• Tuberculosis and Respiratory Diseases
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• v.65 no.4
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• pp.343-350
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• 2008

PD-L1 is expressed in a variety of antigen-presenting cells and provides T cell tolerance via ligation with its receptor PD-1 and B7-1 on T cells. Stimulation with lipopolysaccharide (LPS) can increase the level of PD-L1 expression in B cells and macrophages, which suggests that this molecule plays a role in the immunosuppression observed in severe sepsis. The aim of this study was to identify which of the downstream pathways of TLR4 are involved in the up-regulation of PD-L1 by LPS in macrophages. Flow cytometry was used to examine the expression of PD-L1 in RAW 264.7 macrophages stimulated with LPS. The following chemical inhibitors were used to evaluate the role of each pathway: LY294002 for PI3K/Akt, SB202190 for p38 MAPK, and U0126 for MEK. LPS induced the expression of PD-L1 in a time- and dose-dependent manner. Transfection of siRNA for TLR4 suppressed the induction of PD-L1. Pretreatment with LY294002 and SB202190 decreased the level of PD-L1 expression but U0126 did not. Overall, the PI3K/Akt and p38 MAPK pathways are involved in the up-regulation of PD-L1 expression in RAW 264.7 macrophages stimulated with LPS.

• Proceedings of the Korea Water Resources Association Conference
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• 2001.05a
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• pp.67-75
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• 2001

Anticipated water scarcity in the first half of this century is one of the most concerned international issues. However, even though the issue has an international impact and world wide monitoring is critical, there are limited number of global estimates at present. In this study, annual water availability was derived from annual runoff estimated by land surface models using Total Runoff Integrating Pathways (TRIP) with 0.5 degree by 0.5 degree longitude/latitude resolution globally. Global distribution of water withdrawal for each sector in the same horizontal spatial resolution was estimated based on country-base statistics of municipal water use, industrial water use, and agricultural intake, using global geographical information system with global distributions of population and irrigated crop land area. The total population under water stress estimated for 1995 corresponded very well with former estimates, however, the number is highly depend on how to assume the ratio how much water from outside of the region can be used for water resources within the region. It suggests the importance of regional studies evaluating the possibility of water intake as well as the validity of the investment for water resources withdrawal facilities.

• BMB Reports
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• v.50 no.1
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• pp.1-2
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• 2017

Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/${\beta}$-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced the Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/${\beta}$-catenin signaling to Yap/Taz activities, which are important in tumor initiation. Genetic removal of ${\beta}$-catenin in the liver of the Mst1/2 mutants significantly accelerates tumoriogenesis. Therefore, Wnt/${\beta}$-catenin signaling, known for its oncogenic property, exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study provides new insights in developing novel therapeutic strategies to treat liver tumors.

• Journal of Plant Biotechnology
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• v.48 no.3
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• pp.148-155
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• 2021

Gibberellins (GAs) are essential phytohormones for plant growth that influence developmental processes and crop yields. Recent functional genomic analyses of model plants have yielded good characterizations of the canonical GA signaling pathways and related genes. Although Panax ginseng has long been considered to have economic and medicinal importance, functional genomic studies of the GA signaling pathways in this crucial perennial herb plant have been rarely conducted. Here, we identified and performed functional analysis of the GA signaling-related genes, including PgGID1s, PgSLY1s, and PgRGAs. We confirmed that the physiological role of GA signaling components in P. ginseng was evolutionarily conserved. In addition, the important functional domains and amino acid residues for protein interactions among active GA, GID1, SCF^SLY1, and RGA were also functionally conserved. Prediction and comparison of crystallographic structural similarities between PgGID1s and AtGID1a supported their function as GA receptors. Moreover, the subcellular localization and GA-dependent promotion of DELLA degradation in P. ginseng was similar to the canonical GA signaling pathways in other plants. Finally, we found that overexpression of PgRGA2 and PgSLY1-1 was sufficient to complement the GA-related phenotypes of atgid1a/c double- and rga quintuple-mutants, respectively. This critical information for these GA signaling genes has the potential to facilitate future genetic engineering and breeding of P. ginseng for increased crop yield and production of useful substances.

