Sample records for ability pathways rap

  1. RAP-1 and the RAL-1/exocyst pathway coordinate hypodermal cell organization in Caenorhabditis elegans

    PubMed Central

    Frische, Ester W; Pellis-van Berkel, Wendy; van Haaften, Gijs; Cuppen, Edwin; Plasterk, Ronald H A; Tijsterman, Marcel; Bos, Johannes L; Zwartkruis, Fried J T

    2007-01-01

    The small Ras-like GTPase Rap1 has been identified as a regulator of integrin activation and cadherin-mediated cell–cell contacts. Surprisingly, null mutants of RAP-1 in Caenorhabditis elegans are viable and fertile. In a synthetic lethal RNAi screen with C. elegans rap-1 mutants, the Ras-like GTPase ral-1 emerged as one of seven genes specifically required for viability. Depletion of exoc-8 and sec-5, encoding two putative RAL-1 effectors and members of the exocyst complex, also caused lethality of rap-1 mutants, but did not affect wild-type worms. The RAP-1 and the RAL-1/exocyst pathway appear to coordinate hypodermal cell movement and elongation during embryonic development. They mediate their effect in part through targeting the α-catenin homologue HMP-1 to the lateral membrane. Genetic interactions show that the RAP-1 and RAL-1/exocyst pathway also act in parallel during larval stages. Together these data provide in vivo evidence for the exocyst complex as a downstream RAL-1 effector in cell migration. PMID:17989692

  2. RAP-1 and the RAL-1/exocyst pathway coordinate hypodermal cell organization in Caenorhabditis elegans.

    PubMed

    Frische, Ester W; Pellis-van Berkel, Wendy; van Haaften, Gijs; Cuppen, Edwin; Plasterk, Ronald H A; Tijsterman, Marcel; Bos, Johannes L; Zwartkruis, Fried J T

    2007-12-12

    The small Ras-like GTPase Rap1 has been identified as a regulator of integrin activation and cadherin-mediated cell-cell contacts. Surprisingly, null mutants of RAP-1 in Caenorhabditis elegans are viable and fertile. In a synthetic lethal RNAi screen with C. elegans rap-1 mutants, the Ras-like GTPase ral-1 emerged as one of seven genes specifically required for viability. Depletion of exoc-8 and sec-5, encoding two putative RAL-1 effectors and members of the exocyst complex, also caused lethality of rap-1 mutants, but did not affect wild-type worms. The RAP-1 and the RAL-1/exocyst pathway appear to coordinate hypodermal cell movement and elongation during embryonic development. They mediate their effect in part through targeting the alpha-catenin homologue HMP-1 to the lateral membrane. Genetic interactions show that the RAP-1 and RAL-1/exocyst pathway also act in parallel during larval stages. Together these data provide in vivo evidence for the exocyst complex as a downstream RAL-1 effector in cell migration.

  3. Rap1 and Rap2 Antagonistically Control Endothelial Barrier Resistance

    PubMed Central

    Pannekoek, Willem-Jan; Linnemann, Jelena R.; Brouwer, Patricia M.; Bos, Johannes L.; Rehmann, Holger

    2013-01-01

    Rap1 and Rap2 are closely related proteins of the Ras family of small G-proteins. Rap1 is well known to regulate cell-cell adhesion. Here, we have analysed the effect of Rap-mediated signalling on endothelial permeability using electrical impedance measurements of HUVEC monolayers and subsequent determination of the barrier resistance, which is a measure for the ease with which ions can pass cell junctions. In line with its well-established effect on cell-cell junctions, depletion of Rap1 decreases, whereas activation of Rap1 increases barrier resistance. Despite its high sequence homology with Rap1, depletion of Rap2 has an opposite, enhancing, effect on barrier resistance. This effect can be mimicked by depletion of the Rap2 specific activator RasGEF1C and the Rap2 effector MAP4K4, establishing Rap2 signalling as an independent pathway controlling barrier resistance. As simultaneous depletion or activation of both Rap1 and Rap2 results in a barrier resistance comparable to control cells, Rap1 and Rap2 control barrier resistance in a reciprocal manner. This Rap1-antagonizing effect of Rap2 is established independent of junctional actin formation. These data establish that endothelial barrier resistance is determined by the combined antagonistic actions of Rap1 and Rap2. PMID:23469100

  4. Creating the Infrastructure for Organizational Change with RAP

    ERIC Educational Resources Information Center

    Shields, Julie; Milstein, Mindy; Robinson, Consuela

    2012-01-01

    In order to thrive, organizations must undergo significant change at various points in their development. Such is the case with Montgomery County Public Schools (MCPS) Emotional Disability Services in the beginning process of implementing Response Ability Pathways (RAP) with staff and students. The impetus for change originated from an…

  5. Rapeseed protein-derived antioxidant peptide RAP alleviates renal fibrosis through MAPK/NF-κB signaling pathways in diabetic nephropathy.

    PubMed

    Zhang, Mingyan; Yan, Zhibin; Bu, Lili; An, Chunmei; Wang, Dan; Liu, Xin; Zhang, Jianfeng; Yang, Wenle; Deng, Bochuan; Xie, Junqiu; Zhang, Bangzhi

    2018-01-01

    Kidney fibrosis is the main pathologic change in diabetic nephropathy (DN), which is the major cause of end-stage renal disease. Current therapeutic strategies slow down but cannot reverse the progression of renal dysfunction in DN. Plant-derived bioactive peptides in foodstuffs are widely used in many fields because of their potential pharmaceutical and nutraceutical benefits. However, this type of peptide has not yet been studied in renal fibrosis of DN. Previous studies have indicated that the peptide YWDHNNPQIR (named RAP), a natural peptide derived from rapeseed protein, has an antioxidative stress effect. The oxidative stress is believed to be associated with DN. The aim of this study was to evaluate the pharmacologic effects of RAP against renal fibrosis of DN and high glucose (HG)-induced mesangial dysfunction. Diabetes was induced by streptozotocin and high-fat diet in C57BL/6 mice and these mice were treated by subcutaneous injection of different doses of RAP (0.1 mg/kg and 0.5 mg/kg, every other day) or PBS for 12 weeks. Later, functional and histopathologic analyses were performed. Parallel experiments verifying the molecular mechanism by which RAP alleviates DN were carried out in HG-induced mesangial cells (MCs). RAP improved the renal function indices, including 24-h albuminuria, triglyceride, serum creatinine, and blood urea nitrogen levels, but did not lower blood glucose levels in DN mice. RAP also simultaneously attenuated extracellular matrix accumulation in DN mice and HG-induced MCs. Furthermore, RAP reduced HG-induced cell proliferation, but it showed no toxicity in MCs. Additionally, RAP inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. RAP can attenuate fibrosis in vivo and in vitro by antagonizing the MAPK and NF-κB pathways.

  6. Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development.

    PubMed

    Maruyama, Takamitsu; Jiang, Ming; Abbott, Alycia; Yu, H-M Ivy; Huang, Qirong; Chrzanowska-Wodnicka, Magdalena; Chen, Emily I; Hsu, Wei

    2017-09-01

    Recent identification and isolation of suture stem cells capable of long-term self-renewal, clonal expanding, and differentiating demonstrate their essential role in calvarial bone development, homeostasis, and injury repair. These bona fide stem cells express a high level of Axin2 and are able to mediate bone regeneration and repair in a cell autonomous fashion. The importance of Axin2 is further demonstrated by its genetic inactivation in mice causing skeletal deformities resembling craniosynostosis in humans. The fate determination and subsequent differentiation of Axin2+ stem cells are highly orchestrated by a variety of evolutionary conserved signaling pathways including Wnt, FGF, and BMP. These signals are often antagonistic of each other and possess differential effects on osteogenic and chondrogenic cell types. However, the mechanisms underlying the interplay of these signaling transductions remain largely elusive. Here we identify Rap1b acting downstream of Axin2 as a signaling interrogator for FGF and BMP. Genetic analysis reveals that Rap1b is essential for development of craniofacial and body skeletons. Axin2 regulates Rap1b through modulation of canonical BMP signaling. The BMP-mediated activation of Rap1b promotes chondrogenic fate and chondrogenesis. Furthermore, by inhibiting MAPK signaling, Rap1b mediates the antagonizing effect of BMP on FGF to repress osteoblast differentiation. Disruption of Rap1b in mice not only enhances osteoblast differentiation but also impairs chondrocyte differentiation during intramembranous and endochondral ossifications, respectively, leading to severe defects in craniofacial and body skeletons. Our findings reveal a dual role of Rap1b in development of the skeletogenic cell types. Rap1b is critical for balancing the signaling effects of BMP and FGF during skeletal development and disease. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  7. Rap G protein signal in normal and disordered lymphohematopoiesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Minato, Nagahiro, E-mail: minato@imm.med.kyoto-u.ac.jp

    2013-09-10

    Rap proteins (Rap1, Rap2a, b, c) are small molecular weight GTPases of the Ras family. Rap G proteins mediate diverse cellular events such as cell adhesion, proliferation, and gene activation through various signaling pathways. Activation of Rap signal is regulated tightly by several specific regulatory proteins including guanine nucleotide exchange factors and GTPase-activating proteins. Beyond cell biological studies, increasing attempts have been made in the past decade to define the roles of Rap signal in specific functions of normal tissue systems as well as in cancer. In the immune and hematopoietic systems, Rap signal plays crucial roles in the developmentmore » and function of essentially all lineages of lymphocytes and hematopoietic cells, and importantly, deregulated Rap signal may lead to unique pathological conditions depending on the affected cell types, including various types of leukemia and autoimmunity. The phenotypical studies have unveiled novel, even unexpected functional aspects of Rap signal in cells from a variety of tissues, providing potentially important clues for controlling human diseases, including malignancy.« less

  8. Dynamin2 controls Rap1 activation and integrin clustering in human T lymphocyte adhesion

    PubMed Central

    Eppler, Felix J.

    2017-01-01

    Leukocyte trafficking is crucial to facilitate efficient immune responses. Here, we report that the large GTPase dynamin2, which is generally considered to have a key role in endocytosis and membrane remodeling, is an essential regulator of integrin-dependent human T lymphocyte adhesion and migration. Chemical inhibition or knockdown of dynamin2 expression significantly reduced integrin-dependent T cell adhesion in vitro. This phenotype was not observed when T cells were treated with various chemical inhibitors which abrogate endocytosis or actin polymerization. We furthermore detected dynamin2 in signaling complexes and propose that it controls T cell adhesion via FAK/Pyk2- and RapGEF1-mediated Rap1 activation. In addition, the dynamin2 inhibitor-induced reduction of lymphocyte adhesion can be rescued by Rap1a overexpression. We demonstrate that the dynamin2 effect on T cell adhesion does not involve integrin affinity regulation but instead relies on its ability to modulate integrin valency. Taken together, we suggest a previously unidentified role of dynamin2 in the regulation of integrin-mediated lymphocyte adhesion via a Rap1 signaling pathway. PMID:28273099

  9. Rap Phosphatase of Virulence Plasmid pXO1 Inhibits Bacillus anthracis Sporulation†

    PubMed Central

    Bongiorni, Cristina; Stoessel, Ricarda; Shoemaker, Dorinda; Perego, Marta

    2006-01-01

    This study shows that the Bacillus anthracis pXO1 virulence plasmid carries a Rap-Phr system, BXA0205, which regulates sporulation initiation in this organism. The BXA0205Rap protein was shown to dephosphorylate the Spo0F response regulator intermediate of the phosphorelay signal transduction system that regulates the initiation of the developmental pathway in response to environmental, metabolic, and cell cycle signals. The activity of the Rap protein was shown to be inhibited by the carboxy-terminal pentapeptide generated through an export-import processing pathway from the associated BXA0205Phr protein. Deregulation of the Rap activity by either overexpression or lack of the Phr pentapeptide resulted in severe inhibition of sporulation. Five additional Rap-Phr encoding systems were identified on the chromosome of B. anthracis, one of which, BA3790-3791, also affected sporulation initiation. The results suggest that the plasmid-borne Rap-Phr system may provide a selective advantage to the virulence of B. anthracis. PMID:16385039

  10. Rap phosphatase of virulence plasmid pXO1 inhibits Bacillus anthracis sporulation.

    PubMed

    Bongiorni, Cristina; Stoessel, Ricarda; Shoemaker, Dorinda; Perego, Marta

    2006-01-01

    This study shows that the Bacillus anthracis pXO1 virulence plasmid carries a Rap-Phr system, BXA0205, which regulates sporulation initiation in this organism. The BXA0205Rap protein was shown to dephosphorylate the Spo0F response regulator intermediate of the phosphorelay signal transduction system that regulates the initiation of the developmental pathway in response to environmental, metabolic, and cell cycle signals. The activity of the Rap protein was shown to be inhibited by the carboxy-terminal pentapeptide generated through an export-import processing pathway from the associated BXA0205Phr protein. Deregulation of the Rap activity by either overexpression or lack of the Phr pentapeptide resulted in severe inhibition of sporulation. Five additional Rap-Phr encoding systems were identified on the chromosome of B. anthracis, one of which, BA3790-3791, also affected sporulation initiation. The results suggest that the plasmid-borne Rap-Phr system may provide a selective advantage to the virulence of B. anthracis.

  11. A signaling pathway contributing to platelet storage lesion development: targeting PI3-kinase–dependent Rap1 activation slows storage-induced platelet deterioration

    PubMed Central

    Schubert, Peter; Thon, Jonathan N.; Walsh, Geraldine M.; Chen, Cindy H.I.; Moore, Edwin D.; Devine, Dana V.; Kast, Juergen

    2015-01-01

    BACKGROUND The term platelet storage lesion (PSL) describes the structural and biochemical changes in platelets (PLTs) during storage. These are typified by alterations of morphologic features and PLT metabolism leading to reduced functionality and hence reduced viability for transfusion. While the manifestations of the storage lesion are well characterized, the biochemical pathways involved in the initiation of this process are unknown. STUDY DESIGN AND METHODS A complementary proteomic approach has recently been applied to analyze changes in the PLT proteome during storage. By employing stringent proteomic criteria, 12 proteins were identified as significantly and consistently changing in relative concentration over a 7-day storage period. Microscopy, Western blot analysis, flow cytometry, and PLT functionality analyses were used to unravel the involvement of a subset of these 12 proteins, which are connected through integrin signaling in one potential signaling pathway underlying storage lesion development. RESULTS Microscopic analysis revealed changes in localization of glycoprotein IIIa, Rap1, and talin during storage. Rap1 activation was observed to correlate with expression of the PLT activation marker CD62P. PLTs incubated for 7 days with the PI3-kinase inhibitor LY294002 showed diminished Rap1 activation as well as a moderate reduction in integrin αIIbβ3 activation and release of α-granules. Furthermore, this inhibitor seemed to improve PLT integrity and quality during storage as several in vitro probes showed a deceleration of PLT activation. CONCLUSION These results provide the first evidence for a signaling pathway mediating PSL in which PI3-kinase–dependent Rap1 activation leads to integrin αIIbβ3 activation and PLT degranulation. PMID:19497060

  12. Positive Use of Rap Music in the Classroom.

    ERIC Educational Resources Information Center

    Anderson, Edward

    As an extension of African-Americans' rich language and musical heritage and abilities, rap music has some value in the educational setting. Rap music started as a dance fad beginning in the mid-1970s among Blacks and Hispanics in New York's outer boroughs. It is another generational brand of Black language and musical usage and an extension of…

  13. Structural Basis of Rap Phosphatase Inhibition by Phr Peptides

    PubMed Central

    Gallego del Sol, Francisca; Marina, Alberto

    2013-01-01

    Two-component systems, composed of a sensor histidine kinase and an effector response regulator (RR), are the main signal transduction devices in bacteria. In Bacillus, the Rap protein family modulates complex signaling processes mediated by two-component systems, such as competence, sporulation, or biofilm formation, by inhibiting the RR components involved in these pathways. Despite the high degree of sequence homology, Rap proteins exert their activity by two completely different mechanisms of action: inducing RR dephosphorylation or blocking RR binding to its target promoter. However the regulatory mechanism involving Rap proteins is even more complex since Rap activity is antagonized by specific signaling peptides (Phr) through a mechanism that remains unknown at the molecular level. Using X-ray analyses, we determined the structure of RapF, the anti-activator of competence RR ComA, alone and in complex with its regulatory peptide PhrF. The structural and functional data presented herein reveal that peptide PhrF blocks the RapF-ComA interaction through an allosteric mechanism. PhrF accommodates in the C-terminal tetratricopeptide repeat domain of RapF by inducing its constriction, a conformational change propagated by a pronounced rotation to the N-terminal ComA-binding domain. This movement partially disrupts the ComA binding site by triggering the ComA disassociation, whose interaction with RapF is also sterically impaired in the PhrF-induced conformation of RapF. Sequence analyses of the Rap proteins, guided by the RapF-PhrF structure, unveil the molecular basis of Phr recognition and discrimination, allowing us to relax the Phr specificity of RapF by a single residue change. PMID:23526880

  14. Identification of a transcriptional activation domain in yeast repressor activator protein 1 (Rap1) using an altered DNA-binding specificity variant

    PubMed Central

    Johnson, Amanda N.; Weil, P. Anthony

    2017-01-01

    Repressor activator protein 1 (Rap1) performs multiple vital cellular functions in the budding yeast Saccharomyces cerevisiae. These include regulation of telomere length, transcriptional repression of both telomere-proximal genes and the silent mating type loci, and transcriptional activation of hundreds of mRNA-encoding genes, including the highly transcribed ribosomal protein- and glycolytic enzyme-encoding genes. Studies of the contributions of Rap1 to telomere length regulation and transcriptional repression have yielded significant mechanistic insights. However, the mechanism of Rap1 transcriptional activation remains poorly understood because Rap1 is encoded by a single copy essential gene and is involved in many disparate and essential cellular functions, preventing easy interpretation of attempts to directly dissect Rap1 structure-function relationships. Moreover, conflicting reports on the ability of Rap1-heterologous DNA-binding domain fusion proteins to serve as chimeric transcriptional activators challenge use of this approach to study Rap1. Described here is the development of an altered DNA-binding specificity variant of Rap1 (Rap1AS). We used Rap1AS to map and characterize a 41-amino acid activation domain (AD) within the Rap1 C terminus. We found that this AD is required for transcription of both chimeric reporter genes and authentic chromosomal Rap1 enhancer-containing target genes. Finally, as predicted for a bona fide AD, mutation of this newly identified AD reduced the efficiency of Rap1 binding to a known transcriptional coactivator TFIID-binding target, Taf5. In summary, we show here that Rap1 contains an AD required for Rap1-dependent gene transcription. The Rap1AS variant will likely also be useful for studies of the functions of Rap1 in other biological pathways. PMID:28196871

  15. The Fluids RAP

    NASA Astrophysics Data System (ADS)

    Nedyalkov, Ivaylo

    2016-11-01

    After fifteen years of experience in rap, and ten in fluid mechanics, "I am coming here with high-Reynolds-number stamina; I can beat these rap folks whose flows are... laminar." The rap relates fluid flows to rap flows. The fluid concepts presented in the song have varying complexity and the listeners/viewers will be encouraged to read the explanations on a site dedicated to the rap. The music video will provide an opportunity to share high-quality fluid visualizations with a general audience. This talk will present the rap lyrics, the vision for the video, and the strategy for outreach. Suggestions and comments will be welcomed.

  16. RAP80, ubiquitin and SUMO in the DNA damage response.

    PubMed

    Lombardi, Patrick M; Matunis, Michael J; Wolberger, Cynthia

    2017-08-01

    A decade has passed since the first reported connection between RAP80 and BRCA1 in DNA double-strand break repair. Despite the initial identification of RAP80 as a factor localizing BRCA1 to DNA double-strand breaks and potentially promoting homologous recombination, there is increasing evidence that RAP80 instead suppresses homologous recombination to fine-tune the balance of competing DNA repair processes during the S/G 2 phase of the cell cycle. RAP80 opposes homologous recombination by inhibiting DNA end-resection and sequestering BRCA1 into the BRCA1-A complex. Ubiquitin and SUMO modifications of chromatin at DNA double-strand breaks recruit RAP80, which contains distinct sequence motifs that recognize ubiquitin and SUMO. Here, we review RAP80's role in repressing homologous recombination at DNA double-strand breaks and how this role is facilitated by its ability to bind ubiquitin and SUMO modifications.

  17. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions.

    PubMed

    Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L; Chen, Siyu S; Ng, Amy; Xu, Yong; Morozov, Alexei; Fukuda, Makoto

    2016-09-13

    The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Multiple Rap1 effectors control Epac1-mediated tightening of endothelial junctions.

    PubMed

    Pannekoek, Willem-Jan; Vliem, Marjolein J; Bos, Johannes L

    2018-02-17

    Epac1 and Rap1 mediate cAMP-induced tightening of endothelial junctions. We have previously found that one of the mechanisms is the inhibition of Rho-mediated tension in radial stress fibers by recruiting the RhoGAP ArhGAP29 in a complex containing the Rap1 effectors Rasip1 and Radil. However, other mechanisms have been proposed as well, most notably the induction of tension in circumferential actin cables by Cdc42 and its GEF FGD5. Here, we have investigated how Rap1 controls FGD5/Cdc42 and how this interconnects with Radil/Rasip1/ArhGAP29. Using endothelial barrier measurements, we show that Rho inhibition is not sufficient to explain the barrier stimulating effect of Rap1. Indeed, Cdc42-mediated tension is induced at cell-cell contacts upon Rap1 activation and this is required for endothelial barrier function. Depletion of potential Rap1 effectors identifies AF6 to mediate Rap1 enhanced tension and concomitant Rho-independent barrier function. When overexpressed in HEK293T cells, AF6 is found in a complex with FGD5 and Radil. From these results we conclude that Rap1 utilizes multiple pathways to control tightening of endothelial junctions, possibly through a multiprotein effector complex, in which AF6 functions to induce tension in circumferential actin cables.

  19. Synergistic regulation of competence development in Bacillus subtilis by two Rap-Phr systems.

    PubMed

    Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

    2005-07-01

    The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity.

  20. Infant Information Processing and Family History of Specific Language Impairment: Converging Evidence for RAP Deficits from Two Paradigms

    ERIC Educational Resources Information Center

    Choudhury, Naseem; Leppanen, Paavo H. T.; Leevers, Hilary J.; Benasich, April A.

    2007-01-01

    An infant's ability to process auditory signals presented in rapid succession (i.e. rapid auditory processing abilities [RAP]) has been shown to predict differences in language outcomes in toddlers and preschool children. Early deficits in RAP abilities may serve as a behavioral marker for language-based learning disabilities. The purpose of this…

  1. Synergistic Regulation of Competence Development in Bacillus subtilis by Two Rap-Phr Systems† ‡

    PubMed Central

    Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

    2005-01-01

    The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity. PMID:15968044

  2. Cytoplasmic RAP1 mediates cisplatin resistance of non-small cell lung cancer.

    PubMed

    Xiao, Lu; Lan, Xiaoying; Shi, Xianping; Zhao, Kai; Wang, Dongrui; Wang, Xuejun; Li, Faqian; Huang, Hongbiao; Liu, Jinbao

    2017-05-18

    Cytotoxic chemotherapy agents (e.g., cisplatin) are the first-line drugs to treat non-small cell lung cancer (NSCLC) but NSCLC develops resistance to the agent, limiting therapeutic efficacy. Despite many approaches to identifying the underlying mechanism for cisplatin resistance, there remains a lack of effective targets in the population that resist cisplatin treatment. In this study, we sought to investigate the role of cytoplasmic RAP1, a previously identified positive regulator of NF-κB signaling, in the development of cisplatin resistance in NSCLC cells. We found that the expression of cytoplasmic RAP1 was significantly higher in high-grade NSCLC tissues than in low-grade NSCLC; compared with a normal pulmonary epithelial cell line, the A549 NSCLC cells exhibited more cytoplasmic RAP1 expression as well as increased NF-κB activity; cisplatin treatment resulted in a further increase of cytoplasmic RAP1 in A549 cells; overexpression of RAP1 desensitized the A549 cells to cisplatin, and conversely, RAP1 depletion in the NSCLC cells reduced their proliferation and increased their sensitivity to cisplatin, indicating that RAP1 is required for cell growth and has a key mediating role in the development of cisplatin resistance in NSCLC cells. The RAP1-mediated cisplatin resistance was associated with the activation of NF-κB signaling and the upregulation of the antiapoptosis factor BCL-2. Intriguingly, in the small portion of RAP1-depleted cells that survived cisplatin treatment, no induction of NF-κB activity and BCL-2 expression was observed. Furthermore, in established cisplatin-resistant A549 cells, RAP1 depletion caused BCL2 depletion, caspase activation and dramatic lethality to the cells. Hence, our results demonstrate that the cytoplasmic RAP1-NF-κB-BCL2 axis represents a key pathway to cisplatin resistance in NSCLC cells, identifying RAP1 as a marker and a potential therapeutic target for cisplatin resistance of NSCLC.

  3. Krit 1 interactions with microtubules and membranes are regulated by Rap1 and integrin cytoplasmic domain associated protein-1

    PubMed Central

    Béraud-Dufour, Sophie; Gautier, Romain; Albiges-Rizo, Corinne; Chardin, Pierre; Faurobert, Eva

    2007-01-01

    The small G protein Rap1 regulates diverse cellular processes such as integrin activation, cell adhesion, cell-cell junction formation and cell polarity. It is crucial to identify Rap1 effectors to better understand signalling pathways controlling these processes. Krit1, a FERM protein, was identified as a Rap1 partner in a yeast two-hydrid screen, but this interaction was not confirmed in subsequent studies. As evidence suggests a role for Krit1 in Rap1-dependent pathways, we readdressed this question. Here, we demonstrate by biochemical assays that Krit1 is a specific Rap1 effector. We show that, like other FERM proteins, Krit1 adopts two conformations: a closed conformation in which its N-terminal NPAY motif interacts with its C-terminus and an opened conformation bound to ICAP-1, a negative regulator of focal adhesion assembly. We show that a ternary complex can form in vitro between Krit1, Rap1 and ICAP-1 and that Rap1 binds Krit1 FERM domain in both closed and opened conformations. Unlike ICAP-1, Rap1 does not open Krit1. Using sedimentation assays, we show that Krit1 binds in vitro to microtubules through its N and C-termini and that Rap1 and ICAP-1 inhibit Krit1 binding to microtubules. Consistently, YFP-Krit1 localizes on CFP-labelled microtubules in BHK cells and is delocalized from microtubules upon co-expression with activated Rap1V12. Finally, we show that Krit1 binds to PIP2 containing liposomes and that Rap1 enhances this binding. Based on these results, we propose a model in which Krit1 would be delivered by microtubules to the plasma membrane where it would be captured by Rap1 and ICAP-1. PMID:17916086

  4. Infant information processing and family history of specific language impairment: converging evidence for RAP deficits from two paradigms

    PubMed Central

    Choudhury, Naseem; Leppanen, Paavo H.T.; Leevers, Hilary J.; Benasich, April A.

    2007-01-01

    An infant’s ability to process auditory signals presented in rapid succession (i.e. rapid auditory processing abilities [RAP]) has been shown to predict differences in language outcomes in toddlers and preschool children. Early deficits in RAP abilities may serve as a behavioral marker for language-based learning disabilities. The purpose of this study is to determine if performance on infant information processing measures designed to tap RAP and global processing skills differ as a function of family history of specific language impairment (SLI) and/or the particular demand characteristics of the paradigm used. Seventeen 6- to 9-month-old infants from families with a history of specific language impairment (FH+) and 29 control infants (FH−) participated in this study. Infants’ performance on two different RAP paradigms (head-turn procedure [HT] and auditory-visual habituation/recognition memory [AVH/RM]) and on a global processing task (visual habituation/recognition memory [VH/RM]) was assessed at 6 and 9 months. Toddler language and cognitive skills were evaluated at 12 and 16 months. A number of significant group differences were seen: FH+ infants showed significantly poorer discrimination of fast rate stimuli on both RAP tasks, took longer to habituate on both habituation/recognition memory measures, and had lower novelty preference scores on the visual habituation/recognition memory task. Infants’ performance on the two RAP measures provided independent but converging contributions to outcome. Thus, different mechanisms appear to underlie performance on operantly conditioned tasks as compared to habituation/recognition memory paradigms. Further, infant RAP processing abilities predicted to 12- and 16-month language scores above and beyond family history of SLI. The results of this study provide additional support for the validity of infant RAP abilities as a behavioral marker for later language outcome. Finally, this is the first study to use a

  5. RAP "Rapid Refresh" Products

    Science.gov Websites

    HOME PAGE Image of NCEP Logo WHERE AMERICA'S CLIMATE AND WEATHER SERVICES BEGIN NCEP Products Inventory Image of horizontal rule Rapid Refresh (RAP) Products Updated: 11/28/2016 * Information about the rap.tccz.awp243fxx.grib2 Not Available RAP - BUFR Sounding products Model Runs every hour (00z-23z) Filename Inventory

  6. RAP workshop : Buda-TxAPA, Texas, August 27, 2009.

    DOT National Transportation Integrated Search

    2009-08-27

    Presentation Outline : RAP overview : RAP stockpile survey: state of practice : RAP processing and RAP variability : RAP characterization : RAP mix design : Field performance of Texas high RAP test sections

  7. Decoding telomere protein Rap1: Its telomeric and nontelomeric functions and potential implications in diabetic cardiomyopathy.

