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Sample records for zeb1 links p63

  1. Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells.

    PubMed

    Maturi, Varun; Enroth, Stefan; Heldin, Carl-Henrik; Moustakas, Aristidis

    2018-05-10

    Zinc finger E-box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial-mesenchymal transition (EMT). Triple-negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple-negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR-Cas9-mediated 30 bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage-independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro-tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple-negative mesenchymal breast cancer cells into more differentiated, epithelial-like clones, but can reduce tumorigenic potential, suggesting that not all pro-tumorigenic actions of ZEB1 are linked to the EMT. © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

  2. Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis.

    PubMed

    Liu, Yongqing; Lu, Xiaoqin; Huang, Li; Wang, Wei; Jiang, Guomin; Dean, Kevin C; Clem, Brian; Telang, Sucheta; Jenson, Alfred B; Cuatrecasas, Miriam; Chesney, Jason; Darling, Douglas S; Postigo, Antonio; Dean, Douglas C

    2014-12-01

    Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancer-initiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

  3. ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC.

    PubMed

    Lazarova, Darina; Bordonaro, Michael

    2017-01-01

    We discuss the hypothesis that ZEB1-Wnt-p300 signaling integrates epithelial to mesenchymal transition (EMT) and resistance to histone deacetylase inhibitors (HDACis) in colorectal cancer (CRC) cells. The HDACi butyrate, derived from dietary fiber, has been linked to CRC prevention, and other HDACis have been proposed as therapeutic agents against CRC. We have previously discussed that resistance to butyrate likely contributes to colonic carcinogenesis, and we have demonstrated that butyrate resistance leads to cross-resistance to cancer therapeutic HDACis. Deregulated Wnt signaling is the major initiating event in most CRC cases. One mechanism whereby butyrate and other HDACis exert their anti-CRC effects is via Wnt signaling hyperactivation, which promotes CRC cell apoptosis. The histone acetylases (HATs) CBP and p300 are mediators of Wnt transcriptional activity, and play divergent roles in the downstream consequences of Wnt signaling. CBP-mediated Wnt signaling is associated with cell proliferation and stem cell maintenance; whereas, p300-mediated Wnt activity is associated with differentiation. We have found that CBP and p300 differentially affect the ability of butyrate to influence Wnt signaling, apoptosis, and proliferation. ZEB 1 is a Wnt signaling-targeted gene, whose product is a transcription factor expressed at the invasive front of carcinomas where it promotes malignant progression and EMT. ZEB1 is typically a transcriptional repressor; however, when associated with p300, ZEB1 enhances transcription. These changes in ZEB1 activity likely affect the cancer cell phenotype. ZEB1 has been shown to promote resistance to chemotherapeutic agents, and expression of ZEB1 is upregulated in butyrate-resistant CRC cells that lack p300 expression. Since the expression of ZEB1 correlates with poor outcomes in cancer, ZEB represents a relevant therapeutic target. Here we propose that targeting the signaling network established by ZEB1, Wnt signaling, and p300

  4. ZEB1 expression is a potential indicator of invasive endometriosis.

    PubMed

    Furuya, Masataka; Masuda, Hirotaka; Hara, Kanako; Uchida, Hiroshi; Sato, Kenji; Sato, Suguru; Asada, Hironori; Maruyama, Tetsuo; Yoshimura, Yasunori; Katabuchi, Hidetaka; Tanaka, Mamoru; Saya, Hideyuki

    2017-09-01

    Although endometriosis is a benign disease, it shares some features with cancers, such as invasiveness and the potential to metastasize. This study sought to investigate the epithelial-mesenchymal transition status in human endometriotic lesions. Thirteen endometriosis patients and 10 control women without endometriosis undergoing surgery for benign indications were recruited. We examined the expression of E-cadherin, vimentin, and epithelial-mesenchymal transition-induced transcriptional factors, such as Snail and ZEB1, by immunohistochemistry. We evaluated the expression of each marker in epithelial cells of both endometriotic lesions (ovarian endometrioma, deep infiltrating endometriosis, adenomyosis) and normal endometria. The correlation between ZEB1 expression and serum level of CA125 was also investigated. Immunohistochemical analysis revealed that although E-cadherin, vimentin, and Snail were expressed in epithelia of normal endometria and endometriotic lesions, ZEB1 expression was only expressed in epithelia of endometriotic lesions. Additionally, ZEB1 was most frequently observed in epithelial cells of invasive endometriosis. The endometriosis patients with high serum CA125 level were more likely to have ZEB1-positive lesions. This is the first observation of ZEB1 expression in epithelial cells of benign disease. The preferential expression of ZEB1 in epithelial cells of endometriotic lesions suggests that these cells may have, at least in part, a higher level of mesenchymal features possibly via ZEB1-driven epithelial-mesenchymal transition than normal endometria and that ZEB1 can be a potential indicator of invasiveness or severity of endometriosis. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

  5. Interplay between long noncoding RNA ZEB1-AS1 and miR-101/ZEB1 axis regulates proliferation and migration of colorectal cancer cells.

    PubMed

    Xiong, Wan-Cheng; Han, Na; Wu, Nan; Zhao, Ke-Lei; Han, Chen; Wang, Hui-Xin; Ping, Guan-Fang; Zheng, Peng-Fei; Feng, Hailong; Qin, Lei; He, Peng

    2018-01-01

    Long noncoding RNAs (lncRNAs) are dysregulated in many diseases. MicroRNA-101 (miR-101) functions as a tumor suppressor by directly targeting ZEB1 in various cancers. However, the potential mechanism of lncRNA ZEB1-AS1 and miR-101/ZEB1 axis in CRC remains unknown. In this study, we further investigated the potential interplay between miR-101/ZEB1 axis and lncRNA ZEB1-AS1 in colorectal cancer (CRC). Results showed that ZEB1-AS1 was upregulated in CRC tissues and cells. MiR-101 was downregulated in CRC tissues and negatively correlated with ZEB1-AS1 and ZEB1 expression levels in CRC. Functional experiments showed that, consistent with ZEB1-AS1 depletion, miR-101 overexpression and ZEB1 depletion inhibited the proliferation and migration of CRC cells. Overexpression of miR-101 partially abolished the effects of ZEB1-AS1 on the proliferation and migration of these cells. Moreover, combined ZEB1-AS1 depletion and miR-101 overexpression significantly inhibited cell proliferation and migration of the CRC cells. Hence, ZEB1-AS1 functioned as a molecular sponge for miR-101 and relieved the inhibition of ZEB1 caused by miR-101. This study revealed a novel regulatory mechanism between ZEB1-AS1 and miR-101/ZEB1 axis. The interplay between ZEB1-AS1 and miR-101/ZEB1 axis contributed to the proliferation and migration of CRC cells, and targeting this interplay could be a promising strategy for CRC treatment.

  6. Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression.

    PubMed

    Liu, Yongqing; Sánchez-Tilló, Ester; Lu, Xiaoqin; Huang, Li; Clem, Brian; Telang, Sucheta; Jenson, Alfred B; Cuatrecasas, Miriam; Chesney, Jason; Postigo, Antonio; Dean, Douglas C

    2013-04-19

    Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the transcription factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion.

  7. ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy

    NASA Astrophysics Data System (ADS)

    Fang, Shengtao; Wu, Lei; Li, Mingxing; Yi, Huqiang; Gao, Guanhui; Sheng, Zonghai; Gong, Ping; Ma, Yifan; Cai, Lintao

    2014-08-01

    Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA-DOX-NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA-NP or siRNA-DOX-NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment.Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced

  8. Cellular heterogeneity contributes to subtype-specific expression of ZEB1 in human glioblastoma.

    PubMed

    Euskirchen, Philipp; Radke, Josefine; Schmidt, Marc Sören; Schulze Heuling, Eva; Kadikowski, Eric; Maricos, Meron; Knab, Felix; Grittner, Ulrike; Zerbe, Norman; Czabanka, Marcus; Dieterich, Christoph; Miletic, Hrvoje; Mørk, Sverre; Koch, Arend; Endres, Matthias; Harms, Christoph

    2017-01-01

    The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its function in epithelial-mesenchymal transition, DNA repair, stem cell biology and tumor-induced immunosuppression, but its role in gliomas with respect to invasion and prognostic value is controversial. We characterized ZEB1 expression at single cell level in 266 primary brain tumors and present a comprehensive dataset of high grade gliomas with Ki67, p53, IDH1, and EGFR immunohistochemistry, as well as EGFR FISH. ZEB1 protein expression in glioma stem cell lines was compared to their parental tumors with respect to gene expression subtypes based on RNA-seq transcriptomic profiles. ZEB1 is widely expressed in glial tumors, but in a highly variable fraction of cells. In glioblastoma, ZEB1 labeling index is higher in tumors with EGFR amplification or IDH1 mutation. Co-labeling studies showed that tumor cells and reactive astroglia, but not immune cells contribute to the ZEB1 positive population. In contrast, glioma cell lines constitutively express ZEB1 irrespective of gene expression subtype. In conclusion, our data indicate that immune infiltration likely contributes to differential labelling of ZEB1 and confounds interpretation of bulk ZEB1 expression data.

  9. Effects of ZEB1 on regulating osteosarcoma cells via NF-κB/iNOS.

    PubMed

    Xu, X-M; Liu, W; Cao, Z-H; Liu, M-X

    2017-03-01

    Osteosarcoma is one common malignant bone tumors, as it frequently has invasion, metastasis and recurrence, causing unfavorable prognosis of patients. Osteosarcoma has complicated pathogenesis, which has not been elucidated fully. Therefore, the identification of effective molecular target of osteosarcoma onset can help to improve treatment efficacy and prognosis of osteosarcoma. Zinc finger E-box binding homeobox 1 (ZEB1) protein is one member of zinc finger E-box binding protein family, and participates in embryonic genesis and development. A recent study found the participation of ZEB1 in mediating multiple tumor onset and its up-regulation of osteosarcoma. The regulatory mechanism of ZEB1 in osteosarcoma has not been illustrated yet. In vitro cultured osteosarcoma MG-63 cells were transfected with ZEB1 siRNA. Real-time PCR and Western blot were tested for ZEB1 mRNA/protein expression. MTT was used to test MG-63 cell proliferation, whilst cell invasion was used to describe the effect of ZEB1 on MG-63 cells. Caspase-3 activity assay was employed to test MG-63 cell apoptosis. Western blot was employed to detect nuclear factor kappa B (NF-kB) and inducible nitric oxide synthase (iNOS) protein expression. After transfecting with ZEB1 siRNA, MG-63 cell proliferation or invasion was inhibited accompanied with lower ZEB1 mRNA/protein expression. Caspase3 activity was also increased after transfection (p < 0.05), along with down-regulation of NF-kB and iNOS proteins in MG-63 cells (p < 0.05). Inhibition of ZEB1 can facilitate osteosarcoma cell apoptosis and inhibit cell proliferation or invasion via down-regulating NF-kB/iNOS signal pathway.

  10. Vasculogenic mimicry in bladder cancer and its association with the aberrant expression of ZEB1

    PubMed Central

    Li, Baimou; Mao, Xiaopeng; Wang, Hua; Su, Guanyu; Mo, Chengqiang; Cao, Kaiyuan; Qiu, Shaopeng

    2018-01-01

    The aim of the present study was to investigate the associations between vasculogenic mimicry (VM) and zinc finger E-box binding homeobox 1 (ZEB1) in bladder cancer. VM structure and ZEB1 expression were analyzed by cluster of differentiation 34/periodic acid Schiff (PAS) double staining and immunohistochemical staining in 135 specimens from patients with bladder cancer, and a further 12 specimens from normal bladder tissues. Three-dimensional (3-D) culture was used to detect VM formation in the bladder transitional cancer cell lines UM-UC-3 and J82, and the immortalized human bladder epithelium cell line SV-HUC-1 in vitro. ZEB1 expression in these cell lines was compared by reverse transcription-quantitative polymerase chain reaction and western blot assays. In addition, small interfering RNA was used to inhibit ZEB1 in UM-UC-3 and J82 cells, followed by 3-D culturing of treated cell lines. As a result, VM was observed in 31.1% of specimens from bladder cancer tissues, and cases with high ZEB1 expression accounted for 60.0% of patients with bladder cancer. In addition, ZEB1 expression was closely associated with VM (r=0.189; P<0.05), and also increased as the grade and stage of the tumor developed. In an in vitro assay, UM-UC-3 and J82 cells exhibited VM formation, however, SV-HUC-1 did not. Furthermore, VM-forming cancer cell lines UM-UC-3 and J82 exhibited higher ZEB1 expression. Notably, VM formation was inhibited following knockdown of ZEB1. In conclusion, ZEB1 may be associated with VM in bladder cancer and serve an important role in the process of VM formation. However, its detailed mechanism requires further study. PMID:29552157

  11. ZEB1 limits adenoviral infectability by transcriptionally repressing the Coxsackie virus and Adenovirus Receptor

    PubMed Central

    2011-01-01

    Background We have previously reported that RAS-MEK (Cancer Res. 2003 May 1;63(9):2088-95) and TGF-β (Cancer Res. 2006 Feb 1;66(3):1648-57) signaling negatively regulate coxsackie virus and adenovirus receptor (CAR) cell-surface expression and adenovirus uptake. In the case of TGF-β, down-regulation of CAR occurred in context of epithelial-to-mesenchymal transition (EMT), a process associated with transcriptional repression of E-cadherin by, for instance, the E2 box-binding factors Snail, Slug, SIP1 or ZEB1. While EMT is crucial in embryonic development, it has been proposed to contribute to the formation of invasive and metastatic carcinomas by reducing cell-cell contacts and increasing cell migration. Results Here, we show that ZEB1 represses CAR expression in both PANC-1 (pancreatic) and MDA-MB-231 (breast) human cancer cells. We demonstrate that ZEB1 physically associates with at least one of two closely spaced and conserved E2 boxes within the minimal CAR promoter here defined as genomic region -291 to -1 relative to the translational start ATG. In agreement with ZEB1's established role as a negative regulator of the epithelial phenotype, silencing its expression in MDA-MB-231 cells induced a partial Mesenchymal-to-Epithelial Transition (MET) characterized by increased levels of E-cadherin and CAR, and decreased expression of fibronectin. Conversely, knockdown of ZEB1 in PANC-1 cells antagonized both the TGF-β-induced down-regulation of E-cadherin and CAR and the reduction of adenovirus uptake. Interestingly, even though ZEB1 clearly contributes to the TGF-β-induced mesenchymal phenotype of PANC-1 cells, TGF-β did not seem to affect ZEB1's protein levels or subcellular localization. These findings suggest that TGF-β may inhibit CAR expression by regulating factor(s) that cooperate with ZEB1 to repress the CAR promoter, rather than by regulating ZEB1 expression levels. In addition to the negative E2 box-mediated regulation the minimal CAR promoter is

  12. p63 expression defines a lethal subset of muscle-invasive bladder cancers.

    PubMed

    Choi, Woonyoung; Shah, Jay B; Tran, Mai; Svatek, Robert; Marquis, Lauren; Lee, I-Ling; Yu, Dasom; Adam, Liana; Wen, Sijin; Shen, Yu; Dinney, Colin; McConkey, David J; Siefker-Radtke, Arlene

    2012-01-01

    p63 is a member of the p53 family that has been implicated in maintenance of epithelial stem cell compartments. Previous studies demonstrated that p63 is downregulated in muscle-invasive bladder cancers, but the relationship between p63 expression and survival is not clear. We used real-time PCR to characterize p63 expression and several genes implicated in epithelial-to-mesenchymal transition (EMT) in human bladder cancer cell lines (n = 15) and primary tumors (n = 101). We correlated tumor marker expression with stage, disease-specific (DSS), and overall survival (OS). Expression of E-cadherin and p63 correlated directly with one another and inversely with expression of the mesenchymal markers Zeb-1, Zeb-2, and vimentin. Non-muscle-invasive (Ta and T1) bladder cancers uniformly expressed high levels of E-cadherin and p63 and low levels of the mesenchymal markers. Interestingly, a subset of muscle-invasive (T2-T4) tumors maintained high levels of E-cadherin and p63 expression. As expected, there was a strongly significant correlation between EMT marker expression and muscle invasion (p<0.0001). However, OS was shorter in patients with muscle-invasive tumors that retained p63 (p = 0.007). Our data confirm that molecular markers of EMT are elevated in muscle-invasive bladder cancers, but interestingly, retention of the "epithelial" marker p63 in muscle-invasive tumors is associated with a worse outcome.

  13. Inactivation of p53 in pterygium influence miR-200a expression resulting in ZEB1/ZEB2 up-regulation and EMT processing.

    PubMed

    Wu, Chueh-Wei; Peng, Mei-Ling; Yeh, Ken-Tu; Tsai, Yi-Yu; Chiang, Chun-Chi; Cheng, Ya-Wen

    2016-05-01

    Loss of p53 function has been linked to progression of pterygium. MiR-200a is known to be controlled by p53. Here, we hypothesize that expression of miR-200a and downstream ZEB1/ZEB2 genes are regulated epithelial-mesenchymal transition (EMT) involved in the pathogenesis and recurrence of pterygium. For this study, 120 primary pterygial samples were collected. Immunohistochemistry and real-time RT-PCR were performed to determine the expression of p53, p53 down-stream EMT associated protein and miR-200a. The molecular correlation of p53, miR-200a and downstream genes were confirmed using primary pterygium cells (PECs). Expression of miR-200a in pterygium tissues was significantly lower than in conjunctiva controls (p = 0.015). Up-regulated miR-200a levels were positively correlated with and p53 protein expression (p < 0.001). The miR-200a downstream ZEB1/ZEB1 protein expression were negative correlated with miR-200a expression. Cell model studies demonstrated that miR-200a controlled the EMT of PECs through up-regulated ZEB1, ZEB2 and Snail gene expression. Our study demonstrated that inactivation of p53 in pterygium may influence miR-200a, resulting in ZEB1/ZEB2 up-regulation and EMT processing of pterygium. Therefore, we suggest that expression of miR-200a play an important role in EMT processing and recurrence of pterygium. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors.

    PubMed

    Richard, Geoffrey; Dalle, Stéphane; Monet, Marie-Ambre; Ligier, Maud; Boespflug, Amélie; Pommier, Roxane M; de la Fouchardière, Arnaud; Perier-Muzet, Marie; Depaepe, Lauriane; Barnault, Romain; Tondeur, Garance; Ansieau, Stéphane; Thomas, Emilie; Bertolotto, Corine; Ballotti, Robert; Mourah, Samia; Battistella, Maxime; Lebbé, Céleste; Thomas, Luc; Puisieux, Alain; Caramel, Julie

    2016-10-01

    Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF V 600 -mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITF low /p75 high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  15. FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition

    PubMed Central

    Abshire, C F; Carroll, J L; Dragoi, A-M

    2016-01-01

    Cancer metastasis remains a significant challenge and the leading cause of cancer-associated deaths. It is postulated that during metastasis cells undergo epithelial-to-mesenchymal transition (EMT), a process characterized by loss of cell–cell contacts and increased migratory and invasive potential. ZEB1 is one the most prominent transcriptional repressors of genes associated with EMT. We identified caspase-8-associated protein 2 (CASP8AP2 or FLASH) as a novel posttranscriptional regulator of ZEB1. Here we demonstrate that FLASH protects ZEB1 from proteasomal degradation brought by the action of the ubiquitin ligases SIAH1 and F-box protein FBXO45. As a result, loss of FLASH rapidly destabilized ZEB1 and reversed EMT cellular characteristics. Importantly, loss of FLASH blocked transforming growth factor-β-induced EMT and enhanced sensitivity to chemotherapy. Thus, we propose that FLASH–ZEB1 interplay may be a protective mechanism against ZEB1 degradation in cells undergoing EMT and may be an efficacious target for therapies aimed to block EMT progression. PMID:27526108

  16. Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells

    PubMed Central

    Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cao, Mei; Ferretti, Max; Cunha, Gerald R.; Baskin, Laurence S.

    2012-01-01

    INTRODUCTION ZEB1 is overexpressed in patients with severe hypospadias. We examined the interaction between ZeB1 and the androgen receptor (AR) in vitro and the expression of AR in boys with hypospadias. RESULTS ZEB1 and AR colocalize to the nucleus. Estrogen upregulated ZEB1 and AR expression. Chromatin immunoprecipitation (ChIP) demonstrated that ZEB1 binds to an E-box sequence in the AR gene promoter. AR expression is higher in subjects with severe hypospadias than those with mild hypospadias and control subjects (P < 0.05). ZEB1 physically interacts with AR in human foreskin cells. DISCUSSION AR is overexpressed in patients with severe hypospadias. Environmental estrogenic compounds may increase the risk of hypospadias by facilitating the interaction between ZEB1 and AR. METHODS Hs68 cells, a fibroblast cell line derived from neonatal human foreskin, were exposed to 0, 10, and 100 nmol/l of estrogen, after which the cellular localization of ZEB1 and AR was assessed using immunocytochemistry. To determine if ZEB1 interacted with the AR gene, ChIP was performed using ZEB1 antibody and polymerase chain reaction (PCR) for AR. Second, AR expression was quantified using real-time PcR and western blot in normal subjects (n = 32), and subjects with mild (n = 16) and severe hypospadia (n = 16). PMID:22391641

  17. ZEB1 expression is correlated with tumor metastasis and reduced prognosis of breast carcinoma in Asian patients.

    PubMed

    Xiang, Shuai; Liu, Ya-Min; Chen, Xu; Wang, Ya-Wen; Ma, Ran-Ran; Wu, Xiao-Juan; Gao, Peng

    2015-07-01

    Tumor metastasis is one of the key events leading to tumor relapse and poor prognosis. Nowadays, increasing evidences demonstrated that ZEB1 was implicated in human carcinogenesis. However, involvement of ZEB1 deregulation in tumorigenesis in Asian patients with breast carcinoma remains elusive. The present study included 102 Asian patients with breast carcinoma treated by surgery from January of 2005 to December of 2006, and the expression of ZEB1 was evaluated by immunohistochemistry. To further assess the prognostic value of ZEB1, Kaplan-Meier curves were constructed. In this study, elevated levels of ZEB1 expression was found in carcinomas with higher aggressive potential. We also correlated expression of ZEB1 with lymph node metastasis (P = 0.021), advanced clinical stage (P = 0.012) in all cases, and high tumor grade (P = 0.047) in invasive ductal carcinoma. Furthermore, our data suggested an elevated level of Ki-67 expression in cases with positive expression of ZEB1. Clinically, reduced overall survival and disease-free survival were observed in cases with positive ZEB1 expression than that in negative cases. Our results correlated ZEB1 with aggressive potentials of breast carcinoma and revealed a possibility for ZEB1 as a prognostic marker in breast carcinoma.

  18. [Knock-down of ZEB1 inhibits the proliferation, invasion and migration of gastric cancer cells].

    PubMed

    Chen, Dengyu; Chu, Yifan; Zheng, Qingwei; Xu, Zhiben; Zhou, Ping; Li, Sheng

    2017-08-01

    Objective To down-regulate the expression of zinc-finger E-box binding homeobox 1 (ZEB1) gene by shRNA, and investigate its effect on invasion, migration and proliferation, as well as the related gene expressions of lncRNA HOTAIR and E-cadherin in human gastric cancer BGC823 cells. Methods RNA interfering (RNAi) was used to knock down ZEB1 in gastric cancer BGC823 cells. The recombinant plasmid shZEB1 was constructed and transfected into the gastric cancer BGC823 cells by Lipofectamine TM 2000, and the stably transfected cells were isolated by G418 selection and limited dilution. The expression of ZEB1 mRNA and protein was detected by real-time quantitative PCR and Western blot analysis. Cell proliferation was determined by MTT assay, and the invasion and migration abilities of BGC823 cells were monitored by Transwell TM invasion assay and wound healing assay, respectively. The expressions of lncRNA HOTAIR and E-cadherin mRNA were detected by real-time quantitative PCR. Results After ZEB1 expression was successfully down-regulated in BGC823 cells by siRNA, the proliferation, invasion and migration rates in shZEB1 transfection group were significantly lower than those in control group; meanwhile, the expression of lncRNA HOTAIR was reduced and E-cadherin expression was enhanced. Conclusion Knock-down of ZEB1 expression by RNA interference can decease lncRNA HOTAIR expression and restrain cell proliferation, invasion and migration in gastric cancer BGC823 cells.

  19. miR-340 alleviates chemoresistance of osteosarcoma cells by targeting ZEB1.

    PubMed

    Yan, Haibin; Zhang, Bingyun; Fang, Chongbin; Chen, Liqiu

    2018-06-01

    Chemoresistance during treatment of osteosarcoma (OS) is attracting more and more attention as the main clinical obstacle. The purpose of this study was to elucidate the role of miR-340 in chemoresistance of OS. Plasmid construction and transfection, miRNA arrays, PCR analyses, and western blot analysis, as well as MTT, apoptosis, and luciferase assays were carried out in MG-63 cells and MG-63/cisplatin (DDP)-resistant cells. The results showed that miR-340 was downregulated in OS tissues and drug-resistant OS cells. Moreover, a negative correlation was observed between miR-340 and ZEB1 expression in OS tissues. Forced expression of miR-340 in drug-resistant OS cells significantly reduced multidrug resistance-1 and P-gp expression. Overexpression of miR-340 enhanced sensitivity to DDP by inhibiting viability and promoting apoptosis. The luciferase assay and western blot analysis identified ZEB1 as a direct target of miR-340, and miR-340 negatively regulated ZEB1 expression. Ectopic expression of ZEB1 reversed the effects of miR-340 on P-gp expression, cell viability, and apoptosis. miR-340 alleviated chemoresistance of OS cells by targeting ZEB1. Our results indicate that targeting miR-340 may be a potential therapeutic approach to treat drug-resistant OS.

  20. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. | Office of Cancer Genomics

    Cancer.gov

    Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-β) or oncogenetic (MYC) factors.

  1. Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1.

    PubMed

    Carriere, Patrick P; Llopis, Shawn D; Naiki, Anna C; Nguyen, Gina; Phan, Tina; Nguyen, Mary M; Preyan, Lynez C; Yearby, Letitia; Pratt, Jamal; Burks, Hope; Davenport, Ian R; Nguyen, Thu A; Parker-Lemieux, KiTani; Payton-Stewart, Florastina; Williams, Christopher C; Boué, Stephen M; Burow, Matthew E; Collins-Burow, Bridgette; Hilliard, Aaron; Davidson, A Michael; Tilghman, Syreeta L

    2015-12-22

    Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.

  2. Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1

    PubMed Central

    Carriere, Patrick P.; Llopis, Shawn D.; Naiki, Anna C.; Nguyen, Gina; Phan, Tina; Nguyen, Mary M.; Preyan, Lynez C.; Yearby, Letitia; Pratt, Jamal; Burks, Hope; Davenport, Ian R.; Nguyen, Thu A.; Parker-Lemieux, KiTani; Payton-Stewart, Florastina; Williams, Christopher C.; Boué, Stephen M.; Burow, Matthew E.; Collins-Burow, Bridgette; Hilliard, Aaron; Davidson, A. Michael; Tilghman, Syreeta L.

    2015-01-01

    Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a −3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer. PMID:26703648

  3. The zinc finger E-box-binding homeobox 1 (Zeb1) promotes the conversion of mouse fibroblasts into functional neurons.

    PubMed

    Yan, Long; Li, Yue; Shi, Zixiao; Lu, Xiaoyin; Ma, Jiao; Hu, Baoyang; Jiao, Jianwei; Wang, Hongmei

    2017-08-04

    The zinc finger E-box-binding transcription factor Zeb1 plays a pivotal role in the epithelial-mesenchymal transition. Numerous studies have focused on the molecular mechanisms by which Zeb1 contributes to this process. However, the functions of Zeb1 beyond the epithelial-mesenchymal transition remain largely elusive. Using a transdifferentiation system to convert mouse embryonic fibroblasts (MEFs) into functional neurons via the neuronal transcription factors achaete-scute family bHLH (basic helix-loop-helix) transcription factor1 ( Ascl1 ), POU class 3 homeobox 2 (POU3F2/ Brn2 ), and neurogenin 2 (Neurog2, Ngn2 ) (ABN), we found that Zeb1 was up-regulated during the early stages of transdifferentiation. Knocking down Zeb1 dramatically attenuated the transdifferentiation efficiency, whereas Zeb1 overexpression obviously increased the efficiency of transdifferentiation from MEFs to neurons. Interestingly, Zeb1 improved the transdifferentiation efficiency induced by even a single transcription factor ( e.g. Asc1 or Ngn2 ). Zeb1 also rapidly promoted the maturation of induced neuron cells to functional neurons and improved the formation of neuronal patterns and electrophysiological characteristics. Induced neuron cells could form functional synapse in vivo after transplantation. Genome-wide RNA arrays showed that Zeb1 overexpression up-regulated the expression of neuron-specific genes and down-regulated the expression of epithelial-specific genes during conversion. Taken together, our results reveal a new role for Zeb1 in the transdifferentiation of MEFs into neurons. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. ZEB1-mediated vasculogenic mimicry formation associates with epithelial-mesenchymal transition and cancer stem cell phenotypes in prostate cancer.

    PubMed

    Wang, Hua; Huang, Bin; Li, Bai Mou; Cao, Kai Yuan; Mo, Chen Qiang; Jiang, Shuang Jian; Pan, Jin Cheng; Wang, Zong Ren; Lin, Huan Yi; Wang, Dao Hu; Qiu, Shao Peng

    2018-05-12

    The zinc finger E-box-binding homeobox 1 (ZEB1) induced the epithelial-mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid-Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1-induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT-related and CSC-associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p-Src 527 level but not p-Src 416 level, while ZEB1 knockdown also down-regulated the level of p-Src 527 in PC3 and DU-145 cells. PP2 treatment also significantly reduced the expression of VE-cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  5. Interplay Between Long Noncoding RNA ZEB1-AS1 and miR-200s Regulates Osteosarcoma Cell Proliferation and Migration.

    PubMed

    Liu, Chibo; Pan, Chunqin; Cai, Yanqun; Wang, Haibao

    2017-08-01

    In our previous study, we found long noncoding RNA ZEB1-AS1 is upregulated and functions as an oncogene in osteosarcoma. MiR-200 family (miR-200s) functions as tumor suppressor via directly targeting ZEB1 in various cancers. In this study, we further investigate the potential interplay between ZEB1-AS1, miR-200s, and ZEB1 in osteosarcoma. Our results showed that ZEB1-AS1 functions as a molecular sponge for miR-200s and relieves the inhibition of ZEB1 caused by miR-200s. ZEB1-AS1 and miR-200s reciprocally negatively regulate each other. MiR-200s are downregulated in osteosarcoma tissues, and negatively correlated with ZEB1-AS1 and ZEB1 expression levels in osteosarcoma. Functional experiments showed that consistent with ZEB1-AS1 depletion, miR-200s overexpression and ZEB1 depletion both inhibit osteosarcoma cell proliferation and migration. Overexpression of miR-200s partially abolished the effects of ZEB1-AS1 on osteosarcoma cell proliferation and migration. Moreover, the combination of ZEB1-AS1 depletion and miR-200s overexpression significantly inhibits osteosarcoma cell proliferation and migration. In conclusion, this study revealed a novel regulatory mechanism between ZEB1-AS1, miR-200s, and ZEB1. The interplay between ZEB1-AS1 and miR-200s contributes to osteosarcoma cell proliferation and migration, and targeting this interplay could be a promising strategy for osteosarcoma treatment. J. Cell. Biochem. 118: 2250-2260, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. ZEB1 promotes the progression and metastasis of cervical squamous cell carcinoma via the promotion of epithelial-mesenchymal transition

    PubMed Central

    Ma, Yihui; Zheng, Xiangyu; Zhou, Jun; Zhang, Ying; Chen, Kuisheng

    2015-01-01

    Objective: The process of epithelial-mesenchymal transition (EMT) clearly contributes to cancer metastasis. The aim of this study was to investigate the expression of the EMT-related transcription repressor ZEB1 and the expression of EMT-associated markers (E-cadherin, β-catenin and N-cadherin) in cervical squamous cell carcinoma. In addition, the role of ZEB1 and these EMT-associated markers in the progression and metastasis of cervical squamous cell carcinoma was explored. Methods: The expression of ZEB1, E-cadherin, β-catenin and N-cadherin was evaluated in 81 specimens of cervical squamous cell carcinoma by immunohistochemistry; the clinicopathological significance of these markers was then analyzed. Results: 1) Of the 81 samples, 37 cases (45.7%) were positive for ZEB1, and nuclear expression of ZEB1 in tumor cells was positively associated with the differentiation status of the tumor tissue (P < 0.05), vascular invasion (P < 0.05) and lymph node metastasis (P < 0.05). 2) The loss of E-cadherin and β-catenin expression in tumor cells and the acquisition of N-cadherin expression were positively associated with the differentiation status of the tumor tissue (P < 0.05) and with the occurrence of vascular invasion (P < 0.05). 3) A significant negative correlation was observed between ZEB1 and E-cadherin expression (Spearman = -0.636, P < 0.05) and between ZEB1 and β-catenin expression (Spearman = -0.417, P < 0.05). Moreover, a significant positive correlation was observed between ZEB1 and N-cadherin expression (Spearman = 0.557, P < 0.05). Conclusions: These results emphasize the role of EMT in cervical squamous cell carcinoma. The upregulation of ZEB1 is associated with the abnormal expression of E-cadherin, β-catenin and N-cadherin, which might promote the progression and metastasis of cervical squamous cell carcinoma. PMID:26617850

  7. Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT

    PubMed Central

    Kanska, Justyna; Aspuria, Paul-Joseph P.; Taylor-Harding, Barbie; Spurka, Lindsay; Funari, Vincent; Orsulic, Sandra; Karlan, Beth Y.; Wiedemeyer, W. Ruprecht

    2017-01-01

    Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression. We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells. NNMT depletion reversed metabolic plasticity in glucose-restricted cells and prevented de novo formation of glucose-restricted colonies. In addition to its role in glucose independence, we found that NNMT was required for other ZEB1-induced phenotypes, such as increased migration. NNMT protein levels were also elevated in metastatic and recurrent tumors compared to matched primary carcinomas, while normal ovary and fallopian tube tissue had no detectable NNMT expression. Our studies define a novel ZEB1/NNMT signaling axis, which elicits mesenchymal gene expression, as well as phenotypic and metabolic plasticity in ovarian cancer cells upon chronic glucose starvation. Understanding the causes of cancer cell plasticity is crucial for the development of therapeutic strategies to counter intratumoral heterogeneity, acquired drug resistance and recurrence in high-grade serous ovarian cancer (HGSC). PMID:28412735

  8. OXTR and ZEB1 expression before and after progesterone dosing in pregnant women with threatened premature labor.

    PubMed

    Xu, Y-J; Ren, L-D; Zhai, S-S; Ran, L-M; Hu, L-L; Luo, X-H; Hong, T; Liu, R; Yu, Y-R; Ban, Y-J

    2017-07-01

    To investigate changes in the peripheral blood mRNA levels of oxytocin receptor (OXTR) and Zinc finger E-box-binding homeobox 1 (ZEB1) before and after progesterone dosing in pregnant women with threatened premature labor. Blood samples were collected from 30 healthy pregnant women with 28- to 33+6-week gestational age and singleton pregnancy (group A) and from 30 pregnant women with singleton pregnancy and threatened premature labor before and 48 hours after progesterone dosing (groups B and C, respectively) for quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay to assess the OXTR and ZEB1 mRNA levels. The OXTR mRNA level was higher in the group B than in the groups A and C, and the ZEB1 mRNA level was lower in the group B than in the groups A and C. Notably, no significant difference was found in the mRNA level of OXTR or ZEB1 between group A and group C. The peripheral blood mRNA level of OXTR was increased, and that of ZEB1 was decreased in pregnant women with threatened premature labor. Progesterone helped to maintain pregnancy by readjusting the mRNA levels of OXTR and ZEB1.

  9. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.

    PubMed

    Chen, Limo; Gibbons, Don L; Goswami, Sangeeta; Cortez, Maria Angelica; Ahn, Young-Ho; Byers, Lauren A; Zhang, Xuejun; Yi, Xiaohui; Dwyer, David; Lin, Wei; Diao, Lixia; Wang, Jing; Roybal, Jonathon; Patel, Mayuri; Ungewiss, Christin; Peng, David; Antonia, Scott; Mediavilla-Varela, Melanie; Robertson, Gordon; Suraokar, Milind; Welsh, James W; Erez, Baruch; Wistuba, Ignacio I; Chen, Lieping; Peng, Di; Wang, Shanshan; Ullrich, Stephen E; Heymach, John V; Kurie, Jonathan M; Qin, F Xiao-Feng

    2014-10-28

    Immunosuppression of tumour-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8(+) TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T-cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.

  10. Epithelial-mesenchymal transition, a novel target of sulforaphane via COX-2/MMP2, 9/Snail, ZEB1 and miR-200c/ZEB1 pathways in human bladder cancer cells.

    PubMed

    Shan, Yujuan; Zhang, Lanwei; Bao, Yongping; Li, Baolong; He, Canxia; Gao, Mingming; Feng, Xue; Xu, Weili; Zhang, Xiaohong; Wang, Shuran

    2013-06-01

    Metastasis and recurrence of bladder cancer are the main reasons for its poor prognosis and high mortality rates. Because of its biological activity and high metabolic accumulation in urine, sulforaphane, a phytochemical exclusively occurring in cruciferous vegetables, has a powerful and specific potential for preventing bladder cancer. In this paper, sulforaphane is shown to significantly suppress a variety of biochemical pathways including the attachment, invasion, migration and chemotaxis motion in malignant transitional bladder cancer T24 cells. Transfection with cyclooxygenase-2 (COX-2) overexpression plasmid largely abolished inhibition of MMP2/9 expression as well as cell invasive capability by sulforaphane. Moreover, sulforaphane inhibited the epithelial-to-mesenchymal transition (EMT) process which underlies tumor cell invasion and migration mediated by E-cadherin induction through reducing transcriptional repressors, such as ZEB1 and Snail. Under conditions of over-expression of COX-2 and/or MMP2/9, sulforaphane was still able to induce E-cadherin or reduce Snail/ZEB1 expression, suggesting that additional pathways might be involved. Further studies indicated that miR-200c played a role in the regulation of E-cadherin via the ZEB1 repressor but not by the Snail repressor. In conclusion, the EMT and two recognized signaling pathways (COX-2/MMP2,9/ ZEB1, Snail and miR-200c/ZEB1) are all targets for sulforaphane. This study indicated that sulforaphane may possess therapeutic potential in preventing recurrence of human bladder cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Knockdown of BAG3 induces epithelial-mesenchymal transition in thyroid cancer cells through ZEB1 activation.

    PubMed

    Meng, X; Kong, D-H; Li, N; Zong, Z-H; Liu, B-Q; Du, Z-X; Guan, Y; Cao, L; Wang, H-Q

    2014-02-27

    The process by which epithelial features are lost in favor of a mesenchymal phenotype is referred to as epithelial-mesenchymal transition (EMT). Most carcinomas use this mechanism to evade into neighboring tissues. Reduction or a loss of E-cadherin expression is a well-established hallmark of EMT. As a potent suppressor of E-cadherin, transcription factor ZEB1 is one of the key inducers of EMT, whose expression promotes tumorigenesis and metastasis of carcinomas. Bcl-2-associated athanogene 3 (BAG3) affects multifaceted cellular functions, including proliferation, apoptosis, cell adhesion and invasion, viral infection, and autophagy. Recently, we have reported a novel role of BAG3 implicated in EMT, while the mechanisms are poorly elucidated. The current study demonstrated that knockdown of BAG3 induced EMT, and increased cell migratory and invasiveness in thyroid cancer cells via transcriptional activation of ZEB1. We also found that BAG3 knockdown led to nuclear accumulation of β-catenin, which was responsible for the transcriptional activation of ZEB1. These results indicate BAG3 as a regulator of ZEB1 expression in EMT and as a regulator of metastasis in thyroid cancer cells, providing potential targets to prevent and/or treat thyroid cancer cell invasion and metastasis.

  12. Knockdown of BAG3 induces epithelial–mesenchymal transition in thyroid cancer cells through ZEB1 activation

    PubMed Central

    Meng, X; Kong, D-H; Li, N; Zong, Z-H; Liu, B-Q; Du, Z-X; Guan, Y; Cao, L; Wang, H-Q

    2014-01-01

    The process by which epithelial features are lost in favor of a mesenchymal phenotype is referred to as epithelial–mesenchymal transition (EMT). Most carcinomas use this mechanism to evade into neighboring tissues. Reduction or a loss of E-cadherin expression is a well-established hallmark of EMT. As a potent suppressor of E-cadherin, transcription factor ZEB1 is one of the key inducers of EMT, whose expression promotes tumorigenesis and metastasis of carcinomas. Bcl-2-associated athanogene 3 (BAG3) affects multifaceted cellular functions, including proliferation, apoptosis, cell adhesion and invasion, viral infection, and autophagy. Recently, we have reported a novel role of BAG3 implicated in EMT, while the mechanisms are poorly elucidated. The current study demonstrated that knockdown of BAG3 induced EMT, and increased cell migratory and invasiveness in thyroid cancer cells via transcriptional activation of ZEB1. We also found that BAG3 knockdown led to nuclear accumulation of β-catenin, which was responsible for the transcriptional activation of ZEB1. These results indicate BAG3 as a regulator of ZEB1 expression in EMT and as a regulator of metastasis in thyroid cancer cells, providing potential targets to prevent and/or treat thyroid cancer cell invasion and metastasis. PMID:24577090

  13. ZEB1 is Estrogen Responsive In Vitro in Human Foreskin Cells and is Over Expressed in Penile Skin in Patients With Severe Hypospadias

    PubMed Central

    Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cunha, Gerald R.; Baskin, Laurence

    2012-01-01

    Purpose We determined the effect of estrogen on ZEB1 in vitro and tested the hypothesis that ZEB1 is over expressed in the penile skin of subjects with hypospadias. Materials and Methods Hs68 cells, a fibroblast cell line derived from human foreskin, were exposed to 0, 1, 10 and 100 nM estrogen, and the expression level of ZEB1 was assessed using reverse transcription real-time polymerase chain reaction, Western blot and immunocytochemical analysis. Next, preputial skin was prospectively collected from case and control subjects at hypospadias repair (37 cases) and circumcision (11). Hypospadias was classified as severe (13 cases) or mild (24) based on the position of the urethral meatus. ZEB1 expression was quantified using reverse transcription real-time polymerase chain reaction, Western blot and immunohistochemical analysis. Results Estrogen increased ZEB1 expression at the mRNA and protein levels in Hs68 cells in a concentration dependent fashion (p <0.01). Subjects with severe hypospadias had significantly higher ZEB1 mRNA levels and protein expression compared to controls or subjects with mild hypospadias (both p <0.01). Subjects with severe hypospadias had increased expression of ZEB1 in the basal layers of the preputial epidermis. Conclusions Estrogen increases ZEB1 expression in a human foreskin fibroblast cell line in vitro. Furthermore, ZEB1 is significantly over expressed in the penile skin of subjects with severe hypospadias. We propose that ZEB1 overexpression may contribute to development of hypospadias and may mediate the effect of estrogen on developing external male genitalia. PMID:21421232

  14. Long non-coding RNA ZEB1-AS1 is associated with poor prognosis in gastric cancer and promotes cancer cell metastasis.

    PubMed

    Liu, X-J; Li, S-L; Li, J-S; Lu, H; Yin, L-L; Zheng, W-F; Wang, W-C

    2018-05-01

    To investigate the expression of long non-coding RNA zinc-finger E-box binding homeobox 1-AS1 (lncRNA ZEB1-AS1) in gastric cancer cells and tissues, to study its effect on the gastric cancer cell metastasis capacity, and analyze its clinical significance. The relative expression level of lncRNA ZEB1-AS1 in gastric cancer cells was detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Transwell assay was used to detect the effects of lncRNA ZEB1-AS1 on the invasion and metastasis capacities of gastric cancer cells. qRT-PCR was used to detect the relative expression level of lncRNA ZEB1-AS1 in 75 pairs of gastric cancer tissues, and the correlations of its expression with the pathological characteristics and prognosis of patients were statistically analyzed. qRT-PCR showed that compared with that in the normal gastric epithelial cell (GES-1), the expression level of lncRNA ZEB1-AS1 was up-regulated in gastric cancer cells (MKN28, MKN45, BGC823, MGC803, KATOIII, and SGC7901). LncRNA ZEB1-AS1 interfering sequence was transfected into model cells, and Transwell assay showed that the cell invasion and migration capacities were significantly inhibited. qRT-PCR also revealed that the expression of lncRNA ZEB1-AS1 was up-regulated in 55 out of 75 cases of gastric cancer and para-carcinoma tissues (fold change > 1). Statistical analysis showed that the high expression of lncRNA ZEB1-AS1 was positively correlated with TNM staging (p = 0.002), lymph node metastasis (p = 0.002), and invasion degree (p = 0.004). The survival time of patients with high expression of lncRNA ZEB1-AS1 in gastric cancer tissues was shorter than that of patients with low expression (p = 0.004). LncRNA ZEB1-AS1 is highly expressed in gastric cancer tissues and cells, and it is expected to be a new prognostic marker of gastric cancer used for the clinical diagnosis and prognostic evaluation. After intervention in lncRNA ZEB1-AS1 expression, the cell invasion and migration

  15. Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells.

    PubMed

    Cencioni, Chiara; Spallotta, Francesco; Savoia, Matteo; Kuenne, Carsten; Guenther, Stefan; Re, Agnese; Wingert, Susanne; Rehage, Maike; Sürün, Duran; Siragusa, Mauro; Smith, Jacob G; Schnütgen, Frank; von Melchner, Harald; Rieger, Michael A; Martelli, Fabio; Riccio, Antonella; Fleming, Ingrid; Braun, Thomas; Zeiher, Andreas M; Farsetti, Antonella; Gaetano, Carlo

    2018-03-29

    Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.

  16. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer.

    PubMed

    Sahay, Debashish; Leblanc, Raphael; Grunewald, Thomas G P; Ambatipudi, Srikant; Ribeiro, Johnny; Clézardin, Philippe; Peyruchaud, Olivier

    2015-08-21

    Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.

  17. ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma.

    PubMed

    Romero-Pérez, Laura; López-García, M Ángeles; Díaz-Martín, Juan; Biscuola, Michele; Castilla, M Ángeles; Tafe, Laura J; Garg, Karuna; Oliva, Esther; Matias-Guiu, Xavier; Soslow, Robert A; Palacios, José

    2013-11-01

    Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (∼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis

  18. Novel Mutations in the ZEB1 Gene Identified in Czech and British Patients With Posterior Polymorphous Corneal Dystrophy

    PubMed Central

    Liskova, Petra; Tuft, Stephen J.; Gwilliam, Rhian; Ebenezer, Neil D.; Jirsova, Katerina; Prescott, Quincy; Martincova, Radka; Pretorius, Marike; Sinclair, Neil; Boase, David L.; Jeffrey, Margaret J.; Deloukas, Panos; Hardcastle, Alison J.; Filipec, Martin; Bhattacharya, Shomi S.

    2009-01-01

    We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD. PMID:17437275

  19. ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.

    PubMed

    Meidhof, Simone; Brabletz, Simone; Lehmann, Waltraut; Preca, Bogdan-Tiberius; Mock, Kerstin; Ruh, Manuel; Schüler, Julia; Berthold, Maria; Weber, Anika; Burk, Ulrike; Lübbert, Michael; Puhr, Martin; Culig, Zoran; Wellner, Ulrich; Keck, Tobias; Bronsert, Peter; Küsters, Simon; Hopt, Ulrich T; Stemmler, Marc P; Brabletz, Thomas

    2015-06-01

    Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  20. Knockdown of long noncoding RNA linc-ITGB1 suppresses migration, invasion of hepatocellular carcinoma via regulating ZEB1.

    PubMed

    Yu, W-W; Wang, K; Liao, G-J

    2017-11-01

    This research focuses on the influence of linc-ITGB1 on the metastasis of hepatocellular carcinoma and further explores its underlying mechanism. A total of 70 hepatocellular carcinoma patients were chosen for our study. RT-qPCR was used for detecting the expression level of linc-ITGB1 in their cancer tissues. Moreover, the expression level of linc-ITGB1 was also detected in hepatocellular carcinoma cell lines. Furthermore, whether linc-ITGB1 could affect the migrated and invaded ability of hepatocellular carcinoma cells was determined by wound healing assay and transwell assay. We further explored the potential mechanism by RT-qPCR and Western blot assay. Linc-ITGB1 expression level in hepatocellular carcinoma tissues was remarkably higher than that in adjacent tissues. Moreover, migrated and invaded ability of hepatocellular carcinoma cells was inhibited through knockdown of linc-ITGB1. Further study revealed that silenced linc-ITGB1 inhibited the expression of ZEB1 and then suppressed epithelial to mesenchymal transition (EMT), which was important during the metastasis of hepatocellular carcinoma. Moreover, the inhibition of cell invasion by silenced linc-ITGB1 could be rescued through overexpression of ZEB1 in hepatocellular carcinoma. The results indicate that linc-ITGB1, a novel oncogene in tumorigenesis, could promote the metastasis and EMT via ZEB1, which may offer a possible therapeutic target in hepatocellular carcinoma.

  1. The utility of long non-coding RNA ZEB1-AS1 as a prognostic biomarker in human solid tumors: A meta-analysis.

    PubMed

    Zuo, Xue-Liang; Cai, Juan; Chen, Zhi-Qiang; Zhang, Yao; Liang, Lin-Hu; Wang, Jun-Feng; Wang, Jin-Guo; Wu, Jian; Mao, Jia-Ding

    2018-06-12

    This meta-analysis aims to assess the prognostic value of long non-coding RNA ZEB1-AS1 in human solid tumors. We searched the available databases up to January 2018. Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to examine the prognostic impact of ZEB1-AS1 on patient survival. Eight eligible studies with a total of 586 patients were enrolled. A significant association was observed between ZEB1-AS1 overexpression and poor overall survival (OS; HR = 2.195, 95% CI: 1.749-2.755) as well as unfavorable recurrence-free survival (pooled HR = 2.205, 95% CI: 1.486-3.270), and no heterogeneity was found across these studies (p = .962, I 2  = 0%). Subsequent subgroup analyses showed that cancer type, sample size, follow up months, and HR estimation method did not alter the significant prognostic value of ZEB1-AS1. ZEB1-AS1 expression was indicated to be an independent prognostic factor for tumor OS (pooled HR = 2.177, 95% CI:1.545-3.069). Furthermore, we found that increased ZEB1-AS1 expression was significantly associated with tumor stage [III-IV vs. I-II: odds ratio (OR) = 1.644, 95% CI: 1.201-2.249] and lymph node metastasis (Positive vs. Negative: OR = 2.413, 95% CI: 1.504-3.873). High expression level of ZEB1-AS1 was associated with unfavorable survival outcome for cancer patients, and ZEB1-AS1 could be used as a prognostic predictor for cancers. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells.

    PubMed

    Wang, Jun; Lee, Seungsoo; Teh, Charis En-Yi; Bunting, Karen; Ma, Lina; Shannon, M Frances

    2009-03-01

    Activation of T cells leads to the induction of many cytokine genes that are required for appropriate immune responses, including IL-2, a key cytokine for T cell proliferation and homeostasis. The activating transcription factors such as nuclear factor of activated T cells, nuclear factor kappaB/Rel and activated protein-1 family members that regulate inducible IL-2 gene expression have been well documented. However, negative regulation of the IL-2 gene is less studied. Here we examine the role of zinc finger E-box-binding protein (ZEB) 1, a homeodomain/Zn finger transcription factor, as a repressor of IL-2 gene transcription. We show here that ZEB1 is expressed in non-stimulated and stimulated T cells and using chromatin immunoprecipitation assays we show that ZEB1 binds to the IL-2 promoter. Over-expression of ZEB1 can repress IL-2 promoter activity, as well as endogenous IL-2 mRNA production in EL-4 T cells, and this repression is dependent on the ZEB-binding site at -100. ZEB1 cooperates with the co-repressor C-terminal-binding protein (CtBP) 2 and with histone deacetylase 1 to repress the IL-2 promoter and this cooperation depends on the ZEB-binding site in the promoter as well as the Pro-X-Asp-Leu-Ser protein-protein interaction domain in CtBP2. Thus, ZEB1 may function to recruit a repressor complex to the IL-2 promoter.

  3. p63 regulates glutaminase 2 expression

    PubMed Central

    Giacobbe, Arianna; Bongiorno-Borbone, Lucilla; Bernassola, Francesca; Terrinoni, Alessandro; Markert, Elke Katrin; Levine, Arnold J.; Feng, Zhaohui; Agostini, Massimilano; Zolla, Lello; Agrò, Alessandro Finazzi; Notterman, Daniel A.; Melino, Gerry; Peschiaroli, Angelo

    2013-01-01

    The transcription factor p63 is critical for many biological processes, including development and maintenance of epidermal tissues and tumorigenesis. Here, we report that the TAp63 isoforms regulate cell metabolism through the induction of the mitochondrial glutaminase 2 (GLS2) gene both in primary cells and tumor cell lines. By ChIP analysis and luciferase assay, we confirmed that TAp63 binds directly to the p53/p63 consensus DNA binding sequence within the GLS2 promoter region. Given the critical role of p63 in epidermal differentiation, we have investigated the regulation of GLS2 expression during this process. GLS2 and TAp63 expression increases during the in vitro differentiation of primary human keratinocytes, and depletion of GLS2 inhibits skin differentiation both at molecular and cellular levels. We found that GLS2 and TAp63 expression are concomitantly induced in cancer cells exposed to oxidative stresses. siRNA-mediated depletion of GLS2 sensitizes cells to ROS-induced apoptosis, suggesting that the TAp63/GLS2 axis can be functionally important as a cellular antioxidant pathway in the absence of p53. Accordingly, we found that GLS2 is upregulated in colon adenocarcinoma. Altogether, our findings demonstrate that GLS2 is a bona fide TAp63 target gene, and that the TAp63-dependent regulation of GLS2 is important for both physiological and pathological processes. PMID:23574722

  4. Identification of a PEAK1/ZEB1 signaling axis during TGFβ/fibronectin-induced EMT in breast cancer

    SciTech Connect

    Agajanian, Megan; Runa, Farhana; Kelber, Jonathan A., E-mail: jonathan.kelber@csun.edu

    Transforming Growth Factor beta (TGFβ) is the archetypal member of the TGFβ superfamily of ligands and has pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer. In epithelial cancers TGFβ signaling can either suppress tumor growth or promote metastasis via the induction of a well-characterized epithelial–mesenchymal transition (EMT) program. We recently reported that PEAK1 kinase mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways and functions as a critical molecular regulator of TGFβ-induced breast cancer cell proliferation, migration, EMT and metastasis. Here, we examined the breast cancer cell contexts in which TGFβ induces bothmore » EMT and PEAK1, and discovered this event to be unique to oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells. Using the Cancer BioPortal database, we identified PEAK1 co-expressors across multiple malignancies that are also common to the TGFβ response gene signature (TBRS). We then used the ScanSite database to identify predicted protein–protein binding partners of PEAK1 and the PEAK1-TBRS co-expressors. Analysis of the Cytoscape interactome and Babelomics-derived gene ontologies for a novel gene set including PEAK1, CRK, ZEB1, IL11 and COL4A1 enabled us to hypothesize that PEAK1 may be regulating TGFβ-induced EMT via its interaction with or regulation of these other genes. In this regard, we have demonstrated that PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT in the context of fibronectin/ITGB3 activation. These studies and future mechanistic studies will pave the way toward identifying the context in which TGFβ blockade may significantly improve breast cancer patient outcomes. - Highlights: • PEAK1 is upregulated in mammary epithelial cells during TGFβ-induced EMT. • TGFβ-induced EMT upregulates PEAK1 in triple negative breast cancer. • PEAK1 is necessary for

  5. The clinicopathological and prognostic value of long non-coding RNA ZEB1-AS1 in solid tumors: A meta-analysis.

    PubMed

    Liang, Chaojie; Liu, Jing; Ge, Hua; Xu, Yingchen; Li, Guangming; Wu, Jixiang

    2018-05-17

    Studies have reported that Zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) is overexpressed in many malignant tumors. However, the sample size in those studies was limited, so the clinicopathological and prognostic value of ZEB1-AS1 in solid tumors remains undetermined, Accordingly, the aim of this meta-analysis was to evaluate the relationship between the expression of lncRNA ZEB1-AS1 and clinicopathological characteristics and prognosis in patients with solid tumors. Pooled odds ratios (ORs) and hazard ratios (HRs) were estimated with 95% confidence interval (CI) to assess the relation between ZEB1-AS1 and the clinicopathological characteristics and prognosis of patients with cancer. A total of 10 studies, comprising 861 patients, were included in this meta-analysis. The pooled results suggested that high ZEB1-AS1 expression was related to low differentiation (low vs. high + moderate: OR = 2.99, 95% CI = [2.03, 4.39]), increased lymph node metastasis (YES vs. NO: OR = 4.62, 95% CI = [2.90, 7.37]) and advanced TNM stage (I + II vs. III + IV: OR = 0.41, 95% CI = [0.23, 0.75]), but not to gender and tumor size. Moreover, high ZEB1-AS1 expression was associated with poor overall survival (OS; HR = 1.86, 95% CI = [1.57, 2.14]) and disease-free survival (DFS; HR = 2.03, 95% CI = [1.28, 2.77]). Thus, ZEB1-AS1 could be an independent predictive factor for OS (HR = 2.07, 95% CI = [1.57, 2.56]) in patients with cancers. High expression of ZEB1-AS1 was associated with advanced clinicopathological characteristics, and ZEB1-AS1overexpression may be a potential prognostic biomarker in human cancer. However, more studies involving various tumor types and large sample size are needed. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network

    PubMed Central

    Gubelmann, Carine; Schwalie, Petra C; Raghav, Sunil K; Röder, Eva; Delessa, Tenagne; Kiehlmann, Elke; Waszak, Sebastian M; Corsinotti, Andrea; Udin, Gilles; Holcombe, Wiebke; Rudofsky, Gottfried; Trono, Didier; Wolfrum, Christian; Deplancke, Bart

    2014-01-01

    Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.03346.001 PMID:25163748

  7. miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells

    SciTech Connect

    Liu, Huaize; Wang, Han; Liu, Xiaoxiao

    Pancreatic cancer (PC) remains one of the most lethal types of cancer in adults. The purpose of this study was to determine the role of miR-1271 in regulation of epithelial mesenchymal transition (EMT) and metastasis of pancreatic cancer cells. miR-1271 was identified to be significantly down-regulated in PC tissues by miRNA array. Also, an increase of EMT-regulators ZEB1 and TWIST1 expression level is accompanied by a decrease of miR-1271. We showed that expression of miR-1271 was significantly down-regulated in PC tissues as compared with that in normal tissues. In addition, our results showed that miR-1271 expression levels were decreased whilemore » ZEB1 and TWIST1 expression levels were increased in detected PC cell lines. Moreover, ectopic expression of miR-1271 suppressed and antagomiR-1271 promoted proliferation, migration, and invasion in SW1990 and PANC-1 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-1271 inhibited expression of ZEB1 and TWIST1, which are master regulators of tumor metastasis. Our study first indicates that miR-1271 functions as a suppressor in regulating of pancreatic cancer EMT by targeting ZEB1 and TWIST1, and it promise as a therapeutic target and prognostic marker for metastatic pancreatic cancer. - Highlights: • miR-1271 is downregulated in pancreatic cancer tissues and cell lines. • miR-1271 regulates cell metastasis ability and EMT marker expression. . • miR-1271 directly targets ZEB1 and TWIST1. • ZEB1 and TWIST1 are functionally related to the effects of miR-1271.« less

  8. p63 in skin development and ectodermal dysplasias

    PubMed Central

    Koster, Maranke I.

