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  • 1
    Publication Date: 2018-11-06
    Description: The variable lymphocyte receptor (VLR) B of jawless vertebrates functions as a secreted Ab of jawed vertebrates and has emerged as an alternative Ab with a single polypeptide chain. After observing an upregulated VLRB response in hagfish immunized with avian influenza virus (AIV) subtype H9N2, we screened AIV H9N2–specific VLRB using a mammalian expression system. To improve the binding avidity of the Ag-specific VLRB to the Ag, we enabled multimerization of the VLRB by conjugating it with C-terminal domain of human C4b-binding protein. To dramatically enhance the expression and secretion of the Ag-specific VLRB, we introduced a glycine–serine linker and the murine Ig leader sequence. The practical use of the Ag-specific VLRB was also demonstrated through various immunoassays, detected by anti-VLRB Ab (11G5). Finally, we found that the Ag-specific VLRB decreased the infectivity of AIV H9N2. Together, our findings suggest that the generated Ag-specific VLRB could be used for various immunoapplications.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 2
    Publication Date: 2018-01-03
    Description: Ten-eleven translocation methylcytosine dioxygenase 1 ( Tet1 ) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as Egr1 , c-fos , Arc , and Bdnf , followed by the activation of intracellular calcium signals ( i.e. , CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits ( Gabra2 and Gabra4 ) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the Egr1 promoter in vitro . Tet1 enhanced Egr1 expression, which may have led to alterations in Gabra2 and Gabra4 expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.—Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.
    Print ISSN: 0892-6638
    Electronic ISSN: 1530-6860
    Topics: Biology
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  • 3
    Publication Date: 2018-01-03
    Description: Simultaneous sequencing of the genome and transcriptome at the single-cell level is a powerful tool for characterizing genomic and transcriptomic variation and revealing correlative relationships. However, it remains technically challenging to analyze both the genome and transcriptome in the same cell. Here, we report a novel method for simultaneous isolation of genomic DNA and total RNA (SIDR) from single cells, achieving high recovery rates with minimal cross-contamination, as is crucial for accurate description and integration of the single-cell genome and transcriptome. For reliable and efficient separation of genomic DNA and total RNA from single cells, the method uses hypotonic lysis to preserve nuclear lamina integrity and subsequently captures the cell lysate using antibody-conjugated magnetic microbeads. Evaluating the performance of this method using real-time PCR demonstrated that it efficiently recovered genomic DNA and total RNA. Thorough data quality assessments showed that DNA and RNA simultaneously fractionated by the SIDR method were suitable for genome and transcriptome sequencing analysis at the single-cell level. The integration of single-cell genome and transcriptome sequencing by SIDR (SIDR-seq) showed that genetic alterations, such as copy-number and single-nucleotide variations, were more accurately captured by single-cell SIDR-seq compared with conventional single-cell RNA-seq, although copy-number variations positively correlated with the corresponding gene expression levels. These results suggest that SIDR-seq is potentially a powerful tool to reveal genetic heterogeneity and phenotypic information inferred from gene expression patterns at the single-cell level.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-10-27
    Description: The key component currently missing for the next generation of transparent and flexible displays is a high-performance polymer material that is flexible, while showing optical and thermal properties of glass. It must be transparent to visible light and show a low coefficient of thermal expansion (CTE). While specialty plastics such as aromatic polyimides are promising, reducing their CTE and improving transparency simultaneously proved challenging, with increasing coloration the main problem to be resolved. We report a new poly(amide-imide) material that is flexible and displays glass-like behavior with a CTE value of 4 parts per million/°C. This novel polymer was successfully used as a substrate to fabricate transparent and flexible indium-gallium-zinc oxide thin-film transistors.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    Publication Date: 2018-12-01
    Description: Background/Aim: This study aimed to determine the effect of different BRCA1 exonal mutations on the clinical course of epithelial ovarian cancer (EOC). Patients and Methods: Clinicopathological variables and survival outcomes were compared among 53 primary EOC patients with pathogenic BRCA1 mutations in exons 1-11 (5’ mutations) and in exons 12-24 (3’ mutations). Results: BRCA1 5’ exonal mutations were found in 35 (66.0%) patients. The median follow-up period was 40 months. Clinicopathological variables remained unchanged between the two groups. Patients with 5’ mutations had a significantly longer progression-free survival than those with C-terminal mutations (p=0.034), better predicting progression-free survival [2.923 (1.402-6.093), p=0.004], but not overall survival in cases of multiple relapses (p=0.497). Conclusion: N-terminal BRCA1 mutations in EOC patients are associated with favourable primary progression-free survival, a trend observed only in primary progression-free survival, not in overall survival.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 6