    PubMed

    Cai, Yin; Kandula, Vidya; Kosuru, Ramoji; Ye, Xiaodong; Irwin, Michael G; Xia, Zhengyuan

    2017-10-02

    Mammalian Rap1, the most conserved telomere-interacting protein, beyond its role within nucleus for the maintenance of telomeric functions, is also well known for its pleiotropic functions in various physiological and pathological conditions associated with metabolism, inflammation and oxidative stress. For all these, nowadays Rap1 is the subject of critical investigations aimed to unveil its molecular signaling pathways and to scrutinize the applicability of its modulation as a promising therapeutic strategy with clinical relevance. However, the underlying intimate mechanisms of Rap1 are not extensively studied, but any modulation of this protein level has been associated with pathologies like inflammation, oxidative stress and deregulated metabolism. This is considerably important in light of the recent discovery of Rap1 modulation in diseases like cancer and cardiac metabolic disorders. In this review, we focus on both the telomeric and nontelomeric functions of Rap1 and its modulation in various health risks, especially on the heart.

  8. Neuronal Rap1 regulates energy balance, glucose homeostasis, and leptin actions

    USDA-ARS?s Scientific Manuscript database

    The Central Nervous System (CNS) contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in...

  9. The Ras-related Protein, Rap1A, Mediates Thrombin-stimulated, Integrin-dependent Glioblastoma Cell Proliferation and Tumor Growth*

    PubMed Central

    Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha; Quilliam, Lawrence A.; Stupack, Dwayne G.; Brown, Joan Heller

    2014-01-01

    Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a β1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with β1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/β1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo. PMID:24790104

  10. Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor.

    PubMed

    Freeman, Spencer A; Christian, Sonja; Austin, Pamela; Iu, Irene; Graves, Marcia L; Huang, Lin; Tang, Shuo; Coombs, Daniel; Gold, Michael R; Roskelley, Calvin D

    2017-01-01

    Although it is known that a stiffening of the stroma and the rearrangement of collagen fibers within the extracellular matrix facilitate the movement of tumor cells away from the primary lesion, the underlying mechanisms responsible are not fully understood. We now show that this invasion, which can be initiated by applying tensional loads to a three-dimensional collagen gel matrix in culture, is dependent on the Rap1 GTPases (Rap1a and Rap1b, referred to collectively as Rap1). Under these conditions Rap1 activity stimulates the formation of focal adhesion structures that align with the tensional axis as single tumor cells move into the matrix. These effects are mediated by the ability of Rap1 to induce the polarized polymerization and retrograde flow of actin, which stabilizes integrins and recruits vinculin to preformed adhesions, particularly those near the leading edge of invasive cells. Rap1 activity also contributes to the tension-induced collective invasive elongation of tumor cell clusters and it enhances tumor cell growth in vivo Thus, Rap1 mediates the effects of increased extracellular tension in multiple ways that are capable of contributing to tumor progression when dysregulated. © 2017. Published by The Company of Biologists Ltd.

  11. A novel approach to prevent endothelial hyperpermeability: the Crataegus extract WS® 1442 targets the cAMP/Rap1 pathway.

    PubMed

    Bubik, Martin F; Willer, Elisabeth A; Bihari, Peter; Jürgenliemk, Guido; Ammer, Hermann; Krombach, Fritz; Zahler, Stefan; Vollmar, Angelika M; Fürst, Robert

    2012-01-01

    Endothelial hyperpermeability followed by edema formation is a hallmark of many severe disorders. Effective drugs directly targeting endothelial barrier function are widely lacking. We hypothesized that the hawthorn (Crataegus spp.) extract WS® 1442, a proven multi-component drug against moderate forms of heart failure, would prevent vascular leakage by affecting endothelial barrier-regulating systems. In vivo, WS® 1442 inhibited the histamine-evoked extravasation of FITC-dextran from mouse cremaster muscle venules. In cultured human endothelial cells, WS® 1442 blocked the thrombin-induced FITC-dextran permeability. By applying biochemical and microscopic techniques, we revealed that WS® 1442 abrogates detrimental effects of thrombin on adherens junctions (vascular endothelial-cadherin), the F-actin cytoskeleton, and the contractile apparatus (myosin light chain). Mechanistically, WS® 1442 inhibited the thrombin-induced rise of intracellular calcium (ratiometric measurement), followed by an inactivation of PKC and RhoA (pulldown assay). Moreover, WS® 1442 increased endothelial cAMP levels (ELISA), which consequently activated PKA and Rap1 (pulldown assay). Utilizing pharmacological inhibitors or siRNA, we found that PKA is not involved in barrier protection, whereas Epac1, Rap1, and Rac1 play a crucial role in the WS® 1442-induced activation of cortactin, which triggers a strong cortical actin rearrangement. In summary, WS® 1442 effectively protects against endothelial barrier dysfunction in vitro and in vivo. It specifically interacts with endothelial permeability-regulating systems by blocking the Ca(2+)/PKC/RhoA and activating the cAMP/Epac1/Rap1 pathway. As a proven safe herbal drug, WS® 1442 opens a novel pharmacological approach to treat hyperpermeability-associated diseases. This in-depth mechanistic work contributes to a better acceptance of this herbal remedy. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Site-specific bioalkylation of rapamycin by the RapM 16-O-methyltransferase.

    PubMed

    Law, Brian J C; Struck, Anna-Winona; Bennett, Matthew R; Wilkinson, Barrie; Micklefield, Jason

    2015-05-01

    The methylation of natural products by S -adenosyl methionine (AdoMet, also known as SAM)-dependent methyltransferase enzymes is a common tailoring step in many biosynthetic pathways. The introduction of methyl substituents can affect the biological and physicochemical properties of the secondary metabolites produced. Recently it has become apparent that some AdoMet-dependent methyltransferases exhibit promiscuity and will accept AdoMet analogues enabling the transfer of alternative alkyl groups. In this study we have characterised a methyltransferase, RapM, which is involved in the biosynthesis of the potent immunosuppressive agent rapamycin. We have shown that recombinant RapM regioselectively methylates the C16 hydroxyl group of desmethyl rapamycin precursors in vitro and is promiscuous in accepting alternative co-factors in addition to AdoMet. A coupled enzyme system was developed, including a mutant human enzyme methionine adenosyl transferase (MAT), along with RapM, which was used to prepare alkylated rapamycin derivatives (rapalogs) with alternative ethyl and allyl ether groups, derived from simple S -ethyl or S -allyl methionine analogues. There are two other methyltransferases RapI and RapQ which provide methyl substituents of rapamycin. Consequently, using the enzymatic approach described here, it should be possible to generate a diverse array of alkylated rapalogs, with altered properties, that would be difficult to obtain by traditional synthetic approaches.

  13. A Health Newsletter To Teach Science Knowledge: BioRAP!

    ERIC Educational Resources Information Center

    Froman, Robin D.; Owen, Steven V.; Del Rio-Parent, Lourdes

    This research describes the evaluation of a science curriculum newsletter called BioRAP which serves as a vehicle to teach current health science content. The research objectives were to estimate the relationships of socioeconomic status, ethnic group, gender, grade, student ability, and classroom use characteristics with student knowledge and…

  14. Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes

    PubMed Central

    Chymkowitch, Pierre; Nguéa P, Aurélie; Aanes, Håvard; Koehler, Christian J.; Thiede, Bernd; Lorenz, Susanne; Meza-Zepeda, Leonardo A.; Klungland, Arne; Enserink, Jorrit M.

    2015-01-01

    Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Genome-wide expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs. PMID:25800674

  15. Rap1, Canoe and Mbt cooperate with Bazooka to promote zonula adherens assembly in the fly photoreceptor

    PubMed Central

    Burki, Mubarik

    2018-01-01

    ABSTRACT In Drosophila epithelial cells, apical exclusion of Bazooka (the Drosophila Par3 protein) defines the position of the zonula adherens (ZA), which demarcates the apical and lateral membrane and allows cells to assemble into sheets. Here, we show that the small GTPase Rap1, its effector Canoe (Cno) and the Cdc42 effector kinase Mushroom bodies tiny (Mbt), converge in regulating epithelial morphogenesis by coupling stabilization of the adherens junction (AJ) protein E-Cadherin and Bazooka retention at the ZA. Furthermore, our results show that the localization of Rap1, Cno and Mbt at the ZA is interdependent, indicating that their functions during ZA morphogenesis are interlinked. In this context, we find the Rap1-GEF Dizzy is enriched at the ZA and our results suggest that it promotes Rap1 activity during ZA morphogenesis. Altogether, we propose the Dizzy, Rap1 and Cno pathway and Mbt converge in regulating the interface between Bazooka and AJ material to promote ZA morphogenesis. PMID:29507112

  16. "Everybody Gotta Have a Dream": Rap-centered Aspirations among Young Black Males Involved in Rap Music Production - A Qualitative Study.

    PubMed

    Foster, B Brian

    Youth express diverse desires for their educational and occupational futures. Sometimes these aspirations are directed towards somewhat unconventional careers such as rapping and other types of involvement in rap music production. Although many studies have examined traditional educational and occupational aspirations, less is known about the factors that give rise to rap-centered aspirations and how individuals pursue them, particularly as they transition to early adulthood. Drawing on 54 semi- and unstructured interviews with 29 black young men involved in rap music production, I find that rap-centered aspirations are shaped by a range of factors, most notably feedback regarding one's rap skills, access to recording and production equipment, and the financial means to maintain involvement in rap music production while also ensuring personal and family economic stability. The young men in the study attached different meanings to their aspirations and sometimes recast their motivations for participating in rap music production in response to various social and economic factors.

  17. The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth.

    PubMed

    Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha; Quilliam, Lawrence A; Stupack, Dwayne G; Brown, Joan Heller

    2014-06-20

    Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a β1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with β1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/β1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. The transcription factor Rap1p is required for tolerance to cell-wall perturbing agents and for cell-wall maintenance in Saccharomyces cerevisiae.

    PubMed

    Azad, Gajendra Kumar; Singh, Vikash; Baranwal, Shivani; Thakare, Mayur Jankiram; Tomar, Raghuvir S

    2015-01-02

    Yeast repressor activator protein (Rap1p) is involved in genomic stability and transcriptional regulation. We explored the function of Rap1p in yeast physiology using Rap1p truncation mutants. Our results revealed that the N-terminal truncation of Rap1p (Rap1ΔN) leads to hypersensitivity towards elevated temperature and cell-wall perturbing agents. Cell wall analysis showed an increase in the chitin and glucan content in Rap1ΔN cells as compared with wild type cells. Accordingly, mutant cells had a twofold thicker cell wall, as observed by electron microscopy. Furthermore, Rap1ΔN cells had increased levels of phosphorylated Slt2p, a MAP kinase of the cell wall integrity pathway. Mutant cells also had elevated levels of cell wall integrity response transcripts. Taken together, our findings suggest a connection between Rap1p and cell wall homeostasis. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  19. An Atypical Phr Peptide Regulates the Developmental Switch Protein RapH ▿ †

    PubMed Central

    Mirouze, Nicolas; Parashar, Vijay; Baker, Melinda D.; Dubnau, David A.; Neiditch, Matthew B.

    2011-01-01

    Under conditions of nutrient limitation and high population density, the bacterium Bacillus subtilis can initiate a variety of developmental pathways. The signaling systems regulating B. subtilis differentiation are tightly controlled by switch proteins called Raps, named after the founding members of the family, which were shown to be response regulator aspartate phosphatases. A phr gene encoding a secreted pentapeptide that regulates the activity of its associated Rap protein was previously identified downstream of 8 of the chromosomally encoded rap genes. We identify and validate here the sequence of an atypical Phr peptide, PhrH, by in vivo and in vitro analyses. Using a luciferase reporter bioassay combined with in vitro experiments, we found that PhrH is a hexapeptide (TDRNTT), in contrast to the other characterized Phr pentapeptides. We also determined that phrH expression is driven by a promoter lying within rapH. Unlike the previously identified dedicated σH-driven phr promoters, it appears that phrH expression most likely requires σA. Furthermore, we show that PhrH can antagonize both of the known activities of RapH: the dephosphorylation of Spo0F and the sequestration of ComA, thus promoting the development of spores and the competent state. Finally, we propose that PhrH is the prototype of a newly identified class of Phr signaling molecules consisting of six amino acids. This class likely includes PhrI, which regulates RapI and the expression, excision, and transfer of the mobile genetic element ICEBs1. PMID:21908671

  20. Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes.

    PubMed

    Chymkowitch, Pierre; Nguéa, Aurélie P; Aanes, Håvard; Koehler, Christian J; Thiede, Bernd; Lorenz, Susanne; Meza-Zepeda, Leonardo A; Klungland, Arne; Enserink, Jorrit M

    2015-06-01

    Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Genome-wide expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs. © 2015 Chymkowitch et al.; Published by Cold Spring Harbor Laboratory Press.

  1. Rap-Music Attitude and Perception Scale: A Validation Study

    ERIC Educational Resources Information Center

    Tyson, Edgar H.

    2006-01-01

    Objective: This study tests the validity of the Rap-music Attitude and Perception (RAP) Scale, a 1-page, 24-item measure of a person's thoughts and feelings surrounding the effects and content of rap music. The RAP was designed as a rapid assessment instrument for youth programs and practitioners using rap music and hip hop culture in their work…

  2. Preventing the activation or cycling of the Rap1 GTPase alters adhesion and cytoskeletal dynamics and blocks metastatic melanoma cell extravasation into the lungs.

    PubMed

    Freeman, Spencer A; McLeod, Sarah J; Dukowski, Janet; Austin, Pamela; Lee, Crystal C Y; Millen-Martin, Brandie; Kubes, Paul; McCafferty, Donna-Marie; Gold, Michael R; Roskelley, Calvin D

    2010-06-01

    The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. This correlated with a decreased ability of the tumor cells to undergo transendothelial migration (TEM) in vitro and form dynamic, F-actin-rich pseudopodia that penetrate capillary endothelial walls in vivo. Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM. Copyright 2010 AACR.

  3. Structural Basis of Response Regulator Dephosphorylation by Rap Phosphatases

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    V Parashar; N Mirouze; D Dubnau

    2011-12-31

    Bacterial Rap family proteins have been most extensively studied in Bacillus subtilis, where they regulate activities including sporulation, genetic competence, antibiotic expression, and the movement of the ICEBs1 transposon. One subset of Rap proteins consists of phosphatases that control B. subtilis and B. anthracis sporulation by dephosphorylating the response regulator Spo0F. The mechanistic basis of Rap phosphatase activity was unknown. Here we present the RapH-Spo0F X-ray crystal structure, which shows that Rap proteins consist of a 3-helix bundle and a tetratricopeptide repeat domain. Extensive biochemical and genetic functional studies reveal the importance of the observed RapH-Spo0F interactions, including the catalyticmore » role of a glutamine in the RapH 3-helix bundle that inserts into the Spo0F active site. We show that in addition to dephosphorylating Spo0F, RapH can antagonize sporulation by sterically blocking phosphoryl transfer to and from Spo0F. Our structure-function analysis of the RapH-Spo0F interaction identified Rap protein residues critical for Spo0F phosphatase activity. This information enabled us to assign Spo0F phosphatase activity to a Rap protein based on sequence alone, which was not previously possible. Finally, as the ultimate test of our newfound understanding of the structural requirements for Rap phosphatase function, a non-phosphatase Rap protein that inhibits the binding of the response regulator ComA to DNA was rationally engineered to dephosphorylate Spo0F. In addition to revealing the mechanistic basis of response regulator dephosphorylation by Rap proteins, our studies support the previously proposed T-loop-Y allostery model of receiver domain regulation that restricts the aromatic 'switch' residue to an internal position when the {beta}4-{alpha}4 loop adopts an active-site proximal conformation.« less

  4. “Everybody Gotta Have a Dream”: Rap-centered Aspirations among Young Black Males Involved in Rap Music Production – A Qualitative Study

    PubMed Central

    Foster, B. Brian

    2015-01-01

    Youth express diverse desires for their educational and occupational futures. Sometimes these aspirations are directed towards somewhat unconventional careers such as rapping and other types of involvement in rap music production. Although many studies have examined traditional educational and occupational aspirations, less is known about the factors that give rise to rap-centered aspirations and how individuals pursue them, particularly as they transition to early adulthood. Drawing on 54 semi- and unstructured interviews with 29 black young men involved in rap music production, I find that rap-centered aspirations are shaped by a range of factors, most notably feedback regarding one’s rap skills, access to recording and production equipment, and the financial means to maintain involvement in rap music production while also ensuring personal and family economic stability. The young men in the study attached different meanings to their aspirations and sometimes recast their motivations for participating in rap music production in response to various social and economic factors. PMID:26005703

  5. Properties of asphalt mixtures containing RAP.

    DOT National Transportation Integrated Search

    2009-12-01

    A typical NHDOT Hot Mix Asphalt (HMA) concrete mixture contains at least 15% Reclaimed Asphalt Pavement (RAP). The increasing cost of virgin asphalt and aggregate has increased the interest in using higher percentages of RAP in HMA mixtures. The purp...

  6. Rap Music Genres and Deviant Behaviors in French-Canadian Adolescents

    ERIC Educational Resources Information Center

    Miranda, Dave; Claes, Michel

    2004-01-01

    This study investigated the links between the preference for 4 rap music genres (American rap, French rap, hip hop/soul, and gangsta/hardcore rap) and 5 types of deviant behaviors in adolescence (violence, theft, street gangs, mild drug use, and hard drug use). The effects of peers' deviancy, violent media, and importance given to lyrics were…

  7. RAP/RAS workshop.

    DOT National Transportation Integrated Search

    2013-01-01

    : RAP & RAS increases mix stiffness : : Most WMA additives decrease stiffness : : Tear-Off shingles are stiffer than Man-waste shingles : : Using multiple recycled bins improves consistency : : Finer RAS material improves consiste...

  8. The Rap GTPase Activator Drosophila PDZ-GEF Regulates Cell Shape in Epithelial Migration and Morphogenesis▿

    PubMed Central

    Boettner, Benjamin; Van Aelst, Linda

    2007-01-01

    Epithelial morphogenesis is characterized by an exquisite control of cell shape and position. Progression through dorsal closure in Drosophila gastrulation depends on the ability of Rap1 GTPase to signal through the adherens junctional multidomain protein Canoe. Here, we provide genetic evidence that epithelial Rap activation and Canoe effector usage are conferred by the Drosophila PDZ-GEF (dPDZ-GEF) exchange factor. We demonstrate that dPDZ-GEF/Rap/Canoe signaling modulates cell shape and apicolateral cell constriction in embryonic and wing disc epithelia. In dPDZ-GEF mutant embryos with strong dorsal closure defects, cells in the lateral ectoderm fail to properly elongate. Postembryonic dPDZ-GEF mutant cells generated in mosaic tissue display a striking extension of lateral cell perimeters in the proximity of junctional complexes, suggesting a loss of normal cell contractility. Furthermore, our data indicate that dPDZ-GEF signaling is linked to myosin II function. Both dPDZ-GEF and cno show strong genetic interactions with the myosin II-encoding gene, and myosin II distribution is severely perturbed in epithelia of both mutants. These findings provide the first insight into the molecular machinery targeted by Rap signaling to modulate epithelial plasticity. We propose that dPDZ-GEF-dependent signaling functions as a rheostat linking Rap activity to the regulation of cell shape in epithelial morphogenesis at different developmental stages. PMID:17846121

  9. Differential Processing of Propeptide Inhibitors of Rap Phosphatases in Bacillus subtilis†

    PubMed Central

    Jiang, Min; Grau, Roberto; Perego, Marta

    2000-01-01

    In the phosphorelay signal transduction system for sporulation initiation in Bacillus subtilis, the opposing activities of histidine kinases and aspartyl phosphate phosphatases determine the cell's decision whether to continue with vegetative growth or to initiate the differentiation process. Regulated dephosphorylation of the Spo0A and Spo0F response regulators allows a variety of negative signals from physiological processes that are antithetical to sporulation to impact on the activation level of the phosphorelay. Spo0F∼P is the known target of two related phosphatases, RapA and RapB. In addition to RapA and RapB, a third member of the Rap family of phosphatases, RapE, specifically dephosphorylated the Spo0F∼P intermediate in response to competence development. RapE phosphatase activity was found to be controlled by a pentapeptide (SRNVT) generated from within the carboxy-terminal domain of the phrE gene product. A synthetic PhrE pentapeptide could (i) complement the sporulation deficiency caused by deregulated RapE activity of a phrE mutant and (ii) inhibit RapE-dependent dephosphorylation of Spo0F∼P in in vitro experiments. The PhrE pentapeptide did not inhibit the phosphatase activity of RapA and RapB. These results confirm previous conclusions that the specificity for recognition of the target phosphatase is contained within the amino acid sequence of the pentapeptide inhibitor. PMID:10629174

  10. The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

    PubMed Central

    He, Yuan; Kapoor, Ashish; Cook, Sara; Liu, Shubai; Xiang, Yang; Rao, Christopher V.; Kenis, Paul J. A.; Wang, Fei

    2011-01-01

    Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell–extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon Gi-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL–C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells. PMID:21628423

  11. Rap1 and Canoe/afadin are essential for establishment of apical–basal polarity in the Drosophila embryo

    PubMed Central

    Choi, Wangsun; Harris, Nathan J.; Sumigray, Kaelyn D.; Peifer, Mark

    2013-01-01

    The establishment and maintenance of apical–basal cell polarity is critical for assembling epithelia and maintaining organ architecture. Drosophila embryos provide a superb model. In the current view, apically positioned Bazooka/Par3 is the initial polarity cue as cells form during cellularization. Bazooka then helps to position both adherens junctions and atypical protein kinase C (aPKC). Although a polarized cytoskeleton is critical for Bazooka positioning, proteins mediating this remained unknown. We found that the small GTPase Rap1 and the actin-junctional linker Canoe/afadin are essential for polarity establishment, as both adherens junctions and Bazooka are mispositioned in their absence. Rap1 and Canoe do not simply organize the cytoskeleton, as actin and microtubules become properly polarized in their absence. Canoe can recruit Bazooka when ectopically expressed, but they do not obligatorily colocalize. Rap1 and Canoe play continuing roles in Bazooka localization during gastrulation, but other polarity cues partially restore apical Bazooka in the absence of Rap1 or Canoe. We next tested the current linear model for polarity establishment. Both Bazooka and aPKC regulate Canoe localization despite being “downstream” of Canoe. Further, Rap1, Bazooka, and aPKC, but not Canoe, regulate columnar cell shape. These data reshape our view, suggesting that polarity establishment is regulated by a protein network rather than a linear pathway. PMID:23363604

  12. Unwrapping Rap: A Literacy of Lived Experience.

    ERIC Educational Resources Information Center

    Brown, Stephen G.

    The adversarial forces of governmental censorship, freedom of expression, and capitalistic appropriation are engaged in an acrimonious debate over "Gangsta' Rap" that is being played out in the public spaces of popular culture. However, as a literacy of lived experience, Gangsta' Rap warrants critical investigation. Many postmodern…

  13. Cytotoxic-T-lymphocyte antigen 4 receptor signaling for lymphocyte adhesion is mediated by C3G and Rap1.

    PubMed

    Kloog, Yoel; Mor, Adam

    2014-03-01

    T-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders.

  14. Cytotoxic-T-Lymphocyte Antigen 4 Receptor Signaling for Lymphocyte Adhesion Is Mediated by C3G and Rap1

    PubMed Central

    Kloog, Yoel

    2014-01-01

    T-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders. PMID:24396067

  15. Bacillus subtilis RapA phosphatase domain interaction with its substrate, phosphorylated Spo0F, and its inhibitor, the PhrA peptide.

    PubMed

    Diaz, Alejandra R; Core, Leighton J; Jiang, Min; Morelli, Michela; Chiang, Christina H; Szurmant, Hendrik; Perego, Marta

    2012-03-01

    Rap proteins in Bacillus subtilis regulate the phosphorylation level or the DNA-binding activity of response regulators such as Spo0F, involved in sporulation initiation, or ComA, regulating competence development. Rap proteins can be inhibited by specific peptides generated by the export-import processing pathway of the Phr proteins. Rap proteins have a modular organization comprising an amino-terminal alpha-helical domain connected to a domain formed by six tetratricopeptide repeats (TPR). In this study, the molecular basis for the specificity of the RapA phosphatase for its substrate, phosphorylated Spo0F (Spo0F∼P), and its inhibitor pentapeptide, PhrA, was analyzed in part by generating chimeric proteins with RapC, which targets the DNA-binding domain of ComA, rather than Spo0F∼P, and is inhibited by the PhrC pentapeptide. In vivo analysis of sporulation efficiency or competence-induced gene expression, as well as in vitro biochemical assays, allowed the identification of the amino-terminal 60 amino acids as sufficient to determine Rap specificity for its substrate and the central TPR3 to TPR5 (TPR3-5) repeats as providing binding specificity toward the Phr peptide inhibitor. The results allowed the prediction and testing of key residues in RapA that are essential for PhrA binding and specificity, thus demonstrating how the widespread structural fold of the TPR is highly versatile, using a common interaction mechanism for a variety of functions in eukaryotic and prokaryotic organisms.

  16. SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

    PubMed Central

    Côte, Marjorie; Fos, Camille; Canonigo-Balancio, Ann J.; Ley, Klaus; Bécart, Stéphane; Altman, Amnon

    2015-01-01

    ABSTRACT SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca2+ signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and affinity maturation of LFA-1 in CD4+ T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4+ T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT-deficient (Def6−/−) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling. PMID:26483383

  17. SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1.

    PubMed

    Côte, Marjorie; Fos, Camille; Canonigo-Balancio, Ann J; Ley, Klaus; Bécart, Stéphane; Altman, Amnon

    2015-12-01

    SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca(2+) signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and affinity maturation of LFA-1 in CD4(+) T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT-deficient (Def6(-/-)) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling. © 2015. Published by The Company of Biologists Ltd.

  18. HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion.

    PubMed

    Patzak, Irene M; Königsberger, Sebastian; Suzuki, Akira; Mak, Tak W; Kiefer, Friedemann

    2010-11-01

    The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.

  19. Required Academic Proficiency (RAP) Program: Final Report.

    ERIC Educational Resources Information Center

    Ronacher, Karl; And Others

    The Required Academic Proficiency (RAP) program was established by the Houston (Texas) Independent School District to reduce and remediate the academic failure of students. The purpose of the RAP program was twofold: (1) to provide supplemental instruction to students identified as being at risk of failing academic subjects; and (2) to provide…

  20. YBX1 is a modulator of MIA/CD-RAP-dependent chondrogenesis.

    PubMed

    Schmid, Rainer; Meyer, Katharina; Spang, Rainer; Schittek, Birgit; Bosserhoff, Anja Katrin

    2013-01-01

    MIA/CD-RAP is a small, secreted protein involved in cartilage differentiation and melanoma progression. We recently revealed that p54(nrb) acts as a mediator of MIA/CD-RAP action to promote chondrogenesis and the progression of malignant melanoma. As the molecular mechanism of MIA/CD-RAP action in cartilage has not been defined in detail until now, we aimed to understand the regulation of p54(nrb) transcription in chondrogenesis. We concentrated on the previously described MIA/CD-RAP-dependent regulatory region in the p54(nrb) promoter and characterized the transcriptional regulation of p54(nrb) by MIA/CD-RAP in cartilage. A series of truncated p54(nrb) promoter constructs and mutagenesis analysis revealed that the transcription factor YBX1, which has not been investigated in chondrogenesis thus far, is the mediator of MIA/CD-RAP dependent activation of p54(nrb) transcription. A systematic analysis of genes carrying this binding site in their promoter region revealed further potential MIA/CD-RAP-regulated genes that have been implicated in cartilage differentiation. In summary, we described the effects of MIA/CD-RAP on transcriptional regulation in chondrocytes. Understanding the regulation of p54(nrb) via YBX1 contributes to the understanding of chondrogenesis. Uncovering new downstream effectors that function via the activation of YBX1 supports the important role of MIA/CD-RAP in these processes.

  1. 40 CFR 270.135 - What must the Director include in a draft RAP?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... draft RAP? 270.135 Section 270.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Action Plans (RAPs) Getting A Rap Approved § 270.135 What must the Director include in a draft RAP? If the Director prepares a draft RAP, it must include the: (a) Information required under § 270.110(a...

