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Find video protocols related to scientific articles indexed in Pubmed.
Recovery time of platelet function after aspirin withdrawal.
Curr Ther Res Clin Exp
PUBLISHED: 12-01-2014
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Inappropriate antiplatelet therapy discontinuation increases the risk of thrombotic complications and bleeding after dental procedures. To determine the platelet reactivity recovery time after aspirin withdrawal in vivo, our study was conducted in patients with low-risk cardiovascular disease who can stop aspirin administration following the guidelines stipulated by the American College of Chest Physicians. The time it takes for platelet activity to normalize and the diagnostic accuracy of testing methods were assessed for a residual antiplatelet activity with multiple electrode aggregometry. Our study included patients with clinically indicated hypertension preparing for a dental extraction procedure.
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Mortality and Outcomes in Very Elderly Patients 90 Years of Age or Older Admitted to the ICU.
Respir Care
PUBLISHED: 11-20-2014
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We evaluated the clinical characteristics and factors associated with mortality in very elderly patients ? 90 y of age admitted to the ICU.
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Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-19-2014
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In the fasted state, increases in catecholamine signaling promote adipocyte function via the protein kinase A-mediated phosphorylation of cyclic AMP response element binding protein (CREB). CREB activity is further up-regulated in obesity, despite reductions in catecholamine signaling, where it contributes to the development of insulin resistance. Here we show that obesity promotes the CREB binding protein (CBP)-mediated acetylation of CREB at Lys136 in adipose. Under lean conditions, CREB acetylation was low due to an association with the energy-sensing NAD(+)-dependent deacetylase SirT1; amounts of acetylated CREB were increased in obesity, when SirT1 undergoes proteolytic degradation. Whereas CREB phosphorylation stimulated an association with the KIX domain of CBP, Lys136 acetylation triggered an interaction with the CBP bromodomain (BRD) that augmented recruitment of this coactivator to the promoter. Indeed, coincident Ser133 phosphorylation and Lys136 acetylation of CREB stimulated the formation of a ternary complex with the KIX and BRD domains of CBP by NMR analysis. As disruption of the CREB:BRD complex with a CBP-specific BRD inhibitor blocked effects of CREB acetylation on target gene expression, our results demonstrate how changes in nutrient status modulate cellular gene expression in response to hormonal signals.
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Inappropriate Continued Use of Empirical Vancomycin in a Hospital with a High Prevalence of MRSA.
Antimicrob. Agents Chemother.
PUBLISHED: 11-19-2014
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Vancomycin is frequently inappropriately prescribed, especially as empirical treatment. The aim of this study was to evaluate (1) the amount of inappropriate continued use of empirical vancomycin as a proportion of total vancomycin use, and (2) the risk factors associated with inappropriate continued use of empirical vancomycin.
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Psychiatry in former socialist countries: implications for north korean psychiatry.
Psychiatry Investig
PUBLISHED: 10-20-2014
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Very little information is available regarding psychiatry in North Korea, which is based on the legacy of Soviet psychiatry. This paper reviews the characteristics of psychiatry in former socialist countries and discusses its implications for North Korean psychiatry. Under socialism, psychiatric disorders were attributed primarily to neurophysiologic or neurobiological origins. Psychosocial or psychodynamic etiology was denied or distorted in line with the political ideology of the Communist Party. Psychiatry was primarily concerned with psychotic disorders, and this diagnostic category was sometimes applied based on political considerations. Neurotic disorders were ignored by psychiatry or were regarded as the remnants of capitalism. Several neurotic disorders characterized by high levels of somatization were considered to be neurological or physical in nature. The majority of "mental patients" were institutionalized for a long periods in large-scale psychiatric hospitals. Treatment of psychiatric disorders depended largely on a few outdated biological therapies. In former socialist countries, psychodynamic psychotherapy was not common, and psychiatric patients were likely to experience social stigma. According to North Korean doctors living in South Korea, North Korean psychiatry is heavily influenced by the aforementioned traditions of psychiatry. During the post-socialist transition, the suicide rate in many of these countries dramatically increased. Given such mental health crises in post-socialist transitional societies, the field of psychiatry may face major challenges in a future unified Korea.
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P2Y2R activation by nucleotides released from the highly metastatic breast cancer cell MDA-MB-231 contributes to pre-metastatic niche formation by mediating lysyl oxidase secretion, collagen crosslinking, and monocyte recruitment.
Oncotarget
PUBLISHED: 09-20-2014
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Tumor microenvironmental hypoxia induces hypoxia inducible factor-1? (HIF-1?) overexpression, leading to the release of lysyl oxidase (LOX), which crosslinks collagen at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Our previous study showed that activation of the P2Y2 receptor (P2Y2R) by ATP released from MDA-MB-231 cells increased MDA-MB-231 cell invasion through endothelial cells. Therefore, in this study, we investigated the role of P2Y2R in breast cancer cell metastasis to distant sites. ATP or UTP released from hypoxia-treated MDA-MB-231 cells induced HIF-1? expression and LOX secretion by the activation of P2Y2R, and this phenomenon was significantly reduced in P2Y2R-depleted MDA-MB-231 cells. Furthermore, P2Y2R-mediated LOX release induced collagen crosslinking in an in vitro model. Finally, nude mice injected with MDA-MB-231 cells showed high levels of LOX secretion, crosslinked collagen and CD11b+ BMDC recruitment in the lung; however, mice that were injected with P2Y2R-depleted MDA-MB-231 cells did not exhibit these changes. These results demonstrate that P2Y2R plays an important role in activation of the HIF-1?-LOX axis, the induction of collagen crosslinking and the recruitment of CD11b+ BMDCs. Furthermore, P2Y2R activation by nucleotides recruits THP-1 monocytes, resulting in primary tumor progression and pre-metastatic niche formation.
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Large Solid Hemangioblastoma in the Cerebellopontine Angle: Complete Resection Using the Transcondylar Fossa Approach.
Brain Tumor Res Treat
PUBLISHED: 09-01-2014
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Hemangioblastomas (HBMs) in the cerebellopontine angle (CPA) have rarely been reported. When they are within the CPA, they may be misdiagnosed as vestibular schwannoma (VS) or cystic meningioma. Therefore, differential diagnosis is important for the safe treatment of the lesion. Large solid HBMs, similar to intracranial arteriovenous malformations (AVMs), are difficult to surgically remove from an eloquent area because of their location and hypervascularity. We report a case of an HBM in the CPA, which manifested as a hearing impairment or VS. Similar to AVM surgery, the tumor was widely opened and removed en bloc without a new neurological complication using the modified transcondylar fossa approach without resection of the jugular tubercle. Accurate diagnosis, pre-operative embolization, and a tailored approach were essential for the safe treatment of the HBM in the CPA.
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Use of APACHE II and SAPS II to predict mortality for hemorrhagic and ischemic stroke patients.
J Clin Neurosci
PUBLISHED: 08-26-2014
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We studied the applicability of the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score II (SAPS II) in patients admitted to the intensive care unit (ICU) with acute stroke and compared the results with the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS). We also conducted a comparative study of accuracy for predicting hemorrhagic and ischemic stroke mortality. Between January 2011 and December 2012, ischemic or hemorrhagic stroke patients admitted to the ICU were included in the study. APACHE II and SAPS II-predicted mortalities were compared using a calibration curve, the Hosmer-Lemeshow goodness-of-fit test, and the receiver operating characteristic (ROC) curve, and the results were compared with the GCS and NIHSS. Overall 498 patients were included in this study. The observed mortality was 26.3%, whereas APACHE II and SAPS II-predicted mortalities were 35.12% and 35.34%, respectively. The mean GCS and NIHSS scores were 9.43 and 21.63, respectively. The calibration curve was close to the line of perfect prediction. The ROC curve showed a slightly better prediction of mortality for APACHE II in hemorrhagic stroke patients and SAPS II in ischemic stroke patients. The GCS and NIHSS were inferior in predicting mortality in both patient groups. Although both the APACHE II and SAPS II systems can be used to measure performance in the neurosurgical ICU setting, the accuracy of APACHE II in hemorrhagic stroke patients and SAPS II in ischemic stroke patients was superior.
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P2Y2 receptor activation by nucleotides released from highly metastatic breast cancer cells increases tumor growth and invasion via crosstalk with endothelial cells.
Breast Cancer Res.
PUBLISHED: 08-26-2014
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Extracellular nucleotides are released and detectable in a high concentration within the tumor microenvironment. G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is activated equipotently by adenosine triphosphate (ATP) and uridine 5[prime]-triphosphate (UTP), which mediate proinflammatory responses such as cell migration and proliferation. However, the role of P2Y2R in the process of cancer metastasis remains unclear. This study aimed to determine the role of P2Y2R in the proliferation, migration and invasion of highly metastatic MDA-MB-231 breast cancer cells through crosstalk with endothelial cells (ECs).
