels, and examine the possible modifiers in the association among a general population of Chinese adults. Design A cross-sectional study. Setting The study was conducted within 21 communities in Lianyungang of Jiangsu province, China. Participants A total of 26 648 participants aged ≥35 years and with no antihypertensive drug use were included in the final analysis. Results Overall, there was a positive association between tHcy concentrations and SBP (per 5 μmol/L tHcy increase: adjusted β=0.45 mm Hg; 95% CI 0.29 to 0.61) or DBP levels (per 5 μmol/L tHcy increase: adjusted β=0.47 mm Hg; 95% CI 0.35 to 0.59). Compared with participants with tHcy 〈10 μmol/L, significantly higher SBP levels were found in those with tHcy concentrations of 10 to 〈15 (adjusted β=0.80 mm Hg; 95% CI 0.32 to 1.28) and ≥15 µmol/L (adjusted β=1.79 mm Hg; 95% CI 1.20 to 2.37; p for trend 〈0.001). Consistently, significantly higher DBP levels were found in participants with tHcy concentrations of 10 to 〈15 (adjusted β=0.86 mm Hg; 95% CI 0.49 to 1.22) and ≥15 µmol/L (adjusted β=2.01 mm Hg; 95% CI 1.57 to 2.46; p for trend 〈0.001), respectively as compared with those with 〈10 μmol/L. Furthermore, a stronger association between tHcy and SBP (p for interaction=0.009) or DBP (p for interaction=0.067) was found in current alcohol drinkers. Conclusion Serum tHcy concentrations were positively associated with both SBP and DBP levels in a general Chinese adult population. The association was stronger in current alcohol drinkers.
    Keywords: Open access, Epidemiology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 3
    Publication Date: 2018-05-17
    Description: Aims To fully elucidate the clinicopathological features of breast carcinoma in sclerosing adenosis (SA-BC). Methods Clinical and histological characteristics of 206 SA-BCs from 180 patients were retrospectively evaluated. Immunohistochemical phenotype was examined. The clinicopathological relevance of the topographical pattern of SA-BCs was analysed. Results Overall, up to 46 patients (25.6%) had contralateral cancer, either SA associated or not. Of 99 cases who underwent core needle biopsy (CNB), 36 were underestimated as adenosis or atypical ductal hyperplasia at CNB, 5 invasive cases were misinterpreted as in situ carcinomas, whereas 4 ductal carcinoma in situ (DCIS) cases were overdiagnosed as invasive carcinoma. Microscopically, 163 tumours were in situ, including 136 DCIS, 19 lobular carcinomas in situ (LCIS) and 8 mixed DCIS/LCIS; of these carcinomas in situ (CIS), 37 had microinvasion. The DCIS group exhibited low, intermediate and high grades in 53.7%, 34.6% and 11.8% of cases, respectively, mostly with solid (43.4%) or cribriform (41.9%) pattern. Forty out of 43 invasive cases were invasive ductal carcinoma (IDC), mostly DCIS predominant. Immunophenotypically, luminal A phenotype was identified in 55.1%, 63.2% and 45.0% of DCIS, LCIS and IDC cases, respectively. Topographical type A group (carcinoma being entirely confined to SA, n=176) was characterised by smaller size, less invasiveness, lower grade and more frequency of luminal A immunophenotype compared with type B group (≥ 50% but not all of the carcinomatous lesion being located in SA, n=30) (all P〈0.05). Conclusions CIS, especially non-high-grade DCIS, represents the most common variant of SA-BC, and luminal A is the most predominant immunophenotype. CNB assessment might be challenging in some SA-BCs. The topographical pattern has great clinicopathological relevance. Careful evaluation of the contralateral breast and long-term follow-up for patients with SA-BC is necessary given its high prevalence of bilaterality.
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
    Publication Date: 2018-03-15
    Description: Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase–1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N -ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE)–mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor–α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor B pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 5
    Publication Date: 2018-01-04
    Description: Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor ( EGFR ) mutation-positive NSCLC patients with LM. Results: The status of EGFR -activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 6
    Publication Date: 2018-01-05
    Description: Zhaoying Yang, Xiaocui Zhao, Jiashen Xu, Weina Shang, and Chao Tong Mitochondria–ER contact sites (MERCs) enable communication between the ER and mitochondria and serve as platforms for many cellular events, including autophagy. Nonetheless, the molecular organization of MERCs is not known, and there is no bona fide marker of these contact sites in mammalian cells. In this study, we designed a genetically encoded reporter using split GFP protein for labeling MERCs. We subsequently analyzed its distribution and dynamics during the cell cycle and under stressful cellular conditions such as starvation, apoptosis and ER stress. We found that MERCs are dynamic structures that undergo remodeling within minutes. Mitochondrial morphology, but not ER morphology, affected the distribution of MERCs. We also found that carbonyl cyanidem-chlorophenyl hydrazone (CCCP) and oligomycin A treatment enhanced MERC formation. The stimulations that led to apoptosis or autophagy increased the MERC signal. By contrast, increasing cellular lipid droplet load did not change the pattern of MERCs.
