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Lee, Ah-Young,Chang, Sun-Young,Kim, Jung-Im,Cha, Hye-Ran,Jang, Myoung Ho,Yamamoto, Masafumi,Kweon, Mi-Na WILEY-VCH Verlag 2008 European journal of immunology Vol.38 No.4
<P>This study examined dendritic cells (DC) following intrarectal (IR) vaccination with the mucosal adjuvant cholera toxin (CT). Three rounds of IR vaccination with ovalbumin (OVA) and CT resulted in brisk levels of systemic and mucosal Ig responses. Immunohistochemical studies revealed that CD11c<SUP>+ </SUP>MHC class II<SUP>+</SUP> cells accumulated primarily in the colonic patches (CP) and lamina propria of the large intestine (LI-LP), iliac LN (ILN) and MLN following IR vaccination with CT. Adoptively transferred CFSE-labeled OVA-specific CD4<SUP>+</SUP> T cells proliferated significantly, secreting predominantly Th1-type cytokines in the CP (48 h after IR vaccination with CT) and Th2-type cytokines in the ILN (96 h after IR vaccination with CT). Following three IR vaccinations, CP-null mice that were generated by in utero treatment with anti-IL-7R Ab showed reduced levels of serum IgG and fecal IgA antibodies, suggesting a crucial role for CP in the initiation of systemic and mucosal immune responses. Of most interest, IR vaccination reduced IgA levels in fecal extracts significantly more in the CCR7<SUP>–/–</SUP> mice than in the wild-type mice. These results indicate that IR vaccination primarily mobilizes CD11c<SUP>+</SUP> cells in the CP and ILN to induce optimal mucosal immune responses by CCR7 interaction.</P>
학교조직풍토와 교수몰입 간의 관계에서 교수효능감의 매개효과
이혜란(Hey Ran Lee),김아영(Ah Young Kim),차정은(Jung Eun Cha) 한국교육심리학회 2011 敎育心理硏究 Vol.25 No.3
이 연구의 목적은 교사가 지각하는 학교조직풍토, 교수효능감과 교수몰입 간에 어떠한 관계가 있는지 탐색한 후, 교수몰입에 대한 학교조직풍토의 영향을 교수효능감이 매개하는가를 구조모형을 통해 검증하는 것이다. 이를 위해 수도권 소재 초, 중, 고등학교에 재직 중인 교사들을 대상으로 실시한 설문자료 총 674부를 분석하였다. 분석결과, 학교조직풍토 하위요인 중에서 교사의 친교적 행동과 헌신적 행동, 그리고 교장의 인간지향적 행동과 목표지향적 행동과 같은 긍정적인 행동들은 교수효능감 및 교수몰입과 정적인 상관을 보이고, 교사의 방관적 행동과 교장의 관료지향적인 행동은 교수효능감 및 교수몰입과 높지는 않지만 부적인 관련성을 보이는 경향이 나타났다. 구조모형에 대한 분석결과에서는 교사의 헌신적 행동과 인간지향적 행동의 영향이 교수효능감을 통해서 교수몰입에 영향을 주는 경로가 유의한 것으로 나타나 학교조직풍토의 영향을 교수효능감이 매개하는 것을 확인하였다. 또한 교수효능감은 교수몰입에 대해 강력한 영향력을 행사하는 변인임이 확인되었다. 연구결과를 교육현장에 대한 시사점을 중심으로 논의하였다. The purpose of this study was to examine the relationships among organizational climate of schools, teaching efficacy, and teaching flow, and to confirm the mediating effect of teaching efficacy in the relationship between organizational climate and teaching flow using covariance structural equation modeling analysis. To accomplish the purpose, we have gathered responses of self-reported questionnaires assessing organizational climate of schools, teaching efficacy, and teaching flow from 682 teachers in 34 elementary, middle, and high schools around Seoul and the metropolitan area. The results revealed that there was positive correlation between teaching efficacy and teaching flow. Among the sub-factors in the school climate scale, positive sub-factors such as teachers` intimate and dedicated behaviors, and principals` people-oriented behaviors and goal-oriented behaviors were positively correlated with teaching efficacy and teaching flow, whereas negative sub-factors such as teachers` negligent behaviors and principals` bureaucratic behaviors were negatively correlated with teaching efficacy and teaching flow. However, the structural analysis results revealed that the effects of the teachers` intimate and dedicated behaviors on the teaching flow were mediated by the teaching efficacy. Results were discussed in relations to the educational practice in Korea.
Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
Yoo, Young Dong,Lee, Dae‐,Hee,Cha‐,Molstad, Hyunjoo,Kim, Hyungsin,Mun, Su Ran,Ji, Changhoon,Park, Seong Hye,Sung, Ki Sa,Choi, Seung Ah,Hwang, Joonsung,Park, Deric M,Kim, Seung‐,Ki,Pa EMBO 2017 EMBO reports Vol.18 No.1
<P>Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to >> 100 mu M). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-jB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR. ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.</P>
Shon, Ji-Hong,Yoon, Young-Ran,Kim, Min-Jung,Kim, Kyoung-Ah,Lim, Young-Chae,Liu, Kwang-Hyeon,Shin, Dong-Hoon,Lee, Chung Han,Cha, In-June,Shin, Jae-Gook Blackwell Science Ltd 2005 British journal of clinical pharmacology Vol.59 No.5
<P>Aims</P><P>We evaluated the involvement of cytochrome P450 (CYP) isoforms 2C9 and 2C19 in chlorpropamide 2-hydroxylation <I>in vitro</I> and in chlorpropamide disposition <I>in vivo</I>.</P><P>Methods</P><P>To identify CYP isoforms(s) that catalyse 2-hydroxylation of chlorpropamide, the incubation studies were conducted using human liver microsomes and recombinant CYP isoforms. To evaluate whether genetic polymorphisms of CYP2C9 and/or CYP2C19 influence the disposition of chlorpropamide, a single oral dose of 250 mg chlorpropamide was administered to 21 healthy subjects pregenotyped for CYP2C9 and CYP2C19.</P><P>Results</P><P>In human liver microsomal incubation studies, the formation of 2-hydroxychlorpropamide (2-OH-chlorpropamide), a major chlorpropamide metabolite in human, has been best described by a one-enzyme model with estimated <I>K</I><SUB><I>m</I></SUB> and <I>V</I><SUB>max</SUB> of 121.7 ± 19.9 µ<SMALL>M</SMALL> and 16.1 ± 5.0 pmol min<SUP>−1</SUP> mg<SUP>−1</SUP> protein, respectively. In incubation studies using human recombinant CYP isoforms, however, 2-OH-chlorpropamide was formed by both CYP2C9 and CYP2C19 with similar intrinsic clearances (CYP2C9 <I>vs.</I> CYP2C19: 0.26 <I>vs.</I> 0.22 µl min<SUP>−1</SUP> nmol<SUP>−1</SUP> protein). Formation of 2-OH-chlorpropamide in human liver microsomes was significantly inhibited by sulfaphenazole, but not by <I>S</I>-mephenytoin, ketoconazole, quinidine, or furafylline. In <I>in vivo</I> clinical trials, eight subjects with the <I>CYP2C9</I>*<I>1/</I>*<I>3</I> genotype exhibited significantly lower nonrenal clearance [*<I>1/</I>*<I>3 vs.</I>*<I>1/</I>*<I>1</I>: 1.8 ± 0.2 <I>vs.</I> 2.4 ± 0.1 ml h<SUP>−1</SUP> kg<SUP>−1</SUP>, <I>P</I> < 0.05; 95% confidence interval (CI) on the difference 0.2, 1.0] and higher metabolic ratios (of chlorpropamide/2-OH-chlorpropamide in urine: *<I>1/</I>*<I>3 vs.</I>*<I>1/</I>*<I>1</I>: 1.01 ± 0.19 <I>vs.</I> 0.56 ± 0.08, <I>P</I> < 0.05; 95% CI on the difference − 0.9, − 0.1) than did 13 subjects with <I>CYP2C9</I>*<I>1/</I>*<I>1</I> genotype. In contrast, no differences in chlorpropamide pharmacokinetics were observed for subjects with the <I>CYP2C19</I> extensive metabolizer <I>vs.</I> poor metabolizer genotypes.</P><P>Conclusions</P><P>These results suggest that chlorpropamide disposition is principally determined by CYP2C9 activity <I>in vivo</I>, although both CYP2C9 and CYP2C19 have a catalysing activity of chlorpropamide 2-hydroxylation pathway.</P>
The N-Degron Pathway Mediates ER-phagy
Ji, Chang Hoon,Kim, Hee Yeon,Heo, Ah Jung,Lee, Su Hyun,Lee, Min Ju,Kim, Su Bin,Srinivasrao, Ganipisetti,Mun, Su Ran,Cha-Molstad, Hyunjoo,Ciechanover, Aaron,Choi, Cheol Yong,Lee, Hee Gu,Kim, Bo Yeon,Kw Elsevier 2019 Molecular cell Vol.75 No.5
<P><B>Summary</B></P> <P>The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The autophagic adaptor p62 mediates autophagic degradation of the ER (ER-phagy) </LI> <LI> The ER membrane E3 ligase TRIM13 is a ubiquitin-dependent ER-phagy receptor to p62 </LI> <LI> N-terminal arginylation is an ER-phagy degron via binding to the ZZ domain of p62 </LI> <LI> p62-TRIM13-Nt-Arg circuit mediates ER protein quality control and homeostasis </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>