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This study identified single nucleotide polymorphisms (SNPs) that affect the body weight of chickens. Analysis of body weight showed that the Cornish breed had the highest body weight, and the Korean native chicken (Gray Brown) had the lowest body weight. TSH is composed of an α-subunit and a β-subunit, and the TSH-β gene encoding the β-subunit has been reported to be associated with obesity. In chickens, it is located on chromosome 26 and is reported to be associated with growth. The calcium-sensing receptor gene (CaSR) plays a role in the regulation of extracellular calcium homeostasis and is responsible for calcium absorption in the urinary tract, which affects the eggshell quality in poultry. It was shown that TSH-β was strongly correlated with weight in Cornish and Korean native (Gray Brown) chickens, particularly in those with the CC trait. However, CaSR showed no association with body weight in poultry; it was associated with calcium and the eggshell. Thus, selection for TSH-β can be used to produce individuals with more favorable traits in terms of body weight.

Quaternized multiblock poly(phenylene-co-arylene ether)s (QPPs) are synthesized from a pre-aminated monomer and a series of chlorine-terminated oligo(arylene-ethers) via a nickel coupling reaction....

Background: Bisphosphonates are antiresorptive and antiangiogenic drugs that prevent and treat bone loss and mineralization in women with postmenopausal osteoporosis and cancer patients. Medication-related osteonecrosis of the jaw (MRONJ) is commonly caused by tooth extraction and dental trauma. Although genetic and pathological studies about MRONJ have been conducted, the pathogenesis of MRONJ still remains unclear. Methods: We aimed to identify genetic variants associated with MRONJ, using whole-exome sequencing (WES). Ten MRONJ patients prescribed bisphosphonates were recruited for WES, and jawbone tissue and blood samples were collected from the patients. Results: The analysis of the WES data found a total of 1866 SNP and 40 InDel variants which are specific to MRONJ. The functional classification assay using Gene Ontology and pathway analysis discovered that genes bearing the MRONJ variants are significantly enriched for keratinization and calcium ion transport. Some of the variants are potential pathogenic variants (24 missense mutations and seven frameshift mutations) with MAF < 0.01. Conclusions: The variants are located in eight different genes (KRT18, MUC5AC, NBPF9, PABPC3, MST1L, ASPN, ATN1, and SLAIN1). Nine deleterious SNPs significantly associated with MRONJ were found in the KRT18 and PABPC3 genes. It suggests that KRT18 and PABPC3 could be MRONJ-related key genes.

Ovarian granulosa cell tumor (OGCT) is a rare ovarian tumor that accounts for about 2-5% of all ovarian tumors. Despite the low grade of ovarian tumors, high and late recurrences are common in OGCT patients. Even though this tumor usually occurs in adult women with high estrogen levels, the cause of OGCT is still unknown. To screen genetic variants associated with OGCT, we collected normal and matched-tumor formalin-fixed paraffin-embedded (FFPE) from 11 OGCT patients and performed whole-exome sequencing (WES) using Illumina NovaSeq 6000. A total of 1,067,219 single nucleotide polymorphisms (SNPs) and 162,155 insertions/deletions (indels) were identified from 11 pairs of samples. Of these, we identified 44 tumor-specific SNPs in 22 genes and four tumor-specific indels in one gene that were common to 11 patients. We used three cancer databases (TCGA, COSMIC, and ICGC) to investigate genes associated with ovarian cancers. Nine genes (SEC22B, FEZ2, ANKRD36B, GYPA, MUC3A, PRSS3, NUTM2A, OR8U1, and KRTAP10-6) associated with ovarian cancers were found in all three databases. In addition, we identified seven rare variants with MAF ≤ 0.05 in two genes (PRSS3 and MUC3A). Of seven rare variants, five variants in MUC3A are potentially pathogenic. Furthermore, we conducted gene enrichment analysis of tumor-specific 417 genes in SNPs and 106 genes in indels using cytoscape and metascape. In GO analysis, these genes were highly enriched in “selective autophagy”, and “regulation of anoikis”. Taken together, we suggest that MUC3A is implicated in OGCT development, and MUC3A could be used as a potential biomarker for OGCT diagnosis.

Neuropathic pain is associated with an increased sensitivity to painful stimuli or abnormal sensitivity to otherwise innocuous stimuli. However, in addition to adverse effects, currently available drugs have shown limited response in patients with neuropathic pain, which provides a rationale to explore new drug classes acting on novel targets and with better efficacy and safety profiles. Here, we found that saikosaponins potently inhibit agonist-induced activation of the transient receptor potential A1 (TRPA1) channel, which has been reported to mediate neuropathic pain by sensing a variety of chemical irritants. Molecular docking and site-directed mutagenesis analyses suggested that saikosaponins bind to the hydrophobic pocket in TRPA1 near the Asn855 residue, which, when mutated to Ser, was previously associated with enhanced pain perception in humans. In support of these findings, saikosaponin D significantly attenuated agonist-induced nociceptive responses and vincristine-induced mechanical hypersensitivity in mice. These results indicate that saikosaponins are TRPA1 antagonists and provide a basis for further elaboration of saikosaponin derivatives for the development of new therapeutics for neuropathic pain.