    2010-01-01

    The transcription factor p63 is critically important for skin development and maintenance. Processes that require p63 include epidermal lineage commitment, epidermal differentiation, cell adhesion, and basement membrane formation. Not surprisingly, alterations in the p63 pathway underlie a subset of ectodermal dysplasias, developmental syndromes in which the skin and skin appendages do not develop normally. This review summarizes the current understanding of the role of p63 in normal development and ectodermal dysplasias. PMID:20445549

  9. A Symphony of Regulations Centered on p63 to Control Development of Ectoderm-Derived Structures

    PubMed Central

    Guerrini, Luisa; Costanzo, Antonio; Merlo, Giorgio R.

    2011-01-01

    The p53-related transcription factor p63 is critically important for basic cellular functions during development of the ectoderm and derived structure and tissues, including skin, limb, palate, and hair. On the one side, p63 is required to sustain the proliferation of keratinocyte progenitors, while on the other side it is required for cell stratification, commitment to differentiate, cell adhesion, and epithelial-mesenchymal signaling. Molecules that are components or regulators of the p63 pathway(s) are rapidly being identified, and it comes with no surprise that alterations in the p63 pathway lead to congenital conditions in which the skin and other ectoderm-derived structures are affected. In this paper, we summarize the current knowledge of the molecular and cellular regulations centered on p63, derived from the comprehension of p63-linked human diseases and the corresponding animal models, as well as from cellular models and high-throughput molecular approaches. We point out common themes and features, that allow to speculate on the possible role of p63 downstream events and their potential exploitation in future attempts to correct the congenital defect in preclinical studies. PMID:21716671

  10. Long non-coding RNA CASC15 regulates gastric cancer cell proliferation, migration and epithelial mesenchymal transition by targeting CDKN1A and ZEB1.

    PubMed

    Wu, Qiong; Xiang, Shihao; Ma, Jiali; Hui, Pingping; Wang, Ting; Meng, Wenying; Shi, Min; Wang, Yugang

    2018-06-01

    Long non-coding RNA (lncRNA) is responsible for a diverse range of cellular functions, such as transcriptional and translational regulation and variance in gene expression. The lncRNA CASC15 (cancer susceptibility candidate 15) is a long intergenic non-coding RNA (lincRNA) locus in chromosome 6p22.3. Previous research shows that lncRNA CASC15 is implicated in the biological behaviors of several cancers such as neuroblastoma and melanoma. Here, we aimed to explore in detail how CASC15 contributes to the growth of gastric cancer (GC). As predicted, the expression of CASC15 was enriched in GC tissues and cell lines as compared with healthy tissues and cells using qRT-PCR. The Kaplan-Meier method was used to demonstrate that high expression of CASC15 is linked to a poor prognosis for patients suffering from GC. Additionally, functional experiments proved that the down- or up-regulation of CASC15 inhibited or facilitated cell proliferation via the induction of cell cycle arrest and apoptosis, and also suppressed or accelerated cell migration and invasion by affecting the progression of the epithelial-to-mesenchymal transition (EMT). In vivo experiments showed that the knockdown of CASC15 lessened the tumor volume and weight and influenced the EMT process. This was confirmed by western blot assays and immunohistochemistry, indicating impaired metastatic ability in nude mice. CASC15 involvement in the tumorigenesis of GC occurs when CASC15 interacts with EZH2 and WDR5 to modulate CDKN1A in nucleus. Additionally, the knockdown of CASC15 triggered the silencing of ZEB1 in cytoplasm, which was shown to be associated with the competitive binding of CASC15 to miR-33a-5p. © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  11. Repression of the expression of PPP3CC by ZEB1 confers activation of NF-κB and contributes to invasion and growth in glioma cells.

    PubMed

    Wang, Hongquan; Zhao, Shuli; Chen, Bo; Fu, Chuhua; Dang, Yanwei; Fang, Peihai; Wang, Jun; Wang, Ning; Liu, Lijun

    2018-02-01

    Gliomas are highly malignant brain tumors. Aberrant activation of NF-κB plays a crucial role in tumor progression. ELISA assay was used to detect NF-κB activity in glimoas cells with different treatments. PPP3CC expression was evaluated by qRT-PCR and western blot assay. Kaplan-Meier analysis estimated the overall survival rates according to the protein level of PPP3CC. Transwell and MTS assay were performed to determine cell invasion and growth. Chromatin immunoprecipitation combined with luciferase reporter assays illustrated the transcriptional regulation of PPP3CC. We showed that PPP3CC decrease was responsible for constitutive activation of NF-κB in gliomas. Restored PPP3CC expression inhibited activation of NF-κB. PPP3CC was frequently decreased in gliomas and that repression of the expression of PPP3CC correlated glioma progression. The ectopic expression of PPP3CC inhibited the invasive potential of glioma cells, and inhibited glioma cells proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E-box-binding homeobox 1(ZEB1) was increased in gliomas and was negatively correlated with clinical outcomes of glioma patients. ZEB1 inversely correlated with the expression of PPP3CC. ZEB1 was also confirmed to physically bind to the PPP3CC promoter. ZEB1 knockdown resulted in an increase in the expression of PPP3CC and elevation of PPP3CC promoter activity in glioma cells. These findings indicated that the down-regulation of PPP3CC by ZEB1 resulted in activation of NF-κB is a critical oncogenic event in gliomas. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. ZEB1 induces LOXL2-mediated collagen stabilization and deposition in the extracellular matrix to drive lung cancer invasion and metastasis.

    PubMed

    Peng, D H; Ungewiss, C; Tong, P; Byers, L A; Wang, J; Canales, J R; Villalobos, P A; Uraoka, N; Mino, B; Behrens, C; Wistuba, I I; Han, R I; Wanna, C A; Fahrenholtz, M; Grande-Allen, K J; Creighton, C J; Gibbons, D L

    2017-04-06

    Lung cancer is the leading cause of cancer-related deaths, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) regulated by various transcription factors, including a double-negative feedback loop between the microRNA-200 (miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent EMT promotes malignancy remain largely undefined. Although the cell-intrinsic effects of EMT are important for tumor progression, the reciprocal dynamic crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is equally critical in regulating invasion and metastasis. Investigating the collaborative effect of EMT and ECM in the metastatic process reveals increased collagen deposition in metastatic tumor tissues as a direct consequence of amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer cells. In addition, collagen fibers in metastatic lung tumors exhibit greater linearity and organization as a result of collagen crosslinking by the lysyl oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is directly regulated by miR-200 and ZEB1, respectively, and their upregulation in metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. Functionally, LOXL2, as opposed to LOX, is the principal isoform that crosslinks and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells by crosslinked collagen in the ECM. Our study is the first to validate direct regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism driving tumor metastasis, delineates collagen as a prognostic marker, and identifies LOXL2 as a potential therapeutic target against tumor progression.

  13. ZEB1 Induces LOXL2-Mediated Collagen Stabilization and Deposition in the Extracellular Matrix to Drive Lung Cancer Invasion and Metastasis

    PubMed Central

    Peng, David H.; Ungewiss, Christin; Tong, Pan; Byers, Lauren A.; Wang, Jing; Canales, Jaime Rodriguez; Villalobos, Pamela A.; Uraoka, Naohiro; Mino, Barbara; Behrens, Carmen; Wistuba, Ignacio I.; Han, Richard I; Wanna, Charles A.; Fahrenholtz, Monica; Grande-Allen, Kathryn Jane; Creighton, Chad J.; Gibbons, Don L.

    2016-01-01

    Lung cancer is the leading cause of cancer-related death, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) regulated by many transcription factors, including double-negative feedback loop between the microRNA-200 (miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent EMT promotes malignancy remain largely undefined. While the cell-intrinsic effects of EMT are important for tumor progression, the reciprocal dynamic crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is equally critical in regulating invasion and metastasis. Investigating the collaborative effect of EMT and ECM in the metastatic process reveals increased collagen deposition in metastatic tumor tissues as a direct consequence of amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer cells. Additionally, collagen fibers in metastatic lung tumors exhibit greater linearity and organization as a result of collagen crosslinking by the lysyl oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is directly regulated by miR-200 and ZEB1, respectively, and their upregulation in metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. Functionally, LOXL2, as opposed to LOX, is the principle isoform that crosslinks and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells by crosslinked collagen in the ECM. Our study is the first to validate direct regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism driving tumor metastasis, delineates collagen as a prognostic marker, and identifies LOXL2 as a potential therapeutic target against tumor progression. PMID:27694892

  14. Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2

    PubMed Central

    Cieply, Benjamin; Farris, Joshua; Denvir, James; Ford, Heide; Frisch, Steven M.

    2013-01-01

    Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and by the E-box-binding transcription factors Twist, Snail and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel and suppressed the emergence of CD44highCD24low cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression. PMID:23943797

  15. Immunohistochemical Analysis of P63 Expression in Odontogenic Lesions

    PubMed Central

    Atarbashi Moghadam, Saede; Atarbashi Moghadam, Fazele; Eini, Ebrahim

    2013-01-01

    P63 may have a role in tumorigenesis and cytodifferentiation of odontogenic lesions. We investigated the immunohistochemical expression of P63 in a total of 30 cases of odontogenic cysts and tumors. The percentage of positive cells was calculated in the lining of odontogenic cysts and islands of ameloblastoma. P63 expression was evident in all types of odontogenic lesions. P63 was expressed throughout the lining epithelium of odontogenic keratocyst except surface parakeratinized layer. In addition, calcifying odontogenic cyst showed P63 expression in all layers. In almost all radicular and dentigerous cysts, the basal and parabasal layers were immunoreactive. Peripheral cells of ameloblastoma expressed P63; however, stellate reticulum had weaker immunostaining. No significant difference in P63 expression was observed between studied lesions (P = 0.86). Expression of P63 in odontogenic lesions suggests that this protein is important in differentiation and proliferation of odontogenic epithelial cells. However, it seems that it could not be a useful marker to differentiate between aggressive and nonaggressive lesions. P63 also represents a progenitor or basal cell marker, and it is not expressed in mature differentiated cells. PMID:24350278

  16. Structure and Kinetic Stability of the p63 Tetramerization Domain

    PubMed Central

    Natan, Eviatar; Joerger, Andreas C.

    2012-01-01

    The p53 family of transcription factors—comprising p53, p63 and p73—plays an important role in tumor prevention and development. Essential to their function is the formation of tetramers, allowing cooperative binding to their DNA response elements. We solved crystal structures of the human p63 tetramerization domain, showing that p63 forms a dimer of dimers with D2 symmetry composed of highly intertwined monomers. The primary dimers are formed via an intramolecular β-sheet and hydrophobic helix packing (H1), a hallmark of all p53 family members. Like p73, but unlike p53, p63 requires a second helix (H2) to stabilize the architecture of the tetramer. In order to investigate the impact of structural differences on tetramer stability, we measured the subunit exchange reaction of p53 family homotetramers by nanoflow electrospray mass spectrometry. There were differences in both the kinetics and the pattern of the exchange reaction, with the p53 and p63 tetramers exhibiting much faster exchange kinetics than p73. The structural similarity between p63 and p73 rationalizes previous observations that p63 and p73 form mixed tetramers, and the kinetic data reveal the dissociation of the p73 homotetramers as the rate-limiting step for heterotetramer formation. Differential stability of the tetramers may play an important role in the cross talk between different isoforms and regulation of p53, p63 and p73 function in the cell cycle. PMID:22100306

  17. [Expression of calponin and P63 in human submandibular glands].

    PubMed

    Lu, Yu-he; Gao, Yan

    2007-02-01

    To observe the expression of new myoepithelial cell markers calponin and P63 in human submandibular glands. Calponin and P63 antigen in routinely processed human submandibular gland tissues were immunohistochemically demonstrated by monoclonal antibodies to calponin and P63. Calponin expressed around all acinus and intercalated ducts as linear or punctuate pattern. Positive staining was also noted in peripheral area of some thin striated ducts that connect to intercalated ducts. Subulate or trigonal calponin expression was sometimes seen between the duct dells of striated ducts. P63 expressed mainly in the nucleus of the basal cells of excretory duct. Calponin is an ideal gland. P63 labels mainly the basal cells of excretory duct. marker for myoepithelial cells of human submandibular

  18. A p21-ZEB1 Complex Inhibits Epithelial-Mesenchymal Transition through the MicroRNA 183-96-182 Cluster

    PubMed Central

    Li, Xiao Ling; Hara, Toshifumi; Choi, Youngeun; Subramanian, Murugan; Francis, Princy; Bilke, Sven; Walker, Robert L.; Pineda, Marbin; Zhu, Yuelin; Yang, Yuan; Luo, Ji; Wakefield, Lalage M.; Brabletz, Thomas; Park, Ben Ho; Sharma, Sudha; Chowdhury, Dipanjan; Meltzer, Paul S.

    2014-01-01

    The tumor suppressor p21 acts as a cell cycle inhibitor and has also been shown to regulate gene expression by functioning as a transcription corepressor. Here, we identified p21-regulated microRNAs (miRNAs) by sequencing small RNAs from isogenic p21+/+ and p21−/− cells. Three abundant miRNA clusters, miR-200b-200a-429, miR-200c-141, and miR-183-96-182, were downregulated in p21-deficient cells. Consistent with the known function of the miR-200 family and p21 in inhibition of the epithelial-mesenchymal transition (EMT), we observed EMT upon loss of p21 in multiple model systems. To explore a role of the miR-183-96-182 cluster in EMT, we identified its genome-wide targets and found that miR-183 and miR-96 repressed common targets, including SLUG, ZEB1, ITGB1, and KLF4. Reintroduction of miR-200, miR-183, or miR-96 in p21−/− cells inhibited EMT, cell migration, and invasion. Conversely, antagonizing miR-200 and miR-183-96-182 cluster miRNAs in p21+/+ cells increased invasion and elevated the levels of VIM, ZEB1, and SLUG mRNAs. Furthermore, we found that p21 forms a complex with ZEB1 at the miR-183-96-182 cluster promoter to inhibit transcriptional repression of this cluster by ZEB1, suggesting a reciprocal feedback loop. PMID:24277930

  19. miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM.

    PubMed

    Yue, Sihai; Wang, Lihua; Zhang, Hui; Min, Youhui; Lou, Yongli; Sun, Hongshan; Jiang, Yu; Zhang, Wenjin; Liang, Aming; Guo, Yongkun; Chen, Ping; Lv, Guowei; Wang, Liuxiang; Zong, Qinghua; Li, Yong

    2015-09-01

    Invasion and migration of glioblastoma multiforme (GBM) is a multistep process and an important phenotype that causes this disease to invade surrounding tissues in the brain. Recent studies have highlighted that miRNAs play a pivotal role in controlling GBM cell plasticity. In this report, we used wound healing and transwell assays to identify a novel role of miR-139-5p in inhibition of GBM cell migration and invasion. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-139-5p inhibited expression of ZEB1 and ZEB2, which are master regulators of tumor metastasis. MiR-139-5p specifically interacts with the 3'-UTR regions of ZEB1 and ZEB2, attenuating their expression in GBM cells. To corroborate this finding, we rescued ZEB1 and ZEB2 expression and found partial but significant increases in miR-139-5p-suppressed invasion of GBM cells. The biological relevance of our study was validated by analyzing levels of miR-139-5p in GBM tissue. We found that its expression significantly downregulated compared to normal tissue and shorter overall survival rates in patients with lower miR-139-5p expression. These results confirm that miR-139-5p suppresses GBM migration and invasion and highlight its potential as a biomarker and therapeutic target for treating GBM.

  20. Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness.

    PubMed

    Wu, Kaijie; Ning, Zhongyun; Zeng, Jin; Fan, Jinhai; Zhou, Jiancheng; Zhang, Tingting; Zhang, Linlin; Chen, Yule; Gao, Yang; Wang, Bin; Guo, Peng; Li, Lei; Wang, Xinyang; He, Dalin

    2013-12-01

    Muscle-invasive bladder cancer is associated with a high frequency of metastasis, and fewer therapies substantially prolong survival. Silibinin, a nontoxic natural flavonoid, has been shown to exhibit pleiotropic anticancer effects in many cancer types, including bladder cancer. Our and other previous studies have demonstrated that silibinin induced apoptosis and inhibited proliferation of bladder cancer cells, whether silibinin could suppress bladder cancer metastasis has not been elucidated. In the present study, we utilized a novel highly metastatic T24-L cell model, and found that silibinin treatment not only resulted in the suppression of cell migration and invasion in vitro, but also decreased bladder cancer lung metastasis and prolonged animal survival in vivo. Mechanistically, silibinin could inhibit glycogen synthase kinase-3β (GSK3β) phosphorylation, β-catenin nuclear translocation and transactivation, and ZEB1 gene transcription that subsequently regulated the expression of cytokeratins, vimentin and matrix metalloproteinase-2 (MMP2) to reverse epithelial-mesenchymal transition (EMT). On the other hand, silibinin inhibited ZEB1 expression and then suppressed the properties of cancer stem cells (CSCs), which were evidenced as decreased spheroid colony formation, side population, and the expression of stem cell factor CD44. Overall, this study reveals a novel mechanism for silibinin targeting bladder cancer metastasis, in which inactivation of β-catenin/ZEB1 signaling by silibinin leads to dual-block of EMT and stemness. © 2013.

  1. Upregulation of LncRNA-HIT promotes migration and invasion of non-small cell lung cancer cells by association with ZEB1.

    PubMed

    Jia, Xiaojing; Wang, Zhicheng; Qiu, Ling; Yang, Yanming; Wang, Yunlong; Chen, Zhishen; Liu, Zhongshan; Yu, Lei

    2016-12-01

    Lung cancer is the most common solid tumor and the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. The main reason of lung cancer-related deaths is due to tumor metastasis. But, the mechanisms of NSCLC metastasis remains poorly understood. LncRNAs play pivotal roles in multiple biological processes. LncRNA-HIT (HOXA transcript induced by TGFβ) was recently identified. LncRNA-HIT promotes cell migration, invasion, tumor growth, and metastasis. However, the detailed role of lncRNA-HIT in NSCLC remains unknown. In this study, for the first time, we revealed a novel role of lncRNA-HIT in the migration and invasion of NSCLC cells. The expression of lncRNA-HIT was significantly upregulated in NSCLC tissues and cell lines, and the expression level of lncRNA-HIT correlates with advanced disease stage and predicts unfavorable prognosis of NSCLC patients. Functional assays demonstrated that lncRNA-HIT markedly increased the ability of NSCLC cells to migrate and invade. Furthermore, the molecular mechanism by which lncRNA-HIT affects NSCLC cells was associated with regulation of ZEB1 stability. LncRNA-HIT functions as a prometastasis oncogene by directly associating with ZEB1 to regulate NSCLC. The interaction of lncRNA-HIT and ZEB1 may be a potential target for NSCLC therapy. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. p63 Adjusts Sugar Taste of Epidermal Layers.

    PubMed

    Amelio, Ivano; Melino, Gerry; Candi, Eleonora

    2017-06-01

    p63 is a master regulator of epidermal biology, sustaining stemness and renewal capacity of the proliferating keratinocyte compartment. Hamanaka and Mutlu propose that p63 regulates the keratinocyte proliferation/differentiation switch by affecting the cellular glycolic rate through a direct transcriptional regulation of the metabolic enzyme PFKFB3. This finding sheds light on mechanisms underlining p63 function in the skin and suggests a role for energetic metabolism in epidermal biology. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Structure and kinetic stability of the p63 tetramerization domain.

    PubMed

    Natan, Eviatar; Joerger, Andreas C

    2012-01-20

    The p53 family of transcription factors--comprising p53, p63 and p73--plays an important role in tumor prevention and development. Essential to their function is the formation of tetramers, allowing cooperative binding to their DNA response elements. We solved crystal structures of the human p63 tetramerization domain, showing that p63 forms a dimer of dimers with D₂ symmetry composed of highly intertwined monomers. The primary dimers are formed via an intramolecular β-sheet and hydrophobic helix packing (H1), a hallmark of all p53 family members. Like p73, but unlike p53, p63 requires a second helix (H2) to stabilize the architecture of the tetramer. In order to investigate the impact of structural differences on tetramer stability, we measured the subunit exchange reaction of p53 family homotetramers by nanoflow electrospray mass spectrometry. There were differences in both the kinetics and the pattern of the exchange reaction, with the p53 and p63 tetramers exhibiting much faster exchange kinetics than p73. The structural similarity between p63 and p73 rationalizes previous observations that p63 and p73 form mixed tetramers, and the kinetic data reveal the dissociation of the p73 homotetramers as the rate-limiting step for heterotetramer formation. Differential stability of the tetramers may play an important role in the cross talk between different isoforms and regulation of p53, p63 and p73 function in the cell cycle. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Different regulation of limb development by p63 transcript variants.

    PubMed

    Kawata, Manabu; Taniguchi, Yuki; Mori, Daisuke; Yano, Fumiko; Ohba, Shinsuke; Chung, Ung-Il; Shimogori, Tomomi; Mills, Alea A; Tanaka, Sakae; Saito, Taku

    2017-01-01

    The apical ectodermal ridge (AER), located at the distal end of each limb bud, is a key signaling center which controls outgrowth and patterning of the proximal-distal axis of the limb through secretion of various molecules. Fibroblast growth factors (FGFs), particularly Fgf8 and Fgf4, are representative molecules produced by AER cells, and essential to maintain the AER and cell proliferation in the underlying mesenchyme, meanwhile Jag2-Notch pathway negatively regulates the AER and limb development. p63, a transcription factor of the p53 family, is expressed in the AER and indispensable for limb formation. However, the underlying mechanisms and specific roles of p63 variants are unknown. Here, we quantified the expression of p63 variants in mouse limbs from embryonic day (E) 10.5 to E12.5, and found that ΔNp63γ was strongly expressed in limbs at all stages, while TAp63γ expression was rapidly increased in the later stages. Fluorescence-activated cell sorting analysis of limb bud cells from reporter mouse embryos at E11.5 revealed that all variants were abundantly expressed in AER cells, and their expression was very low in mesenchymal cells. We then generated AER-specific p63 knockout mice by mating mice with a null and a flox allele of p63, and Msx2-Cre mice (Msx2-Cre;p63Δ/fl). Msx2-Cre;p63Δ/fl neonates showed limb malformation that was more obvious in distal elements. Expression of various AER-related genes was decreased in Msx2-Cre;p63Δ/fl limb buds and embryoid bodies formed by p63-knockdown induced pluripotent stem cells. Promoter analyses and chromatin immunoprecipitation assays demonstrated Fgf8 and Fgf4 as transcriptional targets of ΔNp63γ, and Jag2 as that of TAp63γ. Furthermore, TAp63γ overexpression exacerbated the phenotype of Msx2-Cre;p63Δ/fl mice. These data indicate that ΔNp63 and TAp63 control limb development through transcriptional regulation of different target molecules with different roles in the AER. Our findings contribute to

  5. Epithelial to mesenchymal transition-related proteins ZEB1, β-catenin, and β-tubulin-III in idiopathic pulmonary fibrosis.

    PubMed

    Chilosi, Marco; Caliò, Anna; Rossi, Andrea; Gilioli, Eliana; Pedica, Federica; Montagna, Licia; Pedron, Serena; Confalonieri, Marco; Doglioni, Claudio; Ziesche, Rolf; Grubinger, Markus; Mikulits, Wolfgang; Poletti, Venerino

    2017-01-01

    Epithelial to mesenchymal transition has been suggested as a relevant contributor to pulmonary fibrosis, but how and where this complex process is triggered in idiopathic pulmonary fibrosis is not fully understood. Beta-tubulin-III (Tubβ3), ZEB1, and β-catenin are partially under the negative control of miR-200, a family of micro-RNAs playing a major role in epithelial to mesenchymal transition, that are reduced in experimental lung fibrosis and idiopathic pulmonary fibrosis. We wonder whether in situ expression of these proteins is increased in idiopathic pulmonary fibrosis, to better understand the significance of miR-200 feedback loop and epithelial to mesenchymal transition. We investigated the immunohistochemical and immunofluorescent expression and precise location of ZEB1, Tubβ3, and β-catenin in tissue samples from 34 idiopathic pulmonary fibrosis cases and 21 controls (5 normal lungs and 16 other interstitial lung diseases). In 100% idiopathic pulmonary fibrosis samples, the three proteins were concurrently expressed in fibroblastic foci, as well in damaged epithelial cells overlying these lesions and in pericytes within neo-angiogenesis areas. These results were also confirmed by immunofluorescence assay. In controls the abnormal expression of the three proteins was absent or limited. This is the first study that relates concurrent expression of Tubβ3, ZEB1, and β-catenin to abnormal epithelial and myofibroblast differentiation in idiopathic pulmonary fibrosis, providing indirect but robust evidence of miR-200 deregulation and epithelial to mesenchymal transition activation in idiopathic pulmonary fibrosis. The abnormal expression and localization of these proteins in bronchiolar fibro-proliferative lesions are unique for idiopathic pulmonary fibrosis, and might represent a disease-specific marker in challenging lung biopsies.

  6. Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior.

    PubMed

    Huang, Wei-Ting; Kuo, Sung-Hsin; Cheng, Ann-Lii; Lin, Chung-Wu

    2014-08-01

    Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosa-associated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P=0.03), to achieve complete remission (75% vs 43%, P=0.001), and had a better 5-year disease-free survival rate (73% vs 29%, P<0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

  7. p63 in Development and Maintenance of the Prostate Epithelium

    DTIC Science & Technology

    2010-03-01

    R Montironi, E Pikarsky, G Pizov, M A Rubin, H Samaratunga, T Sebo, I A Sesterhenn, RB Shah, S Signoretti, J Simko ,G Thomas , P Troncoso, T Tsuzuki...and Beverly A. Teicher. 2009. 11. Sabbisetti S, Di Napoli A, Seeley A, Amato AM, O’Regan E, Ghebremichael M, Loda M, Signoretti S. p63 Promotes

  8. Molecular Mechanism of MicroRNA-200c Regulating Transforming Growth Factor-β (TGF-β)/SMAD Family Member 3 (SMAD3) Pathway by Targeting Zinc Finger E-Box Binding Homeobox 1 (ZEB1) in Hypospadias in Rats.

    PubMed

    Qian, Chong; Dang, Xiangyang; Wang, Xianglin; Xu, Wei; Pang, Guijian; Chen, Yifeng; Liu, Chengbei

    2016-10-29

    BACKGROUND The aim of this study was to explore effects of microRNA-200c regulating TGF-β/Smad3 pathway by targeting Zeb1 on the occurrence and development of hypospadias and to evaluate the relationship between microRNA-200c and occurrence of hypospadias. MATERIAL AND METHODS Pregnant rats with a gestational age of 12 days were allocated into 2 groups; one received gavage of DEHP-contained soybean oil (1 ml/day, 8 days; Group A) and the other had gavage of normal soybean oil (1 ml/day, 8 days; Group B). Baby rats with hypospadias from Group A were assigned to the model group (n=20) and healthy baby rats from Group B were assigned to the control group (n=20). Real-time quantitative polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot analysis were performed to detect microRNA-200c, Zeb1, TGF-β, and Smad3 mRNA and protein expressions in the model group (n=20) and the control group (n=20). The relationship between microRNA-200c and Zeb1 was detected using a dual-luciferase reporter gene experiment. After the in vitro intervention experiment in fetal rat penises, Western blot was used to detect the expression of Zeb1, TGF-β, and Smad3. RESULTS In the model group, microRNA-200c was expressed at a low level, and microRNA-200c expression in control group was 2.1 times higher than in the model group (P<0.05). When compared with the control group, mRNA expressions, protein expressions, and positive rates of Zeb1, TGF-β, and Smad3 were higher in the model group (all P<0.01). Luciferase gene report determined that Zeb1 is a target gene of microRNA-200c. The in vitro intervention experiment in fetal rat penises found that a high concentration of microRNA-200c inhibited hypospadias occurrence by suppressing the expression of Zeb1, TGF-β, and Smad3. CONCLUSIONS MicroRNA-200c was expressed in hypospadias penis tissues at low levels and was negatively correlated with Zeb1 expression. MicroRNA-200c up-regulated Zeb1 expression to regulate the TGF

  9. Molecular Mechanism of MicroRNA-200c Regulating Transforming Growth Factor-β (TGF-β)/SMAD Family Member 3 (SMAD3) Pathway by Targeting Zinc Finger E-Box Binding Homeobox 1 (ZEB1) in Hypospadias in Rats

    PubMed Central

    Qian, Chong; Dang, Xiangyang; Wang, Xianglin; Xu, Wei; Pang, Guijian; Chen, Yifeng; Liu, Chengbei

    2016-01-01

    Background The aim of this study was to explore effects of microRNA-200c regulating TGF-β/Smad3 pathway by targeting Zeb1 on the occurrence and development of hypospadias and to evaluate the relationship between microRNA-200c and occurrence of hypospadias. Material/Methods Pregnant rats with a gestational age of 12 days were allocated into 2 groups; one received gavage of DEHP-contained soybean oil (1 ml/day, 8 days; Group A) and the other had gavage of normal soybean oil (1 ml/day, 8 days; Group B). Baby rats with hypospadias from Group A were assigned to the model group (n=20) and healthy baby rats from Group B were assigned to the control group (n=20). Real-time quantitative polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot analysis were performed to detect microRNA-200c, Zeb1, TGF-β, and Smad3 mRNA and protein expressions in the model group (n=20) and the control group (n=20). The relationship between microRNA-200c and Zeb1 was detected using a dual-luciferase reporter gene experiment. After the in vitro intervention experiment in fetal rat penises, Western blot was used to detect the expression of Zeb1, TGF-β, and Smad3. Results In the model group, microRNA-200c was expressed at a low level, and microRNA-200c expression in control group was 2.1 times higher than in the model group (P<0.05). When compared with the control group, mRNA expressions, protein expressions, and positive rates of Zeb1, TGF-β, and Smad3 were higher in the model group (all P<0.01). Luciferase gene report determined that Zeb1 is a target gene of microRNA-200c. The in vitro intervention experiment in fetal rat penises found that a high concentration of microRNA-200c inhibited hypospadias occurrence by suppressing the expression of Zeb1, TGF-β, and Smad3. Conclusions MicroRNA-200c was expressed in hypospadias penis tissues at low levels and was negatively correlated with Zeb1 expression. MicroRNA-200c up-regulated Zeb1 expression to regulate the TGF-β/Smad3

  10. Rg1 inhibits high glucose-induced mesenchymal activation and fibrosis via regulating miR-2113/RP11-982M15.8/Zeb1 pathway.

    PubMed

    Xue, Li-Ping; Fu, Xiao-Lin; Hu, Min; Zhang, Li-Wei; Li, Ya-Di; Peng, Ya-Li; Ding, Peng

    2018-07-02

    Recent study has showed that Ginsenoside Rg1, the mian active compound of Panax ginseng, could ameliorate oxidative stress and myocardial apoptosis in diabetes mellitus. However, the roles and mechanisms of Rg1 in proliferative diabetic retinopathy (PDR) are still unclear. In the present study, we aimed to investigate the effects of Rg1 on mesenchymal activation of high-glucose (HG) cultured müller cells. High glucose conditions up-regulate MMP-2, MMP-9 and down-regulate TIMP-2, and promote mesenchymal activation in Müller cells. And Rg1 inhibits the HG-induced mesenchymal activation and HG-increased MMP-2 and MMP-9 and HG-decreased TIMP-2 in Müller cells. HG up-regulates Zeb1 and lncRNA RP11-982M15.8, and down-regulates miR-2113, and Rg1 inhibits these effects of HG. Both inhibition of miR-2113 and over-expression of RP11-982M15.8 significantly restored the HG induced mesenchymal activasion. Taken together, our findings suggested that Rg1 inhibited HG-induced mesenchymal activation and fibrosis via regulating miR-2113/RP11-982M15.8/Zeb1 pathway. Copyright © 2018. Published by Elsevier Inc.

  11. SNHG16/miR-216-5p/ZEB1 signal pathway contributes to the tumorigenesis of cervical cancer cells.

    PubMed

    Zhu, Hong; Zeng, Yan; Zhou, Chen-Chen; Ye, Weiping

    2018-01-01

    Long non-coding RNAs (lncRNAs) have been confirmed as crucial regulators in tumorgenesis. Small nucleolar RNA host gene 16 (SNHG16) has been recently uncovered to be a potential oncogene in several types of cancers. However, its expression level and potential role in cervical cancer remain uncertain. In our research, we assessed the expression level of SNHG16 in clinical cervical cancer tissues and cells. We made use of functional assays to determine the biological effects of SNHG16 on cell proliferation and migration of cervical cancer. By employing the bioinformatics analysis tools, we revealed that miR-216-5p could interact with SNHG16 and there existed a negative correlation between the expression levels of miR-216-5p and SNHG16 in cervical cancer specimens. Furthermore, RIP assay, RNA pulldown system and dual luciferase reporter assays confirmed that SNHG16 directly targeted miR-216-5p by harboring the binding sites of microRNA in the SNHG16 sequence. Additionally, bioinformatics analysis provided an evidence that ZEB1 was a potential target of miR-216-5p. Collectively, it was suggested that SNHG16 could serve as an oncogene that promoted tumor progression by acting as an endogenous 'sponge' to regulate miR-216A-5p/ZEB1. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR-196b-5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease.

    PubMed

    Porretti, Juliana; Dalton, Guillermo N; Massillo, Cintia; Scalise, Georgina D; Farré, Paula L; Elble, Randolph; Gerez, Esther N; Accialini, Paula; Cabanillas, Ana M; Gardner, Kevin; De Luca, Paola; De Siervi, Adriana

    2018-03-14

    Prostate cancer (PCa) is the most common cancer among men. Metabolic syndrome (MeS) is associated with increased PCa aggressiveness and recurrence. Previously, we proposed C-terminal binding protein 1 (CTBP1), a transcriptional co-repressor, as a molecular link between these two conditions. Notably, CTBP1 depletion decreased PCa growth in MeS mice. The aim of this study was to investigate the molecular mechanisms that explain the link between MeS and PCa mediated by CTBP1. We found that CTBP1 repressed chloride channel accessory 2 (CLCA2) expression in prostate xenografts developed in MeS animals. CTBP1 bound to CLCA2 promoter and repressed its transcription and promoter activity in PCa cell lines. Furthermore, we found that CTBP1 formed a repressor complex with ZEB1, EP300 and HDACs that modulates the CLCA2 promoter activity. CLCA2 promoted PCa cell adhesion inhibiting epithelial-mesenchymal transition (EMT) and activating CTNNB1 together with epithelial marker (CDH1) induction, and mesenchymal markers (SNAI2 and TWIST1) repression. Moreover, CLCA2 depletion in PCa cells injected subcutaneously in MeS mice increased the circulating tumor cells foci compared to control. A microRNA (miRNA) expression microarray from PCa xenografts developed in MeS mice, showed 21 miRNAs modulated by CTBP1 involved in angiogenesis, extracellular matrix organization, focal adhesion and adherents junctions, among others. We found that miR-196b-5p directly targets CLCA2 by cloning CLCA2 3'UTR and performing reporter assays. Altogether, we identified a new molecular mechanism to explain PCa and MeS link based on CLCA2 repression by CTBP1 and miR-196b-5p molecules that might act as key factors in the progression onset of this disease. © 2018 UICC.

  13. p63 supports aerobic respiration through hexokinase II

    PubMed Central

    Viticchiè, Guiditta; Agostini, Massimiliano; Lena, Anna Maria; Mancini, Mara; Zhou, Huiqing; Zolla, Lello; Dinsdale, David; Saintigny, Gaelle; Melino, Gerry; Candi, Eleonora

    2015-01-01

    Short p63 isoform, ΔNp63, is crucial for epidermis formation, and it plays a pivotal role in controlling the turnover of basal keratinocytes by regulating the expression of a subset of genes involved in cell cycle and cell adhesion programs. The glycolytic enzyme hexokinase 2 (HK2) represents the first step of glucose utilization in cells. The family of HKs has four isoforms that differ mainly in their tissue and subcellular distribution. The preferential mitochondrial localization of HK2 at voltage-dependent anion channels provides access to ATP generated by oxidative phosphorylation and generates an ADP/ATP recycling mechanism to maintain high respiration rates and low electron leak. Here, we report that ΔNp63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show ΔNp63-dependent regulation of HK2 expression, and we use ChIP, validated by p63-Chip sequencing genomewide profiling analysis, and luciferase assays to demonstrate the presence of one p63-specific responsive element within the 15th intronic region of the HK2 gene, providing evidence of a direct interaction. Our data support the notion of ΔNp63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The ΔNp63–HK2 axis is also present in epithelial cancer cells, suggesting that ΔNp63 could participate in cancer metabolic reprogramming. PMID:26324887

  14. Dendrosomal curcumin inhibits metastatic potential of human SW480 colon cancer cells through Down-regulation of Claudin1, Zeb1 and Hef1-1 gene expression.

    PubMed

    Dehghan Esmatabadi, Mohammad Javad; Farhangi, Baharak; Safari, Zahra; Kazerooni, Hanif; Shirzad, Hadi; Zolghadr, Fatemeh; Sadeghizadeh, Majid

    2015-01-01

    Colon cancer is one of the leading causes of cancer-associated death worldwide. The prognosis for advanced colorectal cancers remains dismal, mainly due to the propensity for metastatic progression. Accordingly, there is a need for effective anti-metastasis therapeutic agents. Since a great body of research has indicated anticancer effects for curcumin, we investigated the effects of dendrosomal curcumin (DNC) on cellular migration and adhesion of human SW480 cells and possible molecular mechanisms involved. Different methods were applied in this study including MTT, Scratch and adhesion assays as well as real-time PCR and transwell chamber assays. Based on the results obtained, DNC inhibits metastasis by decreasing Hef 1, Zeb 1 and Claudin 1 mRNA levels and can reduce SW480 cell proliferation with IC50values of 15.9, 11.6 and 7.64 μM at 24, 48 and 72 h post-treatment. Thus it might be considered as a safe formulation for therapeutic purpose in colorectal cancer cases.

  15. Family matters: sibling rivalry and bonding between p53 and p63 in cancer.

    PubMed

    Romano, Rose-Anne; Sinha, Satrajit

    2014-04-01

    The p53 family (p53, p63 and p73) is intimately linked with an overwhelming number of cellular processes during normal physiological as well as pathological conditions including cancer. The fact that these proteins are expressed in myriad isoforms, each with unique biochemical properties and distinct effects on tumorigenesis, complicates their study. A case in point is Squamous Cell Carcinoma (SCC) where p53 is often mutated and the ΔNp63 isoform is overexpressed. Given that p53 and p63 can hetero-dimerize, bind to quite similar DNA elements and share common co-factors, any alterations in their individual expression levels, activity and/or mutation can severely disrupt the family equilibrium. The burgeoning genomics data sets and new additions to the experimental toolbox are offering crucial insights into the complex role of the p53 family in SCC, but more mechanistic studies are needed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. ZNF750 is a p63 Target Gene that Induces KLF4 to Drive Terminal Epidermal Differentiation

    PubMed Central

    Sen, George L.; Boxer, Lisa D.; Webster, Dan E.; Bussat, Rose T.; Qu, Kun; Zarnegar, Brian J.; Johnston, Danielle; Siprashvili, Zurab; Khavari, Paul A.

    2012-01-01

    SUMMARY Disrupted epidermal differentiation characterizes numerous diseases that impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for ZNF750 in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation. ZNF750 binds to KLF4 at multiple sites flanking the transcriptional start site and controls its expression. ZNF750 thus directly links a tissue-specifying factor, p63, to an effector of terminal differentiation, KLF4, and represents a potential future target for disorders of this process. PMID:22364861

  17. A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR-574-5p-ZEB1 axis in triple negative breast cancer.

    PubMed

    Wang, Po-Shun; Chou, Cheng-Han; Lin, Cheng-Han; Yao, Yun-Chin; Cheng, Hui-Chuan; Li, Hao-Yi; Chuang, Yu-Chung; Yang, Chia-Ning; Ger, Luo-Ping; Chen, Yu-Chia; Lin, Forn-Chia; Shen, Tang-Long; Hsiao, Michael; Lu, Pei-Jung

    2018-05-14

    Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.

  18. Immunohistochemical panel to characterize canine prostate carcinomas according to aberrant p63 expression.

    PubMed

    Fonseca-Alves, Carlos Eduardo; Kobayashi, Priscila Emiko; Rivera Calderón, Luis Gabriel; Felisbino, Sérgio Luis; Rinaldi, Jaqueline de Carvalho; Drigo, Sandra Aparecida; Rogatto, Silvia Regina; Laufer-Amorim, Renée

    2018-01-01

    An unusual variant of prostate adenocarcinoma (PC) expressing nuclear p63 in secretory cells instead of the typical basal expression has been reported in men. Nevertheless, the biological behavior and clinical significance of this phenomenon is unknown. In dogs, this unusual PC subtype has not been described. In this study, p63 immunoexpression was investigated in 90 canine PCs and 20 normal prostate tissues (NT). The p63 expression pattern in luminal or basal cells was confirmed in a selected group of 26 PCs and 20 NT by immunohistochemistry and/or Western blotting assays. Eleven canine PC samples aberrantly expressing p63 (p63+) in secretory cells were compared with 15 p63 negative (p63-) cases in the context of several molecular markers (high molecular weight cytokeratin-HMWC, CK8/18, CK5, AR, PSA, chromogranin, NKX3.1, PTEN, AKT and C-MYC). P63+ samples were positive for CK5, HMWC and CK8/18 and negative for PSA, NKX3.1, PTEN and chromogranin. Five p63+ PCs were negative for AR, and the remaining six samples had low AR expression. In contrast, p63- PC showed AR and PSA positive expression in all 15 samples. Only five p63- PCs were positive for CK5. Both p63+ and p63- PC samples showed higher cytoplasmic AKT expression and nuclear C-MYC staining in comparison with normal tissues. Metastatic (N = 12) and non-metastatic (N = 14) PCs showed similar immunoexpression for all markers tested. In contrast to human PC, canine PC aberrantly expressing p63 showed higher expression levels of HMWC and CK5 and lower levels of NKX3.1. Canine p63+ PC is a very rare PC group showing a distinct phenotype compared to typical canine PC, including AR and PSA negative expression. Although in a limited number of cases, p63 expression was not associated with metastasis in canine PC, and cytoplasmic p63 expression was observed in animals with shorter survival time, similar to human PC cases.

  19. ΔN-P63α and TA-P63α exhibit intrinsic differences in transactivation specificities that depend on distinct features of DNA target sites

    PubMed Central

    Foggetti, Giorgia; Raimondi, Ivan; Campomenosi, Paola; Menichini, Paola

    2014-01-01

    TP63 is a member of the TP53 gene family that encodes for up to ten different TA and ΔN isoforms through alternative promoter usage and alternative splicing. Besides being a master regulator of gene expression for squamous epithelial proliferation, differentiation and maintenance, P63, through differential expression of its isoforms, plays important roles in tumorigenesis. All P63 isoforms share an immunoglobulin-like folded DNA binding domain responsible for binding to sequence-specific response elements (REs), whose overall consensus sequence is similar to that of the canonical p53 RE. Using a defined assay in yeast, where P63 isoforms and RE sequences are the only variables, and gene expression assays in human cell lines, we demonstrated that human TA- and ΔN-P63α proteins exhibited differences in transactivation specificity not observed with the corresponding P73 or P53 protein isoforms. These differences 1) were dependent on specific features of the RE sequence, 2) could be related to intrinsic differences in their oligomeric state and cooperative DNA binding, and 3) appeared to be conserved in evolution. Since genotoxic stress can change relative ratio of TA- and ΔN-P63α protein levels, the different transactivation specificity of each P63 isoform could potentially influence cellular responses to specific stresses. PMID:24926492

  20. Role of the p53 Tumor Suppressor Homolog, p63, in Breast Cancer

    DTIC Science & Technology

    2007-05-01

    paradigms. To understand the mechanisms of transcriptional regulation by p63, we analyzed p63 DNA-binding sites in vivo across the entire human ...biological function in human cells. Molecular Cell 24, 593-602 (*these authors contributed equally). Suh EK*, YANG A*, Kettenbach A*, Bamberger C... human genes. Results and details of these experiments are described in Yang et al., (2006), “Relationships between p63 binding, DNA sequence

  1. The Use of P63 Immunohistochemistry for the Identification of Squamous Cell Carcinoma of the Lung

    PubMed Central

    Conde, Esther; Angulo, Bárbara; Redondo, Pilar; Toldos, Oscar; García-García, Elena; Suárez-Gauthier, Ana; Rubio-Viqueira, Belén; Marrón, Carmen; García-Luján, Ricardo; Sánchez-Céspedes, Montse; López-Encuentra, Angel; Paz-Ares, Luis; López-Ríos, Fernando

    2010-01-01

    Introduction While some targeted agents should not be used in squamous cell carcinomas (SCCs), other agents might preferably target SCCs. In a previous microarray study, one of the top differentially expressed genes between adenocarcinomas (ACs) and SCCs is P63. It is a well-known marker of squamous differentiation, but surprisingly, its expression is not widely used for this purpose. Our goals in this study were (1) to further confirm our microarray data, (2) to analize the value of P63 immunohistochemistry (IHC) in reducing the number of large cell carcinoma (LCC) diagnoses in surgical specimens, and (3) to investigate the potential of P63 IHC to minimize the proportion of “carcinoma NOS (not otherwise specified)” in a prospective series of small tumor samples. Methods With these goals in mind, we studied (1) a tissue-microarray comprising 33 ACs and 99 SCCs on which we performed P63 IHC, (2) a series of 20 surgically resected LCCs studied for P63 and TTF-1 IHC, and (3) a prospective cohort of 66 small thoracic samples, including 32 carcinoma NOS, that were further classified by the result of P63 and TTF-1 IHC. Results The results in the three independent cohorts were as follows: (1) P63 IHC was differentially expressed in SCCs when compared to ACs (p<0.0001); (2) half of the 20 (50%) LCCs were positive for P63 and were reclassified as SCCs; and (3) all P63 positive cases (34%) were diagnosed as SCCs. Conclusions P63 IHC is useful for the identification of lung SCCs. PMID:20808915

  2. P63 EXPRESSION LEVELS IN SIDE POPULATION AND LOW LIGHT SCATTERING OCULAR SURFACE EPITHELIAL CELLS

    PubMed Central

    Epstein, Seth P; Wolosin, J. Mario; Asbell, Penny A

    2005-01-01

    Purpose Because stem cells exhibit high self-renewal capacity, slow cycling, and high proliferative potential, and one of many markers postulated for epithelial stem cells, p63, is challenged by widespread expression within stem cell–free regions, we examined p63 expression in these stem cell–associated cohorts compared with their controls. Methods Rabbit limbocorneal cryosections, cytospun cell-sorted (by fluorescence-activated cell sorter) side population (SP) and low side scatter (LSSC) cells, and limbal epithelial cells over feeders were stained for p63 by indirect immunofluorescence. Clones were fixed and stained daily for 7 days. Image analysis measured p63 intensity, plotting it against colony size. Results All basal limbal cells were positive for p63, yet only 5% to 7% expressed high p63 intensities, 40% intermediate, and the majority low. Side population cells were less than 1% of total cells. The average intensity of SP staining was three times that of controls. Subpopulations displaying stemlike features exhibited highest p63 expression. Replication rates of isolated cells differed. Day 5 colonies contained 256 (16 hours/cycle) to two (96 hours/cycle) cells. Whereas all cells were positive for p63, intensity in slow-cycling cells was three to four times that in rapidly proliferating congeners. Increased cell doublings did not decrease fluorescence. Conclusions Results suggest that p63 concentration is maximal in stem cells and decreases with differentiation. High p63 levels seem to correlate with cells of the SP and LSSC phenotypes, indicating high cell stemness. With identification of stem cells, further studies can elucidate their use in supporting ocular surface health. PMID:17057802

  3. p63 Silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte-like cells.

    PubMed

    Patel, Vivekkumar; Singh, Vivek P; Pinnamaneni, Jaya Pratap; Sanagasetti, Deepthi; Olive, Jacqueline; Mathison, Megumi; Cooney, Austin; Flores, Elsa R; Crystal, Ronald G; Yang, Jianchang; Rosengart, Todd K

    2018-04-13

    Reprogramming of fibroblasts into induced cardiomyocytes represents a potential new therapy for heart failure. We hypothesized that inactivation of p63, a p53 gene family member, may help overcome human cell resistance to reprogramming. p63 Knockout ( -/- ) and knockdown murine embryonic fibroblasts (MEFs), p63 -/- adult murine cardiac fibroblasts, and human cardiac fibroblasts were assessed for cardiomyocyte-specific feature changes, with or without treatment by the cardiac transcription factors Hand2-Myocardin (HM). Flow cytometry revealed that a significantly greater number of p63 -/- MEFs expressed the cardiac-specific marker cardiac troponin T (cTnT) in culture compared with wild-type (WT) cells (38% ± 11% vs 0.9% ± 0.9%, P < .05). HM treatment of p63 -/- MEFs increased cTnT expression to 74% ± 3% of cells but did not induce cTnT expression in wild-type murine embryonic fibroblasts. shRNA-mediated p63 knockdown likewise yielded a 20-fold increase in cTnT microRNA expression compared with untreated MEFs. Adult murine cardiac fibroblasts demonstrated a 200-fold increase in cTnT gene expression after inducible p63 knockout and expressed sarcomeric α-actinin as well as cTnT. These p63 -/- adult cardiac fibroblasts exhibited calcium transients and electrically stimulated contractions when co-cultured with neonatal rat cardiomyocytes and treated with HM. Increased expression of cTnT and other marker genes was also observed in p63 knockdown human cardiac fibroblasts procured from patients undergoing procedures for heart failure. Downregulation of p63 facilitates direct cardiac cellular reprogramming and may help overcome the resistance of human cells to reprogramming. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  4. Circulating miR-200c is up-regulated in paediatric patients with familial hypercholesterolaemia and correlates with miR-33a/b levels: implication of a ZEB1-dependent mechanism.

    PubMed

    D'Agostino, Marco; Martino, Francesco; Sileno, Sara; Barillà, Francesco; Beji, Sara; Marchetti, Lorenza; Gangi, Fabio Maria; Persico, Luca; Picozza, Mario; Montali, Anna; Martino, Eliana; Zanoni, Cristina; Avitabile, Daniele; Parrotto, Sandro; Capogrossi, Maurizio Colognesi; Magenta, Alessandra

    2017-09-15

    Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating miR-33a/b expression levels were up-regulated in children with familial hypercholesterolaemia (FH). miR-33a/b control cholesterol homoeostasis and recently miR-33b has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the miR-200 family. Our previous studies showed that the ROS-dependent miR-200c up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating miR-200c was induced in FH children, and whether a correlation existed with miR-33a/b Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and miR-200c levels were measured. We found that miR-200c was up-regulated in FH compared with HS (4.00 ± 0.48-fold increase, P <0.05) and exhibited a positive correlation with miR-33a/b. miR-200c did not correlate with plasma lipids, but correlated with C-reactive protein (CRP) plasma levels and glycaemia (GLI). Ordinary least squares (OLS) regression analysis revealed that miR-200c was significantly affected by GLI and by miR-33a ( P <0.01; P <0.001 respectively). Moreover, we found that miR-33 overexpression, in different cell lines, decreased ZEB1 expression and up-regulated both the intracellular and the extracellular miR-200c expression levels. In conclusion, circulating miR-200c is up-regulated in FH, probably due to oxidative stress and inflammation and via a miR-33a/b -ZEB1-dependent mechanism. The present study could provide the first evidence to point to the use of miR-33a/b and miR-200c , as early biomarkers of CVD, in paediatric FH. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  5. p63 protein is essential for the embryonic development of vibrissae and teeth

    SciTech Connect

    Rufini, Alessandro; Weil, Miguel; McKeon, Frank

    2006-02-17

    Development of skin appendages strongly depends on epithelial-mesenchymal interactions. One of the genes involved in this process is p63, a member of the p53 family of transcription factors, essential for ectodermal development, as elucidated by the phenotype of p63 knock-out mice. Surprisingly, no information on p63 expression in tooth and hair is yet available. Here, we show p63 expression during teeth and vibrissae morphogenesis in mouse embryos and we also show a correlation with the expression patterns of the epithelial marker keratin 5 and the proliferation marker Ki67. Our results show that p63 colocalizes with both K5 and Ki67 inmore » the epithelium of developing vibrissae, while in teeth p63 is expressed, together with K5, in the undifferentiated ectoderm (enamel organ), and in ameloblasts, a subpopulation of differentiated ectodermal cells. Moreover, p63 expression in tooth seems not to be fully colocalized with nuclear Ki67 expression.« less

  6. Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway.

    PubMed

    Song, Yang; Chen, Yong; Li, Yunqian; Lyu, Xiaoyan; Cui, Jiayue; Cheng, Ye; Zhao, Liyan; Zhao, Gang

    2018-01-23

    Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis is still relatively poor. The invasive property of GBM is the major cause of death in patients. Epithelial-to-mesenchymal transition-like process (EMT-like process) is considered to play an important role in the invasive property. Metformin has been reported as a regulator of EMT-like process. In this study, we confirmed that metformin inhibited TGF-β1-induced EMT-like process and EMT-associated migration and invasion in LN18 and U87 GBM cells. Our results also showed that metformin significantly suppressed self-renewal capacity of glioblastoma stem cells (GSCs), and expression of stem cell markers Bmi1, Sox2 and Musashi1, indicating that metformin can inhibit cancer stem-like properties of GBM cells. We further clarified that metformin specifically inhibited TGF-β1 activated AKT, the downstream molecular mTOR and the leading transcription factor ZEB1. Taken together, our data demonstrate that metformin inhibits TGF-β1-induced EMT-like process and cancer stem-like properties in GBM cells via AKT/mTOR/ZEB1 pathway and provide evidence of metformin for further clinical investigation targeted GBM.

  7. Immunoexpression of P63 and SOX2 in triple-negative breast cancers, Indonesia

    PubMed Central

    Kamarlis, Reno K; Lubis, Muhammad ND; Hernowo, Bethy S; Kar, Azmi S

    2018-01-01

    Background: Using immunohistochemical stains to target specific breast cancer markers has become indispensable for evaluation of small diagnostic tissue specimens, and therefore novel marker cocktails for specific breast cancers are required. This study was conducted to assess the immunoexpression of P63 and SOX2 in triple negative breast cancer (TNBC), and to evaluate the predictive diagnostic value of these markers for specific types of TNBC. Methods: Histological slides and paraffin blocks of TNBC cases were collected from Dr. Hasan Sadikin Hospital, Bandung, Indonesia from 5-years period (2011-2015). Each histological slide was subjected to immunohistochemical staining for P63 (nucleus and cytoplasm) and SOX2 (nucleus), with specific primer antibodies. Immunoexpression of P63 and SOX2 was evaluated using immunoreactivity scoring. Associations between P63 and SOX2 immunoexpression and TNBC types were assessed using Mann Whitney tests. In addition, the predictive diagnostic values of these markers were assessed. Results: Forty TNBC histological slides were included, and 23 (57.5%) were Basal-like type TNBC and 17 (42.5%) were Non basal-like type TNBC. Immunoexpression of P63 nucleus and SOX2 was not different between types of TNBC. However, immunoexpression of P63 in the cytoplasm in Basal-like type TNBC was significantly higher than in Non basal-like type TNBC ( p=0.021). Predictor diagnostic value analysis suggested that immunoexpression of P63 in cytoplasm had 56.5% sensitivity and 70.6% specificity for diagnosing Basal-like type TNBC, with area under curve of 0.64.    Conclusions: Immunoexpression of P63 in the cytoplasm has a relatively weak diagnostic value to discriminate Basal-like and Non basal-like types of TNBC. PMID:29527291

  8. Evaluation of ABCG2 and p63 expression in canine cornea and cultivated corneal epithelial cells.

    PubMed

    Morita, Maresuke; Fujita, Naoki; Takahashi, Ayaka; Nam, Eun Ryel; Yui, Sho; Chung, Cheng Shu; Kawahara, Naoya; Lin, Hsing Yi; Tsuzuki, Keiko; Nakagawa, Takayuki; Nishimura, Ryohei

    2015-01-01

    To examine the expressions of ABCG2 and p63 in canine corneal epithelia and to evaluate their significance in corneal regeneration. Canine corneal and limbal epithelial cells were obtained from five healthy beagle dogs. We analyzed the morphological properties of cultivated limbal and corneal epithelial cells. We compared the expressions of ABCG2 and p63 in the limbus and central cornea by immunohistochemistry and real-time quantitative PCR. We analyzed the expression of these markers in cultivated cells by immunocytochemistry and real-time quantitative PCR. The limbal epithelial cells were smaller and proliferated more rapidly than the corneal epithelial cells in primary cultures. The corneal cells failed to be subcultured, whereas the limbal cells could be subcultured with increasing cell size. ABCG2 was localized in the basal layer of the limbal epithelium, and p63 was widely detected in the entire corneal epithelia. ABCG2 expression was significantly higher, and p63 was slightly higher in the limbus compared with the central cornea. ABCG2 was detected only in limbal cells in primary culture, not in corneal cells or passaged limbal cells. p63 was detected in both limbal and corneal cells and decreased gradually in the limbal cells with the cell passages. ABCG2 was localized in canine limbal epithelial cells, and p63 was widely expressed in canine corneal epithelia. ABCG2 and p63 could prove to be useful markers in dogs for putative corneal epithelial stem cells and for corneal epithelial cell proliferation, respectively. © 2014 American College of Veterinary Ophthalmologists.

  9. Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant.

