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  • 1
    Publication Date: 2018-04-17
    Description: SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival, Published online: 17 April 2018; doi:10.1038/s41388-018-0223-2 SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival
    Print ISSN: 0950-9232
    Topics: Medicine
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  • 2
    Publication Date: 2018-12-11
    Description: Trafficking of dendritic cells (DCs) to lymph nodes (LNs) to present Ags is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Matrix metalloproteinase-9 (MMP-9) is the key molecule for DC migration. Thus, blocking MMP-9 to inhibit DC migration may be a novel strategy to treat RA. In this study, we used anti–MMP-9 Ab to treat collagen-induced arthritis (CIA) in DBA/1J mice and demonstrated that anti–MMP-9 Ab treatment significantly suppressed the development of CIA via the modulation of DC trafficking. In anti–MMP-9 Ab–treated CIA mice, the number of DCs in draining LNs was obviously decreased. In vitro, anti–MMP-9 Ab and MMP-9 inhibitor restrained the migration of mature bone marrow–derived DCs in Matrigel in response to CCR7 ligand CCL21. In addition, blocking MMP-9 decreased T and B cell numbers in LNs of CIA mice but had no direct influence on the T cell response to collagen II by CD4 + T cells purified from LNs or spleen. Besides, anti–MMP-9 Ab did not impact on the expression of MHC class II, CD40, CD80, CD86, and chemokine receptors (CCR5 and CCR7) of DCs both in vivo and in vitro. Furthermore, we discovered the number of MMP-9 –/– DCs trafficking from footpads to popliteal LNs was dramatically reduced as compared with wild type DCs in both MMP-9 –/– mice and wild type mice. Taken together, these results indicated that DC-derived MMP-9 is the crucial factor for DC migration, and blocking MMP-9 to inhibit DC migration may constitute a novel strategy of future therapy for RA and other similar autoimmune diseases.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-09
    Description: Nonmuscle myosin II has been implicated in regulation of von Willebrand factor (VWF) release from endothelial Weibel-Palade bodies (WPBs), but the specific role of myosin IIa isoform is poorly defined. Here, we report that myosin IIa is expressed both in primary human endothelial cells and intact mouse vessels, essential for cyclic adenosine monophosphate (cAMP)-mediated endothelial VWF secretion. Downregulation of myosin IIa by shRNAs significantly suppressed both forskolin- and epinephrine-induced VWF secretion. Endothelium-specific myosin IIa knockout mice exhibited impaired epinephrine-stimulated VWF release, prolonged bleeding time, and thrombosis. Further study showed that in resting cells, myosin IIa deficiency disrupted the peripheral localization of Rab27-positive WPBs along stress fibers; on stimulation by cAMP agonists, myosin IIa in synergy with zyxin promotes the formation of a functional actin framework, which is derived from preexisting cortical actin filaments, around WPBs, facilitating fusion and subsequent exocytosis. In summary, our findings not only identify new functions of myosin IIa in regulation of WPB positioning and the interaction between preexisting cortical actin filaments and exocytosing vesicles before fusion but also reveal myosin IIa as a physiological regulator of endothelial VWF secretion in stress-induced hemostasis and thrombosis.
    Keywords: Thrombosis and Hemostasis, Vascular Biology
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-02-16
    Description: Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and antiandrogen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo . Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo . Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC. Clin Cancer Res; 24(4); 834–46. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Although mRNA expression of group IIA secretory phospholipase A2 (sPLA2-IIA) has been implicated in responses to injury in the CNS, information on protein expression remains unclear. In this study, we investigated temporal and spatial expression of sPLA2-IIA mRNA and immunoreactivity in transient focal cerebral ischemia induced in rats by occlusion of the middle cerebral artery. Northern blot analysis showed a biphasic increase in sPLA2-IIA mRNA expression following 60-min of ischemia–reperfusion: an early phase at 30 min and a second increase at a late phase ranging from 12 h to 14 days. In situ hybridization localized the early-phase increase in sPLA2-IIA mRNA to the affected ischemic cortex and the late-phase increase to the penumbral area. Besides sPLA2-IIA mRNA, glial fibrillary acidic protein (GFAP) and cyclo-oxygenase-2 mRNAs, but not cytosolic PLA2, also showed an increase in the penumbral area at 3 days after ischemia–reperfusion. Immunohistochemistry of sPLA2-IIA indicated positive cells in the penumbral area similar to the GFAP-positive astrocytes but different from the isolectin B4-positive microglial cells. Confocal microscopy further confirmed immunoreactivity of sPLA2-IIA in reactive astrocytes but not in microglial cells. Taken together, these results demonstrate for the first time an up-regulation of the inflammatory sPLA2-IIA in reactive astrocytes in response to cerebral ischemia–reperfusion.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-01-03
    Description: Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4 + Foxp3 + regulatory T (T reg ) cells. Those T reg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of T reg cells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2 + T reg cells and more interferon-–positive (IFN- + ) CD8 + cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.