본 연구는 항공사의 CSR 활동에 대한 소비자들의 인식이 CSR 활동의 효과에 미치는 영향에 대해 탐구하고 이를 통해 항공사들이 보다 효과적인 CSR 커뮤니케이션 전략을 수행하기 위한 구체적인 방안을 제안한다. 최근 사회과학 및 심리학 분야에서 많이 논의되고 있는 언더독 효과(underdog effect)를 중심으로 하여 기업의 유형을 분류하여 CSR 활동의 효과를 보다 구체적으로 살펴보고자 한다. 기업의 유형과 후원 대상의 유형을 나누어 살펴보고 소비자들이 이들의 적합성을 어떻게 인식하느냐에 따라CSR 활동에 대한 반응에 차이를 가져온다고 가정한다. 구체적으로, 본 연구는 언더독 효과(underdog effect)를 중심으로 하여 기업과 후원 대상의 유형을 분류하여 CSR 홍보 여부와 CSR 적합성에 따라CSR 활동의 효과가 달라진다는 것을 실증적으로 분석하였다. 탑독 기업이 탑독 후원 대상을, 언더독기업이 언더독 후원 대상을 후원하는 경우, 소비자들이 인식하는 CSR 활동의 적합성이 높아지고 이 결과 CSR 활동의 진정성을 보다 긍정적으로 인식하는지를 살펴보았다. 서울, 경기 및 대전 지역에 위치한 대학생들을 대상으로 2019년 4월 실험을 진행하였으며 첫 번째 연구는 기업 유형을 탑독과 언더독 기업으로 나누어 홍보 여부에 따라 20대 응답자 159명을 대상으로 실험을 진행하였고 두 번째 연구는 2(기업유형: 탑독 vs. 언더독) 2(후원대상: 인기종목 vs. 비인기종목) 집단 간 설계(between subject design)로 구성하였으며 20대 응답자 160명을 대상으로 실험을 진행하였다. 연구 결과, 탑독이나 언더독과 같은 기업의 유형이 소비자들이 인식하는 CSR 활동의 진정성과 적합성에 차별적 영향을 주며, 소비자들은 언더독 기업의 CSR 활동의 진정성과 적합성을 탑독 기업의 CSR 활동보다 더 높게 인식하는 것으로 나타났다. 구체적으로 살펴보면, CSR 홍보 여부는 탑독 항공사의 경우 CSR 활동의 홍보효과가 나타나지 않았으나 언더독 항공사의 경우는 홍보를 하지 않을 때 오히려 CSR 활동의 진정성과 적합성이 높게 평가되었다. 언더독 기업의 CSR 활동이 탑독 기업의 CSR 활동보다 CSR의 진정성과 적합성을 소비자들이 더 높게 인식하는 것을 알 수 있다. 다음으로 CSR 적합성의 경우, 탑독 항공사는 탑독 후원대상을 선택하는 것이 언더독 후원 대상을 후원하는 것 보다 소비자들의 CSR 적합성 인식 및 브랜드 태도에 더 긍정적 영향을 준다는 것을 확인하였다. 반면, 언더독 항공사의 경우 후원 대상의 유형에 따른 차이가 소비자들의 CSR의 진정성이나 적합성 인식의 차이를 가져오지는 않으나 브랜드에 대한 소비자들의 태도에 있어서는 언더독을 후원을 하는 경우가 CSR 활동 인식에 더 긍정적 영향을 미치는 것으로 나타났다. 실무적 관점에서 본 연구는 전략적인 CSR 활동이 기업의 브랜드 이미지에 긍정적인 영향을 미친다는 것을 실증적으로 분석함으로써 향후 기업들이 CSR 활동을 브랜드 커뮤니케이션의 중요한 수단으로 바라볼 수 있는 단서를 제공하였다. 기업이 자신들의 기업 유형을 어떠한 방식으로 포지셔닝 하느냐에 맞추어 보다 적합한 후원 대상을 정하여 보다 효과적인 CSR 커뮤니케이션 활동을 전개하는데 본 연구가 기여할 수 있을 것이다.

Long interspersed elements-1 (LINE-1s or L1s) and Alu elements are most successful retrotransposons that have generated genetic diversity and genomic fluidity in the primate genome. They account for ~ 27.7% of the primate genome. Interestingly, a previous study has shown that the retrotransposition rate of Alu elements is nine times higher in baboons than in humans. The expansion of Alu copies could be dependent on the activity of L1-encoded proteins. Thus, we aimed to investigate full-length baboon-specific L1s and characterize structurally and functionally intact baboon-specific L1s (ORF1p/ORF2p and ORF2p only) that could induce trans-mobilization of Alu elements in the baboon genome. A total of 673 baboon-specific L1 candidates (> 4 kb) were identified through the comparative genomic analysis. Applying the baboon-specific correction value obtained from the experimental validation, it demonstrated that approximately 446 baboon-specific L1s (> 4 kb) were present in the baboon reference genome (papAnu2). In addition, we observed phylogenetic relationship of the baboon-specific L1s through the neighbor-joining method and they diverged from the L1PA6 consensus sequence. Finally, we identified 36 full-length baboon-specific L1s that were intact both ORF1p and ORF2p. The number of baboon-specific full-length L1s is fewer than the number of human-specific full-length L1s. Therefore, there is possibility that the “L1 master gene” or “L1 source gene” is more abundant in the baboon genome, or that in trans retrotransposition activity of baboon-specific L1s is relatively stronger than in the other genomes.