    PubMed

    Bellomaria, A; Barbato, Gaetano; Melino, G; Paci, M; Melino, Sonia

    2010-09-15

    The E3 ubiquitin ligase Itch mediates the degradation of the p63 protein. Itch contains four WW domains which are pivotal for the substrate recognition process. Indeed, this domain is implicated in several signalling complexes crucially involved in human diseases including Muscular Dystrophy, Alzheimer's Disease and Huntington Disease. WW domains are highly compact protein-protein binding modules that interact with short proline-rich sequences. The four WW domains present in Itch belong to the Group I type, which binds polypeptides with a PY motif characterized by a PP xY consensus sequence, where x can be any residue. Accordingly, the Itch-p63 interaction results from a direct binding of Itch-WW2 domain with the PY motif of p63. Here, we report a structural analysis of the Itch-p63 interaction by fluorescence, CD and NMR spectroscopy. Indeed, we studied the in vitro interaction between Itch-WW2 domain and p63(534-551), an 18-mer peptide encompassing a fragment of the p63 protein including the PY motif. In addition, we evaluated the conformation and the interaction with Itch-WW2 of a site specific mutant of p63, I549T, that has been reported in both Hay-Wells syndrome and Rapp-Hodgkin syndrome. Based on our results, we propose an extended PP xY motif for the Itch recognition motif (P-P-P-Y-x(4)-[ST]-[ILV]), which includes these C-terminal residues to the PP xY motif.

  10. Anti-invasive effect of Cyclamen pseudibericum extract on A549 non-small cell lung carcinoma cells via inhibition of ZEB1 mediated by miR-200c.

    PubMed

    Karagur, Ege Riza; Ozay, Cennet; Mammadov, Ramazan; Akca, Hakan

    2018-06-01

    Scientists are increasingly focusing attention on natural products of plant origin for use as agents in cancer protection and treatment. Cyclamen L. tuber extracts contain saponin glycosides that have been shown to have anti-cancer and other biological activities. The epithelial-to-mesenchymal transition (EMT) is thought to enhance malignant tumour progress. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is an important inducer of EMT in different human tumours and has recently been shown to boost invasion by tumour cells. In this study, we investigated the effects of endemic Cyclamen pseudibericum (CP) saponin-rich tuber extract on the capacity of non-small cell lung cancer line A549 cells to proliferate, invade and migrate and also examined the expression levels of several invasion-migration-related microRNAs (miRNAs) to identify those which directly targeted ZEB1. The cytotoxicity effect of the CP extract on the A549 cancer cells was determined by the luminometric method. The half-minimal (50%) inhibitory concentration dose in the A549 cells was determined to be 41.64 ± 2.35 µg/mL. Using the Matrigel invasion chamber system and the wound healing assay we observed that the CP extract suppressed the invasion and migration capacity of A549 cells, respectively. The expression of miRNAs in A549 cells was evaluated by real-time PCR. Our data showed that overexpression of miRNA miR-200c hindered the EMT by increasing the expression of E-cadherin and decreasing the expression of both N-cadherin and vimentin through the direct targeting of ZEB1. These findings suggest that the saponin-rich tuber extract of CP may have considerable anti-cancer properties in lung cancer. Further studies are required to examine in detail the molecular-based mechanism involved in the EMT process of the extract along with isolation and identification of active saponin components.

  11. A mutation of the p63 gene in non‐syndromic cleft lip

    PubMed Central

    Leoyklang, P; Siriwan, P; Shotelersuk, V

    2006-01-01

    Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non‐syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non‐syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non‐synonymous changes: S90L, R313G, and D564H. The R313G was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. Our data strongly suggest, for the first time, a causative role of a heterozygous mutation in the p63 gene in non‐syndromic CL/P, highlighting the wide phenotypic spectrum of p63 gene mutations. PMID:16740912

  12. SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

    PubMed Central

    Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M.; Pedamallu, Chandra Sekhar; DeLuca, David S.; Brooks, Angela N.; Wang, Su; Que, Jianwen; Rustgi, Anil K.; Wong, Kwok-kin; Ligon, Keith L.; Liu, X. Shirley; Marto, Jarrod A.; Meyerson, Matthew; Bass, Adam J.

    2014-01-01

    The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology. PMID:24590290

  13. SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

    PubMed

    Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M; Pedamallu, Chandra Sekhar; DeLuca, David S; Brooks, Angela N; Wang, Su; Que, Jianwen; Rustgi, Anil K; Wong, Kwok-kin; Ligon, Keith L; Liu, X Shirley; Marto, Jarrod A; Meyerson, Matthew; Bass, Adam J

    2014-04-01

    The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

  14. Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63

    PubMed Central

    Testoni, Barbara; Mantovani, Roberto

    2006-01-01

    p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon–Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly–Ectodermal dysplasia–Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G2/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and ΔNp63α are associated in vivo and a conserved α-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. ΔNp63α, but not the AEC mutants repress CCAAT-dependent transcription of G2/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G2/M promoters, while normally present on 14-3-3σ, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G2/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations. PMID:16473849

  15. Recognition mechanism of p63 by the E3 ligase Itch

    PubMed Central

    Bellomaria, Alessia; Barbato, Gaetano; Melino, Gerry; Paci, Maurizio; Melino, Sonia

    2012-01-01

    The HECT-containing E3 ubiquitin ligase Itch mediates the degradation of several proteins, including p63 and p73, involved in cell specification and fate. Itch contains four WW domains, which are essential for recognition on the target substrate, which contains a short proline-rich sequence. Several signaling complexes containing these domains have been associated with human diseases such as muscular dystrophy, Alzheimer’s or Huntington’s diseases. To gain further insight into the structural determinants of the Itch-WW2 domain, we investigated its interaction with p63. We assigned, by 3D heteronuclear NMR experiments, the backbone and side chains of the uniformly ¹³C-¹⁵N-labeled Itch-WW2. In vitro interaction of Itch-WW2 domain with p63 was studied using its interactive p63 peptide, pep63. Pep63 is an 18-mer peptide corresponding to the region from 534–551 residue of p63, encompassing the PPxY motif that interacts with the Itch-WW domains, and we identified the residues involved in this molecular recognition. Moreover, here, a strategy of stabilization of the conformation of the PPxY peptide has been adopted, increasing the WW-ligand binding. We demonstrated that cyclization of pep63 leads to an increase of both the biological stability of the peptide and of the WW-ligand complex. Stable metal-binding complexes of the pep63 have been also obtained, and localized oxidative damage on Itch-WW2 domain has been induced, demonstrating the possibility of use of metal-pep63 complexes as models for the design of metal drugs to inhibit the Itch-WW-p63 recognition in vivo. Thus, our data suggest a novel strategy to study and inhibit the recognition mechanism of Itch E3-ligase. PMID:22935697

  16. p63 and Ki-67 immunostainings in laryngeal squamous cell carcinoma are related to survival.

    PubMed

    Re, M; Zizzi, A; Ferrante, L; Stramazzotti, D; Goteri, G; Gioacchini, F M; Olivieri, F; Magliulo, G; Rubini, C

    2014-06-01

    To examine the prognostic significance of the immunohistochemical expression of p63 and Ki-67 oncoproteins in patients with laryngeal squamous cell carcinoma, a retrospective evaluation was carried out on a cohort of 108 patients with primary laryngeal squamous cell carcinoma (LSCC) treated by primary surgery. For the immunohistochemical evaluation, tissue section obtained by formalin-fixed and paraffin-embedded tissue blocks from resection of each patient was used. Clinicopathologic data were associated with the immunostaining results. The association among the considered variables was assessed by Fisher's exact test, Mann-Whitney test, non-parametric χ(2) test, and Spearman's rho rank test was used to assess the relations among them. Differences in p63 and Ki-67 immunoreactivity among the different groups were compared via Kruskal-Wallis test and post hoc tests were performed using Mann-Whitney test with Bonferroni correction. The overall survival rate was estimated via Kaplan-Meier method, and the cumulative incidence functions for different groups were compared using log-rank statistics. Cox proportional hazard model was employed in a multivariate analysis to assess the effect of prognostic factors in the overall survival rate. Furthermore, taking into account death due to other causes, we estimated LSCC-related survival and disease-free survival rates using competing risk analysis. The results of immunohistochemical examination showed a statistically significant relationship between the up-regulation of P63 and Ki-67, an increase in histological grading, and primary tumours associated with lymph node metastases. p63 and Ki-67 up-regulation was related to a shorter disease-free survival and a significant association was found between p63 and Ki-67 percentage of positive cells and patient survival. Finally, we noticed a significant relation between p63 and Ki-67 (ρ = 0.87). On the other hand, no statistically significant associations were found between p63 and

  17. EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.

    PubMed

    Monti, Paola; Russo, Debora; Bocciardi, Renata; Foggetti, Giorgia; Menichini, Paola; Divizia, Maria T; Lerone, Margherita; Graziano, Claudio; Wischmeijer, Anita; Viadiu, Hector; Ravazzolo, Roberto; Inga, Alberto; Fronza, Gilberto

    2013-06-01

    TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild-type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN-P63α-specific REs derived from genes closely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability. © 2013 Wiley Periodicals, Inc.

  18. Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

    PubMed

    Liao, Wenjuan; Liu, Hongbing; Zhang, Yiwei; Jung, Ji Hoon; Chen, Jiaxiang; Su, Xiaohua; Kim, Yeong C; Flores, Elsa R; Wang, San Ming; Czarny-Ratajczak, Malwina; Li, Wen; Zeng, Shelya X; Lu, Hua

    2017-08-21

    TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

  19. p40 (ΔNp63) expression in breast disease and its correlation with p63 immunohistochemistry

    PubMed Central

    Kim, Sang Kyum; Jung, Woo Hee; Koo, Ja Seung

    2014-01-01

    p63 protein is widely used to identify myoepithelial cells in breast disease. There have been no comparative studies of the p63 antibodies which detect different isoforms. In this study, we examine the expression profiles of p63 protein in benign proliferative diseases and malignant tumors of the breast using pan-p63 and p40 antibodies, and analyze their diagnostic utility and clinical implications. We selected 32 adenoses, 34 intraductal papillomas, 31 ductal carcinoma in situ (DCIS), 257 invasive ductal carcinoma (IDC), and 36 metaplastic carcinomas, and created tissue microarray blocks from them. Immunohistochemical assays for p63 protein were performed on these samples. We investigated the expression patterns of the pan-p63 (TP63, 4A4, Dako, 1:700), p40 antibody [5-17, CalBiochem/EMD Biosciences, 1:2000, p40 (CB)], and p40 antibody [polyclonal, Diagnostic BioSystems, 1:100, p40 (DB)] in various forms of breast disease. We determined that p63 and p40 (DB) expression in myoepithelial cells was broadly similar and showed cognate clinicopathologic features, unlike p40 (CB). p40 (CB) was more sensitive (99.0%) but less specific (85.8%), and p63 was less sensitive (93.8%) in adenosis, IP, and DCIS. In IDCs, p63 and p40 (DB) had similar expression in cancer cells; p40 (CB) expression, however, was statistically different. In metaplastic carcinomas, both p63 and p40 (DB) had distinct expression profiles, according to their histologic subtypes. We conclude that p40 antibodies as well as pan-p63 antibody are specific and sensitive myoepithelial cell markers. Interpretation of p40 positivity in cancer cells, however, should be considered carefully, due to their relatively lower specificity. PMID:24696720

  20. Generation of a TALEN-mediated, p63 knock-in in human induced pluripotent stem cells.

    PubMed

    Kobayashi, Yuki; Hayashi, Ryuhei; Quantock, Andrew J; Nishida, Kohji

    2017-12-01

    The expression of p63 in surface ectodermal cells during development of the cornea, skin, oral mucosa and olfactory placodes is integral to the process of cellular self-renewal and the maintenance of the epithelial stem cell status. Here, we used TALEN technology to generate a p63 knock-in (KI) human induced pluripotent stem (hiPS) cell line in which p63 expression can be visualized via enhanced green fluorescent protein (EGFP) expression. The KI-hiPS cells maintained pluripotency and expressed the stem cell marker gene, ΔNp63α. They were also able to successfully differentiate into functional corneal epithelial cells as assessed by p63 expression in reconstructed corneal epithelium. This approach enables the tracing of p63-expressing cell lineages throughout epithelial development, and represents a promising application in the field of stem cell research. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Involvement of p63 in the herpes simplex virus-1-induced demise of corneal cells.

    PubMed

    Orosz, László; Gallyas, Eva; Kemény, Lajos; Mándi, Yvette; Facskó, Andrea; Megyeri, Klára

    2010-06-07

    The transcription factor p63 plays a pivotal role in the development and maintenance of epithelial tissues, including the ocular surface. In an effort to gain insight into the pathogenesis of keratitis caused by HSV-1, we determined the expression patterns of the p63 and Bax proteins in the Staatens Seruminstitute Rabbit Cornea cell line (SIRC). SIRC cells were infected with HSV-1 at various multiplicities and maintained for different periods of time. Virus replication was measured by indirect immunofluorescence assay and Western blot analysis. Cell viability was determined by MTT assay. The apoptotic response of the infected cells was quantified by ELISA detecting the enrichment of nucleosomes in the cytoplasm. Western blot analysis was used to determine the levels of p63 and Bax proteins. Indirect immunofluorescence assays and Western blot analyses demonstrated the presence of HSV-1 glycoprotein D (gD) in the infected SIRC cell line, and the pattern of gD expression was consistent with efficient viral replication. The results of MTT and ELISA assays showed that HSV-1 elicited a strong cytopathic effect, and apoptosis played an important role in the demise of the infected cells. Mock-infected SIRC cells displayed the constitutive expression of DeltaNp63alpha. The expressions of the Bax-beta and TAp63gamma isoforms were considerably increased, whereas the level of DeltaNp63alpha was decreased in the HSV-1-infected SIRC cells. Experiments involving the use of acyclovir showed that viral DNA replication was necessary for the accumulation of TAp63gamma. These data suggest that a direct, virus-mediated cytopathic effect may play an important role in the pathogenic mechanism of herpetic keratitis. By disturbing the delicate balance between the pro-survival DeltaN and the pro-apoptotic TA isoforms, HSV-1 may cause profound alterations in the viability of the ocular cells and in the tissue homeostasis of the ocular surface.

  2. p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

    PubMed Central

    Melino, Sonia; Bellomaria, Alessia; Nepravishta, Ridvan; Paci, Maurizio; Melino, Gerry

    2014-01-01

    Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S)pPtransPPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition. PMID:25485500

  3. p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch.

    PubMed

    Melino, Sonia; Bellomaria, Alessia; Nepravishta, Ridvan; Paci, Maurizio; Melino, Gerry

    2014-01-01

    Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S)pPtransPPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

  4. P63 Positive Mucoepidermoid Tumor of the Lacrimal Sac with Associated Papilloma.

    PubMed

    Iordanous, Yiannis; Belrose, Jillian C; Cadieux, Dani C; Chakrabarti, Subrata; Farmer, James P; Allen, Larry H

    2015-01-01

    We report a case of a 44-year-old man who presented with a left medial canthal mass and epiphora. Imaging was suggestive of a mass continuous with the nasolacrimal sac. Subsequent surgical exploration revealed a mass adherent to bone with invasion of the lacrimal system. Histological examination revealed a squamous/transitional cell papilloma overlying a low-grade mucoepidermoid carcinoma (MEC). Complete surgical resection was completed and pathology confirmed the diagnosis. This is the first case in which a MEC has been reported concurrently with an overlying papilloma, providing support for the hypothesis that MECs arise from papillomas in the lacrimal sac. Additionally, the tissue stained positive for p63, which is congruent with MEC immunoreactivity in the salivary gland. The description of these unique histopathological findings may assist in definitive diagnosis and improve our understanding of the pathophysiology underlying lacrimal sac MEC tumors.

  5. A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues.

    PubMed

    Sethi, Isha; Romano, Rose-Anne; Gluck, Christian; Smalley, Kirsten; Vojtesek, Borivoj; Buck, Michael J; Sinha, Satrajit

    2015-08-07

    The transcription factor p63 belongs to the p53/p63/p73 family and plays key functional roles during normal epithelial development and differentiation and in pathological states such as squamous cell carcinomas. The human TP63 gene, located on chromosome 3q28 is driven by two promoters that generate the full-length transactivating (TA) and N-terminal truncated (ΔN) isoforms. Furthermore alternative splicing at the C-terminus gives rise to additional α, β, γ and likely several other minor variants. Teasing out the expression and biological function of each p63 variant has been both the focus of, and a cause for contention in the p63 field. Here we have taken advantage of a burgeoning RNA-Seq based genomic data-sets to examine the global expression profiles of p63 isoforms across commonly utilized human cell-lines and major tissues and organs. Consistent with earlier studies, we find ΔNp63 transcripts, primarily that of the ΔNp63α isoforms, to be expressed in most cells of epithelial origin such as those of skin and oral tissues, mammary glands and squamous cell carcinomas. In contrast, TAp63 is not expressed in the majority of normal cell-types and tissues; rather it is selectively expressed at moderate to high levels in a subset of Burkitt's and diffuse large B-cell lymphoma cell lines. We verify this differential expression pattern of p63 isoforms by Western blot analysis, using newly developed ΔN and TA specific antibodies. Furthermore using unsupervised clustering of human cell lines, tissues and organs, we show that ΔNp63 and TAp63 driven transcriptional networks involve very distinct sets of molecular players, which may underlie their different biological functions. In this study we report comprehensive and global expression profiles of p63 isoforms and their relationship to p53/p73 and other potential transcriptional co-regulators. We curate publicly available data generated in part by consortiums such as ENCODE, FANTOM and Human Protein Atlas to

  6. Well-differentiated neuroendocrine tumors in skin: Terminology and diagnostic utility of cytokeratin 5/6 and p63.

    PubMed

    Panse, Gauri; Cowper, Shawn E; Leffell, David J; Pulitzer, Melissa; Ko, Christine J

    2017-06-01

    Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms. We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases. All 10 cases were negative with both CK5/6 and p63. Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Temperature dependence of an AlInP 63Ni betavoltaic cell

    NASA Astrophysics Data System (ADS)

    Butera, S.; Lioliou, G.; Krysa, A. B.; Barnett, A. M.

    2016-10-01

    In this paper, the performance of an Al0.52In0.48P 63Ni radioisotope cell is reported over the temperature range of -20 °C to 140 °C. A 400 μm diameter p+-i-n+ (2 μm i-layer) Al0.52In0.48P mesa photodiode was used as a conversion device in a novel betavoltaic cell. Dark current measurements on the Al0.52In0.48P detector showed that the saturation current increased increasing the temperature, while the ideality factor decreased. The effects of the temperature on the key cell parameters were studied in detail showing that the open circuit voltage, the maximum output power, and the internal conversion efficiency decreased when the temperature was increased. At -20 °C, an open circuit voltage and a maximum output power of 0.52 V and 0.28 pW, respectively, were measured.

  8. Human Papillomavirus Infection and Its Possible Correlation with p63 Expression in Cervical Cancer in Japan, Mongolia, and Myanmar

    PubMed Central

    Shirendeb, Ulziibat; Hishikawa, Yoshitaka; Moriyama, Shingo; Win, Ne; Thu, Minn Minn Myint; Mar, Khin Swe; Khatanbaatar, Gerlee; Masuzaki, Hideaki; Koji, Takehiko

    2009-01-01

    Although human papillomavirus (HPV) 16 is the cause of cervical cancer in most countries including Japan, the involvement of cervical cancer with HPV types in Mongolian and Myanmar populations is largely unknown. We examined the expression of HPV in formalin-fixed and paraffin-embedded cervical tissues from 40 Japanese, 32 Mongolian, and 30 Myanmar cervical cancer patients. We performed immunohistochemistry using anti-HPV16 and anti-HPV 1, 6, 11, 16, 18 and 31 cocktail and then correlated it with the expression of Ki-67 and p63. HPV 16 was detected in 72%, 65% and 50% of Japanese, Mongolian and Myanmar cervical cancer patients, respectively, whereas 5 (13%) of the 40 patients, 8 (25%) of the 32 patients and 7 (23%) of the 30 patients in HPV 16-negative cancers were positive for other HPV types included in the cocktail, respectively. Ki-67 labeling index (LI) as well as p63 LI was significantly higher in HPV 16-positive patients than in HPV 16-negative ones in the Japanese and Mongolian samples. p63 expression was significantly associated with stage III and IV in Japan and Mongolia. These findings suggest that HPV 16 may be associated with cell proliferative activity and tumor progression, possibly depending upon the expression of p63 in the cervical cancer. In addition, immunohistochemical detection for distinguishing the type of HPV may also be useful for cervical cancer in the clinical setting. PMID:20126571

  9. The herpes simplex virus-induced demise of keratinocytes is associated with a dysregulated pattern of p63 expression.

    PubMed

    Megyeri, Klára; Orosz, László; Kormos, Bernadett; Pásztor, Katalin; Seprényi, György; Ocsovszki, Imre; Mándi, Yvette; Bata-Csörgo, Zsuzsanna; Kemény, Lajos

    2009-01-01

    p63 plays a pivotal role in the development and maintenance of stratified epithelial tissues. In an effort to gain insight into the pathogenic mechanisms of skin infections caused by HSV-1 and HSV-2, we determined the patterns of p63 expression in primary keratinocytes and in the HaCaT cell line. The levels of DeltaNp63alpha and a 50kDa p73 isoform were decreased, Bax-alpha remained unaffected, while the expressions of the Bax-beta, TAp63gamma and a 44.5kDa p73 isoform were highly increased in both HSV-1-infected HaCaT cells and primary keratinocytes. In contrast, in response to HSV-2 infection the levels of DeltaNp63alpha, a 50kDa p73 isoform and a 44.5kDa p73 protein were decreased, Bax-alpha and TAp63gamma remained unaffected, while the expression of Bax-beta was slightly increased. The knockdown of TAp63 expression enhanced the viability of HSV-1-infected cells. Thus, HSV-1 and HSV-2 modulate the patterns of p63 and Bax expression in a serotype-specific manner. The dysregulated pattern of p63 expression observed in HSV-infected keratinocytes may comprise part of a mechanism by which these viruses perturb the functions of keratinocytes and lead to their demise.

  10. Maspin, p53, p63, and Ki-67 in epithelial lesions of the tongue: from hyperplasia through dysplasia to carcinoma.

    PubMed

    Vered, Marilena; Allon, Irit; Dayan, Dan

    2009-03-01

    The pattern of changes in the expression of mammary serine protease inhibitor (maspin) tumor suppressor protein in tongue epithelial lesions [hyperplasia (HP), mild dysplasia (MD), moderate-to-severe dysplasia (MSD) and squamous cell carcinoma (SCC)] was investigated and correlated to the expression of maspin-regulating factors p53 and p63, and the proliferation marker Ki-67. Cases of HP (n = 16), MD (n = 12), MSD (n = 11), and SCC (n = 22) were immunostained for maspin, p53, p63, and Ki-67. Maspin expression was scored separately for the basal, middle, and upper thirds of the epithelial width, and as the total sum of all 'thirds' (maspin-total). p53, p63, and Ki-67 were immuno-morphometrically assessed for the entire epithelial width. Maspin expression was differential and progressive extending to higher epithelial layers as dysplastic changes aggravated and culminated in carcinoma. Strong expression was related to MSD in the middle third and to carcinoma in the upper third. It was frequently lost at the invasion front, where the tumor was less differentiated. The changes in mean scores of maspin-total in the different study groups were positively correlated to the mean scores of p63 (r = 0.5, P < 0.001), p53 (r = 0.4, P = 0.004), and Ki-67 (r = 0.5, P < 0.001). Strong expression of maspin in the middle third of the epithelium may be considered a diagnostic sign of mild-to-moderate dysplasia and an indication of carcinoma in the upper third. The correlations between maspin and controlling factors (e.g. p63 and p53) may be events with key roles in the development of tongue carcinoma.

  11. Polymorphous low grade adenocarcinoma has a consistent p63+/p40- immunophenotype that helps distinguish it from adenoid cystic carcinoma and cellular pleomorphic adenoma.

    PubMed

    Rooper, Lisa; Sharma, Rajni; Bishop, Justin A

    2015-03-01

    Polymorphous low grade adenocarcinoma (PLGA) is a tumor of minor salivary glands that exhibits considerable morphologic overlap with adenoid cystic carcinoma and cellular pleomorphic adenoma, especially in small biopsy specimens. Unlike these other tumor types. PLGAs do not harbor a myoepithelial component, yet their frequent positivity for p63 diminishes the usefulness of this particular myoepithelial marker as a discriminating immunostain. p40 is an antibody that recognizes ΔNp63, a p63 isoform that is more specific for true myoepithelial differentiation. As such, p40 immunostaining could help distinguish PLGAs from adenoid cystic carcinomas and pleomorphic adenomas. In this study, p63 and p40 immunohistochemistry was performed on paraffin embedded, formalin fixed tissue from 11 PLGAs, 101 adenoid cystic carcinomas, and 31 pleomorphic adenomas. All 11 PLGAs (100 %) were positive for p63 but completely negative for p40. Among adenoid cystic carcinomas, 91 of 101 (90 %) were positive for p63 and 90/101 (89 %) were positive for p40. The single discordant p63+/p40- adenoid cystic carcinoma exhibited solid architecture and high grade features not typically seen in PLGA. Among pleomorphic adenomas, 21/31 (68 %) were positive for p63 and 13/31 (42 %) were positive for p40. For the pleomorphic adenomas, the discordant p63+/p40- staining pattern was seen only in the overtly mesenchymal chondromyxoid stroma. The cellular epithelial component of the pleomorphic adenomas demonstrated concordant p63+/p40+ or p63-/p40- immunophenotypes. PLGA consistently exhibits a p63+/p40- immunophenotype that can help distinguish it from adenoid cystic carcinoma and cellular pleomorphic adenoma, tumors that characteristically demonstrate concordant p63 and p40 immunostaining patterns. A p63/p40 immunohistochemical panel can provide a valuable tool for making the distinction between these morphologically similar but clinically divergent entities.

  12. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    SciTech Connect

    Kim, Soyeon; Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul; Lee, Jae-Jung

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effectmore » of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR

  13. Split-Hand/Split-Foot Malformation Is Caused by Mutations in the p63 Gene on 3q27

    PubMed Central

    Ianakiev, Peter; Kilpatrick, Michael W.; Toudjarska, Iva; Basel, Donald; Beighton, Peter; Tsipouras, Petros

    2000-01-01

    Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A→G, which predicts amino acid substitution K194E, and 982T→C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R→H and 304R→Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA. PMID:10839977

  14. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

    PubMed Central

    Bae, Eun Joo; Chen, Bai Hui; Yan, Bing Chun; Shin, Bich Na; Cho, Jeong Hwi; Kim, In Hye; Ahn, Ji Hyeon; Lee, Jae Chul; Tae, Hyun-Jin; Hong, Seongkweon; Kim, Dong Won; Cho, Jun Hwi; Lee, Yun Lyul; Won, Moo-Ho; Park, Joon Ha

    2015-01-01

    The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1–3) between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults. PMID:26199612

  15. Application of CD56, P63 and CK19 immunohistochemistry in the diagnosis of papillary carcinoma of the thyroid

    PubMed Central

    El Demellawy, Dina; Nasr, Ahmed; Alowami, Salem

    2008-01-01

    Papillary carcinoma of the thyroid (PTC) is the commonest thyroid cancer. In the recent decades an obvious increase in the incidence of PTC has occurred. The pathological diagnosis of PTC is usually an easy diagnosis in the majority of cases. However since the introduction of follicular variant of PTC and the wide threshold range in interpretation of the clearly set pathological criteria for diagnosis of PTC, between pathologists including experts, the diagnosis in some cases became quite difficult. Unfortunately some cases are unjustifiably over-called as follicular variant of PTC as a result of the wide inter observable variability between pathologists, including thyroid pathologists. Ancillary studies such as immmunohistochemistry may be helpful, but till now there is no 100% consistent marker(s), that distinct between PTC and other follicular thyroid lesions and tumors. We assessed expression of antibodies against CD56, CK19, P63 and E-Cadherin in PTC and other follicular thyroid lesions and neoplasms. A total of 175 cases were studied. The neoplastic cases included 75 carcinomas (72 papillary, 2 follicular, 1 Hurthle cell) and 35 adenomas (32 follicular and 3 Hurthle cell). The non-neoplastic thyroids included 65 cases, (25 nodular hyperplasia, 5 thyrotoxic hyperplasia (Grave's disease), 19 lymphocytic thyroiditis and 6 Hashimoto's thyroiditis). All cases were evaluated by immunohistochemistry for the expression of the above mentioned markers. The markers' patterns and intensities of staining were scored. Positive expression of the markers equal or >10% of the follicular epithelium within the tumor or lesional cells was considered positive. An expression of <10% was considered to be negative. Our results showed CD56 positive in all the lesions and tumors except for PTC in all cases (100%). CD56 was negative in all PTC cases (100%). CK 19 showed positive expression in PTC accounting for 85% of cases and in 26% of non PTC lesions/tumors. P63 showed selective

  16. Identification of p63+ keratinocyte progenitor cells in circulation and their matrix-directed differentiation to epithelial cells

    PubMed Central

    2013-01-01

    Introduction In the event of chronic diabetes or burn wounds, accomplishing skin regeneration is a major concern. Autologous skin grafting is the most effective remedy, but the tissue harvest may create more nonhealing wounds. Currently available skin substitutes have a limited clinical outcome because of immune reactions arising from the xenobiotic scaffold or allogenous cells. Autologous stem cells that can be collected without an additional injury may be a viable option for skin-tissue engineering. Presence of a low number of keratinocyte progenitor cells (KPCs) within the peripheral blood mononuclear cell (PBMNC) population has been indicated. Identification, isolation, expansion, and differentiation of KPCs is necessary before they are considered for skin regeneration, which is the focus of this study. Methods Culture of isolated human PBMNCs on a cell-specific matrix was carried out to induce differentiation of KPCs. Flow cytometry and reverse transcriptase polymerase chain reaction were done for epithelial stem cell marker p63 and lineage markers cytokeratin 5 and cytokeratin 14, to track differentiation. Proliferation was confirmed by quantifying the proliferating cell nuclear antigen-expressing cells. Immunostaining with epithelial cell markers, involucrin and filaggrin, was carried out to establish terminal differentiation. Microscopic analysis confirmed growth and survival of KPCs on the dermal fibroblast monolayer and on a transplantable fibrin sheet. Results We demonstrated that KPCs are p63+ and CD34-. The specifically designed composition of the extracellular matrix was found to support selective adhesion, proliferation, and differentiation of p63+ KPCs. The PBMNC culture for 12 days under controlled conditions resulted in a homogenous population that expressed cytokeratins, and >90% of the cells were found to proliferate. Subculture for 5 days resulted in expression of filaggrin and involucrin, suggesting terminal differentiation. Transfer of matrix

  17. Gene p63: In ectrodactyly-ectodermal dysplasia clefting, ankyloblepharon-ectodermal dysplasia, Rapp-Hodgkin syndrome.

    PubMed

    van Straten, Cornelia; Butow, Kurt-W

    2013-01-01

    An analysis was made of three different syndromes associated with p63 gene mutations, known as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC), ankyloblepharon-ectodermal dysplasia clefting syndrome (AEC or Hay-Wells) and Rapp-Hodgkin syndrome (RHS). The postoperative complications associated with their cleft reconstructions were also evaluated. Extensive demographic information, in particular of the clinical appearances, associated malformations, and the types and complications of the reconstructive surgical procedures, were recorded of these syndromic cases occurring in a database of 3621 facial cleft deformity patients. The data was analyzed using the Microsoft Excel program. A total of 10 (0.28%) cases of p63 associated syndromes were recorded: EEC (6), RHS (3), and AEC (1). The following clinical cleft appearances were noted - EEC = 6: CLA 1 -right side unilateral (female); CLAP 4 - right side (1) + left side (1) unilateral (male + female); bilateral (2) (males); hPsP 1 (female) (divided in 3 Black, 2 White, 1 Indian); RHS = 3: CLAP 2 (White males); hPsP 1 (White female); AEC = 1: CLAP bilateral (White male). Other features of the syndromes were: skin, hand, foot, tooth, hair and nail involvement, and light sensitivity. Postoperative complications included: (i) stenosis of nasal opening, especially after reconstruction of the bilateral cleft lip and the columella lengthening (2 cases), (ii) premaxilla-prolabium fusion (2 cases), (iii) repeated occurrence of oro-nasal fistula in the hard palate (4 cases), and (iv) dysgnathial development of midfacial structures (3 cases). Three different p63 associated syndromes (EEC, AEC, and RHS) were diagnosed (0.27% of the total facial cleft deformities database). The majority of the cases presented with a bilateral CLAP in males only. A number of females and males had unilateral CLA. The hPsP-cleft was recorded in females only. The associated ectodermal component most probably had a profoundly negative influence

  18. Identification of p63+ keratinocyte progenitor cells in circulation and their matrix-directed differentiation to epithelial cells.

    PubMed

    Nair, Renjith P; Krishnan, Lissy K

    2013-04-11

    In the event of chronic diabetes or burn wounds, accomplishing skin regeneration is a major concern. Autologous skin grafting is the most effective remedy, but the tissue harvest may create more nonhealing wounds. Currently available skin substitutes have a limited clinical outcome because of immune reactions arising from the xenobiotic scaffold or allogenous cells. Autologous stem cells that can be collected without an additional injury may be a viable option for skin-tissue engineering. Presence of a low number of keratinocyte progenitor cells (KPCs) within the peripheral blood mononuclear cell (PBMNC) population has been indicated. Identification, isolation, expansion, and differentiation of KPCs is necessary before they are considered for skin regeneration, which is the focus of this study. Culture of isolated human PBMNCs on a cell-specific matrix was carried out to induce differentiation of KPCs. Flow cytometry and reverse transcriptase polymerase chain reaction were done for epithelial stem cell marker p63 and lineage markers cytokeratin 5 and cytokeratin 14, to track differentiation. Proliferation was confirmed by quantifying the proliferating cell nuclear antigen-expressing cells. Immunostaining with epithelial cell markers, involucrin and filaggrin, was carried out to establish terminal differentiation. Microscopic analysis confirmed growth and survival of KPCs on the dermal fibroblast monolayer and on a transplantable fibrin sheet. We demonstrated that KPCs are p63(+) and CD34-. The specifically designed composition of the extracellular matrix was found to support selective adhesion, proliferation, and differentiation of p63(+) KPCs. The PBMNC culture for 12 days under controlled conditions resulted in a homogenous population that expressed cytokeratins, and >90% of the cells were found to proliferate. Subculture for 5 days resulted in expression of filaggrin and involucrin, suggesting terminal differentiation. Transfer of matrix-selected KPCs to a

  19. Immunohistochemical expression of CK7, CK5/6, CK19, and p63 in Warthin tumor.

    PubMed

    Dăguci, Luminiţa; Stepan, A; Mercuţ, Veronica; Dăguci, C; Bătăiosu, Marilena; Florescu, Alma

    2012-01-01

    Our study included a number of 24 cases with Warthin tumor, diagnosed between 2007-2011, which were analyzed in terms of clinical, histopathological and immunohistochemistry point of view, using CK7, CK5/6, CK19, and p63 antibodies. Warthin tumor is most often a tumor with a slow evolution, painless, usually affecting males (M/F 3.2/1) in the seventh decade of life. Histopathologically, it is distinguished the predominance of the typical forms of the tumor, with a balanced ratio epithelium/stroma. The immunostaining for CK7 showed positivity in all the investigated cases both in the columnar luminal cells and basal cells. The immunostaining for CK5/6 was positive in all the investigated cases in bilayer epithelial basal cells, both in the structure of the cysts and the papillae. In the case of the immunostaining for p63 we noticed limited nuclear positivity in the basal cells, while the columnar cells' nucleus were negative. The immunohistochemical study of the bilayer epithelial component of Warthin tumor showed different immunstaining of the two types of epithelia, the oncocytary columnar and the basal on, similar to those found in the salivary gland ducts.

  20. RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR-203 and p63.

    PubMed

    Warshauer, Emily; Samuelov, Liat; Sarig, Ofer; Vodo, Dan; Bindereif, Albrecht; Kanaan, Moien; Gat, Uri; Fuchs-Telem, Dana; Shomron, Noam; Farberov, Luba; Pasmanik-Chor, Metsada; Nardini, Gil; Winkler, Eyal; Meilik, Benjamin; Petit, Isabelle; Aberdam, Daniel; Paus, Ralf; Sprecher, Eli; Nousbeck, Janna

    2015-08-01

    Alopecia-neurological defects-endocrinopathy (ANE) syndrome is a rare inherited hair disorder, which was shown to result from decreased expression of the RNA-binding motif protein 28 (RBM28). In this study, we attempted to delineate the role of RBM28 in hair biology. First, we sought to obtain evidence for the direct involvement of RBM28 in hair growth. When RBM28 was downregulated in human hair follicle (HF) organ cultures, we observed catagen induction and HF growth arrest, indicating that RBM28 is necessary for normal hair growth. We also aimed at identifying molecular targets of RBM28. Given that an RBM28 homologue was recently found to regulate miRNA biogenesis in C. elegans and given the known pivotal importance of miRNAs for proper hair follicle development, we studied global miRNA expression profile in cells knocked down for RBM28. This analysis revealed that RBM28 controls the expression of miR-203. miR-203 was found to regulate in turn TP63, encoding the transcription factor p63, which is critical for hair morphogenesis. In conclusion, RBM28 contributes to HF growth regulation through modulation of miR-203 and p63 activity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. PAX8 (+)/p63 (-) immunostaining pattern in renal collecting duct carcinoma (CDC): a useful immunoprofile in the differential diagnosis of CDC versus urothelial carcinoma of upper urinary tract.

    PubMed

    Albadine, Roula; Schultz, Luciana; Illei, Peter; Ertoy, Dilek; Hicks, Jessica; Sharma, Rajni; Epstein, Jonathan I; Netto, George J

    2010-07-01

    Collecting duct carcinoma (CDC) is a relatively rare but aggressive type of renal malignancy with variable morphologic features. One of the World Health Organization diagnostic criteria for CDC is the exclusion of urothelial carcinoma of renal pelvis from the differential diagnosis. PAX8 is a novel lineage restricted transcription factor expressed in renal tubules. We investigated the expression pattern of PAX8 in CDC and its utility, in combination with p63, in resolving the differential diagnosis of CDC versus upper tract urothelial carcinoma (UUC). Archival tissues from 21 CDC and 34 UUC were retrieved from our institutional files. Immunohistochemistry for PAX8 and p63 were performed on routine and tissue microarray sections using standard immunohistochemistry protocol. Intensity of nuclear staining was evaluated for each marker and assigned an incremental 0, 1+, 2+, and 3+ score. Extent of staining was categorized as focal (<25%), nonfocal (25% to 75%), or diffuse (>75%). CDC: All 21 (100%) CDC were positive for PAX8. Intensity of expression was moderate to strong (2+/3+) in 19 cases (90%). Extent of staining was diffuse in 13 of 21 tumors. The p63 was positive in 3 of 21 (14%) CDC cases (PAX8+/p63+). UUC: The 34 UUC included 5 pT1, 4 pT2, and 25 pT3/pT4 tumors. Thirty-one of 34 (91.2%) UUC were negative for PAX8, whereas 33 of 34 (97%) were p63 positive. Staining intensity was moderate in 15 cases (44%), of which 12 were nonfocal or diffuse. The unique p63-negative UUC was a pT1 tumor that was also negative for PAX8 (PAX8-/p63-). We propose the use of the combination of PAX8 and p63 in the diagnosis of poorly differentiated renal sinus epithelial neoplasms where the differential diagnosis includes CDC versus UUC. The immunoprofile of PAX8+/p63- supports the diagnosis of CDC with a sensitivity of 85.7% and a specificity of 100%. In contrast, a (PAX8-/p63+) profile supports the diagnosis of UUC with a sensitivity of 88.2% and a specificity of 100%. The inverse

  2. p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells

    PubMed Central

    Fatt, M P; Cancino, G I; Miller, F D; Kaplan, D R

    2014-01-01

    The p53 family members p73 and p63 have been implicated in various aspects of stem cell regulation. Here, we have asked whether they work together to regulate stem cell biology, focusing upon neural precursor cells (NPCs) in the adult murine brain. By studying mice that are haploinsufficient for p63 and/or p73, we show that these two proteins cooperate to ensure appropriate NPC self-renewal and long-term maintenance in the hippocampus and forebrain, and that when both are haploinsufficient, the NPC deficits are significantly greater than haploinsufficiency for either alone. We show that, in the case of p63+/− mice, this decrease in adult NPCs is caused by enhanced apoptosis. However, when p73 is coincidently haploinsufficient, this rescues the enhanced apoptosis of p63+/− NPCs under both basal conditions and following genotoxic stress, instead causing increased cellular senescence. This increase in cellular senescence is likely due, at least in part, to increased levels of basal DNA damage and p53 activation, as genetic ablation of p53 completely rescues the senescence phenotype observed in p63+/−; p73+/− mice. Thus, the presence of p73 determines whether p63+/− NPCs exhibit increased p53-dependent apoptosis or senescence. Together, these studies demonstrate that p63 and p73 cooperate to maintain adult NPC pools through regulation of p53 function; p63 antagonizes p53 to promote cellular survival, whereas p73 regulates self-renewal and p53-mediated apoptosis versus senescence. PMID:24809925

  3. Evolutionary re-wiring of p63 and the epigenomic regulatory landscape in keratinocytes and its potential implications on species-specific gene expression and phenotypes

    PubMed Central

    Sethi, Isha; Gluck, Christian; Zhou, Huiqing

    2017-01-01

    Abstract Although epidermal keratinocyte development and differentiation proceeds in similar fashion between humans and mice, evolutionary pressures have also wrought significant species-specific physiological differences. These differences between species could arise in part, by the rewiring of regulatory network due to changes in the global targets of lineage-specific transcriptional master regulators such as p63. Here we have performed a systematic and comparative analysis of the p63 target gene network within the integrated framework of the transcriptomic and epigenomic landscape of mouse and human keratinocytes. We determined that there exists a core set of ∼1600 genomic regions distributed among enhancers and super-enhancers, which are conserved and occupied by p63 in keratinocytes from both species. Notably, these DNA segments are typified by consensus p63 binding motifs under purifying selection and are associated with genes involved in key keratinocyte and skin-centric biological processes. However, the majority of the p63-bound mouse target regions consist of either murine-specific DNA elements that are not alignable to the human genome or exhibit no p63 binding in the orthologous syntenic regions, typifying an occupancy lost subset. Our results suggest that these evolutionarily divergent regions have undergone significant turnover of p63 binding sites and are associated with an underlying inactive and inaccessible chromatin state, indicative of their selective functional activity in the transcriptional regulatory network in mouse but not human. Furthermore, we demonstrate that this selective targeting of genes by p63 correlates with subtle, but measurable transcriptional differences in mouse and human keratinocytes that converges on major metabolic processes, which often exhibit species-specific trends. Collectively our study offers possible molecular explanation for the observable phenotypic differences between the mouse and human skin and broadly

  4. Dynamic expression of the p53 family members p63 and p73 in the mouse and human telencephalon during development and in adulthood.

    PubMed

    Hernández-Acosta, N Carolina; Cabrera-Socorro, Alfredo; Morlans, Mercedes Pueyo; Delgado, Francisco J González; Suárez-Solá, M Luisa; Sottocornola, Roberta; Lu, Xin; González-Gómez, Miriam; Meyer, Gundela

    2011-02-04

    p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and death of mammalian cells. They display high homology and may act in concert. The p73 gene is relevant for brain development, and p73-deficient mice display important malformations of the telencephalon. In turn, p63 is essential for the development of stratified epithelia and may also play a part in neuronal survival and aging. We show here that p63 and p73 are dynamically expressed in the embryonic and adult mouse and human telencephalon. During embryonic stages, Cajal-Retzius cells derived from the cortical hem co-express p73 and p63. Comparison of the brain phenotypes of p63- and p73- deficient mice shows that only the loss of p73 function leads to the loss of Cajal-Retzius cells, whereas p63 is apparently not essential for brain development and Cajal-Retzius cell formation. In postnatal mice, p53, p63, and p73 are present in cells of the subventricular zone (SVZ) of the lateral ventricle, a site of continued neurogenesis. The neurogenetic niche is reduced in size in p73-deficient mice, and the numbers of young neurons near the ventricular wall, marked with doublecortin, Tbr1 and calretinin, are dramatically decreased, suggesting that p73 is important for SVZ proliferation. In contrast to their restricted expression during brain development, p73 and p63 are widely detected in pyramidal neurons of the adult human cortex and hippocampus at protein and mRNA levels, pointing to a role of both genes in neuronal maintenance in adulthood. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Aberrant p63 and WT-1 expression in myoepithelial cells of pregnancy-associated breast cancer: implications for tumor aggressiveness and invasiveness

    PubMed Central

    Xu, Zheli; Wang, Wan; Deng, Chu-Xia; Man, Yan-gao

    2009-01-01

    Our recent studies revealed that focal alterations in breast myoepithelial cell layers significantly impact the biological presentation of associated epithelial cells. As pregnancy-associated breast cancer (PABC) has a significantly more aggressive clinical course and mortality rate than other forms of breast malignancies, our current study compared tumor suppressor expression in myoepithelial cells of PABC and non-PABC, to determine whether myoepithelial cells of PABC may have aberrant expression of tumor suppressors. Tissue sections from 20 cases of PABC and 20 cases of stage, grade, and age matched non-PABC were subjected to immunohistochemistry, and the expression of tumor suppressor maspin, p63, and Wilms' tumor 1 (WT-1) in calponin positive myoepithelial cells were statistically compared. The expression profiles of maspin, p63, and WT-1 in myoepithelial cells of all ducts encountered were similar between PABC and non-PABC. PABC, however, displayed several unique alterations in terminal duct and lobular units (TDLU), acini, and associated tumor tissues that were not seen in those of non-PABC, which included the absence of p63 and WT-1 expression in a vast majority of the myoepithelial cells, cytoplasmic localization of p63 in the entire epithelial cell population of some lobules, and substantially increasing WT-1 expression in vascular structures of the invasive cancer component. All or nearly all epithelial cells with aberrant p63 and WT-1 expression lacked the expression of estrogen receptor and progesterone receptor, whereas they had a substantially higher proliferation index than their counterparts with p63 and WT-1 expression. Hyperplastic cells with cytoplasmic p63 expression often adjacent to, and share a similar immunohistochemical and cytological profile with, invasive cancer cells. To our best knowledge, our main finings have not been previously reported. Our findings suggest that the functional status of myoepithelial cells may be significantly

  6. Correlation of p63 immunohistochemistry with histology and contrast enhanced MRI in characteristic lesions induced by minimally invasive thermal treatments in a dog prostate

    NASA Astrophysics Data System (ADS)

    Pascal, A.; Butts-Pauly, K.; Plata, J.; Sommer, G.; Daniel, B.; Bouley, D. M.

    2017-03-01

    Thermal ablation techniques are important tools to treat low grade tumors in the prostate gland. The use of Magnetic Resonance Imaging (MRI) has been an excellent tool to visualize and assess the thermally ablated areas in real time. In this study slides from dog prostates previously treated with cryoablation or High Intensity Focal Ultrasound (HIFU) were immunohistochemically stained with the biomarker p63, in order to determine if this marker would be helpful for differentiatiating between viable, sub lethally damaged and normal glands. Digitized slides were analyzed using Sedeen Viewer software, and compared with corresponding representative H&E slides and MR images. p63 staining in the cryoablated acute duration prostates was negative in the coagulation necrosis zone (region of interest subjected to the coldest temperatures). In acute duration HIFU treated prostates, the central heat-fixed zone (region of interest subjected to the hottest temperatures) still displayed + p63 staining. Cryoablated or HIFU subacute duration treated prostates were very hemorrhagic, but presented the same stain pattern in the treated areas as the acute duration prostates, and in chronic duration prostates, whether treated with cryo or HIFU, glands displayed robust p63 staining most prevalent in the outer edges of the lesion where there was extensive glandular regeneration. In conclusion, this study demonstrates the value of p63 IHC and its usefulness in detecting viable prostate basal cells in normal dog prostates following either cryoablation of HIFU. Our results suggest that the portions of the lesion with complete loss of p63 staining correspond well to the non-enhancing region in cryoablated prostates, as viewed with MRI. However, p63 staining in the heat-fixed zone in acute harvested HIFU treated prostates remains positive, suggesting either inadequate heat to destroy basal cells, or heat-fixation of the p63 antigen and false positive staining. Therefore p63 staining does not

  7. Signaling efficiency of Gαq through its effectors p63RhoGEF and GEFT depends on their subcellular location.

    PubMed

    Goedhart, Joachim; van Unen, Jakobus; Adjobo-Hermans, Merel J W; Gadella, Theodorus W J

    2013-01-01

    The p63RhoGEF and GEFT proteins are encoded by the same gene and both members of the Dbl family of guanine nucleotide exchange factors. These proteins can be activated by the heterotrimeric G-protein subunit Gαq. We show that p63RhoGEF is located at the plasma membrane, whereas GEFT is confined to the cytoplasm. Live-cell imaging studies yielded quantitative information on diffusion coefficients, association rates and encounter times of GEFT and p63RhoGEF. Calcium signaling was examined as a measure of the signal transmission, revealing more efficient signaling through the membrane-associated p63RhoGEF. A rapamycin dependent recruitment system was used to dynamically alter the subcellular location and concentration of GEFT, showing efficient signaling through GEFT only upon membrane recruitment. Together, our results show efficient signal transmission through membrane located effectors, and highlight a role for increased concentration rather than increased encounter times due to membrane localization in the Gαq mediated pathways to p63RhoGEF and PLCβ.

  8. Recognition mechanism of p63 by the E3 ligase Itch: novel strategy in the study and inhibition of this interaction.

    PubMed

    Bellomaria, Alessia; Barbato, Gaetano; Melino, Gerry; Paci, Maurizio; Melino, Sonia

    2012-10-01

    The HECT-containing E3 ubiquitin ligase Itch mediates the degradation of several proteins, including p63 and p73, involved in cell specification and fate. Itch contains four WW domains, which are essential for recognition on the target substrate, which contains a short proline-rich sequence. Several signaling complexes containing these domains have been associated with human diseases such as muscular dystrophy, Alzheimer's or Huntington's diseases. To gain further insight into the structural determinants of the Itch-WW2 domain, we investigated its interaction with p63. We assigned, by 3D heteronuclear NMR experiments, the backbone and side chains of the uniformly (13)C-(15)N-labeled Itch-WW2. In vitro interaction of Itch-WW2 domain with p63 was studied using its interactive p63 peptide, pep63. Pep63 is an 18-mer peptide corresponding to the region from 534-551 residue of p63, encompassing the PPxY motif that interacts with the Itch-WW domains, and we identified the residues involved in this molecular recognition. Moreover, here, a strategy of stabilization of the conformation of the PPxY peptide has been adopted, increasing the WW-ligand binding. We demonstrated that cyclization of pep63 leads to an increase of both the biological stability of the peptide and of the WW-ligand complex. Stable metal-binding complexes of the pep63 have been also obtained, and localized oxidative damage on Itch-WW2 domain has been induced, demonstrating the possibility of use of metal-pep63 complexes as models for the design of metal drugs to inhibit the Itch-WW-p63 recognition in vivo. Thus, our data suggest a novel strategy to study and inhibit the recognition mechanism of Itch E3-ligase.

  9. Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence.

    PubMed

    Djelloul, Siham; Tarunina, Marina; Barnouin, Karin; Mackay, Alan; Jat, Parmjit S

    2002-02-07

    P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit. To determine whether p63 proteins, members of the family of p53-related genes, are also involved in this process, we examined their expression in serially passaged rat embryo fibroblasts. Upon senescence, two truncated DeltaNp63 proteins decreased in abundance whereas two TAp63 isoforms accumulated. 2-D gel analysis showed that the DeltaNp63 proteins underwent post-translational modifications in both proliferating and senescent cells. Direct binding of DeltaNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells. In contrast p63alpha isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells. An interaction of p63alpha proteins with SV40 large tumour antigen was also detected and ectopic expression of DeltaNp63alpha can extend the lifespan of rat embryo fibroblasts. Taken together the results indicate that p63 proteins may play a role in replicative senescence either by competition for p53 DNA binding sites or by direct interaction with p53 protein bound to DNA.

  10. [Application of PLA Method for Detection of p53/p63/p73 Complexes in Situ in Tumour Cells and Tumour Tissue].

    PubMed

    Hrabal, V; Nekulová, M; Nenutil, R; Holčaková, J; Coates, P J; Vojtěšek, B

    2017-01-01

    PLA (proximity ligation assay) can be used for detection of protein-protein interactions in situ directly in cells and tissues. Due to its high sensitivity and specificity it is useful for detection, localization and quantification of protein complexes with single molecule resolution. One of the mechanisms of mutated p53 gain of function is formation of proten-protein complexes with other members of p53 family - p63 and p73. These interactions influences chemosensitivity and invasivity of cancer cells and this is why these complexes are potential targets of anti-cancer therapy. The aim of this work is to detect p53/p63/p73 interactions in situ in tumour cells and tumour tissue using PLA method. Unique in-house antibodies for specific detection of p63 and p73 isoforms were developed and characterized. Potein complexes were detected using PLA in established cell lines SVK14, HCC1806 and FaDu and in paraffin sections of colorectal carcinoma tissue. Cell lines were also processed to paraffin blocks. p53/T-antigen and ΔNp63/T-antigen protein complexes were detected in SVK14 cells using PLA. Interactions of ΔNp63 and TAp73 isoforms were found in HCC1806 cell line with endogenous expression of these proteins. In FaDu cell line mut-p53/TAp73 complex was localized but not mut-p53/ΔNp63 complex. p53 tetramer was detected directly in colorectal cancer tissue. During development of PLA method for detection of protein complexes between p53 family members we detected interactions of p53 and p63 with T-antigen and mut-p53 and ΔNp63 with TAp73 tumour suppressor in tumour cell lines and p53 tetramers in paraffin sections of colorectal cancer tissue. PLA will be further used for detection of p53/p63, p53/p73 and p63/p73 interactions in tumour tissues and it could be also used for screening of compounds that can block formation of p53/p63/p73 protein complexes.Key words: p53 protein family - protein interaction mapping - immunofluorescence This work was supported by MEYS - NPS I

  11. Spatially correlated phenotyping reveals K5-positive luminal progenitor cells and p63-K5/14-positive stem cell-like cells in human breast epithelium.

    PubMed

    Boecker, Werner; van Horn, Laura; Stenman, Göran; Stürken, Christine; Schumacher, Udo; Loening, Thomas; Liesenfeld, Lukas; Korsching, Eberhard; Gläser, Doreen; Tiemann, Katharina; Buchwalow, Igor

    2018-05-09

    Understanding the mechanisms regulating human mammary epithelium requires knowledge of the cellular constituents of this tissue. Different and partially contradictory definitions and concepts describing the cellular hierarchy of mammary epithelium have been proposed, including our studies of keratins K5 and/or K14 as markers of progenitor cells. Furthermore, we and others have suggested that the p53 homolog p63 is a marker of human breast epithelial stem cells. In this investigation, we expand our previous studies by testing whether immunohistochemical staining with monospecific anti-keratin antibodies in combination with an antibody against the stem cell marker p63 might help refine the different morphologic phenotypes in normal breast epithelium. We used in situ multilabel staining for p63, different keratins, the myoepithelial marker smooth muscle actin (SMA), the estrogen receptor (ER), and Ki67 to dissect and quantify the cellular components of 16 normal pre- and postmenopausal human breast epithelial tissue samples at the single-cell level. Importantly, we confirm the existence of K5+ only cells and suggest that they, in contrast to the current view, are key luminal precursor cells from which K8/18+ progeny cells evolve. These cells are further modified by the expression of ER and Ki67. We have also identified a population of p63+K5+ cells that are only found in nipple ducts. Based on our findings, we propose a new concept of the cellular hierarchy of human breast epithelium, including K5 luminal lineage progenitors throughout the ductal-lobular axis and p63+K5+ progenitors confined to the nipple ducts.

  12. The clinical use of a P63/cytokeratin7/18/cytokeratin5/14 antibody cocktail in diagnostic breast pathology.

    PubMed

    Reisenbichler, Emily S; Ross, John R; Hameed, Omar

    2014-12-01

    An antibody cocktail directed against p63, cytokeratin (CK)5/14, and CK7/18 is reported to be useful in distinguishing noninvasive from invasive breast lesions and for the characterization of intraductal epithelial proliferations. However, limited studies evaluate its use in clinical practice. A retrospective review of breast material at a university medical center identified cases that were immunostained with the above antibody cocktail. Additional p63 immunostaining alone was performed to further determine the utility of the antibody cocktail in the evaluation of invasion. Of 50 breast cases identified, the antibody cocktail was used to confirm or exclude invasion in 44 (88%). Twenty-two (50%) of these had easily identifiable p63/CK5/14-positive myoepithelial cells, whereas the remainder lacked such staining, confirming the diagnosis of invasive carcinoma. In 27 cases with available diagnostic material for additional p63 immunostaining, the cocktail better highlighted myoepithelial cells by staining nuclei and cytoplasm. Easier identification of invasion was also facilitated by CK7/18 expression in invasive foci, especially those composed of single cells. Ten cases were immunostained to help determine the nature of an intraductal proliferation. The cocktail demonstrated a mosaic staining pattern of both CK7/18- and CK5/14-positive epithelial cells in 3 (30%) cases consistent with usual hyperplasia; homogenous CK7/18 expression in the remaining cases supported the diagnosis of atypical ductal hyperplasia or carcinoma in situ. In summary, the p63/CK7/18/CK5/14 cocktail stain appears to be a useful tool in diagnostic breast pathology, in the evaluation of possible invasion, particularly in the setting of minute foci of invasion as well as in epithelial proliferations. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Increase of poorly proliferated p63+ /Ki67+ basal cells forming multiple layers in the aberrant remodeled epithelium in nasal polyps.