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The expression of aminoacyl-tRNA-synthetase-interacting multifunctional protein-1 (Aimp1) is regulated by estrogen in the mouse uterus.
Mol. Cell. Endocrinol.
PUBLISHED: 08-15-2014
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Aimp1 is known as a multifunctional cytokine in various cellular events. Recent study showed Aimp1 is localized in glandular epithelial, endothelial, and stromal cells in functionalis and basalis layers of the endometrium. However, the regulatory mechanism of Aimp1 in the uterus remains unknown. In the present study, we found that Aimp1 is expressed in the mouse uterus. Aimp1 transcripts were decreased at diestrus stage. However, the level of Aimp1 protein was significantly increased in the luminal epithelium in the uterine endometrium at estrus stage during the estrous cycle. We found that treatment of estrogen increased the expression of Aimp1 in the uterus in ovarectomized mice. We identified one estrogen receptor binding element (ERE) on mouse Aimp1 promoter. The activity of Aimp1 promoter was increased with estrogen treatment. Our findings indicate that Aimp1 might act as an important regulator to remodel the uterine endometrium and its expression might be regulated by estrogen during the estrous cycle. This will give us better understanding of the dynamic change of uterine remodeling during the estrous cycle.
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Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions.
J. Cell. Mol. Med.
PUBLISHED: 08-11-2014
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Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1 R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and -4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and -4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-?B and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-?, IL-6 and IL-1?) production and NF-?B activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1 R in THP-1 cells or CHO cells, which were devoid of AT1 R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2, -4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation.
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The associations between bridal pregnancy and obstetric outcomes among live births in Korea: population-based study.
PLoS ONE
PUBLISHED: 08-08-2014
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In East Asia the recently increased number of marriages in response to pregnancy is an important social issue. This study evaluated the association of marriage preceded by pregnancy (bridal pregnancy) with obstetric outcomes among live births in Korea.
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Influenza vaccination and associated factors among Korean cancer survivors : a cross-sectional analysis of the Fourth & Fifth Korea National Health and Nutrition Examination Surveys.
J. Korean Med. Sci.
PUBLISHED: 07-30-2014
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Influenza vaccination is important for cancer survivors, a population with impaired immunity. This study was designed to assess influenza vaccination patterns among Korean cancer survivors. In this cross-sectional analysis, data were obtained from standardized questionnaires from 943 cancer survivors and 41,233 non-cancer survivors who participated in the Fourth and Fifth Korea National Health and Nutrition Examination Surveys (2007-2011). We identified the adjusted influenza vaccination rates and assessed factors associated with influenza vaccination using multivariate logistic regression. Cancer survivors tended to have a higher adjusted influenza vaccination rate than the general population. The rates for influenza vaccination in specific cancer types such as stomach, hepatic, colon, and lung cancers were significantly higher than non-cancer survivors. Among all cancer survivors, those with chronic diseases, elderly subjects, and rural dwellers were more likely to receive influenza vaccination; those with cervical cancer were less likely to receive influenza vaccination. Cancer survivors were more likely to receive influenza vaccinations than non-cancer survivors, but this was not true for particular groups, especially younger cancer survivors. Cancer survivors represent a sharply growing population; therefore, immunization against influenza among cancer survivors should be concerned as their significant preventative healthcare services.
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Tauroursodeoxycholic Acid, a Bile Acid, Promotes Blood Vessel Repair by Recruiting Vasculogenic Progenitor Cells.
Stem Cells
PUBLISHED: 07-29-2014
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Although serum bile acid concentrations are ~10 ?M in healthy subjects, the cross-talk between the biliary system and vascular repair has never been investigated. In this study, tauroursodeoxycholic acid (TUDCA) induced dissociation of CD34(+) hematopoietic stem cells (HSCs) from stromal cells by reducing adhesion molecule expression. TUDCA increased CD34(+) /Sca1(+) progenitors in mice peripheral blood (PB), and CD34(+) , CD31(+) , and c-kit(+) progenitors in human PB. In addition, TUDCA increased differentiation of CD34(+) HSCs into EPC lineage cells via Akt activation. EPC invasion was increased by TUDCA, which was mediated by fibroblast activating protein (FAP) via Akt activation. Interestingly, TUDCA induced integration of EPCs into human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. In the mouse hindlimb ischemia model, TUDCA promoted blood perfusion by enhancing angiogenesis through recruitment of Flk-1(+) /CD34(+) and Sca-1(+) /c-kit(+) progenitors into damaged tissue. In GFP(+) bone marrow-transplanted hindlimb ischemia, TUDCA induced recruitment of GFP(+) /c-kit(+) progenitors to the ischemic area, resulting in an increased blood perfusion ratio. Histological analysis suggested that GFP(+) progenitors mobilized from bone marrow, integrated into blood vessels, and differentiated into VEGFR(+) cells. In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide. Transplantation of TUDCA-primed senescent EPCs in hindlimb ischemia significantly improved blood vessel regeneration, as compared with senescent EPCs. Our results suggested that TUDCA promoted neovascularization by enhancing the mobilization of stem/progenitor cells from bone marrow, their differentiation into EPCs, and their integration with preexisting endothelial cells. This article is protected by copyright. All rights reserved.
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Isolation of adipose-derived stem cells by using a subfractionation culturing method.
Expert Opin Biol Ther
PUBLISHED: 07-29-2014
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Adipose-derived stem cells (ASCs) isolated from subcutaneous adipose tissue have been tested in clinical trials. However, ASCs isolated by enzyme digestion and centrifugation are heterogeneous and exhibit wide variation in regenerative potential and clinical outcomes. Therefore, we developed a new method for isolating clonal ASCs (cASCs) that does not use enzyme digestion or centrifugation steps.
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SMAD4 suppresses AURKA-induced Metastatic Phenotypes via Degradation of AURKA in a TGF-beta-independent manner.
Mol. Cancer Res.
PUBLISHED: 07-24-2014
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SMAD4 has been suggested to inhibit the activity of WNT/beta-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/beta-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of beta-catenin/T cell factor (TCF) complex by stabilizing beta-catenin through the inhibition of GSK-3beta. Here, SMAD4 modulated AURKA in a TGF-beta-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA, induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the beta-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of beta-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and beta-catenin was independent of TGF-beta signaling because blockage of TGF-betaR1 or restoration of TGF-beta signaling did not prevent suppression of AURKA and beta-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by down-regulation of beta-catenin transcriptional activity via AURKA degradation in a TGF-beta-independent manner. Implications: SMAD4 interacts with AURKA and antagonizes its tumor promoting potential, thus demonstrating a novel mechanism of tumor suppression.
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High-efficiency lentiviral transduction of primary human CD34(+) hematopoietic cells with low-dose viral inocula.
Biotechnol. Lett.
PUBLISHED: 07-09-2014
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Lentivirus-based vectors have the potential to transduce non-dividing primary stem cells. However, primary cells tend to be less susceptible to manipulation and require a high concentration of virus inoculum. Furthermore, increasing the concentration of the lentivirus inoculum may raise safety risks. Therefore, to develop a technique that allows high transduction efficiency at low multiplicities of infection (MOIs), we optimized a lentivirus-based system for cell lines and primary cells by determining the best condition using various parameters. When progenitor cell assays were conducted using human CD34(+) bone marrow and mononuclear cells, the transduction condition yielded a great number of eGFP(+) colonies with lower-dose viral inocula compared to that of current lentivirus-based transduction technologies. In conclusion, this system is anticipated to produce stable expression of a gene introduced into primary cells for preclinical studies with lower safety risks.
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Functional Regulation of Adipose-derived Stem Cells by PDGF-D.