    Keywords: Imaging
    Print ISSN: 0021-9533
    Electronic ISSN: 1477-9137
    Topics: Biology , Medicine
    Published by Company of Biologists
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  • 7
    Publication Date: 2018-01-23
    Description: Xin Gao, Chunliang Xu, Noboru Asada, and Paul S. Frenette Hematopoietic stem cells (HSCs) develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver, and finally to the bone marrow, where most HSCs reside throughout adult life. These niches provide supportive microenvironments that specify, expand and maintain HSCs. Understanding the constituents and molecular regulation of HSC niches is of considerable importance as it could shed new light on the mechanistic principles of HSC emergence and maintenance, and provide novel strategies for regenerative medicine. However, controversy exists concerning the cellular complexity of the bone marrow niche, and our understanding of the different HSC niches during development remains limited. In this Review, we summarize and discuss what is known about the heterogeneity of the HSC niches at distinct stages of their ontogeny, from the embryo to the adult bone marrow, drawing predominantly on data from mouse studies.
    Keywords: Stem cells & regeneration
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 8
    Publication Date: 2014-02-22
    Description: The high cost of powerful, large-stroke, high-stress artificial muscles has combined with performance limitations such as low cycle life, hysteresis, and low efficiency to restrict applications. We demonstrated that inexpensive high-strength polymer fibers used for fishing line and sewing thread can be easily transformed by twist insertion to provide fast, scalable, nonhysteretic, long-life tensile and torsional muscles. Extreme twisting produces coiled muscles that can contract by 49%, lift loads over 100 times heavier than can human muscle of the same length and weight, and generate 5.3 kilowatts of mechanical work per kilogram of muscle weight, similar to that produced by a jet engine. Woven textiles that change porosity in response to temperature and actuating window shutters that could help conserve energy were also demonstrated. Large-stroke tensile actuation was theoretically and experimentally shown to result from torsional actuation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haines, Carter S -- Lima, Marcio D -- Li, Na -- Spinks, Geoffrey M -- Foroughi, Javad -- Madden, John D W -- Kim, Shi Hyeong -- Fang, Shaoli -- Jung de Andrade, Monica -- Goktepe, Fatma -- Goktepe, Ozer -- Mirvakili, Seyed M -- Naficy, Sina -- Lepro, Xavier -- Oh, Jiyoung -- Kozlov, Mikhail E -- Kim, Seon Jeong -- Xu, Xiuru -- Swedlove, Benjamin J -- Wallace, Gordon G -- Baughman, Ray H -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):868-72. doi: 10.1126/science.1246906.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Alan G. MacDiarmid NanoTech Institute, University of Texas at Dallas, Richardson, TX 75083, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24558156" target="_blank"〉PubMed〈/a〉
    Keywords: *Cotton Fiber ; Humans ; Muscles/chemistry/ultrastructure ; *Nylons ; Polymers ; Porosity ; *Tensile Strength ; *Torsion, Mechanical
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-05-02
    Description: Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1alpha and nuclear lamina-heterochromatin anchoring protein LAP2beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Weiqi -- Li, Jingyi -- Suzuki, Keiichiro -- Qu, Jing -- Wang, Ping -- Zhou, Junzhi -- Liu, Xiaomeng -- Ren, Ruotong -- Xu, Xiuling -- Ocampo, Alejandro -- Yuan, Tingting -- Yang, Jiping -- Li, Ying -- Shi, Liang -- Guan, Dee -- Pan, Huize -- Duan, Shunlei -- Ding, Zhichao -- Li, Mo -- Yi, Fei -- Bai, Ruijun -- Wang, Yayu -- Chen, Chang -- Yang, Fuquan -- Li, Xiaoyu -- Wang, Zimei -- Aizawa, Emi -- Goebl, April -- Soligalla, Rupa Devi -- Reddy, Pradeep -- Esteban, Concepcion Rodriguez -- Tang, Fuchou -- Liu, Guang-Hui -- Belmonte, Juan Carlos Izpisua -- F32 AG047770/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. Epub 2015 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ; Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ; State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. ; Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; College