Design and Characterization of Heteroaromatic ??-Conjugated Semiconducting Materials

Department of Energy EngineeringOver the past few decades, ??-conjugated molecules have been attended due to the exotic properties and widely used for the devices such as organic photovoltaics (OPVs), field effect transistors (FETs) and light emitting diodes (LEDs). Especially, ??-conjugated frameworks of fused aromatic compounds incorporated with heteroatoms exhibited distinguishable features such like high electron affinity and strengthen intermolecular interaction without significant steric effect. Among of previously reported frameworks, dithienosilole (DTSi) and dithienogermole (DTGe) have been considered as one of the outstanding ??-conjugated molecules. In this contribution, I investigated study about the effects of introducing the cyclic chain onto the fused heteroaromatic compounds with comparisons of heteroaromatic compounds incorporating non-cyclic chain in chapter 1. Furthermore, I synthesized these two types of ??-conjugated molecules depends on central heteroatom with characterization and investigated optoelectrical, electrochemical properties and crystalline structure of thin film. And then, these four ??-conjugated molecules applied finally as a donor material of OPVs. In chapter 2, effects of introducing fluorine atom (F) on different position in benzothiadiazole (BT) unit with different end capping group were investigated. Modification of fluorine position exhibited totally different crystalline structures in blending system caused by dissimilar interaction. Furthermore, we have established foundation for the rational designing of ??-conjugated molecules with measurement of molecular frontier energy, and light absorption properties. in chapter 3, I attempted replacement of C-C covalent bond embedded on fused aromatic compounds B???N coordination bond. B???N unit which is isoelectronic and isosteric with C-C unit have exhibited exotic properties in previously reported literatures. In this thesis, I attempted to investigated effects of introducing the B???N unit onto the fused aromatic compounds.ope

Attenuating MKRN1 E3 ligase-mediated AMPKα suppression increases tolerance against metabolic stresses in mice

The 5′ adenosine monophosphate-activated protein kinase (AMPK) is an essential energy sensor in the cell, which, at low energy levels, instigates the cellular energy-generating systems along with suppression of the anabolic signaling pathways. The activation of AMPK through phosphorylation is a well-known process; however, activation alone is not sufficient, and knowledge about the other regulatory networks of post-translational modifications connecting the activities of AMPK to systemic metabolic syndromes is important, which is still lacking. The recent studies on Makorin Ring Finger Protein 1 (MKRN1) mediating the ubiquitination and proteasome-dependent degradation of AMPKa implicate that the post-translational modification of AMPK, regulating its protein homeostasis, could impose significant systemic metabolic effects (Lee et al. Nat Commun 9:3404). In this study, MKRN1 was identified as a novel E3 ligase for both AMPKα1 and α2. Mouse embryonic fibroblasts, genetically deleted for Mkrmn1, and Ampkα1 and α2, became stabilized with the suppression of lipogenesis pathways and an increase in nutrient consumption and mitochondria regeneration. Of note, the Mkrn1 knockout mice fed normal chow displayed no obvious phenotypic defects or abnormality, whereas the Mkrn1-null mice exhibited strong tolerance to metabolic stresses induced by high-fat diet (HFD). Thus, these mice, when compared with the HFD-induced wild type, were resistant to obesity, diabetes, and non-alcoholic fatty liver disease. Interestingly, in whole-body Mkrn1 knockout mouse, only the liver and white and brown adipose tissues displayed anincrease in the active phosphorylated AMPK levels, but no other organs, such as the hypothalamus, skeletal muscles, or pancreas, displayed such increases. Specific ablation of MKRN1 in the mouse liver using adenovirus prevented HFD-induced lipid accumulation in the liver and blood, implicating MKRN1 as a possible therapeutic target for metabolic syndromes, such as obesity, type II diabetes, and fat liver diseases. This study would provide a crucial perspective on the importance of post-translational regulation of AMPK in metabolic pathways and will help researchers develop novel therapeutic strategies that target not only AMPK but also its regulators

The chromatin remodeler Ino80 mediates RNAPII pausing site determination

Background Promoter-proximal pausing of RNA polymerase II (RNAPII) is a critical step for the precise regulation of gene expression. Despite the apparent close relationship between promoter-proximal pausing and nucleosome, the role of chromatin remodeler governing this step has mainly remained elusive. Results Here, we report highly confined RNAPII enrichments downstream of the transcriptional start site in Saccharomyces cerevisiae using PRO-seq experiments. This non-uniform distribution of RNAPII exhibits both similar and different characteristics with promoter-proximal pausing in Schizosaccharomyces pombe and metazoans. Interestingly, we find that Ino80p knockdown causes a significant upstream transition of promoter-proximal RNAPII for a subset of genes, relocating RNAPII from the main pausing site to the alternative pausing site. The proper positioning of RNAPII is largely dependent on nucleosome context. We reveal that the alternative pausing site is closely associated with the + 1 nucleosome, and nucleosome architecture around the main pausing site of these genes is highly phased. In addition, Ino80p knockdown results in an increase in fuzziness and a decrease in stability of the + 1 nucleosome. Furthermore, the loss of INO80 also leads to the shift of promoter-proximal RNAPII toward the alternative pausing site in mouse embryonic stem cells. Conclusions Based on our collective results, we hypothesize that the highly conserved chromatin remodeler Ino80p is essential in establishing intact RNAPII pausing during early transcription elongation in various organisms, from budding yeast to mouse.This work was supported by a National Research Foundation (NRF) of Korea Grant funded by the Ministry of Science and ICT (MSIT) (2018R1A5A1024261, SRC), and the Collaborative Genome Program for Fostering New Post-Genome Industry of the NRF funded by the MSIT (2018M3C9A6065070)