    PubMed

    Zhao, L; Li, Y Y; Li, C W; Chao, S S; Liu, J; Nam, H N; Dung, N T N; Shi, L; Wang, D Y

    2017-06-01

    Aberrant epithelial remodeling with the ectopic expression of p63 (basal cell markers) is an important pathologic phenomenon seen in chronically inflamed airway epithelium such as in nasal polyps (NPs). Biopsies were obtained from 55 NP patients and 18 healthy controls (inferior turbinate). Among NP patients, 15 were treated with oral and nasal steroids, so that two sets of NP biopsies were taken before and after the treatments. p63, Ki67, type IV β-tubulin, and cell cycle markers were investigated in these specimens. The number of p63 + cells is significantly higher in both hyperplastic (1.53-fold, P < 0.0001) and squamous metaplastic (2.02-fold, P < 0.0001) epithelium from NPs than from healthy controls. There are three types of proliferative basal cells (p63 + /Ki67 + ) which are in different phases of the cell cycle, such as G1 phase (type I cells), S to G2 phase (type II cells), and mitosis (type III cells). Of importance, some type I cells may arrest after proliferation although they may still be p63 + /Ki67 + . In healthy epithelium, the ratio of the type I and II cells is almost 50:50. However, less type II cells are found in hyperplastic epithelium (34.85%, P = 0.012) and in squamous metaplastic epithelium (30.77%, P = 0.02) together with the presence of type III cells (3.45%, P = 0.01). These findings were not changed after steroid treatments. An increase of poorly proliferated basal cells forming multiple layers, which may stain for basal cell markers but does not form a proper epidermal barrier, is an important histopathologic phenomenon in aberrant remodeled epithelium of NPs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Impact of cadmium, cobalt and nickel on sequence-specific DNA binding of p63 and p73 in vitro and in cells

    SciTech Connect

    Adámik, Matej; Bažantová, Pavla; Department of Biology and Ecology, Faculty of Science, University of Ostrava, Chittussiho 10, 701 03 Ostrava

    Highlights: • DNA binding of p53 family core domains is inhibited by cadmium, cobalt and nickel. • Binding to DNA protects p53 family core domains from metal induced inhibition. • Cadmium, cobalt and nickel induced inhibition was reverted by EDTA in vitro. - Abstract: Site-specific DNA recognition and binding activity belong to common attributes of all three members of tumor suppressor p53 family proteins: p53, p63 and p73. It was previously shown that heavy metals can affect p53 conformation, sequence-specific binding and suppress p53 response to DNA damage. Here we report for the first time that cadmium, nickel and cobalt,more » which have already been shown to disturb various DNA repair mechanisms, can also influence p63 and p73 sequence-specific DNA binding activity and transactivation of p53 family target genes. Based on results of electrophoretic mobility shift assay and luciferase reporter assay, we conclude that cadmium inhibits sequence-specific binding of all three core domains to p53 consensus sequences and abolishes transactivation of several promoters (e.g. BAX and MDM2) by 50 μM concentrations. In the presence of specific DNA, all p53 family core domains were partially protected against loss of DNA binding activity due to cadmium treatment. Effective cadmium concentration to abolish DNA–protein interactions was about two times higher for p63 and p73 proteins than for p53. Furthermore, we detected partial reversibility of cadmium inhibition for all p53 family members by EDTA. DTT was able to reverse cadmium inhibition only for p53 and p73. Nickel and cobalt abolished DNA–p53 interaction at sub-millimolar concentrations while inhibition of p63 and p73 DNA binding was observed at millimolar concentrations. In summary, cadmium strongly inhibits p53, p63 and p73 DNA binding in vitro and in cells in comparison to nickel and cobalt. The role of cadmium inhibition of p53 tumor suppressor family in carcinogenesis is discussed.« less

  15. Toll-like Receptor 3 (TLR3) Induces Apoptosis via Death Receptors and Mitochondria by Up-regulating the Transactivating p63 Isoform α (TAP63α)*

    PubMed Central

    Sun, Ruili; Zhang, Yu; Lv, Qingshan; Liu, Bei; Jin, Miao; Zhang, Weijia; He, Qing; Deng, Minjie; Liu, Xueting; Li, Guancheng; Li, Yuehui; Zhou, Guohua; Xie, Pingli; Xie, Xiumei; Hu, Jinyue; Duan, Zhaojun

    2011-01-01

    Toll-like receptor 3 (TLR3), a member of the pathogen recognition receptors, is widely expressed in various cells and has been shown to activate immune signaling pathways by recognizing viral double-stranded RNA. Recently, it was reported that the activation of TLR3 induced apoptosis in some cells, but the detailed molecular mechanism is not fully understood. In this study, we found that in endothelial cells polyinosinic-polycytidylic acid (poly(I-C)) induced dose- and time-dependent cell apoptosis, which was elicited by TLR3 activation, as TLR3 neutralization and down-regulation repressed the apoptosis. Poly(I-C) induced the activation of both caspases 8 and 9, indicating that TLR3 triggered the signaling of both the extrinsic and intrinsic apoptotic pathways. Poly(I-C) up-regulated tumor necrosis factor-related apoptosis-inducing ligand and its receptors, death receptors 4/5, resulting in initiating the extrinsic pathway. Furthermore, poly(I-C) down-regulated anti-apoptotic protein, B cell lymphoma 2 (Bcl-2), and up-regulated Noxa, a key Bcl-2 homology 3-only antagonist of Bcl-2, leading to the priming of the intrinsic pathway. A p53-related protein, the transactivating p63 isoform α (TAp63α), was induced by TLR3 activation and contributed to the activation of both the intrinsic and extrinsic apoptotic pathways. Both the cells deficient in p63 gene expression by RNA interference and cells that overexpressed the N-terminally truncated p63 isoform α (ΔNp63α), a dominant-negative variant of TAp63α, by gene transfection, survived TLR3 activation. Taken together, TAp63α is a crucial regulator downstream of TLR3 to induce cell death via death receptors and mitochondria. PMID:21367858

  16. Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A.

    PubMed

    Wolchinsky, Zohar; Shivtiel, Shoham; Kouwenhoven, Evelyn Nathalie; Putin, Daria; Sprecher, Eli; Zhou, Huiqing; Rouleau, Matthieu; Aberdam, Daniel

    2014-01-01

    The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ΔNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development. © 2013.

  17. Using an AMACR (P504S)/34betaE12/p63 cocktail for the detection of small focal prostate carcinoma in needle biopsy specimens.

    PubMed

    Jiang, Zhong; Li, Cuizhen; Fischer, Andrew; Dresser, Karen; Woda, Bruce A

    2005-02-01

    We assessed the usefulness of immunohistochemical analysis with a 3-antibody cocktail (alpha-methylacyl coenzyme A racemase [AMACR, or P504S], 34betaE12, p63) and a double-chromogen reaction for detection of limited prostate cancer in 138 needle biopsy specimens, including 82 with small foci of prostatic adenocarcinoma and 56 benign prostates. When carcinoma was present, red cytoplasmic granular staining (AMACR) in the malignant glands and cells and dark brown nuclear (p63) and cytoplasmic (34betaE12) staining in basal cells of adjacent nonmalignant glands were found. Of 82 cases of small foci of prostatic adenocarcinoma, 78 (95%) expressed AMACR; all malignant glands were negative for basal cell staining. All benign glands adjacent to malignant glands were recognized easily by basal cell marker positivity and little or no AMACR expression. No benign glands were simultaneously positive for AMACR and negative for basal cell markers (specificity, 100%). There were no differences in intensity and numbers of positive glands with double-chromogen staining compared with using 1-color staining. Our results indicate that immunohistochemistry with a 3-antibody cocktail and double chromogen is a simple and easy assay that can be used as a routine test, which overcomes the problems of studying small lesions in prostate needle biopsies with multiple immunohistochemical stains.

  18. Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

    PubMed

    Patrick, B A; Jaiswal, A K

    2012-10-04

    Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBPα) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of the NQO1 gene in mice and mouse keratinocytes led to degradation of C/EBPα and loss of p63 gene expression. p63 promoter mutagenesis, transfection and chromatin immunoprecipitation assays identified a C/EBPα-binding site between nucleotide position -185 and -174 that bound to C/EBPα and upregulated p63 gene expression. Co-immunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBPα. NQO1 direct interaction with C/EBPα led to stabilization of C/EBPα against 20S proteasomal degradation. NQO1 protection of C/EBPα required binding of NADH with NQO1. Exposure of skin and keratinocytes to the chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBPα protein, resulting in an increase in p63 RNA and protein in wild-type but not in NQO1-/- mice. Collectively, the current data combined with previous data suggest that stress induction of NQO1 through both stabilization of C/EBPα and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation, leading to protection against chemical-induced skin carcinogenesis. The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases.

  19. Genome-Wide Profiling of p63 DNA–Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus

    PubMed Central

    Oti, Martin; Dutilh, Bas E.; Alonso, M. Eva; de la Calle-Mustienes, Elisa; Smeenk, Leonie; Rinne, Tuula; Parsaulian, Lilian; Bolat, Emine; Jurgelenaite, Rasa; Huynen, Martijn A.; Hoischen, Alexander; Veltman, Joris A.; Brunner, Han G.; Roscioli, Tony; Oates, Emily; Wilson, Meredith; Manzanares, Miguel; Gómez-Skarmeta, José Luis; Stunnenberg, Hendrik G.; Lohrum, Marion; van Bokhoven, Hans; Zhou, Huiqing

    2010-01-01

    Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA–binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP–seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes. PMID:20808887

  20. Effectiveness of computer-aided diagnosis (CADx) of breast pathology using immunohistochemistry results of core needle biopsy samples for synaptophysin, oestrogen receptor and CK14/p63 for classification of epithelial proliferative lesions of the breast.

    PubMed

    Maeda, Ichiro; Kubota, Manabu; Ohta, Jiro; Shinno, Kimika; Tajima, Shinya; Ariizumi, Yasushi; Doi, Masatomo; Oana, Yoshiyasu; Kanemaki, Yoshihide; Tsugawa, Koichiro; Ueno, Takahiko; Takagi, Masayuki

    2017-12-01

    The aim of this study was to develop a computer-aided diagnosis (CADx) system for identifying breast pathology. Two sets of 100 consecutive core needle biopsy (CNB) specimens were collected for test and validation studies. All 200 CNB specimens were stained with antibodies targeting oestrogen receptor (ER), synaptophysin and CK14/p63. All stained slides were scanned in a whole-slide imaging system and photographed. The photographs were analysed using software to identify the proportions of tumour cells that were positive and negative for each marker. In the test study, the cut-off values for synaptophysin (negative and positive) and CK14/p63 (negative and positive) were decided using receiver operating characteristic (ROC) analysis. For ER analysis, samples were divided into groups with <10% positive or >10% positive cells and decided using receiver operating characteristic (ROC) analysis. Finally, these two groups categorised as ER-low, ER-intermediate (non-low and non-high) and ER-high groups. In the validation study, the second set of immunohistochemical slides were analysed using these cut-off values. The cut-off values for synaptophysin, <10% ER positive, >10% ER positive and CK14/p63 were 0.14%, 2.17%, 77.93% and 18.66%, respectively. The positive predictive value for malignancy (PPV) was 100% for synaptophysin-positive/ER-high/(CK14/p63)-any or synaptophysin-positive/ER-low/(CK14/p63)-any. The PPV was 25% for synaptophysin-positive/ER-intermediate/(CK14/p63)-positive. For synaptophysin-negative/(CK14/p63)-negative, the PPVs for ER-low, ER-intermediate and ER-high were 100%, 80.0% and 95.8%, respectively. The PPV was 4.5% for synaptophysin-negative/ER-intermediate/(CK14/p63)-positive. The CADx system was able to analyse sufficient data for all types of epithelial proliferative lesions of the breast including invasive breast cancer. This system may be useful for pathological diagnosis of breast CNB in routine investigations. © Article author(s) (or

  1. Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal breast epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the breast.

    PubMed

    Boecker, Werner; Stenman, Göran; Schroeder, Tina; Schumacher, Udo; Loening, Thomas; Stahnke, Lisa; Löhnert, Catharina; Siering, Robert Michael; Kuper, Arthur; Samoilova, Vera; Tiemann, Markus; Korsching, Eberhard; Buchwalow, Igor

    2017-05-01

    We contend that knowledge about the cellular composition of normal breast epithelium is a prerequisite for understanding proliferative breast disease. Against this background, we used multicolor immunofluorescence to study normal breast epithelium and two types of intraepithelial proliferative breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal breast epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal breast epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal breast epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal breast epithelium and proliferative breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the breast.

  2. Significance of DNA Replication Licensing Proteins (MCM2, MCM5 and CDC6), p16 and p63 as Markers of Premalignant Lesions of the Uterine Cervix: Its Usefulness to Predict Malignant Potential

    PubMed Central

    Saritha, VN; Veena, VS; Krishna, KM Jagathnath; Somanathan, Thara; Sujathan, K

    2018-01-01

    Cervical cancer continues to be a leading cancer among women in many parts of the world. Nation-wide screening with the Pap smear has not been implemented in India due to the lack of adequately trained cytologists. Identification of biomarkers to predict malignant potential of the identified low risk lesions is essential to avoid excessive retesting and follow up. The current study analyzed the expression patterns of DNA replication licensing proteins, proliferation inhibitor protein p16INK4A and tumor suppresser protein p63 in cervical tissues and smears to assess the ability of these proteins to predict progression. Methods: Cervical smears and corresponding tissues were immunostained using mouse monoclonal antibodies against MCM2, MCM5, CDC6, p16 and p63. Smears were treated with a non-ionic surfactant sodium deoxycholate prior to immuno-cytochemistry. The standard ABC method of immunohistochemistry was performed using DAB as the chromogen. The immunostained samples were scored on a 0-3+ scale and staining patterns of smears were compared with those of tissue sections. Sensitivity and specificity for each of these markers were calculated taking histopathology as the gold standard. Result: All the markers were positive in malignant and dysplastic cells. MCM protein expression was found to be up-regulated in LSIL, HSIL and in malignancies to a greater extent than p16 as well as p63. CDC6 protein was preferentially expressed in high grade lesions and in invasive squamous cell carcinomas. A progressive increase in the expression of DNA replication licensing proteins in accordance with the grades of cervical intraepithelial lesion suggests these markers as significant to predict malignant potential of low grade lesions in cervical smears. Conclusion: MCMs and CDC6 can be applied as biomarkers to predict malignant potential of low grade lesions identified in screening programmes and retesting / follow up might be confined to those with high risk lesions alone so that

  3. A Novel Hydroxamate-Based Compound WMJ-J-09 Causes Head and Neck Squamous Cell Carcinoma Cell Death via LKB1-AMPK-p38MAPK-p63-Survivin Cascade.

    PubMed

    Yen, Chia-Sheng; Choy, Cheuk-Sing; Huang, Wei-Jan; Huang, Shiu-Wen; Lai, Pin-Ye; Yu, Meng-Chieh; Shiue, Ching; Hsu, Ya-Fen; Hsu, Ming-Jen

    2018-01-01

    Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09's enhancing effects in p63 phosphorylation, p21 elevation and survivin reduction. Moreover, WMJ-J-09 caused an increase in α-tubulin acetylation and interfered with microtubule assembly. Furthermore, WMJ-J-09 suppressed the growth of subcutaneous FaDu xenografts in vivo . Taken together, WMJ-J-09-induced FaDu cell death may involve LKB1-AMPK-p38MAPK-p63-survivin signaling cascade. HDACs inhibition and disruption of microtubule assembly may also contribute to WMJ-J-09's actions in FaDu cells. This study suggests that WMJ-J-09 may be a potential lead compound and warrant the clinical development in the treatment of HNSCC.

  4. miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1.

    PubMed

    Sun, Xianglun; Li, Youkong; Yu, Jie; Pei, Hong; Luo, Pengcheng; Zhang, Jie

    2015-05-01

    Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Flight Investigation of Effect of Various Vertical-Tail Modifications on the Directional Stability and Control Characteristics of the P-63A-1 Airplane (AAF No. 42-68889)

    NASA Technical Reports Server (NTRS)

    Johnson, Harold I.

    1946-01-01

    Because the results of preliminary flight tests had indicated. the P-63A-1 airplane possessed insufficient directional stability, the NACA and the manufacturer (Bell Aircraft Corporation) suggested three vertical-tail modifications to remedy the deficiencies in the directional characteristics. These modifications included an enlarged vertical tail formed by adding a tip extension to the original vertical tail, a large sharp-edge ventral fin, and a small dorsal fin. The enlarged vertical tail involved only a slight increase in total vertical-tail area from 23.73 to 26.58 square feet but a relatively much larger increase in geometric aspect ratio from 1.24 to 1.73 based on height and area above the horizontal tail. At the request of the Air Material Command, Army Air Forces, flight tests were made to determine the effect of these modifications and of some combinations of these modifications on the directional stability and control characteristics of the airplane, In all, six different vertical-tail. configurations were investigated to determine the lateral and directional oscillation characteristics of the airplane, the sideslip characteristics, the yaw due to ailerons in rudder-fixed rolls from turns and pull-outs, the trim changes due to speed changes; and the trim changes due to power changes. Results of the tests showed that the enlarged vertical tail approximately doubled the directional stability of the airplane and that the pilots considered the directional stability provided by the enlarged vertical tail to be satisfactory. Calculations based on sideslip data obtained at an indicated airspeed of 300 miles per hour showed that the directional stability of the airplane with the original vertical tail corresponded to a value of 0(sub n beta) of -0.00056 whereas for the enlarged vertical tail the estimated va1ue of C(sub n beta) was -0.00130, The ventral fin was found to increase by a moderate amount the directional stability of the airplane with the original

  6. Links | CTIO

    Science.gov Websites

    MNRAS New Astronomy New Scientist PASP SAO/NASA ADS Science StarHeads (people) Newsletters, Newspapers & Other Links 4th Region Info Astronomy Pic of the Day AstroWeb CDS AstroResources STScI BBC news

  7. Soilcrust Links

    Science.gov Websites

    Soil Crust Home Crust 101 Advanced Gallery References CCERS Site Links updated: April 24, 2006 /soils.htm This site has information on soil crusts, as well other information about the park. Biological Soil Crusts - Webs of Life in the Desert Two page, color handout on biological soils crusts. (303k PDF

  8. An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: III. expressions of EMA, CEA, CA19-9, CDX-2, p53, Ki-67 antigen, TTF-1, vimentin, and p63 in normal mucosa and in 42 cases

    PubMed Central

    Terada, Tadashi

    2013-01-01

    There have no comprehensive immunohistochemical studies of primary signet ring cell carcinoma (SRCC) in the stomach and colorectum. The author examined the expression of nine common antigens (EMA, CEA, CA19-9, CDX-2, p53, Ki-67 antigen, TTF-1, vimentin, and p63) in the non-tumorous normal epithelium of the stomach and colorectum and in 42 cases of primary SRCC of the stomach (30 cases) and colorectum (12 cases). The normal epithelium of the stomach and colon consistently (100%) expressed EMA, CEA, CA19-9, CDX-2, and Ki-67 (labeling <15%). Normal epithelium of these locations never expressed p53, TTF-1, vimentin, and p63. In the primary gastric SRCC, the expression percentage of EMA was 57% (17/30), CEA 100% (30/30), CA19-9 100% (30/30), CDX-2 43% (13/30), p53 83% (25/30), Ki-67 100% (30/30) (labeling index= 36 ± 23 %), TTF-1 0% (0/30), vimentin 0% (0/30), and p63 0% (0/30). In primary colorectal SRCC, the expression percentage of EMA was 25% (3/12), CEA 100% (12/12), CA19-9 100% (12/12), CDX-2 93% (28/30), p53 75% (9/12), Ki-67 100% (30/30) (labeling index= 47% ± 26 %), TTF-1 0% (0/12), vimentin 0% (0/12), and p63 0% (0/12). A comparative statistical analysis showed significant difference in EMA (gastric SRCC 57% vs colorectal SRCC 25%) and CDX-2 (43% vs 93%). There were no significant differences in the other seven antigens’ expression between primary gastric SRCC and primary colorectal SRCC. These findings provide much knowledge of primary SRCC of the stomach and colorectum. The data indicated primary gastric SRCC frequently express EMA but not CDX-2 whereas primary colorectal SRCC frequently express CDX-2 but not EMA. These findings also suggest that EMA and CDX-2 are down-regulated during the gastric SRCC carcinogenesis. This down regulations may be associated with the malignant transformation of gastric SRCC. The data of colorectal SRCC suggest EMA is markedly down-regulated and also suggest that this EMA down-regulation may be associated with the

  9. Acquisition of Epithelial-Mesenchymal Transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway

    PubMed Central

    Wang, Zhiwei; Li, Yiwei; Kong, Dejuan; Banerjee, Sanjeev; Ahmad, Aamir; Azmi, Asfar Sohail; Ali, Shadan; Abbruzzese, James L.; Gallick, Gary E.; Sarkar, Fazlul H

    2009-01-01

    Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat, in part due to de novo and acquired chemo- and radio-resistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype which is reminiscent of “cancer stem-like cells (CSC)”; however the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study demonstrates that Notch-2 and its ligand Jagged-1 are highly up-regulated in GR cells, which is consistent with the role of Notch signaling pathway in the acquisition of EMT and CSC phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition (MET), which was associated with decreased expression of vimentin, ZEB1, Slug, Snail and NF-κB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemo-resistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemo-resistance toward the prevention of tumor progression and/or treatment of metastatic PC. PMID:19276344

  10. Sex-linked dominant

    MedlinePlus

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  11. p63 in Development and Maintenance of the Prostate Epithelium

    DTIC Science & Technology

    2009-03-01

    S Signoretti, J Simko ,G Thomas , P Troncoso, T Tsuzuki, G JLH van Leenders, XJ Yang, M Zhou, W D Figg, A Hoque and M S Lucia. A working group...cell proliferation and cancer progression. Cancer Cell. 2008;14(2):146-55. 8. Sabbisetti V, Di Napoli A, Seeley A, Amato AM, O’Regan E, Ghebremichael

  12. Novel Insights into p63 Expression and Function in Prostate

    DTIC Science & Technology

    2004-07-15

    Gene Family, In Metastatic Prostate Cancer Cells (1999) 49. Kononen, J., Bubendorf, L., Kallioniemi, A., Barlund, M., Schraml, P., Leighton , S... Christiansen -Weber, T., and Haas, M. Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell

  13. Linking Policy | Smokefree 60+

    Cancer.gov

    Links to individual pages within the Smokefree 60+ website are permissible, provided attribution is made to 60plus.smokefree.gov and any descriptive notes accurately reflect the content of the linked page(s).

  14. SciLinks

    Science.gov Websites

    SciLinks Forgot your login? Sign up for FREE access Log In I'm a ... Teacher Student User Name questions and satisfy their curiosity Learn More Sign up for Free Access Sites in the SciLinks program . SciLinks-Targeted, Grade-Specific Web Content for your Books Free web content to extend and expand student

  15. Synthesising topological links

    DOE PAGES

    Baas, Nils A.; Seeman, Nadrian C.; Stacey, Andrew

    2014-10-14

    In this paper, we discuss the chemical synthesis of topological links, in particular higher order links which have the Brunnian property (namely that removal of any one component unlinks the entire system). Finally, we suggest how to obtain both two dimensional and three dimensional objects (surfaces and solids, respectively) which also have this Brunnian property.

  16. Broken Links Tools

    EPA Pesticide Factsheets

    Some of these tools can be used on Drupal pages that are not published yet, or on non-Drupal content. Some, such as the Bookmarklet tools, can help make checking and correcting your links easier when used alongside Drupal's link reports.

  17. TWSTFT Link Calibration Report

    DTIC Science & Technology

    2015-09-01

    1 Annex II. TWSTFT link calibration with a GPS calibrator Calibration reference: CI-888-2015 Version history: ZJ/V0/25Feb2015, V0a,b/HE/ZJ...7Mar; V0s/VZ9Mar; V0d,e,f+/DM10,17Mar; V1.0/1Apr; Final version 1Sept2015 TWSTFT link calibration report -- Calibration of the Lab(k)-PTB UTC...bipm.org * Coordinator Abstract This report includes the calibration results of the Lab(k)-PTB TWSTFT link and closure measurements of the BIPM

  18. Cross-linked polyethylene does not reduce wear in total knee arthroplasty.

    PubMed

    Lasurt-Bachs, S; Torner, P; Maculé, F; Prats, E; Menéndez-García, F; Ríos-Guillermo, J; Torrents, A

    To compare two different types of inserts: Ultra-high molecular weight polyethylene (UHMWPE) and cross-linked polyethylene with a quantitative and qualitative study of polyethylene wear particles in synovial fluid 3 years after total knee arthroplasty. A prospective, randomized, controlled cohort study with blinded evaluation was carried out on 25 patients undergoing staged bilateral total knee replacement, 6 months apart. Knee arthrocentesis was performed on 12 patients 3 years after surgery, and the polyethylene particles were analyzed. No significant differences were found in the number of particles generated by the two different types of inserts at 3 years from total knee arthroplasty (3,000×: x¯ cross-linked=849.7; x¯ UHMWPE=796.9; P=.63; 20,000×: x¯ cross-linked=66.3; x¯ UHMWPE=73.1; P=.76). Likewise, no differences in the probability of finding elongated (χ 2 =0.19; P=.66) or rounded (χ 2 =1.44; P=.23) particles in both types of inserts were observed. However, the probability of finding fibrillar particles is 3.08 times greater in UHMWPE. Cross-linked polyethylene does not significantly reduce the generation of polyethylene particles in patients with total knee arthroplasty, 3 years after the surgical procedure. Copyright © 2018 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. CERES Web Links

    Atmospheric Science Data Center

    2013-03-21

    ...   Web Links to Relevant CERES Information Relevant information about CERES, CERES references, ... Instrument Working Group Home Page Aerosol Retrieval Web Page  (Center for Satellite Applications and Research) ...

  20. Deep Space Quantum Link

    NASA Astrophysics Data System (ADS)

    Mohageg, M.; Strekalov, D.; Dolinar, S.; Shaw, M.; Yu, N.

    2018-02-01

    The Deep Space Quantum Link will test the effects of gravity on quantum systems, test the non-locality of quantum states at deep space distances, and perform long distance quantum teleportation to an Earth-based receiver.

  1. Sex-linked recessive

    MedlinePlus

    X-linked recessive diseases most often occur in males. Males have only one X chromosome. A single recessive ... half of the XY gene pair in the male. However, the Y chromosome doesn't contain most ...

  2. Linked Ocean Data

    NASA Astrophysics Data System (ADS)

    Leadbetter, Adam; Arko, Robert; Chandler, Cynthia; Shepherd, Adam

    2014-05-01

    "Linked Data" is a term used in Computer Science to encapsulate a methodology for publishing data and metadata in a structured format so that links may be created and exploited between objects. Berners-Lee (2006) outlines the following four design principles of a Linked Data system: Use Uniform Resource Identifiers (URIs) as names for things. Use HyperText Transfer Protocol (HTTP) URIs so that people can look up those names. When someone looks up a URI, provide useful information, using the standards (Resource Description Framework [RDF] and the RDF query language [SPARQL]). Include links to other URIs so that they can discover more things. In 2010, Berners-Lee revisited his original design plan for Linked Data to encourage data owners along a path to "good Linked Data". This revision involved the creation of a five star rating system for Linked Data outlined below. One star: Available on the web (in any format). Two stars: Available as machine-readable structured data (e.g. An Excel spreadsheet instead of an image scan of a table). Three stars: As two stars plus the use of a non-proprietary format (e.g. Comma Separated Values instead of Excel). Four stars: As three stars plus the use of open standards from the World Wide Web Commission (W3C) (i.e. RDF and SPARQL) to identify things, so that people can point to your data and metadata. Five stars: All the above plus link your data to other people's data to provide context Here we present work building on the SeaDataNet common vocabularies served by the NERC Vocabulary Server, connecting projects such as the Rolling Deck to Repository (R2R) and the Biological and Chemical Oceanography Data Management Office (BCO-DMO) and other vocabularies such as the Marine Metadata Interoperability Ontology Register and Repository and the NASA Global Change Master Directory to create a Linked Ocean Data cloud. Publishing the vocabularies and metadata in standard RDF XML and exposing SPARQL endpoints renders them five-star Linked

  3. Airborne Data Link Study Report

    DOT National Transportation Integrated Search

    1996-01-01

    This report represents evaluations of Data Link products and services in a simulated aviation opearation. The study addresses key issues related to alerting schemes for Data Link messages, positioning of Data Link displays, and mode of presentation o...

  4. Australian Curriculum Linked Lessons

    ERIC Educational Resources Information Center

    Hurrell, Derek; O'Neil, Jennifer

    2011-01-01

    In providing a continued focus on tasks and activities that help to illustrate key ideas embedded in the new Australian Curriculum, this issue the authors focus, on Geometry in the Measurement and Geometry strand with strong links for an integrated focus on the Statistics and Probability strand. The small unit of work on the sorting and…

  5. Linking assumptions in amblyopia

    PubMed Central

    LEVI, DENNIS M.

    2017-01-01

    Over the last 35 years or so, there has been substantial progress in revealing and characterizing the many interesting and sometimes mysterious sensory abnormalities that accompany amblyopia. A goal of many of the studies has been to try to make the link between the sensory losses and the underlying neural losses, resulting in several hypotheses about the site, nature, and cause of amblyopia. This article reviews some of these hypotheses, and the assumptions that link the sensory losses to specific physiological alterations in the brain. Despite intensive study, it turns out to be quite difficult to make a simple linking hypothesis, at least at the level of single neurons, and the locus of the sensory loss remains elusive. It is now clear that the simplest notion—that reduced contrast sensitivity of neurons in cortical area V1 explains the reduction in contrast sensitivity—is too simplistic. Considerations of noise, noise correlations, pooling, and the weighting of information also play a critically important role in making perceptual decisions, and our current models of amblyopia do not adequately take these into account. Indeed, although the reduction of contrast sensitivity is generally considered to reflect “early” neural changes, it seems plausible that it reflects changes at many stages of visual processing. PMID:23879956

  6. The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus.

    PubMed

    Richoz, Olivier; Tabibian, David; Hammer, Arthur; Majo, François; Nicolas, Michael; Hafezi, Farhad

    2014-07-22

    When treating peripheral ectatic disease-like pellucid marginal degeneration (PMD), corneal cross-linking with UV-A and riboflavin (CXL) must be applied eccentrically to the periphery of the lower cornea, partly irradiating the corneal limbus. Here, we investigated the effect of standard and double-standard fluence corneal cross-linking with riboflavin and UV-A (CXL) on cornea and corneal limbus in the rabbit eye in vivo. Epithelium-off CXL was performed in male New Zealand White rabbits with two irradiation diameters (7 mm central cornea, 13 mm cornea and limbus), using standard fluence (5.4 J/cm(2)) and double-standard fluence (10.8 J/cm(2)) settings. Controls were subjected to epithelial removal and riboflavin instillation, but were not irradiated with UV-A. Following CXL, animals were examined daily until complete closure of the epithelium, and at 7, 14, 21, and 28 days. Animals were killed and a corneoscleral button was excised and processed for light microscopy and immunohistochemistry. For both irradiation diameters and fluences tested, no signs of endothelial damage or limbal vessel thrombosis were observed, and time to re-epithelialization was similar to untreated controls. Histological and immunohistochemical analysis revealed no differences in the p63 putative stem cell marker expression pattern. Even when using fluence twice as high as the one used in current clinical CXL settings, circumferential UV-A irradiation of the corneal limbus does not alter the regenerative capacity of the limbal epithelial cells, and the expression pattern of the putative stem cell marker p63 remains unchanged. This suggests that eccentric CXL may be performed safely in PMD. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  7. Hamilton's missing link.

    PubMed

    van Veelen, Matthijs

    2007-06-07

    Hamilton's famous rule was presented in 1964 in a paper called "The genetical theory of social behaviour (I and II)", Journal of Theoretical Biology 7, 1-16, 17-32. The paper contains a mathematical genetical model from which the rule supposedly follows, but it does not provide a link between the paper's central result, which states that selection dynamics take the population to a state where mean inclusive fitness is maximized, and the rule, which states that selection will lead to maximization of individual inclusive fitness. This note provides a condition under which Hamilton's rule does follow from his central result.

  8. EEE Links. Volume 5

    NASA Technical Reports Server (NTRS)

    Humphrey, Robert (Editor)

    1999-01-01

    The EEE Links Newsletter is a quarterly publication produced by Code 562 in support of the NASA HQ funded NASA Electronic Parts and Packaging (NEPP) Program. The newsletter is produced as an electronic format deliverable made available via the referenced www site administered by Code 562, The newsletter publishes brief articles on topics of interest to NASA programs and projects in the area of electronic parts and packaging. The newsletter does not provide information pertaining to patented or proprietary information. The information provided is at the level of that produced by industry and university researchers and is published at national and international conferences.

  9. ACES microwave link requirements.

    PubMed

    Uhrich, P M; Guillernot, P; Aubry, P; Gonzalez, F; Salomon, C

    2000-01-01

    Atomic Clock Ensemble in Space (ACES) is a project of the European Space Agency on-board the future International Space Station (ISS). The payload consists mainly of two atomic frequency standards, one space hydrogen maser (SHM) prepared by the Observatoire de Neuchatel (Switzerland), and one cold atom caesium clock called PHARAO prepared by the CNES (France), with the participation of the BNM-LPTF, the ENS-LKB, and the CNRS-LHA. Because of the anticipated performances of these clocks on-board the ISS, the requirements of the links between the payload and the clocks on the Earth are at the limits of the known potential of the optical or microwave techniques. The microwave link (MWL) requirements are described in this paper. Taking into account the characteristics of the ISS orbit, and fixing an arbitrary limit to the additional noise brought to the clock readings by the MWL, the computation of the required stability leads to two kinds of requirements: the first one at the subpicosecond level over each single continuous pass of the ISS above any Earth station, and the second one at the level of one part in 10(16) and below over a one day or more averaging period. Moreover, the ISS orbit parameters should lead to a knowledge of the ACES clock position at the m level, and of the ACES clock speed at the mm/s level.

  10. Predicting missing links and identifying spurious links via likelihood analysis

    NASA Astrophysics Data System (ADS)

    Pan, Liming; Zhou, Tao; Lü, Linyuan; Hu, Chin-Kun

    2016-03-01

    Real network data is often incomplete and noisy, where link prediction algorithms and spurious link identification algorithms can be applied. Thus far, it lacks a general method to transform network organizing mechanisms to link prediction algorithms. Here we use an algorithmic framework where a network’s probability is calculated according to a predefined structural Hamiltonian that takes into account the network organizing principles, and a non-observed link is scored by the conditional probability of adding the link to the observed network. Extensive numerical simulations show that the proposed algorithm has remarkably higher accuracy than the state-of-the-art methods in uncovering missing links and identifying spurious links in many complex biological and social networks. Such method also finds applications in exploring the underlying network evolutionary mechanisms.

  11. Predicting missing links and identifying spurious links via likelihood analysis

    PubMed Central

    Pan, Liming; Zhou, Tao; Lü, Linyuan; Hu, Chin-Kun

    2016-01-01

    Real network data is often incomplete and noisy, where link prediction algorithms and spurious link identification algorithms can be applied. Thus far, it lacks a general method to transform network organizing mechanisms to link prediction algorithms. Here we use an algorithmic framework where a network’s probability is calculated according to a predefined structural Hamiltonian that takes into account the network organizing principles, and a non-observed link is scored by the conditional probability of adding the link to the observed network. Extensive numerical simulations show that the proposed algorithm has remarkably higher accuracy than the state-of-the-art methods in uncovering missing links and identifying spurious links in many complex biological and social networks. Such method also finds applications in exploring the underlying network evolutionary mechanisms. PMID:26961965

  12. Multilevel DC link inverter

    DOEpatents

    Su, Gui-Jia

    2003-06-10

    A multilevel DC link inverter and method for improving torque response and current regulation in permanent magnet motors and switched reluctance motors having a low inductance includes a plurality of voltage controlled cells connected in series for applying a resulting dc voltage comprised of one or more incremental dc voltages. The cells are provided with switches for increasing the resulting applied dc voltage as speed and back EMF increase, while limiting the voltage that is applied to the commutation switches to perform PWM or dc voltage stepping functions, so as to limit current ripple in the stator windings below an acceptable level, typically 5%. Several embodiments are disclosed including inverters using IGBT's, inverters using thyristors. All of the inverters are operable in both motoring and regenerating modes.

  13. Link for Injured Kids

    PubMed Central

    Ramirez, Marizen; Toussaint, Maisha; Woods-Jaeger, Briana; Harland, Karisa; Wetjen, Kristel; Wilgenbusch, Tammy; Pitcher, Graeme; Jennissen, Charles

    2017-01-01

    Objective Injury, the most common type of pediatric trauma, can lead to a number of adverse psychosocial outcomes, including posttraumatic stress disorder. Currently, few evidence-based parent programs exist to support children hospitalized after a traumatic injury. Using methods in evaluation and intervention research, we completed a formative research study to develop a new program of psychological first aid, Link for Injured Kids, aimed to educate parents in supporting their children after a severe traumatic injury. Methods Using qualitative methods, we held focus groups with parents and pediatric trauma providers of children hospitalized at a Level I Children's Hospital because of an injury in 2012. We asked focus group participants to describe reactions to trauma and review drafts of our intervention materials. Results Health professionals and caregivers reported a broad spectrum of emotional responses by their children or patients; however, difficulties were experienced during recovery at home and upon returning to school. All parents and health professionals recommended that interventions be offered to parents either in the emergency department or close to discharge among admissions. Conclusions Results from this study strongly indicate a need for posttrauma interventions, particularly in rural settings, to support families of children to address the psychosocial outcomes in the aftermath of an injury. Findings presented here describe the process of intervention development that responds to the needs of an affected population. PMID:26428077

  14. [Hospitals as vital links].

    PubMed

    Klink, A

    2013-01-01

    The reform of the system in 2006 aimed at reducing waiting lists in an efficient manner. Performance-linked funding and regulated competition did indeed lead to improved efficiency. The other side of the coin is overtreatment, and expensive and not infrequently damaging growth in volume. In order to control costs, three strategies have been determined: agreements with an annual cap on volume; (b) collaboration of regional health-care providers with the mission of improving results in health care (with profit-sharing if costs fall); and (c) fusions reducing the number of hospitals which reduces the burden of injuries (supply no longer creates its own demand). This article comments on these strategies. The author argues for a fourth approach: if the quality of health care improves, the number of complications will fall, overtreatment will decline and the outcome will be a decrease in burden of injuries. This requires the health care insurers to modify the way they manage their contracts and methods of payment, and stimulates competition based on quality.

  15. Linking to the Future

    NASA Astrophysics Data System (ADS)

    Moore, John W.

    1999-09-01

    my copy of JCE in the mail each month, and I expect you do too. I can glance at the cover to get an overview of an issue's content, and I usually am enticed inside by intriguing cover art. I can scan the table of contents to find articles I want to read, or I can just browse through the issue to see what looks interesting. Usually the editors have juxtaposed related articles so that I often find a small treasure trove. The printed Journal is quite portable and can be read in a car or airplane. It will last a long time, and until the paper deteriorates, I will never have a problem reading back issues. I have almost every issue from the first day I subscribed and have even added some older ones from collections of retired colleagues who no longer had shelf space for them. I certainly would not want to give up my printed copies, and I want to keep getting them. I find that JCE Online provides a different kind of resource that is equally valuable. It contains more information, and information that is more appropriate in electronic form. It links related ideas into a much more complex web of information than is possible in print. And it opens pathways to lots of information that is not part of JCE but resides elsewhere. Using this issue as an example, let's take a tour of what JCE Online can do.

    • Point your Web browser to http://jchemed.chem.wisc.edu
    • Click on Journal and then on Current Issue (unless September 1999 is no longer the current issue, in which case you will find it in Past Issues).
    • In the table of contents, find the article "UV Catalysis, Cyanotype Photography, and Sunscreens". Click on the title.
    • When the abstract appears, click on Full Text (PDF) to see the article, just as it appears on page 1199 in this issue.
    • When you are prompted, enter the name and subscriber number from your address label.
    • At the end of the article you will find that supplementary materials are available (including a procedure for testing

    • Object linking in repositories

      NASA Technical Reports Server (NTRS)

      Eichmann, David (Editor); Beck, Jon; Atkins, John; Bailey, Bill

      1992-01-01

      This topic is covered in three sections. The first section explores some of the architectural ramifications of extending the Eichmann/Atkins lattice-based classification scheme to encompass the assets of the full life cycle of software development. A model is considered that provides explicit links between objects in addition to the edges connecting classification vertices in the standard lattice. The second section gives a description of the efforts to implement the repository architecture using a commercially available object-oriented database management system. Some of the features of this implementation are described, and some of the next steps to be taken to produce a working prototype of the repository are pointed out. In the final section, it is argued that design and instantiation of reusable components have competing criteria (design-for-reuse strives for generality, design-with-reuse strives for specificity) and that providing mechanisms for each can be complementary rather than antagonistic. In particular, it is demonstrated how program slicing techniques can be applied to customization of reusable components.

    • Protective link for superconducting coil

      DOEpatents

      Umans, Stephen D [Belmont, MA

      2009-12-08

      A superconducting coil system includes a superconducting coil and a protective link of superconducting material coupled to the superconducting coil. A rotating machine includes first and second coils and a protective link of superconducting material. The second coil is operable to rotate with respect to the first coil. One of the first and second coils is a superconducting coil. The protective link is coupled to the superconducting coil.

    • Using ATM over SATCOM links

      NASA Technical Reports Server (NTRS)

      Comparetto, Gary M.

      1995-01-01

      The Asynchronous Transfer Mode (ATM) protocol is studied from the standpoint of determining what limitations, if any, exist in using it over satellite links. It is concluded that, while there is nothing intrinsic about ATM that would generally preclude its use over satellite links, there are, however, several intrinsic characteristics of satellite links, as well as some satellite system configuration-specific issues, that must be taken into account.

    • The chain of cross-contamination: link-by-link.

      PubMed

      Schwartz, Jeanne

      2002-01-01

      Conscious efforts must be made to break the chain of cross-contamination--link-by-link. Pay attention to detail Avoid being careless Avoid touching objects while wearing soiled gloves Frequently wash hands (15-second hand washing) to remove pathogens--before and after gloving, and before handling food or drink Wear all PPE, and change accordingly.

    • Interpreting Linked Psychomotor Performance Scores

      ERIC Educational Resources Information Center

      Looney, Marilyn A.

      2013-01-01

      Given that equating/linking applications are now appearing in kinesiology literature, this article provides an overview of the different types of linked test scores: equated, concordant, and predicted. It also addresses the different types of evidence required to determine whether the scores from two different field tests (measuring the same…

  1. Game Changer: Linked Learning Detroit

    ERIC Educational Resources Information Center

    ConnectEd: The California Center for College and Career, 2016

    2016-01-01

    JP Morgan Chase joins the Skillman Foundation, the Ford Foundation, and the Ford Motor Company Fund, whose grants total $7 million and will connect 10,000 Detroit high school students to career education and work experiences over the next three years through Linked Learning Detroit. Learn about Linked Learning Detroit through interviews with…

  2. SUNREL Related Links | Buildings | NREL

    Science.gov Websites

    SUNREL Related Links SUNREL Related Links DOE Simulation Software Tools Directory a directory of 301 building software tools for evaluation of energy efficiency, renewable energy, and sustainability in buildings. TREAT Software Program a computer program that uses SUNREL and is designed to provide

  3. [Sex-linked juvenile retinoschisis].

    PubMed

    François, P; Turut, P; Soltysik, C; Hache, J C

    1976-02-01

    About 13 observations of sexe linked juvenile retinoschisis, the authors describe the ophthalmoscopic, fluorographic and functional aspects of the disease whose caracteristics are:--its sexe linked recessive heredity; --its clinical characterestics associating: a microcystic macular degeneration, peripheral retinal lesions, vitreous body alterations, --an electroretinogram of the negative type.

  4. The Missing Link: The Use of Link Words and Phrases as a Link to Manuscript Quality

    ERIC Educational Resources Information Center

    Onwuegbuzie, Anthony J.

    2016-01-01

    In this article, I provide a typology of transition words/phrases. This typology comprises 12 dimensions of link words/phrases that capture 277 link words/phrases. Using QDA Miner, WordStat, and SPSS--a computer-assisted mixed methods data analysis software, content analysis software, and statistical software, respectively--I analyzed 74…

  5. Multipurpose broadcast data link architecture

    DOT National Transportation Integrated Search

    2000-04-07

    The aviation community has recently expressed significant interest in a broadcast mode of data link services. A broadcast mode of delivery is well suited for applications of a general interest to many users and for applications that require periodic ...

  6. Linking to NSCEP's Online Publications

    EPA Pesticide Factsheets

    Each online document has a permanent URL that can be linked to for future reference. To find the short URL for a document you need to be in the document and able to view the icon bar above the document.

  7. LinkMind: Link Optimization in Swarming Mobile Sensor Networks

    PubMed Central

    Ngo, Trung Dung

    2011-01-01

    A swarming mobile sensor network is comprised of a swarm of wirelessly connected mobile robots equipped with various sensors. Such a network can be applied in an uncertain environment for services such as cooperative navigation and exploration, object identification and information gathering. One of the most advantageous properties of the swarming wireless sensor network is that mobile nodes can work cooperatively to organize an ad-hoc network and optimize the network link capacity to maximize the transmission of gathered data from a source to a target. This paper describes a new method of link optimization of swarming mobile sensor networks. The new method is based on combination of the artificial potential force guaranteeing connectivities of the mobile sensor nodes and the max-flow min-cut theorem of graph theory ensuring optimization of the network link capacity. The developed algorithm is demonstrated and evaluated in simulation. PMID:22164070

  8. LinkMind: link optimization in swarming mobile sensor networks.

    PubMed

    Ngo, Trung Dung

    2011-01-01

    A swarming mobile sensor network is comprised of a swarm of wirelessly connected mobile robots equipped with various sensors. Such a network can be applied in an uncertain environment for services such as cooperative navigation and exploration, object identification and information gathering. One of the most advantageous properties of the swarming wireless sensor network is that mobile nodes can work cooperatively to organize an ad-hoc network and optimize the network link capacity to maximize the transmission of gathered data from a source to a target. This paper describes a new method of link optimization of swarming mobile sensor networks. The new method is based on combination of the artificial potential force guaranteeing connectivities of the mobile sensor nodes and the max-flow min-cut theorem of graph theory ensuring optimization of the network link capacity. The developed algorithm is demonstrated and evaluated in simulation.

  9. Seismic link at plate boundary

    NASA Astrophysics Data System (ADS)

    Ramdani, Faical; Kettani, Omar; Tadili, Benaissa

    2015-06-01

    Seismic triggering at plate boundaries has a very complex nature that includes seismic events at varying distances. The spatial orientation of triggering cannot be reduced to sequences from the main shocks. Seismic waves propagate at all times in all directions, particularly in highly active zones. No direct evidence can be obtained regarding which earthquakes trigger the shocks. The first approach is to determine the potential linked zones where triggering may occur. The second step is to determine the causality between the events and their triggered shocks. The spatial orientation of the links between events is established from pre-ordered networks and the adapted dependence of the spatio-temporal occurrence of earthquakes. Based on a coefficient of synchronous seismic activity to grid couples, we derive a network link by each threshold. The links of high thresholds are tested using the coherence of time series to determine the causality and related orientation. The resulting link orientations at the plate boundary conditions indicate that causal triggering seems to be localized along a major fault, as a stress transfer between two major faults, and parallel to the geothermal area extension.

  10. The OceanLink Project

    NASA Astrophysics Data System (ADS)

    Narock, T.; Arko, R. A.; Carbotte, S. M.; Chandler, C. L.; Cheatham, M.; Finin, T.; Hitzler, P.; Krisnadhi, A.; Raymond, L. M.; Shepherd, A.; Wiebe, P. H.

    2014-12-01

    A wide spectrum of maturing methods and tools, collectively characterized as the Semantic Web, is helping to vastly improve the dissemination of scientific research. Creating semantic integration requires input from both domain and cyberinfrastructure scientists. OceanLink, an NSF EarthCube Building Block, is demonstrating semantic technologies through the integration of geoscience data repositories, library holdings, conference abstracts, and funded research awards. Meeting project objectives involves applying semantic technologies to support data representation, discovery, sharing and integration. Our semantic cyberinfrastructure components include ontology design patterns, Linked Data collections, semantic provenance, and associated services to enhance data and knowledge discovery, interoperation, and integration. We discuss how these components are integrated, the continued automated and semi-automated creation of semantic metadata, and techniques we have developed to integrate ontologies, link resources, and preserve provenance and attribution.

  11. When He Said Linking, He Really Meant Linking

    ERIC Educational Resources Information Center

    Chudnov, Daniel

    2009-01-01

    There are many reasons to improve web links, starting with their design. The author tends to think about "design" on the web in terms of two things: (1) graphic/industrial design; and (2) human usability. A nice, clean URI (uniform resource identifier) that does not change, is readable to humans, is amenable to common web behaviors such as…

  12. Fix Broken and Redirected Links Using Group Dashboard Link Report

    EPA Pesticide Factsheets

    Learn how to use the tools provided by Drupal in the Group Dashboard to find and correct links on your site that are broken (404 and 403 error codes), or that redirect (301 and 302), for example to a homepage rather than the originally intended content.

  13. micromap: A Package for Linked Micromaps

    EPA Science Inventory

    The R package micromap is used to create linked micromaps, which display statistical summaries associated with areal units, or polygons. Linked micromaps provide a means to simultaneously summarize and display both statistical and geographic distributions by linking statistical ...

  14. Genetics Home Reference: X-linked thrombocytopenia

    MedlinePlus

    ... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

  15. Linking Sculpture to Core Subjects.

    ERIC Educational Resources Information Center

    Khilnani, Sharda; Culhane, Douglas

    1995-01-01

    This article describes a cooperative project between a teacher and sculptor to link sculpture with academic subjects within a self-contained class for 13-year-old students with learning disabilities. The nine-week project focused on biological habitats and included the construction of three-dimensional habitats on pieces of wood. (DB)

  16. Linking Learning, Teaching, and Development.

    ERIC Educational Resources Information Center

    Fiddler, Morris; Marienau, Catherine

    1995-01-01

    Learning-centered teaching links learning and development by creating a climate of exchange; using assessment to increase awareness of learning needs; promoting learning to learn; holding learners accountable; using multiple strategies for different learning styles; and involving learners in realistic and challenging goals. (SK)

  17. Simmondsia chinensis (Link) Schneid.: jojoba

    Treesearch

    Susan E. Meyer

    2008-01-01

    The Simmondsiaceae (jojoba family), has only 1 genus, Simmondsia, which consists of only 1 species, jojoba - S. chinensis (Link) Schneid. Once considered an isolated member of the box family (Buxaceae), jojoba is now regarded as sufficiently distinct to be placed in its own family. Jojoba is found from coastal and cis-montane southern California east to central Arizona...

  18. Linking HRD Practice and Research.

    ERIC Educational Resources Information Center

    1999

    This document contains four symposium papers on linking human resource development (HRD) theory and practice. "Partnership Research: Ensuring More Useful HRD Collaborations" (Ronald L. Jacobs), which proceeds from the premise that most HRD research has limited impact on practice because research problems are usually generated devoid of a…

  19. Linking Leadership to Student Learning

    ERIC Educational Resources Information Center

    Leithwood, Kenneth; Seashore-Louis, Karen

    2011-01-01

    "Linking Leadership to Student Learning" clearly shows how school leadership improves student achievement. The book is based on an ambitious five-year study on educational leadership that was sponsored by The Wallace Foundation. The authors studied 43 districts, across 9 states and 180 elementary, middle, and secondary schools. In this book,…

  20. Linking Outcomes to Organizational Planning.

    ERIC Educational Resources Information Center

    Ligon, Glynn; Jackson, Elaine

    Linking Outcomes to Organizational Planning (LOOP) was initiated during the 1984-85 school year in the Austin (Texas) Independent School District. LOOP was designed to ensure that evaluation, research, and informal findings became part of the instructional planning loop; to provide information to the Superintendent on progress toward priorities…

  1. Develop, Link, Foster, and Encourage

    ERIC Educational Resources Information Center

    Hyslop, Alisha

    2008-01-01

    The third recommendation in ACTE's postsecondary reform position statement is to develop curriculum and instructional offerings that link to careers, foster lifelong learning, and encourage completion. Concrete linkages must be developed between middle and high school, postsecondary education and work, with lifelong postsecondary learning a part…

  2. Linking to MedlinePlus

    MedlinePlus

    ... want to link patients or healthcare providers from electronic health record (EHR) systems to relevant MedlinePlus information, use MedlinePlus ... updates Subscribe to RSS Follow us Disclaimers Copyright Privacy Accessibility Quality Guidelines Viewers & Players MedlinePlus Connect for ...

  3. The intersubjective links in perversion.

    PubMed

    Eiguer, Alberto

    2007-10-01

    The author studies the intersubjective links which the pervert maintains with analyst or partner, attempting to indicate the differences between the investments in each case. Rather than accepting that empathy towards these patients is impossible to achieve and disturbs the countertransference profoundly, it attempts to show that these difficulties may be overcome if they are reinterpreted in the light of the theory of the intersubjective link. The author examines the theories and the practice of intersubjectivity and gives a definition of his approach to the link between two subjects. He applies these ideas to the case of a sexually masochistic female patient. The countertransference is marked successively by indifference, rejection and smothering. The analysis of the analyst's dream allows the situation to evolve. Failures in primary identification can result in domination over others and utilitarianism. The author examines the place of the challenge to the 'Law' and the father (in the attempt by the patient to put a theory to the test) in order to identify the figure of the witness in the pervert's intersubjective links. The desire of the transference would be marked by the figure of the witness rather than by that of the analyst as accomplice.

  4. Performance Assessment Links in Science.

    ERIC Educational Resources Information Center

    Quellmalz, Edys; Schank, Patricia; Hinojosa, Thomas; Padilla, Christine

    1999-01-01

    Describes work in progress at SRI International in the Performance Assessment Links in Science (PALS) project, which is developing an online, standards-based, interactive resource bank of science performance assessments. Coupled with the development of the resource bank is a program of research on effective use of these resources. (SLD)

  5. X-linked congenital panhypopituitarism.

    PubMed

    Schimke, R N; Spaulding, J J; Hollowell, J G

    1971-05-01

    Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

  6. Links between metabolism and cancer

    PubMed Central

    Dang, Chi V.

    2012-01-01

    Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes. PMID:22549953

  7. Object links in the repository

    NASA Technical Reports Server (NTRS)

    Beck, Jon; Eichmann, David

    1991-01-01

    Some of the architectural ramifications of extending the Eichmann/Atkins lattice-based classification scheme to encompass the assets of the full life-cycle of software development are explored. In particular, we wish to consider a model which provides explicit links between objects in addition to the edges connecting classification vertices in the standard lattice. The model we consider uses object-oriented terminology. Thus, the lattice is viewed as a data structure which contains class objects which exhibit inheritance. A description of the types of objects in the repository is presented, followed by a discussion of how they interrelate. We discuss features of the object-oriented model which support these objects and their links, and consider behavior which an implementation of the model should exhibit. Finally, we indicate some thoughts on implementing a prototype of this repository architecture.

  8. [Linking learning theory with practice].

    PubMed

    Ávalos-Carranza, María Teresa; Amador-Olvera, Eric; Zerón-Gutiérrez, Lydia

    2016-01-01

    It is often said that it is easier to learn what is observed and practiced on a daily basis; to the need to effectively link theory with practice considered in the process of teaching and learning, many strategies have been developed to allow this process to be carried out in a more efficiently maner. It is, therefore, very important to recognize that an appropriate teacher/student relationship is essential for students to acquire the skills and abilities required.

  9. HLA-linked rheumatoid arthritis

    SciTech Connect

    Hasstedt, S.J.; Clegg, D.O.; Ingles, L.

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. Inmore » addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. 79 refs., 9 tabs.« less

  10. Managing Your Team's Weakest Link.

    PubMed

    Hills, Laura

    2015-01-01

    Do you have a poor-performing employee on your medical practice team? If so, you're not alone. Unfortunately, this is a problem that many medical practice managers face. This article describes the best strategies for managing your team's weakest link. It explores common yet very difficult circumstances that cause low employee performance and that test the patience, heart, and skills of a practice manager. It guides readers through a process of self-discovery to determine whether their negative biases or grudges may be causing employees to perform poorly. It suggests several possible other reasons for weak employee performance, including problems with the job, practice, leadership, communication, and fit between the employee and the job. This article also suggests the best strategy for communicating concerns about performance to the weakest-link employee. It offers guidance to practice managers about protecting their time and energy when handling a poor performer. It provides a simple formula for calculating the cost of a low-performing employee, 10 possible personal reasons for the employee's poor work performance, specific questions to ask to uncover the reasons for poor performance, and an eight-rule strategy for confronting poor performance effectively. Finally, this article offers practice managers a practical strategy for handling resistance from their weakest link, illustrated with a sample dialogue.

  11. Brazil-Africa geological links

    NASA Astrophysics Data System (ADS)

    Torquato, Joaquim Raul; Cordani, Umberto G.

    1981-04-01

    In this work, the main evidence and conclusions regarding geological links between Brazil and Africa are summarized, with emphasis on the geochronological aspects. Taking into account the geographical position, as well as the similarities in the geochronological pattern, the following main provinces of the two continents are correlated: The Imataca and Falawatra complexes in the Guayana Shield and the Liberian Province of West Africa. The Paraguay-Araguaia and the Rockelide Fold Belts. The Sa˜o Luiz and the West African cratonic areas. The Caririan Fold Belt of northeastern Brazil and the Pan-Africa Belt of Nigeria and Cameroon. The JequiéComplex of Bahia, the Ntem Complex of Cameroon and similar rocks of Gabon and Angola. The Ribeira Fold Belt in Brazil and the West Congo and Damara Belts in West and South Africa. In addition, other geological links are considered, such as some of the major linear fault zones which can be traced across the margins of South America and Africa, in the pre-drift reconstructions. Correlations are also made of the tectonic and stratigraphic evolution of the Paranáand Karroo syneclises, and the Brazilian and African marginal basins around the South Atlantic, during their initial stages. Finally, several similarities in the tectonic evolution of South America and Africa, during and after the onset of drifting, are shown to be compatible with a recent origin for the South Atlantic floor, as required by sea-floor spreading and continental drift between South America and Africa.

  12. Production and Consumption of University Linked Data

    ERIC Educational Resources Information Center

    Zablith, Fouad; Fernandez, Miriam; Rowe, Matthew

    2015-01-01

    Linked Data increases the value of an organisation's data over the web by introducing explicit and machine processable links at the data level. We have adopted this new stream of data representation to produce and expose existing data within The Open University (OU) as Linked Data. We present in this paper our approach for producing the data,…

  13. Learning to Link Visual Contours

    PubMed Central

    Li, Wu; Piëch, Valentin; Gilbert, Charles D.