    Print ISSN: 1945-0877
    Topics: Medicine
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  • 7
    Publication Date: 2018-02-09
    Description: The Hulunbuir short-tailed sheep ( Ovis aries ) is a breed native to China, in which the short-tail phenotype is the result of artificial and natural selection favoring a specific set of genetic mutations. Here, we analyzed the genetic differences between short-tail and normal-tail phenotypes at the genomic level. Selection signals were identified in genome-wide sequences. From 16 sheep, we identified 72,101,346 single nucleotide polymorphisms. Selection signals were detected based on the fixation index and heterozygosity. Seven genomic regions under putative selection were identified, and these regions contained nine genes. Among these genes, T was the strongest candidate as T is related to vertebral development. In T , a nonsynonymous mutation at c.G334T resulted in p.G112W substitution. We inferred that the c.G334T mutation in T leads to functional changes in Brachyury—encoded by this gene—resulting in the short-tail phenotype. Our findings provide a valuable insight into the development of the short-tail phenotype in sheep and other short-tailed animals.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 8
    Publication Date: 2018-09-20
    Description: The objectives of this study were to remove heavy metals from wastewater through the biosorption method with modified biomass as an effective sorbent and to prepare metal/biomass composites with the same modified biomass as a direct template. Eggshell membrane (ESM) was selected and modified to adsorb heavy metals. Adsorption of metal ions on the modified ESM (MESM) might be attributed to electrostatic interaction, ion exchange and coordination effect with chelating ligands containing N and S on the surface of the MESM. The pH of the solution was a key factor affecting the adsorption. The Cu–Ag/MESM composites with uniform Cu–Ag NPs were prepared with MESM as matrices, and with Cu 2+ and Ag + adsorbed as metal sources. The Cu–Ag/MESM showed excellent catalytic performance in the reduction of 4-nitrophenol to 4-aminophenol in the aqueous phase. Because of the high stability of the Cu–Ag NPs supported on the macro-dimension supporter, Cu–Ag/MESM can be easily separated after the catalytic reaction and recycled.
    Keywords: green chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 9
    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" 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/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2011-07-12
    Description: Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Potato Genome Sequencing Consortium -- Xu, Xun -- Pan, Shengkai -- Cheng, Shifeng -- Zhang, Bo -- Mu, Desheng -- Ni, Peixiang -- Zhang, Gengyun -- Yang, Shuang -- Li, Ruiqiang -- Wang, Jun -- Orjeda, Gisella -- Guzman, Frank -- Torres, Michael -- Lozano, Roberto -- Ponce, Olga -- Martinez, Diana -- De la Cruz, German -- Chakrabarti, S K -- Patil, Virupaksh U -- Skryabin, Konstantin G -- Kuznetsov, Boris B -- Ravin, Nikolai V -- Kolganova, Tatjana V -- Beletsky, Alexey V -- Mardanov, Andrei V -- Di Genova, Alex -- Bolser, Daniel M -- Martin, David M A -- Li, Guangcun -- Yang, Yu -- Kuang, Hanhui -- Hu, Qun -- Xiong, Xingyao -- Bishop, Gerard J -- Sagredo, Boris -- Mejia, Nilo -- Zagorski, Wlodzimierz -- Gromadka, Robert -- Gawor, Jan -- Szczesny, Pawel -- Huang, Sanwen -- Zhang, Zhonghua -- Liang, Chunbo -- He, Jun -- Li, Ying -- He, Ying -- Xu, Jianfei -- Zhang, Youjun -- Xie, Binyan -- Du, Yongchen -- Qu, Dongyu -- Bonierbale, Merideth -- Ghislain, Marc -- Herrera, Maria del Rosario -- Giuliano, Giovanni -- Pietrella, Marco -- Perrotta, Gaetano -- Facella, Paolo -- O'Brien, Kimberly -- Feingold, Sergio E -- Barreiro, Leandro E -- Massa, Gabriela A -- Diambra, Luis -- Whitty, Brett R -- Vaillancourt, Brieanne -- Lin, Haining -- Massa, Alicia N -- Geoffroy, Michael -- Lundback, Steven -- DellaPenna, Dean -- Buell, C Robin -- Sharma, Sanjeev Kumar -- Marshall, David F -- Waugh, Robbie -- Bryan, Glenn J -- Destefanis, Marialaura -- Nagy, Istvan -- Milbourne, Dan -- Thomson, Susan J -- Fiers, Mark -- Jacobs, Jeanne M E -- Nielsen, Kare L -- Sonderkaer, Mads -- Iovene, Marina -- Torres, Giovana A -- Jiang, Jiming -- Veilleux, Richard E -- Bachem, Christian W B -- de Boer, Jan -- Borm, Theo -- Kloosterman, Bjorn -- van Eck, Herman -- Datema, Erwin -- Hekkert, Bas te Lintel -- Goverse, Aska -- van Ham, Roeland C H J -- Visser, Richard G F -- BB/F012640/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/F012640/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2011 Jul 10;475(7355):189-95. doi: 10.1038/nature10158.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Chinese Ministry of Agricultural, Key Lab of Genomics, Beishan Industrial Zone, Yantian District, Shenzhen 518083, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21743474" target="_blank"〉PubMed〈/a〉
    Keywords: Evolution, Molecular ; Gene Duplication ; Gene Expression Regulation, Plant ; Genes, Plant/genetics ; Genetic Variation ; Genome, Plant/*genetics ; *Genomics ; Haplotypes/genetics ; Heterozygote ; Homozygote ; Immunity, Innate ; Inbreeding ; Molecular Sequence Annotation ; Molecular Sequence Data ; Plant Diseases/genetics ; Ploidies ; Solanum tuberosum/*genetics/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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