Stem Cells
PUBLISHED: 06-27-2014
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Platelet-derived growth factor-D (PDGF-D) was recently identified, and acts as potent mitogen for mesenchymal cells. PDGF-D also induces cellular transformation and promotes tumor growth. However, the functional role of PDGF-D in adipose-derived stem cells (ASCs) has not been identified. Therefore, we primarily investigated the autocrine and paracrine roles of PDGF-D in the present study. Furthermore, we identified the signaling pathways and the molecular mechanisms involved in PDGF-D-induced stimulation of ASCs. It is of interest that PDGF-B is not expressed, but PDGF-D and PDGF receptor-? are expressed in ASCs. PDGF-D showed the strongest mitogenic effect on ASCs, and PDGF-D regulates the proliferation and migration of ASCs through the PI3K/Akt pathways. PDGF-D also increases the proliferation and migration of ASCs through generation of mitochondrial reactive oxygen species (mtROS) and mitochondrial fission. mtROS generation and fission were mediated by p66Shc phosphorylation, and BCL2A1 and SERPINE1 mediated the proliferation and migration of ASCs. In addition, PDGF-D up-regulated the mRNA expression of diverse growth factors such as VEGFA, FGF1, FGF5, LIF, INHBA, IL11 and HBEGF. Therefore, the preconditioning of PDGF-D enhanced the hair-regenerative potential of ASCs. PDGF-D-induced growth factor expression was attenuated by a pharmacological inhibitor of mitogen-activated protein kinase pathway. In summary, PDGF-D is highly expressed by ASCs, where it acts as a potent mitogenic factor. PDGF-D also up-regulates growth factor expression in ASCs. Therefore, PDGF-D can be considered a novel ASC stimulator, and used as a preconditioning agent before ASC transplantation. Stem Cells 2014.
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Magnolia officinalis attenuates free fatty acid-induced lipogenesis via AMPK phosphorylation in hepatocytes.
J Ethnopharmacol
PUBLISHED: 06-20-2014
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Magnolia officinalis (MO) is a traditional Chinese herbal medicine that has been used in clinical practice to treat liver disease. The aim of this study is to examine the effects of MO on the development of nonalcoholic fatty liver in hepatocytes.
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P2Y2 R activation by nucleotides promotes skin wound-healing process.
Exp. Dermatol.
PUBLISHED: 05-08-2014
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P2Y2 R has been shown to be upregulated in a variety of tissues in response to stress or injury and to mediate tissue regeneration through its ability to activate multiple signalling pathways. This study aimed to investigate the role of P2Y2 R in the wound-healing process and the mechanisms by which P2Y2 R activation promotes wound healing in fibroblasts. The role of P2Y2 R in skin wound healing was examined using a full-thickness skin wound model in wildtype (WT) and P2Y2 R(-/-) mice and an in vitro scratch wound model in control or P2Y2 R siRNA-transfected fibroblasts. WT mice showed significantly decreased wound size compared with P2Y2 R(-/-) mice at day 14 post-wounding, and immunohistochemical analysis showed that a proliferation marker Ki67 and extracellular matrix (ECM)-related proteins VEGF, collagen I, fibronectin and ?-SMA were overexpressed in WT mice, which were reduced in P2Y2 R(-/-) mice. Scratch-wounded fibroblasts increased ATP release, which peaked at 5 min. In addition, scratch wounding increased the level of P2Y2 R mRNA. Activation of P2Y2 R by ATP or UTP enhanced proliferation and migration of fibroblasts in in vitro scratch wound assays and were blocked by P2Y2 R siRNA. Finally, ATP or UTP also increased the levels of ECM-related proteins through the activation of P2Y2 R in fibroblasts. This study suggests that P2Y2 R may be a potential therapeutic target to promote wound healing in chronic wound diseases.
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Difference in adherence to and influencing factors of a healthy lifestyle between middle-aged and elderly people in Korea: A multilevel analysis.
Geriatr Gerontol Int
PUBLISHED: 05-02-2014
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Comprehensive research for factors related to healthy lifestyles of the elderly is limited. The present study aimed to elucidate the factors associated with adherence to a healthy lifestyle by age groups.
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Acute esophageal necrosis occurring in a patient undergoing percutaneous coronary intervention.
Korean J. Intern. Med.
PUBLISHED: 04-29-2014
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Acute esophageal necrosis is uncommon in the literature. Its etiology is unknown, although cardiovascular disease, hemodynamic compromise, gastric outlet obstruction, alcohol ingestion, hypoxemia, hypercoagulable state, infection, and trauma have all been suggested as possible causes. A 67-year-old female underwent a coronary angiography (CAG) for evaluation of chest pain. CAG findings showed coronary three-vessel disease. We planned percutaneous coronary intervention (PCI). Coronary arterial dissection during the PCI led to sudden hypotension. Six hours after the index procedure, the patient experienced a large amount of hematemesis. Emergency gastrofibroscopy was performed and showed mucosal necrosis with a huge adherent blood clot in the esophagus. After conservative treatment for 3 months, the esophageal lesion was completely improved. She was diagnosed with acute esophageal necrosis. We report herein a case of acute esophageal necrosis occurring in a patient undergoing percutaneous coronary intervention.
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Dehydrocostuslactone inhibits LPS-induced inflammation by p38MAPK-dependent induction of hemeoxygenase-1 in vitro and improves survival of mice in CLP-induced sepsis in vivo.
Int. Immunopharmacol.
PUBLISHED: 04-25-2014
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We investigated the hypothesis that the administration of dehydrocostuslactone (DL), a sesquiterpene lactone found in Saussurea lappa Clarke (Compositae), might reduce organ failure and increase survival in a cecal ligation and puncture (CLP)-induced mouse model of sepsis due to HO-1 induction. Treatment of RAW264.7 cells with DL increased HO-1 expression in a time- and concentration-dependent manner, and this up-regulation of HO-1 by DL was significantly inhibited by silencing either Nrf2 and p38 or treating cells with SB203580 (a p38MAPK inhibitor), but it was not inhibited in the presence of SP600125 (an ERK inhibitor), PD98059 (a JNK inhibitor), or LY294002 (PI3K inhibitor). As expected, DL concentration dependently inhibited the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and the productions of NO and PGE2 in LPS-activated cells, and these inhibitions were reversed by silencing HO-1. Most importantly, administration of DL significantly reduced mortality and reduced serum IL-1? and TNF-? and the infiltration of macrophages into liver tissues of CLP-mice. Inducible NOS expression in lung and liver tissues of CLP-mice was reduced by DL, which was reversed by the co-administration of zinc-protoporphyrin IX (ZnPPIX; a competitive inhibitor of HO-1). Our findings indicate that DL might be useful for the treatment of sepsis.
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Association between the awareness of osteoporosis and the quality of care for bone health among Korean women with osteoporosis.
BMC Musculoskelet Disord
PUBLISHED: 04-04-2014
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The prevalence of osteoporosis is increasing and is a socio-economic burden worldwide. Although screening tests for osteoporosis in Korea are easily accessible, this condition remains undertreated. Evaluating post-diagnostic behavior changes may be helpful for improving the quality of care for bone health in osteoporotic patients.
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COPD patients with exertional desaturation are at a higher risk of rapid decline in lung function.
Yonsei Med. J.
PUBLISHED: 04-01-2014
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A recent study demonstrated that exertional desaturation is a predictor of rapid decline in lung function in patients with chronic obstructive pulmonary disease (COPD); however, the study was limited by its method used to detect exertional desaturation. The main purpose of this study was to explore whether exertional desaturation assessed using nadir oxygen saturation (SpO?) during the 6-minute walk test (6MWT) can predict rapid lung function decline in patients with COPD.
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Diagnostic value of direct fluorescence antibody staining for detecting Pneumocystis jirovecii in expectorated sputum from patients with HIV infection.
Med. Mycol.
PUBLISHED: 03-25-2014
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Direct fluorescent antibody (DFA) staining of induced sputum is frequently used to diagnose Pneumocystis pneumonia (PCP) in patients infected with human immunodeficiency virus, although induction can provoke nausea and bronchospasm. Since the diagnostic value of expectorated sputum examined with DFA stain has not been well evaluated, we reviewed the medical records of HIV-infected patients who were clinically diagnosed as having PCP between 1999 and 2011. Over this 13-year period, we found 76 patients whose records included the results of DFA staining of expectorated sputum and noted that 42 (55.3%) were positive. Polymerase chain reaction to detect Pneumocystis in the sputum of 65 of the patients resulted in the finding of 43 (66.2%) who were positive. Our findings suggest that DFA staining of expectorated sputum could be a useful initial diagnostic method in HIV-infected patients with PCP.
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The molecular mechanism underlying the proliferating and preconditioning effect of vitamin C on adipose-derived stem cells.
Stem Cells Dev.