    2008-01-01

    SUMMARY In complex visual scenes, linking related contour elements is important for object recognition. This process, thought to be stimulus driven and hard wired, has substrates in primary visual cortex (V1). Here, however, we find contour integration in V1 to depend strongly on perceptual learning and top-down influences that are specific to contour detection. In naive monkeys the information about contours embedded in complex backgrounds is absent in V1 neuronal responses, and is independent of the locus of spatial attention. Training animals to find embedded contours induces strong contour-related responses specific to the trained retinotopic region. These responses are most robust when animals perform the contour detection task, but disappear under anesthesia. Our findings suggest that top-down influences dynamically adapt neural circuits according to specific perceptual tasks. This may serve as a general neuronal mechanism of perceptual learning, and reflect top-down mediated changes in cortical states. PMID:18255036

  14. Electrospun cross linked rosin fibers

    NASA Astrophysics Data System (ADS)

    Baek, Woo-il; Nirmala, R.; Barakat, Nasser A. M.; El-Newehy, Mohamed H.; Al-Deyab, Salem S.; Kim, Hak Yong

    2011-12-01

    In this study, we describe the first reported preparation of rosin in fiber form through use of an electrospinning technique utilizing various solvent systems. The polymer concentration of the formed fiber was studied by using various solvents such as chloroform, ethanol, N-N dimethylformamide (DMF), tetrahydrofuran (THF), acetone, and methylene chloride (MC). An electrospray of the solution resulted in the beaded form of the rosin. By varying the polymer concentration with MC, we were then able to obtain uniform fibers. However, the fibers exhibited large diameter. We believe that it is possible to reduce the diameter of the rosin fibers through appropriate selection of electrospinning parameters. In addition, the morphological transitions from beads, to beaded fiber, to fiber were studied at different polymer concentrations. We propose a possible physical cross linking mechanism for the formation of rosin fibers during the electrospinning process. Our results demonstrate the feasibility of producing fiber nanostructures of rosin by using an electrospinning technique.

  15. Linking brain, mind and behavior.

    PubMed

    Makeig, Scott; Gramann, Klaus; Jung, Tzyy-Ping; Sejnowski, Terrence J; Poizner, Howard

    2009-08-01

    Cortical brain areas and dynamics evolved to organize motor behavior in our three-dimensional environment also support more general human cognitive processes. Yet traditional brain imaging paradigms typically allow and record only minimal participant behavior, then reduce the recorded data to single map features of averaged responses. To more fully investigate the complex links between distributed brain dynamics and motivated natural behavior, we propose the development of wearable mobile brain/body imaging (MoBI) systems that continuously capture the wearer's high-density electrical brain and muscle signals, three-dimensional body movements, audiovisual scene and point of regard, plus new data-driven analysis methods to model their interrelationships. The new imaging modality should allow new insights into how spatially distributed brain dynamics support natural human cognition and agency.

  16. Security Concepts for Satellite Links

    NASA Astrophysics Data System (ADS)

    Tobehn, C.; Penné, B.; Rathje, R.; Weigl, A.; Gorecki, Ch.; Michalik, H.

    2008-08-01

    The high costs to develop, launch and maintain a satellite network makes protecting the assets imperative. Attacks may be passive such as eavesdropping on the payload data. More serious threat are active attacks that try to gain control of the satellite, which may lead to the total lost of the satellite asset. To counter these threats, new satellite and ground systems are using cryptographic technologies to provide a range of services: confidentiality, entity & message authentication, and data integrity. Additionally, key management cryptographic services are required to support these services. This paper describes the key points of current satellite control and operations, that are authentication of the access to the satellite TMTC link and encryption of security relevant TM/TC data. For payload data management the key points are multi-user ground station access and high data rates both requiring frequent updates and uploads of keys with the corresponding key management methods. For secure satellite management authentication & key negotiation algorithms as HMAC-RIPEMD160, EC- DSA and EC-DH are used. Encryption of data uses algorithms as IDEA, AES, Triple-DES, or other. A channel coding and encryption unit for payload data provides download data rates up to Nx250 Mbps. The presented concepts are based on our experience and heritage of the security systems for all German MOD satellite projects (SATCOMBw2, SAR-Lupe multi- satellite system and German-French SAR-Lupe-Helios- II systems inter-operability) as well as for further international (KOMPSAT-II Payload data link system) and ESA activities (TMTC security and GMES).

  17. Track with overlapping links for dry coal extrusion pumps

    DOEpatents

    Saunders, Timothy; Brady, John D

    2014-01-21

    A chain for a particulate material extrusion pump includes a plurality of links, each of the plurality of links having a link body and a link ledge, wherein each link ledge of the plurality of links at least partially overlaps the link body of an adjacent one of the plurality of links.

  18. Library links on medical school home pages.

    PubMed

    Thomas, Sheila L

    2011-01-01

    The purpose of this study was to assess the websites of American Association of Medical Colleges (AAMC)-member medical schools for the presence of library links. Sixty-one percent (n = 92) of home pages of the 150 member schools of the AAMC contain library links. For the 58 home pages not offering such links, 50 provided a pathway of two or three clicks to a library link. The absence of library links on 39% of AAMC medical school home pages indicates that the designers of those pages did not consider the library to be a primary destination for their visitors.

  19. Link prediction with node clustering coefficient

    NASA Astrophysics Data System (ADS)

    Wu, Zhihao; Lin, Youfang; Wang, Jing; Gregory, Steve

    2016-06-01

    Predicting missing links in incomplete complex networks efficiently and accurately is still a challenging problem. The recently proposed Cannistrai-Alanis-Ravai (CAR) index shows the power of local link/triangle information in improving link-prediction accuracy. Inspired by the idea of employing local link/triangle information, we propose a new similarity index with more local structure information. In our method, local link/triangle structure information can be conveyed by clustering coefficient of common-neighbors directly. The reason why clustering coefficient has good effectiveness in estimating the contribution of a common-neighbor is that it employs links existing between neighbors of a common-neighbor and these links have the same structural position with the candidate link to this common-neighbor. In our experiments, three estimators: precision, AUP and AUC are used to evaluate the accuracy of link prediction algorithms. Experimental results on ten tested networks drawn from various fields show that our new index is more effective in predicting missing links than CAR index, especially for networks with low correlation between number of common-neighbors and number of links between common-neighbors.

  20. Adjustable link for kinematic mounting systems

    DOEpatents

    Hale, Layton C.

    1997-01-01

    An adjustable link for kinematic mounting systems. The adjustable link is a low-cost, passive device that provides backlash-free adjustment along its single constraint direction and flexural freedom in all other directions. The adjustable link comprises two spheres, two sockets in which the spheres are adjustable retain, and a connection link threadly connected at each end to the spheres, to provide a single direction of restraint and to adjust the length or distance between the sockets. Six such adjustable links provide for six degrees of freedom for mounting an instrument on a support. The adjustable link has applications in any machine or instrument requiring precision adjustment in six degrees of freedom, isolation from deformations of the supporting platform, and/or additional structural damping. The damping is accomplished by using a hollow connection link that contains an inner rod and a viscoelastic separation layer between the two.

  1. Adjustable link for kinematic mounting systems

    DOEpatents

    Hale, L.C.

    1997-07-01

    An adjustable link for kinematic mounting systems is disclosed. The adjustable link is a low-cost, passive device that provides backlash-free adjustment along its single constraint direction and flexural freedom in all other directions. The adjustable link comprises two spheres, two sockets in which the spheres are adjustable retain, and a connection link threadly connected at each end to the spheres, to provide a single direction of restraint and to adjust the length or distance between the sockets. Six such adjustable links provide for six degrees of freedom for mounting an instrument on a support. The adjustable link has applications in any machine or instrument requiring precision adjustment in six degrees of freedom, isolation from deformations of the supporting platform, and/or additional structural damping. The damping is accomplished by using a hollow connection link that contains an inner rod and a viscoelastic separation layer between the two. 3 figs.

  2. Open loop model for WDM links

    NASA Astrophysics Data System (ADS)

    D, Meena; Francis, Fredy; T, Sarath K.; E, Dipin; Srinivas, T.; K, Jayasree V.

    2014-10-01

    Wavelength Division Multiplexing (WDM) techniques overfibrelinks helps to exploit the high bandwidth capacity of single mode fibres. A typical WDM link consisting of laser source, multiplexer/demultiplexer, amplifier and detectoris considered for obtaining the open loop gain model of the link. The methodology used here is to obtain individual component models using mathematical and different curve fitting techniques. These individual models are then combined to obtain the WDM link model. The objective is to deduce a single variable model for the WDM link in terms of input current to system. Thus it provides a black box solution for a link. The Root Mean Square Error (RMSE) associated with each of the approximated models is given for comparison. This will help the designer to select the suitable WDM link model during a complex link design.

  3. Links demystified: Periodontitis and cancer

    PubMed Central

    Pendyala, Gowri; Joshi, Saurabh; Chaudhari, Shantanu; Gandhage, Dhananjay

    2013-01-01

    Cancer is marked by the uncontrolled growth of cells, tissue invasion and metastasis to various organs via the circulatory and lymphatic systems. Recent data have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival, and migration. Periodontal disease, a chronic inflammatory condition is characterized by an oral bacterial infection leading to inflammation within the supporting tissues of the teeth, which often leads to the destruction of the periodontal tissues and alveolar bone that support the teeth. This oral inflammation often has systemic effects leading to an increased concentration of circulating inflammatory markers with the severity of disease being correlated directly with levels of serum inflammatory markers. Periodontal infection has been linked to organ and systemic diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers, and periodontal disease. This articles reviews and summarizes the possible biological mechanisms involved between periodontal infection and cancer. PMID:24379856

  4. Links demystified: Periodontitis and cancer.

    PubMed

    Pendyala, Gowri; Joshi, Saurabh; Chaudhari, Shantanu; Gandhage, Dhananjay

    2013-11-01

    Cancer is marked by the uncontrolled growth of cells, tissue invasion and metastasis to various organs via the circulatory and lymphatic systems. Recent data have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival, and migration. Periodontal disease, a chronic inflammatory condition is characterized by an oral bacterial infection leading to inflammation within the supporting tissues of the teeth, which often leads to the destruction of the periodontal tissues and alveolar bone that support the teeth. This oral inflammation often has systemic effects leading to an increased concentration of circulating inflammatory markers with the severity of disease being correlated directly with levels of serum inflammatory markers. Periodontal infection has been linked to organ and systemic diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers, and periodontal disease. This articles reviews and summarizes the possible biological mechanisms involved between periodontal infection and cancer.

  5. Saturn and Enceladus Electrical Link

    NASA Image and Video Library

    2011-04-20

    This graphic shows how Saturn and its moon Enceladus are electrically linked. Magnetic field lines, invisible to the human eye but detectable by the fields and particles instruments on NASA's Cassini spacecraft, arc from Saturn's north polar region to south polar region. Enceladus resides in the arc of a set of the field lines and feeds charged particles into the Saturn atmosphere. As Enceladus orbits around Saturn, the "footprint" of its connection to Saturn's north polar region, visible in ultraviolet light, also rotates. A doughnut of plasma, or hot ionized gas, revolves around Saturn at the same pace as the planet turns. The interaction of this plasma cloud with Enceladus shoots electrons along the magnetic field lines into the polar region of Saturn. The rain of electrons into Saturn's atmosphere creates an ultraviolet glow in an aurora-like phenomenon. Cassini's radio and plasma wave science instrument has detected a "hiss-like" radio noise generated by electrons moving along magnetic field lines from Enceladus to the glowing patch of ultraviolet light on Saturn. An animation is available at http://photojournal.jpl.nasa.gov/catalog/PIA13897

  6. O-linked oligosaccharides on insulin receptor

    SciTech Connect

    Collier, E.; Gorden, P.

    1991-02-01

    The insulin receptor, an integral membrane glycoprotein, is synthesized as a single-chain precursor that is cleaved to produce two mature subunits, both of which contain N-linked oligosaccharide chains and covalently linked fatty acids. We report that the beta-subunit also contains O-linked oligosaccharides. The proreceptor, alpha-subunit, and beta-subunit were labeled with (3H)mannose and (3H)galactose in the presence or absence of an inhibitor of O-linked glycosylation. Tryptic peptides from each component were separated by reverse-phase high-performance liquid chromatography. N- and O-linked oligosaccharide chains were identified on these peptides by specific enzymatic digestions. The proreceptor and alpha-subunit contained only N-linked oligosaccharides, whereas themore » beta-subunit contained both N- and O-linked oligosaccharides. The O-linked oligosaccharide chains were attached to a single tryptic fraction of the beta-subunit, which also contained N-linked chains. This fraction was further localized to the NH2-terminal tryptic peptide of the beta-subunit by specific immunoprecipitation with an anti-peptide antibody with specificity for this region. Binding of insulin and autophosphorylation of the beta-subunit were not dependent on O-linked glycosylation, because cells grown in the presence of the inhibitor exhibited a normal dose response to insulin. Therefore, the insulin receptor contains O-linked oligosaccharides on the NH2-terminal tryptic peptide of the beta-subunit, and these O-linked oligosaccharides are not necessary to the binding or autophosphorylation function of the receptor.« less

  7. External Link Policy | Division of Cancer Prevention

    Cancer.gov

    The following graphic notice means that you are leaving the DCP Web site: (link is external)This external link provides additional information that is consistent with the intended purpose of DCP.The National Cancer Institute (NCI) cannot attest to the accuracy of a non-federal site.Linking to a non-federal site does not constitute an endorsement by HHS or any of its employees

  8. The read-write Linked Data Web.

    PubMed

    Berners-Lee, Tim; O'Hara, Kieron

    2013-03-28

    This paper discusses issues that will affect the future development of the Web, either increasing its power and utility, or alternatively suppressing its development. It argues for the importance of the continued development of the Linked Data Web, and describes the use of linked open data as an important component of that. Second, the paper defends the Web as a read-write medium, and goes on to consider how the read-write Linked Data Web could be achieved.

  9. Using expert knowledge for test linking.

    PubMed

    Bolsinova, Maria; Hoijtink, Herbert; Vermeulen, Jorine Adinda; Béguin, Anton

    2017-12-01

    Linking and equating procedures are used to make the results of different test forms comparable. In the cases where no assumption of random equivalent groups can be made some form of linking design is used. In practice the amount of data available to link the two tests is often very limited due to logistic and security reasons, which affects the precision of linking procedures. This study proposes to enhance the quality of linking procedures based on sparse data by using Bayesian methods which combine the information in the linking data with background information captured in informative prior distributions. We propose two methods for the elicitation of prior knowledge about the difference in difficulty of two tests from subject-matter experts and explain how these results can be used in the specification of priors. To illustrate the proposed methods and evaluate the quality of linking with and without informative priors, an empirical example of linking primary school mathematics tests is presented. The results suggest that informative priors can increase the precision of linking without decreasing the accuracy. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  10. Link prediction based on local community properties

    NASA Astrophysics Data System (ADS)

    Yang, Xu-Hua; Zhang, Hai-Feng; Ling, Fei; Cheng, Zhi; Weng, Guo-Qing; Huang, Yu-Jiao

    2016-09-01

    The link prediction algorithm is one of the key technologies to reveal the inherent rule of network evolution. This paper proposes a novel link prediction algorithm based on the properties of the local community, which is composed of the common neighbor nodes of any two nodes in the network and the links between these nodes. By referring to the node degree and the condition of assortativity or disassortativity in a network, we comprehensively consider the effect of the shortest path and edge clustering coefficient within the local community on node similarity. We numerically show the proposed method provide good link prediction results.

  11. Linking Language and Categorization in Infancy

    ERIC Educational Resources Information Center

    Ferguson, Brock; Waxman, Sandra

    2017-01-01

    Language exerts a powerful influence on our concepts. We review evidence documenting the developmental origins of a precocious link between language and object categories in very young infants. This collection of studies documents a cascading process in which early links between language and cognition provide the foundation for later, more precise…

  12. CTS/Comstar communications link characterization experiment

    NASA Technical Reports Server (NTRS)

    Hodge, D. B.; Taylor, R. C.

    1980-01-01

    Measurements of angle of arrival and amplitude fluctuations on millimeter wavelength Earth-space communication links are described. Measurement of rainfall attenuation and radiometric temperature statistics and the assessment of the performance of a self-phased array as a receive antenna on an Earth-space link are also included.

  13. Linking Item Parameters to a Base Scale

    ERIC Educational Resources Information Center

    Kang, Taehoon; Petersen, Nancy S.

    2012-01-01

    This paper compares three methods of item calibration--concurrent calibration, separate calibration with linking, and fixed item parameter calibration--that are frequently used for linking item parameters to a base scale. Concurrent and separate calibrations were implemented using BILOG-MG. The Stocking and Lord in "Appl Psychol Measure"…

  14. Optimal Linking Design for Response Model Parameters

    ERIC Educational Resources Information Center

    Barrett, Michelle D.; van der Linden, Wim J.

    2017-01-01

    Linking functions adjust for differences between identifiability restrictions used in different instances of the estimation of item response model parameters. These adjustments are necessary when results from those instances are to be compared. As linking functions are derived from estimated item response model parameters, parameter estimation…

  15. Mapping the x-linked lymphoproliferative syndrome

    SciTech Connect

    Skare, J.C.; Milunsky, A.; Byron, K.S.

    1987-04-01

    The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

  16. Classifying quantum entanglement through topological links

    NASA Astrophysics Data System (ADS)

    Quinta, Gonçalo M.; André, Rui

    2018-04-01

    We propose an alternative classification scheme for quantum entanglement based on topological links. This is done by identifying a nonrigid ring to a particle, attributing the act of cutting and removing a ring to the operation of tracing out the particle, and associating linked rings to entangled particles. This analogy naturally leads us to a classification of multipartite quantum entanglement based on all possible distinct links for a given number of rings. To determine all different possibilities, we develop a formalism that associates any link to a polynomial, with each polynomial thereby defining a distinct equivalence class. To demonstrate the use of this classification scheme, we choose qubit quantum states as our example of physical system. A possible procedure to obtain qubit states from the polynomials is also introduced, providing an example state for each link class. We apply the formalism for the quantum systems of three and four qubits and demonstrate the potential of these tools in a context of qubit networks.

  17. Radio Links for the NASA ABTS

    NASA Technical Reports Server (NTRS)

    Jeutter, Dean C.

    1996-01-01

    Goals Determine Out-Link FSK Bandwidth Develop FSK Outlink Transmitter Develop Wideband Outlink FSK Receiver Develop OOK In-Link Transmitter Develop OOK In-Link Receiver Marry Out-Link & In-Link Components Outlink FSK Bandwidth preliminary inlink transmitter were accomplished in Summer 1995 visit. The calculation of FSK bandwidth is repeated in these notes. Spectrum analyzer measurements of the actual FSK spectrum agree well with the calculations. The goal to develop a wideband FSK receiver for outlink data was given first priority for end of Summer 1996 completion. The goal of developing OOK inlink transmitter and receiver system components and interfacing all outlink and inlink components into an operating closed loop prototypical system was given a December 1, 1996 completion date.

  18. The Pendulum Weaves All Knots and Links

    NASA Astrophysics Data System (ADS)

    Starrett, John

    2003-08-01

    From a topological point of view, periodic orbits of three dimensional dynamical systems are knots, that is, circles (S∧1) embedded in the three sphere (S∧3) or in R∧3. The ensemble of periodic orbits comprising the skeleton of a 3-D strange attractor form a link: a collection of (not necessarily linked) knots. Joan Birman and Robert Williams used a topological device known as the template, a branched two-manifold that results when the stable direction is collapsed out of an attractor, to analyze the knot and link types appearing in the geometric Lorenz attractor. More recently, Robert Ghrist has shown the existence of universal templates: templates that support all knot and link types. I show that the template constructed from the geometric attractor of a forced physical pendulum contains a universal template as a subtemplate, and therefore the orbit set of the pendulum contains every knot and link type.

  19. Ubiquitousness of link-density and link-pattern communities in real-world networks

    NASA Astrophysics Data System (ADS)

    Šubelj, L.; Bajec, M.

    2012-01-01

    Community structure appears to be an intrinsic property of many complex real-world networks. However, recent work shows that real-world networks reveal even more sophisticated modules than classical cohesive (link-density) communities. In particular, networks can also be naturally partitioned according to similar patterns of connectedness among the nodes, revealing link-pattern communities. We here propose a propagation based algorithm that can extract both link-density and link-pattern communities, without any prior knowledge of the true structure. The algorithm was first validated on different classes of synthetic benchmark networks with community structure, and also on random networks. We have further applied the algorithm to different social, information, technological and biological networks, where it indeed reveals meaningful (composites of) link-density and link-pattern communities. The results thus seem to imply that, similarly as link-density counterparts, link-pattern communities appear ubiquitous in nature and design.

  20. Measuring Link-Resolver Success: Comparing 360 Link with a Local Implementation of WebBridge

    ERIC Educational Resources Information Center

    Herrera, Gail

    2011-01-01

    This study reviewed link resolver success comparing 360 Link and a local implementation of WebBridge. Two methods were used: (1) comparing article-level access and (2) examining technical issues for 384 randomly sampled OpenURLs. Google Analytics was used to collect user-generated OpenURLs. For both methods, 360 Link out-performed the local…

  1. Property Values Associated with the Failure of Individual Links in a System with Multiple Weak and Strong Links.

    SciTech Connect

    Helton, Jon C.; Brooks, Dusty Marie; Sallaberry, Cedric Jean-Marie.

    Representations are developed and illustrated for the distribution of link property values at the time of link failure in the presence of aleatory uncertainty in link properties. The following topics are considered: (i) defining properties for weak links and strong links, (ii) cumulative distribution functions (CDFs) for link failure time, (iii) integral-based derivation of CDFs for link property at time of link failure, (iv) sampling-based approximation of CDFs for link property at time of link failure, (v) verification of integral-based and sampling-based determinations of CDFs for link property at time of link failure, (vi) distributions of link properties conditional onmore » time of link failure, and (vii) equivalence of two different integral-based derivations of CDFs for link property at time of link failure.« less

  2. Porous Cross-Linked Polyimide Networks

    NASA Technical Reports Server (NTRS)

    Meador, Mary Ann B. (Inventor); Guo, Haiquan (Inventor)

    2015-01-01

    Porous cross-linked polyimide networks are provided. The networks comprise an anhydride end-capped polyamic acid oligomer. The oligomer (i) comprises a repeating unit of a dianhydride and a diamine and terminal anhydride groups, (ii) has an average degree of polymerization of 10 to 50, (iii) has been cross-linked via a cross-linking agent, comprising three or more amine groups, at a balanced stoichiometry of the amine groups to the terminal anhydride groups, and (iv) has been chemically imidized to yield the porous cross-linked polyimide network. Also provided are porous cross-linked polyimide aerogels comprising a cross-linked and imidized anhydride end-capped polyamic acid oligomer, wherein the oligomer comprises a repeating unit of a dianhydride and a diamine, and the aerogel has a density of 0.10 to 0.333 g/cm.sup.3 and a Young's modulus of 1.7 to 102 MPa. Also provided are thin films comprising aerogels, and methods of making porous cross-linked polyimide networks.

  3. Covalently Linked Tandem Lesions in DNA

    PubMed Central

    Patrzyc, Helen B.; Dawidzik, Jean B.; Budzinski, Edwin E.; Freund, Harold G.; Wilton, John H.; Box, Harold C.

    2013-01-01

    Reactive oxygen species (ROS) generate a type of DNA damage called tandem lesions, two adjacent nucleotides both modified. A subcategory of tandem lesions consists of adjacent nucleotides linked by a covalent bond. Covalently linked tandem lesions generate highly characteristic liquid chromotography-tandem mass spectrometry (LC-MS/MS) elution profiles. We have used this property to comprehensively survey X-irradiated DNA for covalently linked tandem lesions. A total of 15 tandem lesions were detected in DNA irradiated in deoxygenated aqueous solution, five tandem lesions were detected in DNA that was irradiated in oxygenated solution. PMID:23106212

  4. Coherent inductive communications link for biomedical applications

    NASA Technical Reports Server (NTRS)

    Hogrefe, Arthur F. (Inventor); Radford, Wade E. (Inventor)

    1985-01-01

    A two-way coherent inductive communications link between an external transceiver and an internal transceiver located in a biologically implanted programmable medical device. Digitally formatted command data and programming data is transmitted to the implanted medical device by frequency shift keying the inductive communications link. Internal transceiver is powered by the inductive field between internal and external transceivers. Digitally formatted data is transmitted to external transceiver by internal transceiver amplitude modulating inductive field. Immediate verification of the establishment of a reliable communications link is provided by determining existence of frequency lock and bit phase lock between internal and external transceivers.

  5. Light-induced cross-linking and post-cross-linking modification of polyglycidol.

    PubMed

    Marquardt, F; Bruns, M; Keul, H; Yagci, Y; Möller, M

    2018-02-08

    The photoinduced radical generation process has received renewed interest due to its economic and ecological appeal. Herein the light-induced cross-linking of functional polyglycidol and its post-cross-linking modification are presented. Linear polyglycidol was first functionalized with a tertiary amine in a two-step reaction. Dimethylaminopropyl functional polyglycidol was cross-linked in a UV-light mediated reaction with camphorquinone as a type II photoinitiator. The cross-linked polyglycidol was further functionalized by quaternization with various organoiodine compounds. Aqueous dispersions of the cross-linked polymers were investigated by means of DLS and zeta potential measurements. Polymer films were evaluated by DSC and XPS.

  6. An evidential link prediction method and link predictability based on Shannon entropy

    NASA Astrophysics Data System (ADS)

    Yin, Likang; Zheng, Haoyang; Bian, Tian; Deng, Yong

    2017-09-01

    Predicting missing links is of both theoretical value and practical interest in network science. In this paper, we empirically investigate a new link prediction method base on similarity and compare nine well-known local similarity measures on nine real networks. Most of the previous studies focus on the accuracy, however, it is crucial to consider the link predictability as an initial property of networks itself. Hence, this paper has proposed a new link prediction approach called evidential measure (EM) based on Dempster-Shafer theory. Moreover, this paper proposed a new method to measure link predictability via local information and Shannon entropy.

  7. Nano and micro mechanical properties of uncross-linked and cross-linked chitosan films

    PubMed Central

    Aryaei, Ashkan; Jayatissa, Ahalapitiya H.; Jayasuriya, A. Champa

    2016-01-01

    The aim of this study is to determine the nano and micro mechanical properties for uncross-linked and cross-linked chitosan films. Specifically, we looked at nanoindentation hardness, microhardness, and elastic modulus. It is important to study the nano and microscale mechanical properties of chitosan since chitosan has been widely used for biomedical applications. Using the solvent-cast method, the chitosan films were prepared at room temperature on the cleaned glass plates. The chitosan solution was prepared by dissolving chitosan in acetic acid 1% (v/v). Tripolyphosphate (TPP) was used to create the cross-links between amine groups in chitosan and phosphate groups in TPP. In this study, atomic force microscopy was used to measure the nanoindentation hardness and surface topography of the uncross-linked and cross-linked chitosan films. Elastic modulus was then calculated from the nanoindentation results. The effective elastic modulus was determined by microhardness with some modifications to previous theories. The microhardness of the chitosan films were measured using Vicker’s hardness meter under three different loads. Our results show that the microhardness and elastic modulus for cross-linked chitosan films are higher than the uncross-linked films. However, the cross-linked chitosan films show increased brittleness when compared to uncross-linked films. By increasing the load magnitude, the microhardness increases for both uncross-linked and cross-linked chitosan films. PMID:22100082

  8. User Interaction with the CNPC Link

    NASA Technical Reports Server (NTRS)

    Hobbs, Alan; Lyall, Elizabeth A.

    2014-01-01

    As part of NASAs UAS in the NAS project, human factor guidelines are being developed for the ground control station of unmanned aircraft systems. A critical task for the pilot of a UAS is the management and control of the terrestrial radio links used to provide control of the vehicle and relay communications with air traffic control. An analysis of the task of the UAS pilot has been conducted to identify areas where guidelines are required. This analysis has identified a set of information requirements that must be supported by the radio equipment used to provide Control and Non-payload Communication (CNPC). Key requirements include the need for an alert when the link is lost, information on the current quality and latency of the link, and information to enable the future quality of the link to be anticipated as the aircraft changes location. These identified requirements can assist in the development of minimum operational performance standards for CNPC equipment.

  9. Alcohol Alert: Link Between Stress and Alcohol

    MedlinePlus

    ... Alert Number 85 Print Version The Link Between Stress and Alcohol Today, more and more servicemen and ... in alleviating and perpetuating stress. Common Types of Stress Most causes of stress can be grouped into ...

  10. Broadcasting satellite feeder links - Characteristics and planning

    NASA Technical Reports Server (NTRS)

    Kiebler, J. W.

    1982-01-01

    The paper presents the results of recent studies by the Feeder Link Sub-Working Group of the FCC Advisory Committee for the 1983 Regional Administrative Radio Conference (RARC). These studies conclude that specification of a few key parameters will make feeder link planning relatively straightforward. Feeder links can be located anywhere within a country if satellite orbit locations are separated by 10 deg for adjacent service areas and key parameter values presented in the paper are adopted. Colocated satellites serving a common service area need special attention to attain sufficient isolation between a desired channel and its adjacent cross-polarized channels and alternate co-polarized channels. In addition to presenting planning conclusions by the Advisory Committee, the paper presents and analyzes actions of the International Radio Consultative Committee's Conference Planning Meeting (CPM) concerning feeder links. The CPM reached conclusions similar to, and compatible with, those of the Advisory Committee.

  11. Prenatal Inflammation Linked to Autism Risk

    MedlinePlus

    ... Thursday, January 24, 2013 Prenatal inflammation linked to autism risk Maternal inflammation during early pregnancy may be related to an increased risk of autism in children, according to new findings supported by ...

  12. Predicting missing links via correlation between nodes

    NASA Astrophysics Data System (ADS)

    Liao, Hao; Zeng, An; Zhang, Yi-Cheng

    2015-10-01

    As a fundamental problem in many different fields, link prediction aims to estimate the likelihood of an existing link between two nodes based on the observed information. Since this problem is related to many applications ranging from uncovering missing data to predicting the evolution of networks, link prediction has been intensively investigated recently and many methods have been proposed so far. The essential challenge of link prediction is to estimate the similarity between nodes. Most of the existing methods are based on the common neighbor index and its variants. In this paper, we propose to calculate the similarity between nodes by the Pearson correlation coefficient. This method is found to be very effective when applied to calculate similarity based on high order paths. We finally fuse the correlation-based method with the resource allocation method, and find that the combined method can substantially outperform the existing methods, especially in sparse networks.

  13. Evaluation of linking pavement related databases.

    DOT National Transportation Integrated Search

    2007-03-01

    In general, the objectives of this study were to identify and solve various issues in linking pavement performance related database. The detailed objectives were: to evaluate the state-of-the-art in information technology for data integration and dat...

  14. DefenseLink Feature: Travels with Gates

    Science.gov Websites

    . Gates and U.S. Secretary of State Condoleezza Rice (right) discuss issues at the Kremlin in Moscow Freedom of Information Privacy & Security External Link Disclaimer Web Policy Contact Us

  15. DefenseLink Special: Military Working Dogs

    Science.gov Websites

    DefenseLink.mil Aug. 04, 2015 War on Terror Transformation News Products Press Resources Images Websites Contact Terror War * Military Working Dogs, Handlers Train for Mission Success Working Roles * 'Dog Teams' Take

  16. Nonequilibrium Chromosome Looping via Molecular Slip Links

    NASA Astrophysics Data System (ADS)

    Brackley, C. A.; Johnson, J.; Michieletto, D.; Morozov, A. N.; Nicodemi, M.; Cook, P. R.; Marenduzzo, D.

    2017-09-01

    We propose a model for the formation of chromatin loops based on the diffusive sliding of molecular slip links. These mimic the behavior of molecules like cohesin, which, along with the CTCF protein, stabilize loops which contribute to organizing the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable nonequilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favor of convergent CTCF-mediated chromosome loops observed experimentally. We also find that the diffusive motion of multiple slip links along chromatin is rectified by an intriguing ratchet effect that arises if slip links bind to the chromatin at a preferred "loading site." This emergent collective behavior favors the extrusion of loops which are much larger than the ones formed by single slip links.

  17. Website Policies / Important Links | Data Explorer

    Science.gov Websites

    : Collaborations: Publication Date: to Sort: Relevance (highest to lowest) Publication Date (newest first ) Publication Date (oldest first) Close Clear All Find DOE Data Explorer Website Policies / Important Links

  18. Development Issues on Linked Data Weblog Enrichment

    NASA Astrophysics Data System (ADS)

    Ruiz-Rube, Iván; Cornejo, Carlos M.; Dodero, Juan Manuel; García, Vicente M.

    In this paper, we describe the issues found during the development of LinkedBlog, a Linked Data extension for WordPress blogs. This extension enables to enrich text-based and video information contained in blog entries with RDF triples that are suitable to be stored, managed and exploited by other web-based applications. The issues have to do with the generality, usability, tracking, depth, security, trustiness and performance of the linked data enrichment process. The presented annotation approach aims at maintaining web-based contents independent from the underlying ontological model, by providing a loosely coupled RDFa-based approach in the linked data application. Finally, we detail how the performance of annotations can be improved through a semantic reasoner.

  19. Highly cross-linked nanoporous polymers

    DOEpatents

    Steckle, Jr., Warren P.; Apen, Paul G.; Mitchell, Michael A.

    1998-01-01

    Condensation polymerization followed by a supercritical extraction step can be used to obtain highly cross-linked nanoporous polymers with high surface area, controlled pore sizes and rigid structural integrity. The invention polymers are useful for applications requiring separation membranes.

  20. Highly cross-linked nanoporous polymers

    DOEpatents

    Steckle, Jr., Warren P.; Apen, Paul G.; Mitchell, Michael A.

    1997-01-01

    Condensation polymerization followed by a supercritical extraction step can be used to obtain highly cross-linked nanoporous polymers with high surface area, controlled pore sizes and rigid structural integrity. The invention polymers are useful for applications requiring separation membranes.

  1. Infant Formula Not Linked to Diabetes

    MedlinePlus

    ... or may have given the wrong impression. Related Stories Building Social Bonds Sound Health Managing Diabetes Reducing Children’s Chances of Asthma Links Managing Diabetes: New Technologies Can Make It Easier ​ Diabetes Increases in Children ...

  2. Indoor airPLUS Web Linking Guidelines

    EPA Pesticide Factsheets

    As an Indoor airPLUS partner, your organization is listed on the EPA Indoor airPLUS Partner List. Your listing can also include a link to your organization's website when you meet the following requirements.

  3. Linking ecosystem services, rehabilitation and river hydrogeomorphology

    EPA Science Inventory

    Assignment of values for natural ecological benefits and anthropocentric ecosystem services in riverine landscapes has been problematic, because a firm scientific basis linking these to the river's physical structure has been absent. We highlight some inherent problems in this pr...

  4. External Link Disclaimer - Naval Oceanography Portal

    Science.gov Websites

    , the United States Department of the Navy or [command name] of the linked web sites, or the information purpose of this DoD web site. USNO Master Clock Time Javascript must be Enabled The Sky This Week The Sky | navy.com | Freedom of Information Act (FOIA) | External Link Disclaimer This is an official U.S. Navy web

  5. PRELIM: Predictive Relevance Estimation from Linked Models

    DTIC Science & Technology

    2014-10-14

    code ) 14-10-2014 Final Report 11-07-2014 to 14-10-2014 PRELIM: Predictive Relevance Estimation from Linked Models N00014-14-P-1185 10257H. Van Dyke...Parunak, Ph.D. Soar Technology, Inc. 1 Executive  Summary   PRELIM (Predictive Relevance Estimation from Linked Models) draws on semantic models...The central challenge in proactive decision support is to anticipate the decision and information needs of decision-makers, in the light of likely

  6. Channel CAT: A Tactical Link Analysis Tool

    DTIC Science & Technology

    1997-09-01

    NAVAL POSTGRADUATE SCHOOL Monterey, California THESIS CHANNEL CAT : A TACTICAL LINK ANALYSIS TOOL by Michael Glenn Coleman September 1997 Thesis...REPORT TYPE AND DATES COVERED September 1997 Master’s Thesis 4. TITLE AND SUBTITLE CHANNEL CAT : A TACTICAL LINK ANALYSIS TOOL 5. FUNDING NUMBERS 6...tool, the Channel Capacity Analysis Tool (Channel CAT ), designed to provide an automated tool for the anlysis of design decisions in developing client

  7. Intersatellite link application to commercial communications satellites

    NASA Technical Reports Server (NTRS)

    Lee, Young S.; Atia, Ali E.; Ponchak, Denise S.

    1988-01-01

    The fundamental characteristics of intersatellite link (ISL) systems, and their application to domestic, regional, and global satellite communications, are described. The quantitative advantages of using ISLs to improve orbit utilization, spectrum occupancy, transmission delay (compared to multi-hop links), coverage, and connectivity, and to reduce the number of earth station antennas, are also presented. Cost-effectiveness and other systems benefits of using ISLs are identified, and the technical and systems planning aspects of ISL systems implementation are addressed.

  8. External Link Policy | Cancer Prevention Fellowship Program

    Cancer.gov

    The following graphic notice means that you are leaving the CPFP Web site: This external link provides additional information that is consistent with the intended purpose of CPFP. The National Cancer Institute (NCI) cannot attest to the accuracy of a non-federal site. Linking to a non-federal site does not constitute an endorsement by HHS or any of its employees of the sponsors or the information a

  9. Towards Linked Open Services and Processes

    NASA Astrophysics Data System (ADS)

    Krummenacher, Reto; Norton, Barry; Marte, Adrian

    The combination of semantic technology and Web services in form of 'Semantic Web Services' has until now been oriented towards extension of the WS-* stack with ontology-based descriptions. The same time, there is a strong movement away from this stack - for which the 'Web' part is little more than branding - towards RESTful services. The Linked Open Data initiative is a keen adopter of this approach and exposes many datasets via SPARQL endpoints and RESTful services. Our developing approach of 'Linked Open Services', whose current state is described in this paper, accommodates such Linked Data endpoints and general RESTful services alongside WS-* stack-based services with descriptions based on RDF and SPARQL. This capitalises on the Linked Data Cloud and makes service description and comprehension more easy and direct to the growing Linked Data community. Along the way, we show how the existing link between service messaging and the semantic viewpoint, commonly called 'lifting and lowering', is usually unduly restricted to ontology-based classification and misses how the effect of a service contributes to the knowledge of its consumer. Our SPARQL-based approach helps also in the composition of services as knowledge-centric processes, and encourages the development and exposure of services that communicate RDF.

  10. Emerging semantics to link phenotype and environment

    PubMed Central

    Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramírez, Martín J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments. PMID:26713234

  11. Emerging semantics to link phenotype and environment.

    PubMed

    Thessen, Anne E; Bunker, Daniel E; Buttigieg, Pier Luigi; Cooper, Laurel D; Dahdul, Wasila M; Domisch, Sami; Franz, Nico M; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J; Midford, Peter E; Mungall, Christopher J; Ramírez, Martín J; Specht, Chelsea D; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L; White, Jeffrey W; Zhang, Guanyang; Deans, Andrew R; Huala, Eva; Lewis, Suzanna E; Mabee, Paula M

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  12. RF Photonic Technology in Optical Fiber Links

    NASA Astrophysics Data System (ADS)

    Chang, William S. C.

    2007-06-01

    List of contributors; Introduction and preface; 1. Figures of merit and performance analysis of photonic microwave links Charles Cox and William S. C. Chang; 2. RF subcarrier links in local access networks Xiaolin Lu; 3. Analog modulation of semiconductor lasers Joachim Piprek and John E. Bowers; 4. LiNbO3 external modulators and their use in high performance analog links Gary E. Betts; 5. Broadband traveling wave modulators in LiNbO3 Marta M. Howerton and William K. Burns; 6. Multiple quantum well electroabsorption modulators for RF photonic links William S. C. Chang; 7. Polymer modulators for RF photonics Timothy Van Eck; 8. Photodiodes for high performance analog links P. K. L. Yu and Ming C. Wu; 9. Opto-electronic oscillators X. Steve Yao; 10. Photonic link techniques for microwave frequency conversion Stephen A. Pappert, Roger Helkey and Ronald T. Logan Jr; 11. Antenna-coupled millimeter-wave electro-optical modulators William B. Bridges; 12. System design and performance of wideband photonic phased array antennas Greg L. Tangonan, Willie Ng, Daniel Yap and Ron Stephens; Acknowledgements; References; Index.

  13. Emerging semantics to link phenotype and environment

    DOE PAGES

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; ...

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies aremore » well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.« less

  14. Toward link predictability of complex networks

    PubMed Central

    Lü, Linyuan; Pan, Liming; Zhou, Tao; Zhang, Yi-Cheng; Stanley, H. Eugene

    2015-01-01

    The organization of real networks usually embodies both regularities and irregularities, and, in principle, the former can be modeled. The extent to which the formation of a network can be explained coincides with our ability to predict missing links. To understand network organization, we should be able to estimate link predictability. We assume that the regularity of a network is reflected in the consistency of structural features before and after a random removal of a small set of links. Based on the perturbation of the adjacency matrix, we propose a universal structural consistency index that is free of prior knowledge of network organization. Extensive experiments on disparate real-world networks demonstrate that (i) structural consistency is a good estimation of link predictability and (ii) a derivative algorithm outperforms state-of-the-art link prediction methods in both accuracy and robustness. This analysis has further applications in evaluating link prediction algorithms and monitoring sudden changes in evolving network mechanisms. It will provide unique fundamental insights into the above-mentioned academic research fields, and will foster the development of advanced information filtering technologies of interest to information technology practitioners. PMID:25659742

  15. Effect of Link Flexibility on tip position of a single link robotic arm

    NASA Astrophysics Data System (ADS)

    Madhusudan Raju, E.; Siva Rama Krishna, L.; Mouli, Y. Sharath Chandra; Nageswara Rao, V.

    2015-12-01

    The flexible robots are widely used in space applications due to their quick response, lower energy consumption, lower overall mass and operation at high speed compared to conventional industrial rigid link robots. These robots are inherently flexible, so that the kinematics of flexible robots can't be solved with rigid body assumptions. The flexibility in links and joints affects end-point positioning accuracy of the robot. It is important to model the link kinematics with precision which in turn simplifies modelling of dynamics of flexible robots. The main objective of this paper is to evaluate the effect of link flexibility on a tip position of a single link robotic arm for a given motion. The joint is assumed to be rigid and only link flexibility is considered. The kinematics of flexible link problem is evaluated by Assumed Modes Method (AMM) using MAT LAB Programming. To evaluate the effect of link flexibility (with and without payload) of robotic arm, the normalized tip deviation is found for flexible link with respect to a rigid link. Finally, the limiting inertia for payload mass is found if the allowable tip deviation is 5%.

  16. Link Analysis in the Mission Planning Lab

    NASA Technical Reports Server (NTRS)

    McCarthy, Jessica A.; Cervantes, Benjamin W.; Daugherty, Sarah C.; Arroyo, Felipe; Mago, Divyang

    2011-01-01

    The legacy communications link analysis software currently used at Wallops Flight Facility involves processes that are different for command destruct, radar, and telemetry. There is a clear advantage to developing an easy-to-use tool that combines all the processes in one application. Link Analysis in the Mission Planning Lab (MPL) uses custom software and algorithms integrated with Analytical Graphics Inc. Satellite Toolkit (AGI STK). The MPL link analysis tool uses pre/post-mission data to conduct a dynamic link analysis between ground assets and the launch vehicle. Just as the legacy methods do, the MPL link analysis tool calculates signal strength and signal- to-noise according to the accepted processes for command destruct, radar, and telemetry assets. Graphs and other custom data are generated rapidly in formats for reports and presentations. STK is used for analysis as well as to depict plume angles and antenna gain patterns in 3D. The MPL has developed two interfaces with the STK software (see figure). The first interface is an HTML utility, which was developed in Visual Basic to enhance analysis for plume modeling and to offer a more user friendly, flexible tool. A graphical user interface (GUI) written in MATLAB (see figure upper right-hand corner) is also used to quickly depict link budget information for multiple ground assets. This new method yields a dramatic decrease in the time it takes to provide launch managers with the required link budgets to make critical pre-mission decisions. The software code used for these two custom utilities is a product of NASA's MPL.

  17. Link!: Potential Field Guidance Algorithm for In-Flight Linking of Multi-Rotor Aircraft

    NASA Technical Reports Server (NTRS)

    Cooper, John R.; Rothhaar, Paul M.

    2017-01-01

    Link! is a multi-center NASA e ort to study the feasibility of multi-aircraft aerial docking systems. In these systems, a group of vehicles physically link to each other during flight to form a larger ensemble vehicle with increased aerodynamic performance and mission utility. This paper presents a potential field guidance algorithm for a group of multi-rotor vehicles to link to each other during flight. The linking is done in pairs. Each vehicle first selects a mate. Then the potential field is constructed with three rules: move towards the mate, avoid collisions with non-mates, and stay close to the rest of the group. Once a pair links, they are then considered to be a single vehicle. After each pair is linked, the process repeats until there is only one vehicle left. The paper contains simulation results for a system of 16 vehicles.

  18. Wallops Low Elevation Link Analysis for the Constellation Launch/Ascent Links

    NASA Technical Reports Server (NTRS)

    Cheung, Keith; Ho, C.; Kantak, A.; Lee, C.; Tye, R.; Richards, E.; Sham, C.; Schlesinger, A.; Barritt, B.

    2011-01-01

    To execute the President's Vision for Space Exploration, the Constellation Program (CxP) was formed to build the next generation spacecraft Orion and launch vehicles Ares, to transport human and cargo to International Space Station (ISS), moon, and Mars. This paper focuses on the detailed link analysis for Orion/Ares s launch and ascent links with Wallops 11.3m antenna (1) Orion's Dissimilar Voice link: 10.24 Kbps, 2-way (2) Ares Developmental Flight Instrument link, 20 Mbps, downlink. Three launch trajectories are considered: TD7-E, F (Feb), and G (Aug). In certain launch scenarios, the critical events of main engine cutoff (MECO) and Separation occur during the low elevation regime of WFF s downrange -- less than 5 degree elevation angle. The goal of the study is to access if there is enough link margins for WFF to track the DV and DFI links.

  19. Publishing Data on Physical Samples Using the GeoLink Ontology and Linked Data Platforms

    NASA Astrophysics Data System (ADS)

    Ji, P.; Arko, R. A.; Lehnert, K. A.; Song, L.; Carter, M. R.; Hsu, L.

    2015-12-01

    Interdisciplinary Earth Data Alliance (IEDA), one of partners in EarthCube GeoLink project, seeks to explore the extent to which the use of GeoLink reusable Ontology Design Patterns (ODPs) and linked data platforms in IEDA data infrastructure can make research data more easily accessible and valuable. Linked data for the System for Earth Sample Registration (SESAR) is the first effort of IEDA to show how linked data enhance the presentation of IEDA data system architecture. SESAR Linked Data maps each table and column in SESAR database to RDF class and property based on GeoLink view, which build on the top of GeoLink ODPs. Then, uses D2RQ dumping the contents of SESAR database into RDF triples on the basis of mapping results. And, the dumped RDF triples is loaded into GRAPHDB, an RDF graph database, as permanent data in the form of atomic facts expressed as subjects, predicates and objects which provide support for semantic interoperability between IEDA and other GeoLink partners. Finally, an integrated browsing and searching interface build on Callimachus, a highly scalable platform for publishing linked data, is introduced to make sense of data stored in triplestore. Drill down and through features are built in the interface to help users locating content efficiently. The drill down feature enables users to explore beyond the summary information in the instance list of a specific class and into the detail from the specific instance page. The drill through feature enables users to jump from one instance to another one by simply clicking the link of the latter nested in the former region. Additionally, OpenLayers map is embedded into the interface to enhance the attractiveness of the presentation of instance which has geospatial information. Furthermore, by linking instances in the SESAR datasets to matching or corresponding instances in external sets, the presentation has been enriched with additional information about related classes like person, cruise, etc.

  20. A novel time series link prediction method: Learning automata approach

    NASA Astrophysics Data System (ADS)

    Moradabadi, Behnaz; Meybodi, Mohammad Reza

    2017-09-01

    Link prediction is a main social network challenge that uses the network structure to predict future links. The common link prediction approaches to predict hidden links use a static graph representation where a snapshot of the network is analyzed to find hidden or future links. For example, similarity metric based link predictions are a common traditional approach that calculates the similarity metric for each non-connected link and sort the links based on their similarity metrics and label the links with higher similarity scores as the future links. Because people activities in social networks are dynamic and uncertainty, and the structure of the networks changes over time, using deterministic graphs for modeling and analysis of the social network may not be appropriate. In the time-series link prediction problem, the time series link occurrences are used to predict the future links In this paper, we propose a new time series link prediction based on learning automata. In the proposed algorithm for each link that must be predicted there is one learning automaton and each learning automaton tries to predict the existence or non-existence of the corresponding link. To predict the link occurrence in time T, there is a chain consists of stages 1 through T - 1 and the learning automaton passes from these stages to learn the existence or non-existence of the corresponding link. Our preliminary link prediction experiments with co-authorship and email networks have provided satisfactory results when time series link occurrences are considered.

  1. Adaptive laser link reconfiguration using constraint propagation

    NASA Technical Reports Server (NTRS)

    Crone, M. S.; Julich, P. M.; Cook, L. M.

    1993-01-01

    This paper describes Harris AI research performed on the Adaptive Link Reconfiguration (ALR) study for Rome Lab, and focuses on the application of constraint propagation to the problem of link reconfiguration for the proposed space based Strategic Defense System (SDS) Brilliant Pebbles (BP) communications system. According to the concept of operations at the time of the study, laser communications will exist between BP's and to ground entry points. Long-term links typical of RF transmission will not exist. This study addressed an initial implementation of BP's based on the Global Protection Against Limited Strikes (GPALS) SDI mission. The number of satellites and rings studied was representative of this problem. An orbital dynamics program was used to generate line-of-site data for the modeled architecture. This was input into a discrete event simulation implemented in the Harris developed COnstraint Propagation Expert System (COPES) Shell, developed initially on the Rome Lab BM/C3 study. Using a model of the network and several heuristics, the COPES shell was used to develop the Heuristic Adaptive Link Ordering (HALO) Algorithm to rank and order potential laser links according to probability of communication. A reduced set of links based on this ranking would then be used by a routing algorithm to select the next hop. This paper includes an overview of Constraint Propagation as an Artificial Intelligence technique and its embodiment in the COPES shell. It describes the design and implementation of both the simulation of the GPALS BP network and the HALO algorithm in COPES. This is described using a 59 Data Flow Diagram, State Transition Diagrams, and Structured English PDL. It describes a laser communications model and the heuristics involved in rank-ordering the potential communication links. The generation of simulation data is described along with its interface via COPES to the Harris developed View Net graphical tool for visual analysis of communications

  2. Age differences in search of web pages: the effects of link size, link number, and clutter.

    PubMed

    Grahame, Michael; Laberge, Jason; Scialfa, Charles T

    2004-01-01

    Reaction time, eye movements, and errors were measured during visual search of Web pages to determine age-related differences in performance as a function of link size, link number, link location, and clutter. Participants (15 young adults, M = 23 years; 14 older adults, M = 57 years) searched Web pages for target links that varied from trial to trial. During one half of the trials, links were enlarged from 10-point to 12-point font. Target location was distributed among the left, center, and bottom portions of the screen. Clutter was manipulated according to the percentage of used space, including graphics and text, and the number of potentially distracting nontarget links was varied. Increased link size improved performance, whereas increased clutter and links hampered search, especially for older adults. Results also showed that links located in the left region of the page were found most easily. Actual or potential applications of this research include Web site design to increase usability, particularly for older adults.

  3. Japan Link Center (JaLC): link management and DOI assignment for Japanese electronic scholarly contents

    NASA Astrophysics Data System (ADS)

    Kato, Takafumi; Tsuchiya, Eri; Kubota, Soichi; Miyagawa, Yoshiyuki

    JST, cooperated with several national institutes, is currently developing “Japan Link Center”, which manages Japanese electronic scholarly contents (journal articles, books, dissertations etc.) in an integrated fashion using Digital Object Identifier (DOI). Japan Link Center will manage metadata and whereabouts information of the contents in the digital environment and provide domestic and international linking information, cite/cited information to activate dissemination of S&T information, furthermore, to strengthen transmission of S&T information from Japan. Japan Link Center is expected to be appointed as the 9th DOI registration agency (RA) in the world by the International DOI Foundation (IDF) this spring.

  4. A generalized theory of preferential linking

    NASA Astrophysics Data System (ADS)

    Hu, Haibo; Guo, Jinli; Liu, Xuan; Wang, Xiaofan

    2014-12-01

    There are diverse mechanisms driving the evolution of social networks. A key open question dealing with understanding their evolution is: How do various preferential linking mechanisms produce networks with different features? In this paper we first empirically study preferential linking phenomena in an evolving online social network, find and validate the linear preference. We propose an analyzable model which captures the real growth process of the network and reveals the underlying mechanism dominating its evolution. Furthermore based on preferential linking we propose a generalized model reproducing the evolution of online social networks, and present unified analytical results describing network characteristics for 27 preference scenarios. We study the mathematical structure of degree distributions and find that within the framework of preferential linking analytical degree distributions can only be the combinations of finite kinds of functions which are related to rational, logarithmic and inverse tangent functions, and extremely complex network structure will emerge even for very simple sublinear preferential linking. This work not only provides a verifiable origin for the emergence of various network characteristics in social networks, but bridges the micro individuals' behaviors and the global organization of social networks.

  5. Cross-linking Chemistry of Squid Beak*

    PubMed Central

    Miserez, Ali; Rubin, Daniel; Waite, J. Herbert

    2010-01-01

    In stark contrast to most aggressive predators, Dosidicus gigas (jumbo squids) do not use minerals in their powerful mouthparts known as beaks. Their beaks instead consist of a highly sclerotized chitinous composite with incremental hydration from the tip to the base. We previously reported l-3,4-dihydroxyphenylalanine (dopa)-histidine (dopa-His) as an important covalent cross-link providing mechanical strengthening to the beak material. Here, we present a more complete characterization of the sclerotization chemistry and describe additional cross-links from D. gigas beak. All cross-links presented in this report share common building blocks, a family of di-, tri-, and tetra-histidine-catecholic adducts, that were separated by affinity chromatography and high performance liquid chromatography (HPLC) and identified by tandem mass spectroscopy and proton nuclear magnetic resonance (1H NMR). The data provide additional insights into the unusually high cross-link density found in mature beaks. Furthermore, we propose both a low molecular weight catechol, and peptidyl-dopa, to be sclerotization agents of squid beak. This appears to represent a new strategy for forming hard tissue in animals. The interplay between covalent cross-linking and dehydration on the graded properties of the beaks is discussed. PMID:20870720

  6. Cross-linking chemistry of squid beak.

    PubMed

    Miserez, Ali; Rubin, Daniel; Waite, J Herbert

    2010-12-03

    In stark contrast to most aggressive predators, Dosidicus gigas (jumbo squids) do not use minerals in their powerful mouthparts known as beaks. Their beaks instead consist of a highly sclerotized chitinous composite with incremental hydration from the tip to the base. We previously reported l-3,4-dihydroxyphenylalanine (dopa)-histidine (dopa-His) as an important covalent cross-link providing mechanical strengthening to the beak material. Here, we present a more complete characterization of the sclerotization chemistry and describe additional cross-links from D. gigas beak. All cross-links presented in this report share common building blocks, a family of di-, tri-, and tetra-histidine-catecholic adducts, that were separated by affinity chromatography and high performance liquid chromatography (HPLC) and identified by tandem mass spectroscopy and proton nuclear magnetic resonance ((1)H NMR). The data provide additional insights into the unusually high cross-link density found in mature beaks. Furthermore, we propose both a low molecular weight catechol, and peptidyl-dopa, to be sclerotization agents of squid beak. This appears to represent a new strategy for forming hard tissue in animals. The interplay between covalent cross-linking and dehydration on the graded properties of the beaks is discussed.

  7. [Suicidality and musical preferences: a possible link?].

    PubMed

    Mikolajczak, Gladys; Desseilles, Martin

    2012-01-01

    Music is an important part of young people's lives. In this article, we attempt to answer two questions on the links between music et suicide. First, we examine if certain types of music favor suicidal process (ideation and acting out); and, secondly, we examine if music can constitute a tool to reduce the risk of suicide. Several factors possibly involved in links between musical preferences and the suicidal process are developed: the Velten effect and the musical mood induction procedure, the identification and the learning by imitation, the media influence as well as the individual characteristics. A multifactor approach is necessary to understand the complex and birectional links that unite musical preferences and suicide risk.

  8. Why should we publish Linked Data?

    NASA Astrophysics Data System (ADS)

    Blower, Jon; Riechert, Maik; Koubarakis, Manolis; Pace, Nino

    2016-04-01

    We use the Web every day to access information from all kinds of different sources. But the complexity and diversity of scientific data mean that discovering accessing and interpreting data remains a large challenge to researchers, decision-makers and other users. Different sources of useful information on data, algorithms, instruments and publications are scattered around the Web. How can we link all these things together to help users to better understand and exploit earth science data? How can we combine scientific data with other relevant data sources, when standards for describing and sharing data vary so widely between communities? "Linked Data" is a term that describes a set of standards and "best practices" for sharing data on the Web (http://www.w3.org/standards/semanticweb/data). These principles can be summarised as follows: 1. Create unique and persistent identifiers for the important "things" in a community (e.g. datasets, publications, algorithms, instruments). 2. Allow users to "look up" these identifiers on the web to find out more information about them. 3. Make this information machine-readable in a community-neutral format (such as RDF, Resource Description Framework). 4. Within this information, embed links to other things and concepts and say how these are related. 5. Optionally, provide web service interfaces to allow the user to perform sophisticated queries over this information (using a language such as SPARQL). The promise of Linked Data is that, through these techniques, data will be more discoverable, more comprehensible and more usable by different communities, not just the community that produced the data. As a result, many data providers (particularly public-sector institutions) are now publishing data in this way. However, this area is still in its infancy in terms of real-world applications. Data users need guidance and tools to help them use Linked Data. Data providers need reassurance that the investments they are making in

  9. Linking remote sensing, land cover and disease.

    PubMed

    Curran, P J; Atkinson, P M; Foody, G M; Milton, E J

    2000-01-01

    Land cover is a critical variable in epidemiology and can be characterized remotely. A framework is used to describe both the links between land cover and radiation recorded in a remotely sensed image, and the links between land cover and the disease carried by vectors. The framework is then used to explore the issues involved when moving from remotely sensed imagery to land cover and then to vector density/disease risk. This exploration highlights the role of land cover; the need to develop a sound knowledge of each link in the predictive sequence; the problematic mismatch between the spatial units of the remotely sensed and epidemiological data and the challenges and opportunities posed by adding a temporal mismatch between the remotely sensed and epidemiological data. The paper concludes with a call for both greater understanding of the physical components of the proposed framework and the utilization of optimized statistical tools as prerequisites to progress in this field.