Long interspersed element-1 (LINE-1 or L1) is the most abundant retrotransposons in the primate genome. They have approximately 520,000 copies and make up ~ 17% of the primate genome. Full-length L1s can mobilize to a new genomic location using their enzymatic machinery. Gorilla is the second closest species to humans after the chimpanzee, and human-gorilla split 7–12 million years ago. The gorilla genome provides an opportunity to explore primate origins and evolution. L1s have contributed to genome diversity and variations during primate evolution. This study aimed to identify gorilla-specific L1s using a more recent version of the gorilla reference genome (Mar. 2016 GSMRT3/gorGor5). We collected gorilla-specific L1 candidates through computational analysis and manual inspection. L1Xplorer was used to identify whether full-length gorilla-specific L1s were intact. In addition, to determine the level of sequence conservation between intact fulllength gorilla-specific L1s, two ORFs of intact L1s were aligned with the L1PA2 consensus sequence. 2002 gorilla-specific L1 candidates were identified through computational analysis. Among them, we manually inspected 1,883 gorilla-specific L1s, among which most of them belong to the L1PA2 subfamily and 12 were intact L1s that could influence genomic variations in the gorilla genome. Interestingly, the 12 intact full-length gorilla-specific L1s have 14 highly conserved nonsynonymous mutations, including 6 mutations and 8 mutations in ORF1 and ORF2, respectively. In comparison to the intact full-length chimpanzee-specific L1s and human-specific hot-L1s, two of these in ORF1 (L256F and E293G) were shown as gorilla-specific nonsynonymous mutations. The gorilla-specific L1s may have had significantly affected the gorilla genome to compose a genome different form that of other primates during primate evolution.

Recently, many researchers focus on the best way to produce high-quality meat, as the trend in food consumption today is to focus on quality. In general, consumers’ preferences in beef differ depending on taste and meatiness. Therefore, researchers are interested in how the marbling score affects the flavors of meat or the various factors that make up the meatiness to captivate the consumers’ tastes. This study identifies single nucleotide polymorphisms (SNPs) or gene combinations that affect the carcass traits of Korean cattle (Hanwoo) by using the multifactor dimensionality reduction (MDR) method. We collected the candidate SNPs to identify SNPs related to marbling scores from whole-exome sequencing and bovine SNP genotyping data. Using 96 Hanwoo samples, we performed PCR amplification to investigate the polymorphism status. In addition, we investigated genetic relationships between carcass traits and SNPs using 612 Hanwoo samples. Furthermore, each candidate SNP genotype and the combinations of SNP genotypes were verified to improve the accuracy of genetic relationships using MDR method. Twenty-four candidate SNPs associated with carcass trait and marbling scores were identified from SNP genotyping and whole-exome sequencing. Among them, three SNP markers (c.459 T > C of the PLCB1 gene, c.271 A > C of the C/EBPα gene, and g.17257 A > G of the TDRKH gene) were showed statistically significant differences between intramuscular fat and genotypes. Especially, two candidate SNPs, including c.459 T > C located in the PLCB1 gene and c.271 A > C located in the C/EBPα gene, could be highly associated with the intramuscular fat of Hanwoo quality grade. In addition, the combination of SNP genotypes is showed higher significant differences with carcass weight, backfat thickness, and longissimus dorsi muscle area. Three SNP genotypes and the combination of SNP genotypes in the PLCB1, C/EBPα, and TDRKH genes may be useful genetic markers for improving beef quality.

Callose is a plant cell wall polymer in the form of β-1,3-glucan, which regulates symplasmic channel size at plasmodesmata (PD). It plays a crucial role in a variety of processes in plants through the regulation of intercelluar symplasmic continuity. However, how to maintain callose homeostasis at PD in the molecular levels is poorly understood. To further elucidate the mechanism of PD callose homeostasis, we screened and identified an Arabidopsis mutant plant that exhibited excessive callose deposition at PD. Based on the Next-generation sequencing (NGS)-based mapping, other mutant allele analysis, and complementation assay, the mutated gene was shown to be α1-COP, which encodes a member of the COPI coatomer complex comprised of α, β, β′, γ, δ, ε, and ζ subunits. Since there is no report on the link between COPI and callose/PD, it was extremely curious to know the roles of α1-COP or COPI in PD regulation through callose deposition. Here, we report that loss-of-function of α1-COP directly elevates the callose accumulation at PD by affecting subcellular protein localization of callose degradation enzyme PdBG2. This process is linked to ERH1, an inositol phosphoryl ceramide synthase (IPCS), and glucosylceramide synthase (GCS) functions through physical interactions with the α1-COP protein. In addition, the loss-of-function of α1-COP also alters the subcellular localization of ERH1 and GCS proteins, results in a reduction of GlcCers and GlcHCers molecules, which are the key SL species for lipid raft formation. According to our findings, we propose that α1-COP protein, together with the SL modifiers controlling lipid raft compositions, regulates the function of GPI-anchored PD proteins and hence the callose turnover at PD and symplastic movement of biomolecules. Our findings provide the first key clue to link the COPI-mediated intracellular trafficking pathway to the callose-mediated intercellular signaling pathway through PD.One-sentence summaryPlant-specific coatomer protein functions as a negative regulator of callose accumulation by regulating the translocation of sphingolipid enzymes.