• Molecules and Cells
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• v.42 no.4
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• pp.292-300
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• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.56-64
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• 2024

Biased signaling or functional selectivity refers to the ability of an agonist or receptor to selectively activate a subset of transducers such as G protein and arrestin in the case of G protein-coupled receptors (GPCRs). Although signaling through arrestin has been reported from various GPCRs, only a few studies have examined side-by-side how it differs from signaling via G protein. In this study, two signaling pathways were compared using dopamine D₂ receptor (D₂R) mutants engineered via the evolutionary tracer method to selectively transduce signals through G protein or arrestin (D₂G and D₂Arr, respectively). D₂G mediated the inhibition of cAMP production and ERK activation in the cytoplasm. D₂Arr, in contrast, mediated receptor endocytosis accompanied by arrestin ubiquitination and ERK activation in the nucleus as well as in the cytoplasm. D₂Arr-mediated ERK activation occurred in a manner dependent on arrestin3 but not arrestin2, accompanied by the nuclear translocation of arrestin3 via importin1. D₂R-mediated ERK activation, which occurred in both the cytosol and nucleus, was limited to the cytosol when cellular arrestin3 was depleted. This finding supports the results obtained with D₂Arr and D₂G. Taken together, these observations indicate that biased signal transduction pathways activate distinct downstream mechanisms and that the subcellular regions in which they occur could be different when the same effectors are involved. These findings broaden our understanding on the relation between biased receptors and the corresponding downstream signaling, which is critical for elucidating the functional roles of biased pathways.

• Korean Journal of Adult Nursing
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• v.12 no.4
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• pp.517-532
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• 2000

The purpose of this study was to develop a critical pathway for case management of patients who have received Lumbar Laminectomy because of low back pain, arm and leg numbness, and radiating pain in the leg. For this study, a preliminary critical pathway was developed through a review of the literature including five critical pathways which are currently being used in the USA. In order to identify the overall service contents required by these patients, 30 cases were analyzed. These cases were taken from medical records of those with Lumbar Laminectomy between January, 1998 and December, 1998 in the department of neurosurgery at the Pusan National University Hospital in Pusan. An expert validity test was done for the preliminary critical pathway, a clinical validity test was also done using 12 patients with Lumbar Laminectomy between October 1, 1999 and January 31, 2000. After these processes, the final critical pathway was developed. The results are summarized as follows. 1. The vertical axis of the critical pathway includes the following eight items: assessment, consultation, diet, test, medication, treatment, activity, education/ discharge planning. The horizontal axis includes the time from the start of hospitalization to discharge. Analysis of the 30 medical records was done. analysis of the service contents showed the horizontal axis of the preliminary critical pathway was set from hospitalization to the 12th post operation day and the vertical axis was set to include eight items, the contents which should have occurred, according to the time frames of the horizontal axis. 2. As a result of the expert validity test, it was found that among the 233 items, 203 showed over 88% agreement and 30 of them showed less than 88% agreement, which were then revised or deleted from the critical pathway. At the preliminary meeting for the clinical validity test, the time of hospitalization on the horizontal axis was shortened to the 10th post operation day. A clinical validity test was done with 12 patients with Lumbar Laminectomy. All the cases progressed according to the critical pathway although some variances were noted in assessment, consultation, test, medication, and treatment. 3. Based on these results, a final critical pathway was determined. In conclusion, this critical pathway is partially applicable to the care of patients with Lumbar Laminectomy and needs further investigation.