  2. 40 CFR 270.135 - What must the Director include in a draft RAP?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... draft RAP? 270.135 Section 270.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Action Plans (RAPs) Getting A Rap Approved § 270.135 What must the Director include in a draft RAP? If the Director prepares a draft RAP, it must include the: (a) Information required under § 270.110(a...

  3. 40 CFR 270.135 - What must the Director include in a draft RAP?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... draft RAP? 270.135 Section 270.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Action Plans (RAPs) Getting A Rap Approved § 270.135 What must the Director include in a draft RAP? If the Director prepares a draft RAP, it must include the: (a) Information required under § 270.110(a...

  4. 40 CFR 270.135 - What must the Director include in a draft RAP?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... draft RAP? 270.135 Section 270.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Action Plans (RAPs) Getting A Rap Approved § 270.135 What must the Director include in a draft RAP? If the Director prepares a draft RAP, it must include the: (a) Information required under § 270.110(a...

  5. 40 CFR 270.135 - What must the Director include in a draft RAP?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... draft RAP? 270.135 Section 270.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Action Plans (RAPs) Getting A Rap Approved § 270.135 What must the Director include in a draft RAP? If the Director prepares a draft RAP, it must include the: (a) Information required under § 270.110(a...

  6. Apical accumulation of the Sevenless receptor tyrosine kinase during Drosophila eye development is promoted by the small GTPase Rap1.

    PubMed

    Baril, Caroline; Lefrançois, Martin; Sahmi, Malha; Knævelsrud, Helene; Therrien, Marc

    2014-08-01

    The Ras/MAPK-signaling pathway plays pivotal roles during development of metazoans by controlling cell proliferation and cell differentiation elicited, in several instances, by receptor tyrosine kinases (RTKs). While the internal mechanism of RTK-driven Ras/MAPK signaling is well understood, far less is known regarding its interplay with other co-required signaling events involved in developmental decisions. In a genetic screen designed to identify new regulators of RTK/Ras/MAPK signaling during Drosophila eye development, we identified the small GTPase Rap1, PDZ-GEF, and Canoe as components contributing to Ras/MAPK-mediated R7 cell differentiation. Rap1 signaling has recently been found to participate in assembling cadherin-based adherens junctions in various fly epithelial tissues. Here, we show that Rap1 activity is required for the integrity of the apical domains of developing photoreceptor cells and that reduced Rap1 signaling hampers the apical accumulation of the Sevenless RTK in presumptive R7 cells. It thus appears that, in addition to its role in cell-cell adhesion, Rap1 signaling controls the partitioning of the epithelial cell membrane, which in turn influences signaling events that rely on apico-basal cell polarity. Copyright © 2014 by the Genetics Society of America.

  7. Mutations in CDK5RAP2 cause Seckel syndrome.

    PubMed

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-09-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

  8. Mutations in CDK5RAP2 cause Seckel syndrome

    PubMed Central

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-01-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152. PMID:26436113

  9. Bacillus subtilis RapA Phosphatase Domain Interaction with Its Substrate, Phosphorylated Spo0F, and Its Inhibitor, the PhrA Peptide

    PubMed Central

    Diaz, Alejandra R.; Core, Leighton J.; Jiang, Min; Morelli, Michela; Chiang, Christina H.; Szurmant, Hendrik

    2012-01-01

    Rap proteins in Bacillus subtilis regulate the phosphorylation level or the DNA-binding activity of response regulators such as Spo0F, involved in sporulation initiation, or ComA, regulating competence development. Rap proteins can be inhibited by specific peptides generated by the export-import processing pathway of the Phr proteins. Rap proteins have a modular organization comprising an amino-terminal alpha-helical domain connected to a domain formed by six tetratricopeptide repeats (TPR). In this study, the molecular basis for the specificity of the RapA phosphatase for its substrate, phosphorylated Spo0F (Spo0F∼P), and its inhibitor pentapeptide, PhrA, was analyzed in part by generating chimeric proteins with RapC, which targets the DNA-binding domain of ComA, rather than Spo0F∼P, and is inhibited by the PhrC pentapeptide. In vivo analysis of sporulation efficiency or competence-induced gene expression, as well as in vitro biochemical assays, allowed the identification of the amino-terminal 60 amino acids as sufficient to determine Rap specificity for its substrate and the central TPR3 to TPR5 (TPR3-5) repeats as providing binding specificity toward the Phr peptide inhibitor. The results allowed the prediction and testing of key residues in RapA that are essential for PhrA binding and specificity, thus demonstrating how the widespread structural fold of the TPR is highly versatile, using a common interaction mechanism for a variety of functions in eukaryotic and prokaryotic organisms. PMID:22267516

  10. The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.

    PubMed

    Myhr, Courtney B; Hulme, Maigan A; Wasserfall, Clive H; Hong, Peter J; Lakshmi, Priya Saikumar; Schatz, Desmond A; Haller, Michael J; Brusko, Todd M; Atkinson, Mark A

    2013-08-01

    Type 1 Diabetes (T1D) is an autoimmune disorder characterized by aberrant T cell responses. Innate immune activation defects may facilitate a T helper 1 (Th1) phenotype. The cytokine IL-18 synergizes with IL-12 to induce IFNγ production and Th1 differentiation. The IL-18R subunit (IL18RAP) SNP rs917997 has been linked to decreased IL18RAP gene expression. Prior reports link rs917997 allele A with protection from T1D, and conversely with susceptibility to Celiac disease. However, few studies have investigated the IL-18 pathway in T1D. In this study, we analyzed responsiveness to IL-18 in T1D, and the effect of rs917997 genotype on IL18RAP gene expression post-activation. Upon IL-12 and IL-18 treatment, peripheral blood mononuclear cells from subjects carrying susceptibility alleles at rs917997 produced higher levels of IFNγ than those with protective genotypes. Additionally, the SNP modified IL18RAP surface protein expression by NK cells and gene expression in activated T cells. Taken together, these data suggest that the disease-associated rs917997 allele G permits hyperresponsiveness to IL-18, providing a novel target for therapeutic intervention in T1D. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. RAP: RNA-Seq Analysis Pipeline, a new cloud-based NGS web application.

    PubMed

    D'Antonio, Mattia; D'Onorio De Meo, Paolo; Pallocca, Matteo; Picardi, Ernesto; D'Erchia, Anna Maria; Calogero, Raffaele A; Castrignanò, Tiziana; Pesole, Graziano

    2015-01-01

    The study of RNA has been dramatically improved by the introduction of Next Generation Sequencing platforms allowing massive and cheap sequencing of selected RNA fractions, also providing information on strand orientation (RNA-Seq). The complexity of transcriptomes and of their regulative pathways make RNA-Seq one of most complex field of NGS applications, addressing several aspects of the expression process (e.g. identification and quantification of expressed genes and transcripts, alternative splicing and polyadenylation, fusion genes and trans-splicing, post-transcriptional events, etc.). In order to provide researchers with an effective and friendly resource for analyzing RNA-Seq data, we present here RAP (RNA-Seq Analysis Pipeline), a cloud computing web application implementing a complete but modular analysis workflow. This pipeline integrates both state-of-the-art bioinformatics tools for RNA-Seq analysis and in-house developed scripts to offer to the user a comprehensive strategy for data analysis. RAP is able to perform quality checks (adopting FastQC and NGS QC Toolkit), identify and quantify expressed genes and transcripts (with Tophat, Cufflinks and HTSeq), detect alternative splicing events (using SpliceTrap) and chimeric transcripts (with ChimeraScan). This pipeline is also able to identify splicing junctions and constitutive or alternative polyadenylation sites (implementing custom analysis modules) and call for statistically significant differences in genes and transcripts expression, splicing pattern and polyadenylation site usage (using Cuffdiff2 and DESeq). Through a user friendly web interface, the RAP workflow can be suitably customized by the user and it is automatically executed on our cloud computing environment. This strategy allows to access to bioinformatics tools and computational resources without specific bioinformatics and IT skills. RAP provides a set of tabular and graphical results that can be helpful to browse, filter and export

  12. Performance Evaluation of Hot Mix Asphalt with Different Proportions of RAP Content

    NASA Astrophysics Data System (ADS)

    Kamil Arshad, Ahmad; Awang, Haryati; Shaffie, Ekarizan; Hashim, Wardati; Rahman, Zanariah Abd

    2018-03-01

    Reclaimed Asphalt Pavement (RAP) is old asphalt pavement that has been removed from a road by milling or full depth removal. The use of RAP in hot mix asphalt (HMA) eliminates the need to dispose old asphalt pavements and conserves asphalt binders and aggregates, resulting in significant cost savings and benefits to society. This paper presents a study on HMA with different RAP proportions carried out to evaluate the volumetric properties and performance of asphalt mixes containing different proportions of RAP. Marshall Mix Design Method was used to produce control mix (0% RAP) and asphalt mixes containing 15% RAP, 25% RAP and 35% RAP in accordance with Specifications for Road Works of Public Works Department, Malaysia for AC14 dense graded asphalt gradation. Volumetric analysis was performed to ensure that the result is compliance with specification requirements. The resilient modulus test was performed to measure the stiffness of the mixes while the Modified Lottman test was conducted to evaluate the moisture susceptibility of these mixes. The Hamburg wheel tracking test was used to evaluate the rutting performance of these mixes. The results obtained showed that there were no substantial difference in Marshall Properties, moisture susceptibility, resilient modulus and rutting resistance between asphalt mixes with RAP and the control mix. The test results indicated that recycled mixes performed as good as the performance of conventional HMA in terms of moisture susceptibility and resilient modulus. It is recommended that further research be carried out for asphalt mixes containing more than 35% RAP material.

  13. Cultural Studies and Rap: The Poetry of an Urban Lyricist

    ERIC Educational Resources Information Center

    Parmar, Priya

    2005-01-01

    In this article, the author explores the many other faces of rap that do not get the media exposure that they rightfully deserve. As this article attempts to reveal, rap music, as a form of cultural pedagogy and critical literacy, is only one way to achieve the goals of a "critical education." Rap lyrics can also be used as a tool to help the…

  14. miR-203a is involved in HBx-induced inflammation by targeting Rap1a

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, AiRong; Chen, Huo; Xu, ChunFang

    Hepatitis B virus (HBV) causes acute and chronic hepatitis, and is one of the major causes of cirrhosis and hepatocellular carcinoma. Accumulating evidence suggests that inflammation is the key factor for liver cirrhosis and hepatocellular carcinoma. MicroRNAs play important roles in many biological processes. Here, we aim to explore the function of microRNAs in the HBX-induced inflammation. First, microarray experiment showed that HBV{sup +} liver samples expressed higher level of miR-203a compared to HBV{sup -} liver samples. To verify these alterations, HBx-coding plasmid was transfected into HepG2 cells to overexpress HBx protein. The real-time PCR results suggested that over-expression ofmore » HBx could induce up-regulation of miR-203a. To define how up-regulation of miR-203a can induce liver cells inflammation, we over-expressed miR-203a in HepG2 cells. Annexin V staining and BrdU staining suggested that overexpression of miR-203a significantly increased the cell apoptosis and proliferation, meanwhile, over-expression of miR-203a could lead to a decrease in G0/G1 phase cells and an increase in G2/M phase cells. Some cytokines production including IL-6 and IL-8 were significantly increased, but TGFβ and IFNγ were decreased in miR-203a over-expressed HepG2 cells. Luciferase reporter assay experiments, protein mass-spectrum assay and real-time PCR all together demonstrated that Rap1a was the target gene of miR-203a. Further experiments showed that these alterations were modulated through PI3K/ERK/p38/NFκB pathways. These data suggested that HBV-infection could up-regulate the expression of miR-203a, thus down regulated the expression of Rap1a and affected the PI3K/ERK/p38/NFκB pathways, finally induced the hepatitis inflammation. - Highlights: • HBX induces the over-expression of miR-203a in HepG2 cells. • miR-203a targets Rap1a to induce the inflammation in HepG2 cells. • miR-203a regulates the apoptosis and cell cycles of HepG2 cells. • miR-203a

  15. Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis–associated glomerular injury

    PubMed Central

    Potla, Uma; Ni, Jie; Vadaparampil, Justin; Yang, Guozhe; Leventhal, Jeremy S.; Campbell, Kirk N.; Chuang, Peter Y.; Morozov, Alexei; He, John C.; D’Agati, Vivette D.; Klotman, Paul E.; Kaufman, Lewis

    2014-01-01

    Injury to the specialized epithelial cells of the glomerulus (podocytes) underlies the pathogenesis of all forms of proteinuric kidney disease; however, the specific genetic changes that mediate podocyte dysfunction after injury are not fully understood. Here, we performed a large-scale insertional mutagenic screen of injury-resistant podocytes isolated from mice and found that increased expression of the gene Rap1gap, encoding a RAP1 activation inhibitor, ameliorated podocyte injury resistance. Furthermore, injured podocytes in murine models of disease and kidney biopsies from glomerulosclerosis patients exhibited increased RAP1GAP, resulting in diminished glomerular RAP1 activation. In mouse models, podocyte-specific inactivation of Rap1a and Rap1b induced massive glomerulosclerosis and premature death. Podocyte-specific Rap1a and Rap1b haploinsufficiency also resulted in severe podocyte damage, including features of podocyte detachment. Over-expression of RAP1GAP in cultured podocytes induced loss of activated β1 integrin, which was similarly observed in kidney biopsies from patients. Furthermore, preventing elevation of RAP1GAP levels in injured podocytes maintained β1 integrin–mediated adhesion and prevented cellular detachment. Taken together, our findings suggest that increased podocyte expression of RAP1GAP contributes directly to podocyte dysfunction by a mechanism that involves loss of RAP1-mediated activation of β1 integrin. PMID:24642466

  16. 40 CFR 270.80 - What is a RAP?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., store, or dispose of hazardous remediation waste (as defined in § 260.10 of this chapter) at a remediation waste management site. A RAP may only be issued for the area of contamination where the remediation wastes to be managed under the RAP originated, or areas in close proximity to the contaminated...

  17. Effect of Rap1 binding on DNA distortion and potassium permanganate hypersensitivity.

    PubMed

    Le Bihan, Yann-Vaï; Matot, Béatrice; Pietrement, Olivier; Giraud-Panis, Marie-Josèphe; Gasparini, Sylvaine; Le Cam, Eric; Gilson, Eric; Sclavi, Bianca; Miron, Simona; Le Du, Marie-Hélène

    2013-03-01

    Repressor activator protein 1 (Rap1) is an essential factor involved in transcription and telomere stability in the budding yeast Saccharomyces cerevisiae. Its interaction with DNA causes hypersensitivity to potassium permanganate, suggesting local DNA melting and/or distortion. In this study, various Rap1-DNA crystal forms were obtained using specifically designed crystal screens. Analysis of the DNA conformation showed that its distortion was not sufficient to explain the permanganate reactivity. However, anomalous data collected at the Mn edge using a Rap1-DNA crystal soaked in potassium permanganate solution indicated that the DNA conformation in the crystal was compatible with interaction with permanganate ions. Sequence-conservation analysis revealed that double-Myb-containing Rap1 proteins all carry a fully conserved Arg580 at a position that may favour interaction with permanganate ions, although it is not involved in the hypersensitive cytosine distortion. Permanganate reactivity assays with wild-type Rap1 and the Rap1[R580A] mutant demonstrated that Arg580 is essential for hypersensitivity. AFM experiments showed that wild-type Rap1 and the Rap1[R580A] mutant interact with DNA over 16 successive binding sites, leading to local DNA stiffening but not to accumulation of the observed local distortion. Therefore, Rap1 may cause permanganate hypersensitivity of DNA by forming a pocket between the reactive cytosine and Arg580, driving the permanganate ion towards the C5-C6 bond of the cytosine.

  18. Detection of recycled asphalt pavement (RAP) in bituminous mixtures

    DOT National Transportation Integrated Search

    2004-06-01

    The overall goal of this study was to assist the Illinois Department of Transportation (IDOT) in identifying and developing methods for quality assurance of hot-mix asphalt (HMA) containing recycled asphalt pavement (RAP). Although the use of RAP can...

  19. Development of laboratory mix design procedures for RAP mixes.

    DOT National Transportation Integrated Search

    2013-12-01

    The objective of this study was to evaluate the amount of blending that occurs between RAP and virgin asphalt : binders in plant produced HMA in which RAP is incorporated. This objective was accomplished by testing plant : produced mixture from three...

  20. Determining asphalt content for recycled asphalt pavement (RAP) materials.

    DOT National Transportation Integrated Search

    2003-07-01

    The State of Oregon uses significant amounts of Recycled Asphalt Pavement (RAP) in dense-graded mixes on State : highways. The design process for these mixes relies on accurately knowing the amount of asphalt cement in the RAP : materials being used....

  1. Rap1 GTPase is required for mouse lens epithelial maintenance and morphogenesis

    PubMed Central

    Maddala, Rupalatha; Nagendran, Tharkika; Lang, Richard A.; Morozov, Alexei; Rao, Ponugoti V.

    2015-01-01

    Rap1, a Ras-like small GTPase, plays a crucial role in cell-matrix adhesive interactions, cell-cell junction formation, cell polarity and migration. The role of Rap1 in vertebrate organ development and tissue architecture, however, remains elusive. We addressed this question in a mouse lens model system using a conditional gene targeting approach. While individual germline deficiency of either Rap1a or Rap1b did not cause overt defects in mouse lens, conditional double deficiency (Rap1 cKO) prior to lens placode formation led to an ocular phenotype including microphthalmia and lens opacification in embryonic mice. The embryonic Rap1 cKO mouse lens exhibited striking defects including loss of E-cadherin- and ZO-1-based cell-cell junctions, disruption of paxillin and β1-integrin-based cell adhesive interactions along with abnormalities in cell shape and apical-basal polarity of epithelium. These epithelial changes were accompanied by increased levels of α-smooth muscle actin, vimentin and N-cadherin, and expression of transcriptional suppressors of E-cadherin (Snai1, Slug and Zeb2), and a mesenchymal metabolic protein (Dihydropyrimidine dehydrogenase). Additionally, while lens differentiation was not overtly affected, increased apoptosis and dysregulated cell cycle progression were noted in epithelium and fibers in Rap1 cKO mice. Collectively these observations uncover a requirement for Rap1 in maintenance of lens epithelial phenotype and morphogenesis. PMID:26212757

  2. Changing images of violence in Rap music lyrics: 1979-1997.

    PubMed

    Herd, Denise

    2009-12-01

    Rap music has been at the center of concern about the potential harmful effects of violent media on youth social behavior. This article explores the role of changing images of violence in rap music lyrics from the 1970s to the 1990s. The results indicate that there has been a dramatic and sustained increase in the level of violence in rap music. The percentage of songs mentioning violence increased from 27 per cent during 1979-1984 to 60 per cent during 1994-1997. In addition, portrayals of violence in later songs are viewed in a more positive light as shown by their increased association with glamor, wealth, masculinity, and personal prowess. Additional analyses revealed that genre, specifically gangster rap, is the most powerful predictor of the increased number of violent references in songs. The discussion suggests that violence in rap music has increased in response to the complex interplay of changing social conditions such as the elevated levels of youth violence in the 1980s and changing commercial practices within the music industry.

  3. Representative Agricultural Pathways: A Trans-Disciplinary Approach to Agricultural Model Inter-comparison, Improvement, Climate Impact Assessment and Stakeholder Engagement

    NASA Astrophysics Data System (ADS)

    Antle, J. M.; Valdivia, R. O.; Claessens, L.; Nelson, G. C.; Rosenzweig, C.; Ruane, A. C.; Vervoort, J.

    2013-12-01

    The global change research community has recognized that new pathway and scenario concepts are needed to implement impact and vulnerability assessment that is logically consistent across local, regional and global scales. For impact and vulnerability assessment, new socio-economic pathway and scenario concepts are being developed. Representative Agricultural Pathways (RAPs) are designed to extend global pathways to provide the detail needed for global and regional assessment of agricultural systems. In addition, research by the Agricultural Model Inter-comparison and Improvement Project (AgMIP) shows that RAPs provide a powerful way to engage stakeholders in climate-related research throughout the research process and in communication of research results. RAPs are based on the integrated assessment framework developed by AgMIP. This framework shows that both bio-physical and socio-economic drivers are essential components of agricultural pathways and logically precede the definition of adaptation and mitigation scenarios that embody associated capabilities and challenges. This approach is based on a trans-disciplinary process for designing pathways and then translating them into parameter sets for bio-physical and economic models that are components of agricultural integrated assessments of climate impact, adaptation and mitigation. RAPs must be designed to be part of a logically consistent set of drivers and outcomes from global to regional and local. Global RAPs are designed to be consistent with higher-level global socio-economic pathways, but add key agricultural drivers such as agricultural growth trends that are not specified in more general pathways, as illustrated in a recent inter-comparison of global agricultural models. To create pathways at regional or local scales, further detail is needed. At this level, teams of scientists and other experts with knowledge of the agricultural systems and regions work together through a step-wise process. Experiences

  4. TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1

    PubMed Central

    Grolez, Guillaume P.; Bernardini, Michela; Richard, Elodie; Scianna, Marco; Lemonnier, Loic; Munaron, Luca; Mattot, Virginie; Prevarskaya, Natalia; Gkika, Dimitra

    2017-01-01

    Endothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein–protein interaction, thus preventing its cytoplasm–plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration. PMID:28550110

  5. RAP2.4a Is Transported through the Phloem to Regulate Cold and Heat Tolerance in Papaya Tree (Carica papaya cv. Maradol): Implications for Protection Against Abiotic Stress.

    PubMed

    Figueroa-Yañez, Luis; Pereira-Santana, Alejandro; Arroyo-Herrera, Ana; Rodriguez-Corona, Ulises; Sanchez-Teyer, Felipe; Espadas-Alcocer, Jorge; Espadas-Gil, Francisco; Barredo-Pool, Felipe; Castaño, Enrique; Rodriguez-Zapata, Luis Carlos

    2016-01-01

    Plants respond to stress through metabolic and morphological changes that increase their ability to survive and grow. To this end, several transcription factor families are responsible for transmitting the signals that are required for these changes. Here, we studied the transcription factor superfamily AP2/ERF, particularly, RAP2.4 from Carica papaya cv. Maradol. We isolated four genes (CpRap2.4a, CpRAap2.4b, CpRap2.1 and CpRap2.10), and an in silico analysis showed that the four genes encode proteins that contain a conserved APETALA2 (AP2) domain located within group I and II transcription factors of the AP2/ERF superfamily. Semiquantitative PCR experiments indicated that each CpRap2 gene is differentially expressed under stress conditions, such as extreme temperatures. Moreover, genetic transformants of tobacco plants overexpressing CpRap2.4a and CpRap2.4b genes show a high level of tolerance to cold and heat stress compared to non-transformed plants. Confocal microscopy analysis of tobacco transgenic plants showed that CpRAP2.4a and CpRAP2.4b proteins were mainly localized to the nuclei of cells from the leaves and roots and also in the sieve elements. Moreover, the movement of CpRap2.4a RNA in tobacco grafting was analyzed. Our results indicate that CpRap2.4a and CpRap2.4b RNA in the papaya tree have a functional role in the response to stress conditions such as exposure to extreme temperatures via direct translation outside the parental RNA cell.

  6. RAP2.4a Is Transported through the Phloem to Regulate Cold and Heat Tolerance in Papaya Tree (Carica papaya cv. Maradol): Implications for Protection Against Abiotic Stress

    PubMed Central

    Arroyo-Herrera, Ana; Rodriguez-Corona, Ulises; Sanchez-Teyer, Felipe; Espadas-Alcocer, Jorge; Espadas-Gil, Francisco; Barredo-Pool, Felipe; Castaño, Enrique; Rodriguez-Zapata, Luis Carlos

    2016-01-01

    Plants respond to stress through metabolic and morphological changes that increase their ability to survive and grow. To this end, several transcription factor families are responsible for transmitting the signals that are required for these changes. Here, we studied the transcription factor superfamily AP2/ERF, particularly, RAP2.4 from Carica papaya cv. Maradol. We isolated four genes (CpRap2.4a, CpRAap2.4b, CpRap2.1 and CpRap2.10), and an in silico analysis showed that the four genes encode proteins that contain a conserved APETALA2 (AP2) domain located within group I and II transcription factors of the AP2/ERF superfamily. Semiquantitative PCR experiments indicated that each CpRap2 gene is differentially expressed under stress conditions, such as extreme temperatures. Moreover, genetic transformants of tobacco plants overexpressing CpRap2.4a and CpRap2.4b genes show a high level of tolerance to cold and heat stress compared to non-transformed plants. Confocal microscopy analysis of tobacco transgenic plants showed that CpRAP2.4a and CpRAP2.4b proteins were mainly localized to the nuclei of cells from the leaves and roots and also in the sieve elements. Moreover, the movement of CpRap2.4a RNA in tobacco grafting was analyzed. Our results indicate that CpRap2.4a and CpRap2.4b RNA in the papaya tree have a functional role in the response to stress conditions such as exposure to extreme temperatures via direct translation outside the parental RNA cell. PMID:27764197

  7. BSE Rap: intergenerational ties to save lives.

    PubMed

    Ehmann, J L

    1993-09-01

    This article presents an innovative public-education strategy that was created to promote breast health awareness and early breast cancer detection among minority and low-income adolescent females. Given the importance of teaching breast self-examination (BSE), program development focused on creation of the BSE Rap, a lively music-video presentation. Increasing adolescents' knowledge and awareness of BSE is viewed as a springboard for disseminating information to their mothers and grandmothers. Funding was obtained for production of a video and a breast health diary, which are the program's key components. Marketing strategies included contacts with community organizations and healthcare professionals. Program evaluations reveal that the BSE Rap serves as a positive motivator for participants to discuss BSE and mammography with their mothers and grandmothers. The BSE Rap offers oncology nurses the opportunity to save lives using a unique and creative tool that focuses on intergenerational ties.

  8. Balanced RAP/RAS mix design and performance evaluation for project - specific service conditions.

    DOT National Transportation Integrated Search

    2013-01-01

    This presentation summarizes Projects 0-6092/0-6614. It includes accomplishments, best practices, field performance data of RAP/RAS test sections, balanced RAP/RAS mix design for project-specific conditions, and approaches for improving RAP/RAS mix p...

  9. RAP: RNA-Seq Analysis Pipeline, a new cloud-based NGS web application

    PubMed Central

    2015-01-01

    Background The study of RNA has been dramatically improved by the introduction of Next Generation Sequencing platforms allowing massive and cheap sequencing of selected RNA fractions, also providing information on strand orientation (RNA-Seq). The complexity of transcriptomes and of their regulative pathways make RNA-Seq one of most complex field of NGS applications, addressing several aspects of the expression process (e.g. identification and quantification of expressed genes and transcripts, alternative splicing and polyadenylation, fusion genes and trans-splicing, post-transcriptional events, etc.). Moreover, the huge volume of data generated by NGS platforms introduces unprecedented computational and technological challenges to efficiently analyze and store sequence data and results. Methods In order to provide researchers with an effective and friendly resource for analyzing RNA-Seq data, we present here RAP (RNA-Seq Analysis Pipeline), a cloud computing web application implementing a complete but modular analysis workflow. This pipeline integrates both state-of-the-art bioinformatics tools for RNA-Seq analysis and in-house developed scripts to offer to the user a comprehensive strategy for data analysis. RAP is able to perform quality checks (adopting FastQC and NGS QC Toolkit), identify and quantify expressed genes and transcripts (with Tophat, Cufflinks and HTSeq), detect alternative splicing events (using SpliceTrap) and chimeric transcripts (with ChimeraScan). This pipeline is also able to identify splicing junctions and constitutive or alternative polyadenylation sites (implementing custom analysis modules) and call for statistically significant differences in genes and transcripts expression, splicing pattern and polyadenylation site usage (using Cuffdiff2 and DESeq). Results Through a user friendly web interface, the RAP workflow can be suitably customized by the user and it is automatically executed on our cloud computing environment. This strategy

  10. Phospholipase D1 regulates lymphocyte adhesion via upregulation of Rap1 at the plasma membrane.

    PubMed

    Mor, Adam; Wynne, Joseph P; Ahearn, Ian M; Dustin, Michael L; Du, Guangwei; Philips, Mark R

    2009-06-01

    Rap1 is a small GTPase that modulates adhesion of T cells by regulating inside-out signaling through LFA-1. The bulk of Rap1 is expressed in a GDP-bound state on intracellular vesicles. Exocytosis of these vesicles delivers Rap1 to the plasma membrane, where it becomes activated. We report here that phospholipase D1 (PLD1) is expressed on the same vesicular compartment in T cells as Rap1 and is translocated to the plasma membrane along with Rap1. Moreover, PLD activity is required for both translocation and activation of Rap1. Increased T-cell adhesion in response to stimulation of the antigen receptor depended on PLD1. C3G, a Rap1 guanine nucleotide exchange factor located in the cytosol of resting cells, translocated to the plasma membranes of stimulated T cells. Our data support a model whereby PLD1 regulates Rap1 activity by controlling exocytosis of a stored, vesicular pool of Rap1 that can be activated by C3G upon delivery to the plasma membrane.

