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  • 1
    Publication Date: 2014-07-22
    Description: The gamma-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-beta, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human gamma-secretase complex at 4.5 A resolution, determined by cryo-electron-microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the gamma-secretase complex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134323/" 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/PMC4134323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Peilong -- Bai, Xiao-chen -- Ma, Dan -- Xie, Tian -- Yan, Chuangye -- Sun, Linfeng -- Yang, Guanghui -- Zhao, Yanyu -- Zhou, Rui -- Scheres, Sjors H W -- Shi, Yigong -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2014 Aug 14;512(7513):166-70. doi: 10.1038/nature13567. Epub 2014 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK [2]. ; 1] Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043039" target="_blank"〉PubMed〈/a〉
    Keywords: Amyloid Precursor Protein Secretases/*chemistry ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Humans ; *Models, Molecular ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-03-06
    Description: The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning. Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT(-) cells, release the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425585/" 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/PMC4425585/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saunders, Arpiar -- Oldenburg, Ian A -- Berezovskii, Vladimir K -- Johnson, Caroline A -- Kingery, Nathan D -- Elliott, Hunter L -- Xie, Tiao -- Gerfen, Charles R -- Sabatini, Bernardo L -- F31 MH093026/MH/NIMH NIH HHS/ -- F31 NS074842/NS/NINDS NIH HHS/ -- F31-MH093026-01A1/MH/NIMH NIH HHS/ -- NS072030/NS/NINDS NIH HHS/ -- P30 EY002520/EY/NEI NIH HHS/ -- P30 EY012196/EY/NEI NIH HHS/ -- P30 EY12196/EY/NEI NIH HHS/ -- P30 NS072030/NS/NINDS NIH HHS/ -- R01 NS046579/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 May 7;521(7550):85-9. doi: 10.1038/nature14179. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Neurobiology Imaging Facility, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Image and Data Analysis Core, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739505" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-05-24
    Description: The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155806/" 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/PMC3155806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Batista, Luis F Z -- Pech, Matthew F -- Zhong, Franklin L -- Nguyen, Ha Nam -- Xie, Kathleen T -- Zaug, Arthur J -- Crary, Sharon M -- Choi, Jinkuk -- Sebastiano, Vittorio -- Cherry, Athena -- Giri, Neelam -- Wernig, Marius -- Alter, Blanche P -- Cech, Thomas R -- Savage, Sharon A -- Reijo Pera, Renee A -- Artandi, Steven E -- R01 AG033747/AG/NIA NIH HHS/ -- R01 AG033747-02/AG/NIA NIH HHS/ -- R01 CA111691/CA/NCI NIH HHS/ -- R01 CA111691-05/CA/NCI NIH HHS/ -- R01 CA125453/CA/NCI NIH HHS/ -- R01 CA125453-05/CA/NCI NIH HHS/ -- RC1 HL100361/HL/NHLBI NIH HHS/ -- RC1 HL100361-01/HL/NHLBI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 May 22;474(7351):399-402. doi: 10.1038/nature10084.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21602826" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/genetics/metabolism ; Cell Division ; Cellular Reprogramming ; Dyskeratosis Congenita/*genetics/*pathology ; Fibroblasts ; Gene Expression Regulation ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*pathology ; Nuclear Proteins/genetics/metabolism ; RNA/genetics ; Telomerase/genetics/metabolism ; Telomere/enzymology/genetics/metabolism/*pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-08-15
    Description: The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1-8, and removes Nedd8 modifications from target proteins. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pan, Lei -- Wang, Su -- Lu, Tinglin -- Weng, Changjiang -- Song, Xiaoqing -- Park, Joseph K -- Sun, Jin -- Yang, Zhi-Hao -- Yu, Junjing -- Tang, Hong -- McKearin, Dennis M -- Chamovitz, Daniel A -- Ni, Jianquan -- Xie, Ting -- GM64428/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):233-6. doi: 10.1038/nature13562.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China [3]. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA [3]. ; 1] Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [2]. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA. ; 1] Department of Molecular Biology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA. ; Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China. ; Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, 15 Da Tun Road, Beijing 100101, China. ; Department of Plant Sciences, Tel Aviv University, Tel Aviv 69978, Israel. ; 1] Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA [2] Department of Cell Biology and Anatomy, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119050" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Binding, Competitive ; *Cell Differentiation ; Cell Proliferation ; DNA Helicases/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*cytology/*metabolism ; Female ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Multiprotein Complexes/*chemistry/*metabolism ; Ovary/cytology ; Peptide Hydrolases/*chemistry/*metabolism ; Protein Binding ; Stem Cells/*cytology/*metabolism ; Ubiquitins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-12-18
    Description: The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 A, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338550/" 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/PMC4338550/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Zhen -- Bai, Xiao-chen -- Yan, Chuangye -- Wu, Jianping -- Li, Zhangqiang -- Xie, Tian -- Peng, Wei -- Yin, Chang-cheng -- Li, Xueming -- Scheres, Sjors H W -- Shi, Yigong -- Yan, Nieng -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Jan 1;517(7532):50-5. doi: 10.1038/nature14063. Epub 2014 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; 1] Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; Department of Biophysics, the Health Science Center &Center for Protein Science, Peking University, Beijing 100191, China. ; Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517095" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Allosteric Regulation ; Animals ; Cryoelectron Microscopy ; Ion Channel Gating ; Models, Molecular ; Molecular Weight ; Protein Multimerization ; Protein Structure, Tertiary ; Rabbits ; Ryanodine Receptor Calcium Release Channel/*chemistry/metabolism/*ultrastructure ; Sarcoplasmic Reticulum/chemistry ; Tacrolimus Binding Protein 1A/chemistry/metabolism/ultrastructure ; Zinc Fingers