PUBLISHED: 03-21-2014
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Although adipose-derived stem cells (ASCs) show promise for cell therapy, there is a tremendous need for developing ASC activators. In the present study, we investigated whether or not vitamin C increases the survival, proliferation, and hair-regenerative potential of ASCs. In addition, we tried to find the molecular mechanisms underlying the vitamin C-mediated stimulation of ASCs. Sodium-dependent vitamin C transporter 2 (SVCT2) is expressed in ASCs, and mediates uptake of vitamin C into ASCs. Vitamin C increased the survival and proliferation of ASCs in a dose-dependent manner. Vitamin C increased ERK1/2 phosphorylation, and inhibition of the mitogen-activated protein kinase (MAPK) pathway attenuated the proliferation of ASCs. Microarray and quantitative polymerase chain reaction showed that vitamin C primarily upregulated expression of proliferation-related genes, including Fos, E2F2, Ier2, Mybl1, Cdc45, JunB, FosB, and Cdca5, whereas Fos knock-down using siRNA significantly decreased vitamin C-mediated ASC proliferation. In addition, vitamin C-treated ASCs accelerated the telogen-to-anagen transition in C3H/HeN mice, and conditioned medium from vitamin C-treated ASCs increased the hair length and the Ki67-positive matrix keratinocytes in hair organ culture. Vitamin C increased the mRNA expression of HGF, IGFBP6, VEGF, bFGF, and KGF, which may mediate hair growth promotion. In summary, vitamin C is transported via SVCT2, and increased ASC proliferation is mediated by the MAPK pathway. In addition, vitamin C preconditioning enhanced the hair growth promoting effect of ASCs. Because vitamin C is safe and effective, it could be used to increase the yield and regenerative potential of ASCs.
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Special licorice extracts containing lowered glycyrrhizin and enhanced licochalcone a prevented Helicobacter pylori-initiated, salt diet-promoted gastric tumorigenesis.
Helicobacter
PUBLISHED: 03-20-2014
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In spite of cytoprotective and anti-inflammatory actions, conventional licorice extracts (c-lico) were limitedly used due to serious side effects of glycyrrhizin. As our group had successfully isolated special licorice extracts (s-lico) lowering troublesome glycyrrhizin, but increasing licochalcone A, we have compared anti-inflammatory, antioxidative, and cytoprotective actions of s-lico and c-lico against either in vitro or in vivo Helicobacter pylori infection.
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Factors associated with ciprofloxacin- and cefotaxime-resistant Escherichia coli in women with acute pyelonephritis in the emergency department.
Int. J. Infect. Dis.
PUBLISHED: 03-19-2014
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High rates of antimicrobial resistance in Escherichia coli isolated from patients with urinary tract infections have been reported worldwide. The aim of this study was to identify risk factors for resistance to ciprofloxacin (CIP) and cefotaxime (CTX) in E. coli isolated from patients with acute pyelonephritis (APN).
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CKD712, a synthetic isoquinoline alkaloid, enhances the anti-cancer effects of paclitaxel in MDA-MB-231 cells through regulation of PTEN.
Life Sci.
PUBLISHED: 03-05-2014
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It has been reported that in human glioblastoma cells, phosphotase and tensin homolog (PTEN) positive cells are more prone to paclitaxel-induced apoptosis than PTEN-negative cells. We investigated whether (S)-1-(?-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) enhances the therapeutic effects of paclitaxel (including effects on cellular proliferation, invasion and apoptosis) in MDA-MB-231 cells through PTEN and NF-?B activity.
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Optimized scheduling technique of null subcarriers for peak power control in 3GPP LTE downlink.
ScientificWorldJournal
PUBLISHED: 02-28-2014
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Orthogonal frequency division multiple access (OFDMA) is a key multiple access technique for the long term evolution (LTE) downlink. However, high peak-to-average power ratio (PAPR) can cause the degradation of power efficiency. The well-known PAPR reduction technique, dummy sequence insertion (DSI), can be a realistic solution because of its structural simplicity. However, the large usage of subcarriers for the dummy sequences may decrease the transmitted data rate in the DSI scheme. In this paper, a novel DSI scheme is applied to the LTE system. Firstly, we obtain the null subcarriers in single-input single-output (SISO) and multiple-input multiple-output (MIMO) systems, respectively; then, optimized dummy sequences are inserted into the obtained null subcarrier. Simulation results show that Walsh-Hadamard transform (WHT) sequence is the best for the dummy sequence and the ratio of 16 to 20 for the WHT and randomly generated sequences has the maximum PAPR reduction performance. The number of near optimal iteration is derived to prevent exhausted iterations. It is also shown that there is no bit error rate (BER) degradation with the proposed technique in LTE downlink system.
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Low compliance with national guidelines for preventing transmission of group 1 nationally notifiable infectious diseases in Korea.
Yonsei Med. J.
PUBLISHED: 02-18-2014
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This study was performed to evaluate the compliance with, and adequacy of, the Korean national guidelines which had been recommended until 2011 for isolation of patients with group 1 nationally notifiable infectious diseases (NNIDs), namely cholera, typhoid fever, paratyphoid fever, shigellosis, and enterohemorrhagic Escherichia coli (EHEC) infection.
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BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K.
Cell Metab.
PUBLISHED: 02-11-2014
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Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family that is known to play a role as tumor suppressors. Here, we show that BRD7 is a component of the unfolded protein response (UPR) signaling through its ability to regulate X-box binding protein 1 (XBP1) nuclear translocation. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) and increases the nuclear translocation of both p85? and p85? and the spliced form of XBP1 (XBP1s). Deficiency of BRD7 blocks the nuclear translocation of XBP1s. Furthermore, our in vivo studies have shown that BRD7 protein levels are reduced in the liver of obese mice, and reinstating BRD7 levels in the liver restores XBP1s nuclear translocation, improves glucose homeostasis, and ultimately reduces the blood glucose levels in the obese and diabetic mouse models.
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A comparison between the efficiency of the Xpert MTB/RIF assay and nested PCR in identifying Mycobacterium tuberculosis during routine clinical practice.
J Thorac Dis
PUBLISHED: 01-23-2014
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Polymerase chain reaction (PCR) for the detection of Mycobacterium tuberculosis (MTB) is more sensitive, specific, and rapid than the conventional methods of acid-fast bacilli (AFB) smear and culture. The aim of this study was to determine if the Xpert MTB/rifampicin (RIF) assay had additional advantages over nested PCR for the detection of MTB in a geographical area with intermediate tuberculosis (TB) incidence.
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Sequential sludge digestion after diverse pre-treatment conditions: sludge removal, methane production and microbial community changes.
Bioresour. Technol.
PUBLISHED: 01-23-2014
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A lab-scale sequential sludge digestion process which consists of a mesophilic anaerobic digester (MAD) and a thermophilic aerobic digester (TAD) was developed. Thermal, thermal-alkaline and long-term alkaline pre-treatments were applied to the feed sludge to examine their effects on sludge removal and methane production. Especially after thermal-alkaline pre-treatment, high COD removal was maintained; methane production rate was also drastically increased by improving the hydrolysis step of sludge degradation. Polymerase chain reaction-denaturing gel gradient electrophoresis indicated that bacterial communities were represented by three phyla (Firmicutes, Proteobacteria, Actinobacteria) and that Clostridium straminisolvens was the major bacterial species in MAD. Quantitative real-time PCR results indicated that Methanosaeta concilli was the major archaeal species in MAD, and that Ureibacillus sp. was the most abundant bacterial species in TAD.
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Association between insulin resistance and bone mass in men.
J. Clin. Endocrinol. Metab.
PUBLISHED: 01-16-2014
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The association between insulin resistance and bone mass is still not clear.
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P2Y(2)R activation by nucleotides released from oxLDL-treated endothelial cells (ECs) mediates the interaction between ECs and immune cells through RAGE expression and reactive oxygen species production.
Free Radic. Biol. Med.
PUBLISHED: 01-14-2014
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Lipoprotein oxidation, inflammation, and immune responses involving the vascular endothelium and immune cells contribute to the pathogenesis of atherosclerosis. In an atherosclerotic animal model, P2Y2 receptor (P2Y2R) upregulation and stimulation were previously shown to induce intimal hyperplasia and increased intimal monocyte infiltration. Thus, we investigated the role of P2Y2R in oxidized low-density lipoprotein (oxLDL)-mediated oxidative stress and the subsequent interaction between endothelial cells (ECs) and immune cells. The treatment of human ECs with oxLDL caused the rapid release of ATP (maximum after 5 min). ECs treated with oxLDL or the P2Y2R agonists ATP/UTP for 1h exhibited significant reactive oxygen species (ROS) production, but this effect was not observed in P2Y2R siRNA-transfected ECs. In addition, oxLDL and ATP/UTP both induced RAGE expression, which was P2Y2R dependent. Oxidized LDL- and ATP/UTP-mediated ROS production was diminished in RAGE siRNA-transfected ECs, suggesting that RAGE is an important mediator in P2Y2R-mediated ROS production. Treatment with oxLDL for 24h induced P2Y2R expression in the human monocyte cell line THP-1 and increased THP-1 cell migration toward ECs. The addition of apyrase, an enzyme that hydrolyzes nucleotides, or diphenyleneiodonium (DPI), a well-known inhibitor of NADPH oxidase, significantly inhibited the increase in cell migration caused by oxLDL. P2Y2R siRNA-transfected THP-1 cells did not migrate in response to oxLDL or ATP/UTP treatment, indicating a critical role for P2Y2R and nucleotide release in oxLDL-induced monocyte migration. Last, oxLDL and ATP/UTP effectively increased ICAM-1 and VCAM-1 expression and the subsequent binding of THP-1 cells to ECs, which was inhibited by pretreatment with DPI or by siRNA against P2Y2R or RAGE, suggesting that P2Y2R is an important mediator in oxLDL-mediated monocyte adhesion to ECs through the regulation of ROS-dependent adhesion molecule expression in ECs. Taken together, our findings suggest that P2Y2R could be a therapeutic target for the prevention of vascular disorders, including atherosclerosis.