  11. Chance Encounters: Rap Music as a Relational and Pedagogical Resource in Clinical Pastoral Education.

    PubMed

    Gilmore, Jeremy

    2018-03-01

    Music has long been regarded as a valuable tool for educators. Over the last three decades, rap music has grown to become a global phenomenon. However, due to historical and cultural factors, rap music is often underutilized in Clinical Pastoral Education. This article discusses the social significance of rap music, highlights how rap music informed my supervision of a clinical pastoral education student, and examines Chance the Rapper's mixtape Coloring Book as a case study on the utilization of rap music as a relational and pedagogical resource in spiritual education.

  12. Literature review : performance of RAP/RAS mixes and new direction.

    DOT National Transportation Integrated Search

    2014-04-01

    In the last several years reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) have been : widely used in asphalt mixes in Texas. The use of RAP/RAS can significantly reduce the initial cost of : asphalt mixtures, conserve energy, and...

  13. Rap Music Use, Perceived Peer Behavior, and Sexual Initiation Among Ethnic Minority Youth.

    PubMed

    Johnson-Baker, Kimberly A; Markham, Christine; Baumler, Elizabeth; Swain, Honora; Emery, Susan

    2016-03-01

    Research shows that rap music use is associated with risky sexual behavior in ethnic minority youth; however, it is unknown whether rap music use impacts sexual initiation specifically and, if so, which factors mediate this impact. Thus, we investigated the longitudinal relationship between hours spent listening to rap music in seventh grade and sexual initiation in ninth grade. We also examined the role of perceived peer sexual behavior as a potential mediator of this relationship. We analyzed data from students (n = 443) enrolled in a school-based randomized controlled trial of a sexual health education curriculum collected at baseline and at 18-month follow-up. Rap music use and perceived peer sexual behavior were assessed in seventh grade, whereas sexual initiation was assessed in ninth grade. Univariate, multivariate, and mediation analyses were conducted. At baseline, rap music use was significantly associated with race/ethnicity, parental music rules, and sexual behavior, but not with gender or parental education. Rap music use was a significant predictor of sexual initiation on univariate analysis but not multivariate analysis. Mediation analysis showed that the association between hours spent listening to rap music and sexual initiation was significantly mediated by perceived peer sexual behavior. Rap music use in early adolescence significantly impacts sexual initiation in late adolescence, partially mediated by perceived peer sexual behavior. More research is needed to understand how rap music influences perceptions of peer sexual behavior, which, in turn, influence early sexual initiation. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  14. Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells.

    PubMed

    Renaud, Emilie; Barascu, Aurelia; Rosselli, Filippo

    2016-01-29

    To rescue collapsed replication forks cells utilize homologous recombination (HR)-mediated mechanisms to avoid the induction of gross chromosomal abnormalities that would be generated by non-homologous end joining (NHEJ). Using DNA interstrand crosslinks as a replication barrier, we investigated how the Fanconi anemia (FA) pathway promotes HR at stalled replication forks. FA pathway inactivation results in Fanconi anemia, which is associated with a predisposition to cancer. FANCD2 monoubiquitination and assembly in subnuclear foci appear to be involved in TIP60 relocalization to the chromatin to acetylates histone H4K16 and prevents the binding of 53BP1 to its docking site, H4K20Me2. Thus, FA pathway loss-of-function results in accumulation of 53BP1, RIF1 and RAP80 at damaged chromatin, which impair DNA resection at stalled replication fork-associated DNA breaks and impede HR. Consequently, DNA repair in FA cells proceeds through the NHEJ pathway, which is likely responsible for the accumulation of chromosome abnormalities. We demonstrate that the inhibition of NHEJ or deacetylase activity rescue HR in FA cells. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Listening to Rap: Cultures of Crime, Cultures of Resistance

    ERIC Educational Resources Information Center

    Tanner, Julian; Asbridge, Mark; Wortley, Scot

    2009-01-01

    This research compares representations of rap music with the self-reported criminal behavior and resistant attitudes of the music's core audience. Our database is a large sample of Toronto high school students (n = 3,393) from which we identify a group of listeners, whose combination of musical likes and dislikes distinguish them as rap univores.…

  16. Creative Technology and Rap

    ERIC Educational Resources Information Center

    Ch'ien, Evelyn

    2011-01-01

    This paper describes how a linguistic form, rap, can evolve in tandem with technological advances and manifest human-machine creativity. Rather than assuming that the interplay between machines and technology makes humans robotic or machine-like, the paper explores how the pressure of executing artistic visions using technology can drive…

  17. Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling

    PubMed Central

    Cahill, Michael E.; Bagot, Rosemary C.; Gancarz, Amy M.; Walker, Deena M.; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A.; Feng, Jian; Kennedy, Pamela J.; Koo, Ja Wook; Cates, Hannah M.; Neve, Rachael L.; Shen, Li; Dietz, David M.

    2016-01-01

    Summary Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens, a primary brain reward region, are seen at early vs. late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local-synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce “metaplasticity” in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

  18. The Effect of Rap/Hip-Hop Music on Young Adult Smoking: An Experimental Study.

    PubMed

    Harakeh, Zeena; Bogt, Tom F M Ter

    2018-02-16

    Music may influence young people's behavior through its lyrics. Substance use references occur more frequently in rap/hip-hop than in other music genres. The aim was to examine whether the exposure to rap/hip-hop lyrics referring to substance use affected cigarette smoking. An experiment with a 3-group between subject design was conducted among 74 daily-smoking young adults ranging in age from 17 to 25 years old. Three conditions were tested in a mobile lab (camper vehicle) from May to December 2011, i.e., regular chart pop music (N = 28), rap/hip-hop with non-frequent references to substance use (N = 24), and rap/hip-hop with frequent references to substance use (N = 22). One-way ANOVA showed that participants listening to substance use infused rap/hip-hop songs felt significantly less pleasant, liked the songs less, and comprehended the songs less compared to participants listening to pop songs. Poisson loglinear analyses revealed that compared to the pop music condition, none of the two rap/hip-hop music conditions had a significant effect on acute smoking. Thus, contrary to expectations, the two different rap/hip-hop conditions did not have a significantly different effect on acute smoking. Listening to rap/hip-hop, even rap hip/hop with frequent referrals to substance use (primarily alcohol and drug use, and general smoking referrals), does not seem to encourage cigarette smoking among Dutch daily-smoking young adults, at least short term.

  19. Rapid Fabrication of Lightweight SiC Optics using Reactive Atom Plasma (RAP) Processing

    NASA Technical Reports Server (NTRS)

    Fiske, Peter S.

    2006-01-01

    Reactive Atom Plasma (RAP) processing is a non-contact, plasma-based processing technology that can be used to generate damage-free optical surfaces. We have developed tools and processes using RAP that allow us to shape extremely lightweight mirror Surfaces made from extremely hard-to-machine materials (e.g. SiC). We will describe our latest results using RAP in combination with other technologies to produce finished lightweight SiC mirrors and also discuss applications for RAP in the rapid fabrication of mirror segments for reflective and grazing incidence telescopes.

  20. Rap and Race: It's Got a Nice Beat, but What about the Message?

    ERIC Educational Resources Information Center

    Sullivan, Rachel E.

    2003-01-01

    Examined racial differences in black and white adolescents' preferences for and interpretations of rap music. Surveys of midwestern U.S. adolescents highlighted limited racial differences in the popularity of rap music. African American youth were more committed to rap and more likely to see it as life affirming. Though both groups had favorable…

  1. Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase.

    PubMed

    Gold, M R; Ingham, R J; McLeod, S J; Christian, S L; Scheid, M P; Duronio, V; Santos, L; Matsuuchi, L

    2000-08-01

    In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap 1 in B-cell receptor (BCR) signaling. PI3K produces lipids that recruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner. Akt phosphorylates several transcription factors as well as proteins that regulate apoptosis and protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinase whose substrates include the nuclear factor of activated T cells (NF-AT)cl and beta-catenin transcriptional activators. In addition to Akt, PI3K-derived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI3K to the plasma membrane where its substrates are located. This is mediated by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine-containing sequences on membrane-associated docking proteins. The docking proteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perhaps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containing inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dependent signaling. In contrast to PI3K, little is known about the Rap1 GTPase. We showed that the BCR activates Rap1 via phospholipase C-dependent production of diacylglycerol. Since Rap1 is thought to regulate cell adhesion and cell polarity, it may be involved in B-cell migration.

  2. Allosteric Activation of Bacterial Swi2/Snf2 (Switch/Sucrose Non-fermentable) Protein RapA by RNA Polymerase

    PubMed Central

    Kakar, Smita; Fang, Xianyang; Lubkowska, Lucyna; Zhou, Yan Ning; Shaw, Gary X.; Wang, Yun-Xing; Jin, Ding Jun; Kashlev, Mikhail; Ji, Xinhua

    2015-01-01

    Members of the Swi2/Snf2 (switch/sucrose non-fermentable) family depend on their ATPase activity to mobilize nucleic acid-protein complexes for gene expression. In bacteria, RapA is an RNA polymerase (RNAP)-associated Swi2/Snf2 protein that mediates RNAP recycling during transcription. It is known that the ATPase activity of RapA is stimulated by its interaction with RNAP. It is not known, however, how the RapA-RNAP interaction activates the enzyme. Previously, we determined the crystal structure of RapA. The structure revealed the dynamic nature of its N-terminal domain (Ntd), which prompted us to elucidate the solution structure and activity of both the full-length protein and its Ntd-truncated mutant (RapAΔN). Here, we report the ATPase activity of RapA and RapAΔN in the absence or presence of RNAP and the solution structures of RapA and RapAΔN either ligand-free or in complex with RNAP. Determined by small-angle x-ray scattering, the solution structures reveal a new conformation of RapA, define the binding mode and binding site of RapA on RNAP, and show that the binding sites of RapA and σ70 on the surface of RNAP largely overlap. We conclude that the ATPase activity of RapA is inhibited by its Ntd but stimulated by RNAP in an allosteric fashion and that the conformational changes of RapA and its interaction with RNAP are essential for RNAP recycling. These and previous findings outline the functional cycle of RapA, which increases our understanding of the mechanism and regulation of Swi2/Snf2 proteins in general and of RapA in particular. The new structural information also leads to a hypothetical model of RapA in complex with RNAP immobilized during transcription. PMID:26272746

  3. Affiliation and Alienation: Hip-Hop, Rap, and Urban Science Education

    ERIC Educational Resources Information Center

    Emdin, Christopher

    2010-01-01

    The critiques of rap artists and other participants in hip-hop culture provide data for teachers and researchers to investigate the attitudes of US urban youth towards schooling. This study explores the complex relationships between hip-hop and science education by examining how rap lyrics project beliefs about schooling, the relevance of existing…

  4. Characterization of low-temperature properties of plant-produced rap mixtures in the Northeast

    NASA Astrophysics Data System (ADS)

    Medeiros, Marcelo S., Junior

    The dissertation outlined herein results from a Federal Highway Administration sponsored project intended to investigate the impacts of high percentages of RAP material in the performance of pavements under cold climate conditions. It is comprised of two main sections that were incorporated into the body of this dissertation as Part I and Part II. In Part I a reduced testing framework for analysis of HMA mixes was proposed to replace the IDT creep compliance and strength testing by dynamic modulus and fatigue tests performed on an AMPT device. A continuum damage model that incorporates the nonlinear constitutive behavior of the HMA mixtures was also successfully implemented and validated. Mixtures with varying percentages of reclaimed material (RAP) ranging from 0 to 40% were used in this research effort in order to verify the applicability of the proposed methodology to RAP mixtures. Part II is concerned with evaluating the effects of various binder grades on the properties of plant-produced mixtures with various percentages of RAP. The effects of RAP on mechanical and rheological properties of mixtures and extracted binders were studied in order to identify some of the deficiencies in the current production methodologies. The results of this dissertation will help practitioners to identify optimal RAP usage from a material property perspective. It also establishes some guidelines and best practices for the use of higher RAP percentages in HMA.

  5. The ability of GAP1IP4BP to function as a Rap1 GTPase-activating protein (GAP) requires its Ras GAP-related domain and an arginine finger rather than an asparagine thumb.

    PubMed

    Kupzig, Sabine; Bouyoucef-Cherchalli, Dalila; Yarwood, Sam; Sessions, Richard; Cullen, Peter J

    2009-07-01

    GAP1(IP4BP) is a member of the GAP1 family of Ras GTPase-activating proteins (GAPs) that includes GAP1(m), CAPRI, and RASAL. Composed of a central Ras GAP-related domain (RasGRD), surrounded by amino-terminal C2 domains and a carboxy-terminal PH/Btk domain, these proteins, with the notable exception of GAP1(m), possess an unexpected arginine finger-dependent GAP activity on the Ras-related protein Rap1 (S. Kupzig, D. Deaconescu, D. Bouyoucef, S. A. Walker, Q. Liu, C. L. Polte, O. Daumke, T. Ishizaki, P. J. Lockyer, A. Wittinghofer, and P. J. Cullen, J. Biol. Chem. 281:9891-9900, 2006). Here, we have examined the mechanism through which GAP1(IP4BP) can function as a Rap1 GAP. We show that deletion of domains on either side of the RasGRD, while not affecting Ras GAP activity, do dramatically perturb Rap1 GAP activity. By utilizing GAP1(IP4BP)/GAP1(m) chimeras, we establish that although the C2 and PH/Btk domains are required to stabilize the RasGRD, it is this domain which contains the catalytic machinery required for Rap1 GAP activity. Finally, a key residue in Rap1-specific GAPs is a catalytic asparagine, the so-called asparagine thumb. By generating a molecular model describing the predicted Rap1-binding site in the RasGRD of GAP1(IP4BP), we show that mutagenesis of individual asparagine or glutamine residues that lie in close proximity to the predicted binding site has no detectable effect on the in vivo Rap1 GAP activity of GAP1(IP4BP). In contrast, we present evidence consistent with a model in which the RasGRD of GAP1(IP4BP) functions to stabilize the switch II region of Rap1, allowing stabilization of the transition state during GTP hydrolysis initiated by the arginine finger.

  6. 40 CFR 270.85 - When do I need a RAP?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... remediation wastes in a manner that requires a RCRA permit under § 270.1, you must either obtain: (1) A RCRA... that use combustion of hazardous remediation wastes at a remediation waste management site are not eligible for RAPs under this subpart. (c) You may obtain a RAP for managing hazardous remediation waste at...

  7. Evaluation of the RapID-ANA system for identification of anaerobic bacteria of veterinary origin.

    PubMed

    Adney, W S; Jones, R L

    1985-12-01

    This study evaluated the ability of the RapID-ANA system (Innovative Diagnostic Systems, Inc., Atlanta, Ga.) to accurately identify a spectrum of freshly isolated veterinary anaerobes. A total of 183 isolates were tested and included 7 Actinomyces spp., 53 Bacteroides spp., 32 Clostridium spp., 2 Eubacterium spp., 65 Fusobacterium spp., 1 Peptococcus spp., 22 Peptostreptococcus spp., and 1 Propionibacterium spp. All isolates were initially identified by conventional biochemical testing and gas-liquid chromatography of short-chain fatty acid metabolites. Additional tests were performed as required by the RapID-ANA system. Of these isolates, 81.4% were correctly identified to the genus level, including 59.6% to the species level, 14.2% were incorrectly identified at the genus level, and 4.4% were not identified. Initially, 20.2% of the strains were not identified because the microcodes were not in the code book. The majority of the incorrect identifications were caused by the misidentification of Fusobacterium spp. as Bacteroides spp. Errors also occurred when veterinary anaerobes not included in the data base were assigned an identification from the existing data base. The RapID-ANA system appears to be a promising new method for rapid identification of veterinary anaerobes; however, further evaluation with an extended data base is needed before the system can accurately identify all clinically significant anaerobes.

  8. 40 CFR 270.200 - How may I renew my RAP if it is expiring?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false How may I renew my RAP if it is expiring? 270.200 Section 270.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... renew my RAP if it is expiring? If you wish to renew your expiring RAP, you must follow the process for...

  9. Validation of RAP and/or RAS in hydraulic cement concrete : technical report.

    DOT National Transportation Integrated Search

    2017-05-01

    The increasing maintenance and rehabilitation actions lead to considerable amounts of reclaimed asphalt pavement : (RAP) left in stockpiles in the United States. The possible use of RAP in Portland cement concrete (PCC) as aggregate : replacement not...

  10. Epac2-Rap1 Signaling Regulates Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias

    PubMed Central

    Yang, Zhaokang; Kirton, Hannah M.; Al-Owais, Moza; Thireau, Jérôme; Richard, Sylvain; Peers, Chris

    2017-01-01

    Abstract Aims: In the heart, β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function. The aim of the present study was to investigate the influence of Epac2-Rap1 signaling on the heart using both in vivo and in vitro approaches. Results: Inhibition of Epac2 signaling induced early afterdepolarization arrhythmias in ventricular myocytes. The underlying mechanism involved an increase in mitochondrial reactive oxygen species (ROS) and activation of the late sodium current (INalate). Arrhythmias were blocked by inhibition of INalate or the mitochondria-targeted antioxidant, mitoTEMPO. In vivo, inhibition of Epac2 caused ventricular tachycardia, torsades de pointes, and sudden death. The in vitro and in vivo effects of Epac2 inhibition were mimicked by inhibition of geranylgeranyltransferase-1, which blocks interaction of Rap1 with downstream targets. Innovation: Our findings show for the first time that Rap1 acts as a negative regulator of mitochondrial ROS production in the heart and that impaired Epac2-Rap1 signaling causes arrhythmias due to ROS-dependent activation of INalate. This has implications for the use of chemotherapeutics that target Epac2-Rap1 signaling. However, selective inhibition of INalate provides a promising strategy to prevent arrhythmias caused by impaired Epac2-Rap1 signaling. Conclusion: Epac2-Rap1 signaling attenuates mitochondrial ROS production and reduces myocardial arrhythmia susceptibility. Antioxid. Redox Signal. 27, 117–132. PMID:27649969

  11. GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.

    PubMed

    Ramanan, Vijay K; Risacher, Shannon L; Nho, Kwangsik; Kim, Sungeun; Shen, Li; McDonald, Brenna C; Yoder, Karmen K; Hutchins, Gary D; West, John D; Tallman, Eileen F; Gao, Sujuan; Foroud, Tatiana M; Farlow, Martin R; De Jager, Philip L; Bennett, David A; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Toga, Arthur W; Green, Robert C; Jagust, William J; Weiner, Michael W; Saykin, Andrew J

    2015-10-01

    Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Validation of RAP and/or RAS in hydraulic cement concrete : project summary.

    DOT National Transportation Integrated Search

    2017-01-31

    Reclaimed or recycled asphalt pavement (RAP) : and recycled asphalt shingles (RAS) have been : widely used in hot-mix asphalt (HMA) in Texas. : However, a high volume of RAP is still available : in stockpiles along the Texas Department of : Transport...

  13. Development of Mix Designs for RAP Concrete for Florida Concrete Test Road

    DOT National Transportation Integrated Search

    2017-12-01

    The main objective of this study was to develop mix designs for concrete incorporating Reclaimed Asphalt Pavement (RAP) materials to be used in the Florida Concrete Test Road. Two different FDOT-approved RAP sources were selected and used in this stu...

  14. Representative Agricultural Pathways and Climate Impact Assessment for Pacific Northwest Agricultural Systems

    NASA Astrophysics Data System (ADS)

    MU, J.; Antle, J. M.; Zhang, H.; Capalbo, S. M.; Eigenbrode, S.; Kruger, C.; Stockle, C.; Wolfhorst, J. D.

    2013-12-01

    Representative Agricultural Pathways (RAPs) are projections of plausible future biophysical and socio-economic conditions used to carry out climate impact assessments for agriculture. The development of RAPs iss motivated by the fact that the various global and regional models used for agricultural climate change impact assessment have been implemented with individualized scenarios using various data and model structures, often without transparent documentation or public availability. These practices have hampered attempts at model inter-comparison, improvement, and synthesis of model results across studies. This paper aims to (1) present RAPs developed for the principal wheat-producing region of the Pacific Northwest, and to (2) combine these RAPs with downscaled climate data, crop model simulations and economic model simulations to assess climate change impacts on winter wheat production and farm income. This research was carried out as part of a project funded by the USDA known as the Regional Approaches to Climate Change in the Pacific Northwest (REACCH). The REACCH study region encompasses the major winter wheat production area in Pacific Northwest and preliminary research shows that farmers producing winter wheat could benefit from future climate change. However, the future world is uncertain in many dimensions, including commodity and input prices, production technology, and policies, as well as increased probability of disturbances (pests and diseases) associated with a changing climate. Many of these factors cannot be modeled, so they are represented in the regional RAPS. The regional RAPS are linked to global agricultural and shared social-economic pathways, and used along with climate change projections to simulate future outcomes for the wheat-based farms in the REACCH region.

  15. CDK5RAP2 Is an Essential Scaffolding Protein of the Corona of the Dictyostelium Centrosome.

    PubMed

    Pitzen, Valentin; Askarzada, Sophie; Gräf, Ralph; Meyer, Irene

    2018-04-23

    Dictyostelium centrosomes consist of a nucleus-associated cylindrical, three-layered core structure surrounded by a corona consisting of microtubule-nucleation complexes embedded in a scaffold of large coiled-coil proteins. One of them is the conserved CDK5RAP2 protein. Here we focus on the role of Dictyostelium CDK5RAP2 for maintenance of centrosome integrity, its interaction partners and its dynamic behavior during interphase and mitosis. GFP-CDK5RAP2 is present at the centrosome during the entire cell cycle except from a short period during prophase, correlating with the normal dissociation of the corona at this stage. RNAi depletion of CDK5RAP2 results in complete disorganization of centrosomes and microtubules suggesting that CDK5RAP2 is required for organization of the corona and its association to the core structure. This is in line with the observation that overexpressed GFP-CDK5RAP2 elicited supernumerary cytosolic MTOCs. The phenotype of CDK5RAP2 depletion was very reminiscent of that observed upon depletion of CP148, another scaffolding protein of the corona. BioID interaction assays revealed an interaction of CDK5RAP2 not only with the corona markers CP148, γ-tubulin, and CP248, but also with the core components Cep192, CP75, and CP91. Furthermore, protein localization studies in both depletion strains revealed that CP148 and CDK5RAP2 cooperate in corona organization.

  16. Determination of the PG binder grade to use in a RAP mix

    DOT National Transportation Integrated Search

    2001-04-01

    The use of Recycled Asphalt Pavement (RAP) in new Hot Mix Asphalt (HMA) has become routine in the part few years. This practice is spurred by the increased amounts of pavement being milled off prior to overlaying. Using RAP has economical and environ...

  17. Site-specific bioalkylation of rapamycin by the RapM 16-O-methyltransferase† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5sc00164a

    PubMed Central

    Law, Brian J. C.; Struck, Anna-Winona; Bennett, Matthew R.; Wilkinson, Barrie

    2015-01-01

    The methylation of natural products by S-adenosyl methionine (AdoMet, also known as SAM)-dependent methyltransferase enzymes is a common tailoring step in many biosynthetic pathways. The introduction of methyl substituents can affect the biological and physicochemical properties of the secondary metabolites produced. Recently it has become apparent that some AdoMet-dependent methyltransferases exhibit promiscuity and will accept AdoMet analogues enabling the transfer of alternative alkyl groups. In this study we have characterised a methyltransferase, RapM, which is involved in the biosynthesis of the potent immunosuppressive agent rapamycin. We have shown that recombinant RapM regioselectively methylates the C16 hydroxyl group of desmethyl rapamycin precursors in vitro and is promiscuous in accepting alternative co-factors in addition to AdoMet. A coupled enzyme system was developed, including a mutant human enzyme methionine adenosyl transferase (MAT), along with RapM, which was used to prepare alkylated rapamycin derivatives (rapalogs) with alternative ethyl and allyl ether groups, derived from simple S-ethyl or S-allyl methionine analogues. There are two other methyltransferases RapI and RapQ which provide methyl substituents of rapamycin. Consequently, using the enzymatic approach described here, it should be possible to generate a diverse array of alkylated rapalogs, with altered properties, that would be difficult to obtain by traditional synthetic approaches. PMID:29403635

  18. Vitek 2 ANC card versus BBL Crystal Anaerobe and RapID ANA II for identification of clinical anaerobic bacteria.

    PubMed

    Blairon, Laurent; Maza, Mengi L; Wybo, Ingrid; Piérard, Denis; Dediste, Anne; Vandenberg, Olivier

    2010-08-01

    The Vitek 2 Anaerobe and Corynebacterium Identification Card (ANC) was recently evaluated in a multicentre study. In the present work, this system was compared with the BBL Crystal Anaerobe and RapID ANA II panels. These kits were tested using 196 strains of anaerobes that had been previously identified by gas-liquid chromatography. Identification to the species or to the genus level was 75.0%, 81.1% and 70.9% for Crystal, RapID and Vitek, respectively. Vitek ANC failed to provide any identification in 20.4% of the strains, but it had fewer misidentifications than RapID. The confidence factors provided on the results report of each kit were not always correlated with a lower risk of major errors, with the exception of Vitek 2 in which a confidence factor higher than 0.86 excluded the risk of misidentification in more than 87% of isolates. The lower rate of identification by the Vitek and Crystal panels is mostly due the lower ability of these systems to identify the Clostridia. Overall, the three panels are comparable but need improvement to a better accuracy. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  19. Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims.

    PubMed

    Dwivedi, Yogesh; Mondal, Amal C; Rizavi, Hooriyah S; Faludi, Gabor; Palkovits, Miklos; Sarosi, Andrea; Conley, Robert R; Pandey, Ghanshyam N

    2006-06-01

    Depression is a major public health problem. Despite many years of research, the molecular mechanisms associated with depression remain unclear. Rap-1, activated in response to many extracellular stimuli, is one of the major substrates of protein kinase A, which participates in myriad physiologic functions in the brain, including cell survival and synaptic plasticity. Rap-1 is also activated directly by cyclic adenosine monophosphate through Epac, and thus participates in mediating physiologic functions independent of protein kinase A. To examine whether the pathogenesis of depression is associated with altered activation and expression of Rap-1, as well as expression of Epac, in depressed suicide victims. Postmortem study. Tissues were obtained from the Lenhossek Human Brain Program, Semmelweis University, Budapest, Hungary, and the Brain Collection Program of the Maryland Psychiatric Research Center, Baltimore. Postmortem brains of 28 depressed suicide victims and 28 nonpsychiatric control subjects. Examination of brain tissues. Rap-1 activation as well as messenger RNA and protein levels of Rap-1 and Epac in prefrontal cortex, hippocampus, and cerebellum. Rap-1 activation was significantly reduced (P<.001) in prefrontal cortex and hippocampus in the suicide group. This was associated with significant reductions in Rap-1 messenger RNA and protein levels (P<.001). In contrast, protein level of only Epac-2 (P<.001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects. These changes were present whether the 2 cohorts were analyzed together or separately. None of the measures showed any significant change in cerebellum in the suicide group. Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.

  20. Development of low-cost open source 3D gel printer "RepRap SWIM-ER"

    NASA Astrophysics Data System (ADS)

    Sato, Kei; Basher, Samiul; Ota, Takafumi; Tase, Taishi; Takamatsu, Kyuichiro; Saito, Azusa; Khosla, Ajit; Kawakami, Masaru; Furuawa, Hidemitsu

    2017-04-01

    Gels are soft and wet materials having low friction, good biocompatibility, and material permeability. It is expected that gel materials will be used as new kinds of industrial materials in the engineering and medical applications. But it cannot build a complicated shape. Soft & Wet Matter Engineering Laboratory developed a 3D gel Printer "SWIM-ER", has enabled modeling of complex shapes of the gel. However, this is expensive. Therefore not all of the gel researchers and the companies have such a device. To solve this problem, we manufacture a low-cost open-source 3D gel printer "RepRap SWIM-ER" from the RepRap. We made the components required to manufacture the "RepRap SWIM-ER" from the 3D printer and chose a light source. In addition, we produced the P-DN gel for RepRap SWIM-ER and conducted the molding test to confirm whether RepRap SWIM-ER can used it.

  1. RapA, SWI/SNF subunit of Escherichia coli RNA polymerase promotes the release of nascent RNA from transcription complexes

    PubMed Central

    Yawn, Brandon; Zhang, Lin; Mura, Cameron; Sukhodolets, Maxim V.