  10. Precipitation links (PrecipLinks) - a prototype directory for precipitation information

    NASA Technical Reports Server (NTRS)

    Velanthapillia, Balendran; Stocker, Erich Franz

    2006-01-01

    This poster describes a web directory of research oriented precipitation links. In this era of sophisticated search engines and web agents, it might seem counterproductive to establish such a directory of links. However, entering precipitation into a search engine like google will yield over one million hits. To further exacerbate this situation many of the returned links are dead, duplicates of other links, incomplete, or only marginally related to research precipitation or even the broader precipitation area. Sometimes connecting the linked URL causes the browser to lose context and not be able to get back to the original page. Even using more sophisticated search engines query parameters or agents while reducing the overall return doesn't eliminate all of the other issues listed. As part of the development of the measurement-based Precipitation Processing System (PPS) that will support Tropical Rainfall Measuring Mission (TRMM) version 7 reprocessing and the Global Precipitation Measurement (GPM) mission a precipitation links (PrecipLinks) facility is being developed. PrecipLinks is intended to share locations of other sites that contain information or data pertaining to precipitation research. Potential contributors can log-on to the PrecipLinks website and register their site for inclusion in the directory. The price for inclusion is the requirement to place a link back to PrecipLinks on the webpage that is registered. This ensures that users will be able to easily get back to PrecipLinks regardless of any context issues that browsers might have. Perhaps more importantly users while visiting one site that they know can be referred to a location that has many others sites with which they might not be familiar. PrecipLinks is designed to have a very flat structure. This poster summarizes these categories (information, data, services) and the reasons for their selection. Providers may register multiple pages to which they wish to direct users. However, each page

  11. Link-N: The missing link towards intervertebral disc repair is species-specific

    PubMed Central

    Bach, Frances C.; Laagland, Lisanne T.; Grant, Michael P.; Creemers, Laura B.; Ito, Keita; Meij, Björn P.; Mwale, Fackson

    2017-01-01

    Introduction Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells. If Link-N appears to be effective in canines, this would facilitate translation of Link-N into the clinic using the dog as an in vivo large animal model for human IVD degeneration. Materials and methods This study’s objective was to determine the effect of the human and canine variant of Link-N and short (s) Link-N on canine chondrocyte-like cells (CLCs) and compare this to those on already studied species, i.e. human and bovine CLCs. Extracellular matrix (ECM) production was determined by measuring glycosaminoglycan (GAG) content and histological evaluation. Additionally, the micro-aggregates’ DNA content was measured. Phosphorylated (p) Smad1 and -2 levels were determined using ELISA. Results Human (s)Link-N induced GAG deposition in human and bovine CLCs, as expected. In contrast, canine (s)Link-N did not affect ECM production in human CLCs, while it mainly induced collagen type I and II deposition in bovine CLCs. In canine CLCs, both canine and human (s)Link-N induced negligible GAG deposition. Surprisingly, human and canine (s)Link-N did not induce Smad signaling in human and bovine CLCs. Human and canine (s)Link-N only mildly increased pSmad1 and Smad2 levels in canine CLCs. Conclusions Human and canine (s)Link-N exerted species-specific effects on CLCs from early degenerated IVDs. Both variants, however, lacked the potency as canine IVD regeneration agent. While these studies demonstrate the challenges of translational studies in large animal models, (s)Link

  12. Link-N: The missing link towards intervertebral disc repair is species-specific.

    PubMed

    Bach, Frances C; Laagland, Lisanne T; Grant, Michael P; Creemers, Laura B; Ito, Keita; Meij, Björn P; Mwale, Fackson; Tryfonidou, Marianna A

    2017-01-01

    Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells. If Link-N appears to be effective in canines, this would facilitate translation of Link-N into the clinic using the dog as an in vivo large animal model for human IVD degeneration. This study's objective was to determine the effect of the human and canine variant of Link-N and short (s) Link-N on canine chondrocyte-like cells (CLCs) and compare this to those on already studied species, i.e. human and bovine CLCs. Extracellular matrix (ECM) production was determined by measuring glycosaminoglycan (GAG) content and histological evaluation. Additionally, the micro-aggregates' DNA content was measured. Phosphorylated (p) Smad1 and -2 levels were determined using ELISA. Human (s)Link-N induced GAG deposition in human and bovine CLCs, as expected. In contrast, canine (s)Link-N did not affect ECM production in human CLCs, while it mainly induced collagen type I and II deposition in bovine CLCs. In canine CLCs, both canine and human (s)Link-N induced negligible GAG deposition. Surprisingly, human and canine (s)Link-N did not induce Smad signaling in human and bovine CLCs. Human and canine (s)Link-N only mildly increased pSmad1 and Smad2 levels in canine CLCs. Human and canine (s)Link-N exerted species-specific effects on CLCs from early degenerated IVDs. Both variants, however, lacked the potency as canine IVD regeneration agent. While these studies demonstrate the challenges of translational studies in large animal models, (s)Link-N still holds a regenerative potential for humans.

  13. Urban rainfall estimation employing commercial microwave links

    NASA Astrophysics Data System (ADS)

    Overeem, Aart; Leijnse, Hidde; Uijlenhoet, Remko; ten Veldhuis, Marie-claire

    2015-04-01

    Urban areas often lack rainfall information. To increase the number of rainfall observations in cities, microwave links from operational cellular telecommunication networks may be employed. Although this new potential source of rainfall information has been shown to be promising, its quality needs to be demonstrated more extensively. In the Rain Sense kickstart project of the Amsterdam Institute for Advanced Metropolitan Solutions (AMS), sensors and citizens are preparing Amsterdam for future weather. Part of this project is rainfall estimation using new measurement techniques. Innovative sensing techniques will be utilized such as rainfall estimation from microwave links, umbrellas for weather sensing, low-cost sensors at lamp posts and in drainage pipes for water level observation. These will be combined with information provided by citizens in an active way through smartphone apps and in a passive way through social media posts (Twitter, Flickr etc.). Sensor information will be integrated, visualized and made accessible to citizens to help raise citizen awareness of urban water management challenges and promote resilience by providing information on how citizens can contribute in addressing these. Moreover, citizens and businesses can benefit from reliable weather information in planning their social and commercial activities. In the end city-wide high-resolution rainfall maps will be derived, blending rainfall information from microwave links and weather radars. This information will be used for urban water management. This presentation focuses on rainfall estimation from commercial microwave links. Received signal levels from tens of microwave links within the Amsterdam region (roughly 1 million inhabitants) in the Netherlands are utilized to estimate rainfall with high spatial and temporal resolution. Rainfall maps will be presented and compared to a gauge-adjusted radar rainfall data set. Rainfall time series from gauge(s), radars and links will be compared.

  14. Thermometric enzyme linked immunosorbent assay: TELISA.

    PubMed

    Mattiasson, B; Borrebaeck, C; Sanfridson, B; Mosbach, K

    1977-08-11

    A new method, thermometric enzyme linked immunosorbent assay (TELISA), for the assay of endogenous and exogenous compounds in biological fluids is described. It is based on the previously described enzyme linked immunosorbent assay technique, ELISA, but utilizes enzymic heat formation which is measured in an enzyme thermistor unit. In the model system studied determination of human serum albumin down to a concentration of 10(-10) M (5 ng/ml) was achieved, with both normal and catalase labelled human serum albumin competing for the binding sites on the immunosorbent, which was rabbit antihuman serum albumin immobilized onto Sepharose CL-4B.

  15. Communications Link Characterization Experiment (CLCE), volume 3

    NASA Technical Reports Server (NTRS)

    1977-01-01

    The results of data which were acquired, reduced and analyzed as of June 1977, from the Communications Link Characterization Experiment while utilizing the Communications Link Characterization Experiment while utilizing the Communications Technology Satellite is presented. The long term yearly and worst month propagation data from both stations are presented for the defined yearly period and the test results of the Goddard Television Experiment are described. The data for the continuing path length analysis are updated. Progress on the continuing analysis of utilizing the weather radars for attenuation prediction is given and the concept of the weather radar ratio is presented.

  16. Aging and cancer: are sirtuins the link?

    PubMed

    Rodriguez, Ramon M; Fraga, Mario F

    2010-06-01

    Classically, aging has been defined as a general degeneration process that leads to the loss of corporal function. The loss of function caused by degeneration limits the maximum lifespan of all organisms and is linked to disease and cancer. Nevertheless, the molecular mechanisms behind aging and their connection to cancer are not well understood. NAD-dependent protein deacetylase enzymes, sirtuins, are emerging as a novel molecular link between aging and cancer due to their specific role in cell cycle regulation, antistress response and cell survival. This article reviews the contribution of sirtuins and environmental factors to ontogenic development, senescence and cancer.

  17. Enterprise Linked Data as Core Business Infrastructure

    NASA Astrophysics Data System (ADS)

    Harris, Steve; Ilube, Tom; Tuffield, Mischa

    This chapter describes Garlik's motivation, interest, and experiences of using Linked Data technologies in its online services. It describes the methodologies and approaches that were taken in order to deploy online services to hundreds of thousands of users, and describes the trade-offs inherent in our choice of these technologies for our production systems. In order to help illustrate and aid the arguments for the adoption of SemanticWeb technologies this chapter will focus on two of our customer facing products, DataPatrol, a consumer-centric personal information protection product, and QDOS a Linked Data service that is used to measure peoples' online activity

  18. A link representation for gravity amplitudes

    NASA Astrophysics Data System (ADS)

    He, Song

    2013-10-01

    We derive a link representation for all tree amplitudes in supergravity, from a recent conjecture by Cachazo and Skinner. The new formula explicitly writes amplitudes as contour integrals over constrained link variables, with an integrand naturally expressed in terms of determinants, or equivalently tree diagrams. Important symmetries of the amplitude, such as supersymmetry, parity and (partial) permutation invariance, are kept manifest in the formulation. We also comment on rewriting the formula in a GL( k)-invariant manner, which may serve as a starting point for the generalization to possible Grassmannian contour integrals.

  19. The Time Link Between CSAO and CRL

    DTIC Science & Technology

    2000-11-01

    lhx@ms.sxso. ac.cn Abstract There are and will be a few techniques for time link between CSAO and CRL. The TWSTFT was set up in October 1998 via a...Japanese communication satellite. The CSAO-CRL TWSTFT data have been accumulated for more than 1 year since the date when the link was established...for the time comparison at CSAO have been continued for 2 years. Two-way Satellite Time and Frequency Transfer ( TWSTFT ) is one of the most advanced

  20. ADIPOCYTOKINES AND OBESITY-LINKED DISORDERS

    PubMed Central

    OUCHI, NORIYUKI; OHASHI, KOJI; SHIBATA, REI; MUROHARA, TOYOAKI

    2012-01-01

    ABSTRACT Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit anti-inflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases. PMID:22515108

  1. CLEAR: Communications Link Expert Assistance Resource

    NASA Technical Reports Server (NTRS)

    Hull, Larry G.; Hughes, Peter M.

    1987-01-01

    Communications Link Expert Assistance Resource (CLEAR) is a real time, fault diagnosis expert system for the Cosmic Background Explorer (COBE) Mission Operations Room (MOR). The CLEAR expert system is an operational prototype which assists the MOR operator/analyst by isolating and diagnosing faults in the spacecraft communication link with the Tracking and Data Relay Satellite (TDRS) during periods of realtime data acquisition. The mission domain, user requirements, hardware configuration, expert system concept, tool selection, development approach, and system design were discussed. Development approach and system implementation are emphasized. Also discussed are system architecture, tool selection, operation, and future plans.

  2. Migraines and Gastrointestinal Problems: Is There a Link?

    MedlinePlus

    ... there a link? Is there any link between migraines and gastrointestinal problems? Answers from Jerry W. Swanson, ... link. Nausea and vomiting are often associated with migraine attacks. In young children, several syndromes that cause ...

  3. Genetics Home Reference: X-linked severe combined immunodeficiency

    MedlinePlus

    ... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

  4. Genetics Home Reference: X-linked dilated cardiomyopathy

    MedlinePlus

    ... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

  5. Genetics Home Reference: X-linked adrenal hypoplasia congenita

    MedlinePlus

    ... Home Health Conditions X-linked adrenal hypoplasia congenita X-linked adrenal hypoplasia congenita Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked adrenal hypoplasia congenita is a disorder that ...

  6. Genetics Home Reference: X-linked myotubular myopathy

    MedlinePlus

    ... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

  7. Genetics Home Reference: X-linked congenital stationary night blindness

    MedlinePlus

    ... Health Conditions X-linked congenital stationary night blindness X-linked congenital stationary night blindness Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked congenital stationary night blindness is a disorder ...

  8. Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

    MedlinePlus

    ... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

  9. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    MedlinePlus

    ... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

  10. Genetics Home Reference: X-linked chondrodysplasia punctata 1

    MedlinePlus

    ... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

  11. Genetics Home Reference: X-linked sideroblastic anemia

    MedlinePlus

    ... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

  12. Genetics Home Reference: X-linked intellectual disability, Siderius type

    MedlinePlus

    ... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

  13. Link Correlated Military Data for Better Decision Support

    DTIC Science & Technology

    2011-06-01

    automatically translated into URI based links, thus can greatly reduce man power cost on software development. 3 Linked Data Technique Tim Berners - Lee ...Linked Data - while Linked Data is usually considered as part of Semantic Web, or “the Semantic Web done right” as described by Tim himself - has been...Required data of automatic link construction mechanism on more kinds of correlations. References [1] B. L. Tim , “The next Web of open, linked data

  14. Improving local clustering based top-L link prediction methods via asymmetric link clustering information

    NASA Astrophysics Data System (ADS)

    Wu, Zhihao; Lin, Youfang; Zhao, Yiji; Yan, Hongyan

    2018-02-01

    Networks can represent a wide range of complex systems, such as social, biological and technological systems. Link prediction is one of the most important problems in network analysis, and has attracted much research interest recently. Many link prediction methods have been proposed to solve this problem with various techniques. We can note that clustering information plays an important role in solving the link prediction problem. In previous literatures, we find node clustering coefficient appears frequently in many link prediction methods. However, node clustering coefficient is limited to describe the role of a common-neighbor in different local networks, because it cannot distinguish different clustering abilities of a node to different node pairs. In this paper, we shift our focus from nodes to links, and propose the concept of asymmetric link clustering (ALC) coefficient. Further, we improve three node clustering based link prediction methods via the concept of ALC. The experimental results demonstrate that ALC-based methods outperform node clustering based methods, especially achieving remarkable improvements on food web, hamster friendship and Internet networks. Besides, comparing with other methods, the performance of ALC-based methods are very stable in both globalized and personalized top-L link prediction tasks.

  15. Improving personalized link prediction by hybrid diffusion

    NASA Astrophysics Data System (ADS)

    Liu, Jin-Hu; Zhu, Yu-Xiao; Zhou, Tao

    2016-04-01

    Inspired by traditional link prediction and to solve the problem of recommending friends in social networks, we introduce the personalized link prediction in this paper, in which each individual will get equal number of diversiform predictions. While the performances of many classical algorithms are not satisfactory under this framework, thus new algorithms are in urgent need. Motivated by previous researches in other fields, we generalize heat conduction process to the framework of personalized link prediction and find that this method outperforms many classical similarity-based algorithms, especially in the performance of diversity. In addition, we demonstrate that adding one ground node that is supposed to connect all the nodes in the system will greatly benefit the performance of heat conduction. Finally, better hybrid algorithms composed of local random walk and heat conduction have been proposed. Numerical results show that the hybrid algorithms can outperform other algorithms simultaneously in all four adopted metrics: AUC, precision, recall and hamming distance. In a word, this work may shed some light on the in-depth understanding of the effect of physical processes in personalized link prediction.

  16. Link prediction in multiplex online social networks.

    PubMed

    Jalili, Mahdi; Orouskhani, Yasin; Asgari, Milad; Alipourfard, Nazanin; Perc, Matjaž

    2017-02-01

    Online social networks play a major role in modern societies, and they have shaped the way social relationships evolve. Link prediction in social networks has many potential applications such as recommending new items to users, friendship suggestion and discovering spurious connections. Many real social networks evolve the connections in multiple layers (e.g. multiple social networking platforms). In this article, we study the link prediction problem in multiplex networks. As an example, we consider a multiplex network of Twitter (as a microblogging service) and Foursquare (as a location-based social network). We consider social networks of the same users in these two platforms and develop a meta-path-based algorithm for predicting the links. The connectivity information of the two layers is used to predict the links in Foursquare network. Three classical classifiers (naive Bayes, support vector machines (SVM) and K-nearest neighbour) are used for the classification task. Although the networks are not highly correlated in the layers, our experiments show that including the cross-layer information significantly improves the prediction performance. The SVM classifier results in the best performance with an average accuracy of 89%.

  17. Great Schools Have Great Principals: Link Crew

    ERIC Educational Resources Information Center

    Roberts, Rebecca

    2013-01-01

    The author describes the Link Crew transition program that she implemented in 2012 as assistant principal for curriculum and guidance at Villa Park High School in California. She states that administrative and counseling teams at her school had noticed that ninth-grade students struggled in their transitions to high school, with over half of the…

  18. Linking Large-Scale Reading Assessments: Comment

    ERIC Educational Resources Information Center

    Hanushek, Eric A.

    2016-01-01

    E. A. Hanushek points out in this commentary that applied researchers in education have only recently begun to appreciate the value of international assessments, even though there are now 50 years of experience with these. Until recently, these assessments have been stand-alone surveys that have not been linked, and analysis has largely focused on…

  19. Searching for climate-conflict links

    NASA Astrophysics Data System (ADS)

    Hendrix, Cullen S.

    2018-03-01

    Environmental scarcity caused by climate change has been implicated as a driver of violent conflict. Now, research shows significant bias in the regions analysed for climate-conflict links. This may limit understanding of the socioeconomic and political conditions in which such conflict occurs, and how these conflicts could be prevented.

  20. Visualizing Transmedia Networks: Links, Paths and Peripheries

    ERIC Educational Resources Information Center

    Ruppel, Marc Nathaniel

    2012-01-01

    'Visualizing Transmedia Networks: Links, Paths and Peripheries' examines the increasingly complex rhetorical intersections between narrative and media ("old" and "new") in the creation of transmedia fictions, loosely defined as multisensory and multimodal stories told extensively across a diverse media set. In order…

  1. A Simulation of X-Linked Inheritance.

    ERIC Educational Resources Information Center

    Harrell, Pamela Esprivalo

    1997-01-01

    Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

  2. Self-assembly of knots and links

    NASA Astrophysics Data System (ADS)

    Orlandini, Enzo; Polles, Guido; Marenduzzo, Davide; Micheletti, Cristian

    2017-03-01

    Guiding the self-assembly of identical building blocks towards complex three-dimensional structures with a set of desired properties is a major goal in material science, chemistry and physics. A particularly challenging problem, especially explored in synthetic chemistry, is that of self-assembling closed structures with a target topology starting by simple geometrical templates. Here we overview and revisit recent advancements, based on stochastic simulations, where the geometry of rigid helical templates with functionalised sticky ends has been designed for self-assembling efficiently and reproducibly into a wide range of three-dimensional closed structures. Notably, these include non trivial topologies of links and knots, including the 819 knot that we had predicted to be highly encodable and that has only recently been obtained experimentally. By appropriately tuning the parameters that define the template shape, we show that, for fixed concentration of templates, the assembly process can be directed towards the formation of specific knotted and linked structures such as the trefoils, pentafoil knots, Hopf and Solomon links. More exotic and unexpected knots and links are also found. Our results should be relevant to the design of new protocols that can both increase and broaden the population of synthetise molecular knots and catenanes.

  3. DefenseLink Special: September 11, 2005

    Science.gov Websites

    DefenseLink.mil Jun. 29, 2015 War on Terror Transformation News Products Press Resources Images Websites Contact " motorcycle ride visited families of fallen troops in the terror war to personally thank them for anniversary of the Sept. 11, 2001, terror attacks, Kelly Freudenberg has no doubt that her son gave his life

  4. New initiative links scientists and entertainers

    NASA Astrophysics Data System (ADS)

    Gwynne, Peter

    2009-01-01

    The US National Academy of Sciences has teamed up with Hollywood to improve the quality of science portrayed in films, TV shows and video games. The new Science and Entertainment Exchange (SEE) aims to create better links between entertainment-industry professionals and scientists to improve the credibility of programming related to science.

  5. EPA ExpoBox Related Links

    EPA Pesticide Factsheets

    EPA ExpoBox is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases,

  6. Highly cross-linked nanoporous polymers

    DOEpatents

    Steckle, W.P. Jr.; Apen, P.G.; Mitchell, M.A.

    1998-01-20

    Condensation polymerization followed by a supercritical extraction step can be used to obtain highly cross-linked nanoporous polymers with high surface area, controlled pore sizes and rigid structural integrity. The invention polymers are useful for applications requiring separation membranes. 1 fig.

  7. Pseudo-Equivalent Groups and Linking

    ERIC Educational Resources Information Center

    Haberman, Shelby J.

    2015-01-01

    Adjustment by minimum discriminant information provides an approach to linking test forms in the case of a nonequivalent groups design with no satisfactory common items. This approach employs background information on individual examinees in each administration so that weighted samples of examinees form pseudo-equivalent groups in the sense that…

  8. Sociocognitive Correlates of Gender-Linked Conduct.

    ERIC Educational Resources Information Center

    Bussey, Kay

    This study of the processes guiding children's gender-linked conduct focused on ages prior to the development of self-regulatory control through the exercise of self-evaluative reactions. The study sample consisted of 29 boys and 33 girls in Australia between 17 and 48 months old. Measures included: (1) a videotaped toy play session in which…

  9. Analysis Links Zoning Policies and Disparities

    ERIC Educational Resources Information Center

    Shah, Nirvi

    2012-01-01

    Location, location, location. This mantra of real estate agents and their clients alike is now the target of a new report from the Brookings Institution linking housing prices and zoning practices to effectively depriving low-income students of high-quality schools. Using test scores from schools in the 100 largest metropolitan areas in the…

  10. Considerations for the retrofit of data link

    NASA Technical Reports Server (NTRS)

    Corwin, William H.; Mccauley, Hugo W.

    1990-01-01

    Human factors issues related to the retrofit of data link in commercial transport aircraft are discussed. Topics that must be considered for data link implementation include, the loss of the party line, (i.e., the availability to all aircraft of information transmitted on a common voice frequency), and the scheduling of information to the flight crew. This paper focuses primarily on the human factors issues related to retrofit of Mode S. Retrofits is a difficult task because panel space accessible to flight crew members is limited. As with all cockpit equipment, data link implementation will have to comply with Federal Aviation Regulation 25.1523, which requires the manufacturer to address the conspicuity and ease of use of the data link device, and to assess the impact on crew workload. Operational sequence diagrams are provided to illustrate a methodology that can be used to decompose the flight crew body channel utilization of candidate avionics configurations in order to optimize the pilot-vehicle interface.

  11. Link prediction in multiplex online social networks

    NASA Astrophysics Data System (ADS)

    Jalili, Mahdi; Orouskhani, Yasin; Asgari, Milad; Alipourfard, Nazanin; Perc, Matjaž

    2017-02-01

    Online social networks play a major role in modern societies, and they have shaped the way social relationships evolve. Link prediction in social networks has many potential applications such as recommending new items to users, friendship suggestion and discovering spurious connections. Many real social networks evolve the connections in multiple layers (e.g. multiple social networking platforms). In this article, we study the link prediction problem in multiplex networks. As an example, we consider a multiplex network of Twitter (as a microblogging service) and Foursquare (as a location-based social network). We consider social networks of the same users in these two platforms and develop a meta-path-based algorithm for predicting the links. The connectivity information of the two layers is used to predict the links in Foursquare network. Three classical classifiers (naive Bayes, support vector machines (SVM) and K-nearest neighbour) are used for the classification task. Although the networks are not highly correlated in the layers, our experiments show that including the cross-layer information significantly improves the prediction performance. The SVM classifier results in the best performance with an average accuracy of 89%.

  12. Linking Individual Creativity to Organizational Innovation

    ERIC Educational Resources Information Center

    Litchfield, Robert C.; Ford, Cameron M.; Gentry, Richard J.

    2015-01-01

    We draw on 146 employee-co-worker-supervisor triads from 146 organizations to examine the role of individual perspective-taking and team creative environment in the association between individual creativity and organizational innovation. Adopting an interactionist perspective, we find that the link between individual creativity and organizational…

  13. Cytisus scoparius (L.) Link: Scotch broom

    Treesearch

    Susan E. Meyer

    2008-01-01

    The genus Cytisus comprises about 80 species native to Eurasia and North Africa. Many are cultivated as ornamentals, and several of these have become more or less naturalized in the United States, especially in California (Munz and Keck 1959). Scotch broom - C. scoparius (L.) Link - was planted extensively for erosion control during the first half of the century (Gill...

  14. Extracting Macroscopic Information from Web Links.

    ERIC Educational Resources Information Center

    Thelwall, Mike

    2001-01-01

    Discussion of Web-based link analysis focuses on an evaluation of Ingversen's proposed external Web Impact Factor for the original use of the Web, namely the interlinking of academic research. Studies relationships between academic hyperlinks and research activities for British universities and discusses the use of search engines for Web link…

  15. Women and Systems: Is There a Link?

    ERIC Educational Resources Information Center

    Carter, Ruth

    There may be a link between the systems movement and the women's movement. The systems approach allows an observer to identify important relationships and behavior within a system. This approach recognizes that observers of a system will be taking differing and subjective views of the system, depending on their own perspectives. Among the various…

  16. Linking Staff Development and Teacher Induction.

    ERIC Educational Resources Information Center

    Reiman, Alan J.; And Others

    1988-01-01

    This article describes a six-year effort to link inservice training for experienced teachers with teacher preservice and induction for the novice teacher. It provides a rationale for using staff development training to strengthen preservice and induction programs, and discusses program goals, training components, program outcomes, and…

  17. Genetics Home Reference: X-linked agammaglobulinemia

    MedlinePlus

    ... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

  18. Utility and Validity of NAEP Linking Efforts

    ERIC Educational Resources Information Center

    Linn, Robert L.; McLaughlin, Donald; Thissen, David

    2009-01-01

    There are a number of practical situations in which it would be desirable to be able to use the results of the administration of one assessment to estimate what the results would have been if another assessment had been administered. Test linking refers to the idea that results obtained from the administration of one test might be used to infer…

  19. The Missing Link: Research on Teacher Education

    ERIC Educational Resources Information Center

    Wiens, Peter D.

    2012-01-01

    Teacher education has recently come under attack for its perceived lack of efficacy in preparing teachers for classroom duty. A lack of comprehensive research in teacher education makes it difficult to understand the effects of teacher education programs on student learning. There is a missing link between what happens in teacher education…

  20. Thiazolothiazole-linked porous organic polymers

    DOE PAGES

    Zhu, Xiang; Tian, Chengcheng; Jin, Tian; ...

    2014-10-07

    In this study, thiazolothiazole-linked porous organic polymers have been synthesized from a facile catalyst-free condensation reaction between aldehydes and dithiooxamide under solvothermal conditions. The resultant porous frameworks exhibit a highly selective uptake of CO 2 over N 2 under ambient conditions.

  1. Physical Samples Linked Data in Action

    NASA Astrophysics Data System (ADS)

    Ji, P.; Arko, R. A.; Lehnert, K.; Bristol, S.

    2017-12-01

    Most data and metadata related to physical samples currently reside in isolated relational databases driven by diverse data models. How to approach the challenge for sharing, interchanging and integrating data from these difference relational databases motivated us to publish Linked Open Data for collections of physical samples, using Semantic Web technologies including the Resource Description Framework (RDF), RDF Query Language (SPARQL), and Web Ontology Language (OWL). In last few years, we have released four knowledge graphs concentrated on physical samples, including System for Earth Sample Registration (SESAR), USGS National Geochemical Database (NGDC), Ocean Biogeographic Information System (OBIS), and Earthchem Database. Currently the four knowledge graphs contain over 12 million facets (triples) about objects of interest to the geoscience domain. Choosing appropriate domain ontologies for representing context of data is the core of the whole work. Geolink ontology developed by Earthcube Geolink project was used as top level to represent common concepts like person, organization, cruise, etc. Physical sample ontology developed by Interdisciplinary Earth Data Alliance (IEDA) and Darwin Core vocabulary were used as second level to describe details about geological samples and biological diversity. We also focused on finding and building best tool chains to support the whole life cycle of publishing linked data we have, including information retrieval, linked data browsing and data visualization. Currently, Morph, Virtuoso Server, LodView, LodLive, and YASGUI were employed for converting, storing, representing, and querying data in a knowledge base (RDF triplestore). Persistent digital identifier is another main point we concentrated on. Open Researcher & Contributor IDs (ORCIDs), International Geo Sample Numbers (IGSNs), Global Research Identifier Database (GRID) and other persistent identifiers were used to link different resources from various graphs with

  2. Node, Node-Link, and Node-Link-Group Diagrams: An Evaluation.

    PubMed

    Saket, Bahador; Simonetto, Paolo; Kobourov, Stephen; Börner, Katy

    2014-12-01

    Effectively showing the relationships between objects in a dataset is one of the main tasks in information visualization. Typically there is a well-defined notion of distance between pairs of objects, and traditional approaches such as principal component analysis or multi-dimensional scaling are used to place the objects as points in 2D space, so that similar objects are close to each other. In another typical setting, the dataset is visualized as a network graph, where related nodes are connected by links. More recently, datasets are also visualized as maps, where in addition to nodes and links, there is an explicit representation of groups and clusters. We consider these three Techniques, characterized by a progressive increase of the amount of encoded information: node diagrams, node-link diagrams and node-link-group diagrams. We assess these three types of diagrams with a controlled experiment that covers nine different tasks falling broadly in three categories: node-based tasks, network-based tasks and group-based tasks. Our findings indicate that adding links, or links and group representations, does not negatively impact performance (time and accuracy) of node-based tasks. Similarly, adding group representations does not negatively impact the performance of network-based tasks. Node-link-group diagrams outperform the others on group-based tasks. These conclusions contradict results in other studies, in similar but subtly different settings. Taken together, however, such results can have significant implications for the design of standard and domain snecific visualizations tools.

  3. A comprehensive comparison of network similarities for link prediction and spurious link elimination

    NASA Astrophysics Data System (ADS)

    Zhang, Peng; Qiu, Dan; Zeng, An; Xiao, Jinghua

    2018-06-01

    Identifying missing interactions in complex networks, known as link prediction, is realized by estimating the likelihood of the existence of a link between two nodes according to the observed links and nodes' attributes. Similar approaches have also been employed to identify and remove spurious links in networks which is crucial for improving the reliability of network data. In network science, the likelihood for two nodes having a connection strongly depends on their structural similarity. The key to address these two problems thus becomes how to objectively measure the similarity between nodes in networks. In the literature, numerous network similarity metrics have been proposed and their accuracy has been discussed independently in previous works. In this paper, we systematically compare the accuracy of 18 similarity metrics in both link prediction and spurious link elimination when the observed networks are very sparse or consist of inaccurate linking information. Interestingly, some methods have high prediction accuracy, they tend to perform low accuracy in identification spurious interaction. We further find that methods can be classified into several cluster according to their behaviors. This work is useful for guiding future use of these similarity metrics for different purposes.

  4. Towards linked open gene mutations data

    PubMed Central

    2012-01-01

    Background With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. Methods A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. Results We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. Conclusions This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development. The publication of variation information as Linked Data opens new perspectives

  5. Towards linked open gene mutations data.

    PubMed

    Zappa, Achille; Splendiani, Andrea; Romano, Paolo

    2012-03-28

    With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development.The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on

  6. Cross-Linking Studies of Lysozyme Nucleation

    NASA Technical Reports Server (NTRS)

    Forsythe, Elizabeth; Pusey, Marc

    2000-01-01

    Tetragonal chicken egg white crystals consist of 4(sub 3) helices running in alternating directions, the helix rows having a two fold symmetry with each other. The unit cell consists of one complete tetrameric turn from each of two adjacent helices (an octamer). PBC analysis indicates that the helix intermolecular bonds are the strongest in the crystal, therefore likely formed first. AFM analysis of the (110) surface shows only complete helices, no half steps or bisected helices being found, while AFM line scans to measure the growth step increments show that they are multiples of the 4(sub 3) helix tetramer dimensions. This supports our thesis that the growth units are in fact multiples of the four molecule 4(sub 3) helix unit, the "average" growth unit size for the (110) face being an octamer (two turns about the helix) and the (101) growth unit averaging about the size of a hexamer. In an effort to better understand the species involved in the crystal nucleation and growth process, we have initiated an experimental program to study the species formed in solution compared to what is found in the crystal through covalent cross-linking studies. These experiments use the heterobifunctional cross-linking agent aminoethyl-4-azidonitroanaline (AEANA). An aliphatic amine at one end is covalently attached to the protein by a carbodiimide-mediated reaction, and a photo reactive group at the other can be used to initiate crosslinking. Modifications to the parent structure can be used to alter the distance between the two reactive groups and thus the cross-linking agents "reach". In practice, the cross-linking agent is first coupled to the asp101 side chain through the amine group. Asp101 lies within the active site cleft, and previous work with fluorescent probes had shown that derivatives at this site still crystallize in the tetragonal space group. This was also found to be the case with the AEANA derivative, which gave red tetragonal crystals. The protein now has a

  7. Epithelio-mesenchymal transitional attributes in oral sub-mucous fibrosis.

    PubMed

    Das, Raunak Kumar; Anura, Anji; Pal, Mousumi; Bag, Swarnendu; Majumdar, Subhadipa; Barui, Ananya; Chakraborty, Chandan; Ray, Ajoy Kumar; Sengupta, Sanghamitra; Paul, Ranjan Rashmi; Chatterjee, Jyotirmoy

    2013-12-01

    Evaluating molecular attributes in association with its epithelial and sub-epithelial changes of oral sub-mucous fibrosis is meaningful in exploring the plausibility of an epithelio-mesenchymal transition (EMT) and malignant potentiality of this pathosis. In this study histopathological and histochemical attributes for basement membrane and connective tissue in biopsies of oral sub-mucous fibrosis (n = 55) and normal oral mucosa (n = 16) were assessed and expressions of p63, E-cadherin, β-catenin, N-cadherin and TWIST were analyzed immunohistochemically. The p63 and its isoforms (TA and ∆N), PARD3, E-cadherin and β-catenin were also assessed transcriptomically by q-PCR and EMT players like TWIST1, ZEB1, MMP9 and micro-RNA 205 were searched in gene expression microarrays. Oral epithelium demonstrating impairment in progressive maturation in oral sub-mucous fibrosis concomitantly experienced an increase in basement membrane thickness and collagen deposition along with alteration in target molecular expressions. In comparison to non-dysplastic conditions dysplastic stages exhibited significant increase in p63 and p63∆N expressions whereas, E-cadherin and β-catenin exhibited loss from the membrane with concurrent increase in cytoplasm. Further the N-cadherin and TWIST were gained remarkably along with the appearance of nuclear accumulation features of β-catenin. The microarray search had noticed the up-regulation of TWIST1, ZEB1 and MMP9 along with down regulation of micro-RNA 205. The simultaneous increase in basement membrane thickness and sub-epithelial collagen deposition were the plausible indicators for increased matrix stiffness with expected impact on oral epithelial functional homoeostasis. This was corroborated with the increase in expressions of epithelial master regulator p63 and its oncogenic isoform (∆N) along with membranous loss of E-cadherin (EMT hallmark) and its associate β-catein and gain of mesenchymal markers like N-cadherin and TWIST

  8. Linking Schools of Thought to Schools of Practice

    ERIC Educational Resources Information Center

    Hunt, Lucy; Yoshida-Ehrmann, Erin

    2016-01-01

    Project Linking Learning ("Link") was created to target the needs of gifted students in urban school districts with historically underserved populations. Project Linking Learning implemented a linking curriculum between in-class instruction and an afterschool enrichment program for selected students in second through fifth grade.…

  9. A neural link between generosity and happiness

    PubMed Central

    Park, Soyoung Q.; Kahnt, Thorsten; Dogan, Azade; Strang, Sabrina; Fehr, Ernst; Tobler, Philippe N.

    2017-01-01

    Generous behaviour is known to increase happiness, which could thereby motivate generosity. In this study, we use functional magnetic resonance imaging and a public pledge for future generosity to investigate the brain mechanisms that link generous behaviour with increases in happiness. Participants promised to spend money over the next 4 weeks either on others (experimental group) or on themselves (control group). Here, we report that, compared to controls, participants in the experimental group make more generous choices in an independent decision-making task and show stronger increases in self-reported happiness. Generous decisions engage the temporo-parietal junction (TPJ) in the experimental more than in the control group and differentially modulate the connectivity between TPJ and ventral striatum. Importantly, striatal activity during generous decisions is directly related to changes in happiness. These results demonstrate that top–down control of striatal activity plays a fundamental role in linking commitment-induced generosity with happiness. PMID:28696410

  10. Catenanes: Fifty Years of Molecular Links

    PubMed Central

    Gil-Ramírez, Guzmán; Leigh, David A; Stephens, Alexander J

    2015-01-01

    Half a century after Schill and Lüttringhaus carried out the first directed synthesis of a [2]catenane, a plethora of strategies now exist for the construction of molecular Hopf links (singly interlocked rings), the simplest type of catenane. The precision and effectiveness with which suitable templates and/or noncovalent interactions can arrange building blocks has also enabled the synthesis of intricate and often beautiful higher order interlocked systems, including Solomon links, Borromean rings, and a Star of David catenane. This Review outlines the diverse strategies that exist for synthesizing catenanes in the 21st century and examines their emerging applications and the challenges that still exist for the synthesis of more complex topologies. PMID:25951013

  11. Link failure detection in a parallel computer

    DOEpatents

    Archer, Charles J.; Blocksome, Michael A.; Megerian, Mark G.; Smith, Brian E.

    2010-11-09

    Methods, apparatus, and products are disclosed for link failure detection in a parallel computer including compute nodes connected in a rectangular mesh network, each pair of adjacent compute nodes in the rectangular mesh network connected together using a pair of links, that includes: assigning each compute node to either a first group or a second group such that adjacent compute nodes in the rectangular mesh network are assigned to different groups; sending, by each of the compute nodes assigned to the first group, a first test message to each adjacent compute node assigned to the second group; determining, by each of the compute nodes assigned to the second group, whether the first test message was received from each adjacent compute node assigned to the first group; and notifying a user, by each of the compute nodes assigned to the second group, whether the first test message was received.

  12. Link prediction based on nonequilibrium cooperation effect

    NASA Astrophysics Data System (ADS)

    Li, Lanxi; Zhu, Xuzhen; Tian, Hui

    2018-04-01

    Link prediction in complex networks has become a common focus of many researchers. But most existing methods concentrate on neighbors, and rarely consider degree heterogeneity of two endpoints. Node degree represents the importance or status of endpoints. We describe the large-degree heterogeneity as the nonequilibrium between nodes. This nonequilibrium facilitates a stable cooperation between endpoints, so that two endpoints with large-degree heterogeneity tend to connect stably. We name such a phenomenon as the nonequilibrium cooperation effect. Therefore, this paper proposes a link prediction method based on the nonequilibrium cooperation effect to improve accuracy. Theoretical analysis will be processed in advance, and at the end, experiments will be performed in 12 real-world networks to compare the mainstream methods with our indices in the network through numerical analysis.

  13. Optimizing the Galileo space communication link

    NASA Technical Reports Server (NTRS)

    Statman, J. I.

    1994-01-01

    The Galileo mission was originally designed to investigate Jupiter and its moons utilizing a high-rate, X-band (8415 MHz) communication downlink with a maximum rate of 134.4 kb/sec. However, following the failure of the high-gain antenna (HGA) to fully deploy, a completely new communication link design was established that is based on Galileo's S-band (2295 MHz), low-gain antenna (LGA). The new link relies on data compression, local and intercontinental arraying of antennas, a (14,1/4) convolutional code, a (255,M) variable-redundancy Reed-Solomon code, decoding feedback, and techniques to reprocess recorded data to greatly reduce data losses during signal acquisition. The combination of these techniques will enable return of significant science data from the mission.

  14. Linking language and categorization in infancy

    PubMed Central

    Ferguson, Brock; Waxman, Sandra

    2017-01-01

    Language exerts a powerful influence on our concepts. We review evidence documenting the developmental origins of a precocious link between language and object categories in very young infants. This collection of studies documents a cascading process in which early links between language and cognition provide the foundation for later, more precise ones. We propose that, early in life, language promotes categorization at least in part through its status as a social, communicative signal. But over the first year, infants home in on the referential power of language and, by their second year, begin teasing apart distinct kinds of names (e.g., nouns, adjectives) and their relation to distinct kinds of concepts (e.g., object categories, properties). To complement this proposal, we also relate this evidence to several alternative accounts of language’s effect on categorization, appealing to similarity (labels-as-features), familiarity (auditory overshadowing), and communicative biases (natural pedagogy). PMID:27830633

  15. Dissecting the links between cerebellum and dystonia.

    PubMed

    Malone, Ailish; Manto, Mario; Hass, Chris

    2014-12-01

    Dystonia is a common movement disorder characterized by sustained muscle contractions. These contractions generate twisting and repetitive movements or typical abnormal postures, often exacerbated by voluntary movement. Dystonia can affect almost all the voluntary muscles. For several decades, the discussion on the pathogenesis has been focused on basal ganglia circuits, especially striatal networks. So far, although dystonia has been observed in some forms of ataxia such as dominant ataxias, the link between the cerebellum and dystonia has remained unclear. Recent human studies and experimental data mainly in rodents show that the cerebellum circuitry could also be a key player in the pathogenesis of some forms of dystonia. In particular, studies based on behavioral adaptation paradigm shed light on the links between dystonia and cerebellum. The spectrum of movement disorders in which the cerebellum is implicated is continuously expanding, and manipulation of cerebellar circuits might even emerge as a candidate therapy in the coming years.

  16. Quantum and classical optics-emerging links

    NASA Astrophysics Data System (ADS)

    Eberly, J. H.; Qian, Xiao-Feng; Qasimi, Asma Al; Ali, Hazrat; Alonso, M. A.; Gutiérrez-Cuevas, R.; Little, Bethany J.; Howell, John C.; Malhotra, Tanya; Vamivakas, A. N.

    2016-06-01

    Quantum optics and classical optics are linked in ways that are becoming apparent as a result of numerous recent detailed examinations of the relationships that elementary notions of optics have with each other. These elementary notions include interference, polarization, coherence, complementarity and entanglement. All of them are present in both quantum and classical optics. They have historic origins, and at least partly for this reason not all of them have quantitative definitions that are universally accepted. This makes further investigation into their engagement in optics very desirable. We pay particular attention to effects that arise from the mere co-existence of separately identifiable and readily available vector spaces. Exploitation of these vector-space relationships are shown to have unfamiliar theoretical implications and new options for observation. It is our goal to bring emerging quantum-classical links into wider view and to indicate directions in which forthcoming and future work will promote discussion and lead to unified understanding.

  17. Linking language and categorization in infancy.

    PubMed

    Ferguson, Brock; Waxman, Sandra

    2017-05-01

    Language exerts a powerful influence on our concepts. We review evidence documenting the developmental origins of a precocious link between language and object categories in very young infants. This collection of studies documents a cascading process in which early links between language and cognition provide the foundation for later, more precise ones. We propose that, early in life, language promotes categorization at least in part through its status as a social, communicative signal. But over the first year, infants home in on the referential power of language and, by their second year, begin teasing apart distinct kinds of names (e.g. nouns, adjectives) and their relation to distinct kinds of concepts (e.g. object categories, properties). To complement this proposal, we also relate this evidence to several alternative accounts of language's effect on categorization, appealing to similarity ('labels-as-features'), familiarity ('auditory overshadowing'), and communicative biases ('natural pedagogy').

  18. Microwave intersatellite links for communications satellites

    NASA Technical Reports Server (NTRS)

    Welti, G. R.

    1982-01-01

    Applications and interface requirements for intersatellite links (ISLs) between commercial communications satellites are reviewed, ranging from ISLs between widely separated satellites to ISLs between clustered satellites. On-board processing architectures for ISLs employing a variety of modulation schemes are described. These schemes include FM remodulation and QPSK regeneration in combination with switching and buffering. The various architectures are compared in terms of complexity, required performance, antenna size, mass, and power.

  19. Lamellar macular hole in X linked retinoschisis

    PubMed Central

    Kumar, Vinod; Goel, Neha

    2016-01-01

    X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. PMID:27170611

  20. Lamellar macular hole in X linked retinoschisis.

    PubMed

    Kumar, Vinod; Goel, Neha

    2016-05-11

    X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. 2016 BMJ Publishing Group Ltd.

  1. An Accurate Link Correlation Estimator for Improving Wireless Protocol Performance

    PubMed Central

    Zhao, Zhiwei; Xu, Xianghua; Dong, Wei; Bu, Jiajun

    2015-01-01

    Wireless link correlation has shown significant impact on the performance of various sensor network protocols. Many works have been devoted to exploiting link correlation for protocol improvements. However, the effectiveness of these designs heavily relies on the accuracy of link correlation measurement. In this paper, we investigate state-of-the-art link correlation measurement and analyze the limitations of existing works. We then propose a novel lightweight and accurate link correlation estimation (LACE) approach based on the reasoning of link correlation formation. LACE combines both long-term and short-term link behaviors for link correlation estimation. We implement LACE as a stand-alone interface in TinyOS and incorporate it into both routing and flooding protocols. Simulation and testbed results show that LACE: (1) achieves more accurate and lightweight link correlation measurements than the state-of-the-art work; and (2) greatly improves the performance of protocols exploiting link correlation. PMID:25686314

  2. Prostate cancer link to vasectomy is weak.

    PubMed

    1998-03-01

    Health care providers and men seeking vasectomies are still unsure about the nature of the association between vasectomy and prostate cancer. Two large cohort studies published in 1993 found increased relative risks for prostate cancer in vasectomized men of 1.56 and 1.66. However, this level of increased relative risk represents only a weak association between the procedure and cancer. Three other studies of similar design reported no such association. Several divisions of the National Institutes of Health examined the research and issued the joint statement in 1993 that providers should continue to offer vasectomy and perform the procedure, the reversal of vasectomies is unwarranted to prevent prostate cancer, and screening for prostate cancer should not be any different for men who have had a vasectomy than for those who have not. Joel Feigin, MD, associate professor of family medicine at Robert Wood Johnson Medical School in New Brunswick, NJ, and director of the Coventry No-Scalpel Vasectomy Center in Phillipsburg, NJ, recommends dealing proactively with the cancer link as a standard part of counseling. Thomas R. Pritchett, MD, a urologist on the clinical faculty of the University of Washington and the department of urology at Virginia Mason Medical Center in Seattle says that the strongest link to increased risk for prostate cancer is family history. Diet, race, and vasectomy are only weak associations. A definite link also exists between testosterone and prostate cancer, but undergoing vasectomy neither increases nor decreases a man's testosterone level.

  3. Pathways linking parental divorce with adolescent depression.

    PubMed

    Aseltine, R H

    1996-06-01

    This article examines the intervening pathways linking parental divorce with adolescent depression, using both cross-sectional and prospective data from a study of high school students in the Boston metropolitan area. Overall, findings reveal that parental divorce is linked with adolescent depression in two ways: (1) it is a source of numerous secondary problems and stresses that are causally related to depression, and (2) it alters youths' reactivity to these stresses, in some cases enhancing, but in other cases mitigating, their depressive effects. Analyses demonstrated the central role of economic hardship in linking family status with depression, with the strength of this indirect pathway partly attributable to the greater vulnerability of youths in single-parent families to financial stresses. In contrast, family conflict did not account for the distress of youths in single-parent families, largely because of their immunity to the effects of such conflict. Finally, prospective data failed to support the hypothesis that differences between youths in single-parent and intact families predate the divorce.

  4. Percolation of networks with directed dependency links

    NASA Astrophysics Data System (ADS)

    Niu, Dunbiao; Yuan, Xin; Du, Minhui; Stanley, H. Eugene; Hu, Yanqing

    2016-04-01

    The self-consistent probabilistic approach has proven itself powerful in studying the percolation behavior of interdependent or multiplex networks without tracking the percolation process through each cascading step. In order to understand how directed dependency links impact criticality, we employ this approach to study the percolation properties of networks with both undirected connectivity links and directed dependency links. We find that when a random network with a given degree distribution undergoes a second-order phase transition, the critical point and the unstable regime surrounding the second-order phase transition regime are determined by the proportion of nodes that do not depend on any other nodes. Moreover, we also find that the triple point and the boundary between first- and second-order transitions are determined by the proportion of nodes that depend on no more than one node. This implies that it is maybe general for multiplex network systems, some important properties of phase transitions can be determined only by a few parameters. We illustrate our findings using Erdős-Rényi networks.

  5. The complex links between governance and biodiversity.

    PubMed

    Barrett, Christopher B; Gibson, Clark C; Hoffman, Barak; McCubbins, Mathew D

    2006-10-01

    We argue that two problems weaken the claims of those who link corruption and the exploitation of natural resources. The first is conceptual and the second is methodological. Studies that use national-level indicators of corruption fail to note that corruption comes in many forms, at multiple levels, that may affect resource use quite differently: negatively, positively, or not at all. Without a clear causal model of the mechanism by which corruption affects resources, one should treat with caution any estimated relationship between corruption and the state of natural resources. Simple, atheoretical models linking corruption measures and natural resource use typically do not account for other important control variables pivotal to the relationship between humans and natural resources. By way of illustration of these two general concerns, we used statistical methods to demonstrate that the findings of a recent, well-known study that posits a link between corruption and decreases in forests and elephants are not robust to simple conceptual and methodological refinements. In particular, once we controlled for a few plausible anthropogenic and biophysical conditioning factors, estimated the effects in changes rather than levels so as not to confound cross-sectional and longitudinal variation, and incorporated additional observations from the same data sources, corruption levels no longer had any explanatory power.

  6. Active Semi-Supervised Community Detection Based on Must-Link and Cannot-Link Constraints

    PubMed Central

    Cheng, Jianjun; Leng, Mingwei; Li, Longjie; Zhou, Hanhai; Chen, Xiaoyun

    2014-01-01

    Community structure detection is of great importance because it can help in discovering the relationship between the function and the topology structure of a network. Many community detection algorithms have been proposed, but how to incorporate the prior knowledge in the detection process remains a challenging problem. In this paper, we propose a semi-supervised community detection algorithm, which makes full utilization of the must-link and cannot-link constraints to guide the process of community detection and thereby extracts high-quality community structures from networks. To acquire the high-quality must-link and cannot-link constraints, we also propose a semi-supervised component generation algorithm based on active learning, which actively selects nodes with maximum utility for the proposed semi-supervised community detection algorithm step by step, and then generates the must-link and cannot-link constraints by accessing a noiseless oracle. Extensive experiments were carried out, and the experimental results show that the introduction of active learning into the problem of community detection makes a success. Our proposed method can extract high-quality community structures from networks, and significantly outperforms other comparison methods. PMID:25329660

  7. Cross-linking of type I collagen with microbial transglutaminase: identification of cross-linking sites.

    PubMed

    Stachel, Ines; Schwarzenbolz, Uwe; Henle, Thomas; Meyer, Michael

    2010-03-08

    Collagen is a popular biomaterial. To deal with its lack of thermal stability and its weak resistance to proteolytic degradation, collagen-based materials are stabilized via different cross-linking procedures. Regarding the potential toxicity of residual cross-linking agents, enzyme-mediated cross-linking would provide an alternative and nontoxic method for collagen stabilization. The results of this study show that type I collagen is a substrate for mTG. However, epsilon-(gamma-glutamyl)lysine cross-links are only incorporated at elevated temperatures when the protein is partially or completely denatured. A maximum number of 5.4 cross-links per collagen monomer were found for heat-denatured collagen. Labeling with the primary amine monodansylcadaverine revealed that at least half of the cross-links are located within the triple helical region of the collagen molecule. Because the triple helix is highly ordered in its native state, this finding might explain why the glutamine residues are inaccessible for mTG under nondenaturing conditions.

  8. AAH Cage Out-Link and In-Link Antenna Characterization

    NASA Technical Reports Server (NTRS)

    Jeutter, Dean C.

    1998-01-01

    This final report encapsulates the accomplishments of the third year of work on an Advanced Biotelemetry System (ABTS). Overall MU/ABTS project objectives are to provide a biotelemetry system that can collect data from and send commands to an implanted biotransceiver. This system will provide for studies of rodent development in space. The system must be capable of operating in a metal animal cage environment. An important goal is the development of a small, "smart", micropower, implantable biotransceiver with eight-channel data output and single channel command input capabilities with the flexibility for easy customization for a variety of physiologic investigations. The NASA Ames/Marquette University Joint Research work has been devoted to the system design of such a new state of the art biotelemetry system, having multiple physiologic inputs, and bi-directional data transfer capabilities. This work has provided a successful prototype system that connects, by two-way radio links, an addressable biotelemetry system that provides communication between an animal biotelemeter prototype and a personal computer. The operational features of the prototype system are: (1) two-way PCM communication with implanted biotelemeter; (2) microcontroller based biotelemeter; (3) out-link: wideband FSK (60 kBaud); (4) in-link: OOK (2.4 kbaud); (5) septum antenna arrays (In/Out-Links); and (6) personal computer data interface. The important requirement of this third year's work, to demonstrate two-way communication with transmit and receive antennas inside the metal animal cage, has been successfully accomplished. The advances discussed in this report demonstrate that the AAH cage antenna system can provide Out-link and In-link capability for the ABTS bi-directional telemetry system, and can serve as a benchmark for project status. Additions and enhancements to the most recent (April 1997) prototype cage and antenna have been implemented. The implementation, testing, and

  9. The Role of Margin in Link Design and Optimization

    NASA Technical Reports Server (NTRS)

    Cheung, K.

    2015-01-01

    Link analysis is a system engineering process in the design, development, and operation of communication systems and networks. Link models that are mathematical abstractions representing the useful signal power and the undesirable noise and attenuation effects (including weather effects if the signal path transverses through the atmosphere) that are integrated into the link budget calculation that provides the estimates of signal power and noise power at the receiver. Then the link margin is applied which attempts to counteract the fluctuations of the signal and noise power to ensure reliable data delivery from transmitter to receiver. (Link margin is dictated by the link margin policy or requirements.) A simple link budgeting approach assumes link parameters to be deterministic values typically adopted a rule-of-thumb policy of 3 dB link margin. This policy works for most S- and X-band links due to their insensitivity to weather effects. But for higher frequency links like Ka-band, Ku-band, and optical communication links, it is unclear if a 3 dB link margin would guarantee link closure. Statistical link analysis that adopted the 2-sigma or 3-sigma link margin incorporates link uncertainties in the sigma calculation. (The Deep Space Network (DSN) link margin policies are 2-sigma for downlink and 3-sigma for uplink.) The link reliability can therefore be quantified statistically even for higher frequency links. However in the current statistical link analysis approach, link reliability is only expressed as the likelihood of exceeding the signal-to-noise ratio (SNR) threshold that corresponds to a given bit-error-rate (BER) or frame-error-rate (FER) requirement. The method does not provide the true BER or FER estimate of the link with margin, or the required signalto-noise ratio (SNR) that would meet the BER or FER requirement in the statistical sense. In this paper, we perform in-depth analysis on the relationship between BER/FER requirement, operating SNR, and

  10. Musical Preferences are Linked to Cognitive Styles

    PubMed Central

    Greenberg, David M.; Baron-Cohen, Simon; Stillwell, David J.; Kosinski, Michal; Rentfrow, Peter J.

    2015-01-01

    Why do we like the music we do? Research has shown that musical preferences and personality are linked, yet little is known about other influences on preferences such as cognitive styles. To address this gap, we investigated how individual differences in musical preferences are explained by the empathizing-systemizing (E-S) theory. Study 1 examined the links between empathy and musical preferences across four samples. By reporting their preferential reactions to musical stimuli, samples 1 and 2 (Ns = 2,178 and 891) indicated their preferences for music from 26 different genres, and samples 3 and 4 (Ns = 747 and 320) indicated their preferences for music from only a single genre (rock or jazz). Results across samples showed that empathy levels are linked to preferences even within genres and account for significant proportions of variance in preferences over and above personality traits for various music-preference dimensions. Study 2 (N = 353) replicated and extended these findings by investigating how musical preferences are differentiated by E-S cognitive styles (i.e., ‘brain types’). Those who are type E (bias towards empathizing) preferred music on the Mellow dimension (R&B/soul, adult contemporary, soft rock genres) compared to type S (bias towards systemizing) who preferred music on the Intense dimension (punk, heavy metal, and hard rock). Analyses of fine-grained psychological and sonic attributes in the music revealed that type E individuals preferred music that featured low arousal (gentle, warm, and sensual attributes), negative valence (depressing and sad), and emotional depth (poetic, relaxing, and thoughtful), while type S preferred music that featured high arousal (strong, tense, and thrilling), and aspects of positive valence (animated) and cerebral depth (complexity). The application of these findings for clinicians, interventions, and those on the autism spectrum (largely type S or extreme type S) are discussed. PMID:26200656

  11. Optical links in handheld multimedia devices

    NASA Astrophysics Data System (ADS)

    van Geffen, S.; Duis, J.; Miller, R.

    2008-04-01

    Ever emerging applications in handheld multimedia devices such as mobile phones, laptop computers, portable video games and digital cameras requiring increased screen resolutions are driving higher aggregate bitrates between host processor and display(s) enabling services such as mobile video conferencing, video on demand and TV broadcasting. Larger displays and smaller phones require complex mechanical 3D hinge configurations striving to combine maximum functionality with compact building volumes. Conventional galvanic interconnections such as Micro-Coax and FPC carrying parallel digital data between host processor and display module may produce Electromagnetic Interference (EMI) and bandwidth limitations caused by small cable size and tight cable bends. To reduce the number of signals through a hinge, the mobile phone industry, organized in the MIPI (Mobile Industry Processor Interface) alliance, is currently defining an electrical interface transmitting serialized digital data at speeds >1Gbps. This interface allows for electrical or optical interconnects. Above 1Gbps optical links may offer a cost effective alternative because of their flexibility, increased bandwidth and immunity to EMI. This paper describes the development of optical links for handheld communication devices. A cable assembly based on a special Plastic Optical Fiber (POF) selected for its mechanical durability is terminated with a small form factor molded lens assembly which interfaces between an 850nm VCSEL transmitter and a receiving device on the printed circuit board of the display module. A statistical approach based on a Lean Design For Six Sigma (LDFSS) roadmap for new product development tries to find an optimum link definition which will be robust and low cost meeting the power consumption requirements appropriate for battery operated systems.