Lipopolysaccharide (LPS)-induced endotoxemia alters intracochlear homeostasis and potentiates aminoglycoside-induced ototoxicity. However, the pathological mechanisms in the cochlea following systemic LPS-induced inflammation are unclear. In this study, three groups of mice received intraperitoneal injections [group A, saline control (n = 10); group B, 1 mg/kg LPS (n = 10); group C, 10 mg/kg LPS (n = 10)]. After 24 h, gene expression in cochlea samples was analyzed using DNA microarrays covering 28,853 genes in a duplicate manner. A total of 505 differentially expressed genes (DEGs) (≥2.0-fold change; p 0.05) were identified. Interferon- and chemotaxis-related genes, including gbp2, gbp5, cxcl10, and Rnf125, were dose-dependently upregulated by LPS-induced endotoxemia. These results were verified by RT-qPCR. Upregulated DEGs were associated with inflammation, positive regulation of immune responses, and regulation of cell adhesion, while downregulated ones were associated with chemical synaptic transmission and the synaptic vesicle cycle. Protein-protein interaction included four functional clusters associated with interleukin-4, -10, and -13 and G protein-coupled receptor (GPCR) ligand binding; activation of matrix metalloproteinases and collagen degradation; recruitment of amyloid A proteins; and neutrophil degranulation. The findings of this study provide an additional basis on changes in the expression of genes in the cochlea in response to LPS-induced endotoxemia.

Identifying the patterns of gene expression in breast cancers is essential to understanding their pathophysiology and developing anticancer drugs. Breast cancer is a heterogeneous disease with different subtypes determined by distinct biological features. Luminal breast cancer is characterized by a relatively high expression of estrogen receptor (ER) and progesterone receptor (PR) genes, which are expressed in breast luminal cells. In ~25% of invasive breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed; these cancers are categorized as the HER2 type. Triple-negative breast cancer (TNBC), in which the cancer cells do not express ER/PR or HER2, shows highly aggressive clinical outcomes. TNBC can be further classified into specific subtypes according to genomic mutations and cancer immunogenicity. Herein, we discuss the brief history of TNBC classification and its implications for promising treatments.

Several methods to synthesize poly(phenylene) block copolymers through the nickel coupling reaction were attempted to reduce the use of expensive nickel catalysts in polymerization. The model reaction for poly(phenylene) having different types of dichlorobenzene derivative monomers illustrated the potential use of cost-effective catalysts, such as NiBr2 and NiCl2, as alternatives to more expensive catalysts (e.g., bis(1,5-cyclooctadiene)nickel(0) (Ni(COD)2)). By catalyzing the polymerization of multi-block poly(phenylene) with NiBr2 and NiCl2, random copolymers with similar molecular weights could be prepared. However, these catalysts did not result in a high-molecular-weight polymer, limiting their wide scale application. Further, the amount of Ni(COD)2 could be reduced in this study by approximately 50% to synthesize poly(phenylene) multi-block copolymers, representing significant cost savings. Gel permeation chromatography and nuclear magnetic resonance results showed that the degree of polymerization and ion exchange capacity of the copolymers were almost the same as those achieved through conventional polymerization using 2.5 times as much Ni(COD)2. The flexible quaternized membrane showed higher chloride ion conductivity than commercial Fumatech membranes with comparable water uptake and promising chemical stability.