    2009-01-01

    RapA, a prokaryotic member of the SWI/SNF protein superfamily, is an integral part of the RNA polymerase transcription complex. RapA’s function and catalytic mechanism have been linked to nucleic acid remodeling. In this work we show that mutations in the interface between RapA’s SWI/SNF and double-stranded nucleic acid-binding domains significantly alter ATP hydrolysis in purified RapA. The effects of individual mutations on ATP hydrolysis loosely correlated with RapA’s nucleic acid-remodeling activity, indicating that the interaction between these domains may be important for the RapA-mediated remodeling of nonproductive transcription complexes. In this study we introduced a model system for in vitro transcription of a full-length E. coli gene (slyD). To study the function of RapA, we fractionated and identified in vitro transcription reaction intermediates in the presence or absence of RapA. These experiments demonstrated that RapA contributes to the formation of free RNA species during in vitro transcription. This work further refines our models for RapA function in vivo and establishes a new role in RNA management for a representative of the SWI/SNF protein superfamily. PMID:19580329

  2. The Rap on Hip-Hop

    ERIC Educational Resources Information Center

    Piekarski, Bill

    2004-01-01

    From its humble origins some 30 years ago in New York's bombed-out, poverty-ravaged South Bronx, hip-hop has risen to become a dominant cultural force both here and abroad. Strictly defined, the term refers to the entire cultural constellation that accompanies rap music, which in 2001 surpassed country music as the most popular musical genre in…

  3. Rap Music Literacy: A Case Study of Millennial Audience Reception to Rap Lyrics Depicting Independent Women

    ERIC Educational Resources Information Center

    Moody-Ramirez, Mia; Scott, Lakia M.

    2015-01-01

    Using a feminist lens and a constructivist approach as the theoretical framework, we used rap lyrics and videos to help college students explore mass media's representation of the "independent" Black woman and the concept of "independence" in general. Students must be able to formulate their own concept of independence to…

  4. Molecular Basis for Phosphorylation-dependent SUMO Recognition by the DNA Repair Protein RAP80.

    PubMed

    Anamika; Spyracopoulos, Leo

    2016-02-26

    Recognition and repair of double-stranded DNA breaks (DSB) involves the targeted recruitment of BRCA tumor suppressors to damage foci through binding of both ubiquitin (Ub) and the Ub-like modifier SUMO. RAP80 is a component of the BRCA1 A complex, and plays a key role in the recruitment process through the binding of Lys(63)-linked poly-Ub chains by tandem Ub interacting motifs (UIM). RAP80 also contains a SUMO interacting motif (SIM) just upstream of the tandem UIMs that has been shown to specifically bind the SUMO-2 isoform. The RAP80 tandem UIMs and SIM function collectively for optimal recruitment of BRCA1 to DSBs, although the molecular basis of this process is not well understood. Using NMR spectroscopy, we demonstrate that the RAP80 SIM binds SUMO-2, and that both specificity and affinity are enhanced through phosphorylation of the canonical CK2 site within the SIM. The affinity increase results from an enhancement of electrostatic interactions between the phosphoserines of RAP80 and the SIM recognition module within SUMO-2. The NMR structure of the SUMO-2·phospho-RAP80 complex reveals that the molecular basis for SUMO-2 specificity is due to isoform-specific sequence differences in electrostatic SIM recognition modules. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. 40 CFR 270.150 - How will the Director make a final decision on my RAP application?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false How will the Director make a final... PROGRAM Remedial Action Plans (RAPs) Getting A Rap Approved § 270.150 How will the Director make a final decision on my RAP application? (a) The Director must consider and respond to any significant comments...

  6. Hidden Worries

    ERIC Educational Resources Information Center

    Reclaiming Children and Youth, 2013

    2013-01-01

    Sometimes children are stressed about seemingly small events that escalate into problem behavior. In this article, an insightful teacher discusses restoration of emotional balance by mobilizing positive support from both school and family using A Response Ability Pathways (RAP) intervention. The RAP techniques and how they can be used are…

  7. Changes in the prevalence of alcohol in rap music lyrics 1979-2009.

    PubMed

    Herd, Denise

    2014-02-01

    This study examines the prevalence and context of alcohol references in rap music lyrics from 1979 through 2009. Four hundred nine top-ranked rap music songs released were sampled from Billboard magazine rating charts. Songs were analyzed using systematic content analysis and were coded for alcohol beverage types and brand names, drinking behaviors, drinking contexts, attitudes towards alcohol, and consequences of drinking. Trends were analyzed using regression analyses. The results of the study reveal significant increases in the presence of alcohol in rap songs; a decline in negative attitudes towards alcohol; decreases in consequences attributed to alcohol; increases in the association of alcohol with glamour and wealth, drugs, and nightclubs; and increases in references to liquor and champagne.

  8. Performance of the RAPS4/RAPS4-QF for DSM-5 compared to DSM-IV alcohol use disorders in the general population: Data from the 2000-2010 National Alcohol Surveys.

    PubMed

    Cherpitel, Cheryl J; Ye, Yu

    2015-06-01

    A number of relatively short screening instruments have been developed for identifying alcohol use disorders (AUD), but performance has been evaluated against the standard Diagnostic and Statistical Manual of Mental and Behavior Disorders (DSM) criteria, and it is not known how screening instruments may perform based on the newly formulated DSM-5 criteria, which is a radical departure from previous versions of the DSM. Analyzed here is the performance of the RAPS4/RAPS4-QF against DSM-5 criteria for AUD compared to DSM-IV dependence and abuse criteria. Sensitivity and specificity are analyzed in a merged sample of 21,386 respondents from three National Alcohol Surveys of the U.S. general population (2000, 2005, 2010). Sensitivity of the RAPS4 was lower for DSM-5 AUD (62.5%) than for DSM-IV dependence (88%), while the RAPS4-QF was higher for DSM-5 AUD (90.3%) than for DSM-IV abuse (81.3%), or abuse/dependence (85.8%), while maintaining good specificity (84%). Sensitivity of the RAPS4-QF was higher for males (92%) compared to females (86.6%) and highest for whites (93.8%) followed by Hispanics (84.2%) and blacks (82.4%). Screening instruments may not perform similarly for DSM-5 as for DSM-IV AUD, and data here suggest the RAPS4-QF may be a good instrument choice for identifying those meeting criteria for DSM-5 AUD. These data also suggest the need for additional research and a similar evaluation of other commonly used screening instruments for DSM-5 AUD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Analysis of the usage of rubberized asphalt in hot mix asphalt using Reclaimed Asphalt Pavement (RAP)

    NASA Astrophysics Data System (ADS)

    Dwidarma Nataadmadja, Adelia; Prahara, Eduardi; Sumbung, Pierre Christian

    2017-12-01

    There has been an increasing demand in using more environmentally friendly materials in pavement construction. One of the alternative materials that have been widely used is the Reclaimed Asphalt Pavement (RAP) aggregates. The RAP aggregates are derived from the crushed and screened pavement materials that contain asphalt and aggregates. This material is usually combined with natural aggregates and virgin asphalt binder to construct a new pavement. There have been numerous positive feedbacks in using this material although RAP aggregates also have certain weaknesses, such as questionable interaction between virgin and recycled materials and increased stiffness of RAP binder. Moreover, there has been a push on using rubber as an additive to asphalt binder to improve the welfare of rubber farmers. This research combines the usage of both latex and RAP as the ingredients to design hot mix asphalt (HMA) as latex could help in improving the flexibility of HMA and the interaction between the virgin and recycled materials. The main objective of this research is to find a suitable percentage of RAP aggregates to be used in HMA with certain percentage of latex as the binder additive.

  10. Best practices for the design, evaluation and quality control of high percentage RAP mixes.

    DOT National Transportation Integrated Search

    2015-12-01

    Placing reclaimed asphalt pavement (RAP) back on the roadway is a common and popular technique in the paving industry. There are always challenges associated with this type of recycling, especially when the RAP content in the newly paved asphalt mix ...

  11. PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity.

    PubMed

    Mayanagi, Taira; Yasuda, Hiroki; Sobue, Kenji

    2015-10-21

    Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors. These abnormal behaviors are caused by impaired glutamatergic synapse transmission accompanied by tiny-headed immature dendritic spines in the PFC, due to aberrant Rap2 activation, which has roles in synapse formation and plasticity. PSD-Zip70 modulates the Rap2 activity by interacting with SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) in the postsynapse. Furthermore, suppression of the aberrant Rap2 activation in the PFC rescued the behavioral defects in PSD-Zip70KO mice. Our data demonstrate a critical role for PSD-Zip70 in Rap2-dependent spine synapse development in the PFC and underscore the importance of this regulation in PFC-dependent behaviors. PSD-Zip70 deficiency causes behavioral defects in working memory and cognition, and enhanced anxiety due to prefrontal hypofunction. This study revealed that PSD-Zip70 plays essential roles in glutamatergic synapse maturation via modulation of the Rap2 activity in the PFC. PSD-Zip70 interacts with both SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) and modulates the Rap2 activity in postsynaptic sites. Our results provide a novel Rap2-specific regulatory mechanism in synaptic maturation involving PSD-Zip70. Copyright © 2015 the authors 0270-6474/15/3514327-14$15.00/0.

  12. Thermodynamics between RAP/RAS and virgin aggregates during asphalt concrete production : a literature review.

    DOT National Transportation Integrated Search

    2015-09-01

    In hot-mix asphalt (HMA) plants, virgin aggregates are heated and dried separately before being mixed with : RAP/RAS and virgin asphalt binder. RAP/RAS materials are not heated or dried directly by a burner to avoid : burning of aged binder coating o...

  13. Quantitative Assessment of RNA-Protein Interactions with High Throughput Sequencing - RNA Affinity Profiling (HiTS-RAP)

    PubMed Central

    Ozer, Abdullah; Tome, Jacob M.; Friedman, Robin C.; Gheba, Dan; Schroth, Gary P.; Lis, John T.

    2016-01-01

    Because RNA-protein interactions play a central role in a wide-array of biological processes, methods that enable a quantitative assessment of these interactions in a high-throughput manner are in great demand. Recently, we developed the High Throughput Sequencing-RNA Affinity Profiling (HiTS-RAP) assay, which couples sequencing on an Illumina GAIIx with the quantitative assessment of one or several proteins’ interactions with millions of different RNAs in a single experiment. We have successfully used HiTS-RAP to analyze interactions of EGFP and NELF-E proteins with their corresponding canonical and mutant RNA aptamers. Here, we provide a detailed protocol for HiTS-RAP, which can be completed in about a month (8 days hands-on time) including the preparation and testing of recombinant proteins and DNA templates, clustering DNA templates on a flowcell, high-throughput sequencing and protein binding with GAIIx, and finally data analysis. We also highlight aspects of HiTS-RAP that can be further improved and points of comparison between HiTS-RAP and two other recently developed methods, RNA-MaP and RBNS. A successful HiTS-RAP experiment provides the sequence and binding curves for approximately 200 million RNAs in a single experiment. PMID:26182240

  14. Assisted annotation of medical free text using RapTAT

    PubMed Central

    Gobbel, Glenn T; Garvin, Jennifer; Reeves, Ruth; Cronin, Robert M; Heavirland, Julia; Williams, Jenifer; Weaver, Allison; Jayaramaraja, Shrimalini; Giuse, Dario; Speroff, Theodore; Brown, Steven H; Xu, Hua; Matheny, Michael E

    2014-01-01

    Objective To determine whether assisted annotation using interactive training can reduce the time required to annotate a clinical document corpus without introducing bias. Materials and methods A tool, RapTAT, was designed to assist annotation by iteratively pre-annotating probable phrases of interest within a document, presenting the annotations to a reviewer for correction, and then using the corrected annotations for further machine learning-based training before pre-annotating subsequent documents. Annotators reviewed 404 clinical notes either manually or using RapTAT assistance for concepts related to quality of care during heart failure treatment. Notes were divided into 20 batches of 19–21 documents for iterative annotation and training. Results The number of correct RapTAT pre-annotations increased significantly and annotation time per batch decreased by ∼50% over the course of annotation. Annotation rate increased from batch to batch for assisted but not manual reviewers. Pre-annotation F-measure increased from 0.5 to 0.6 to >0.80 (relative to both assisted reviewer and reference annotations) over the first three batches and more slowly thereafter. Overall inter-annotator agreement was significantly higher between RapTAT-assisted reviewers (0.89) than between manual reviewers (0.85). Discussion The tool reduced workload by decreasing the number of annotations needing to be added and helping reviewers to annotate at an increased rate. Agreement between the pre-annotations and reference standard, and agreement between the pre-annotations and assisted annotations, were similar throughout the annotation process, which suggests that pre-annotation did not introduce bias. Conclusions Pre-annotations generated by a tool capable of interactive training can reduce the time required to create an annotated document corpus by up to 50%. PMID:24431336

  15. Preliminary investigation of RAP and RAS in HMAC.

    DOT National Transportation Integrated Search

    2010-02-01

    laboratory study was undertaken to investigate how various proportions of reclaimed asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) added to hot mixed asphalt concrete (HMAC) mixtures affect the Superpave performance grade of the blended ...

  16. Experiential Learning in the Age of Web 2.0: The Rap Video Project

    ERIC Educational Resources Information Center

    Peterson, Mark

    2018-01-01

    The following experiential-learning innovation for Web 2.0 allows students to engage in creativity that is focused on writing poetry about a course-related topic and then recording a three-minute rap video based on this poetry. The rap video project described in this article offers students an opportunity to apply critical- and creative-thinking…

  17. Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA.

    PubMed

    Yu, Xuan; Zhang, Qiao; Zhao, Yan; Schwarz, Benjamin J; Stallone, John N; Heaps, Cristine L; Han, Guichun

    2017-01-01

    Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

  18. Perform an investigation of the effects of increased reclaimed asphalt pavement (RAP) levels in dense graded friction courses : [summary].

    DOT National Transportation Integrated Search

    2015-04-01

    The Florida Department of Transportation currently allows up to 20% recycled asphalt : pavement (RAP) in asphalt mixes to be used for roadway surfaces. The abundance of RAP and : savings in cost and to natural resources make increased use of RAP desi...

  19. Changes in the prevalence of alcohol use in rap song lyrics, 1979-97.

    PubMed

    Herd, Denise

    2005-09-01

    This paper explores the role of changing images of drinking and alcoholic beverage use in rap music from its beginnings in the United States in the late 1970s to the late 1990s. A sample of 341 rap music song lyrics released from 1979 to 1997 were selected using Billboard and Gavin rating charts. Song lyrics were coded for music genres, alcohol beverage types and brand names, drinking behaviors, drinking contexts, intoxication, attitudes towards alcohol and consequences of drinking. From 1979 to 1997, songs with references to alcohol increased fivefold (from 8 to 44%); those exhibiting positive attitudes rose from 43% to 73%; and brand name mentions increased from 46% to 71%. There were also significant increases in songs mentioning champagne and liquor (mainly expensive brand names) when comparing songs released after 1994 with those from previous years. In addition, there were significant increases in references to alcohol to signify glamour and wealth, and using alcohol with drugs and for recreational purposes. The findings also showed that alcohol use in rap music was much more likely to result in positive than negative consequences. Many of these findings are consistent with the idea that rap music has been profoundly affected by commercial forces and the marketing of alcoholic beverages. In addition, it is possible that the increase in references to alcoholic beverages in rap music, particularly spirits, is a reflection of a broader advertising culture which increasingly associates African Americans with alcohol use.

  20. High RAP mixes design methodology with balanced performance.

    DOT National Transportation Integrated Search

    2011-11-01

    "The use of reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) can significantly reduce the increasing cost of hot-mix asphalt paving, conserve energy, and protect the environment. This report presents a comprehensive study focusing...

  1. Molecular Dynamics Simulation of Rap1 Myb-type domain in Saccharomyces cerevisiae

    PubMed Central

    Mukherjee, Koel; Pandey, Dev Mani; Vidyarthi, Ambarish Saran

    2012-01-01

    Telomere is a nucleoprotein complex that plays important role in stability and their maintenance and consists of random repeats of species specific motifs. In budding Saccharomyces cerevisiae, Repressor Activator Protein 1 (Rap1) is a sequence specific protein that involved in transcriptional regulation. Rap1 consist of three active domains like N-terminal BRCT-domain, DNA-binding domain and C-terminal RCT-domain. In this study the unknown 3D structure of Myb-type domain (having 61 residues) within DNAbinding domain was modeled by Modeller7, and verified using different online bioinformatics tools (ProCheck, WhatIf, Verify3D). Dynamics of Myb-type domain of Rap1was carried out through simulation studies using GROMACS software. Time dependent interactions among the molecules were analyzed by Root Mean Square Deviation (RMSD), Radius of Gyration (Rg) and Root Mean Square Fluctuation (RMSF) plots. Motional properties in reduced dimension were also performed by Principal Component Analysis (PCA). Result indicated that Rap1 interacts with DNA major groove through its Helix Turn Helix motifs. Helix 3 was rigid, less amount of fluctuation was found as it interacts with DNA major groove. Helix2 and N-terminal having considerable fluctuation in the time scale. PMID:23144544

  2. Molecular Dynamics Simulation of Rap1 Myb-type domain in Saccharomyces cerevisiae.

    PubMed

    Mukherjee, Koel; Pandey, Dev Mani; Vidyarthi, Ambarish Saran

    2012-01-01

    Telomere is a nucleoprotein complex that plays important role in stability and their maintenance and consists of random repeats of species specific motifs. In budding Saccharomyces cerevisiae, Repressor Activator Protein 1 (Rap1) is a sequence specific protein that involved in transcriptional regulation. Rap1 consist of three active domains like N-terminal BRCT-domain, DNA-binding domain and C-terminal RCT-domain. In this study the unknown 3D structure of Myb-type domain (having 61 residues) within DNAbinding domain was modeled by Modeller7, and verified using different online bioinformatics tools (ProCheck, WhatIf, Verify3D). Dynamics of Myb-type domain of Rap1was carried out through simulation studies using GROMACS software. Time dependent interactions among the molecules were analyzed by Root Mean Square Deviation (RMSD), Radius of Gyration (Rg) and Root Mean Square Fluctuation (RMSF) plots. Motional properties in reduced dimension were also performed by Principal Component Analysis (PCA). Result indicated that Rap1 interacts with DNA major groove through its Helix Turn Helix motifs. Helix 3 was rigid, less amount of fluctuation was found as it interacts with DNA major groove. Helix2 and N-terminal having considerable fluctuation in the time scale.

  3. Determination of usable residual asphalt binder in RAP.

    DOT National Transportation Integrated Search

    2009-01-01

    For current recycled mix designs, the Illinois Department of Transportation (IDOT) assumes 100% contribution of : working binder from Recycled Asphalt Pavement (RAP) materials when added to Hot Mix Asphalt (HMA). However, it is : unclear if this assu...

  4. Ultrastructural and biochemical localization of N-RAP at the interface between myofibrils and intercalated disks in the mouse heart.

    PubMed

    Zhang, J Q; Elzey, B; Williams, G; Lu, S; Law, D J; Horowits, R

    2001-12-11

    N-RAP is a recently discovered muscle-specific protein found at cardiac intercalated disks. Double immunogold labeling of mouse cardiac muscle reveals that vinculin is located immediately adjacent to the fascia adherens region of the intercalated disk membrane, while N-RAP extends approximately 100 nm further toward the interior of the cell. We partially purified cardiac intercalated disks using low- and high-salt extractions followed by density gradient centrifugation. Immunoblots show that this preparation is highly enriched in desmin and junctional proteins, including N-RAP, talin, vinculin, beta1-integrin, N-cadherin, and connexin 43. Electron microscopy and immunolabeling demonstrate that N-RAP and vinculin are associated with the large fragments of intercalated disks that are present in this preparation, which also contains numerous membrane vesicles. Detergent treatment of the partially purified intercalated disks removed the membrane vesicles and extracted vinculin and beta1-integrin. Further separation on a sucrose gradient removed residual actin and myosin and yielded a fraction morphologically similar to fasciae adherentes that was highly enriched in N-RAP, N-cadherin, connexin 43, talin, desmin, and alpha-actinin. The finding that N-RAP copurifies with detergent-extracted intercalated disk fragments even though beta-integrin and vinculin have been completely removed suggests that N-RAP association with the adherens junction region is mediated by the cadherin system. Consistent with this hypothesis, we found that recombinant N-RAP fragments bind alpha-actinin in a gel overlay assay. In addition, immunofluorescence shows that N-RAP remains bound at the ends of isolated, detergent-treated cardiac myofibrils. These results demonstrate that N-RAP remains tightly bound to myofibrils and fasciae adherentes during biochemical purification and may be a key constituent in the mechanical link between these two structures.

  5. Performance of high RAP pavement sections in NH.

    DOT National Transportation Integrated Search

    2015-06-01

    This report summarizes the University of New Hampshire (UNH) results of test pavements used to : determine the effect of using higher amounts of Recycled Asphalt Pavement (RAP) in Hot Mix Asphalt : (HMA). : The New Hampshire Department of Transportat...

  6. Analysis of the finescale timing of repeated signals: does shell rapping in hermit crabs signal stamina?

    PubMed

    Briffa; Elwood

    2000-01-01

    Hermit crabs, Pagurus bernhardus, sometimes exchange shells after a period of shell rapping, when the initiating or attacking crab brings its shell rapidly and repeatedly into contact with the shell of the noninitiator or defender in a series of bouts. Bouts are separated by pauses, and raps within bouts are separated by very short periods called 'gaps'. Since within-contest variation is missed when signals are studied by averaging performance rates over entire contests, we analysed the fine within-bout structure of this repeated, aggressive signal. We found that the pattern is consistent with high levels of fatigue in initiators. The duration of the gaps between individual raps increased both within bouts and from bout to bout, and we conclude that this activity is costly to perform. Furthermore, long pauses between bouts is correlated with increased vigour of rapping in the subsequent bout, which suggests that the pause allows for recovery from fatigue induced by rapping. These between-bout pauses may be assessed by noninitiators and provide a signal of stamina. Copyright 2000 The Association for the Study of Animal Behaviour.

  7. Mortality in American Hip-Hop and Rap Recording Artists, 1987-2014.

    PubMed

    Lawson, Carl J

    2015-12-01

    The deaths of American hip-hop and rap recording artists often receive considerable media attention. However, these artists' deaths have not been examined as a distinct group like the deaths of rock, classical, jazz, and pop music artists. This is a seminal epidemiological analysis on the deaths of an understudied group, American hip-hop and rap music recording artists. Media reports were analyzed of the deaths of American hip-hop and rap music recording artists that occurred from January 1, 1987 to December 31, 2014. The decedents' age, sex, race, cause of death, stage names, and city and state of death were recorded for analysis. The most commonly reported cause of death was homicide. The 280 deaths were categorized as homicide (55%), unintentional injury (13%), cardiovascular (7%), undetermined/undisclosed (7%), cancer (6%), other (5%), suicide (4%), and infectious disease (3%). The mean reported age at death was 30 yrs (range 15-75) and the median was 29 yrs; 97% were male and 92% were black. All but one of the homicides were committed with firearms. Homicide was the most commonly reported cause of death. Public health focus and guidance for hip-hop and rap recording artists should mirror that for African-American men and adolescent males ages 15-54 yrs, for whom the leading causes of death are homicide, unintentional injury, and heart disease. Given the preponderance of homicide deaths in this analysis, premature mortality reduction efforts should focus on violence prevention and conflict mitigation.

  8. Implementation of MEPDG for asphalt pavement with RAP.

    DOT National Transportation Integrated Search

    2013-06-01

    This study explored the potential of using high reclaimed asphalt pavement (RAP) content with hot mix asphalt (HMA) in base and surface courses for conditions prevailing in Oklahoma. A total of eight Superpave mixes (four mixes for each of two field ...

  9. Experiences with lead/acid battery management in remote-area power-supply (RAPS) systems

    NASA Astrophysics Data System (ADS)

    Phillips, S. J.; Pryor, T. L.; Dymond, M. S.; Remmer, D. P.

    Battery management and general storage performance and cost remain major problems in remote-area power-supply (RAPS) systems utilizing renewable energy sources. A brief review of field experiences with lead/acid batteries is presented, together with results from battery tests carried out in the laboratory. It is recommended that further collaboration between battery manufacturers and system designers is established to develop improved storage systems for RAPS applications.

  10. Activation of the Small GTPase Rap1 Inhibits Choroidal Neovascularization by Regulating Cell Junctions and ROS Generation in Rats.

    PubMed

    Li, Jiajia; Zhang, Rong; Wang, Caixia; Wang, Xin; Xu, Man; Ma, Jingxue; Shang, Qingli

    2018-03-30

    Choroidal neovascularization (CNV) is a common vision-threatening complication associated with many  fundus diseases. The retinal pigment epithelial (RPE) cell junction barrier has critical functions in preventing CNV, and oxidative stress can cause compromise of barrier integrity and induce angiogenesis. Rap1, a small guanosine triphosphatase (GTPase), is involved in regulating endothelial and epithelial cell junctions. In this work, we explored the function and mechanism of Rap1 in CNV in vivo. A laser-induced rat CNV model was developed. Rap1 was activated through intravitreal injection of the Rap1 activator 8CPT-2'-O-Me-cAMP (8CPT). At 14 days after laser treatment, CNV size in RPE/choroid flat mounts was measured by fluorescein isothiocyanate-dextran staining. Expression of vascular endothelial growth factor (VEGF) and cell junction proteins in RPE/choroid tissues were analyzed by western blots and quantitative real-time PCR assays. Reactive oxygen species (ROS) in RPE cells were detectedbydichloro-dihydro-fluorescein diacetate assays. The antioxidant apocynin was intraperitoneally injected into rats. Activating Rap1 by 8CPT significantly reduced CNV size and VEGF expression in the rat CNV model. Rap1 activation enhanced protein and mRNA levels of ZO-1 and occludin, two tight junction proteins in the RPE barrier. In addition, reducing ROS generation by injection of apocynin, a NADPH oxidase inhibitor, inhibited CNV formation. Rap1 activation reduced ROS generation and expression of NADPH oxidase 4. Rap1 activation inhibits CNV through regulating barrier integrity and ROS generation of RPE in vivo, and selectively activating Rap1 may be a way to reduce vision loss from CNV.

  11. Whats the Rap about Ecstasy? Popular Music Lyrics and Drug Trends among American Youth

    ERIC Educational Resources Information Center

    Diamond, Sarah; Bermudez, Rey; Schensul, Jean

    2006-01-01

    Trends in ecstasy use in America during the past decade were reflected in mainstream, American rap-music lyrics between 1996 and 2003. Drawing on communication and cultural studies theory, this article provides a content analysis of 69 rap songs mentioning the club drug ecstasy. The songs are coded according to whether they contain positive, mixed…

  12. The relationship between heavy metal and rap music and adolescent turmoil: real or artifact?

    PubMed

    Took, K J; Weiss, D S

    1994-01-01

    Adolescents and their parents were surveyed to investigate the association between heavy metal and rap music and adolescent psychosocial turmoil. Subjects were asked about current and past psychosocial functioning, as well as their music preferences. Adolescents who preferred heavy metal and rap music were compared with those who preferred other types of music. Results indicated that adolescents who preferred heavy metal and rap had a higher incidence of below-average school grades, school behavior problems, sexual activity, drug and alcohol use, and arrests. However, when gender was controlled, only below-average current and elementary school grades and a history of counseling in elementary school for school problems remained significant. Implications of these findings are discussed.

  13. RapGene: a fast and accurate strategy for synthetic gene assembly in Escherichia coli

    PubMed Central

    Zampini, Massimiliano; Stevens, Pauline Rees; Pachebat, Justin A.; Kingston-Smith, Alison; Mur, Luis A. J.; Hayes, Finbarr

    2015-01-01

    The ability to assemble DNA sequences de novo through efficient and powerful DNA fabrication methods is one of the foundational technologies of synthetic biology. Gene synthesis, in particular, has been considered the main driver for the emergence of this new scientific discipline. Here we describe RapGene, a rapid gene assembly technique which was successfully tested for the synthesis and cloning of both prokaryotic and eukaryotic genes through a ligation independent approach. The method developed in this study is a complete bacterial gene synthesis platform for the quick, accurate and cost effective fabrication and cloning of gene-length sequences that employ the widely used host Escherichia coli. PMID:26062748

  14. Effects of using nursing home residents to serve as group activity leaders: lessons learned from the RAP project.

    PubMed

    Skrajner, Michael J; Haberman, Jessica L; Camp, Cameron J; Tusick, Melanie; Frentiu, Cristina; Gorzelle, Gregg

    2014-03-01

    Previous research has demonstrated that persons with early to moderate stage dementia are capable of leading small group activities for persons with more advanced dementia. In this study, we built upon this previous work by training residents in long-term care facilities to fill the role of group activity leaders using a Resident-Assisted Programming (RAP) training regimen. There were two stages to the program. In the first stage, RAP training was provided by researchers. In the second stage, RAP training was provided to residents by activities staff members of long-term care facilities who had been trained by researchers. We examine the effects of RAP implemented by researchers and by activities staff member on long-term care resident with dementia who took part in these RAP activities. We also examined effects produced by two types of small group activities: two Montessori-based activities and an activity which focuses on persons with more advanced dementia, based on the work of Jitka Zgola. Results demonstrate that levels of positive engagement seen in players during RAP (resident-led activities) were typically higher than those observed during standard activities programming led by site staff. In general, Montessori-Based Dementia Programming® produced more constructive engagement than Zgola-based programming (ZBP), though ZBP did increase a positive form of engagement involving observing activities with interest. In addition, RAP implemented by activities staff members produced effects that were, on the whole, similar to those produced when RAP was implemented by researchers. Implications of these findings for providing meaningful social roles for persons with dementia residing in long-term care, and suggestions for further research in this area, are discussed.