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The role of tauroursodeoxycholic acid on adipogenesis of human adipose-derived stem cells by modulation of ER stress.
Biomaterials
PUBLISHED: 01-11-2014
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Obesity has become a serious public health problem in the developed world. Increased mass of adipose tissue in the obese is due to an increase in both the size (hypertrophy) and number (hyperplasia) of adipocytes. The chemical chaperone tauroursodeoxycholic acid (TUDCA) not only decreases endoplasmic reticulum (ER) stress, but also plays a role as a leptin-sensitizing agent for preadipocytes in mice and humans. In this study, we examine whether TUDCA has an effect on adipogenesis from human adipose-derived stem cells (hASCs). Therefore, the effect of TUDCA on ER stress, lipid accumulation, and adipogenic differentiation from hASCs was investigated using histological staining, reverse-transcriptase polymerase chain reaction (RT-PCR), and western blotting in vitro. It was found that TUDCA treatment of hASCs significantly decreases the representative ER stress marker (glucose-regulated protein 78 kDa (GRP78)), adipogenic markers (peroxisome proliferator-activated receptor gamma (PPAR?) and glycerol-3-phosphate dehydrogenase 1 (GPDH)), and lipid accumulation. Furthermore, we confirmed that TUDCA treatment of hASCs significantly decreased in vivo adipogenic tissue formation and ER stress comparing with PBS treatment of hASCs. The results indicate that TUDCA plays a critical role in adipogenesis from hASCs by modulating ER stress and, therefore, has potential pharmacologic and therapeutic applications as an anti-obesity agent.
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Integration of latex protein sequence data provides comprehensive functional overview of latex proteins.
Mol. Biol. Rep.
PUBLISHED: 01-07-2014
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The laticiferous system is one of the most important conduit systems in higher plants, which produces a milky-like sap known as latex. Latex contains diverse secondary metabolites with various ecological functions. To obtain a comprehensive overview of the latex proteome, we integrated available latex proteins sequences and constructed a comprehensive dataset composed of 1,208 non-redundant latex proteins from 20 various latex-bearing plants. The results of functional analyses revealed that latex proteins are involved in various biological processes, including transcription, translation, protein degradation and the plant response to environmental stimuli. The results of the comparative analysis showed that the functions of the latex proteins are similar to those of phloem, suggesting the functional conservation of plant vascular proteins. The presence of latex proteins in mitochondria and plastids suggests the production of diverse secondary metabolites. Furthermore, using a BLAST search, we identified 854 homologous latex proteins in eight plant species, including three latex-bearing plants, such as papaya, caster bean and cassava, suggesting that latex proteins were newly evolved in vascular plants. Taken together, this study is the largest and most comprehensive in silico analysis of the latex proteome. The results obtained here provide useful resources and information for characterizing the evolution of the latex proteome.
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Ultrasound-mediated gene and drug delivery using a microbubble-liposome particle system.
Theranostics
PUBLISHED: 01-01-2014
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Theranostic agents present a promising clinical approach for cancer detection and treatment. We herein introduce a microbubble and liposome complex (MB-Lipo) developed for ultrasound (US) imaging and activation. The MB-Lipo particles have a hybrid structure consisting of a MB complexed with multiple Lipos. The MB components are used to generate high echo signals in US imaging, while the Lipos serve as a versatile carrier of therapeutic materials. MB-Lipo allows high contrast US imaging of tumor sites. More importantly, the application of high acoustic pressure bursts MBs, which releases therapeutic Lipos and further enhances their intracellular delivery through sonoporation effect. Both imaging and drug release could thus be achieved by a single US modality, enabling in situ treatment guided by real-time imaging. The MB-Lipo system was applied to specifically deliver anti-cancer drug and genes to tumor cells, which showed enhanced therapeutic effect. We also demonstrate the clinical potential of MB-Lipo by imaging and treating tumor in vivo.
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Complete mitochondrial genomes of Carcinoscorpius rotundicauda and Tachypleus tridentatus (Xiphosura, Arthropoda) and implications for chelicerate phylogenetic studies.
Int. J. Biol. Sci.
PUBLISHED: 01-01-2014
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Horseshoe crabs (order Xiphosura) are often referred to as an ancient order of marine chelicerates and have been considered as keystone taxa for the understanding of chelicerate evolution. However, the mitochondrial genome of this order is only available from a single species, Limulus polyphemus. In the present study, we analyzed the complete mitochondrial genomes from two Asian horseshoe crabs, Carcinoscorpius rotundicauda and Tachypleus tridentatus to offer novel data for the evolutionary relationship within Xiphosura and their position in the chelicerate phylogeny. The mitochondrial genomes of C. rotundicauda (15,033 bp) and T. tridentatus (15,006 bp) encode 13 protein-coding genes, two ribosomal RNA (rRNA) genes, and 22 transfer RNA (tRNA) genes. Overall sequences and genome structure of two Asian species were highly similar to that of Limulus polyphemus, though clear differences among three were found in the stem-loop structure of the putative control region. In the phylogenetic analysis with complete mitochondrial genomes of 43 chelicerate species, C. rotundicauda and T. tridentatus were recovered as a monophyly, while L. polyphemus solely formed an independent clade. Xiphosuran species were placed at the basal root of the tree, and major other chelicerate taxa were clustered in a single monophyly, clearly confirming that horseshoe crabs composed an ancestral taxon among chelicerates. By contrast, the phylogenetic tree without the information of Asian horseshoe crabs did not support monophyletic clustering of other chelicerates. In conclusion, our analyses may provide more robust and reliable perspective on the study of evolutionary history for chelicerates than earlier analyses with a single Atlantic species.
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Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
PLoS ONE
PUBLISHED: 01-01-2014
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There are few alternatives to glucocorticosteroids for treatment of asthma. We assessed the activity of a novel protein drug designated ISU201, the extracellular domain of the human cell surface protein BST2, stabilised by fusion with the Fc region of IgG, in mouse models of mild chronic asthma and an acute exacerbation of asthma. The ability of ISU201 to suppress airway inflammation and remodelling was compared with that of dexamethasone. Female BALB/c mice were systemically sensitised with ovalbumin, then received controlled low-level challenge with aerosolised ovalbumin for 6 weeks, which induced lesions of mild chronic asthma, and were treated with drugs during the final 2 weeks. Alternatively, sensitised mice received 4 weeks of chronic low-level challenge and were treated 24 and 2 hours before a final single moderate-level challenge, which triggered acute airway inflammation simulating an asthmatic exacerbation. Inflammation and remodelling were quantified, as was the expression of pro-inflammatory cytokines in bronchoalveolar lavage fluid and tissues. To identify cellular targets of ISU201, we assessed the effects of the drug on activated lymphocytes, macrophages and airway epithelial cells. In the model of mild chronic asthma, ISU201 was as effective as dexamethasone in suppressing airway inflammation and most changes of remodelling. In the model of an allergen-induced acute exacerbation of chronic asthma, ISU201 was also an effective anti-inflammatory agent, although it was less active than dexamethasone. The drug acted on multiple cellular targets, suppressing production of pro-inflammatory cytokines by lymphocytes and macrophages. ISU201 significantly reduced acetylation of histone H4 in airway epithelial cells, suggesting at least one potential mechanism of action. We conclude that in these models of asthma, ISU201 is a broad-spectrum inhibitor of both airway inflammation and remodelling. Thus, unlike drugs which target specific mediators, it could potentially be an alternative or an adjunct to glucocorticoids for the treatment of asthma.
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High prevalence of low bone mass and associated factors in Korean HIV-positive male patients undergoing antiretroviral therapy.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Low bone mass is prevalent in HIV-positive patients. However, compared to Western countries, less is known about HIV-associated osteopenia in Asian populations.