Alu elements are most abundant retrotransposons with > 1.2 million copies in the primate genome. AluYb8 subfamily was diverged from AluY lineage, and has accumulated eight diagnostic mutations and 7-bp duplication during primate evolution. A total of 1851 AluYb copies are present in the human genome, and most of them are human-specific. On the other hand, only a few AluYb8 copies were identified in the chimpanzee genome by previous studies on AluYb8. The significantly different number of species-specific AluYb8 elements between human and chimpanzee might result from the incompletion of chimpanzee reference genome sequences at the time of the previous study. AluYb8 elements could generate genomic structural variations in the chimpanzee genome. This study aimed to identify and characterize chimpanzee-specific AluYb elements using the most updated chimpanzee reference genome sequences (Jan. 2018, panTro6). To identify chimpanzee-specific AluYb8, we carried out genomic comparison with non-chimpanzee primate genome using the UCSC table browser. In addition, chimpanzee-specific AluYb8 candidates were manually inspected and experimentally verified using PCR and Sanger sequencing. Among a total of 231 chimpanzee-specific AluYb8 candidates, 11 of the candidates are chimpanzee-specific AluYb8, and 29 elements are shared between the chimpanzee and non-chimpanzee primate genomes. Through the sequence analysis of AluYb8 and other Alu subfamilies, we were able to observe various diagnostic mutations and variable length duplications in 7-bp duplication region of AluYb8 element. In addition, we further validated two of the chimpanzee-specific AluYb8 elements (CS8 and CS20) that were not previously discovered by display PCR and Sanger sequencing. Interestingly, we identified a AluYb8 insertion-mediated deletion (CS8 locus) in the chimpanzee genome. Our study found that AluYb8 elements are much more abundant in the human genome than chimpanzee genome, and that it could be due to the absence of hyperactive “master” AluYb8 elements in the chimpanzee genome.

本研究の目的は、先駆的であると言われている神奈川県川崎市の外国人住民に関連する施策の支援内容を考察し、それに基づいて考えられる多文化共生社会の意味を再検討することである。川崎市の外国人向けの支援が実践されはじめた1960年以降から現在までの支援内容を確認した。現在までの差別や偏見などが存在した外国人への社会的不利を認めることから「多文化共生」が始まると考えられる。社会全般的に「同じであること」のみならず、「異なること」があるからこそ形成される「多様性」について認知し、互いが持っている独自性を大事にする態度が先進的であると考えられる。また、当事者グループを通して自分の意見を主張することが必要になる。それにより、 総務省から出された「多文化共生」である認め合い対等な関係を築き、共に生きることが実現できると考えられる。, The purpose of this study is to consider the content of support for policies related to foreign residents in Kawasaki City, Kanagawa Prefecture, which is said to be a pioneer, and to reconsider the possible meaning of a multicultural coexistence society based on that. As well as to check the contents of the support from 1960s until now, when support for foreigners in Kawasaki City began to implement this practice. It is considered that 'multicultural coexistence' started from the recognition of the social disadvantage of foreigners who had been discriminated against and prejudiced against up to the present day. To form a society of multicultural coexistence, we must be recognize "the diversity" that is formed not only by "the same" but also by "the different" nature of society, and it's important to take an attitude of respecting the individuality of each person. It is also necessary to express one's opinion to the group concerned. Thus, it is considered possible to establish an equality among people, which is a "multicultural coexistence" issued by the Ministry of Internal Affairs and Communications, and to live together., 論文(Article)

Conformational conversion of the normal cellular isoform of the prion protein PrPC into an infectious isoform PrPSc causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrPC binding site, and effectively reduced PrPSc levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies.

In Korean cattle, intramuscular fat (IMF), or marbling, of the longissimus dorsi muscle (LM) cross section is one of the most important indicators of beef quality and are influenced by environmental and genetic factors. This study was to evaluate the effect of SNPs on the beef quality in Korean cattle for functional studies, such as site-directed mutagenesis based on bovine adipocytes. The fatty acid synthase (FASN) gene plays an important role in lipogenesis. FASN is an essential metabolic and multifunctional enzyme in fatty acid synthesis. Several studies have reported that SNPs g.841G, g.16024A, g.16039T, and g.17924G have a significant impact on marbling scores in Korean cattle and Japanese Black cattle population. These SNPs are located in transcription factor binding sites, the beta-ketoacyl reductase, and thioesterase domains. Our results revealed that the g.17924 A>G SNP is located in the thioesterase domain of the FASN protein, and changes from polar, neutral, and hydrophilic to nonpolar, aliphatic, and hydrophobic, respectively. In in vivo LM tissue of Korean cattle, the g.17924A>G SNP has an effect on increasing fat deposition. Therefore, g.17924A>G SNP could be a causal mutation for increasing fat deposition in Korean cattle LM tissue.

Endogenous retrovirus (ERV) integrates into the germline of its host and could remain in the genome as a molecular fossil. ERV is one of sources that cause INDEL and recombination events in the vertebrate genomes, leading to various genomic and genetic changes in their hosts. There have been many studies conducted on ERVs in the vertebrate genomes to elucidate their evolutionary history. However, ERVs have not been studied well in Crocodylus siamensis. Here, we report structural variations among SFV1 elements (simian foamy virus-like), ERVs in C. siamensis. We initially identified 26 SFV1 candidates in the genome and experimentally verified 9 SFV1_1 and 5 SFV1_10 elements using PCR display. Their structural analyses showed that most of them are solitary-LTRs but two SFV1_1 elements are full-length. Through further analyses, we found that the two full-length elements retain intact ORFs. We examined transcription factor binding sites within their LTR sequences to predict promoter/enhancer activities. In sum, we identified 14 crocodile-specific SFV1 elements and the results of their structural analyses suggest that they could contribute to genomic or phenotypic variations in C. siamensis population.