  15. Evaluation of cement and fly ash treated RAP and aggregates for base construction : research project capsule

    DOT National Transportation Integrated Search

    2009-03-01

    INTRODUCTION: Many entities currently use recycled asphalt pavement (RAP) and other aggregates as base material, temporary haul roads, and in hot mix asphalt construction. Several states allow the use of RAP combined with cement for stabilized base c...

  16. Feeling the beat: the meaning of rap music for ethnically diverse Midwestern college students--a phenomenological study.

    PubMed

    Iwamoto, Derek K; Creswell, John; Caldwell, Leon

    2007-01-01

    Despite its national and international appeal, rap is considered one of the most controversial of music genres. Given the political charge it generates, rap music has spawned research across the social and health sciences. The majority of the research has investigated its impact on African Americans. Further, the research has tended to focus on negative aspects of the music; there has been a dearth of in-depth qualitative studies that explore how rap impacts the listener. Our phenomenological study explores that impact on ethnically diverse college students. Results indicate a profound psychological and educational effect and the discussion goes on to highlight the potential and innovative ways rap music can be utilized with adolescents in fields such as education, risk reduction programs, and counseling psychology.

  17. Pharmacological interventions for recurrent abdominal pain (RAP) in childhood.

    PubMed

    Huertas-Ceballos, A; Macarthur, C; Logan, S

    2002-01-01

    Between 4% and 25% of school age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority of such children no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions has been recommended. To determine the effectiveness of medication for recurrent abdominal pain in school-age children. The Cochrane Library (CENTRAL), MEDLINE, EMBASE, CINAHL, ERIC, PsycLIT, LILACS and JICST were searched using a strategy combining (Recurrent OR synonyms) AND (Abdomen OR synonyms) AND (Pain OR synonyms). Where appropriate search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. Any study in which the majority of participants were school age children fulfilling standard criteria for RAP, and who were allocated by random or quasi-random methods to any drug treatment compared with a placebo or no treatment. References identified by the searches were screened against the inclusion criteria by two independent reviewers. Only one trial met the inclusion criteria. This cross-over trial in 14 children who met suggested criteria for "abdominal migraine" compared pizotifen and placebo, each given for one month with no washout period. Participants reported a mean of 8.21 (95% CI 2.93, 13.48) fewer days of pain while taking the active drug. They also reported that the mean difference on an "Index of Severity" was -16.21 (95% CI -26.51, -5.90) and on an "Index of Misery" was -56.07 (95% CI -94.07, -18.07). There is little evidence to suggest that recommended drugs are effective in the management of RAP. At present there seems little justification for the use of these drugs other than in clinical trials. There is an urgent need for trials of all suggested pharmacologic interventions in children with RAP.

  18. Fatigue performance of asphalt pavements containing RAS and RAP.

    DOT National Transportation Integrated Search

    2015-01-01

    Rising oil and gas prices spurs development of methods and technologies for reducing fuel consumption and increased use of : recycled materials. With increased environmental awareness, using reclaimed asphalt pavement (RAP) and reclaimed asphalt : sh...

  19. Ethnic Identity, Self-Esteem and Variability in Perceptions of Rap Music's Empowering and Risky Influences

    ERIC Educational Resources Information Center

    Travis, Raphael; Bowman, Scott W.

    2012-01-01

    Violence, risky sexual behaviors, and substance use are critical targets for improved health behavior. Prior research has linked levels of exposure to rap music with a range of undesirable health behaviors. Contemporary research has also found health-enhancing and other "positive" correlations with rap music exposure. The present study examined…

  20. Images of sexual stereotypes in rap videos and the health of African American female adolescents.

    PubMed

    Peterson, Shani H; Wingood, Gina M; DiClemente, Ralph J; Harrington, Kathy; Davies, Susan

    2007-10-01

    This study sought to determine whether perceiving portrayals of sexual stereotypes in rap music videos was associated with adverse health outcomes among African American adolescent females. African American female adolescents (n = 522) were recruited from community venues. Adolescents completed a survey consisting of questions on sociodemographic characteristics, rap music video viewing habits, and a scale that assessed the primary predictor variable, portrayal of sexual stereotypes in rap music videos. Adolescents also completed an interview that assessed the health outcomes and provided urine for a marijuana screen. In logistic regression analyses, adolescents who perceived more portrayals of sexual stereotypes in rap music videos were more likely to engage in binge drinking (OR 3.8, 95% CI 1.32-11.04, p = 0.01), test positive for marijuana (OR 3.4, 95% CI 1.19-9.85, p = 0.02), have multiple sexual partners (OR 1.9, 95% CI 1.01-3.71, p = 0.04), and have a negative body image (OR 1.5, 95% CI 1.02-2.26, p = 0.04). This is one of the first studies quantitatively examining the relationship between cultural images of sexual stereotypes in rap music videos and a spectrum of adverse health outcomes in African American female adolescents. Greater attention to this social issue may improve the health of all adolescent females.

  1. Rap and Technology Teach the Art of Argument

    ERIC Educational Resources Information Center

    Fink, Rosalie

    2017-01-01

    How can teachers integrate rap and technology strategies to teach students with learning disabilities the art of persuasive argument writing? This teacher research study presents creative new approaches for teaching argument writing. Strategies used in the study helped college freshmen with learning disabilities (LD) succeed in developing…

  2. 40 CFR 270.230 - May I perform remediation waste management activities under a RAP at a location removed from the...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... management activities under a RAP at a location removed from the area where the remediation wastes originated... management activities under a RAP at a location removed from the area where the remediation wastes originated? (a) You may request a RAP for remediation waste management activities at a location removed from the...

  3. 40 CFR 270.230 - May I perform remediation waste management activities under a RAP at a location removed from the...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... management activities under a RAP at a location removed from the area where the remediation wastes originated... management activities under a RAP at a location removed from the area where the remediation wastes originated? (a) You may request a RAP for remediation waste management activities at a location removed from the...

  4. 40 CFR 270.230 - May I perform remediation waste management activities under a RAP at a location removed from the...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false May I perform remediation waste management activities under a RAP at a location removed from the area where the remediation wastes originated... Plans (RAPs) Obtaining A Rap for An Off-Site Location § 270.230 May I perform remediation waste...

  5. Escaping Embarrassment: Face-Work in the Rap Cipher

    ERIC Educational Resources Information Center

    Lee, Jooyoung

    2009-01-01

    How do individuals escape embarrassing moments in interaction? Drawing from ethnographic fieldwork, in-depth interviews, and video recordings of weekly street corner ciphers (impromptu rap sessions), this paper expands Goffman's theory of defensive and protective face-work. The findings reveal formulaic and indirect dimensions of face-work. First,…

  6. Evaluation of the engineering characteristics of RAP/Aggregate blends.

    DOT National Transportation Integrated Search

    2005-07-01

    "This report describes results from a research program that was structured to evaluate the : suitability of using reclaimed and recycled asphalt pavement (RAP) as an additive to crushed : angular aggregate or pit run granular soils. Research and test...

  7. Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids.

    PubMed

    Nanavaty, Vishal; Sandhu, Ranjodh; Jehi, Sanaa E; Pandya, Unnati M; Li, Bibo

    2017-06-02

    Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching. Importantly, TbRAP1 depletion increases the TERRA level, which appears to result from longer read-through into the telomere downstream of the active ES. Depletion of TbRAP1 also results in more telomeric RNA:DNA hybrids and more double strand breaks (DSBs) at telomeres and subtelomeres. In TbRAP1-depleted cells, expression of excessive TbRNaseH1, which cleaves the RNA strand of the RNA:DNA hybrid, brought telomeric RNA:DNA hybrids, telomeric/subtelomeric DSBs and VSG switching frequency back to WT levels. Therefore, TbRAP1-regulated appropriate levels of TERRA and telomeric RNA:DNA hybrid are fundamental to subtelomere/telomere integrity. Our study revealed for the first time an important role of a long, non-coding RNA in antigenic variation and demonstrated a link between telomeric silencing and subtelomere/telomere integrity through TbRAP1-regulated telomere transcription. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  8. Hybrid Texts: Fifth Graders, Rap Music, and Writing

    ERIC Educational Resources Information Center

    Christianakis, Mary

    2011-01-01

    Consistent with a sociocritical frame and the analytic tools of hybridity theory, this article explicates how urban fifth-grade children made language hybrids using rap and poetry to participate in classroom literacy. Ethnographic data from a yearlong study illustrate two key findings. First, standards-based and canon-driven writing models…

  9. Using Chou's general PseAAC to analyze the evolutionary relationship of receptor associated proteins (RAP) with various folding patterns of protein domains.

    PubMed

    Muthu Krishnan, S

    2018-05-14

    The receptor-associated protein (RAP) is an inhibitor of endocytic receptors that belong to the lipoprotein receptor gene family. In this study, a computational approach was tried to find the evolutionarily related fold of the RAP proteins. Through the structural and sequence-based analysis, found various protein folds that are very close to the RAP folds. Remote homolog datasets were used potentially to develop a different support vector machine (SVM) methods to recognize the homologous RAP fold. This study helps in understanding the relationship of RAP homologs folds based on the structure, function and evolutionary history. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke.

    PubMed

    Gore, Aniket V; Lampugnani, Maria Grazia; Dye, Louis; Dejana, Elisabetta; Weinstein, Brant M

    2008-01-01

    Intracranial hemorrhage (ICH) is a particularly severe form of stroke whose etiology remains poorly understood, with a highly variable appearance and onset of the disease (Felbor et al., 2006; Frizzell, 2005; Lucas et al., 2003). In humans, mutations in any one of three CCM genes causes an autosomal dominant genetic ICH disorder characterized by cerebral cavernous malformations (CCM). Recent evidence highlighting multiple interactions between the three CCM gene products and other proteins regulating endothelial junctional integrity suggests that minor deficits in these other proteins could potentially predispose to, or help to initiate, CCM, and that combinations of otherwise silent genetic deficits in both the CCM and interacting proteins might explain some of the variability in penetrance and expressivity of human ICH disorders. Here, we test this idea by combined knockdown of CCM pathway genes in zebrafish. Reducing the function of rap1b, which encodes a Ras GTPase effector protein for CCM1/Krit1, disrupts endothelial junctions in vivo and in vitro, showing it is a crucial player in the CCM pathway. Importantly, a minor reduction of Rap1b in combination with similar reductions in the products of other CCM pathway genes results in a high incidence of ICH. These findings support the idea that minor polygenic deficits in the CCM pathway can strongly synergize to initiate ICH.

  11. Development of RAP Tag, a Novel Tagging System for Protein Detection and Purification.

    PubMed

    Fujii, Yuki; Kaneko, Mika K; Ogasawara, Satoshi; Yamada, Shinji; Yanaka, Miyuki; Nakamura, Takuro; Saidoh, Noriko; Yoshida, Kanae; Honma, Ryusuke; Kato, Yukinari

    2017-04-01

    Affinity tag systems, possessing high affinity and specificity, are useful for protein detection and purification. The most suitable tag for a particular purpose should be selected from many available affinity tag systems. In this study, we developed a novel affinity tag called the "RAP tag" system, which comprises a mouse antirat podoplanin monoclonal antibody (clone PMab-2) and the RAP tag (DMVNPGLEDRIE). This system is useful not only for protein detection in Western blotting, flow cytometry, and sandwich enzyme-linked immunosorbent assay, but also for protein purification.

  12. Hip Hop Therapy: An Exploratory Study of a Rap Music Intervention with At-Risk and Delinquent Youth.

    ERIC Educational Resources Information Center

    Tyson, Edgar H.

    2002-01-01

    Presents an exploratory study of the therapeutic potential of "Hip-Hop" therapy, an "innovative synergy of rap music, bibliotherapy, and music therapy." Finds that the quantitative and qualitative results partially supported the hypothesis that under a specific set of conditions rap music would improve the therapeutic…

  13. RasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating Rap1 small GTPase.

    PubMed

    Tang, Songqing; Chen, Taoyong; Yu, Zhou; Zhu, Xuhui; Yang, Mingjin; Xie, Bin; Li, Nan; Cao, Xuetao; Wang, Jianli

    2014-08-14

    Host immune cells can detect and destruct invading pathogens via pattern-recognition receptors. Small Rap GTPases act as conserved molecular switches coupling extracellular signals to various cellular responses, but their roles as regulators in Toll-like receptor (TLR) signalling have not been fully elucidated. Here we report that Ras guanine nucleotide-releasing protein 3 (RasGRP3), a guanine nucleotide-exchange factor activating Ras and Rap1, limits production of proinflammatory cytokines (especially IL-6) in macrophages by activating Rap1 on activation by low levels of TLR agonists. We demonstrate that RasGRP3, a dominant member of RasGRPs in macrophages, impairs TLR3/4/9-induced IL-6 production and relieves dextrane sulphate sodium-induced colitis and collagen-induced arthritis. In RasGRP3-deficient RAW264.7 cells obtained by CRISPR-Cas9 genome editing, TLR3/4/9-induced activation of Rap1 was inhibited while ERK1/2 activation was enhanced. Our study suggests that RasGRP3 limits inflammatory response by activating Rap1 on low-intensity pathogen infection, setting a threshold for preventing excessive inflammatory response.

  14. 40 CFR 270.145 - What are the procedures for public comment on the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... comment on the draft RAP or notice of intent to deny? 270.145 Section 270.145 Protection of Environment... procedures for public comment on the draft RAP or notice of intent to deny? (a) The Director must: (1) Send... for the public to submit written comments on the draft RAP or notice of intent to deny within at least...

  15. 40 CFR 270.145 - What are the procedures for public comment on the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... comment on the draft RAP or notice of intent to deny? 270.145 Section 270.145 Protection of Environment... procedures for public comment on the draft RAP or notice of intent to deny? (a) The Director must: (1) Send... for the public to submit written comments on the draft RAP or notice of intent to deny within at least...

  16. 40 CFR 270.145 - What are the procedures for public comment on the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... comment on the draft RAP or notice of intent to deny? 270.145 Section 270.145 Protection of Environment... procedures for public comment on the draft RAP or notice of intent to deny? (a) The Director must: (1) Send... for the public to submit written comments on the draft RAP or notice of intent to deny within at least...

  17. 40 CFR 270.145 - What are the procedures for public comment on the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... comment on the draft RAP or notice of intent to deny? 270.145 Section 270.145 Protection of Environment... procedures for public comment on the draft RAP or notice of intent to deny? (a) The Director must: (1) Send... for the public to submit written comments on the draft RAP or notice of intent to deny within at least...

  18. 40 CFR 270.145 - What are the procedures for public comment on the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... comment on the draft RAP or notice of intent to deny? 270.145 Section 270.145 Protection of Environment... procedures for public comment on the draft RAP or notice of intent to deny? (a) The Director must: (1) Send... for the public to submit written comments on the draft RAP or notice of intent to deny within at least...

  19. Effects of recycled shingles and increased RAP percentages : [research brief].

    DOT National Transportation Integrated Search

    2012-01-01

    As asphalt binder becomes more expensive, the use of recycled asphalt materials becomes : more attractive. Recycled asphalt pavement (RAP) and recycled asphalt shingles (RAS) offer a partial substitute for virgin aggregate and binder in asphalt pavem...

  20. Pathways of Intergenerational Transmission of Advantages during Adolescence: Social Background, Cognitive Ability, and Educational Attainment.

    PubMed

    Schulz, Wiebke; Schunck, Reinhard; Diewald, Martin; Johnson, Wendy

    2017-10-01

    Educational attainment in adolescence is of paramount importance for attaining higher education and for shaping subsequent life chances. Sociological accounts focus on the role of differences in socioeconomic resources in intergenerational reproduction of educational inequalities. These often disregard the intergenerational transmission of cognitive ability and the importance of children's cognitive ability to educational attainment. Psychological perspectives stress the importance of cognitive ability for educational attainment but underemphasize potentially different roles of specific socioeconomic resources in shaping educational outcomes, as well as individual differences in cognitive ability. By integrating two strands of research, a clearer picture of the pathways linking the family of origin, cognitive ability, and early educational outcomes can be reached. Using the population-based TwinLife study in Germany, we investigated multidimensional pathways linking parental socioeconomic position to their children's cognitive ability and academic track attendance in the secondary school. The sample included twins (N = 4008), respectively ages 11 and 17, and siblings (N = 801). We observed strong genetic influences on cognitive ability, whereas shared environmental influences were much more important for academic tracking. In multilevel analyses, separate dimensions of socioeconomic resources influenced child cognitive ability, controlling parental cognitive ability. Controlling adolescent cognitive ability and parental cognitive ability, parental socioeconomic resources also directly affected track attendance. This indicated that it is crucial to investigate the intertwined influences on educational outcomes in adolescence of both cognitive ability and the characteristics of the family of origin.

  1. [Cloning of VH and VL Gene of Human anti-IL1RAP McAb and Construction of Recombinant Chimeric Receptor].

    PubMed

    Yin, Ling-Ling; Ruan, Su-Hong; Tian, Yu; Zhao, Kai; Xu, Kai Lin

    2015-10-01

    To clone the variable region genes of human anti-IL1RAP (IL-1 receptor accessory protein) monoclonal antibodies (McAb) and to construct IL1RAP chimeric antigen receptors (CARs). The VH and VL DNA of IL1RAP single chain antibodies were amplified by RACE and overlap extension PCR from total RNA extracted from 3H6E10 and 10D8A7 hybridoma and ligated into specific IL1RAP single-chain variable fragments (scFv). CD8α transmembrane domain, CD137 intracellular domain, TCR ζ chain, human CD8α signal peptide and scFv-anti-IL1RAP were cloned into plasmid LV-lac. Recombinant lentiviruses were generated by co-transfection of recombinant plasmid LV-lac, pMD2. G, and psPAX2 helper vectors into 293FT packing cells. The VH and VL genes of 2 human anti-IL1RAP McAb were acquired. The 3H6E10 VH and VL genes consisted of 402 bp and 393 bp encoding 134 and 131 aminoacid residues, respectively; 10D8A7 VH and VL genes consisted of 423 bp and 381 bp encoding 141 and 127 amine acid residues, respectively. Recombinant expression vertors LV-3H6E10 scFv-ICD and LV-10D8A7 scFv-ICD (ICD: CD8α transmembrane domain-CD137 intracellular domain-TCR ζ chain) were constructed. The target fragments were demonstrated by sequencing analysis. Recombinant plasmids were transfected into 293FT cells and lentiviral particles were acquired. Human anti-IL1RAP recombinant receptors are constructed successfully and lay a good foundation for the construction of IL1RAP-CAR killer T cell vaccine.

  2. RapA2 Is a Calcium-binding Lectin Composed of Two Highly Conserved Cadherin-like Domains That Specifically Recognize Rhizobium leguminosarum Acidic Exopolysaccharides*

    PubMed Central

    Abdian, Patricia L.; Caramelo, Julio J.; Ausmees, Nora; Zorreguieta, Angeles

    2013-01-01

    In silico analyses have revealed a conserved protein domain (CHDL) widely present in bacteria that has significant structural similarity to eukaryotic cadherins. A CHDL domain was shown to be present in RapA, a protein that is involved in autoaggregation of Rhizobium cells, biofilm formation, and adhesion to plant roots as shown by us and others. Structural similarity to cadherins suggested calcium-dependent oligomerization of CHDL domains as a mechanistic basis for RapA action. Here we show by circular dichroism spectroscopy, light scattering, isothermal titration calorimetry, and other methods that RapA2 from Rhizobium leguminosarum indeed exhibits a cadherin-like β-sheet conformation and that its proper folding and stability are dependent on the binding of one calcium ion per protein molecule. By further in silico analysis we also reveal that RapA2 consists of two CHDL domains and expand the range of CHDL-containing proteins in bacteria and archaea. However, light scattering assays at various concentrations of added calcium revealed that RapA2 formed neither homo-oligomers nor hetero-oligomers with RapB (a distinct CHDL protein), indicating that RapA2 does not mediate cellular interactions through a cadherin-like mechanism. Instead, we demonstrate that RapA2 interacts specifically with the acidic exopolysaccharides (EPSs) produced by R. leguminosarum in a calcium-dependent manner, sustaining a role of these proteins in the development of the biofilm matrix made of EPS. Because EPS binding by RapA2 can only be attributed to its two CHDL domains, we propose that RapA2 is a calcium-dependent lectin and that CHDL domains in various bacterial and archaeal proteins confer carbohydrate binding activity to these proteins. PMID:23235153

  3. Installation and operation of a large scale RAPS system in Peru

    NASA Astrophysics Data System (ADS)

    Cole, J. F.

    In 1997, International Lead Zinc Research Organization Inc. (ILZRO), Solar Energy Industries Association (SEIA), and the Ministry of Energy and Mines (MEM) of Peru signed a Memorandum of Understanding to facilitate the installation of hybrid remote area power supply (RAPS) systems in the Amazon region of Peru. Many remote villages in this vast region have either no or limited electricity supplied by diesel generators running a few hours per day. Subsequently, ILZRO sponsored the engineering design of the hybrid RAPS system and SEIA supported a socio-economic study to determine the sustainability of such systems and the locations for pilot installations. In mid-1998, the Peruvian government approved the design of the system. ILZRO then began efforts to obtain governmental and inter-governmental funding to supplement its own funds to underwrite the cost of manufacture and installation of the systems in two villages in the Amazon region. Additional major funding has been received from the Global Environmental Facility (GEF) administered by the United Nations Development Program (UNDP) and from the Common Fund for Commodities (CFC). Funds have also been received from the US Department of Energy, the International Greenhouse Partnership (Australia) and the Peruvian government. The RAPS system consists of modules designed to provide 150 kW h per day of utility grade ac electricity over a 24 h period. Each module contains a diesel generator, battery bank using heavy-duty 2 V VRLA GEL batteries, a battery charger, a photovoltaic array and an ac/dc inverter. The batteries and electrical components are housed in modified shipping containers. The modules can be installed with a new generator or retrofitted to an existing generator. The charging and discharging regime of the batteries has been recommended by a study carried out by CSIRO, which has simulated the RAPS operation. The system will employ a partial-state-of-charge (PSOC) regime in order to optimize the life of the

  4. Open-Source Wax RepRap 3-D Printer for Rapid Prototyping Paper-Based Microfluidics.

    PubMed

    Pearce, J M; Anzalone, N C; Heldt, C L

    2016-08-01

    The open-source release of self-replicating rapid prototypers (RepRaps) has created a rich opportunity for low-cost distributed digital fabrication of complex 3-D objects such as scientific equipment. For example, 3-D printable reactionware devices offer the opportunity to combine open hardware microfluidic handling with lab-on-a-chip reactionware to radically reduce costs and increase the number and complexity of microfluidic applications. To further drive down the cost while improving the performance of lab-on-a-chip paper-based microfluidic prototyping, this study reports on the development of a RepRap upgrade capable of converting a Prusa Mendel RepRap into a wax 3-D printer for paper-based microfluidic applications. An open-source hardware approach is used to demonstrate a 3-D printable upgrade for the 3-D printer, which combines a heated syringe pump with the RepRap/Arduino 3-D control. The bill of materials, designs, basic assembly, and use instructions are provided, along with a completely free and open-source software tool chain. The open-source hardware device described here accelerates the potential of the nascent field of electrochemical detection combined with paper-based microfluidics by dropping the marginal cost of prototyping to nearly zero while accelerating the turnover between paper-based microfluidic designs. © 2016 Society for Laboratory Automation and Screening.

  5. Rasip1 regulates vertebrate vascular endothelial junction stability through Epac1-Rap1 signaling

    PubMed Central

    Wilson, Christopher W.; Parker, Leon H.; Hall, Christopher J.; Smyczek, Tanya; Mak, Judy; Crow, Ailey; Posthuma, George; De Mazière, Ann; Sagolla, Meredith; Chalouni, Cecile; Vitorino, Philip; Roose-Girma, Merone; Warming, Søren; Klumperman, Judith; Crosier, Philip S.

    2013-01-01

    Establishment and stabilization of endothelial tubes with patent lumens is vital during vertebrate development. Ras-interacting protein 1 (RASIP1) has been described as an essential regulator of de novo lumenogenesis through modulation of endothelial cell (EC) adhesion to the extracellular matrix (ECM). Here, we show that in mouse and zebrafish embryos, Rasip1-deficient vessels transition from an angioblast cord to a hollow tube, permit circulation of primitive erythrocytes, but ultimately collapse, leading to hemorrhage and embryonic lethality. Knockdown of RASIP1 does not alter EC-ECM adhesion, but causes cell-cell detachment and increases permeability of EC monolayers in vitro. We also found that endogenous RASIP1 in ECs binds Ras-related protein 1 (RAP1), but not Ras homolog gene family member A or cell division control protein 42 homolog. Using an exchange protein directly activated by cyclic adenosine monophosphate 1 (EPAC1)-RAP1–dependent model of nascent junction formation, we demonstrate that a fraction of the RASIP1 protein pool localizes to cell-cell contacts. Loss of RASIP1 phenocopies loss of RAP1 or EPAC1 in ECs by altering junctional actin organization, localization of the actin-bundling protein nonmuscle myosin heavy chain IIB, and junction remodeling. Our data show that RASIP1 regulates the integrity of newly formed blood vessels as an effector of EPAC1-RAP1 signaling. PMID:23886837

  6. Photometric redshift estimation based on data mining with PhotoRApToR

    NASA Astrophysics Data System (ADS)

    Cavuoti, S.; Brescia, M.; De Stefano, V.; Longo, G.

    2015-03-01

    Photometric redshifts (photo-z) are crucial to the scientific exploitation of modern panchromatic digital surveys. In this paper we present PhotoRApToR (Photometric Research Application To Redshift): a Java/C ++ based desktop application capable to solve non-linear regression and multi-variate classification problems, in particular specialized for photo-z estimation. It embeds a machine learning algorithm, namely a multi-layer neural network trained by the Quasi Newton learning rule, and special tools dedicated to pre- and post-processing data. PhotoRApToR has been successfully tested on several scientific cases. The application is available for free download from the DAME Program web site.

  7. Re-active Passive (RAP) Devices for Control of Noise Transmission through a Panel

    NASA Technical Reports Server (NTRS)

    Carneal, James P.; Giovanardi, Marco; Fuller, Chris R.; Palumbo, Daniel L.

    2008-01-01

    Re-Active Passive (RAP) devices have been developed to control low frequency (<1000 Hz) noise transmission through a panel. These devices use a combination of active, re-active, and passive technologies packaged into a single unit to control a broad frequency range utilizing the strength of each technology over its best suited frequency range. The RAP device uses passive constrained layer damping to cover the relatively high frequency range (>200 Hz), reactive distributed vibration absorber) to cover the medium frequency range (75 to 250 Hz), and active control for controlling low frequencies (<200 Hz). The device was applied to control noise transmission through a panel mounted in a transmission loss test facility. Experimental results are presented for the bare panel, and combinations of passive treatment, reactive treatment, and active control. Results indicate that three RAP devices were able to increase the overall broadband (15-1000 Hz) transmission loss by 9.4 dB. These three devices added a total of 285 grams to the panel mass of 6.0 kg, or approximately 5%, not including control electronics.

  8. Evaluation of stone/RAP interlayers under accelerated loading : technical summary.

    DOT National Transportation Integrated Search

    2008-08-01

    The primary objective of this study was to determine the effectiveness of using an untreated RAP interlayer in lieu of a stone interlayer in a soil-cement asphalt pavement structure under accelerated loading. The secondary objective was to investigat...

  9. Say It Loud! The Story of Rap Music.

    ERIC Educational Resources Information Center

    Jones, K. Maurice

    Rap, a popular music that emerged in the United States during the 1980s and 90s, is described as a creation of young African American culture. It belongs to a centuries old legacy of using language creatively in everyday life. The roots of the music are seen as part of the African-American oral and musical traditions that encompass the hidden…

  10. Product (P1) from project 0-6738 : performance studies and future directions for mixes containing RAP and RAS.

    DOT National Transportation Integrated Search

    2013-01-01

    In recent years both reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) have been widely used in asphalt mixes by the asphalt paving industry in Texas. The use of RAP and RAS can save tax payers money, and it is also good for the...

  11. 40 CFR 270.140 - What else must the Director prepare in addition to the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... addition to the draft RAP or notice of intent to deny? 270.140 Section 270.140 Protection of Environment... the Director prepare in addition to the draft RAP or notice of intent to deny? Once the Director has prepared the draft RAP or notice of intent to deny, he must then: (a) Prepare a statement of basis that...