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A cost-effective 25-Gb/s EML TOSA using all-in-one FPCB wiring and metal optical bench.
Opt Express
PUBLISHED: 11-13-2013
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We present a cost-effective 25-Gb/s electro-absorption modulator integrated laser (EML) transmitter optical sub-assembly (TOSA) using all-in-one flexible printed circuit board (FPCB) wiring and a metal optical bench (MOB). For a low cost and high bandwidth TOSA, internal and external wirings and feed-through of the TOSA to transmit radio-frequency (RF) signal are configured all-in-one using the FPCB. The FPCB is extended from an exterior of the TOSA package up to an EML chip inside the package through the slit formed on a rear sidewall of the package and die-bonded on the MOB. The EML TOSA shows a modulated output power of more than 3.5 dBm and a clear eye pattern with a dynamic extinction ratio of ~8.4 dB at a data rate of 25.78 Gb/s.
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Endoplasmic reticulum stress is sufficient for the induction of IL-1? production via activation of the NF-?B and inflammasome pathways.
Innate Immun
PUBLISHED: 11-11-2013
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The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1? secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1? via NF-?B activation and promotes IL-1? secretion. Enhanced IL-1? secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1? secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.
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Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor ? (PPAR?) stability through its deubiquitinating activity.
J. Biol. Chem.
PUBLISHED: 09-26-2013
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The peroxisome proliferator-activated receptor ? (PPAR?) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPAR?. Both endogenous and exogenous PPAR? associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPAR? through its deubiquitinating activity. Site-directed mutagenesis experiments showed that the Lys(462) residue of PPAR? is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPAR? stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPAR? protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPAR? in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPAR? target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPAR? and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPAR? are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs.
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The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis.
Clin. Nephrol.
PUBLISHED: 09-23-2013
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Despite medical progress, high morbidity and mortality rates have persisted in patients with end-stage renal disease (ESRD). The role in atherosclerosis and cardiovascular disease of klotho, an aging process-related gene, has been highlighted. Genetic variation in klotho has been reported to be a risk factor for coronary artery disease and ischemic stroke. Regarding the significance of cardiovascular disease for the outcome of ESRD patients, we investigated whether genetic variation of klotho was associated with mortality in ESRD patients on hemodialysis. 478 patients on maintenance hemodialysis for more than 3 months at dialysis facilities affiliated with the Western Dialysis Physician Association were enrolled in September 2004. Patient survival was checked annually until September 2007. Genotypings of klotho in terms of G395A in the promoter region, C1818T in exon 4, and KL-VS was performed. 45 deaths (11.2%) occurred over 3 years. Mortality was higher in the GA+AA group than in the GG group (18.9% vs. 6.7%, respectively, p < 0.001). Kaplan-Meier analysis also revealed that the survival of the GA+AA group was worse than that of GG group (p = 0.002). Coxs proportional hazards regression analysis showed that age, A allele carrier status in G395A of klotho, hemoglobin, albumin and HDL cholesterol levels were the significant factors affecting survival of hemodialysis patients. The A allele of the G395A polymorphism of klotho may be associated with the risk of mortality in Korean hemodialysis patients. Age, hemoglobin, albumin and HDLC were also significant prognostic factors for survival in the present study.
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(S)-1-?-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712), promotes wound closure by producing VEGF through HO-1 induction in human dermal fibroblasts and mouse skin.
Br. J. Pharmacol.
PUBLISHED: 08-24-2013
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Given the importance of VEGF and haem oxygenase (HO)-1 in wound healing, the present study tested the hypothesis that CKD712, a synthetic tetrahydroisoquinoline alkaloid, activated VEGF production through the induction of HO-1 in human dermal fibroblasts (HDFs) and in mouse skin to stimulate wound healing.
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Non-microbial approach for Helicobacter pylori as faster track to prevent gastric cancer than simple eradication.
World J. Gastroenterol.
PUBLISHED: 08-16-2013
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Although the International Agency for Research on Cancer declared Helicobacter pylori (H. pylori) as a definite human carcinogen in 1994, the Japanese Society for Helicobacter Research only recently (February 2013) adopted the position that H. pylori infection should be considered as an indication for either amelioration of chronic gastritis or for decreasing gastric cancer mortality. Japanese researchers have found that H. pylori eradication halts progressive mucosal damage and that successful eradication in patients with non-atrophic gastritis most likely prevents subsequent development of gastric cancer. However, those who have already developed atrophic gastritis/gastric atrophy retain potential risk factors for gastric cancer. Because chronic perpetuated progression of H. pylori-associated gastric inflammation is associated with increased morbidity culminating in gastric carcinogenesis, a non-microbial approach to treatment that provides long-term control of gastric inflammation through nutrients and other interventions may be an effective way to decrease this morbidity. This non-microbial approach might represent a new form of prerequisite "rescue" therapy that provides a quicker path to the prevention of gastric cancer as compared to simple eradication.
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Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition.
Int. J. Oncol.
PUBLISHED: 07-22-2013
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Glioblastoma is one of the most lethal and prevalent malignant human brain tumors, with aggressive proliferation and highly invasive properties. There is still no effective cure for patients with glioblastoma. Honokiol, derived from Magnolia officinalis, can cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), making it a strong candidate for an effective drug for the treatment of brain tumors, including glioblastoma. In our previous study, we demonstrated that honokiol effectively induced apoptotic cell death in glioblastoma. Metastasis poses the largest problem to cancer treatment and is the primary cause of death in cancer patients. Thus, in this study, we investigated the effect of honokiol on the cell invasion process of U87MG human glioblastoma cells through brain microvascular endothelial cells (BMECs) and its possible mechanisms. Honokiol dose-dependently inhibited TNF-?-induced VCAM-1 expression in BMECs and adhesion of U87MG to BMECs. Moreover, honokiol effectively blocked U87MG invasion through BMEC-Matrigel-coated transwell membranes. Increased phosphorylation of VE-cadherin and membrane permeability by TNF-? were suppressed by honokiol in BMECs. Furthermore, we investigated the effect of honokiol on the epithelial-mesenchymal transition (EMT) in U87MG cells. Honokiol reduced the expression levels of Snail, N-cadherin and ?-catenin, which are mesenchymal markers, but increased E-cadherin, an epithelial marker. In conclusion, these results suggest that honokiol inhibits metastasis by targeting the interaction between U87MG and BMECs, regulating the adhesion of U87MG to BMECs by inhibiting VCAM-1, and regulating the invasion of U87MG through BMECs by reducing membrane permeability and EMT processes of U87MG cells.
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Effect of intravenous lipid emulsion in patients with acute glyphosate intoxication.
Clin Toxicol (Phila)
PUBLISHED: 07-19-2013
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Although glyphosate intoxication has been considered minimally toxic in animals, severe toxicity has been observed in humans due to surfactant. We aimed to examine the potential therapeutic effects of intravenous lipid emulsion (ILE) on the patients with acute glyphosate intoxication.
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An innovative sewage sludge reduction by using a combined mesophilic anaerobic and thermophilic aerobic process with thermal-alkaline treatment and sludge recirculation.
J. Environ. Manage.
PUBLISHED: 07-02-2013
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Lab-scale High Efficiency Digestion (HED) systems containing a Mesophilic Anaerobic Reactor (MAR), Thermophilic Aerobic Reactor (TAR), liquid/solid separation unit, and thermal-alkaline treatment were developed to evaluate the efficiencies of sludge reduction and methane production. The HED process was divided into three phases to examine the influence of sludge pretreatment and pretreated sludge recirculation using TCOD and VSS reduction, COD solubilization, and methane production. The VSS removal with a solid/liquid separation unit, sludge recirculation, and thermal-alkaline treatment drastically increased up to 95% compared to the feed concentration. In addition, the results of COD solubilization and VSS/TSS showed that the solubilization of cells and organic matters by the thermal-alkaline treatment was highly increased, which was also consistent with the SEM images. In particular, the methane production rate increased 24-fold when the feed sludge and recirculated sludge were pretreated together. Collectively, the HED experiments performed with sludge recirculation and thermal-alkaline treatment demonstrated that the HED systems can be successfully employed for highly efficient sewage sludge reduction and methane gas production.
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A tetrahydroisoquinoline alkaloid THI-28 reduces LPS-induced HMGB1 and diminishes organ injury in septic mice through p38 and PI3K/Nrf2/HO-1 signals.
Int. Immunopharmacol.