We examined the effectiveness of corporate social responsibility (CSR) communication by multinational corporations in terms of the type of message being delivered. Results of Study 1 (N = 122 Korean adults) showed that CSR messages received more positive responses from consumers when temporal distance was low, compared to when it was high. Moreover, emotional message appeals generated more positive product evaluations from consumers than did rational message appeals when framed in the near versus distant future. Results of Study 2 (N = 120 Korean adults) revealed that Korean consumers reacted more positively to CSR messages from domestic companies than to those from multinational corporations when such messages were described concretely versus abstractly. Across the 2 studies, we found that construal levels and message appeals shaped the behavioral processes that generate consumers' responses to CSR messages from multinational corporations.

This study examined consumer evaluation of corporate social responsibility (CSR) activities with a focus on the authenticity and fit of CSR activities and analyzed the influence of consumers&rsquo, individual perception based on CSR involvement. We carried out an empirical survey to test the hypotheses presented by a scenario test using a questionnaire of 315 college students. The results showed that higher CSR fit has a positive effect on CSR authenticity and brand attitude. As a result of verifying the moderating effect of CSR involvement, the higher the CSR involvement is, the lower the impact of CSR fit on CSR authenticity. Therefore, consumers with high CSR involvement are less affected by CSR fit in evaluating the authenticity of CSR.

Naturally occurring diseases in dogs provide an important animal model for studying human disease including cancer, heart disease, and autoimmune disorders. Transposable elements (TEs) make up ~ 31% of the dog (Canis lupus familiaris) genome and are one of main drivers to cause genomic variations and alter gene expression patterns of the host genes, which could result in genetic diseases. To detect structural variations (SVs), we conducted whole-genome sequencing of three different breeds, including Maltese, Poodle, and Yorkshire Terrier. Genomic SVs were detected and visualized using BreakDancer program. We identified a total of 2328 deletion SV events in the three breeds compared with the dog reference genome of Boxer. The majority of the genetic variants were found to be TE insertion polymorphism (1229) and the others were TE-mediated deletion (489), non-TE-mediated deletion (542), simple repeat-mediated deletion (32), and other indel (36). Among the TE insertion polymorphism, 286 elements were full-length LINE-1s (L1s). In addition, the 49 SV candidates located in the genic regions were experimentally verified and their polymorphic rates within each breed were examined using PCR assay. Polymorphism analysis of the genomic variants revealed that some of the variants exist polymorphic in the three dog breeds, suggesting that their SV events recently occurred in the dog genome. The findings suggest that TEs have contributed to the genomic variations among the three dog breeds of Maltese, Poodle, and Yorkshire Terrier. In addition, the polymorphic events between the dog breeds indicate that TEs were recently retrotransposed in the dog genome.

Advances in next-generation sequencing (NGS) technology have made personal genome sequencing possible, and indeed, many individual human genomes have now been sequenced. Comparisons of these individual genomes have revealed substantial genomic differences between human populations as well as between individuals from closely related ethnic groups. Transposable elements (TEs) are known to be one of the major sources of these variations and act through various mechanisms, including de novo insertion, insertion-mediated deletion, and TE–TE recombination-mediated deletion. In this study, we carried out de novo whole-genome sequencing of one Korean individual (KPGP9) via multiple insert-size libraries. The de novo whole-genome assembly resulted in 31,305 scaffolds with a scaffold N50 size of 13.23 Mb. Furthermore, through computational data analysis and experimental verification, we revealed that 182 TE-associated structural variation (TASV) insertions and 89 TASV deletions contributed 64,232 bp in sequence gain and 82,772 bp in sequence loss, respectively, in the KPGP9 genome relative to the hg19 reference genome. We also verified structural differences associated with TASVs by comparative analysis with TASVs in recent genomes (AK1 and TCGA genomes) and reported their details. Here, we constructed a new Korean de novo whole-genome assembly and provide the first study, to our knowledge, focused on the identification of TASVs in an individual Korean genome. Our findings again highlight the role of TEs as a major driver of structural variations in human individual genomes., Genomics: Following the footprints of ‘jumping genes’ A novel strategy for genome analysis offers insights into the distribution and impact on genome variation of transposable elements, DNA sequences that can replicate and relocate themselves at different chromosomal regions. These sequences, also known as ‘jumping genes’, comprise up to 50% of the genome, but it has proven challenging to map them with existing techniques. Seyoung Mun of Dankook University, Cheonan, South Korea, and coworkers have developed a sequencing and computational analysis strategy that allowed them to accurately map transposable elements across the genome of a Korean individual. These data revealed hundreds of insertion and deletion events relative to an existing reference map of the genome, showing significant alterations in the chromosomal structure. The authors speculate that such widespread transposition events could potentially contribute to individual differences in gene expression and risk of disease.

Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders.