  12. 40 CFR 270.140 - What else must the Director prepare in addition to the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... addition to the draft RAP or notice of intent to deny? 270.140 Section 270.140 Protection of Environment... the Director prepare in addition to the draft RAP or notice of intent to deny? Once the Director has prepared the draft RAP or notice of intent to deny, he must then: (a) Prepare a statement of basis that...

  13. 40 CFR 270.140 - What else must the Director prepare in addition to the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... addition to the draft RAP or notice of intent to deny? 270.140 Section 270.140 Protection of Environment... the Director prepare in addition to the draft RAP or notice of intent to deny? Once the Director has prepared the draft RAP or notice of intent to deny, he must then: (a) Prepare a statement of basis that...

  14. 40 CFR 270.140 - What else must the Director prepare in addition to the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... addition to the draft RAP or notice of intent to deny? 270.140 Section 270.140 Protection of Environment... the Director prepare in addition to the draft RAP or notice of intent to deny? Once the Director has prepared the draft RAP or notice of intent to deny, he must then: (a) Prepare a statement of basis that...

  15. Feeling the Beat: The Meaning of Rap Music for Ethnically Diverse Midwestern College Students--A Phenomenological Study

    ERIC Educational Resources Information Center

    Iwamoto, Derek K.; Creswell, John; Caldwell, Leon

    2007-01-01

    Despite its national and international appeal, rap is considered one of the most controversial of music genres. Given the political charge it generates, rap music has spawned research across the social and health sciences. The majority of the research has investigated its impact on African Americans. Further, the research has tended to focus on…

  16. Nitrogen-responsive Regulation of GATA Protein Family Activators Gln3 and Gat1 Occurs by Two Distinct Pathways, One Inhibited by Rapamycin and the Other by Methionine Sulfoximine*

    PubMed Central

    Georis, Isabelle; Tate, Jennifer J.; Cooper, Terrance G.; Dubois, Evelyne

    2011-01-01

    Nitrogen availability regulates the transcription of genes required to degrade non-preferentially utilized nitrogen sources by governing the localization and function of transcription activators, Gln3 and Gat1. TorC1 inhibitor, rapamycin (Rap), and glutamine synthetase inhibitor, methionine sulfoximine (Msx), elicit responses grossly similar to those of limiting nitrogen, implicating both glutamine synthesis and TorC1 in the regulation of Gln3 and Gat1. To better understand this regulation, we compared Msx- versus Rap-elicited Gln3 and Gat1 localization, their DNA binding, nitrogen catabolite repression-sensitive gene expression, and the TorC1 pathway phosphatase requirements for these responses. Using this information we queried whether Rap and Msx inhibit sequential steps in a single, linear cascade connecting glutamine availability to Gln3 and Gat1 control as currently accepted or alternatively inhibit steps in two distinct parallel pathways. We find that Rap most strongly elicits nuclear Gat1 localization and expression of genes whose transcription is most Gat1-dependent. Msx, on the other hand, elicits nuclear Gln3 but not Gat1 localization and expression of genes that are most Gln3-dependent. Importantly, Rap-elicited nuclear Gln3 localization is absolutely Sit4-dependent, but that elicited by Msx is not. PP2A, although not always required for nuclear GATA factor localization, is highly required for GATA factor binding to nitrogen-responsive promoters and subsequent transcription irrespective of the gene GATA factor specificities. Collectively, our data support the existence of two different nitrogen-responsive regulatory pathways, one inhibited by Msx and the other by rapamycin. PMID:22039046

  17. Nitrogen-responsive regulation of GATA protein family activators Gln3 and Gat1 occurs by two distinct pathways, one inhibited by rapamycin and the other by methionine sulfoximine.

    PubMed

    Georis, Isabelle; Tate, Jennifer J; Cooper, Terrance G; Dubois, Evelyne

    2011-12-30

    Nitrogen availability regulates the transcription of genes required to degrade non-preferentially utilized nitrogen sources by governing the localization and function of transcription activators, Gln3 and Gat1. TorC1 inhibitor, rapamycin (Rap), and glutamine synthetase inhibitor, methionine sulfoximine (Msx), elicit responses grossly similar to those of limiting nitrogen, implicating both glutamine synthesis and TorC1 in the regulation of Gln3 and Gat1. To better understand this regulation, we compared Msx- versus Rap-elicited Gln3 and Gat1 localization, their DNA binding, nitrogen catabolite repression-sensitive gene expression, and the TorC1 pathway phosphatase requirements for these responses. Using this information we queried whether Rap and Msx inhibit sequential steps in a single, linear cascade connecting glutamine availability to Gln3 and Gat1 control as currently accepted or alternatively inhibit steps in two distinct parallel pathways. We find that Rap most strongly elicits nuclear Gat1 localization and expression of genes whose transcription is most Gat1-dependent. Msx, on the other hand, elicits nuclear Gln3 but not Gat1 localization and expression of genes that are most Gln3-dependent. Importantly, Rap-elicited nuclear Gln3 localization is absolutely Sit4-dependent, but that elicited by Msx is not. PP2A, although not always required for nuclear GATA factor localization, is highly required for GATA factor binding to nitrogen-responsive promoters and subsequent transcription irrespective of the gene GATA factor specificities. Collectively, our data support the existence of two different nitrogen-responsive regulatory pathways, one inhibited by Msx and the other by rapamycin.

  18. Expanding Biosensing Abilities through Computer-Aided Design of Metabolic Pathways.

    PubMed

    Libis, Vincent; Delépine, Baudoin; Faulon, Jean-Loup

    2016-10-21

    Detection of chemical signals is critical for cells in nature as well as in synthetic biology, where they serve as inputs for designer circuits. Important progress has been made in the design of signal processing circuits triggering complex biological behaviors, but the range of small molecules recognized by sensors as inputs is limited. The ability to detect new molecules will increase the number of synthetic biology applications, but direct engineering of tailor-made sensors takes time. Here we describe a way to immediately expand the range of biologically detectable molecules by systematically designing metabolic pathways that transform nondetectable molecules into molecules for which sensors already exist. We leveraged computer-aided design to predict such sensing-enabling metabolic pathways, and we built several new whole-cell biosensors for molecules such as cocaine, parathion, hippuric acid, and nitroglycerin.

  19. Geeksta Rap: An Example of the Utilization of Elements of Popular Culture in Science Education and Outreach

    NASA Astrophysics Data System (ADS)

    Hall, F.; Otto, A.

    2003-12-01

    Science education and outreach efforts must compete for the attention of students in an environment filled with many distractions. Many of the most compelling of these distractions arise from popular culture. Rather than bemoaning this situation, we propose that we make use of some of those elements of popular culture which garner the most attention. In particular, we propose that we utilize the popularity of current hip-hop and rap music in science education and outreach efforts. To that end, we present some examples of what we call `geeksta rap' and discuss some of the considerations relevant for its preparation. We also discuss various uses of `geeksta rap' in science education and outreach.

  20. Roles of JnRAP2.6-like from the transition zone of black walnut in hormone signaling

    Treesearch

    Zhonglian Huang; Peng Zhao; Jose Medina; Richard Meilan; Keith Woeste

    2013-01-01

    An EST sequence, designated JnRAP2-like, was isolated from tissue at the heartwood/sapwood transition zone (TZ) in black walnut (Juglans nigra L). The deduced amino acid sequence of JnRAP2-like protein consists of a single AP2- containing domain with significant similarity to conserved AP2/ERF DNA-binding domains in other...

  1. CAGE, RAPS4, RAPS4-QF and AUDIT Screening Tests for Men and Women Admitted for Acute Alcohol Intoxication to an Emergency Department: Are Standard Thresholds Appropriate?

    PubMed Central

    Geneste, J.; Pereira, B.; Arnaud, B.; Christol, N.; Liotier, J.; Blanc, O.; Teissedre, F.; Hope, S.; Schwan, R.; Llorca, P.M.; Schmidt, J.; Cherpitel, C.J.; Malet, L.; Brousse, G.

    2012-01-01

    Aims: A number of screening instruments are routinely used in Emergency Department (ED) situations to identify alcohol-use disorders (AUD). We wished to study the psychometric features, particularly concerning optimal thresholds scores (TSs), of four assessment scales frequently used to screen for abuse and/or dependence, the cut-down annoyed guilty eye-opener (CAGE), Rapid Alcohol Problem Screen 4 (RAPS4), RAPS4-quantity-frequency and AUD Identification Test (AUDIT) questionnaires, particularly in the sub-group of people admitted for acute alcohol intoxication (AAI). Methods: All included patients [AAI admitted to ED (blood alcohol level ≥0.8 g/l)] were assessed by the four scales, and with a gold standard (alcohol dependence⁄abuse section of the Mini International Neuropsychiatric Interview), to determine AUD status. To investigate the TSs of the scales, we used Youden's index, efficiency, receiver operating characteristic (ROC) curve techniques and quality ROC curve technique for optimized TS (indices of quality). Results: A total of 164 persons (122 males, 42 females) were included in the study. Nineteen (11.60%) were identified as alcohol abusers alone and 128 (78.1%) as alcohol dependents (DSM-IV). Results suggest a statistically significant difference between men and women (P < 0.05) in performance of the screening tests RAPS4 (≥1) and CAGE (≥2) for detecting abuse. Also, in this population, we show an increase in TSs of RAPS4 (≥2) and CAGE (≥3) for detecting dependence compared with those typically accepted in non-intoxicated individuals. The AUDIT test demonstrates good performance for detecting alcohol abuse and/or alcohol-dependent patients (≥7 for women and ≥12 for men) and for distinguishing alcohol dependence (≥11 for women and ≥14 for men) from other conditions. Conclusion: Our study underscores for the first time the need to adapt, taking into account gender, the thresholds of tests typically used for detection of abuse and

  2. Laboratory testing and economic analysis of high RAP warm mixed asphalt.

    DOT National Transportation Integrated Search

    2009-03-24

    This report contains laboratory testing, economic analysis, literature review, and information obtained from multiple producers throughout the state of Mississippi regarding the use of high RAP (50 % to 100%) mixtures containing warm mix additives. T...

  3. Multilingual Codeswitching in Quebec Rap: Poetry, Pragmatics and Performativity

    ERIC Educational Resources Information Center

    Sarkar, Mela; Winer, Lise

    2006-01-01

    Quebec rap lyrics stand out on the world Hip-Hop scene by virtue of the ease and rapidity with which performers in this multilingual, multiethnic youth community codeswitch, frequently among three or more languages or language varieties (usually over a French and/or English base) in the same song. We construct a framework for understanding…

  4. Migrant Rap in the Periphery: Performing Politics of Belonging

    ERIC Educational Resources Information Center

    Leppänen, Sirpa; Westinen, Elina

    2017-01-01

    Focusing on a YouTube performance by an emergent Finnish Somali rapper and the audience responses it has generated, this paper looks at ways in which rap music engages with the issue of belonging. Drawing on recent theorizations of belonging as a multi-dimensional, contingent and fluid process, along with sociolinguistic work on globalization and…

  5. Comprehensive Chemical Characterization of Rapé Tobacco Products: Nicotine, Un-ionized Nicotine, Tobacco-specific N’-Nitrosamines, Polycyclic Aromatic Hydrocarbons, and Flavor Constituents

    PubMed Central

    Stanfill, Stephen B.; da Silva, André Luiz Oliveira; Lisko, Joseph G.; Lawler, Tameka S.; Kuklenyik, Peter; Tyx, Robert E.; Peuchen, Elizabeth H.; Richter, Patricia; Watson, Clifford H.

    2017-01-01

    Rapé, a diverse group of smokeless tobacco products indigenous to South America, is generally used as a nasal snuff and contains substantial amount of plant material with or without tobacco. Previously uncharacterized, rapé contains addictive and harmful chemicals that may have public health implications for users. Here we report % moisture, pH and the levels of total nicotine, un-ionized nicotine, flavor-related compounds, tobacco-specific N-nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) for manufactured and hand-made rapé. Most rapé products were mildly acidic (pH 5.17 – 6.23) with total nicotine ranging from 6.32 to 47.6 milligram per gram of sample (mg/g). Calculated un-ionized nicotine ranged from 0.03 to 18.5 mg/g with the highest values associated with hand-made rapés (pH 9.75 – 10.2), which contain alkaline ashes. In tobacco-containing rapés, minor alkaloid levels and Fourier transform infrared spectra were used to confirm the presence of Nicotiana rustica, a high nicotine tobacco species. There was a wide concentration range of TSNAs and PAHs among the rapés analyzed. Several TSNAs and PAHs identified in the products are known or probable carcinogens according to the International Agency for Research in Cancer. Milligram quantities of some non-tobacco constituents, such as camphor, coumarin, and eugenol, warrant additional evaluation. PMID:25934468

  6. Comprehensive chemical characterization of Rapé tobacco products: Nicotine, un-ionized nicotine, tobacco-specific N'-nitrosamines, polycyclic aromatic hydrocarbons, and flavor constituents.

    PubMed

    Stanfill, Stephen B; Oliveira da Silva, André Luiz; Lisko, Joseph G; Lawler, Tameka S; Kuklenyik, Peter; Tyx, Robert E; Peuchen, Elizabeth H; Richter, Patricia; Watson, Clifford H

    2015-08-01

    Rapé, a diverse group of smokeless tobacco products indigenous to South America, is generally used as a nasal snuff and contains substantial amount of plant material with or without tobacco. Previously uncharacterized, rapé contains addictive and harmful chemicals that may have public health implications for users. Here we report % moisture, pH, and the levels of total nicotine, un-ionized nicotine, flavor-related compounds, tobacco-specific N-nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) for manufactured and hand-made rapé. Most rapé products were mildly acidic (pH 5.17-6.23) with total nicotine ranging from 6.32 to 47.6 milligram per gram of sample (mg/g). Calculated un-ionized nicotine ranged from 0.03 to 18.5 mg/g with the highest values associated with hand-made rapés (pH 9.75-10.2), which contain alkaline ashes. In tobacco-containing rapés, minor alkaloid levels and Fourier transform infrared spectra were used to confirm the presence of Nicotiana rustica, a high nicotine tobacco species. There was a wide concentration range of TSNAs and PAHs among the rapés analyzed. Several TSNAs and PAHs identified in the products are known or probable carcinogens according to the International Agency for Research on Cancer. Milligram quantities of some non-tobacco constituents, such as camphor, coumarin, and eugenol, warrant additional evaluation. Published by Elsevier Ltd.

  7. "My Mom and Her Boyfriend Fuss": A Five-Minute RAP

    ERIC Educational Resources Information Center

    Laursen, Erik K.; Whindleton, Kendra

    2012-01-01

    Unresolved issues from home often spill over into behavior problems at school. This article discusses the five-minute RAP techniques: (1) connect; (2) clarify; and (3) restore. The authors present a case study wherein this brief restorative intervention had been a successful alternative to punishment and exclusion.

  8. Comprehensive behavioral analysis of mice deficient in Rapgef2 and Rapgef6, a subfamily of guanine nucleotide exchange factors for Rap small GTPases possessing the Ras/Rap-associating domain.

    PubMed

    Maeta, Kazuhiro; Hattori, Satoko; Ikutomo, Junji; Edamatsu, Hironori; Bilasy, Shymaa E; Miyakawa, Tsuyoshi; Kataoka, Tohru

    2018-05-10

    Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap small GTPases, characterized by the possession of the Ras/Rap-associating domain. Previous genomic analyses suggested their possible involvement in the etiology of schizophrenia. We recently demonstrated the development of an ectopic cortical mass (ECM), which resembles the human subcortical band heterotopia, in the dorsal telencephalon-specific Rapgef2 conditional knockout (Rapgef2-cKO) brains. Additional knockout of Rapgef6 in Rapgef2-cKO mice resulted in gross enlargement of the ECM whereas knockout of Rapgef6 alone (Rapgef6-KO) had no discernible effect on the brain morphology. Here, we performed a battery of behavioral tests to examine the effects of Rapgef2 or Rapgef6 deficiency on higher brain functions. Rapgef2-cKO mice exhibited hyperlocomotion phenotypes. They showed decreased anxiety-like behavior in the elevated plus maze and the open-field tests as well as increased depression-like behavior in the Porsolt forced swim and tail suspension tests. They also exhibited increased sociability especially in novel environments. They showed defects in cognitive function as evidenced by reduced learning ability in the Barnes circular maze test and by impaired working memory in the T maze tests. In contrast, although Rapgef6 and Rapgef2 share similarities in biochemical roles, Rapgef6-KO mice exhibited mild behavioral abnormalities detected with a number of behavioral tests, such as hyperlocomotion phenotype in the open-field test and the social interaction test with a novel environment and working-memory defects in the T-maze test. In conclusion, although there were differences in their brain morphology and the magnitude of the behavioral abnormalities, Rapgef2-cKO mice and Rapgef6-KO mice exhibited hyperlocomotion phenotype and working-memory defect, both of which could be recognized as schizophrenia-like behavior.

  9. Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability.

    PubMed

    Truong, D T; Che, A; Rendall, A R; Szalkowski, C E; LoTurco, J J; Galaburda, A M; Holly Fitch, R

    2014-11-01

    Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing (RAP), visual attention and working memory. Genetic variants in Doublecortin domain-containing protein 2 (DCDC2) have been associated with dyslexia, impairments in phonological processing and in short-term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre-pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working vs. reference memory) and rotarod (to examine sensorimotor ability and motor learning), were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in RAP, working memory and reference memory in Dcdc2(del2/del2) mice when compared with matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  10. In vivo topography of Rap1p-DNA complex at Saccharomyces cerevisiae TEF2 UAS(RPG) during transcriptional regulation.

    PubMed

    De Sanctis, Veronica; La Terra, Sabrina; Bianchi, Alessandro; Shore, David; Burderi, Luciano; Di Mauro, Ernesto; Negri, Rodolfo

    2002-04-26

    We have analyzed in detail the structure of RAP1-UAS(RPG) complexes in Saccharomyces cerevisiae cells using multi-hit KMnO(4), UV and micrococcal nuclease high-resolution footprinting. Three copies of the Rap1 protein are bound to the promoter simultaneously in exponentially growing cells, as shown by KMnO(4) multi-hit footprinting analysis, causing extended and diagnostic changes in the DNA structure of the region containing the UAS(RPG). Amino acid starvation does not cause loss of Rap1p from the complex; however, in vivo UV-footprinting reveals the occurrence of structural modifications of the complex. Moreover, low-resolution micrococcal nuclease digestion shows that the chromatin of the entire region is devoid of positioned nucleosomes but is susceptible to changes in accessibility to the nuclease upon amino acid starvation. The implications of these results for the mechanism of Rap1p action are discussed. (c) 2002 Elsevier Science Ltd.

  11. MaRAP2-4, a waterlogging-responsive ERF from Mentha, regulates bidirectional sugar transporter AtSWEET10 to modulate stress response in Arabidopsis.

    PubMed

    Phukan, Ujjal J; Jeena, Gajendra Singh; Tripathi, Vineeta; Shukla, Rakesh Kumar

    2018-01-01

    As waterlogging and successive events severely influence growth and development of economically important plants, we attempted to characterize the role of a waterlogging-responsive group I (A-6) ethylene response factor (MaRAP2-4) from Mentha arvensis. Waterlogging, ethylene and methyl jasmonate rapidly induced the expression of MaRAP2-4. MaRAP2-4 interacted with multiple cis-elements like dehydration response elements (DRE1/2), anoxia/jasmonic acid response element (JARE) and GCC box showing its involvement in multiple responses. MaRAP2-4 localizes in the nucleus and acts as a transcriptional activator. Truncation and internal deletion identified a 20 amino acids potential transactivation domain (PLPSSVDAKLEAICQSLAIN) in MaRAP2-4. MaRAP2-4 transgenic Arabidopsis showed enhanced waterlogging and subsequent oxidative stress tolerance. Microarray analysis revealed that within up-regulated genes 483, 212 and 132 promoters carry either single or multiple copies of DRE, JARE and GCC cis-element/s, respectively. Within these promoters, a large section belongs to carbohydrate metabolism/transport, including many SWEET transporters. Further analysis showed MaRAP2-4 specifically targets two positions in AtSWEEET10 promoter carrying DRE and/or GCC box that might regulate carbohydrate availability and waterlogging tolerance. These results demonstrate that MaRAP2-4 is a positive regulator of waterlogging tolerance, and as energy-consuming processes such as carbohydrate biosynthesis are reduced under waterlogging-induced hypoxia, sugar transport through SWEETs may be the primary option to make sugar available to the required tissue. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  12. Use of High-Volume Reclaimed Asphalt Pavement (RAP) for Asphalt Pavement Rehabilitation Due to Increased Highway Truck Traffic from Freight Transportation

    DOT National Transportation Integrated Search

    2012-06-01

    A recent rise in asphalt binder prices has led state agencies and contractors to use higher quantities of Reclaimed : Asphalt Pavement (RAP). Besides being economic, sustainable, and environmentally friendly, RAP can be replaced : for a portion of ag...

  13. Social Context and Musical Content of Rap Music, 1979-1995

    ERIC Educational Resources Information Center

    Lena, Jennifer C.

    2006-01-01

    There is a link between the context of production and the content of rap music singles. This research finds that when independent labels owned most of the charted singles, lyrics emphasized features of the local environment and hostility to corporate music production and values. In contrast, the major-label dominated market featured lyrics…

  14. Rice Annotation Project Database (RAP-DB): an integrative and interactive database for rice genomics.

    PubMed

    Sakai, Hiroaki; Lee, Sung Shin; Tanaka, Tsuyoshi; Numa, Hisataka; Kim, Jungsok; Kawahara, Yoshihiro; Wakimoto, Hironobu; Yang, Ching-chia; Iwamoto, Masao; Abe, Takashi; Yamada, Yuko; Muto, Akira; Inokuchi, Hachiro; Ikemura, Toshimichi; Matsumoto, Takashi; Sasaki, Takuji; Itoh, Takeshi

    2013-02-01

    The Rice Annotation Project Database (RAP-DB, http://rapdb.dna.affrc.go.jp/) has been providing a comprehensive set of gene annotations for the genome sequence of rice, Oryza sativa (japonica group) cv. Nipponbare. Since the first release in 2005, RAP-DB has been updated several times along with the genome assembly updates. Here, we present our newest RAP-DB based on the latest genome assembly, Os-Nipponbare-Reference-IRGSP-1.0 (IRGSP-1.0), which was released in 2011. We detected 37,869 loci by mapping transcript and protein sequences of 150 monocot species. To provide plant researchers with highly reliable and up to date rice gene annotations, we have been incorporating literature-based manually curated data, and 1,626 loci currently incorporate literature-based annotation data, including commonly used gene names or gene symbols. Transcriptional activities are shown at the nucleotide level by mapping RNA-Seq reads derived from 27 samples. We also mapped the Illumina reads of a Japanese leading japonica cultivar, Koshihikari, and a Chinese indica cultivar, Guangluai-4, to the genome and show alignments together with the single nucleotide polymorphisms (SNPs) and gene functional annotations through a newly developed browser, Short-Read Assembly Browser (S-RAB). We have developed two satellite databases, Plant Gene Family Database (PGFD) and Integrative Database of Cereal Gene Phylogeny (IDCGP), which display gene family and homologous gene relationships among diverse plant species. RAP-DB and the satellite databases offer simple and user-friendly web interfaces, enabling plant and genome researchers to access the data easily and facilitating a broad range of plant research topics.

  15. The Immediate Effects of Homicidal, Suicidal, and Nonviolent Heavy Metal and Rap Songs on the Moods of College Students.

    ERIC Educational Resources Information Center

    Ballard, Mary E.; Coates, Steven

    1995-01-01

    Examined the impact of homicidal, suicidal, and nonviolent heavy metal and rap songs on the moods of male college undergraduates. Students (n=164) completed mood inventories after listening to 1 of 6 songs. Results show no effects of these songs on suicidal ideation, anxiety, or self-esteem. Rap songs elicited greater angry responses than heavy…

  16. CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease.

    PubMed

    Miron, Justin; Picard, Cynthia; Nilsson, Nathalie; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes

    2018-06-01

    Because currently known Alzheimer's disease (AD) single-nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD. Our team performed a genome-wide association study in the Quebec Founder Population isolate to identify novel protective or risk genetic factors for late-onset sporadic AD and examined the impact of these variants on gene expression and AD pathology. The rs10984186 variant is associated with an increased risk of developing AD and with a higher CDK5RAP2 mRNA prevalence in the hippocampus. On the other hand, the rs4837766 variant, which is among the best cis-expression quantitative trait loci in the CDK5RAP2 gene, is associated with lower mild cognitive impairment/AD risk and conversion rate. The rs10984186 risk and rs4837766 protective polymorphic variants of the CDK5RAP2 gene might act as potent genetic modifiers for AD risk and/or conversion by modulating the expression of this gene. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Preliminary investigation of RAP and RAS in HMAC : final report, February 2010.

    DOT National Transportation Integrated Search

    2010-02-01

    A laboratory study was undertaken to investigate how various proportions of reclaimed asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) added to hot mixed asphalt concrete (HMAC) mixtures affect the Superpave performance grade of the blende...

  18. Fundamental evaluation of the interaction between RAS/RAP and virgin asphalt binders.

    DOT National Transportation Integrated Search

    2017-08-01

    A comprehensive laboratory testing program was conducted in this research project to examine the blending between reclaimed asphalt pavement (RAP)/recycled asphalt shingles (RAS) and virgin asphalt binders and to evaluate the factors that may affect ...

  19. An Educational Exploration of Homophobia and Sexism in Rap and Hip Hop: Homo-Thugs and Divas in da House

    ERIC Educational Resources Information Center

    Chiu, Nicholas

    2005-01-01

    In this paper, the author explores the connections between hip hop and rap, sexism and homophobia, and children and teens. He describes the implications or potential consequences of sexism and homophobia within the music and media culture of hip hop and rap (with the focus on how it affects young viewers and fans in terms of gender [identity]…

  20. Rap and Resistance: A Social Movement of the Wu-Tang Clan.

    ERIC Educational Resources Information Center

    Chasteen, Amy L.; Shriver, Thomas

    1998-01-01

    Examines specific collective identity and political expression of the rap group the Wu-Tang Clan. Reveals a multi-layered political strategy that has been conscientiously designed and implemented to instigate a social movement. Prioritizes the voices of marginalized Black peoples and provides raw narratives about oppression. (MMU)

  1. The Dorsal Rather than Ventral Pathway Better Reflects Individual Syntactic Abilities in Second Language

    PubMed Central

    Yamamoto, Kayako; Sakai, Kuniyoshi L.

    2016-01-01

    The left inferior frontal gyrus (IFG) has been reported to be critically involved in syntactic processing, not only in first language (L1), but in second language (L2). Indeed, the leftward lateralization of the IFG has been shown to be correlated with the performance of a syntactic task in L2. Given that posterior language-related regions are systematically connected with the left IFG, the next question is which of the dorsal and ventral pathways is more critical to the individual syntactic abilities in L2. Here we used diffusion magnetic resonance imaging (MRI) and tractography with newly developed semi-automatic methods of defining seeds and selecting regions of interest (ROIs). We calculated mean thickness and fractional anisotropy (FA) in each ROI for the arcuate fasciculus (Arcuate) of the dorsal pathway, as well as for the inferior fronto-occipital fasciculus (IFOF) of the ventral pathway. In Experiment I, we performed partial correlation analyses between FA and the accuracy of the syntactic task, removing the effects of the accuracy of a spelling task, gender, and handedness. Among the two pathways in each hemisphere, only FA of the left Arcuate was significantly correlated with individual accuracy of the syntactic task. In Experiment II, we recruited monozygotic twins and examined to what extent their L2 abilities and their structural properties were similar. Within twin pairs, the highest significant correlation was observed for reaction times of the spelling task, while the correlation for the accuracy of the syntactic task was marginal; these two correlation coefficients were significantly different. Moreover, the thickness of the left Arcuate was highly correlated within pairs, while its FA, as well as the thickness/FA in the ventral pathways, was not significantly correlated. The correlation coefficient for the thickness of the left Arcuate was significantly larger than that of the left IFOF. These results suggest that the thickness of the left

  2. Effect of Bio based rejuvenator on mix design, Energy consumption and GHG Emission of High RAP Mixture

    NASA Astrophysics Data System (ADS)

    Abdullahi Ahmad, Kabiru; Ezree Abdullah, Mohd; Hassan, Norhidayah Abdul; Usman, Nura; Hassan, Mohd Rosli Mohd; Bilema, Munder A. M.; Modibbo Saeed, Saeed; Batari, Ahmad

    2018-04-01

    Concerns about the cost, availability, and environmental impact of using petroleum-based materials have led to increased usage of reclaimed asphalt pavement (RAP). Mean-while, the demand of the road industry to decrease the energy consumptions and reduce the release of greenhouse gases as well as other harmful gases, which cause serious air pollution has increased due to the amount of energy consumed is a major component of pavement construction that significantly contributes to the total cost. This paper evaluates the effects of Biobased rejuvenator known as JCO on the required heat energy and the amount of CO2 produced to increase the temperature of RAP and virgin aggregates and one binder from 25C to the point of mixing. The results showed that incorporating Biobased rejuvenator (JCO) can potentially reduce the required heat energy and amount of greenhouse gas produced by RAP and virgin, respectively.