  12. Musical Preferences are Linked to Cognitive Styles.

    PubMed

    Greenberg, David M; Baron-Cohen, Simon; Stillwell, David J; Kosinski, Michal; Rentfrow, Peter J

    2015-01-01

    Why do we like the music we do? Research has shown that musical preferences and personality are linked, yet little is known about other influences on preferences such as cognitive styles. To address this gap, we investigated how individual differences in musical preferences are explained by the empathizing-systemizing (E-S) theory. Study 1 examined the links between empathy and musical preferences across four samples. By reporting their preferential reactions to musical stimuli, samples 1 and 2 (Ns = 2,178 and 891) indicated their preferences for music from 26 different genres, and samples 3 and 4 (Ns = 747 and 320) indicated their preferences for music from only a single genre (rock or jazz). Results across samples showed that empathy levels are linked to preferences even within genres and account for significant proportions of variance in preferences over and above personality traits for various music-preference dimensions. Study 2 (N = 353) replicated and extended these findings by investigating how musical preferences are differentiated by E-S cognitive styles (i.e., 'brain types'). Those who are type E (bias towards empathizing) preferred music on the Mellow dimension (R&B/soul, adult contemporary, soft rock genres) compared to type S (bias towards systemizing) who preferred music on the Intense dimension (punk, heavy metal, and hard rock). Analyses of fine-grained psychological and sonic attributes in the music revealed that type E individuals preferred music that featured low arousal (gentle, warm, and sensual attributes), negative valence (depressing and sad), and emotional depth (poetic, relaxing, and thoughtful), while type S preferred music that featured high arousal (strong, tense, and thrilling), and aspects of positive valence (animated) and cerebral depth (complexity). The application of these findings for clinicians, interventions, and those on the autism spectrum (largely type S or extreme type S) are discussed.

  13. Honeybee nutrition is linked to landscape composition

    PubMed Central

    Donkersley, Philip; Rhodes, Glenn; Pickup, Roger W; Jones, Kevin C; Wilson, Kenneth

    2014-01-01

    Declines in insect pollinators in Europe have been linked to changes in land use. Pollinator nutrition is dependent on floral resources (i.e., nectar and pollen), which are linked to landscape composition. Here, we present a stratified analysis of the nutritional composition of beebread in managed honeybee hives with a view to examining potential sources of variation in its nutritional composition. Specifically, we tested the hypothesis that beebread composition correlates with local land use and therefore available floral resources. The results demonstrated that the starch, lipid, and moisture contents of beebread are all highly conserved across hives, whereas levels of protein and nonreducing sugar increased as the year progressed, reducing sugars, however, decreased during the first half of the year and then increased toward the end. Local land use around hives was quantified using data from the Countryside Survey 2007 Land Cover Map. Bee-bread protein content was negatively correlated with increasing levels of arable and horticultural farmland surrounding hives and positively correlated with the cover of natural grasslands and broadleaf woodlands. Reducing sugar content was also positively correlated with the amount of broad-leaved woodland in a 3 Km² radius from the hives. Previous studies on a range of invertebrates, including honeybees, indicate that dietary protein intake may have a major impact on correlates of fitness, including longevity and immune function. The finding that beebread protein content correlates with land use suggests that landscape composition may impact on insect pollinator well-being and provides a link between landscape and the nutritional ecology of socially foraging insects in a way not previously considered. PMID:25505544

  14. Linking microarray reporters with protein functions.

    PubMed

    Gaj, Stan; van Erk, Arie; van Haaften, Rachel I M; Evelo, Chris T A

    2007-09-26

    The analysis of microarray experiments requires accurate and up-to-date functional annotation of the microarray reporters to optimize the interpretation of the biological processes involved. Pathway visualization tools are used to connect gene expression data with existing biological pathways by using specific database identifiers that link reporters with elements in the pathways. This paper proposes a novel method that aims to improve microarray reporter annotation by BLASTing the original reporter sequences against a species-specific EMBL subset, that was derived from and crosslinked back to the highly curated UniProt database. The resulting alignments were filtered using high quality alignment criteria and further compared with the outcome of a more traditional approach, where reporter sequences were BLASTed against EnsEMBL followed by locating the corresponding protein (UniProt) entry for the high quality hits. Combining the results of both methods resulted in successful annotation of > 58% of all reporter sequences with UniProt IDs on two commercial array platforms, increasing the amount of Incyte reporters that could be coupled to Gene Ontology terms from 32.7% to 58.3% and to a local GenMAPP pathway from 9.6% to 16.7%. For Agilent, 35.3% of the total reporters are now linked towards GO nodes and 7.1% on local pathways. Our methods increased the annotation quality of microarray reporter sequences and allowed us to visualize more reporters using pathway visualization tools. Even in cases where the original reporter annotation showed the correct description the new identifiers often allowed improved pathway and Gene Ontology linking. These methods are freely available at http://www.bigcat.unimaas.nl/public/publications/Gaj_Annotation/.

  15. Linking microarray reporters with protein functions

    PubMed Central

    Gaj, Stan; van Erk, Arie; van Haaften, Rachel IM; Evelo, Chris TA

    2007-01-01

    Background The analysis of microarray experiments requires accurate and up-to-date functional annotation of the microarray reporters to optimize the interpretation of the biological processes involved. Pathway visualization tools are used to connect gene expression data with existing biological pathways by using specific database identifiers that link reporters with elements in the pathways. Results This paper proposes a novel method that aims to improve microarray reporter annotation by BLASTing the original reporter sequences against a species-specific EMBL subset, that was derived from and crosslinked back to the highly curated UniProt database. The resulting alignments were filtered using high quality alignment criteria and further compared with the outcome of a more traditional approach, where reporter sequences were BLASTed against EnsEMBL followed by locating the corresponding protein (UniProt) entry for the high quality hits. Combining the results of both methods resulted in successful annotation of > 58% of all reporter sequences with UniProt IDs on two commercial array platforms, increasing the amount of Incyte reporters that could be coupled to Gene Ontology terms from 32.7% to 58.3% and to a local GenMAPP pathway from 9.6% to 16.7%. For Agilent, 35.3% of the total reporters are now linked towards GO nodes and 7.1% on local pathways. Conclusion Our methods increased the annotation quality of microarray reporter sequences and allowed us to visualize more reporters using pathway visualization tools. Even in cases where the original reporter annotation showed the correct description the new identifiers often allowed improved pathway and Gene Ontology linking. These methods are freely available at http://www.bigcat.unimaas.nl/public/publications/Gaj_Annotation/. PMID:17897448

  16. Parent characteristics linked with daughters' attachment styles.

    PubMed

    Kilmann, Peter R; Vendemia, Jennifer M C; Parnell, Michele M; Urbaniak, Geoffrey C

    2009-01-01

    This study investigated links between parent characteristics and daughters' attachment styles for 90 female undergraduates and their married biological parents. Parents with a secure attachment pattern were rated as more accepting, less controlling, more competent, and more consistent in showing love and affection to their daughter in contrast to parents with an insecure attachment pattern. Significant positive associations were found between mothers' fearful attachment scores and the fearful, preoccupied, and dismissive attachment scores of daughters. Daughters of matched secure parents were more likely to report a secure attachment style, while daughters of matched insecure parents were more likely to report an insecure attachment style.

  17. Speckle interferometry of Hipparcos link stars. III

    NASA Technical Reports Server (NTRS)

    White, Graeme L.; Jauncey, David L.; Reynolds, John E.; Blackmore, David R.; Matcher, Steven J.

    1991-01-01

    A third list of stars is presented which have been tested by speckle interferometry for use in the Hubble Space Telescope link between the Hipparcos astrometric reference frame and the extragalactic VLBI reference frame. Structural information on angular scales of 0.15-1.2 arcsec for 34 Southern Hemisphere stars is reported from observations made with the Imperial College Speckle Interferometer mounted on the Mount Stromlo 1.9-m telescope. Twenty-four percent of the stars (8 out of the 34) show evidence of multiplicity, in agreement with previous observations in this program.

  18. Data Link Performance Analysis for LVLASO Experiments

    NASA Technical Reports Server (NTRS)

    Mukkamala, Ravi

    1998-01-01

    Low-visibility Landing and Surface Operations System (LVLASO) is currently being prototyped and tested at NASA Langley Research Center. Since the main objective of the system is to maintain the aircraft landings and take-offs even during low-visibility conditions, timely exchange of positional and other information between the aircraft and the ground control is critical. For safety and reliability reasons, there are several redundant sources on the ground (e.g., ASDE, AMASS) that collect and disseminate information about the environment to the aircrafts. The data link subsystem of LVLASO is responsible for supporting the timely transfer of information between the aircrafts and the ground controllers. In fact, if not properly designed, the data link subsystem could become a bottleneck in the proper functioning of LVLASO. Currently, the other components of the system are being designed assuming that the data link has adequate capacity and is capable of delivering the information in a timely manner. During August 1-28, 1997, several flight experiments were conducted to test the prototypes of subsystems developed under LVLASO project, The back-round and details of the tests are described in the next section. The test results have been collected in two CDs by FAA and Rockwell-Collins. Under the current grant, we have analyzed the data and evaluated the performance of the Mode S datalink. In this report, we summarize the results of our analysis. Much of the results are shown in terms of graphs or histograms. The test date (or experiment number) was often taken as the X-axis and the Y-axis denotes whatever metric of focus in that chart. In interpreting these charts, one need to take into account the vehicular traffic during a particular experiment. In general, the performance of the data link was found to be quite satisfactory in terms of delivering long and short Mode S squitters from the vehicles to the ground receiver, Similarly, its performance in delivering control

  19. Topologically non-linked circular duplex DNA.

    PubMed

    Biegeleisen, Ken

    2002-05-01

    The discovery of circular DNA, over 30 years ago, introduced an element of uneasiness in what had been, up to that point, the almost picture-perfect story of the elucidation of the molecular biology of heredity. If DNA indeed has the Watson-Crick right-handed helical secondary structure, then in circular DNA, thousands, or perhaps even millions of twists must be removed in each generation, and re-wound in the next generation. Although enzyme systems adequate for this task have long since been found and characterized, there have nevertheless arisen a number of proposals for alternative DNA structures in which the strands are topologically non-linked, so that they might separate during replication without having to be unwound. These structures have generally been put forth as theory only, and have been largely unaccompanied by experimental evidence to support their applicability to native DNA from living systems. Recently, however, a report has emerged suggesting that it might be possible to separate, intact, the individual single-stranded circular half-chromosomes which constitute the double-stranded circular chromosomes of certain plasmids. This would not be possible unless the chromosomes had one of the alternative, topologically non-linked structures. It is widely believed that after a half-century of worldwide DNA research, any significant change to the Watson-Crick structure is unlikely to stand up to scrutiny. Nevertheless, the present author has found that in many instances in which the behavior of circular duplex DNA is considered to be explicable only in terms of the topologically linked helical model, it is also possible to explain that same behavior in terms of a topologically non-linked model. It is necessary, in these instances, to make certain logical assumptions which cannot be conclusively proven at the present time. The author herein offers an example of one such instance, namely an examination of the behavior of circular duplex DNA in an alkaline

  20. 45 Km Horizontal Path Optical Link Experiment

    NASA Technical Reports Server (NTRS)

    Biswas, A.; Ceniceros, J.; Novak, M.; Jeganathan, M.; Portillo, A.; Erickson, D.; Depew, J.; Sanii, B.; Lesh, J. R.

    2000-01-01

    Mountain-top to mountain-top optical link experiments have been initiated at JPL, in order to perform a systems level evaluation of optical communications. Progress made so far is reported. ne NASA, JPL developed optical communications demonstrator (OCD) is used to transmit a laser signal from Strawberry Peak (SP), located in the San Bernadino mountains of California. This laser beam is received by a 0.6 m aperture telescope at JPL's Table Mountain Facility (TMF), located in Wrightwood, California. The optical link is bi-directional with the TMF telescope transmitting a continuous 4-wave (cw) 780 run beacon and the OCD sending back a 840 nm, 100 - 500 Mbps pseudo noise (PN) modulated, laser beam. The optical link path is at an average altitude of 2 km above sea level, covers a range of 46.8 km and provides an atmospheric channel equivalent to approx. 4 air masses. Average received power measured at either end fall well within the uncertainties predicted by link analysis. The reduction in normalized intensity variance (sigma(sup 2, sub I)) for the 4-beam beacon, compared to each individual beam, at SP, was from approx. 0.68 to 0.22. With some allowance for intra-beam mis-alignment, this is consistent with incoherent averaging. The sigma(sup2, sub I) measured at TMF approx. 0.43 +/- 0.22 exceeded the expected aperture averaged value of less than 0.1, probably because of beam wander. The focused spot sizes of approx. 162 +/- 6 microns at the TMF Coude and approx. 64 +/- 3 microns on the OCD compare to the predicted size range of 52 - 172 microns and 57 - 93 microns, respectively. This is consistent with 4 - 5 arcsec of atmospheric "seeing". The preliminary evaluation of OCD's fine tracking indicates that the uncompensated tracking error is approx. 3.3 micro rad compared to approx. 1.7 micro rad observed in the laboratory. Fine tracking performance was intermittent, primarily due to beacon fades on the OCD tracking sensor. The best bit error rates observed while

  1. Link between microstability and macrostability of plasmas

    SciTech Connect

    Litwin, C.

    A mechanism linking high-frequency microinstabilities and the low-frequencymacrostability is proposed. The coupling is provided by the time-averagedforce, ponderomotive force, of unstable high-frequency waves. Two specificexamples of this phenomenon are discussed. It is shown that an..cap alpha..-particle loss-cone instability stabilizes the flute mode of anignited, axisymmetric mirror plasma. In tokamaks, the ion-whistler instability,driven by an anisotropic population of energetic particles, stabilizes theinternal kink mode for JET range of parameters.

  2. A PYY Q62P variant linked to human obesity

    SciTech Connect

    Ahituv, Nadav; Kavaslar, Nihan; Schackwitz, Wendy

    2005-06-27

    Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysismore » of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.« less

  3. Design and modelling of a link monitoring mechanism for the Common Data Link (CDL)

    NASA Astrophysics Data System (ADS)

    Eichelberger, John W., III

    1994-09-01

    The Common Data Link (CDL) is a full duplex, point-to-point microwave communications system used in imagery and signals intelligence collection systems. It provides a link between two remote Local Area Networks (LAN's) aboard collection and surface platforms. In a hostile environment, there is an overwhelming need to dynamically monitor the link and thus, limit the impact of jamming. This work describes steps taken to design, model, and evaluate a link monitoring system suitable for the CDL. The monitoring system is based on features and monitoring constructs of the Link Control Protocol (LCP) in the Point-to-Point Protocol (PPP) suite. The CDL model is based on a system of two remote Fiber Distributed Data Interface (FDDI) LAN's. In particular, the policies and mechanisms associated with monitoring are described in detail. An implementation of the required mechanisms using the OPNET network engineering tool is described. Performance data related to monitoring parameters is reported. Finally, integration of the FDDI-CDL model with the OPNET Internet model is described.

  4. Dynamic Reconfiguration and Link Fault Tolerance in a Transputer Network

    DTIC Science & Technology

    1989-06-01

    linkO and link3 are connected to the C004s. LinkI and link2 are routed to the P2 edge connector, labelled ConfigUp and ConfiDown for access to...various commands recieved PROC handle.screen (VAL BYTE link.byte, SEQ -place the first byte on screen (source) I F1 linki < 16 -- a link 0 SEQ line.num l...determine characters used on screen for -- display of source & dest IF ((INT(bytel)) < 32) linki : to.slot[INT(bytel)] otherwise linki : 10 IF ((INT(byte2

  5. Spatial-Operator Algebra For Flexible-Link Manipulators

    NASA Technical Reports Server (NTRS)

    Jain, Abhinandan; Rodriguez, Guillermo

    1994-01-01

    Method of computing dynamics of multiple-flexible-link robotic manipulators based on spatial-operator algebra, which originally applied to rigid-link manipulators. Aspects of spatial-operator-algebra approach described in several previous articles in NASA Tech Briefs-most recently "Robot Control Based on Spatial-Operator Algebra" (NPO-17918). In extension of spatial-operator algebra to manipulators with flexible links, each link represented by finite-element model: mass of flexible link apportioned among smaller, lumped-mass rigid bodies, coupling of motions expressed in terms of vibrational modes. This leads to operator expression for modal-mass matrix of link.

  6. Compulsive exercise: links, risks and challenges faced

    PubMed Central

    Lichtenstein, Mia Beck; Hinze, Cecilie Juul; Emborg, Bolette; Thomsen, Freja; Hemmingsen, Simone Daugaard

    2017-01-01

    Compulsive exercise is a condition described since 1970s. It is characterized by a craving for physical training, resulting in uncontrollable excessive exercise behavior with harmful consequences, such as injuries and impaired social relations. It has not been accepted as a mental disorder in either International Classification of Diseases or Diagnostic and Statistical Manual of Mental Disorders. The aim of this literature review was to critically examine the research on links (comorbidity), risks (negative consequences), and challenges faced (problems in a treatment context). This review found that compulsive exercise is associated with eating disorder pathology, perfectionism, neuroticism, narcissism, and obsessive compulsive traits. The most prominent negative consequences were injuries, social impairment, and depression, but more research is needed to uncover the potential dysfunction resulting from compulsive exercise. As the condition is not recognized as a psychiatric disorder, studies on treatment interventions are sparse. Problems with compliance have been reported; therefore, motivational interviewing has been proposed as a treatment approach, in combination with cognitive behavioral therapy. This review summarizes and discusses findings on links/comorbidity, risks/negative consequences, and treatment challenges. We suggest that future studies should pay attention to both prevention and counseling in sports settings, where compulsive exercise appears, as the condition may be associated with harmful consequences. PMID:28435339

  7. Historical links between toxinology and immunology.

    PubMed

    Cavaillon, Jean-Marc

    2018-04-01

    Research on bacterial toxins is closely linked to the birth of immunology. Our understanding of the interaction of bacterial protein toxins with immune cells has helped to decipher immunopathology, develop preventive and curative treatments for infections, and propose anti-cancer immunotherapies. The link started when Behring and Kitasato demonstrated that serotherapy was effective against 'the strangling angel', namely diphtheria, and its dreadful toxin discovered by Roux and Yersin. The antitoxin treatment helped to save thousands of children. Glenny demonstrated the efficacy of the secondary immune response compared to the primary one. Ramon described anatoxins that allowed the elaboration of effective vaccines and discovered the use of adjuvant to boost the antibody response. Similar approaches were later made for the tetanus toxin. Studying antitoxin antibodies Ehrlich demonstrated, for the first time, the transfer of immunity from mother to newborns. In 1989 Marrack and Kappler coined the concept of 'superantigens' to characterize protein toxins that induce T-lymphocyte proliferation, and cytokine release by both T-lymphocytes and antigen presenting cells. More recently, immunotoxins have been designed to kill cancer cells targeted by either specific antibodies or cytokines. Finally, the action of IgE antibodies against toxins may explain their persistence through evolution despite their side effect in allergy.

  8. Compulsive exercise: links, risks and challenges faced.

    PubMed

    Lichtenstein, Mia Beck; Hinze, Cecilie Juul; Emborg, Bolette; Thomsen, Freja; Hemmingsen, Simone Daugaard

    2017-01-01

    Compulsive exercise is a condition described since 1970s. It is characterized by a craving for physical training, resulting in uncontrollable excessive exercise behavior with harmful consequences, such as injuries and impaired social relations. It has not been accepted as a mental disorder in either International Classification of Diseases or Diagnostic and Statistical Manual of Mental Disorders . The aim of this literature review was to critically examine the research on links (comorbidity), risks (negative consequences), and challenges faced (problems in a treatment context). This review found that compulsive exercise is associated with eating disorder pathology, perfectionism, neuroticism, narcissism, and obsessive compulsive traits. The most prominent negative consequences were injuries, social impairment, and depression, but more research is needed to uncover the potential dysfunction resulting from compulsive exercise. As the condition is not recognized as a psychiatric disorder, studies on treatment interventions are sparse. Problems with compliance have been reported; therefore, motivational interviewing has been proposed as a treatment approach, in combination with cognitive behavioral therapy. This review summarizes and discusses findings on links/comorbidity, risks/negative consequences, and treatment challenges. We suggest that future studies should pay attention to both prevention and counseling in sports settings, where compulsive exercise appears, as the condition may be associated with harmful consequences.

  9. Harm mediates the disgust-immorality link.

    PubMed

    Schein, Chelsea; Ritter, Ryan S; Gray, Kurt

    2016-09-01

    Many acts are disgusting, but only some of these acts are immoral. Dyadic morality predicts that disgusting acts should be judged as immoral to the extent that they seem harmful. Consistent with this prediction, 3 studies reveal that perceived harm mediates the link between feelings of disgust and moral condemnation-even for ostensibly harmless "purity" violations. In many cases, accounting for perceived harm completely eliminates the link between disgust and moral condemnation. Analyses also reveal the predictive power of anger and typicality/weirdness in moral judgments of disgusting acts. The mediation of disgust by harm holds across diverse acts including gay marriage, sex acts, and religious blasphemy. Revealing the endogenous presence and moral relevance of harm within disgusting-but-ostensibly harmless acts argues against modular accounts of moral cognition such as moral foundations theory. Instead, these data support pluralistic conceptions of harm and constructionist accounts of morality and emotion. Implications for moral cognition and the concept of "purity" are discussed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  10. Leaf morphology shift linked to climate change.

    PubMed

    Guerin, Greg R; Wen, Haixia; Lowe, Andrew J

    2012-10-23

    Climate change is driving adaptive shifts within species, but research on plants has been focused on phenology. Leaf morphology has demonstrated links with climate and varies within species along climate gradients. We predicted that, given within-species variation along a climate gradient, a morphological shift should have occurred over time due to climate change. We tested this prediction, taking advantage of latitudinal and altitudinal variations within the Adelaide Geosyncline region, South Australia, historical herbarium specimens (n = 255) and field sampling (n = 274). Leaf width in the study taxon, Dodonaea viscosa subsp. angustissima, was negatively correlated with latitude regionally, and leaf area was negatively correlated with altitude locally. Analysis of herbarium specimens revealed a 2 mm decrease in leaf width (total range 1-9 mm) over 127 years across the region. The results are consistent with a morphological response to contemporary climate change. We conclude that leaf width is linked to maximum temperature regionally (latitude gradient) and leaf area to minimum temperature locally (altitude gradient). These data indicate a morphological shift consistent with a direct response to climate change and could inform provenance selection for restoration with further investigation of the genetic basis and adaptive significance of observed variation.

  11. Strengthening links between waterfowl research and management

    USGS Publications Warehouse

    Roberts, Anthony J.; Eadie, John M.; Howerter, David; Johnson, Fred A.; Nichols, James; Runge, Michael C.; Vrtiska, Mark; Williams, Byron K.

    2018-01-01

    Waterfowl monitoring, research, regulation, and adaptive planning are leading the way in supporting science-informed wildlife management. However, increasing societal demands on natural resources have created a greater need for adaptable and successful linkages between waterfowl science and management. We presented a special session at the 2016 North American Duck Symposium, Annapolis, Maryland, USA on the successes and challenges of linking research and management in waterfowl conservation, and we summarize those thoughts in this commentary. North American waterfowl management includes a diversity of actions including management of harvest and habitat. Decisions for waterfowl management are structured using decision analysis by incorporating stakeholder values into formal objectives, identifying research relevant to objectives, integrating scientific knowledge, and choosing an optimal strategy with respect to objectives. Recently, the consideration of the value of information has been proposed as a means to evaluate the utility of research designed to meet objectives. Despite these advances, the ability to conduct waterfowl research with direct management application may be increasingly difficult in research institutions for several reasons including reduced funding for applied research and the lower perceived value of applied versus theoretical research by some university academics. In addition, coordination between researchers and managers may be logistically constrained, and communication may be ineffective between the 2 groups. Strengthening these links would help develop stronger and more coordinated approaches for the conservation of waterfowl and the wetlands upon which they depend.

  12. Porting Initiation and Failure into Linked CHEETAH

    NASA Astrophysics Data System (ADS)

    Souers, Clark; Vitello, Peter

    2007-06-01

    Linked CHEETAH is a thermo-chemical code coupled to a 2-D hydrocode. Initially, a quadratic-pressure dependent kinetic rate was used, which worked well in modeling prompt detonation of explosives of large size, but does not work on other aspects of explosive behavior. The variable-pressure Tarantula reactive flow rate model was developed with JWL++ in order to also describe failure and initiation, and we have moved this model into Linked CHEETAH. The model works by turning on only above a pressure threshold, where a slow turn-on creates initiation. At a higher pressure, the rate suddenly leaps to a large value over a small pressure range. A slowly failing cylinder will see a rapidly declining rate, which pushes it quickly into failure. At a high pressure, the detonation rate is constant. A sequential validation procedure is used, which includes metal-confined cylinders, rate-sticks, corner-turning, initiation and threshold, gap tests and air gaps. The size (diameter) effect is central to the calibration. This work was performed under the auspices of the U.S. Department of Energy by the University of California Lawrence Livermore National Laboratory under contract No. W-7405-Eng-48.

  13. Deep Space Optical Link ARQ Performance Analysis

    NASA Technical Reports Server (NTRS)

    Clare, Loren; Miles, Gregory

    2016-01-01

    Substantial advancements have been made toward the use of optical communications for deep space exploration missions, promising a much higher volume of data to be communicated in comparison with present -day Radio Frequency (RF) based systems. One or more ground-based optical terminals are assumed to communicate with the spacecraft. Both short-term and long-term link outages will arise due to weather at the ground station(s), space platform pointing stability, and other effects. To mitigate these outages, an Automatic Repeat Query (ARQ) retransmission method is assumed, together with a reliable back channel for acknowledgement traffic. Specifically, the Licklider Transmission Protocol (LTP) is used, which is a component of the Disruption-Tolerant Networking (DTN) protocol suite that is well suited for high bandwidth-delay product links subject to disruptions. We provide an analysis of envisioned deep space mission scenarios and quantify buffering, latency and throughput performance, using a simulation in which long-term weather effects are modeled with a Gilbert -Elliot Markov chain, short-term outages occur as a Bernoulli process, and scheduled outages arising from geometric visibility or operational constraints are represented. We find that both short- and long-term effects impact throughput, but long-term weather effects dominate buffer sizing and overflow losses as well as latency performance.

  14. Regulatory mechanisms link phenotypic plasticity to evolvability

    PubMed Central

    van Gestel, Jordi; Weissing, Franz J.

    2016-01-01

    Organisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question – the optimal timing of bacterial sporulation – we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations. PMID:27087393

  15. Porting Inition and Failure to Linked Cheetah

    SciTech Connect

    Vitello, P; Souers, P C

    2007-07-18

    Linked CHEETAH is a thermo-chemical code coupled to a 2-D hydrocode. Initially, a quadratic-pressure dependent kinetic rate was used, which worked well in modeling prompt detonation of explosives of large size, but does not work on other aspects of explosive behavior. The variable-pressure Tarantula reactive flow rate model was developed with JWL++ in order to also describe failure and initiation, and we have moved this model into Linked CHEETAH. The model works by turning on only above a pressure threshold, where a slow turn-on creates initiation. At a higher pressure, the rate suddenly leaps to a large value over amore » small pressure range. A slowly failing cylinder will see a rapidly declining rate, which pushes it quickly into failure. At a high pressure, the detonation rate is constant. A sequential validation procedure is used, which includes metal-confined cylinders, rate-sticks, corner-turning, initiation and threshold, gap tests and air gaps. The size (diameter) effect is central to the calibration.« less

  16. Obesity and Asthma: A Missing Link.

    PubMed

    Gomez-Llorente, Mª Amelia; Romero, Raquel; Chueca, Natalia; Martinez-Cañavate, Ana; Gomez-Llorente, Carolina

    2017-07-11

    Obesity and asthma are two chronic conditions that affect millions of people. Genetic and lifestyle factors such as diet, physical activity, and early exposure to micro-organisms are important factors that may contribute to the escalating prevalence of both conditions. The prevalence of asthma is higher in obese individuals. Recently, two major phenotypes of asthma with obesity have been described: one phenotype of early-onset asthma that is aggravated by obesity, and a second phenotype of later-onset asthma that predominantly affects women. Systemic inflammation and mechanical effect, both due to the expansion of the adipose tissue, have been proposed as the main reasons for the association between obesity and asthma. However, the mechanisms involved are not yet fully understood. Moreover, it has also been suggested that insulin resistance syndrome can have a role in the association between these conditions. The intestinal microbiota is an important factor in the development of the immune system, and can be considered a link between obesity and asthma. In the obese state, higher lipopolysaccharide (LPS) serum levels as a consequence of a microbiota dysbiosis have been found. In addition, changes in microbiota composition result in a modification of carbohydrate fermentation capacity, therefore modifying short chain fatty acid (SCFA) levels. The main objective of this review is to summarize the principal findings that link obesity and asthma.

  17. X linked mental retardation: a clinical guide.

    PubMed

    Raymond, F L

    2006-03-01

    Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

  18. Polychlorinated biphenyls and links to cardiovascular disease.

    PubMed

    Perkins, Jordan T; Petriello, Michael C; Newsome, Bradley J; Hennig, Bernhard

    2016-02-01

    The pathology of cardiovascular disease is multi-faceted, with links to many modifiable and non-modifiable risk factors. Epidemiological evidence now implicates exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), with an increased risk of developing diabetes, hypertension, and obesity; all of which are clinically relevant to the onset and progression of cardiovascular disease. PCBs exert their cardiovascular toxicity either directly or indirectly via multiple mechanisms, which are highly dependent on the type and concentration of PCBs present. However, many PCBs may modulate cellular signaling pathways leading to common detrimental outcomes including induction of chronic oxidative stress, inflammation, and endocrine disruption. With the abundance of potential toxic pollutants increasing globally, it is critical to identify sensible means of decreasing associated disease risks. Emerging evidence now implicates a protective role of lifestyle modifications such as increased exercise and/or nutritional modulation via anti-inflammatory foods, which may help to decrease the vascular toxicity of PCBs. This review will outline the current state of knowledge linking coplanar and non-coplanar PCBs to cardiovascular disease and describe the possible molecular mechanism of this association.

  19. Linking flowability and granulometry of lactose powders.

    PubMed

    Boschini, F; Delaval, V; Traina, K; Vandewalle, N; Lumay, G

    2015-10-15

    The flowing properties of 10 lactose powders commonly used in pharmaceutical industries have been analyzed with three recently improved measurement methods. The first method is based on the heap shape measurement. This straightforward measurement method provides two physical parameters (angle of repose αr and static cohesive index σr) allowing to make a first screening of the powder properties. The second method allows to estimate the rheological properties of a powder by analyzing the powder flow in a rotating drum. This more advanced method gives a large set of physical parameters (flowing angle αf, dynamic cohesive index σf, angle of first avalanche αa and powder aeration %ae) leading to deeper interpretations. The third method is an improvement of the classical bulk and tapped density measurements. In addition to the improvement of the measurement precision, the densification dynamics of the powder bulk submitted to taps is analyzed. The link between the macroscopic physical parameters obtained with these methods and the powder granulometry is analyzed. Moreover, the correlations between the different flowability indexes are discussed. Finally, the link between grain shape and flowability is discussed qualitatively. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Phase slips in superconducting weak links

    SciTech Connect

    Kimmel, Gregory; Glatz, Andreas; Aranson, Igor S.

    2017-01-01

    Superconducting vortices and phase slips are primary mechanisms of dissipation in superconducting, superfluid, and cold-atom systems. While the dynamics of vortices is fairly well described, phase slips occurring in quasi-one- dimensional superconducting wires still elude understanding. The main reason is that phase slips are strongly nonlinear time-dependent phenomena that cannot be cast in terms of small perturbations of the superconducting state. Here we study phase slips occurring in superconducting weak links. Thanks to partial suppression of superconductivity in weak links, we employ a weakly nonlinear approximation for dynamic phase slips. This approximation is not valid for homogeneous superconducting wires andmore » slabs. Using the numerical solution of the time-dependent Ginzburg-Landau equation and bifurcation analysis of stationary solutions, we show that the onset of phase slips occurs via an infinite period bifurcation, which is manifested in a specific voltage-current dependence. Our analytical results are in good agreement with simulations.« less

  1. Obesity and Asthma: A Missing Link

    PubMed Central

    Gomez-Llorente, Mª Amelia; Romero, Raquel; Chueca, Natalia; Martinez-Cañavate, Ana

    2017-01-01

    Obesity and asthma are two chronic conditions that affect millions of people. Genetic and lifestyle factors such as diet, physical activity, and early exposure to micro-organisms are important factors that may contribute to the escalating prevalence of both conditions. The prevalence of asthma is higher in obese individuals. Recently, two major phenotypes of asthma with obesity have been described: one phenotype of early-onset asthma that is aggravated by obesity, and a second phenotype of later-onset asthma that predominantly affects women. Systemic inflammation and mechanical effect, both due to the expansion of the adipose tissue, have been proposed as the main reasons for the association between obesity and asthma. However, the mechanisms involved are not yet fully understood. Moreover, it has also been suggested that insulin resistance syndrome can have a role in the association between these conditions. The intestinal microbiota is an important factor in the development of the immune system, and can be considered a link between obesity and asthma. In the obese state, higher lipopolysaccharide (LPS) serum levels as a consequence of a microbiota dysbiosis have been found. In addition, changes in microbiota composition result in a modification of carbohydrate fermentation capacity, therefore modifying short chain fatty acid (SCFA) levels. The main objective of this review is to summarize the principal findings that link obesity and asthma. PMID:28696379

  2. Linking Deep Astrometric Standards to the ICRF

    NASA Astrophysics Data System (ADS)

    Frey, S.; Platais, I.; Fey, A. L.

    2007-07-01

    The next-generation large aperature and large field-of-view telescopes will address fundamantal questions of astrophysica and cosmology such as the nature of dark matter and dark energy. For a variety of applications, the CCD mosaic detectors in the focal plane arrays require astronomic calibrationat the milli-arcsecond (mas) level. The existing optical reference frames are insufficient to support such calibrations. To address this problem, deep optical astronomic fields are being established near the Galactic plane. In order to achiev a 5-10-mas or better positional accuracyfor the Deepp Astrometric Standards (DAS), and to obtain bsolute stellar proper motions for the study of Galactic structure, it is crucial to link these fields to the International Celestial Reference Frame (ICRF). To this end, we selected 15 candidate compact extragalactic radio sources in the Gemini-Orion-Taurus (GOT) field. These sources were observed with the European VLBI Network (EVN) at 5 GHz in phase-reference mode. The bright compact calibrator source J0603+2159 and seven other sources were detected and imaged at the angular resolution of -1.5-8 mas. Relative astrometric positions were derived for these sources at a milli-arcsecond accuracy level. The detection of the optical counterparts of these extragalactic radio sources will allow us to establish a direct link to the ICRF locally in the GOT field.

  3. Computational advances towards linking BOLD and behavior.

    PubMed

    Serences, John T; Saproo, Sameer

    2012-03-01

    Traditionally, fMRI studies have focused on analyzing the mean response amplitude within a cortical area. However, the mean response is blind to many important patterns of cortical modulation, which severely limits the formulation and evaluation of linking hypotheses between neural activity, BOLD responses, and behavior. More recently, multivariate pattern classification analysis (MVPA) has been applied to fMRI data to evaluate the information content of spatially distributed activation patterns. This approach has been remarkably successful at detecting the presence of specific information in targeted brain regions, and provides an extremely flexible means of extracting that information without a precise generative model for the underlying neural activity. However, this flexibility comes at a cost: since MVPA relies on pooling information across voxels that are selective for many different stimulus attributes, it is difficult to infer how specific sub-sets of tuned neurons are modulated by an experimental manipulation. In contrast, recently developed encoding models can produce more precise estimates of feature-selective tuning functions, and can support the creation of explicit linking hypotheses between neural activity and behavior. Although these encoding models depend on strong - and often untested - assumptions about the response properties of underlying neural generators, they also provide a unique opportunity to evaluate population-level computational theories of perception and cognition that have previously been difficult to assess using either single-unit recording or conventional neuroimaging techniques. Copyright © 2011. Published by Elsevier Ltd.

  4. Disbiome database: linking the microbiome to disease.

    PubMed

    Janssens, Yorick; Nielandt, Joachim; Bronselaer, Antoon; Debunne, Nathan; Verbeke, Frederick; Wynendaele, Evelien; Van Immerseel, Filip; Vandewynckel, Yves-Paul; De Tré, Guy; De Spiegeleer, Bart

    2018-06-04

    Recent research has provided fascinating indications and evidence that the host health is linked to its microbial inhabitants. Due to the development of high-throughput sequencing technologies, more and more data covering microbial composition changes in different disease types are emerging. However, this information is dispersed over a wide variety of medical and biomedical disciplines. Disbiome is a database which collects and presents published microbiota-disease information in a standardized way. The diseases are classified using the MedDRA classification system and the micro-organisms are linked to their NCBI and SILVA taxonomy. Finally, each study included in the Disbiome database is assessed for its reporting quality using a standardized questionnaire. Disbiome is the first database giving a clear, concise and up-to-date overview of microbial composition differences in diseases, together with the relevant information of the studies published. The strength of this database lies within the combination of the presence of references to other databases, which enables both specific and diverse search strategies within the Disbiome database, and the human annotation which ensures a simple and structured presentation of the available data.

  5. Expert communication link management: overview and progress

    NASA Astrophysics Data System (ADS)

    Dunkelberger, Kirk A.

    1998-08-01

    Consider the downsizing of our forces, the increasing complexity of our tactical platforms, and the ever widening array of communication options and the conclusion is inevitable. The need for automated support to reduce communication-related workload is critical to continued task force effectiveness. In a previous era, communication management expertise resided solely in the form of human experts. These experts flew with the pilots, providing the most effective means of communication in real time; they have since been removed from a great number of platforms due to force downsizing and real estate value in the cockpit. This burden has typically been shifted to the pilot, providing another set of tasks in an environment which is already far too taxing. An Expert Communication Link Manger (ECLM) is required -- a trusted, reliable assistant which can determine optimal link, channel, and waveform data for the communication requirements at hand and translate those requirements transparently into communication device control. Technologies are at hand which make ECLM possible; the mixture of these elements in the correct proportions can provide a capable, deployable, and cost effective ECLM in the near term. This paper describes specific applied ECLM research work in progress funded by the USAF under a four year effort. Operational objectives, technical objectives, a reference design, and technical excursions within the broad ECLM scope will be discussed in detail. Results of prototypes built to date in the area of communication inference from speech understanding, dynamic adaptive routing, and packet switching networks in the tactical environment will be presented.

  6. Radio Links for the NASA ABTS

    NASA Technical Reports Server (NTRS)

    Jeutter, Dean C.

    1996-01-01

    The closed loop prototype has operational bi-directional wireless links. The Wideband PCM-FSK receiver has been designed and characterized. Now that both links function, communication performance can be addressed. For example, noise problems with the received outlink signal that caused the PC program to lockup were just recently revealed and minimized by software "enhancements" to the Windows based PC program. A similar problem with inlink communication was uncovered several days before this report: A noise spike or dropout (expected events in the animal Habitat) caused an interrupt to the implant microcontroller which halted outlink transmission. Recovery of outlink transmission did not reliably occur. The problem has been defined and implant software is being modified to better recognize noise from data by changing the timing associated with valid data packet identification and by better utilizing the error flags generated by the microcontroller's SCI circuits. Excellent inlink performance will also require improvements in the implant's receiver. The biggest performance improvement can be provided by antenna design for the Habitat. The quarter wavelength whip antennas used with the demo prototype inlink leave much to be desired.

  7. Cancer-linked targets modulated by curcumin

    PubMed Central

    Hasima, Noor; Aggarwal, Bharat B

    2012-01-01

    In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. PMID:23301199

  8. Vasopressin: the missing link for preeclampsia?

    PubMed

    Sandgren, Jeremy A; Scroggins, Sabrina M; Santillan, Donna A; Devor, Eric J; Gibson-Corley, Katherine N; Pierce, Gary L; Sigmund, Curt D; Santillan, Mark K; Grobe, Justin L

    2015-11-01

    Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5-7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a "tissue rejection" type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by-product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia. Copyright © 2015 the American Physiological Society.

  9. Cross-linked polyimides for integrated optics

    NASA Astrophysics Data System (ADS)

    Singer, Kenneth D.; Kowalczyk, Tony C.; Nguyen, Hung D.; Beuhler, Allyson J.; Wargowski, David A.

    1997-01-01

    We have investigated a promising class of polyimide materials for both passive and active electro-optic devices, namely crosslinkable polyimides. These fluorinated polyimides are soluble in the imidized form and are both thermally and photo-crosslinkable leading to easy processability into waveguide structures and the possibility of stable electro-optic properties. We have fabricated channel and slab waveguides and investigated the mechanism of optical propagation loss using photothermal deflection spectroscopy and waveguide loss spectroscopy, and found the losses to arise from residual absorption due to the formation of charge transfer states. The absorption is inhibited by fluorination leading to propagation losses as low as 0.3 dB/cm in the near infrared. Because of the ability to photocrosslink, channel waveguides are fabricated using a simple wet-etch process. Channel waveguides so formed are observed to have no excess loss over slab structures. Solubility followed by thermal cross-linking allows the formation of multilayer structures. We have produced electro-optic polymers by doping with the nonlinear optical chromophores, DCM and DADC; and a process of concurrent poling and thermal crosslinking. Multilayer structures have been investigated and poling fields optimized in the active layer by doping the cladding with an anti-static agent. The high glass-transition temperature and cross-linking leads to very stable electro-optic properties. We are currently building electro-optic modulators based on these materials. Progress and results in this area also are reported.

  10. Similarity indices based on link weight assignment for link prediction of unweighted complex networks

    NASA Astrophysics Data System (ADS)

    Liu, Shuxin; Ji, Xinsheng; Liu, Caixia; Bai, Yi

    2017-01-01

    Many link prediction methods have been proposed for predicting the likelihood that a link exists between two nodes in complex networks. Among these methods, similarity indices are receiving close attention. Most similarity-based methods assume that the contribution of links with different topological structures is the same in the similarity calculations. This paper proposes a local weighted method, which weights the strength of connection between each pair of nodes. Based on the local weighted method, six local weighted similarity indices extended from unweighted similarity indices (including Common Neighbor (CN), Adamic-Adar (AA), Resource Allocation (RA), Salton, Jaccard and Local Path (LP) index) are proposed. Empirical study has shown that the local weighted method can significantly improve the prediction accuracy of these unweighted similarity indices and that in sparse and weakly clustered networks, the indices perform even better.

  11. EarthCube GeoLink: Semantics and Linked Data for the Geosciences

    NASA Astrophysics Data System (ADS)

    Arko, R. A.; Carbotte, S. M.; Chandler, C. L.; Cheatham, M.; Fils, D.; Hitzler, P.; Janowicz, K.; Ji, P.; Jones, M. B.; Krisnadhi, A.; Lehnert, K. A.; Mickle, A.; Narock, T.; O'Brien, M.; Raymond, L. M.; Schildhauer, M.; Shepherd, A.; Wiebe, P. H.

    2015-12-01

    The NSF EarthCube initiative is building next-generation cyberinfrastructure to aid geoscientists in collecting, accessing, analyzing, sharing, and visualizing their data and knowledge. The EarthCube GeoLink Building Block project focuses on a specific set of software protocols and vocabularies, often characterized as the Semantic Web and "Linked Data", to publish data online in a way that is easily discoverable, accessible, and interoperable. GeoLink brings together specialists from the computer science, geoscience, and library science domains, and includes data from a network of NSF-funded repositories that support scientific studies in marine geology, marine ecosystems, biogeochemistry, and paleoclimatology. We are working collaboratively with closely-related Building Block projects including EarthCollab and CINERGI, and solicit feedback from RCN projects including Cyberinfrastructure for Paleogeosciences (C4P) and iSamples. GeoLink has developed a modular ontology that describes essential geoscience research concepts; published data from seven collections (to date) on the Web as geospatially-enabled Linked Data using this ontology; matched and mapped data between collections using shared identifiers for investigators, repositories, datasets, funding awards, platforms, research cruises, physical specimens, and gazetteer features; and aggregated the results in a shared knowledgebase that can be queried via a standard SPARQL endpoint. Client applications have been built around the knowledgebase, including a Web/map-based data browser using the Leaflet JavaScript library and a simple query service using the OpenSearch format. Future development will include extending and refining the GeoLink ontology, adding content from additional repositories, developing semi-automated algorithms to enhance metadata, and further work on client applications.

  12. AAH Cage Out-Link and In-Link Antenna Characterization

    NASA Technical Reports Server (NTRS)

    Jeutter, Dean C.

    1998-01-01

    This final report encapsulates the accomplishments of the third year of work on an Advanced Biotelemetry System (ABTS). Overall MU/ABTS project objectives are to provide a biotelemetry system that can collect data from and send commands to an implanted biotransceiver. This system will provide for studies of rodent development in space. The system must be capable of operating in a metal animal cage environment. An important goal is the development of a small, "smart", micropower, -channel data output and single channel command implantable biotransceiver with eight input capabilities with the flexibility for easy customization for a variety of physiologic investigations. The NASA Ames/Marquette University Joint Research work has been devoted to the system design of such a new state of the art biotelemetry system, having multiple physiologic inputs, and bi-directional data transfer capabilities. This work has provided a successful prototype system that connects, by two-way radio links, an addressable biotelemetry system that provides communication between an animal biotelemeter prototype and a personal computer. The operational features of the prototype system are listed below: Two-Way PCM Communication with Implanted Biotelemeter Microcontroller Based Biotelemeter Out-Link: Wideband FSK (60 kbaud) In-Link: OOK (2.4 kbaud) Septum Antenna Arrays (In/Out-Links) Personal Computer Data Interface The important requirement of this third year's work, to demonstrate two-way communication with transmit and receive antennas inside the metal animal cage, has been successfully accomplished. The advances discussed in this report demonstrate that the AAH cage antenna system can provide Out-link and In-link capability for the ABTS bi-directional telemetry system, and can serve as a benchmark for project status.

  13. USING LINKED MICROMAP PLOTS TO CHARACTERIZE OMERNIK ECOREGIONS

    EPA Science Inventory

    The paper introduces linked micromap (LM plots for presenting environmental summaries. The LM template includes parallel sequences of micromap, able, and statistical summary graphics panels with attention paid to perceptual grouping, sorting and linking of the summary components...

  14. Impact of data link technology on railroad dispatching operations

    DOT National Transportation Integrated Search

    2004-10-01

    This study examined data link communication as an alternative channel to voice radio for railroad dispatchers. The goal was to compare how data link affected performance compared to voice radio only communications on measures related to safety, produ...

  15. General aviation data link survey analysis : Experimental Aircraft Association

    DOT National Transportation Integrated Search

    1996-07-01

    The Federal Aviation Administration (FAA) is interested in integrating Data Link communications : technology into the General Aviation (GA) community. But, how much does the GA community : know about the Data Link concept, the services that are possi...

  16. General aviation data link survey analysis : National Business Aircraft Association

    DOT National Transportation Integrated Search

    1996-05-01

    The Federal Aviation Administration (FAA) is interested in integrating Data Link communications technology into the General Aviation (GA) community. But, how much does the GA community know about the Data Link concept, the services that are possible,...

  17. General aviation data link survey analysis : flight schools

    DOT National Transportation Integrated Search

    1996-07-01

    The Federal Aviation Administration (FAA) is interested in integrating Data : Link communications technology into the General Aviation (GA) community. But, : how much does the GA community know about the Data Link concept, the services : that are pos...

  18. Making the Link between Libraries and Adult Basic Skills.

    ERIC Educational Resources Information Center

    Clarke, Genevieve

    2002-01-01

    Vital Link is a British program that links national reading and literacy organizations with libraries. The focus is on how libraries can support and motivate existing learners while attracting new learners. (JOW)

  19. VAX-Gerber node link. Revision 1. 0

    SciTech Connect

    Isobe, G.W.

    1985-12-01

    A communications link between the CADDE VAX 11/750 and the Gerber Photo-Plotter 4135 was desired at LLNL. The process of creating this link is discussed and the features of this project are described. 4 figs.

  20. High Speed Link Radiated Emission Reduction

    NASA Astrophysics Data System (ADS)

    Bisognin, P.; Pelissou, P.; Cissou, R.; Giniaux, M.; Vargas, O.

    2016-05-01

    To control the radiated emission of high-speed link and associated unit, the current approach is to implement overall harness shielding on cables bundles. This method is very efficient in the HF/ VHF (high frequency/ very high frequency) and UHF (ultra-high frequency) ranges when the overall harness shielding is properly bonded on EMC back-shell. Unfortunately, with the increasing frequency, the associated half wavelength matches with the size of Sub-D connector that is the case for the L band. Therefore, the unit connectors become the main source of interference emission. For the L-band and S-band, the current technology of EMC back-shell leaves thin aperture matched with the L band half wavelength and therefore, the shielding effectiveness is drastically reduced. In addition, overall harness shielding means significant increases of the harness mass.Airbus D&S Toulouse and Elancourt investigated a new solution to avoid the need of overall harness shielding. The objective is to procure EM (Electro-Magnetic) clean unit connected to cables bundles free of any overall harness shielding. The proposed solution is to implement EMC common mode filtering on signal interfaces directly on unit PCB as close as possible the unit connector.Airbus D&S Elancourt designed and manufactured eight mock-ups of LVDS (Low Voltage Differential Signaling) interface PCBs' with different solutions of filtering. After verification of the signal integrity, three mock-ups were retained (RC filter and two common mode choke coil) in addition to the reference one (without EMC filter).Airbus D&S Toulouse manufactured associated LVDS cable bundles and integrated the RX (Receiver) and TX (Transmitter) LVDS boards in shielded boxes.Then Airbus D&S performed radiated emission measurement of the LVDS links subassemblies (e.g. RX and TX boxes linked by LVDS cables) according to the standard test method. This paper presents the different tested solutions and main conclusions on the feasibility of such

  1. To Cross-Link or Not to Cross-Link? Cross-Linking Associated Foreign Body Response of Collagen-Based Devices

    PubMed Central

    Delgado, Luis M.; Bayon, Yves; Pandit, Abhay

    2015-01-01

    Collagen-based devices, in various physical conformations, are extensively used for tissue engineering and regenerative medicine applications. Given that the natural cross-linking pathway of collagen does not occur in vitro, chemical, physical, and biological cross-linking methods have been assessed over the years to control mechanical stability, degradation rate, and immunogenicity of the device upon implantation. Although in vitro data demonstrate that mechanical properties and degradation rate can be accurately controlled as a function of the cross-linking method utilized, preclinical and clinical data indicate that cross-linking methods employed may have adverse effects on host response, especially when potent cross-linking methods are employed. Experimental data suggest that more suitable cross-linking methods should be developed to achieve a balance between stability and functional remodeling. PMID:25517923

  2. Adaptive control of a manipulator with a flexible link

    NASA Technical Reports Server (NTRS)

    Yang, Y. P.; Gibson, J. S.

    1988-01-01

    An adaptive controller for a manipulator with one rigid link and one flexible link is presented. The performance and robustness of the controller are demonstrated by numerical simulation results. In the simulations, the manipulator moves in a gravitational field and a finite element model represents the flexible link.

  3. Design of Broadband High Dynamic-Range Fiber Optic Links

    NASA Astrophysics Data System (ADS)

    Monsurrò, P.; Tommasino, P.; Trifiletti, A.; Vannucci, A.

    2018-04-01

    An analytic design-oriented model of microwave optical links has been developed. The core of the model is the non-linear and noise model of a Mach-Zehnder LiNbO3 interferometer. Both a 100 MHz-20 GHz link and a linearized microwave link, comprising an auxiliary modulator, have been designed and prototyped by using the model.

  4. Developing and Implementing an Assessment Technique to Measure Linked Concepts

    ERIC Educational Resources Information Center

    Ye, Li; Oueini, Razanne; Lewis, Scott E.

    2015-01-01

    The links students make among chemistry content is considered essential for a robust, enduring understanding in multiple learning theories. This article describes the development and implementation of an assessment technique, termed a Measure of Linked Concepts, designed to inform instructors on students' understanding of linking content…

  5. Knowledge-Linking Perceptions of Late-Elementary Students

    ERIC Educational Resources Information Center

    Schuh, Kathy L.; Kuo, Yi-Lung; Knupp, Tawnya L.

    2014-01-01

    This study describes student perceptions of potential elaborative or generative learning strategies called student knowledge links. This construct was assessed using the Student Knowledge Linking Instrument-Perceptions (SKLIP), a new learning inventory to measure late-elementary student perceptions of the creation of student knowledge links. After…

  6. Linking Gestures: Cross-Cultural Variation during Instructional Analogies

    ERIC Educational Resources Information Center

    Richland, Lindsey Engle

    2015-01-01

    Deictic linking gestures, hand and arm motions that physically embody links being communicated between two or more objects in the shared communicative environment, are explored in a cross-cultural sample of mathematics instruction. Linking gestures are specifically examined here when they occur in the context of communicative analogies designed to…

  7. Teaching Inquiry with Linked Classes and Learning Communities

    ERIC Educational Resources Information Center

    Piercey, Victor; Cullen, Roxanne

    2017-01-01

    In order to improve problem-solving dispositions, a section of an inquiry-based math sequence for first-year business students was linked with a section of our general education English sequence. We describe how the linked classes worked and compare some preliminary results from linked and unlinked sections of the math sequence.

  8. 21 CFR 11.70 - Signature/record linking.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Signature/record linking. 11.70 Section 11.70 Food... RECORDS; ELECTRONIC SIGNATURES Electronic Records § 11.70 Signature/record linking. Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective...

  9. Disclaimer for external Web links | National Oceanic and Atmospheric

    Science.gov Websites

    Web links The appearance of external links on this Web site does not constitute endorsement by the Department of Commerce/National Oceanic and Atmospheric Administration of external Web sites or the . These links are provided consistent with the stated purpose of this Department of Commerce/NOAA Web site

  10. 21 CFR 177.1211 - Cross-linked polyacrylate copolymers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... polyacrylate copolymers consist of: (1) The grafted copolymer of cross-linked sodium polyacrylate identified as... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Cross-linked polyacrylate copolymers. 177.1211... Basic Components of Single and Repeated Use Food Contact Surfaces § 177.1211 Cross-linked polyacrylate...

  11. 21 CFR 177.1211 - Cross-linked polyacrylate copolymers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... polyacrylate copolymers consist of: (1) The grafted copolymer of cross-linked sodium polyacrylate identified as... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Cross-linked polyacrylate copolymers. 177.1211... Basic Components of Single and Repeated Use Food Contact Surfaces § 177.1211 Cross-linked polyacrylate...

  12. 47 CFR 54.411 - Link Up program defined.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... section. (c) A carrier's Link Up program shall allow a consumer to receive the benefit of the Link Up... SERVICE Universal Service Support for Low-Income Consumers § 54.411 Link Up program defined. (a) For... low-income consumers, which an eligible telecommunications carrier shall offer as part of its...

  13. Utility-Based Link Recommendation in Social Networks

    ERIC Educational Resources Information Center

    Li, Zhepeng

    2013-01-01

    Link recommendation, which suggests links to connect currently unlinked users, is a key functionality offered by major online social networking platforms. Salient examples of link recommendation include "people you may know"' on Facebook and "who to follow" on Twitter. A social networking platform has two types of stakeholder:…

  14. "LinkedIn" for Accounting and Business Students

    ERIC Educational Resources Information Center

    Albrecht, W. David

    2011-01-01

    LinkedIn is a social media application that every accounting and business student should join and use. LinkedIn is a database of 90,000,000 business professionals that enables each to connect and interact with their business associates. Five reasons are offered for why accounting students should join LinkedIn followed by 11 hints for use.

  15. Deciding to Change OpenURL Link Resolvers

    ERIC Educational Resources Information Center

    Johnson, Megan; Leonard, Andrea; Wiswell, John

    2015-01-01

    This article will be of interest to librarians, particularly those in consortia that are evaluating OpenURL link resolvers. This case study contrasts WebBridge (an Innovative Interface product) and LinkSource (EBSCO's product). This study assisted us in the decision-making process of choosing an OpenURL link resolver that was sustainable to…

  16. Sharing Epigraphic Information as Linked Data

    NASA Astrophysics Data System (ADS)

    Álvarez, Fernando-Luis; García-Barriocanal, Elena; Gómez-Pantoja, Joaquín-L.

    The diffusion of epigraphic data has evolved in the last years from printed catalogues to indexed digital databases shared through the Web. Recently, the open EpiDoc specifications have resulted in an XML-based schema for the interchange of ancient texts that uses XSLT to render typographic representations. However, these schemas and representation systems are still not providing a way to encode computational semantics and semantic relations between pieces of epigraphic data. This paper sketches an approach to bring these semantics into an EpiDoc based schema using the Ontology Web Language (OWL) and following the principles and methods of information sharing known as "linked data". The paper describes the general principles of the OWL mapping of the EpiDoc schema and how epigraphic data can be shared in RDF format via dereferenceable URIs that can be used to build advanced search, visualization and analysis systems.

  17. Controller⁻Pilot Data Link Communication Security.

    PubMed

    Gurtov, Andrei; Polishchuk, Tatiana; Wernberg, Max

    2018-05-20

    The increased utilization of the new types of cockpit communications, including controller⁻pilot data link communications (CPDLC), puts the airplane at higher risk of hacking or interference than ever before. We review the technological characteristics and properties of the CPDLC and construct the corresponding threat model. Based on the limitations imposed by the system parameters, we propose several solutions for the improved security of the data messaging communication used in air traffic management (ATM). We discuss the applicability of elliptical curve cryptography (ECC), protected aircraft communications addressing and reporting systems (PACARs) and the Host Identity Protocol (HIP) as possible countermeasures to the identified security threats. In addition, we consider identity-defined networking (IDN) as an example of a genuine security solution which implies global changes in the whole air traffic communication system.

  18. Linking Science Fiction and Physics Courses

    NASA Astrophysics Data System (ADS)

    McBride, Krista K.

    2016-05-01

    Generally, cohorts or learning communities enrich higher learning in students. Learning communities consist of conventionally separate groups of students that meet together with common academic purposes and goals. Types of learning communities include paired courses with concurrent student enrollment, living-learning communities, and faculty learning communities. This article discusses a learning community of 21 students that I created with a colleague in the English department. The community encompasses two general education courses: an algebra-based physics course entitled "Intro to Physics" and a literature course entitled "Science Fiction, Science Fact." Students must enroll in both of these courses during the same semester. Additionally, I highlight advantages to linking these courses through surveying the assignments and course materials that we used in our learning community. Figure 1 shows the topics that are covered in both physics and literature courses.

  19. Linking Science Education to the Workplace

    NASA Astrophysics Data System (ADS)

    Hurd, Paul Dehart

    1998-12-01

    This article examines the issue of linking education in the sciences with the world of work for all students. Traditionally, science teaching has been limited to preparing student for research career in science at the university level. The reform movement in science education is focused on intellectual skills that serve to fortify the human capital of all students and the economic productivity of the nation. The educational issue arises from evolutionary changes that are taking place in the practice of science, the development of a global economy, the nation's entrance into an Information Age, and the changing nature of the workplace. To identify and integrate these factors in the practice of science teaching is the goal of this article.