Water molecules inside G-protein coupled receptor have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal waters in GPCR activity, we studied A$_{\text{2A}}$ adenosine receptor using $\mu$sec-molecular dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times slower than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from $\sim\mathcal{O}(10^2)$ psec to $\sim\mathcal{O}(10^2)$ nsec. Especially, water molecules, exhibiting ultraslow relaxation ($\sim\mathcal{O}(10^2)$ nsec) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow waters in the GPCR activation., Comment: 21 pages, 14 figures

L1s are a cis-regulatory elements and contain bidirectional internal promoters within the 5' untranslated region (UTR). L1s provide bidirectional promoters that generate alternative transcripts and affect differential expressions in the human genome. In particular, L1 antisense promoters (L1ASPs) could produce aberrant transcripts in cancer tissues compared to normal tissues. In this study, we identified the L1-chimeric transcripts derived from L1ASPs and analyzed relative expression of L1-chimeric transcripts between normal and matched-cancer tissues. First, we collected 425 L1-chimeric transcripts by referring to previous studies. Through the manual inspection, we identified 144 L1-chimeric transcripts derived from 44 L1 antisense promoters, suggesting that the antisense promoter acted as an alternative promoter. We analyzed relative gene expression levels of 16 L1-chimeric transcripts between matched cancer-normal tissue pair (lung, liver, gastric, kidney, thyroid, breast, ovary, uterus, and prostate) using real-time quantitative PCR (RT-qPCR) and investigated putative transcription factor binding motifs to determine activity of L1ASPs. Taken together, we propose that L1ASPs could contribute to the differential gene expression between normal and cancer tissues.

LINE-1s (L1s) have contributed to gene structure variation and they can affect the expression of nearby genes in the human genome. Here, we collected 35 human-specific L1s that may play a role as alternative promoters. In addition, we identified 54 L1-chimeric transcripts generated from these L1s using bioinformatics’ tools and carried out reverse transcription-PCR to analyze their expressional pattern in 20 human normal tissues and 9 human cancer tissues. Consequently, 30 L1-chimeric transcripts were experimentally confirmed. Most L1-chimeric transcripts were broadly expressed. Interestingly, we found that EST CD709363 derived from C14orf37 gene was expressed in trachea only among normal tissues, but it was expressed in several cancer tissues including brain, lung, skin, and esophagus. We also newly identified three alternative transcripts, which were not in the UCSC genome database. One alternative transcript was derived from RABGAP1L gene and the other two transcripts were from CAMK4 gene. In addition, we analyzed putative transcription binding sites within the four L1s located in the promoter region. These had several transcription factor binding sites related to promoters. Our results show that human-specific L1s could contribute to human transcriptome diversity and transcriptional gene expression in different types of human tissues.

Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors.

In contrast to a number of studies on the humanization of non-human antibodies, the reshaping of a non-human antibody into a chicken antibody has never been attempted. Therefore, nothing is known about the animal species-dependent compatibility of the framework regions (FRs) that sustain the appropriate conformation of the complementarity-determining regions (CDRs). In this study, we attempted the reshaping of the variable domains of the mouse catalytic anti-nucleic acid antibody 3D8 (m3D8) into the FRs of a chicken antibody (“chickenization”) by CDR grafting, which is a common method for the humanization of antibodies. CDRs of the acceptor chicken antibody that showed a high homology to the FRs of m3D8 were replaced with those of m3D8, resulting in the chickenized antibody (ck3D8). ck3D8 retained the biochemical properties (DNA binding, DNA hydrolysis, and cellular internalizing activities) and three-dimensional structure of m3D8 and showed reduced immunogenicity in chickens. Our study demonstrates that CDR grafting can be applied to the chickenization of a mouse antibody, probably due to the interspecies compatibility of the FRs.

Li 1.2 (Mn 0.32 Ni 0.32 Fe 0.16 )O 2 (LMNFO) nanoparticles with and without a chelating agent (adipic acid) were synthesized by sol–gel method. The supercapacitive behaviors of the synthesized materials as a cathode are evaluated with activated carbon (AC) as the anode in a hybrid supercapacitor (HSC) configuration utilizing a non-aqueous electrolyte. The structural, morphological and electrochemical features of the prepared materials are investigated using X-ray diffraction, scanning electron microscopy and cyclic voltammetry (CV) and charge–discharge studies, respectively. The results demonstrated that the LMNFO nanoparticles prepared with the chelating agent, adipic acid (AA), delivered an enhanced specific discharge capacitance (86 F g −1 ) and better cycling stability than the native compound. The CV studies also revealed the same conclusions, based on the stronger current response observed during various scan rates between 0 and 3 V. Moreover, the AA-LMNFO/AC cell delivered maximum energy and power densities of 36 Wh kg −1 and 1.67 W kg −1 , respectively, with a columbic efficiency of over 99% and excellent rate performance.