of Life Sciences, Peking University, Beijing 100871, China. ; The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Universidad Catolica San Antonio de Murcia, Campus de los Jeronimos s/n, 30107 Guadalupe, Murcia, Spain. ; Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu. ; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Beijing Institute for Brain Disorders, Beijing 100069, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu. ; Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25931448" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics/*metabolism ; Animals ; *Cell Aging ; Cell Differentiation ; Centromere/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins/metabolism ; Epigenesis, Genetic ; Exodeoxyribonucleases/genetics/*metabolism ; Gene Knockout Techniques ; HEK293 Cells ; Heterochromatin/chemistry/*metabolism ; Humans ; Membrane Proteins/metabolism ; Mesenchymal Stromal Cells/*metabolism ; Methyltransferases/genetics/metabolism ; Mice ; Models, Biological ; RecQ Helicases/genetics/*metabolism ; Repressor Proteins/genetics/metabolism ; Werner Syndrome/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2015-08-08
    Description: Detailed geodetic imaging of earthquake ruptures enhances our understanding of earthquake physics and associated ground shaking. The 25 April 2015 moment magnitude 7.8 earthquake in Gorkha, Nepal was the first large continental megathrust rupture to have occurred beneath a high-rate (5-hertz) Global Positioning System (GPS) network. We used GPS and interferometric synthetic aperture radar data to model the earthquake rupture as a slip pulse ~20 kilometers in width, ~6 seconds in duration, and with a peak sliding velocity of 1.1 meters per second, which propagated toward the Kathmandu basin at ~3.3 kilometers per second over ~140 kilometers. The smooth slip onset, indicating a large (~5-meter) slip-weakening distance, caused moderate ground shaking at high frequencies (〉1 hertz; peak ground acceleration, ~16% of Earth's gravity) and minimized damage to vernacular dwellings. Whole-basin resonance at a period of 4 to 5 seconds caused the collapse of tall structures, including cultural artifacts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galetzka, J -- Melgar, D -- Genrich, J F -- Geng, J -- Owen, S -- Lindsey, E O -- Xu, X -- Bock, Y -- Avouac, J-P -- Adhikari, L B -- Upreti, B N -- Pratt-Sitaula, B -- Bhattarai, T N -- Sitaula, B P -- Moore, A -- Hudnut, K W -- Szeliga, W -- Normandeau, J -- Fend, M -- Flouzat, M -- Bollinger, L -- Shrestha, P -- Koirala, B -- Gautam, U -- Bhatterai, M -- Gupta, R -- Kandel, T -- Timsina, C -- Sapkota, S N -- Rajaure, S -- Maharjan, N -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1091-5. doi: 10.1126/science.aac6383. Epub 2015 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geology and Planetary Sciences, California Institute of Technology (Caltech), Pasadena, CA 91125, USA. ; BerkeleySeismological Laboratory, University of California (UC)-Berkeley, Berkeley, CA 94720, USA. ; Cecil H. and Ida M. Green Institute of Geophysics and Planetary Physics, Scripps Institution of Oceanography, UC-San Diego, La Jolla, CA 92037, USA. ; Jet Propulsion Laboratory (JPL), Caltech, Pasadena, CA 91109, USA. ; Department of Earth Sciences, University of Cambridge, Cambridge CB2 3EQ, UK. Department of Geology and Planetary Sciences, California Institute of Technology (Caltech), Pasadena, CA 91125, USA. ; Department of Mines and Geology, Lainchour, Kathmandu, Nepal. ; Nepal Academy of Science and Technology, Khumaltar, Lalitpur, Nepal. ; Department of Geological Sciences, Central Washington University (CWU), Ellensberg, WA 98926, USA. ; Tri-Chandra Campus, Tribhuvan University, Ghantaghar, Kathmandu, Nepal. ; U.S. Geological Survey (USGS), Pasadena, CA 91106, USA. ; Pacific Northwest Geodetic Array and Department of Geological Sciences, CWU, Ellensberg, WA 98926, USA. ; UNAVCO, Boulder, CO 80301, USA. ; Departement Analyse et Sureveillance de l'Environnement (DASE), Commissariat a l'Energie Atomique (CEA), 91297 Bruyeres-le-Chatel, Arpajon, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26249228" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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