Phenotypic and Functional Changes of Peripheral Ly6C(+) T Regulatory Cells Driven by Conventional Effector T Cells

A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up-or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C(+) Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C down-regulation was accompanied by proliferation of Ly6C(+) Treg cells and subsequent change into Ly6C-effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C(+) Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance.110Ysciescopu

Young age: an independent risk factor for disease-free survival in women with operable breast cancer

BACKGROUND: The incidence of breast cancer in young women (age < 35) is low. The biology of the disease in this age group is poorly understood, and there are conflicting data regarding the prognosis for these women compared to older patients. METHODS: We retrospectively analyzed 2040 consecutive primary invasive breast cancer patients who underwent surgical procedures at our institution between 1990 and 1999. The younger age group was defined as patients aged <35 years at the time of diagnosis. The clinicopathological characteristics and treatment outcomes were compared between younger and older age groups. RESULTS: A total of 256 (12.5%) patients were aged <35. There was a significantly higher incidence of nuclear grade 3 and medullary histological-type tumors in younger patients compared to older patients. Axillary lymph node status, T stage, histological grade, c-erbB2 expression and estrogen receptor status did not differ significantly between the two age groups. Younger patients had a greater probability of recurrence and death at all time periods. Although there was no significant difference in disease-free survival between the two age groups in lymph node-negative patients, the younger group showed worse prognosis among lymph node-positive patients (p < 0.001). In multivariate analysis, young age remained a significant predictor of recurrence (p = 0.010). CONCLUSION: Young age (<35) is an independent risk factor for relapse in operable breast cancer patients

Gene duplication of type-B ARR transcription factors systematically extends transcriptional regulatory structures in Arabidopsis

Many of duplicated genes are enriched in signaling pathways. Recently, gene duplication of kinases has been shown to provide genetic buffering and functional diversification in cellular signaling. Transcription factors (TFs) are also often duplicated. However, how duplication of TFs affects their regulatory structures and functions of target genes has not been explored at the systems level. Here, we examined regulatory and functional roles of duplication of three major ARR TFs (ARR1, 10, and 12) in Arabidopsis cytokinin signaling using wild-type and single, double, and triple deletion mutants of the TFs. Comparative analysis of gene expression profiles obtained from Arabidopsis roots in wild-type and these mutants showed that duplication of ARR TFs systematically extended their transcriptional regulatory structures, leading to enhanced robustness and diversification in functions of target genes, as well as in regulation of cellular networks of target genes. Therefore, our results suggest that duplication of TFs contributes to robustness and diversification in functions of target genes by extending transcriptional regulatory structures.1

Genetic Polymorphism of Geranylgeranyl Diphosphate Synthase (GGSP1) Predicts Bone Density Response to Bisphosphonate Therapy in Korean Women

Purpose: Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy. Materials and Methods: In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes. Results: Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 +/- 0.127 vs. 0.695 +/- 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.3242.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD. Conclusion: Our Study suggested that GGPS1 -8188A ins/del polymorphism may confer susceptibility to femoral heck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.This work was supported by a grant from Ministry of Health, Welfare and Family of Korea (03-PJ10-PG13- GD01-0002).Guo RT, 2007, P NATL ACAD SCI USA, V104, P10022, DOI 10.1073/pnas.0702254104Gallagher JC, 2006, BONE, V39, P1268, DOI 10.1016/j.bone.2006.06.007Bonnick S, 2006, J CLIN ENDOCR METAB, V91, P2631, DOI 10.1210/jc.2005-2602BONNICK SL, 2006, AM J MED S1, V119, pS25Kim SW, 2005, ENDOCR J, V52, P667Palomba S, 2005, OSTEOPOROSIS INT, V16, P943, DOI 10.1007/s00198-004-1800-5Lewiecki EM, 2003, J CLIN DENSITOM, V6, P307Palomba S, 2003, CLIN ENDOCRINOL, V58, P365Qureshi AM, 2002, CALCIFIED TISSUE INT, V70, P158Turner CH, 2002, OSTEOPOROSIS INT, V13, P97Mann V, 2001, J CLIN INVEST, V107, P899Keen RW, 2001, RHEUMATOLOGY, V40, P48Bergstrom JD, 2000, ARCH BIOCHEM BIOPHYS, V373, P231Crilly RG, 2000, OSTEOPOROSIS INT, V11, P607Eisman JA, 1999, ENDOCR REV, V20, P788Tsukamoto K, 1999, J HUM GENET, V44, P148Keen RW, 1998, BONE, V23, P367Masi L, 1998, BIOCHEM BIOPH RES CO, V248, P190Uitterlinden AG, 1998, NEW ENGL J MED, V338, P1016Mizunuma H, 1997, BONE, V21, P379Kurland ES, 1997, J CLIN ENDOCR METAB, V82, P2799Shiraki M, 1997, J BONE MINER RES, V12, P1438Sainz J, 1997, NEW ENGL J MED, V337, P77Johnson ML, 1997, AM J HUM GENET, V60, P1326Langdahl BL, 1997, BONE, V20, P289SILVERMAN SL, 1992, CALCIFIED TISSUE INT, V50, P101