The kinetic properties of Li insertion in NASICON-type Li 3 V 2 (PO 4 ) 3 cathodes were enhanced substantially by Al 3+ and Cl − multivalent substitutions of various concentrations. Pristine and carbon coated, Al-doped Li 3 V 2 (PO 4 ) 3 were also prepared by a conventional solid-state approach under optimized conditions. Samples phase purity was investigated through X-ray diffractometry. Li insertion was studied in half-cells at 3-4.8 V vs. Li for the removal of 3 mol of Li. Carbon-coated Li 3 V 1.98 Al 0.02 (PO 4 ) 2.99 Cl 0.01 showed the highest reversible insertion of 2.71 mol of Li (178 mAh g −1 ) at a current density of 0.2 mA cm −2 . It showed a capacity retention of over 80% after 100 cycles. Cl − substitution led to improved performance under harsh conditions of 15 C rate and high temperature (50 °C). The enhancement of Li ion kinetics was demonstrated through cyclic voltammetry in a two-electrode configuration and electrochemical impedance spectroscopy confirmed the enhanced conductivity.

To investigate roles played by water molecules in regulating the conformational dynamics of of β2-adrenergic receptor (β2AR), we have performed 2 μsec all-atom molecular dynamics simulations of the receptors with inverse agonist and agonist (with and without Gα) in the orthosteric binding pocket. Quantifying the relaxation time of water molecules in each residue in the extra- and intracellular domains and along the channel formed through the transmembrane domain, we investigated how the motion of internal water in allosteric sites is correlated with the salt-bridge formation of ionic lock in the active and inactive states.

As previously reported, the activity of the large-conductance calcium (Ca(2+))-activated potassium (K(+)) (BK(Ca)) channel is strongly potentiated from the extracellular side of the cell membrane by certain benzofuroindole derivatives. Here, the mechanism of action of one of the most potent activators, 4-chloro-7-(trifluoromethyl)-10H-benzofuro[3,2-b]indole-1-carboxylic acid (CTBIC), is characterized. This compound, Compound 22 in the previous report (Chembiochem 6:1745-1748, 2005), potentiated the activity of the channel by shifting its conductance-voltage relationship toward the more negative direction. Cotreatment with CTBIC reduced the affinity of charybdotoxin, a peptide pore-blocker, whereas that of tetraethylammonium, a small pore-blocking quaternary ammonium, was not significantly altered. Guided by these results, scanning mutagenesis of the outer vestibule of the BK(Ca) channel was launched to uncover the molecular determinants that affect CTBIC binding. Alanine substitution of several amino acid residues in the turret region and the S6 helix of the channel decreased potentiation by CTBIC. Homology modeling and molecular dynamics simulation showed that some of these residues formed a CTBIC binding pocket between two adjacent α-subunits in the outer vestibule of the channel. Thus, it can be envisioned that benzofuroindole derivatives stabilize the open conformation of the channel by binding to the residues clustered across the extracellular part of the subunit interface. The present results indicate that the interface between different α-subunits of the BK(Ca) channel may play a critical role in the modulation of channel activity. Therefore, this interface represents a potential therapeutic target site for the regulation of K(+) channels.

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design.

The acetylcholinesterase (AChE) is important to terminate acetylcholine-mediated neurotransmission at cholinergic synapses. The pivotal role of AChE in apoptosome formation through the interactions with cytochrome c (Cyt c) was demonstrated in recent study. In order to investigate the proper binding conformation between the human AChE (hAChE) and human Cyt c (hCyt c), macro-molecular docking simulation was performed using DOT 2.0 program. The hCyt c was bound to peripheral anionic site (PAS) on hAChE and binding mode of the docked conformation was very similar to the reported crystal structure of the AChE and fasciculin-II (Fas-II) complex. Two 10 ns molecular dynamics (MD) simulations were carried out to refine the binding mode of docked structure and to observe the differences of the binding conformations between the absent (Apo) and presence (Holo) of heme group. The key hydrogen bonding residues between hAChE and hCyt c proteins were found in Apo and Holo systems, as well as each Tyr341 and Trp286 residue of hAChE was participated in cation-pi (π) interactions with Lys79 of hCyt c in Apo and Holo systems, respectively. From the present study, although the final structures of the Apo and Holo systems have similar binding pattern, several differences were investigated in flexibilities, interface interactions, and interface accessible surface areas. Based on these results, we were able to predict the reasonable binding conformation which is indispensable for apoptosome formation.

Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors and their activation induces regulation of fatty acid storage and glucose metabolism. Therefore, the PPARγ is a major target for the treatment of type 2 diabetes mellitus. In order to generate pharmacophore model, 1080 known agonists database was constructed and a training set was selected. The Hypo7, selected from 10 hypotheses, contains four features: three hydrogen-bond acceptors (HBA) and one general hydrophobic (HY). This pharmacophore model was validated by using 862 test set compounds with a correlation coefficient of 0.903 between actual and estimated activity. Secondly, CatScramble method was used to verify the model. Hence, the validated Hypo7 was utilized for searching new lead compounds over 238,819 and 54,620 chemical structures in NCI and Maybridge database, respectively. Then the leads were selected by screening based on the pharmacophore model, predictive activity, and Lipinski’s rules. Candidates were obtained and subsequently the binding affinities to PPARγ were investigated by the molecular docking simulations. Finally the best two compounds were presented and would be useful to treat type 2 diabetes.