  20. Controller–Pilot Data Link Communication Security

    PubMed Central

    Polishchuk, Tatiana; Wernberg, Max

    2018-01-01

    The increased utilization of the new types of cockpit communications, including controller–pilot data link communications (CPDLC), puts the airplane at higher risk of hacking or interference than ever before. We review the technological characteristics and properties of the CPDLC and construct the corresponding threat model. Based on the limitations imposed by the system parameters, we propose several solutions for the improved security of the data messaging communication used in air traffic management (ATM). We discuss the applicability of elliptical curve cryptography (ECC), protected aircraft communications addressing and reporting systems (PACARs) and the Host Identity Protocol (HIP) as possible countermeasures to the identified security threats. In addition, we consider identity-defined networking (IDN) as an example of a genuine security solution which implies global changes in the whole air traffic communication system. PMID:29783791

  1. Robust bidirectional links for photonic quantum networks

    PubMed Central

    Xu, Jin-Shi; Yung, Man-Hong; Xu, Xiao-Ye; Tang, Jian-Shun; Li, Chuan-Feng; Guo, Guang-Can

    2016-01-01

    Optical fibers are widely used as one of the main tools for transmitting not only classical but also quantum information. We propose and report an experimental realization of a promising method for creating robust bidirectional quantum communication links through paired optical polarization-maintaining fibers. Many limitations of existing protocols can be avoided with the proposed method. In particular, the path and polarization degrees of freedom are combined to deterministically create a photonic decoherence-free subspace without the need for any ancillary photon. This method is input state–independent, robust against dephasing noise, postselection-free, and applicable bidirectionally. To rigorously quantify the amount of quantum information transferred, the optical fibers are analyzed with the tools developed in quantum communication theory. These results not only suggest a practical means for protecting quantum information sent through optical quantum networks but also potentially provide a new physical platform for enriching the structure of the quantum communication theory. PMID:26824069

  2. Novel hydroxyapatite biomaterial covalently linked to raloxifene.

    PubMed

    Meme, L; Santarelli, A; Marzo, G; Emanuelli, M; Nocini, P F; Bertossi, D; Putignano, A; Dioguardi, M; Lo Muzio, L; Bambini, F

    2014-01-01

    Since raloxifene, a drug used in osteoporosis therapy, inhibits osteoclast, but not osteoblast functions, it has been suggested to improve recovery during implant surgery. The present paper describes an effective method to link raloxifene, through a covalent bond, to a nano-Hydroxyapatite-based biomaterial by interfacing with (3-aminopropyl)-Triethoxysilane as assessed by Infra Red-Fourier Transformed (IR-FT) spectroscopy and Scanning Electron Microscope (SEM). To evaluate the safety of this modified new material, the vitality of osteoblast-like cells cultured with the new biomaterial was then investigated. Raloxifene-conjugated HAbiomaterial has been shown to be a safe material easy to obtain which could be an interesting starting point for the use of a new functional biomaterial suitable in bone regeneration procedures.

  3. Linking live animals and products: traceability.

    PubMed

    Britt, A G; Bell, C M; Evers, K; Paskin, R

    2013-08-01

    It is rarely possible to successfully contain an outbreak of an infectious animal disease, or to respond effectively to a chemical residue incident, without the use of a system for identifying and tracking animals. The linking of animals at the time they are slaughtered--through the use of identification devices or marks and accompanying movement documentation--with the meat produced from their carcasses, adds further value from the perspective of consumer safety. Over the past decade, animal identification technology has become more sophisticated and affordable. The development of the Internet and mobile communication tools, complemented bythe expanded capacity of computers and associated data management applications, has added a new dimension to the ability of Competent Authorities and industry to track animals and the food they produce for disease control, food safety and commercial purposes.

  4. Single link flexible beam testbed project. Thesis

    NASA Technical Reports Server (NTRS)

    Hughes, Declan

    1992-01-01

    This thesis describes the single link flexible beam testbed at the CLaMS laboratory in terms of its hardware, software, and linear model, and presents two controllers, each including a hub angle proportional-derivative (PD) feedback compensator and one augmented by a second static gain full state feedback loop, based upon a synthesized strictly positive real (SPR) output, that increases specific flexible mode pole damping ratios w.r.t the PD only case and hence reduces unwanted residual oscillation effects. Restricting full state feedback gains so as to produce a SPR open loop transfer function ensures that the associated compensator has an infinite gain margin and a phase margin of at least (-90, 90) degrees. Both experimental and simulation data are evaluated in order to compare some different observer performance when applied to the real testbed and to the linear model when uncompensated flexible modes are included.

  5. Linking axionlike dark matter to neutrino masses

    NASA Astrophysics Data System (ADS)

    Carvajal, C. D. R.; Sánchez-Vega, B. L.; Zapata, O.

    2017-12-01

    We present a framework linking axionlike particles (ALPs) to neutrino masses through the minimal inverse seesaw (ISS) mechanism in order to explain the dark matter (DM) puzzle. Specifically, we explore three minimal ISS cases where mass scales are generated through gravity-induced operators involving a scalar field hosting ALPs. In all of these cases, we find gravity-stable models that provide the observed DM relic density and, simultaneously, are consistent with the phenomenology of neutrinos and ALPs. Remarkably, in one of the ISS cases, the DM can be made of ALPs and sterile neutrinos. Furthermore, other considered ISS cases have ALPs with parameters that are within the reach of proposed ALP experiments.

  6. Multiple Pathways Linking Racism to Health Outcomes

    PubMed Central

    Harrell, Camara Jules P.; Burford, Tanisha I.; Cage, Brandi N.; Nelson, Travette McNair; Shearon, Sheronda; Thompson, Adrian; Green, Steven

    2012-01-01

    This commentary discusses advances in the conceptual understanding of racism and selected research findings in the social neurosciences. The traditional stress and coping model holds that racism constitutes a source of aversive experiences that, when perceived by the individual, eventually lead to poor health outcomes. Current evidence points to additional psychophysiological pathways linking facets of racist environments with physiological reactions that contribute to disease. The alternative pathways emphasize prenatal experiences, subcortical emotional neural circuits, conscious and preconscious emotion regulation, perseverative cognitions, and negative affective states stemming from racist cognitive schemata. Recognition of these pathways challenges change agents to use an array of cognitive and self-controlling interventions in mitigating racism’s impact. Additionally, it charges policy makers to develop strategies that eliminate deep-seated structural aspects of racism in society. PMID:22518195

  7. Empowering pharmacoinformatics by linked life science data

    NASA Astrophysics Data System (ADS)

    Goldmann, Daria; Zdrazil, Barbara; Digles, Daniela; Ecker, Gerhard F.

    2017-03-01

    With the public availability of large data sources such as ChEMBLdb and the Open PHACTS Discovery Platform, retrieval of data sets for certain protein targets of interest with consistent assay conditions is no longer a time consuming process. Especially the use of workflow engines such as KNIME or Pipeline Pilot allows complex queries and enables to simultaneously search for several targets. Data can then directly be used as input to various ligand- and structure-based studies. In this contribution, using in-house projects on P-gp inhibition, transporter selectivity, and TRPV1 modulation we outline how the incorporation of linked life science data in the daily execution of projects allowed to expand our approaches from conventional Hansch analysis to complex, integrated multilayer models.

  8. X‐linked retinoschisis: an update

    PubMed Central

    Sikkink, Stephen K; Biswas, Susmito; Parry, Neil R A; Stanga, Paulo E; Trump, Dorothy

    2007-01-01

    X‐linked retinoschisis is the leading cause of macular degeneration in males and leads to splitting within the inner retinal layers leading to visual deterioration. Many missense and protein truncating mutations have now been identified in the causative retinoschisis gene (RS1) which encodes a 224 amino acid secreting retinal protein, retinoschisin. Retinoschisin octamerises is implicated in cell–cell interactions and cell adhesion perhaps by interacting with β2 laminin. Mutations cause loss of retinoschisin function by one of the three mechanisms: by interfering with protein secretion, by preventing its octamerisation or by reducing function in the secreted octamerised protein. The development of retinoschisis mouse models have provided a model system that closely resembles the human disease. Recent reports of RS1 gene transfer to these models and the sustained restoration of some retinal function and morphology suggest gene replacement may be a possible future therapy for patients. PMID:17172462

  9. Fiber-linked interferometric pressure sensor

    NASA Technical Reports Server (NTRS)

    Beheim, G.; Fritsch, K.; Poorman, R. N.

    1987-01-01

    A fiber-optic pressure sensor is described which uses a diaphragm to modulate the mirror separation of a Fabry-Perot cavity (the sensing cavity). A multimode optical fiber delivers broadband light to the sensing cavity and returns the spectrally modulated light which the cavity reflects. The sensor's output spectrum is analyzed using a tunable Fabry-Perot cavity (the reference cavity) to determine the mismatch in the mirror separations of the two cavities. An electronic servo control uses this result to cause the mirror separation of the reference cavity to equal that of the sensing cavity. The displacement of the pressure-sensing diaphragm is then obtained by measuring the capacitance of the reference cavity's metal-coated mirrors. Relative to other fiber-optic sensors, an important advantage of this instrument is its high immunity to the effects of variations in both the transmissivity of the fiber link and the wavelength of the optical source.

  10. Global sea level linked to global temperature

    PubMed Central

    Vermeer, Martin; Rahmstorf, Stefan

    2009-01-01

    We propose a simple relationship linking global sea-level variations on time scales of decades to centuries to global mean temperature. This relationship is tested on synthetic data from a global climate model for the past millennium and the next century. When applied to observed data of sea level and temperature for 1880–2000, and taking into account known anthropogenic hydrologic contributions to sea level, the correlation is >0.99, explaining 98% of the variance. For future global temperature scenarios of the Intergovernmental Panel on Climate Change's Fourth Assessment Report, the relationship projects a sea-level rise ranging from 75 to 190 cm for the period 1990–2100. PMID:19995972

  11. NICS report links VOCs to respiratory problems

    SciTech Connect

    Kirschner, E.

    1992-04-22

    Children who live near the chemical plants of Kanawha Valley, WV, suffer more acute and chronic respiratory aliments than those farther away, says a Harvard University School of Public Health report. In the $1-million, five-year study commissioned by the National Institute for Chemical Studies (NICS:Charleston, WV) and funded by the Environmental Protection Agency, proximity to chemical plants that emit volatile organic compounds (VOCs) was linked to higher incidence of asthma, acute eye irritation, shortness of breath, and chronic cough. The researchers say they adjusted for most other factors, such as parental smoking and petroleum. {open_quotes}The research hypothesis was whether childrenmore » in the valley had more symptoms,{close_quotes} says NICS president Paul Hill. {open_quotes}Yes, there is a difference.{close_quotes} The study showed that some ailments were up to 28% more prevalent in children in the valley than in other Kanawha County children.« less

  12. Hypothyroidism and obesity: An intriguing link.

    PubMed

    Sanyal, Debmalya; Raychaudhuri, Moutusi

    2016-01-01

    According to common perception, hypothyroidism is held responsible for obesity. However, linking them causally is controversial. Overt hypothyroidism is associated with modest weight gain, but there is a lack of clarity regarding subclinical hypothyroidism. Novel view indicates that changes in thyroid-stimulating hormone (TSH) could well be secondary to obesity. The increasing prevalence of obesity further confounds definition of normal TSH range in population studies. Thyroid autoantibody status may help in establishing the diagnosis of subclinical hypothyroidism in obesity. High leptin levels may play a role in the hyperthyrotropinemia of obesity and also increase susceptibility to thyroid autoimmunity and subsequent hypothyroidism. There is at most a modest effect of L-T4 treatment in overt hypothyroidism in inducing weight loss; benefit in subclinical hypothyroidism is not established with no data supporting thyroid hormone use in euthyroid obese patients.

  13. General protein-protein cross-linking.

    PubMed

    Alegria-Schaffer, Alice

    2014-01-01

    This protocol describes a general protein-to-protein cross-linking procedure using the water-soluble amine-reactive homobifunctional BS(3) (bis[sulfosuccinimidyl] suberate); however, the protocol can be easily adapted using other cross-linkers of similar properties. BS(3) is composed of two sulfo-NHS ester groups and an 11.4 Å linker. Sulfo-NHS ester groups react with primary amines in slightly alkaline conditions (pH 7.2-8.5) and yield stable amide bonds. The reaction releases N-hydroxysuccinimide (see an application of NHS esters on Labeling a protein with fluorophores using NHS ester derivitization). © 2014 Elsevier Inc. All rights reserved.

  14. Understanding the links between education and smoking.

    PubMed

    Maralani, Vida

    2014-11-01

    This study extends the theoretical and empirical literature on the relationship between education and smoking by focusing on the life course links between experiences from adolescence and health outcomes in adulthood. Differences in smoking by completed education are apparent at ages 12-18, long before that education is acquired. I use characteristics from the teenage years, including social networks, future expectations, and school experiences measured before the start of smoking regularly to predict smoking in adulthood. Results show that school policies, peers, and youths' mortality expectations predict smoking in adulthood but that college aspirations and analytical skills do not. I also show that smoking status at age 16 predicts both completed education and adult smoking, controlling for an extensive set of covariates. Overall, educational inequalities in smoking are better understood as a bundling of advantageous statuses that develops in childhood, rather than the effect of education producing better health. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Large and linked in scientific publishing

    PubMed Central

    2012-01-01

    We are delighted to announce the launch of GigaScience, an online open-access journal that focuses on research using or producing large datasets in all areas of biological and biomedical sciences. GigaScience is a new type of journal that provides standard scientific publishing linked directly to a database that hosts all the relevant data. The primary goals for the journal, detailed in this editorial, are to promote more rapid data release, broader use and reuse of data, improved reproducibility of results, and direct, easy access between analyses and their data. Direct and permanent connections of scientific analyses and their data (achieved by assigning all hosted data a citable DOI) will enable better analysis and deeper interpretation of the data in the future. PMID:23587310

  16. Large and linked in scientific publishing.

    PubMed

    Goodman, Laurie; Edmunds, Scott C; Basford, Alexandra T

    2012-07-12

    We are delighted to announce the launch of GigaScience, an online open-access journal that focuses on research using or producing large datasets in all areas of biological and biomedical sciences. GigaScience is a new type of journal that provides standard scientific publishing linked directly to a database that hosts all the relevant data. The primary goals for the journal, detailed in this editorial, are to promote more rapid data release, broader use and reuse of data, improved reproducibility of results, and direct, easy access between analyses and their data. Direct and permanent connections of scientific analyses and their data (achieved by assigning all hosted data a citable DOI) will enable better analysis and deeper interpretation of the data in the future.

  17. X-linked agammaglobulinemia in northern Thailand.

    PubMed

    Trakultivakorn, Muthita; Ochs, Hans D

    2006-03-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by a failure to generate immunoglobulins of all isotypes due to the absence of mature B cells and plasma cells, secondary to mutations in the Bruton's tyrosine kinase (Btk) gene. We report six patients with XLA, confirmed by mutation analysis, from northern Thailand. The mean age of onset was 2.5 years and the mean age at diagnosis was 7.3 years. All patients had a history of otitis media, pneumonia and arthritis at the time of diagnosis, five patients had developed bronchiectasis and 3 patients septicemia. Other infections reported included sinusitis (5/6), pericarditis (1/6), meningitis (1/6) and pyoderma (1/6). Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus were isolated on multiple occasions. One patient died of sepsis at the age of 16 years. These observations demonstrate that early diagnosis and treatment can improve prognosis and quality of life.

  18. Enzyme-Linked Immunosorbent Assay (ELISA).

    PubMed

    Konstantinou, George N

    2017-01-01

    Food allergy is a public health concern especially after recognizing its constantly increased prevalence and severity. Despite careful reading of food ingredient statements, food allergic individuals may experience reactions caused by "hidden", "masked", or "contaminated" proteins that are known major allergens. Many techniques have been developed to detect even small traces of food allergens, for clinical or laboratory purposes. Enzyme-linked immunosorbent assay (ELISA) is one of the best validated and most routinely used immunoassay in allergy research, in allergy diagnosis in allergy-related quality control in various industries. Although as a technique it has been implemented for the last 45 years, the evolution in biochemistry allowed the development of ultrasensitive ELISA variations that are capable of measuring quantities in the scale of picograms, rendering ELISA attractive, robust, and very famous.

  19. Linking Project Procedure Manual for Using Dumb-Barcode Linking on GEAC.

    ERIC Educational Resources Information Center

    Condron, Lyn

    This procedure manual is designed to assist cataloging staff members at a university library through the 10-step process of barcoding and linking books classified by the Library of Congress system to the library's GEAC online computer system. A brief introduction provides background information on the project. The procedures involved in each…

  20. Literature Links: Thematic Units Linking Read-Alouds and Computer Activities

    ERIC Educational Resources Information Center

    Labbo, Linda D.; Love, Mary Susan; Park Prior, Miri; Hubbard, Betty P.; Ryan, Tammy

    2006-01-01

    This book gives the reader ideas for providing primary-grade students with literacy learning opportunities that integrate conventional literacies, such as phonics and comprehension, with new literacies, such as multimedia composition and hyperlink navigation. The reader will find a variety of linked activities, including reading children's books,…

  1. Extending the Wireshark Network Protocol Analyser to Decode Link 16 Tactical Data Link Messages

    DTIC Science & Technology

    2014-01-01

    Interoperability Workshop 2003, Paper No. 03F- SIW -002. 6. Boardman, B., (2008), Introduction to Tactical Data Links in the ADF, accessed from <http...2008, Paper No. 08E- SIW -046. 19. Lamping, U., (2013), Wireshark Developer’s Guide for Wireshark 1.11, accessed from <http://www.wireshark.org/docs

  2. APP Function and Lipids: A Bidirectional Link

    PubMed Central

    Grimm, Marcus O. W.; Mett, Janine; Grimm, Heike S.; Hartmann, Tobias

    2017-01-01

    Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) peptides, are one of the major histopathological hallmarks of Alzheimer’s disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) ε4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations, protective lipids being able to decrease Aβ generation and also potential negative lipids in respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipid metabolism pathways. PMID:28344547

  3. Weak links in high critical temperature superconductors

    NASA Astrophysics Data System (ADS)

    Tafuri, Francesco; Kirtley, John R.

    2005-11-01

    The traditional distinction between tunnel and highly transmissive barriers does not currently hold for high critical temperature superconducting Josephson junctions, both because of complicated materials issues and the intrinsic properties of high temperature superconductors (HTS). An intermediate regime, typical of both artificial superconductor-barrier-superconductor structures and of grain boundaries, spans several orders of magnitude in the critical current density and specific resistivity. The physics taking place at HTS surfaces and interfaces is rich, primarily because of phenomena associated with d-wave order parameter (OP) symmetry. These phenomena include Andreev bound states, the presence of the second harmonic in the critical current versus phase relation, a doubly degenerate state, time reversal symmetry breaking and the possible presence of an imaginary component of the OP. All these effects are regulated by a series of transport mechanisms, whose rules of interplay and relative activation are unknown. Some transport mechanisms probably have common roots, which are not completely clear and possibly related to the intrinsic nature of high-TC superconductivity. The d-wave OP symmetry gives unique properties to HTS weak links, which do not have any analogy with systems based on other superconductors. Even if the HTS structures are not optimal, compared with low critical temperature superconductor Josephson junctions, the state of the art allows the realization of weak links with unexpectedly high quality quantum properties, which open interesting perspectives for the future. The observation of macroscopic quantum tunnelling and the qubit proposals represent significant achievements in this direction. In this review we attempt to encompass all the above aspects, attached to a solid experimental basis of junction concepts and basic properties, along with a flexible phenomenological background, which collects ideas on the Josephson effect in the presence

  4. Smart POI: Open and linked spatial data

    NASA Astrophysics Data System (ADS)

    Cerba, Otakar; Berzins, Raitis; Charvat, Karel; Mildorf, Tomas

    2016-04-01

    The Smart Point of Interest (SPOI) represents an unique seamless spatial data set based on standards recommended for Linked and open data, which are supported by scientist and researchers as well as by several government authorities and European Union. This data set developed in cooperation of partners of SDI4Apps project contains almost 24 millions points of interest focused mainly on tourism, natural features, transport or citizen services. The SPOI data covers almost all countries and territories over the world. It is created as a harmonized combination of global data resources (selected points from OpenStreetMap, Natural Earth and GeoNames.org) and several local data sets (for example data published by the Citadel on the Move project, data from Posumavi region in the Czech Republic or experimental ontologies developed in the University of West Bohemia including ski regions in Europe or historical sights in Rome). The added value of the SDI4Apps approach in comparison to other similar solutions consists in implementation of linked data approach (several objects are connected to DBpedia or GeoNames.org), using of universal RDF format, using of standardized and respected properties or vocabularies (for example FOAF or GeoSPARQL) and development of the completely harmonized data set with uniform data model and common classification (not only a copy of original resources). The SPOI data is published as SPARQL endpoint as well as in the map client. The SPOI dataset is a specific set of POIs which could be "a data fuel" for applications and services related to tourism, local business, statistics or landscape monitoring. It can be used also as a background data layer for thematic maps.

  5. X-linked cardiomyopathy is heterogeneous

    SciTech Connect

    Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

    Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

  6. A Link-Level Simulator of the cdma2000 Reverse-Link Physical Layer

    PubMed Central

    Gharavi, H.; Chin, F.; Ban, K.; Wyatt-Millington, R.

    2003-01-01

    The cdma2000 system is an evolutionary enhancement of the IS-95 standards which support 3G services defined by the International Telecommunications Union (ITU). cdma2000 comes in two phases: 1XRTT and 3XRTT (1X and 3X indicates the number of 1.25 MHz wide radio carrier channels used and RTT stands for Radio Transmission Technology). The cdma2000 1XRTT, which operates within a 1.25 MHz bandwidth, can be utilized in existing IS-95 CDMA channels as it uses the same bandwidth, while 3XRTT requires the commitment of 5 MHz bandwidth to support higher data rates. This paper describes a software model implementation of the cdma2000 reverse link and its application for evaluating the effect of rake receiver design parameters on the system performance under various multipath fading conditions. The cdma2000 models were developed at the National Institute of Standards and Technology (NIST), using SPW (Signal Processing Worksystem) commercial software tools. The model has been developed in a generic manner that includes all the reverse link six radio configurations and their corresponding data rates, according to cdma2000 specifications. After briefly reviewing the traffic channel characteristics of the cdma2000 reverse link (subscriber to base station), the paper discusses the rake receiver implementation including an ideal rake receiver. It then evaluates the performance of each receiver for a Spreading Rate 3 (3XRTT) operation, which is considered as a true “3G” cdma2000 technology. These evaluations are based on the vehicular IMT-2000 (International Mobile Telecommunication 2000) channel model using the link budget defined in cdma2000 specifications for the reverse link. PMID:27413613

  7. 5.6 Gbps optical intersatellite communication link

    NASA Astrophysics Data System (ADS)

    Smutny, Berry; Kaempfner, Hartmut; Muehlnikel, Gerd; Sterr, Uwe; Wandernoth, Bernhard; Heine, Frank; Hildebrand, Ulrich; Dallmann, Daniel; Reinhardt, Martin; Freier, Axel; Lange, Robert; Boehmer, Knut; Feldhaus, Thomas; Mueller, Juergen; Weichert, Andreas; Greulich, Peter; Seel, Stefan; Meyer, Rolf; Czichy, Reinhard

    2009-02-01

    A 5.6 Gbps optical communication link has been verified in-orbit. The intersatellite link uses homodyne BPSK (binary phase shift keying) and allows to transmit data with a duplex data rate of 5.6 Gbps and a bit error rate better than 10-9 between two LEO satellites, NFIRE (U.S.) and TerraSAR-X, Germany). We report on the terminal design and the link performance during the measurement campaign. As an outlook we report on the flight units adapted to LEO-to-GEO intersatellite links that TESAT currently builds and on plans to study GEO-to-ground links.

  8. A note on deep space optical communication link parameters

    NASA Technical Reports Server (NTRS)

    Dolinar, S. J.; Yuen, J. H.

    1982-01-01

    Topical communication in the context of a deep space communication link. Communication link analysis at the optical frequencies differs significantly from that at microwave frequencies such as the traditional S and X-bands used in deep space applications, due to the different technology of transmitter, antenna, modulators, and receivers. In addition, the important role of quantum noise in limiting system performance is quite different than that of thermal noise. The optical link design is put in a design control table format similar to a microwave telecom link design. Key considerations unique to the optical link are discussed.

  9. Correlations between Community Structure and Link Formation in Complex Networks

    PubMed Central

    Liu, Zhen; He, Jia-Lin; Kapoor, Komal; Srivastava, Jaideep

    2013-01-01

    Background Links in complex networks commonly represent specific ties between pairs of nodes, such as protein-protein interactions in biological networks or friendships in social networks. However, understanding the mechanism of link formation in complex networks is a long standing challenge for network analysis and data mining. Methodology/Principal Findings Links in complex networks have a tendency to cluster locally and form so-called communities. This widely existed phenomenon reflects some underlying mechanism of link formation. To study the correlations between community structure and link formation, we present a general computational framework including a theory for network partitioning and link probability estimation. Our approach enables us to accurately identify missing links in partially observed networks in an efficient way. The links having high connection likelihoods in the communities reveal that links are formed preferentially to create cliques and accordingly promote the clustering level of the communities. The experimental results verify that such a mechanism can be well captured by our approach. Conclusions/Significance Our findings provide a new insight into understanding how links are created in the communities. The computational framework opens a wide range of possibilities to develop new approaches and applications, such as community detection and missing link prediction. PMID:24039818

  10. Browsing and Visualization of Linked Environmental Data

    NASA Astrophysics Data System (ADS)

    Nikolaou, Charalampos; Kyzirakos, Kostis; Bereta, Konstantina; Dogani, Kallirroi; Koubarakis, Manolis

    2014-05-01

    Linked environmental data has started to appear on the Web as environmental researchers make use of technologies such as ontologies, RDF, and SPARQL. Many of these datasets have an important geospatial and temporal dimension. The same is true also for the Web of data that is being rapidly populated not only with geospatial information, but also with temporal information. As the real-world entities represented in linked geospatial datasets evolve over time, the datasets themselves get updated and both the spatial and the temporal dimension of data become significant for users. For example, in the Earth Observation and Environment domains, data is constantly produced by satellite sensors and is associated with metadata containing, among others, temporal attributes, such as the time that an image was acquired. In addition, the acquisitions are considered to be valid for specific periods of time, for example until they get updated by new acquisitions. Satellite acquisitions might be utilized in applications such as the CORINE Land Cover programme operated by the European Environment Agency that makes available as a cartographic product the land cover of European areas. Periodically CORINE publishes the changes in the land cover of these areas in the form of changesets. Tools for exploiting the abundance of geospatial information have also started to emerge. However, these tools are designed for browsing a single data source, while in addition they cannot represent the temporal dimension. This is for two reasons: a) the lack of an implementation of a data model and a query language with temporal features covering the various semantics associated with the representation of time (e.g., valid and user-defined), and b) the lack of a standard temporal extension of RDF that would allow practitioners to utilize when publishing RDF data. Recently, we presented the temporal features of the data model stRDF, the query language stSPARQL, and their implementation in the geospatial

  11. Linking Regions between Helices in Bacteriorhodopsin Revealed

    PubMed Central

    Agard, David A.; Stroud, Robert M.

    1982-01-01

    Three-dimensional electron-microscopic structural analysis requires the combination of many different tilted views of the same specimen. The relative difficulty of tilting the sample to high angles >60° without introducing severe distortion due to different focal distances across the specimen entails that the observable range of electron diffraction data is often limited to this range of angles. Thus, it is generally not possible to observe the diffraction maxima that lie within the conical region of reciprocal space around the direction perpendicular to the electron microscope grid. The absence of data in this region leads to a predictable distortion in the object, and for ±60° tilting makes the resolution essentially twice as bad in the direction perpendicular to the grid as it is for the in-plane image. Constrained density map modification and refinement methods can significantly reduce these effects. A method has been developed, tested on model cases, and applied to the electron-microscopic structure determination of bacteriorhodopsin in order to visualize the location of linking regions between helices. Electron-microscopic structural analysis of bacteriorhodopsin (Henderson and Unwin. 1975 Nature [Lond.] 257:28-32.) showed that the molecule consists of seven rods of density each nearly spanning the lipid bilayer. Owing to the distortion introduced by the missing conical region of reciprocal space data, no density was visible for the polypeptide segments linking the α-helices. Density in the refined maps indicates the location of at least five of the extrahelical segments of the polypeptide. The total number of possible ways of interconnecting the helices is reduced from 7! (5,040) to the five most consistent possibilities without recourse to other considerations. In addition, the density for the helical regions is more uniform and cylindrical throughout their length, and the length of the helices increases from 35 to 45 Å, close to the membrane thickness

  12. Linking Quantum Mechanics to Freshman Physics

    NASA Astrophysics Data System (ADS)

    Vandegrift, Guy

    1998-10-01

    First-year quantum mechanics can be linked to introductory physics. One example is the Mossbauer effect, which is explained using a simple solution to Schrodinger's equation involving the Dirac delta function. Generalization to N coupled harmonic oscillators shows that the equality of the forces exerted by winner and loser in the game of "tug-of-war" is only an approximation because Newton's third law of motion is not valid (unless phonon momentum is considered). Another example is a treatment of the Gaussian wavepacket which involves less algebra than found in standard textbooks, yet shows that the peak moves according to the familiar equation of motion x = vt + (1/2)at^2 when the applied force is uniform. Finally, a rendition of "Turkey in the Straw" on the viola illustrates Heisenberg's uncertainty principle, which can be written in the less mysterious form, f=(N+-.1)/T , where N cycles are counted in T seconds. Students experience this uncertainty as they try to measure the frequency of a stretched slinky.

  13. Advanced technologies for encryption of satellite links

    NASA Astrophysics Data System (ADS)

    McMahan, Sherry S.

    The use of encryption on satellite links is discussed. Advanced technology exists to provide transmission security for large earth station with data rates up to 50 megabits per second. One of the major concerns in the use of encryption equipment with very small aperture terminals (VSAT) is the key management issue and the related operational costs. The low cost requirement and the lack of physical protection of remote VSATs place severe constraints on the design of encryption equipment. Encryption may be accomplished by embedding a tamper proof encryption module into the baseband unit of each VSAT. VSAT networks are usually star networks where there is a single large earth station that serves as a hub and all satellite communications takes place between each VSAT and the hub earth station. The hub earth station has the secret master key of each VSAT. These master keys are used to downline load encrypted session keys to each VSAT. A more secure alternative is to use public key techniques where each embedded VSAT encryption module internally generates its own secret and public numbers. The secret number never leaves the module while the public number is sent to the hub at the time of initialization of the encryption module into the VSAT. Physical access control to encryption modules of VSAT systems can be implemented using passwords, smart cards or biometrics.

  14. Linking Fearfulness and Coping Styles in Fish

    PubMed Central

    Martins, Catarina I. M.; Silva, Patricia I. M.; Conceição, Luis E. C.; Costas, Benjamin; Höglund, Erik; Øverli, Øyvind; Schrama, Johan W.

    2011-01-01

    Consistent individual differences in cognitive appraisal and emotional reactivity, including fearfulness, are important personality traits in humans, non-human mammals, and birds. Comparative studies on teleost fishes support the existence of coping styles and behavioral syndromes also in poikilothermic animals. The functionalist approach to emotions hold that emotions have evolved to ensure appropriate behavioral responses to dangerous or rewarding stimuli. Little information is however available on how evolutionary widespread these putative links between personality and the expression of emotional or affective states such as fear are. Here we disclose that individual variation in coping style predicts fear responses in Nile tilapia Oreochromis niloticus, using the principle of avoidance learning. Fish previously screened for coping style were given the possibility to escape a signalled aversive stimulus. Fearful individuals showed a range of typically reactive traits such as slow recovery of feed intake in a novel environment, neophobia, and high post-stress cortisol levels. Hence, emotional reactivity and appraisal would appear to be an essential component of animal personality in species distributed throughout the vertebrate subphylum. PMID:22140511

  15. Linking plant and ecosystem functional biogeography.

    PubMed

    Reichstein, Markus; Bahn, Michael; Mahecha, Miguel D; Kattge, Jens; Baldocchi, Dennis D

    2014-09-23

    Classical biogeographical observations suggest that ecosystems are strongly shaped by climatic constraints in terms of their structure and function. On the other hand, vegetation function feeds back on the climate system via biosphere-atmosphere exchange of matter and energy. Ecosystem-level observations of this exchange reveal very large functional biogeographical variation of climate-relevant ecosystem functional properties related to carbon and water cycles. This variation is explained insufficiently by climate control and a classical plant functional type classification approach. For example, correlations between seasonal carbon-use efficiency and climate or environmental variables remain below 0.6, leaving almost 70% of variance unexplained. We suggest that a substantial part of this unexplained variation of ecosystem functional properties is related to variations in plant and microbial traits. Therefore, to progress with global functional biogeography, we should seek to understand the link between organismic traits and flux-derived ecosystem properties at ecosystem observation sites and the spatial variation of vegetation traits given geoecological covariates. This understanding can be fostered by synergistic use of both data-driven and theory-driven ecological as well as biophysical approaches.

  16. Linking plant and ecosystem functional biogeography

    PubMed Central

    Reichstein, Markus; Bahn, Michael; Mahecha, Miguel D.; Kattge, Jens; Baldocchi, Dennis D.

    2014-01-01

    Classical biogeographical observations suggest that ecosystems are strongly shaped by climatic constraints in terms of their structure and function. On the other hand, vegetation function feeds back on the climate system via biosphere–atmosphere exchange of matter and energy. Ecosystem-level observations of this exchange reveal very large functional biogeographical variation of climate-relevant ecosystem functional properties related to carbon and water cycles. This variation is explained insufficiently by climate control and a classical plant functional type classification approach. For example, correlations between seasonal carbon-use efficiency and climate or environmental variables remain below 0.6, leaving almost 70% of variance unexplained. We suggest that a substantial part of this unexplained variation of ecosystem functional properties is related to variations in plant and microbial traits. Therefore, to progress with global functional biogeography, we should seek to understand the link between organismic traits and flux-derived ecosystem properties at ecosystem observation sites and the spatial variation of vegetation traits given geoecological covariates. This understanding can be fostered by synergistic use of both data-driven and theory-driven ecological as well as biophysical approaches. PMID:25225392

  17. Using ecological production functions to link ecological ...

    EPA Pesticide Factsheets

    Ecological production functions (EPFs) link ecosystems, stressors, and management actions to ecosystem services (ES) production. Although EPFs are acknowledged as being essential to improve environmental management, their use in ecological risk assessment has received relatively little attention. Ecological production functions may be defined as usable expressions (i.e., models) of the processes by which ecosystems produce ES, often including external influences on those processes. We identify key attributes of EPFs and discuss both actual and idealized examples of their use to inform decision making. Whenever possible, EPFs should estimate final, rather than intermediate, ES. Although various types of EPFs have been developed, we suggest that EPFs are more useful for decision making if they quantify ES outcomes, respond to ecosystem condition, respond to stressor levels or management scenarios, reflect ecological complexity, rely on data with broad coverage, have performed well previously, are practical to use, and are open and transparent. In an example using pesticides, we illustrate how EPFs with these attributes could enable the inclusion of ES in ecological risk assessment. The biggest challenges to ES inclusion are limited data sets that are easily adapted for use in modeling EPFs and generally poor understanding of linkages among ecological components and the processes that ultimately deliver the ES. We conclude by advocating for the incorporation into E

  18. Linking Mechanics and Statistics in Epidermal Tissues

    NASA Astrophysics Data System (ADS)

    Kim, Sangwoo; Hilgenfeldt, Sascha

    2015-03-01

    Disordered cellular structures, such as foams, polycrystals, or living tissues, can be characterized by quantitative measurements of domain size and topology. In recent work, we showed that correlations between size and topology in 2D systems are sensitive to the shape (eccentricity) of the individual domains: From a local model of neighbor relations, we derived an analytical justification for the famous empirical Lewis law, confirming the theory with experimental data from cucumber epidermal tissue. Here, we go beyond this purely geometrical model and identify mechanical properties of the tissue as the root cause for the domain eccentricity and thus the statistics of tissue structure. The simple model approach is based on the minimization of an interfacial energy functional. Simulations with Surface Evolver show that the domain statistics depend on a single mechanical parameter, while parameter fluctuations from cell to cell play an important role in simultaneously explaining the shape distribution of cells. The simulations are in excellent agreement with experiments and analytical theory, and establish a general link between the mechanical properties of a tissue and its structure. The model is relevant to diagnostic applications in a variety of animal and plant tissues.

  19. Linking unfounded beliefs to genetic dopamine availability

    PubMed Central

    Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

    2015-01-01

    Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

  20. Three-link Swimming in Sand

    NASA Astrophysics Data System (ADS)

    Hatton, R. L.; Ding, Yang; Masse, Andrew; Choset, Howie; Goldman, Daniel

    2011-11-01

    Many animals move within in granular media such as desert sand. Recent biological experiments have revealed that the sandfish lizard uses an undulatory gait to swim within sand. Models reveal that swimming occurs in a frictional fluid in which inertial effects are small and kinematics dominate. To understand the fundamental mechanics of swimming in granular media (GM), we examine a model system that has been well-studied in Newtonian fluids: the three-link swimmer. We create a physical model driven by two servo-motors, and a discrete element simulation of the swimmer. To predict optimal gaits we use a recent geometric mechanics theory combined with empirically determined resistive force laws for GM. We develop a kinematic relationship between the swimmer's shape and position velocities and construct connection vector field and constraint curvature function visualizations of the system dynamics. From these we predict optimal gaits for forward, lateral and rotational motion. Experiment and simulation are in accord with the theoretical predictions; thus geometric tools can be used to study locomotion in GM.

  1. X-linked intellectual disability update 2017.

    PubMed

    Neri, Giovanni; Schwartz, Charles E; Lubs, Herbert A; Stevenson, Roger E

    2018-04-25

    The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. © 2018 Wiley Periodicals, Inc.

  2. Linking Specialization and Seriousness in Criminal Careers

    PubMed Central

    MacDonald, John M.; Haviland, Amelia; Ramchand, Rajeev; Morral, Andrew R.; Piquero, Alex R.

    2014-01-01

    Some research suggests that recidivistic criminal offending patterns typically progress in a stepping-stone manner from less to more serious forms of offending from childhood to adolescence to adulthood. Whether the progression into more serious types of offending reflects patterns of crime specialization is a matter of debate. Using data from 449 adolescent offenders who were interviewed at six time points between adolescence and adulthood, we present a new method for measuring crime specialization and apply it to an assessment of the link between specialization and offense seriousness. We measure specialization by constructing an empirical measure of how similar crimes are from each other based on the rate at which crimes co-occur within individual crime pathways over a given offender population. We then use these empirically-based population-specific offense similarities to assign a specialization score to each subject at each time period based on the set of crimes they self-report at that time. Finally, we examine how changes over time in specialization, within individuals, is correlated with changes in the seriousness of the offenses they report committing. Results suggest that the progression of crime into increasingly serious forms of offending does not reflect a general pattern of offense specialization. Implications for life course research are noted. PMID:25422597

  3. Linking animals aloft with the terrestrial landscape

    USGS Publications Warehouse

    Buler, Jeffrey J.; Barrow, Wylie; Boone, Matthew; Dawson, Deanna K.; Diehl, Robert H.; Moore, Frank R.; Randall, Lori A.; Schreckengost, Timothy; Smolinsky, Jaclyn A.

    2018-01-01

    Despite using the aerosphere for many facets of their life, most flying animals (i.e., birds, bats, some insects) are still bound to terrestrial habitats for resting, feeding, and reproduction. Comprehensive broad-scale observations by weather surveillance radars of animals as they leave terrestrial habitats for migration or feeding flights can be used to map their terrestrial distributions either as point locations (e.g., communal roosts) or as continuous surface layers (e.g., animal densities in habitats across a landscape). We discuss some of the technical challenges to reducing measurement biases related to how radars sample the aerosphere and the flight behavior of animals. We highlight a recently developed methodological approach that precisely and quantitatively links the horizontal spatial structure of birds aloft to their terrestrial distributions and provides novel insights into avian ecology and conservation across broad landscapes. Specifically, we present case studies that (1) elucidate how migrating birds contend with crossing ecological barriers and extreme weather events, (2) identify important stopover areas and habitat use patterns of birds along their migration routes, and (3) assess waterfowl response to wetland habitat management and restoration. These studies aid our understanding of how anthropogenic modification of the terrestrial landscape (e.g., urbanization, habitat management), natural geographic features, and weather (e.g., hurricanes) can affect the terrestrial distributions of flying animals.

  4. Lewis Information Network (LINK): Background and overview

    NASA Technical Reports Server (NTRS)

    Schulte, Roger R.

    1987-01-01

    The NASA Lewis Research Center supports many research facilities with many isolated buildings, including wind tunnels, test cells, and research laboratories. These facilities are all located on a 350 acre campus adjacent to the Cleveland Hopkins Airport. The function of NASA-Lewis is to do basic and applied research in all areas of aeronautics, fluid mechanics, materials and structures, space propulsion, and energy systems. These functions require a great variety of remote high speed, high volume data communications for computing and interactive graphic capabilities. In addition, new requirements for local distribution of intercenter video teleconferencing and data communications via satellite have developed. To address these and future communications requirements for the next 15 yrs, a project team was organized to design and implement a new high speed communication system that would handle both data and video information in a common lab-wide Local Area Network. The project team selected cable television broadband coaxial cable technology as the communications medium and first installation of in-ground cable began in the summer of 1980. The Lewis Information Network (LINK) became operational in August 1982 and has become the backbone of all data communications and video.

  5. Genetic variants linked to education predict longevity

    PubMed Central

    Marioni, Riccardo E.; Ritchie, Stuart J.; Joshi, Peter K.; Hagenaars, Saskia P.; Fischer, Krista; Adams, Mark J.; Hill, W. David; Davies, Gail; Nagy, Reka; Amador, Carmen; Läll, Kristi; Metspalu, Andres; Liewald, David C.; Wilson, James F.; Hayward, Caroline; Esko, Tõnu; Porteous, David J.; Gale, Catharine R.; Deary, Ian J.

    2016-01-01

    Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members’ polygenic profile score for education to predict their parents’ longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. PMID:27799538

  6. Interpersonal mechanisms linking close relationships to health.

    PubMed

    Pietromonaco, Paula R; Collins, Nancy L

    2017-09-01

    Close relationships play a vital role in human health, but much remains to be learned about specific mechanisms of action and potential avenues for intervention. This article provides an evaluation of research on close relationships processes relevant to health, drawing on themes from major relationship science theories to present a broad conceptual framework for understanding the interpersonal processes and intrapersonal pathways linking relationships to health and disease outcomes. The analysis reveals that both social connection and social disconnection broadly shape biological responses and behaviors that are consequential for health. Furthermore, emerging work offers insights into the types of social dynamics that are most consequential for health, and the potential pathways through which they operate. Following from this analysis, the authors suggest several research priorities to facilitate the translation of discoveries from relationship science into relationship-based interventions and public health initiatives. These priorities include developing finer grained theoretical models to guide research, the systematic investigation of potential mediating pathways such as dyadic influences on health behavior and physiological coregulation, and taking into account individual differences and contextual factors such as attachment style, gender, socioeconomic status, and culture. In addition, a pressing need exists for laboratory and field research to determine which types of interventions are both practical and effective. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  7. Genetic variants linked to education predict longevity.

    PubMed

    Marioni, Riccardo E; Ritchie, Stuart J; Joshi, Peter K; Hagenaars, Saskia P; Okbay, Aysu; Fischer, Krista; Adams, Mark J; Hill, W David; Davies, Gail; Nagy, Reka; Amador, Carmen; Läll, Kristi; Metspalu, Andres; Liewald, David C; Campbell, Archie; Wilson, James F; Hayward, Caroline; Esko, Tõnu; Porteous, David J; Gale, Catharine R; Deary, Ian J

    2016-11-22

    Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.

  8. Lactate: link between glycolytic and oxidative metabolism.

    PubMed

    Brooks, George A

    2007-01-01

    Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilised continuously under fully aerobic conditions. 'Cell-cell' and 'intracellular lactate shuttle' concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges (i) between white-glycolytic and red-oxidative fibres within a working muscle bed; (ii) between working skeletal muscle and heart; and (iii) between tissues of net lactate release and gluconeogenesis. Lactate shuttles exist in diverse tissues including in the brain, where a shuttle between astrocytes and neurons is linked to glutamatergic signalling. Because lactate, the product of glycogenolysis and glycolysis, is disposed of by oxidative metabolism, lactate shuttling unites the two major processes of cellular energy transduction. Lactate disposal is mainly through oxidation, especially during exercise when oxidation accounts for 70-75% of removal and gluconeogenesis the remainder. Lactate flux occurs down proton and concentration gradients that are established by the mitochondrial lactate oxidation complex. Marathon running is a power activity requiring high glycolytic and oxidative fluxes; such activities require lactate shuttling. Knowledge of the lactate shuttle is yet to be imparted to the sport.

  9. Linking energetics and overwintering in temperate insects.

    PubMed

    Sinclair, Brent J

    2015-12-01

    Overwintering insects cannot feed, and energy they take into winter must therefore fuel energy demands during autumn, overwintering, warm periods prior to resumption of development in spring, and subsequent activity. Insects primarily consume lipids during winter, but may also use carbohydrate and proteins as fuel. Because they are ectotherms, the metabolic rate of insects is temperature-dependent, and the curvilinear nature of the metabolic rate-temperature relationship means that warm temperatures are disproportionately important to overwinter energy use. This energy use may be reduced physiologically, by reducing the slope or elevation of the metabolic rate-temperature relationship, or because of threshold changes, such as metabolic suppression upon freezing. Insects may also choose microhabitats or life history stages that reduce the impact of overwinter energy drain. There is considerable capacity for overwinter energy drain to affect insect survival and performance both directly (via starvation) or indirectly (for example, through a trade-off with cryoprotection), but this has not been well-explored. Likewise, the impact of overwinter energy drain on growing-season performance is not well understood. I conclude that overwinter energetics provides a useful lens through which to link physiology and ecology and winter and summer in studies of insect responses to their environment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Produce and Consume Linked Data with Drupal!

    NASA Astrophysics Data System (ADS)

    Corlosquet, Stéphane; Delbru, Renaud; Clark, Tim; Polleres, Axel; Decker, Stefan

    Currently a large number of Web sites are driven by Content Management Systems (CMS) which manage textual and multimedia content but also - inherently - carry valuable information about a site's structure and content model. Exposing this structured information to the Web of Data has so far required considerable expertise in RDF and OWL modelling and additional programming effort. In this paper we tackle one of the most popular CMS: Drupal. We enable site administrators to export their site content model and data to the Web of Data without requiring extensive knowledge on Semantic Web technologies. Our modules create RDFa annotations and - optionally - a SPARQL endpoint for any Drupal site out of the box. Likewise, we add the means to map the site data to existing ontologies on the Web with a search interface to find commonly used ontology terms. We also allow a Drupal site administrator to include existing RDF data from remote SPARQL endpoints on the Web in the site. When brought together, these features allow networked RDF Drupal sites that reuse and enrich Linked Data. We finally discuss the adoption of our modules and report on a use case in the biomedical field and the current status of its deployment.

  11. Exploration of the strength of family links

    NASA Astrophysics Data System (ADS)

    Richmond, Peter; Roehner, Bertrand M.

    2018-07-01

    Ever since the studies of Louis-Adolphe Bertillon in the late 19th century it has been known that marital status and number of children markedly affect death and suicide rates. This led in 1898 Emile Durkheim to conjecture a connection between social isolation (especially at family level) and suicide. However, further progress was long hampered by the limited statistical data available from death certificates. Recently, it was shown by the present authors that disability data from census records can be used as a reliable substitute for mortality data. This opens a new route to investigations of family ties because census information goes much beyond the limited data reported on death certificates. It is shown that the disability rate of adults decreases when they have more family links. More precisely, the reduction of the parents' disability brought about by the presence of a child reveals that the strength of ties between parents and child is highest in the first year after birth and then weakens steadily as the child ages. It will also be seen that the strength of the bond between husband and wife is highest when they are of same age and decreases fairly steadily when the age gap increases.

  12. ESO telbib: Linking In and Reaching Out

    NASA Astrophysics Data System (ADS)

    Grothkopf, U.; Meakins, S.

    2015-04-01

    Measuring an observatory's research output is an integral part of its science operations. Like many other observatories, ESO tracks scholarly papers that use observational data from ESO facilities and uses state-of-the-art tools to create, maintain, and further develop the Telescope Bibliography database (telbib). While telbib started out as a stand-alone tool mostly used to compile lists of papers, it has by now developed into a multi-faceted, interlinked system. The core of the telbib database is links between scientific papers and observational data generated by the La Silla Paranal Observatory residing in the ESO archive. This functionality has also been deployed for ALMA data. In addition, telbib reaches out to several other systems, including ESO press releases, the NASA ADS Abstract Service, databases at the CDS Strasbourg, and impact scores at Altmetric.com. We illustrate these features to show how the interconnected telbib system enhances the content of the database as well as the user experience.

  13. World Space Week: Linking Space and Humanity

    NASA Astrophysics Data System (ADS)

    Stone, D.

    2002-01-01

    World Space Week, October 4-10 annually, is an international celebration of the contribution that space science and technology makes to the betterment of the human condition. Since its official declaration in 1999 by the United Nation, World Space Week has rapidly grown to include over 40 nations. The dates of World Space Week commemorate key milestones in space. October 4, 1957 was the launch date of Sputnik I, the first artificial Earth satellite. The Outer Space Treaty took effect on October 10, 1967. During World Space Week, participants such as government agencies, companies, science museums, teachers, and individuals organize public events, school activities, and Web-based programs related to space. So many synchronized events attract media coverage which reaches a global audience about space. In this way, World Space Week truly links space and humanity. The global organization of World Space Week is discussed as well as the results to date. The benefits of participation and opportunities to do so also identified.

  14. A cannabinoid link between mitochondria and memory.

    PubMed

    Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Román; Bellocchio, Luigi; Soria-Gomez, Edgar; Busquets-Garcia, Arnau; Pagano Zottola, Antonio Christian; Delamarre, Anna; Cannich, Astrid; Vincent, Peggy; Varilh, Marjorie; Robin, Laurie M; Terral, Geoffrey; García-Fernández, M Dolores; Colavita, Michelangelo; Mazier, Wilfrid; Drago, Filippo; Puente, Nagore; Reguero, Leire; Elezgarai, Izaskun; Dupuy, Jean-William; Cota, Daniela; Lopez-Rodriguez, Maria-Luz; Barreda-Gómez, Gabriel; Massa, Federico; Grandes, Pedro; Bénard, Giovanni; Marsicano, Giovanni

    2016-11-24

    Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

  15. Gastrointestinal Manifestations in X-linked Agammaglobulinemia

    PubMed Central

    Barmettler, Sara; Otani, Iris M.; Minhas, Jasmit; Abraham, Roshini S.; Chang, Yenhui; Dorsey, Morna J.; Ballas, Zuhair K.; Bonilla, Francisco A.; Ochs, Hans D.; Walter, Jolan E.

    2017-01-01

    Purpose X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in XLA, the spectrum of gastrointestinal manifestations has not previously been fully explored. Methods We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the USIDNet, a national registry of primary immunodeficiencies. Results In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide-ranging, and management strategies were diverse and mainly experimental. Conclusions Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients. PMID:28236219

  16. Simulation of Controller Pilot Data Link Communications over VHF Digital Link Mode 3

    NASA Technical Reports Server (NTRS)

    Bretmersky, Steven C.; Murawski, Robert; Nguyen, Thanh C.; Raghavan, Rajesh S.

    2004-01-01

    The Federal Aviation Administration (FAA) has established an operational plan for the future Air Traffic Management (ATM) system, in which the Controller Pilot Data Link Communications (CPDLC) is envisioned to evolve into digital messaging that will take on an ever increasing role in controller to pilot communications, significantly changing the way the National Airspace System (NAS) is operating. According to FAA, CPDLC represents the first phase of the transition from the current analog voice system to an International Civil Aviation Organization (ICAO) compliant system in which digital communication becomes the alternate and perhaps primary method of routine communication. The CPDLC application is an Air Traffic Service (ATS) application in which pilots and controllers exchange messages via an addressed data link. CPDLC includes a set of clearance, information, and request message elements that correspond to existing phraseology employed by current Air Traffic Control (ATC) procedures. These message elements encompass altitude assignments, crossing constraints, lateral deviations, route changes and clearances, speed assignments, radio frequency assignments, and various requests for information. The pilot is provided with the capability to respond to messages, to request clearances and information, to report information, and to declare/rescind an emergency. A 'free text' capability is also provided to exchange information not conforming to defined formats. This paper presents simulated results of the aeronautical telecommunication application Controller Pilot Data Link Communications over VHF Digital Link Mode 3 (VDL Mode 3). The objective of this simulation study was to determine the impact of CPDLC traffic loads, in terms of timely message delivery and capacity of the VDL Mode 3 subnetwork. The traffic model is based on and is used for generating air/ground messages with different priorities. Communication is modeled for the en route domain of the Cleveland

  17. A novel multilayer model for missing link prediction and future link forecasting in dynamic complex networks

    NASA Astrophysics Data System (ADS)

    Yasami, Yasser; Safaei, Farshad

    2018-02-01

    The traditional complex network theory is particularly focused on network models in which all network constituents are dealt with equivalently, while fail to consider the supplementary information related to the dynamic properties of the network interactions. This is a main constraint leading to incorrect descriptions of some real-world phenomena or incomplete capturing the details of certain real-life problems. To cope with the problem, this paper addresses the multilayer aspects of dynamic complex networks by analyzing the properties of intrinsically multilayered co-authorship networks, DBLP and Astro Physics, and presenting a novel multilayer model of dynamic complex networks. The model examines the layers evolution (layers birth/death process and lifetime) throughout the network evolution. Particularly, this paper models the evolution of each node's membership in different layers by an Infinite Factorial Hidden Markov Model considering feature cascade, and thereby formulates the link generation process for intra-layer and inter-layer links. Although adjacency matrixes are useful to describe the traditional single-layer networks, such a representation is not sufficient to describe and analyze the multilayer dynamic networks. This paper also extends a generalized mathematical infrastructure to address the problems issued by multilayer complex networks. The model inference is performed using some Markov Chain Monte Carlo sampling strategies, given synthetic and real complex networks data. Experimental results indicate a tremendous improvement in the performance of the proposed multilayer model in terms of sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, F1-score, Matthews correlation coefficient, and accuracy for two important applications of missing link prediction and future link forecasting. The experimental results also indicate the strong predictivepower of the proposed model for the application of

  18. Cross-Link Guided Molecular Modeling with ROSETTA

    PubMed Central

    Leitner, Alexander; Rosenberger, George; Aebersold, Ruedi; Malmström, Lars

    2013-01-01

    Chemical cross-links identified by mass spectrometry generate distance restraints that reveal low-resolution structural information on proteins and protein complexes. The technology to reliably generate such data has become mature and robust enough to shift the focus to the question of how these distance restraints can be best integrated into molecular modeling calculations. Here, we introduce three workflows for incorporating distance restraints generated by chemical cross-linking and mass spectrometry into ROSETTA protocols for comparative and de novo modeling and protein-protein docking. We demonstrate that the cross-link validation and visualization software Xwalk facilitates successful cross-link data integration. Besides the protocols we introduce XLdb, a database of chemical cross-links from 14 different publications with 506 intra-protein and 62 inter-protein cross-links, where each cross-link can be mapped on an experimental structure from the Protein Data Bank. Finally, we demonstrate on a protein-protein docking reference data set the impact of virtual cross-links on protein docking calculations and show that an inter-protein cross-link can reduce on average the RMSD of a docking prediction by 5.0 Å. The methods and results presented here provide guidelines for the effective integration of chemical cross-link data in molecular modeling calculations and should advance the structural analysis of particularly large and transient protein complexes via hybrid structural biology methods. PMID:24069194

  19. Link prediction in the network of global virtual water trade

    NASA Astrophysics Data System (ADS)

    Tuninetti, Marta; Tamea, Stefania; Laio, Francesco; Ridolfi, Luca

    2016-04-01

    Through the international food-trade, water resources are 'virtually' transferred from the country of production to the country of consumption. The international food-trade, thus, implies a network of virtual water flows from exporting to importing countries (i.e., nodes). Given the dynamical behavior of the network, where food-trade relations (i.e., links) are created and dismissed every year, link prediction becomes a challenge. In this study, we propose a novel methodology for link prediction in the virtual water network. The model aims at identifying the main factors (among 17 different variables) driving the creation of a food-trade relation between any two countries, along the period between 1986 and 2011. Furthermore, the model can be exploited to investigate the network configuration in the future, under different possible (climatic and demographic) scenarios. The model grounds the existence of a link between any two nodes on the link weight (i.e., the virtual water flow): a link exists when the nodes exchange a minimum (fixed) volume of virtual water. Starting from a set of potential links between any two nodes, we fit the associated virtual water flows (both the real and the null ones) by means of multivariate linear regressions. Then, links with estimated flows higher than a minimum value (i.e., threshold) are considered active-links, while the others are non-active ones. The discrimination between active and non-active links through the threshold introduces an error (called link-prediction error) because some real links are lost (i.e., missed links) and some non-existing links (i.e., spurious links) are inevitably introduced in the network. The major drivers are those significantly minimizing the link-prediction error. Once the structure of the unweighted virtual water network is known, we apply, again, linear regressions to assess the major factors driving the fluxes traded along (modelled) active-links. Results indicate that, on the one hand

  20. Selective inattention to anxiety-linked stimuli.

    PubMed

    Blum, G S; Barbour, J S

    1979-06-01

    The term selective inattention as used here subsumes those phenomena whose primary function is the active blocking or attenuation of partially processed contents en route to conscious expression. Examples are anxiety-motivated forgetting or perceptual distortion and hypnotically induced negative hallucinations. Studies in the field of selective attention have typically been designed to explain what takes place in a task in which the subject is first instructed to attend to a particular stimulus and then to consciously execute that instruction as well as he can. The rejection of content in process is examined only sceondarily as a consequence of the acceptance of relevant information. In the present experiments and theorizing, the emphasis instead is on inhibitory operations that take place automatically, without conscious intent, in response to a potential anxiety reaction. Experiment 1 explored the interaction of anxiety-linked inattention with strength of a target stimulus. Three female subjects were programmed under hypnosis to respond posthypnotically in the On condition with prescribed degrees of anxiety when certain Blacky pictures popped into mind later ,t the end of experimental trials; in the Off conditionall pictures were to become neutral. With the three female subjects still under hypnosis, each of the loaded pictures was then paired with a four-letter work relevant to the individual's own version of what was happening in the picture. The waking recognition task, carried out with amnesia for the prior hypnotic programming, consisted of tachistoscopic exposure of loaded words and physically similar filler words at four durations within a baseline range of recognition accuracy from 50%--75% correct. The data yielded a curvilinear relationship in which the recognition of only the loaded words was significnatly lower in the On condition at the 60%--70% range of recognition accuracy but not at shorter or longer stimulus durations. Experiment 2, for which the