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2016-03-24
    Description: Primary cilia are solitary, generally non-motile, hair-like protrusions that extend from the surface of cells between cell divisions. Their antenna-like structure leads naturally to the assumption that they sense the surrounding environment, the most common hypothesis being sensation of mechanical force through calcium-permeable ion channels within the cilium. This Ca(2+)-responsive mechanosensor hypothesis for primary cilia has been invoked to explain a large range of biological responses, from control of left-right axis determination in embryonic development to adult progression of polycystic kidney disease and some cancers. Here we report the complete lack of mechanically induced calcium increases in primary cilia, in tissues upon which this hypothesis has been based. We developed a transgenic mouse, Arl13b-mCherry-GECO1.2, expressing a ratiometric genetically encoded calcium indicator in all primary cilia. We then measured responses to flow in primary cilia of cultured kidney epithelial cells, kidney thick ascending tubules, crown cells of the embryonic node, kinocilia of inner ear hair cells, and several cell lines. Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological levels of fluid flow. We conclude that mechanosensation, if it originates in primary cilia, is not via calcium signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851444/" 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/PMC4851444/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delling, M -- Indzhykulian, A A -- Liu, X -- Li, Y -- Xie, T -- Corey, D P -- Clapham, D E -- 5R01 DC000304/DC/NIDCD NIH HHS/ -- P30-HD 18655/HD/NICHD NIH HHS/ -- R01 DC000304/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 31;531(7596):656-60. doi: 10.1038/nature17426. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Image and Data Analysis Core (IDAC), Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007841" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/analysis/*metabolism ; Calcium Signaling ; Cilia/*metabolism ; Embryo, Mammalian/cytology ; Epithelial Cells/cytology ; Female ; Hair Cells, Auditory, Inner/cytology ; Kidney/cytology ; Male ; *Mechanotransduction, Cellular ; Mice ; Mice, Transgenic ; Models, Biological
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2018-10-17
    Description: Circular RNAs (circRNAs) are a novel class of regulatory RNAs. Here, we present a comprehensive investigation of circRNA expression profiles across 11 tissues and four developmental stages in rats, along with cross-species analyses in humans and mice. Although the expression of circRNAs is positively correlated with that of cognate mRNAs, highly expressed genes tend to splice a larger fraction of circular transcripts. Moreover, circRNAs exhibit higher tissue specificity than cognate mRNAs. Intriguingly, while we observed a monotonic increase of circRNA abundance with age in the rat brain, we further discovered a dynamic, age-dependent pattern of circRNA expression in the testes that is characterized by a dramatic increase with advancing stages of sexual maturity and a decrease with aging. The age-sensitive testicular circRNAs are highly associated with spermatogenesis, independent of cognate mRNA expression. The tissue/age implications of circRNAs suggest that they present unique physiological functions rather than simply occurring as occasional by-products of gene transcription.
    Print ISSN: 1355-8382
    Electronic ISSN: 1469-9001
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-03-06
    Description: Introduction Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. Methods and analysis This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. Ethics and dissemination The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. Trial registration number NCT02284750 ; Pre-results.
    Keywords: Open access, Cardiovascular medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 9
    Publication Date: 2018-01-10
    Description: We read with interest the article of recent advances in clinical practice of hepatocellular carcinoma (HCC) treatment by Bruix et al in Gut. 1 In this review, the Barcelona Clinic Liver Cancer (BCLC) Group recommended sorafenib as the standard treatment for BCLC-C stage (advanced stage) HCC. However, application of sorafenib as first treatment for advanced HCC worldwide was low according to a multiregional, large-scale, longitudinal cohort study. 2 This may be attributed to some limitations of sorafenib: low response rate, modest survival advantage, complex mechanism underlying acquired resistance and high-level heterogeneity of individual response. 3 4 Recently, evidence from an individual patient data meta-analysis of phase III randomised controlled trial showed no improvement in overall survival attributable to sorafenib for HBV-related HCC. 5 Therefore, more alternative strategies are highly required. 6 Hepatic arterial infusion (HAI) chemotherapy (HAIC) attracted more attentions in recent...
    Keywords: Gut
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 10
    Publication Date: 2018-02-10
    Description: Mitotic chromosomes fold as compact arrays of chromatin loops. To identify the pathway of mitotic chromosome formation, we combined imaging and Hi-C analysis of synchronous DT40 cell cultures with polymer simulations. Here we show that in prophase, the interphase organization is rapidly lost in a condensin-dependent manner, and arrays of consecutive 60-kilobase (kb) loops are formed. During prometaphase, ~80-kb inner loops are nested within ~400-kb outer loops. The loop array acquires a helical arrangement with consecutive loops emanating from a central "spiral staircase" condensin scaffold. The size of helical turns progressively increases to ~12 megabases during prometaphase. Acute depletion of condensin I or II shows that nested loops form by differential action of the two condensins, whereas condensin II is required for helical winding.
    Keywords: Cell Biology, Molecular Biology, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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