    Keywords: Medicine ; Reproductive Medicine ; Cytology ; Medicine & Public Health ; Reproductive Medicine ; Cell Biology ; Molecular Medicine ; Springer eBooks
    Description / Table of Contents: The importance of oocyte biology for the future of fertility preservation -- The Control of Oocyte Survival by Intrinsic and Extrinsic Factors -- Oocyte Genomic Integrity -- In Vitro Activation of Dormant Follicles for Fertility Preservation -- Primate follicular development in vitro -- Vitrification of oocytes - From Basic Science to Clinical Application -- Memoir of Fertility Preservation
    Abstract: Fertility preservation has become one of the most important and fast growing fields of reproductive medicine.℗ Although there are several strategies for fertility preservation in female, most of them are still considered experimental.℗ It is important to perfect the existing technologies, but also developing new strategies should be actively sought.℗ The future development of fertility preservation strategies should be based on the sound scientific knowledge and principles.℗ One of the main objectives of fertility preservation in females is prevention of oocyte depletion. The mechanisms of oocyte loss and survival in the ovary are complex, which include genetic control both in germ cells and in somatic cells, DNA damage and repair mechanism, apoptosis and autophagy, and other poorly understood molecular mechanisms.℗ To develop clinically effective and safe strategies for fertility preservation, it is essential to know and understand the fundamentals of oocyte and ovarian biology at the molecular level.℗ Thus, the purpose of this edition is to review the current progress in research related to molecular and genetic control of oocyte development that can be applied to fertility preservation. ℗ The main topics that are discussed in this publication include molecular signaling mechanisms of oocyte activation and loss, genomic integrity of oocytes, and epigenetics. ℗
    Pages: X, 97 p. 12 illus., 9 illus. in color. : online resource.
    ISBN: 9781461482147
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  • 7
    Publication Date: 2018-10-11
    Description: Developing and mature chondrocytes constantly interact with and remodel the surrounding extracellular matrix (ECM). Recent research indicates that integrin-ECM interaction is differentially regulated during cartilage formation (chondrogenesis). Integrin signaling is also a key source of the catabolic reactions responsible for joint destruction in both rheumatoid arthritis and osteoarthritis. However, we do not understand how chondrocytes dynamically regulate integrin signaling in such an ECM-rich environment. Here, we found that developing chondrocytes express integrin-β–like 1 ( Itgbl1 ) at specific stages, inhibiting integrin signaling and promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 is secreted and physically interacts with integrins to down-regulate activity. We observed that Itgbl1 expression was strongly reduced in the damaged articular cartilage of patients with osteoarthritis (OA). Ectopic expression of Itgbl1 protected joint cartilage against OA development in the destabilization of the medial meniscus–induced OA mouse model. Our results reveal ITGBL1 signaling as an underlying mechanism of protection against destructive cartilage disorders and suggest the potential therapeutic utility of targeting ITGBL1 to modulate integrin signaling in human disease.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 8
    Publication Date: 2018-02-16
    Description: Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues ( n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo . Results: Overexpression of survivin was significantly associated with lymph nodes' metastatic status ( P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT ( n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN ( n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with -H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions: Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. Clin Cancer Res; 24(4); 858–69. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 9
    Publication Date: 2018-03-06
    Description: Here, we report that CRISPR guide RNAs (gRNAs) with a 5'-triphosphate group (5'-ppp gRNAs) produced via in vitro transcription trigger RNA-sensing innate immune responses in human and murine cells, leading to cytotoxicity. 5'-ppp gRNAs in the cytosol are recognized by DDX58, which in turn activates type I interferon responses, causing up to ~80% cell death. We show that the triphosphate group can be removed by a phosphatase in vitro and that the resulting 5'-hydroxyl gRNAs in complex with Cas9 or Cpf1 avoid innate immune responses and can achieve targeted mutagenesis at a frequency of 95% in primary human CD4 + T cells. These results are in line with previous findings that chemically synthesized sgRNAs with a 5'-hydroxyl group are much more efficient than in vitro–transcribed (IVT) sgRNAs in human and other mammalian cells. The phosphatase treatment of IVT sgRNAs is a cost-effective method for making highly active sgRNAs, avoiding innate immune responses in human cells.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2018-01-03
    Description: Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood–brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1–eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival. Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32–46. ©2017 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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