PUBLISHED: 06-26-2013
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We investigated whether THI-28 [1-4-(hydroxyphenylethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits release of high mobility group box 1 (HMGB1), a late phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells through heme oxygenase (HO)-1 induction so that it shows beneficial effects in the cecal ligation and puncture (CLP)-induced septic mouse model. Silencing of target genes (HO-1, Nrf-2) or pharmacological signal inhibitors was exploited to investigate the HO-1 induction by THI-28. The dependency of HO-1 by THI-28 on survival rate and circulating HMGB1 level was tested in CLP-induced septic mice. Results showed that a time- and concentration-dependent HO-1 induction by THI-28 was significantly reduced by transfection with siNrf2 RNA. The reduction of iNOS/NO and HMGB1 expression by THI-28 was significantly reversed by silencing HO-1 RNA or treatment with SB203580, a p38 MAPK inhibitor, or LY294002, a PI3K inhibitor in LPS-activated cells. Decreasing p-I?B? by THI-28 resulted in inhibition of NF-?B activity which was reversed by silencing HO-1 RNA in LPS-activated cells. Most importantly, increased survival and reduction of liver and kidney injury and circulating HMGB1 levels by THI-28 in CLP-mice were reversed by ZnPPIX, HO-1 inhibitor. Taken together, these findings suggest that the novel compound THI-28 induces the expression of HO-1 by activating the PI3K and p38 MAPK pathways and suppressed HMGB1 and iNOS production in LPS-treated macrophages and septic mice, which may be useful in treating organ injury due to sepsis.
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ARS-interacting multi-functional protein 1 induces proliferation of human bone marrow-derived mesenchymal stem cells by accumulation of ?-catenin via fibroblast growth factor receptor 2-mediated activation of Akt.
Stem Cells Dev.
PUBLISHED: 06-25-2013
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ARS-Interacting Multi-functional Protein 1 (AIMP1) is a cytokine that is involved in the regulation of angiogenesis, immune activation, and fibroblast proliferation. In this study, fibroblast growth factor receptor 2 (FGFR2) was isolated as a binding partner of AIMP peptide (amino acids 6-46) in affinity purification using human bone marrow-derived mesenchymal stem cells (BMMSCs). AIMP1 peptide induced the proliferation of adult BMMSCs by activating Akt, inhibiting glycogen synthase kinase-3?, and thereby increasing the level of ?-catenin. In addition, AIMP1 peptide induced the translocation of ?-catenin to the nucleus and increased the transcription of c-myc and cyclin D1 by activating the ?-catenin/T-cell factor (TCF) complex. By contrast, transfection of dominant negative TCF abolished the effect of AIMP1. The inhibition of Akt, using LY294002, abolished the accumulation and nuclear translocation of ?-catenin induced by AIMP1, leading to a decrease in c-myc and cyclin D1 expression, which decreased the proliferation of BMMSCs. An intraperitoneal injection of AIMP1 peptide into C57/BL6 mice increased the colony formation of fibroblast-like cells. Fluorescence activated cell sorting analysis showed that the colony-forming cells were CD29(+)/CD44(+)/CD90(+)/CD105(+)/CD34(-)/CD45(-), which is characteristic of MSCs. In addition, the fibroblast-like cells differentiated into adipocytes, chondrocytes, and osteocytes. Taken together, these data suggest that AIMP1 peptide promotes the proliferation of BMMSCs by activating the ?-catenin/TCF complex via FGFR2-mediated activation of Akt, which leads to an increase in MSCs in peripheral blood.
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LPS potentiates nucleotide-induced inflammatory gene expression in macrophages via the upregulation of P2Y2 receptor.
Int. Immunopharmacol.
PUBLISHED: 06-07-2013
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Sepsis is a severe systemic inflammatory response that is associated with high morbidity and mortality. A previous study using an animal model of sepsis showed that survival was significantly lower in WT mice than in P2Y2 receptor (P2Y2R)-deficient mice, suggesting that P2Y2R plays a role in septic death. We therefore investigated the role of P2Y2R in the inflammatory responses of RAW264.7 murine macrophages to LPS. LPS time-dependently upregulated P2Y2R mRNA levels, with a prominent increase observed at 4h. In addition, LPS increased ATP release in a time dependent manner (5-120min post LPS treatment). Accordingly, we pretreated cells with LPS for 4h to induce P2Y2R expression and then stimulated the cells with UTP or ATP for 16h. Interestingly, ATP- or UTP-dependent P2Y2R activation in LPS-pretreated cells resulted in dramatically enhanced HMGB1 secretion, COX-2 and iNOS expression, and furthermore PGE2 and NO production compared to LPS treatment alone (4h) or ATP or UTP treatment alone (16h), an effect that was inhibited by P2Y2R silencing. In addition, these increases in HMGB1 secretion, COX-2 and iNOS expression and PGE2 and NO production commonly involved the JNK, PKC and PDK pathways. Taken together, these data demonstrate that LPS-dependent upregulation of P2Y2R plays a critical role in facilitating the inflammatory responses induced by LPS.
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Influence of thermophilic aerobic digestion as a sludge pre-treatment and solids retention time of mesophilic anaerobic digestion on the methane production, sludge digestion and microbial communities in a sequential digestion process.
Water Res.
PUBLISHED: 04-23-2013
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In this study, the changes in sludge reduction, methane production and microbial community structures in a process involving two-stage thermophilic aerobic digestion (TAD) and mesophilic anaerobic digestion (MAD) under different solid retention times (SRTs) between 10 and 40 days were investigated. The TAD reactor (RTAD) was operated with a 1-day SRT and the MAD reactor (RMAD) was operated at three different SRTs: 39, 19 and 9 days. For a comparison, control MAD (RCONTROL) was operated at three different SRTs of 40, 20 and 10 days. Our results reveal that the sequential TAD-MAD process has about 42% higher methane production rate (MPR) and 15% higher TCOD removal than those of RCONTROL when the SRT decreased from 40 to 20 days. Denaturing gradient gel electrophoresis (DGGE) and real-time PCR results indicate that RMAD maintained a more diverse bacteria and archaea population compared to RCONTROL, due to the application of the biological TAD pre-treatment process. In RTAD, Ureibacillus thermophiles and Bacterium thermus were the major contributors to the increase in soluble organic matter. In contrast, Methanosaeta concilii, a strictly aceticlastic methanogen, showed the highest population during the operation of overall SRTs in RMAD. Interestingly, as the SRT decreased to 20 days, syntrophic VFA oxidizing bacteria, Clostridium ultunense sp., and a hydrogenotrophic methanogen, Methanobacterium beijingense were detected in RMAD and RCONTROL. Meanwhile, the proportion of archaea to total microbe in RMAD and RCONTROL shows highest values of 10.5 and 6.5% at 20-d SRT operation, respectively. Collectively, these results demonstrate that the increased COD removal and methane production at different SRTs in RMAD might be attributed to the increased synergism among microbial species by improving the hydrolysis of the rate limiting step in sludge with the help of the biological TAD pre-treatment.
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The influence of lower-extremity function in elderly individuals quality of life (QOL): An analysis of the correlation between SPPB and EQ-5D.
Arch Gerontol Geriatr
PUBLISHED: 04-13-2013
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If an association between a decline in physical performance and subjective QOL is confirmed, the SPPB could be used as a predictor for declining QOL in older people.
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Quantitative comparison of CDKN2B methylation in pediatric and adult myelodysplastic syndromes.
Acta Haematol.
PUBLISHED: 04-03-2013
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Transcriptional repression of tumor suppressor genes is determined by the quantity of promoter hypermethylation. We analyzed the methylation quantity of CDKN2B in pediatric myelodysplastic syndromes (MDS).
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The red clover necrotic mosaic virus capsid protein N-terminal amino acids possess specific RNA binding activity and are required for stable virion assembly.
Virus Res.
PUBLISHED: 03-25-2013
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The red clover necrotic mosaic virus (RCNMV) bipartite RNA genome is packaged into two virion populations containing either RNA-1 and RNA-2 or multiple copies of RNA-2 only. To understand this distinctive packaging scheme, we investigated the RNA-binding properties of the RCNMV capsid protein (CP). Maltose binding protein-CP fusions exhibited the highest binding affinities for RNA probes containing the RNA-2 trans-activator or the 3 non-coding region from RNA-1. Other viral and non-viral RNA probes displayed CP binding but to a much lower degree. Deletion of the highly basic N-terminal 50 residues abolished CP binding to viral RNA transcripts. In planta studies of select CP deletion mutants within this N-terminal region revealed that it was indispensable for stable virion formation and the region spanning CP residues 5-15 is required for systemic movement. Thus, the N-terminal region of the CP is involved in both producing two virion populations due to its RNA binding properties and virion stability.