• Korean Journal of Adult Nursing
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• v.28 no.1
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• pp.43-52
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• 2016

Purpose: The aim of this study was to identify demographic, clinical, physical, and psychosocial factors affecting discharge delay in lumbar spinal surgery patients who were treated according to a critical pathway. Methods: A sample of 170 patients with lumbar spinal surgery agreed to participate in the study, between April 1, 2014 and August 30, 2015. Data were analyzed by mean, standard deviation, t-test, ${\chi}^2$-test, ANCOVA, and logistic regression analysis using SPSS 22.0 program. Results: Approximately fifty-nine percent of the participants was delayed discharge. On logistic regression analysis, female gender (OR=2.63, 95% CI=1.40~4.94), age (OR=1.03, 95% CI=1.01~1.05), spondylolisthesis (OR=4.49, 95% CI=1.90~10.61), and spinal fusion operation (OR=4.14, 95% CI=1.89~9.05) were significant factors predicting discharge delay of the participants. However, discharge delay was not related with pain, physical function, depression, or family support. Conclusion: An analysis of discharge delay may assist in evaluating and revising critical pathway for optimal care. In addition, nurses need to understand the factors affecting discharge delay of the given population who were treated according to a critical pathway.

• Molecules and Cells
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• v.41 no.8
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• pp.762-770
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• 2018

Adiponectin, a hormone produced by adipose tissue, is very abundant in plasma, and its anti- and pro-inflammatory effects are reported. However, the mechanisms of these pro- and anti-inflammatory effects are not fully defined. Herein, we evaluated the dual inflammatory response mechanism of adiponectin in macrophages. Short-term globular adiponectin (gAd) treatment induced $I{\kappa}B{\alpha}$ degradation, $NF-{\kappa}B$ nuclear translocation, and $TNF-{\alpha}$ production in RAW 264.7 cells. Polymyxin B pretreatment did not block gAd-induced $I{\kappa}B{\alpha}$ degradation, and heated gAd was unable to degrade $I{\kappa}B{\alpha}$, suggesting that the effects of gAd were not due to endotoxin contamination. gAd activated IKK and Akt, and inhibition of either IKK or Akt by dominant-negative $IKK{\beta}$ ($DN-IKK{\beta}$) or DN-Akt overexpression blocked gAd-induced $I{\kappa}B{\alpha}$ degradation, suggesting that short-term incubation with gAd mediates inflammatory responses by activating the $I{\kappa}B/NF-{\kappa}B$ and PI3K/Akt pathways. Contrastingly, long-term stimulation with gAd induced, upon subsequent stimulation, tolerance to gAd, lipopolysaccharide, and CpG-oligodeoxynucleotide, which is associated with gAd-induced downregulation of IL-receptor-associated kinase-1 (IRAK-1) due to IRAK-1 transcriptional repression. Conclusively, our findings demonstrate that the pro- and anti-inflammatory responses to gAd in innate immune cells are time-dependent, and mediated by the activation of the $I{\kappa}B/NF-{\kappa}B$ pathway, and IRAK-1 downregulation, respectively.

• Tuberculosis and Respiratory Diseases
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• v.72 no.3
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• pp.275-283
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• 2012

Background: Healthy individuals who develop nontuberculous mycobacteria (NTM) lung disease are likely to have specific susceptibility factors which can lead to a NTM infection. The aim of the present study was to investigate the mechanism underlying innate immune responses, including the role of mitogen-activated protein kinase (MAPK), in Mycobacterium abscessus lung disease. Methods: Extracellular signal-regulated kinase (ERK1/2) and p38 MAPK expression in monocytes from peripheral blood mononuclear cells were measured by Western blot analysis after stimulation by Mycobacterium avium in five patients with M. abscessus lung disease and seven healthy controls. A M. avium-induced cytokine assay was performed after inhibition of ERK1/2 and p38 MAPK pathways. Results: Mycobacterium avium induced p38 and ERK1/2 expression in monocytes from healthy controls and subsequently upregulated tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6, and IL-10 production. In monocytes from patients with M. abscessus lung disease, however, induction of p38 and ERK1/2 expression, and the production of TNF-${\alpha}$, IL-6, and IL-10 were significantly lower. Conclusion: Decreased activity of MAPK and cytokine secretion in monocytes from patients with M. abscessus lung disease may provide an explanation regarding host susceptibility to these uncommon infections.