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Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? A retrospective case-control study.
BMC Infect. Dis.
PUBLISHED: 03-23-2013
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The need for mandatory confirmation of negative conversion in Klebsiella pneumoniae bacteremia (KpB) has not been adequately addressed. We conducted a retrospective case-control study of adult patients with KpB over a 5-year period in two tertiary-care hospitals to determine the risk factors for persistent bacteremia and to reevaluate the necessity of follow-up blood culture in KpB.
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Tailor-made highly luminescent and ambipolar transporting organic mixed stacked charge-transfer crystals: an isometric donor-acceptor approach.
J. Am. Chem. Soc.
PUBLISHED: 03-13-2013
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We have rationally designed a densely packed 1:1 donor-acceptor (D-A) cocrystal system comprising two isometric distyrylbenzene- and dicyanodistyrylbenzene-based molecules, forming regular one-dimensional mixed stacks. The crystal exhibits strongly red-shifted, bright photoluminescence originating from an intermolecular charge-transfer state. The peculiar electronic situation gives rise to high and ambipolar p-/n-type field-effect mobility up to 6.7 × 10(-3) and 6.7 × 10(-2) cm(2) V(-1) s(-1), respectively, as observed in single-crystalline OFETs prepared via solvent vapor annealing process. The unique combination of favorable electric and optical properties arising from an appropriate design concept of isometric D-A cocrystal has been demonstrated as a promising candidate for next generation (opto-)electronic materials.
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Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis: a comparison with bacteremia caused by Enterobacteriaceae.
BMC Infect. Dis.
PUBLISHED: 03-11-2013
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This study was performed to detect risk factors for Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis.
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A Simplified One-Step Nuclear Transfer Procedure Alters the Gene Expression Pattern and Developmental Potential of Cloned Porcine Embryos.
J. Vet. Sci.
PUBLISHED: 02-13-2013
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Various SCNT techniques of mammalian species have been developed to adjust species-specific procedures, for the differences of the oocytes from the species. Since the species-specific SCNT protocols may result in different expression levels of developmentally important genes, they may affect embryonic development and pregnancy. In this study, porcine oocytes treated with demecolcine for facilitation of enucleation with protruded genetic material, and the enucleation and donor cell injection were performed either simultaneously with a single pipette (simplified one-step SCNT; SONT) or separately with each pipettes (conventional two-step SCNT as control; CTNT). After the in vitro culture of the blastocysts from both groups, the expression level of developmentally important genes (OCT4, NANOG, EOMES, CDX2, GLUT-1, PolyA and HSP70) was analyzed by quantitative RT-PCR. Both developmental rate to the blastocyst stage and the expression level of genes(CDX2, EOMES and HSP70) were elevated in SONT groups compared to the CTNT. The genes with elevated expression are known to be related with the formation of the trophectoderm and heating stress-arrest. These results showed that our SONT technique improved the embryonic development of SCNT porcine embryos and increased the expression of genes that are important for placental formation and stress-arrest in the cloned porcine embryo.
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Potential for therapeutic manipulation of the UPR in disease.
Semin Immunopathol
PUBLISHED: 02-11-2013
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Increased endoplasmic reticulum (ER) stress and the activated unfolded protein response (UPR) signaling associated with it play key roles in physiological processes as well as under pathological conditions. The UPR normally protects cells and re-establishes cellular homeostasis, but prolonged UPR activation can lead to the development of various pathologies. These features make the UPR signaling pathway an attractive target for the treatment of diseases whose pathogenesis is characterized by chronic activation of this pathway. Here, we focus on the molecular signaling pathways of the UPR and suggest possible ways to target this response for therapeutic purposes.
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Critical use of balloon angioplasty after recanalization failure with retrievable stent in acute cerebral artery occlusion.
J Korean Neurosurg Soc
PUBLISHED: 02-04-2013
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Sudden major cerebral artery occlusion often resists recanalization with currently available techniques or can results in massive symptomatic intracranial hemorrhage (sICH) after thrombolytic therapy. The purpose of this study was to examine mechanical recanalization with a retrievable self-expanding stent and balloon in acute intracranial artery occlusions.
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Convergent evolution of two different random RNAs for specific interaction with methionyl-tRNA synthetase.
Biochem. Biophys. Res. Commun.
PUBLISHED: 01-29-2013
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Aminoacyl-tRNA synthetases (ARSs) recognize a specific sequence or structural characteristics of their cognate tRNAs. To contribute to the understanding how these recognition sites were selected, we generated two different RNA libraries containing either 42mer or 70mer random sequence and used them to select RNA aptamers that specifically bound to methionyl-tRNA synthetase (MRS) of Mycobacterium tuberculosis. The aptamer pools selected from the two RNA libraries showed strong binding affinity and selectivity to M. tuberculosis MRS compared to that of the homologous Escherichia coli MRS. The RNA aptamers selected from the two completely unrelated RNA pools shared the octamer sequence including CAU and the anticodon sequence of tRNA(Met). The secondary structure prediction suggested that the octamer motif in the selected aptamers would form a loop similar to the anticodon loop of tRNA(Met). The results suggest that the RNA loop containing CAU triplet could selected as a major recognition site for MRS during evolution more or less regarding, and also showed that species-specific ARS inhibitors can be obtained by in vitro evolution.
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Takotsubo cardiomyopathy associated with severe hypocalcemia secondary to idiopathic hypoparathyroidism.
Korean Circ J
PUBLISHED: 01-21-2013
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The etiology and pathophysiology of takotsubo cardiomyopathy have not yet been fully clarified. We report a case of takotsubo cardiomyopathy associated with severe hypocalcemia secondary to hypoparathyroidism. A 69-year-old woman presented with acute pulmonary edema caused by severe left ventricular dysfunction with apical ballooning compatible with takotsubo cardiomyopathy. Laboratory tests revealed severe hypocalcemia secondary to idiopathic hypoparathyroidism. Coronary angiography showed normal coronary artery function. Her symptoms and signs of heart failure improved dramatically with the correction of hypocalcemia through calcium and calcitriol replacement.
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Microbial community structure in a thermophilic aerobic digester used as a sludge pretreatment process for the mesophilic anaerobic digestion and the enhancement of methane production.
Bioresour. Technol.
PUBLISHED: 01-19-2013
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An effective two-stage sewage sludge digestion process, consisting of thermophilic aerobic digestion (TAD) followed by mesophilic anaerobic digestion (MAD), was developed for efficient sludge reduction and methane production. Using TAD as a biological pretreatment, the total volatile suspended solid reduction (VSSR) and methane production rate (MPR) in the MAD reactor were significantly improved. According to denaturing gradient gel electrophoresis (DGGE) analysis, the results indicated that the dominant bacteria species such as Ureibacillus thermophiles and Bacterium thermus in TAD were major routes for enhancing soluble organic matter. TAD pretreatment using a relatively short SRT of 1 day showed highly increased soluble organic products and positively affected an increment of bacteria populations which performed interrelated microbial metabolisms with methanogenic species in the MAD; consequently, a quantitative real-time PCR indicated greatly increased Methanosarcinales (acetate-utilizing methanogens) in the MAD, resulting in enhanced methane production.
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Incidence and risk factors of tuberculosis in patients with human immunodeficiency virus infection.
J. Korean Med. Sci.
PUBLISHED: 01-11-2013
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Korea is a low prevalence country for human immunodeficiency virus (HIV) infection and has an intermediate tuberculosis (TB) burden. We previously reported that the incidence of TB in HIV-infected patients was 9.6 cases per 100 person-years (P-Y) between 1988 and 1997. The aims of the present study were to measure any change in incidence from the previous study, and to identify risk factors for TB in HIV-infected patients. We reviewed all medical records of HIV-infected patients who were followed-up in one tertiary hospital between 1998 and 2010. Over the total observation period of 5858.33 P-Y, TB developed in 70 patients (1.19 cases per 100 P-Y; 95% confidence interval [CI], 0.91-1.47 cases per 100 P-Y). Based on Poisson regression, one risk factor associated with TB was an initial CD4+ cell count below 200 cells/µL (relative risk, 2.34; 95% CI, 1.47-3.73). Mean CD4+ cell counts of pulmonary, extrapulmonary, and both pulmonary and extrapulmonary TB were 179.8 cells/µL, 138.3 cells/µL, and 114.2 cells/µL, respectively (P = 0.55). In conclusion, the incidence of TB in HIV-infected patients has decreased since the previous study. An initial CD4+ cell count below 200 cells/µL is an independent risk factor for development of TB in HIV-infected patients.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.