  3. Evaluation of stone/RAP interlayers under accelerated loading : construction report : interim report.

    DOT National Transportation Integrated Search

    2001-03-01

    Three test lanes were constructed at the Louisiana Pavement Research Facility to study the performance of Reclaimed Asphalt Pavement (RAP) as a stress relieving layer between the cement treated base and asphalt concrete layers in lieu of crushed ston...

  4. Rapping in Catalan in Class and the Empowerment of the Learner

    ERIC Educational Resources Information Center

    Aliagas, Cristina; Fernández, Júlia-Alba; Llonch, Pau

    2016-01-01

    Despite the well-known educational possibilities afforded by "Rhythm And Poetry" (RAP) for the development of musical, lyrical and critical skills [Morrell, E., & Duncan-Andrade, J. M. R. (2002). Promoting Academic Literacy with Urban Youth through Engaging Hip-hop Culture. "The English Journal," 91(6), 88-92. Retrieved…

  5. MiR-203 involves in neuropathic pain development and represses Rap1a expression in nerve growth factor differentiated neuronal PC12 cells.

    PubMed

    Li, Haixia; Huang, Yuguang; Ma, Chao; Yu, Xuerong; Zhang, Zhiyong; Shen, Le

    2015-01-01

    Although microRNAs (miRNAs) have been shown to play a role in numerous biological processes, their function in neuropathic pain is not clear. The rat bilateral sciatic nerve chronic constriction injury (bCCI) is an established model of neuropathic pain, so we examined miRNA expression and function in the spinal dorsal horn in bCCI rats. Microarray and real-time polymerase chain reaction were used to examine the expression of miRNA in nerve system of bCCI rats, and the targets of miRNA were predicted by bioinformatic approaches. The function of specific miRNA was estimated through the methods of gene engineering. This study revealed substantially (∼10-fold) decreased miR-203 expression in the spinal dorsal horns but not the dorsal root ganglions, hippocampus, or anterior cingulate cortexes of bCCI rats. Rap1a protein expression was upregulated in bCCI rat spinal dorsal horns. We further verified that miR-203 directly targeted the 3'-untranslated region of the rap1a gene, thereby decreasing rap1a protein expression in neuron-like cells. Rap1a has diverse neuronal functions and their perturbation is responsible for several mental disorders. For example, Rap1a/MEK/ERK is involved in peripheral sensitization. These data suggest a potential role for miR-203 in regulating neuropathic pain development, and Rap1a is a validated target gene in vitro. Results from our study and others indicate the possibility that Rap1a may be involved in pain. We hope that these results can provide support for future research into miR-203 in gene therapy for neuropathic pain.

  6. Estimation of low temperature properties of RAP binder without extraction : final report.

    DOT National Transportation Integrated Search

    2016-04-01

    In recent years, the use of reclaimed asphalt pavement (RAP) as a component of asphalt mixtures has : become a common practice. For many years, researchers and DOT officials have questioned the adverse : effects, if any, of using solvents to extract ...

  7. Optimizing the durability of the coarse fraction of porous asphalt RAP for effective recycling

    NASA Astrophysics Data System (ADS)

    Holleran, Irina; Wilson, Douglas J.; Black, Philippa; Holleran, Glynn; Walubita, Lubinda F.

    2017-09-01

    Porous asphalt (PA) durability depends not only on the binder used to manufacture the mix, but also on the aggregates chosen, particularly the coarse fraction component. Aggregates for PA should be of the highest quality and highly durable to withstand the effects of weather and traffic. To recycle PA into a new PA mix, without compromising the long-term performance, the durability of the recovered aggregates from PA-derived reclaimed asphalt pavement (RAP) should be assessed alongside the aged binder properties. In this study, the Micro-Deval (MD) Abrasion test, combined with water absorption, was found to be a good predictor of asphalt mix performance for PA. Minerology of the aggregates is an important factor when setting limits for MD loss. New Zealand (NZ) aggregates are significantly younger in geological terms, and chemically and physically less stable compared to the aggregates used in many other countries. This is especially true for greywacke, the most used aggregate in NZ for road construction. If the MD limits reported in some literature are applied to NZ PA-derived RAP aggregates, poor performing material can be erroneously incorporated in asphalt mixes. Findings from this study contributes in understanding how PA-derived RAP can be recycled into new value PA mixes.

  8. Illuminating Chaucer through Poetry, Manuscript Illuminations, and a Critical Rap Album

    ERIC Educational Resources Information Center

    Lynch, Tom Liam

    2007-01-01

    Drawing connections between Chaucer, Eminem, and social issues, New York City high school teacher Tom Liam Lynch helped students become familiar with "The Canterbury Tales." Students wrote poems of rhymed couplets about today's social and political issues, created illuminated manuscripts, and recorded a rap CD. A book and album were…

  9. The High Resolution Accelerometer Package (HiRAP) flight experiment summary for the first 10 flights

    NASA Technical Reports Server (NTRS)

    Blanchard, Robert C.; Larman, K. T.; Barrett, M.

    1992-01-01

    The High Resolution Accelerometer Package (HiRAP) instrument is a triaxial, orthogonal system of gas damped accelerometers with a resolution of 1 x 10(exp -6) g (1 micro-g). The purpose of HiRAP is to measure the low frequency component of the total acceleration along the orbiter vehicle (OV) body axes while the OV descends through the rarefied flow flight regime. Two HiRAP instruments have flown on a total of 10 Space Transport System (STS) missions. The aerodynamic component of the acceleration measurements was separated from the total acceleration. Instrument bias and orbiter mechanical system acceleration effects were incorporated into one bulk bias. The bulk bias was subtracted from the acceleration measurements to produce aerodynamic descent data sets for all 10 flights. The aerodynamic acceleration data sets were input to an aerodynamic coefficient model. The aerodynamic acceleration data and coefficient model were used to estimate the atmospheric density for the altitude range of 140 to 60 km and a downrange distance of 600 km. For 8 of 10 flights results from this model agree with expected results. For the results that do not agree with expected results, a variety of error sources have been explored.

  10. Pathways to fraction learning: Numerical abilities mediate the relation between early cognitive competencies and later fraction knowledge.

    PubMed

    Ye, Ai; Resnick, Ilyse; Hansen, Nicole; Rodrigues, Jessica; Rinne, Luke; Jordan, Nancy C

    2016-12-01

    The current study investigated the mediating role of number-related skills in the developmental relationship between early cognitive competencies and later fraction knowledge using structural equation modeling. Fifth-grade numerical skills (i.e., whole number line estimation, non-symbolic proportional reasoning, multiplication, and long division skills) mapped onto two distinct factors: magnitude reasoning and calculation. Controlling for participants' (N=536) demographic characteristics, these two factors fully mediated relationships between third-grade general cognitive competencies (attentive behavior, verbal and nonverbal intellectual abilities, and working memory) and sixth-grade fraction knowledge (concepts and procedures combined). However, specific developmental pathways differed by type of fraction knowledge. Magnitude reasoning ability fully mediated paths from all four cognitive competencies to knowledge of fraction concepts, whereas calculation ability fully mediated paths from attentive behavior and verbal ability to knowledge of fraction procedures (all with medium to large effect sizes). These findings suggest that there are partly overlapping, yet distinct, developmental pathways from cognitive competencies to general fraction knowledge, fraction concepts, and fraction procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. The Union RAP: Industry-Wide Research-Action Projects to Win Health and Safety Improvements

    PubMed Central

    McQuiston, Thomas H.; Lippin, Tobi Mae; Anderson, Leeann G.; Beach, M. Josie; Frederick, James; Seymour, Thomas A.

    2009-01-01

    Unions are ripe to engage in community-based participatory research (CBPR). We briefly profile 3 United Steelworker CBPR projects aimed at uncovering often-undocumented, industry-wide health and safety conditions in which US industrial workers toil. The results are to be used to advocate improvements at workplace, industry, and national policy levels. We offer details of our CBPR approach (Research-Action Project [RAP]) that engages workers and others in all research stages. Elements of RAPs include strategically constructed teams with knowledge of the industry and health and safety and with skills in research, participatory facilitation, and training; reciprocal training on these knowledge and skill areas; iterative processes of large and small group work; use of technology; and facilitator-developed tools and intermediate products. PMID:19890145

  12. Truncated RAP-MUSIC (TRAP-MUSIC) for MEG and EEG source localization.

    PubMed

    Mäkelä, Niko; Stenroos, Matti; Sarvas, Jukka; Ilmoniemi, Risto J

    2018-02-15

    Electrically active brain regions can be located applying MUltiple SIgnal Classification (MUSIC) on magneto- or electroencephalographic (MEG; EEG) data. We introduce a new MUSIC method, called truncated recursively-applied-and-projected MUSIC (TRAP-MUSIC). It corrects a hidden deficiency of the conventional RAP-MUSIC algorithm, which prevents estimation of the true number of brain-signal sources accurately. The correction is done by applying a sequential dimension reduction to the signal-subspace projection. We show that TRAP-MUSIC significantly improves the performance of MUSIC-type localization; in particular, it successfully and robustly locates active brain regions and estimates their number. We compare TRAP-MUSIC and RAP-MUSIC in simulations with varying key parameters, e.g., signal-to-noise ratio, correlation between source time-courses, and initial estimate for the dimension of the signal space. In addition, we validate TRAP-MUSIC with measured MEG data. We suggest that with the proposed TRAP-MUSIC method, MUSIC-type localization could become more reliable and suitable for various online and offline MEG and EEG applications. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. I Won't Back down from Anyone!

    ERIC Educational Resources Information Center

    Pfeifer, Douglas

    2013-01-01

    Routine life stressors can trigger anger and violence with children who have poor emotional regulation. This article describes "Response Ability Pathways" (RAP) strategies that equip youth in managing these daily challenges. The strategies require establishing steps to gain the young persons trust and providing alternative methods to…

  14. Gendered Pathways: How Mathematics Ability Beliefs Shape Secondary and Postsecondary Course and Degree Field Choices

    PubMed Central

    Perez-Felkner, Lara; Nix, Samantha; Thomas, Kirby

    2017-01-01

    Do mathematics ability beliefs explain gender gaps in the physical science, engineering, mathematics, and computer science fields (PEMC) and other science fields? We leverage U.S. nationally representative longitudinal data to estimate gendered differences in girls' and boys' perceptions of mathematics ability with the most difficult or challenging material. Our analyses examine the potentially interacting effects of gender and these ability beliefs on students' pathways to scientific careers. Specifically, we study how beliefs about ability with challenging mathematics influence girls' and boys' choices to pursue PEMC degrees, evaluating educational milestones over a 6-year period: advanced science course completion in secondary school and postsecondary major retention and selection. Our findings indicate even at the same levels of observed ability, girls' mathematics ability beliefs under challenge are markedly lower than those of boys. These beliefs matter over time, potentially tripling girls' chances of majoring in PEMC sciences, over and above biological science fields, all else being equal. Implications and potential interventions are discussed. PMID:28428762

  15. Gendered Pathways: How Mathematics Ability Beliefs Shape Secondary and Postsecondary Course and Degree Field Choices.

    PubMed

    Perez-Felkner, Lara; Nix, Samantha; Thomas, Kirby

    2017-01-01

    Do mathematics ability beliefs explain gender gaps in the physical science, engineering, mathematics, and computer science fields (PEMC) and other science fields? We leverage U.S. nationally representative longitudinal data to estimate gendered differences in girls' and boys' perceptions of mathematics ability with the most difficult or challenging material. Our analyses examine the potentially interacting effects of gender and these ability beliefs on students' pathways to scientific careers. Specifically, we study how beliefs about ability with challenging mathematics influence girls' and boys' choices to pursue PEMC degrees, evaluating educational milestones over a 6-year period: advanced science course completion in secondary school and postsecondary major retention and selection. Our findings indicate even at the same levels of observed ability, girls' mathematics ability beliefs under challenge are markedly lower than those of boys. These beliefs matter over time, potentially tripling girls' chances of majoring in PEMC sciences, over and above biological science fields, all else being equal. Implications and potential interventions are discussed.

  16. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling

    PubMed Central

    Lu, Gui-Hua; Xu, Cheng-Gui; Xu, Zhe; Tang, Kai; Cheng, Yun-Jiu; Gao, Xiu-Ren; Wu, Su-Hua

    2016-01-01

    Objectives To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. Methods and Results A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. Conclusions The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway. PMID:27611832

  17. Feasibility of reclaimed asphalt pavement (RAP) use as road base and subbase material.

    DOT National Transportation Integrated Search

    2015-01-01

    The purpose of this study was to investigate the current state of the practice with regard to the use of reclaimed asphalt : pavement (RAP) material for road base and subbase applications and the potential for such use by the Virginia Department of :...

  18. Improving Quality Control of Asphalt Pavement with RAP Using a Portable Infrared Spectroscopy Device

    DOT National Transportation Integrated Search

    2016-04-01

    This project has investigated the effectiveness of a Portable Infrared Spectrometer (PIRS) device in estimating percent of Reclaimed Asphalt Pavement (RAP) and its contribution into oxidative aging of a new asphalt mixture immediately after productio...

  19. Allowable residual contamination levels of radionuclides in soil from pathway analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nyquist, J.E.; Baes, C.F. III

    1987-01-01

    The uncertainty regarding radionuclide distributions among Remedial Action Program (RAP) sites and long-term decommissioning and closure options for these sites requires a flexible approach capable of handling different levels of contamination, dose limits, and closure scenarios. We identified a commercially available pathway analysis model, DECOM, which had been used previously in support of remedial activities involving contaminated soil at the Savannah River Plant. The DECOM computer code, which estimates concentrations of radionuclides uniformly distributed in soil that correspond to an annual effective dose equivalent, is written in BASIC and runs on an IBM PC or compatible microcomputer. We obtained themore » latest version of DECOM and modified it to make it more user friendly and applicable to the Oak Ridge National Laboratory (ORNL) RAP. Some modifications involved changes in default parameters or changes in models based on approaches used by the EPA in regulating remedial actions for hazardous substances. We created a version of DECOM as a LOTUS spreadsheet, using the same models as the BASIC version of DECOM. We discuss the specific modeling approaches taken, the regulatory framework that guided our efforts, the strengths and limitations of each approach, and areas for improvement. We also demonstrate how the LOTUS version of DECOM can be applied to specific problems that may be encountered during ORNL RAP activities. 18 refs., 2 figs., 3 tabs.« less

  20. Asphalt mixtures with a high amount of RAP - case study

    NASA Astrophysics Data System (ADS)

    Koudelka, Tomas; Varaus, Michal

    2017-09-01

    A case study of one trial section in the Pilsen region is presented. The pavement in the section was newly constructed in 2015 using one type of an asphalt concrete mixtures with varying RAP content. The constructed surface course comprises of 0% to 50% RAP. In order to restore the aged binder properties and to avoid the embrittlement of the produced mixtures, a rubber-based modifier/rejuvenator was employed. For technological reasons during manufacturing processes, which engage a parallel drying drum, a crude oil-based rejuvenator was also added. This article contains the preliminary data from an on-going project focused on monitoring the properties of bituminous binders contained in asphalt mixtures. The actual bituminous binders were extracted straight after production, after 6 months and after 12 months. The binder characteristics are evaluated using empirical testing as well as functional tests. Low temperature properties are measured by a Bending Beam Rheometer (BBR). The preliminary results show, that the bituminous binders properties change significantly in a relatively short period of time. The progress in binder’ characteristics is contradictory to up-to date knowledge. The probability that the phenomenon of diffusion between aged binder and rejuvenator agents occurs exists. Moreover, the data might indicate that the process of rejuvenator evaporation takes place.

  1. Silencing of AtRAP, a target gene of a bacteria-induced small RNA, triggers antibacterial defense responses through activation of LSU2 and down-regulation of GLK1

    PubMed Central

    Wang, Huan; Seo, Jang-Kyun; Gao, Shang; Cui, Xinping; Jin, Hailing

    2017-01-01

    Summary Plants fine-tune their sophisticated immunity systems in response to pathogen infections. We previously showed that AtlsiRNA-1, a bacteria-induced plant endogenous small interfering RNA, silences the AtRAP gene, which encodes a putative RNA binding protein.In this study, we demonstrate that AtRAP functions as a negative regulator in plant immunity by characterizing molecular and biological responses of the knockout mutant and overexpression lines of AtRAP upon bacterial infection.AtRAP is localized in chloroplasts and physically interacts with Low Sulfur Upregulated 2 (LSU2), which positively regulates plant defense. Our results suggest that AtRAP negatively regulates defense responses by suppressing LSU2 through physical interaction. We also detected downregulation of the transcription factor GOLDEN2-LIKE 1 (GLK1) in atrap-1 using microarray analysis. The glk1 glk2 double mutant showed enhanced resistance to Pseudomonas syringae pv. tomato, which is consistent with a previous study showing enhanced resistance of a glk1 glk2 double mutant to Hyaloperonospora arabidopsidis.Taken together, our data suggest that silencing of AtRAP by AtlsiRNA-1 upon bacterial infection triggers defense responses through regulation of LSU2 and GLK1. PMID:28656601

  2. An Action Research Study on the Influence of Gangsta Rap on Academic and Behavioral Issues of 5th Grade African-American Males

    ERIC Educational Resources Information Center

    Lewis, Shaun; Boes, Susan R.; Chibbaro, Julie S.

    2015-01-01

    This small action research study (ARS) began with a review of the literature examining the relationship of gangsta rap in regards to academic achievement, self-esteem, decision-making, identity issues and development of young African American males. The purpose of the ARS was to examine the correlation between gangsta rap and its influence on 5th…

  3. Balanced RAP/RAS mix design and performance evaluation system for project-specific service conditions.

    DOT National Transportation Integrated Search

    2012-11-01

    The use of reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) can significantly reduce the increasing cost of hot-mix asphalt paving, conserve energy, and protect the environment. However, the premature cracking problem has been a s...

  4. A Musical Color Line: The Problem of Race in White Rap Rhetoric.

    ERIC Educational Resources Information Center

    Riddles, Allison

    An instructor of freshman composition at Ohio University always teaches a section on music in her courses because freshmen jump at the chance to discuss a part of their youth culture that they readily identify with. The problem, however, has been how to incorporate rap music successfully into these discussions with a classroom full of white…

  5. Effect of recovered binders from recycled shingles and increased RAP percentages on resultant binder PG.

    DOT National Transportation Integrated Search

    2011-12-01

    This research evaluated the properties of recycled asphalt binders from Wisconsin sources. Continuous grading : properties were measured for 18 recycled binder sources: 12 reclaimed asphalt pavement (RAP) sources and 6 recycled : asphalt shingle sour...

  6. Testing and refining the Science in Risk Assessment and Policy (SciRAP) web-based platform for evaluating the reliability and relevance of in vivo toxicity studies.

    PubMed

    Beronius, Anna; Molander, Linda; Zilliacus, Johanna; Rudén, Christina; Hanberg, Annika

    2018-05-28

    The Science in Risk Assessment and Policy (SciRAP) web-based platform was developed to promote and facilitate structure and transparency in the evaluation of ecotoxicity and toxicity studies for hazard and risk assessment of chemicals. The platform includes sets of criteria and a colour-coding tool for evaluating the reliability and relevance of individual studies. The SciRAP method for evaluating in vivo toxicity studies was first published in 2014 and the aim of the work presented here was to evaluate and develop that method further. Toxicologists and risk assessors from different sectors and geographical areas were invited to test the SciRAP criteria and tool on a specific set of in vivo toxicity studies and to provide feedback concerning the scientific soundness and user-friendliness of the SciRAP approach. The results of this expert assessment were used to refine and improve both the evaluation criteria and the colour-coding tool. It is expected that the SciRAP web-based platform will continue to be developed and enhanced to keep up to date with the needs of end-users. Copyright © 2018 John Wiley & Sons, Ltd.

  7. Retrospective study of long-term outcome after brain arteriovenous malformation rupture: the RAP score.

    PubMed

    Shotar, Eimad; Debarre, Matthieu; Sourour, Nader-Antoine; Di Maria, Federico; Gabrieli, Joseph; Nouet, Aurélien; Chiras, Jacques; Degos, Vincent; Clarençon, Frédéric

    2018-01-01

    OBJECTIVE The authors aimed to design a score for stratifying patients with brain arteriovenous malformation (BAVM) rupture, based on the likelihood of a poor long-term neurological outcome. METHODS The records of consecutive patients with BAVM hemorrhagic events who had been admitted over a period of 11 years were retrospectively reviewed. Independent predictors of a poor long-term outcome (modified Rankin Scale score ≥ 3) beyond 1 year after admission were identified. A risk stratification scale was developed and compared with the intracranial hemorrhage (ICH) score to predict poor outcome and inpatient mortality. RESULTS One hundred thirty-five patients with 139 independent hemorrhagic events related to BAVM rupture were included in this analysis. Multivariate logistic regression followed by stepwise analysis showed that consciousness level according to the Glasgow Coma Scale (OR 6.5, 95% CI 3.1-13.7, p < 10 -3 ), hematoma volume (OR 1.8, 95% CI 1.2-2.8, p = 0.005), and intraventricular hemorrhage (OR 7.5, 95% CI 2.66-21, p < 10 -3 ) were independently associated with a poor outcome. A 12-point scale for ruptured BAVM prognostication was constructed combining these 3 factors. The score obtained using this new scale, the ruptured AVM prognostic (RAP) score, was a stronger predictor of a poor long-term outcome (area under the receiver operating characteristic curve [AUC] 0.87, 95% CI 0.8-0.92, p = 0.009) and inpatient mortality (AUC 0.91, 95% CI 0.85-0.95, p = 0.006) than the ICH score. For a RAP score ≥ 6, sensitivity and specificity for predicting poor outcome were 76.8% (95% CI 63.6-87) and 90.8% (95% CI 81.9-96.2), respectively. CONCLUSIONS The authors propose a new admission score, the RAP score, dedicated to stratifying the risk of poor long-term outcome after BAVM rupture. This easy-to-use scoring system may help to improve communication between health care providers and consistency in clinical research. Only external prospective cohorts and population

  8. Testing protocols to ensure performance of high asphalt binder replacement mixes using RAP and RAS.

    DOT National Transportation Integrated Search

    2015-12-01

    The use of reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) in asphalt concrete (AC) mixtures can reduce demand for virgin aggregates and asphalt binder, bringing environmental and economic benefits. However, replacing virgin asph...

  9. Modeling the performance properties of RAS and RAP blended asphalt mixes using chemical compositional information.

    DOT National Transportation Integrated Search

    2017-01-01

    Reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) can improve the sustainability of asphalt concrete (AC) due to cost savings and environmental factors, but it is necessary to ensure that pavement performance is not compromised. To...

  10. PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway.

    PubMed

    Fujimoto, Daisuke; Ueda, Yuki; Hirono, Yasuo; Goi, Takanori; Yamaguchi, Akio

    2015-10-27

    The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH2 induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists.

  11. The RAP: A Recreational Activities Project, Academic Service-Learning Course and Qualitative Research Study

    ERIC Educational Resources Information Center

    Parker, Kathlyn

    2008-01-01

    The author (a university instructor) and her community partner (a public school teacher) have collaborated in teaching an academic service-learning course in special education. This collaboration, the RAP (recreational activities project), was completed by university undergraduate students and young adults with cognitive impairment and/or…

  12. The best marker for guiding the clinical management of patients with raised intracranial pressure-the RAP index or the mean pulse amplitude?

    PubMed

    Hall, Allan; O'Kane, Roddy

    2016-10-01

    Raised intracranial pressure is a common problem in a variety of neurosurgical conditions including traumatic brain injury, hydrocephalus and intracranial haemorrhage. The clinical management of these patients is guided by a variety of haemodynamic, biochemical and clinical factors. However to date there is no single parameter that is used to guide clinical management of patients with raised intracranial pressure (ICP). However, the role of ICP indices, specifically the mean pulse amplitude (AMP) and RAP index [correlation coefficient (R) between AMP amplitude (A) and mean ICP pressure (P); index of compensatory reserve], as an indicator of true ICP has been investigated. Whilst the RAP index has been used both as a descriptor of neurological deterioration in TBI patients and as a way of characterising the compensatory reserve in hydrocephalus, more recent studies have highlighted the limitation of the RAP index due to the influence that baseline effect errors have on the mean ICP, which is used in the calculation of the RAP index. These studies have suggested that the ICP mean pulse amplitude may be a more accurate marker of true intracranial pressure due to the fact that it is uninfluenced by the mean ICP and, therefore, the AMP may be a more reliable marker than the RAP index for guiding the clinical management of patients with raised ICP. Although further investigation needs to be undertaken in order to fully assess the role of ICP indices in guiding the clinical management of patients with raised ICP, the studies undertaken to date provide an insight into the potential role of ICP indices to treat raised ICP proactively rather than reactively and therefore help prevent or minimise secondary brain injury.

  13. Sequential sentinel SNP Regional Association Plots (SSS-RAP): an approach for testing independence of SNP association signals using meta-analysis data.

    PubMed

    Zheng, Jie; Gaunt, Tom R; Day, Ian N M

    2013-01-01

    Genome-Wide Association Studies (GWAS) frequently incorporate meta-analysis within their framework. However, conditional analysis of individual-level data, which is an established approach for fine mapping of causal sites, is often precluded where only group-level summary data are available for analysis. Here, we present a numerical and graphical approach, "sequential sentinel SNP regional association plot" (SSS-RAP), which estimates regression coefficients (beta) with their standard errors using the meta-analysis summary results directly. Under an additive model, typical for genes with small effect, the effect for a sentinel SNP can be transformed to the predicted effect for a possibly dependent SNP through a 2×2 2-SNP haplotypes table. The approach assumes Hardy-Weinberg equilibrium for test SNPs. SSS-RAP is available as a Web-tool (http://apps.biocompute.org.uk/sssrap/sssrap.cgi). To develop and illustrate SSS-RAP we analyzed lipid and ECG traits data from the British Women's Heart and Health Study (BWHHS), evaluated a meta-analysis for ECG trait and presented several simulations. We compared results with existing approaches such as model selection methods and conditional analysis. Generally findings were consistent. SSS-RAP represents a tool for testing independence of SNP association signals using meta-analysis data, and is also a convenient approach based on biological principles for fine mapping in group level summary data. © 2012 Blackwell Publishing Ltd/University College London.

  14. The Relationship between Heavy Metal and Rap Music and Adolescent Turmoil: Real or Artifact?

    ERIC Educational Resources Information Center

    Took, Kevin J.; Weiss, David S.

    1994-01-01

    Investigated association between 87 adolescents' music preferences and psychosocial turmoil. Adolescents who preferred heavy metal and rap music had higher incidence of below-average school grades, school behavior problems, sexual activity, drug and alcohol use, and arrests. When gender was controlled, only below-average school grades and history…

  15. GCR1, a transcriptional activator in Saccharomyces cerevisiae, complexes with RAP1 and can function without its DNA binding domain.

    PubMed Central

    Tornow, J; Zeng, X; Gao, W; Santangelo, G M

    1993-01-01

    In Saccharomyces cerevisiae, efficient expression of glycolytic and translational component genes requires two DNA binding proteins, RAP1 (which binds to UASRPG) and GCR1 (which binds to the CT box). We generated deletions in GCR1 to test the validity of several different models for GCR1 function. We report here that the C-terminal half of GCR1, which includes the domain required for DNA binding to the CT box in vitro, can be removed without affecting GCR1-dependent transcription of either the glycolytic gene ADH1 or the translational component genes TEF1 and TEF2. We have also identified an activation domain within a segment of the GCR1 protein (the N-terminal third) that is essential for in vivo function. RAP1 and GCR1 can be co-immunoprecipitated from whole cell extracts, suggesting that they form a complex in vivo. The data are most consistent with a model in which GCR1 is attracted to DNA through contact with RAP1. Images PMID:8508768

  16. Laboratory evaluation of asphalt concrete mixtures containing high contents of reclaimed asphalt pavement (RAP) and binder.

    DOT National Transportation Integrated Search

    2014-11-01

    This study investigated the effect of added asphalt : binder content on the performance and volumetric p : roperties of : asphalt concrete mixtures containing reclaimed asph : alt pavement (RAP) in the amounts of 0%, 20%, and 4 : 0%. A laboratory- : ...

  17. Molecular Basis for Impaired DNA Damage Response Function Associated with the RAP80 ΔE81 Defect*

    PubMed Central

    Anamika; Markin, Craig J.; Rout, Manoj K.; Spyracopoulos, Leo

    2014-01-01

    Signal transduction within the DNA damage response is driven by the flux of protein-protein interaction cascades that ultimately recruit repair complexes to sites of damage. The protein RAP80 plays a central role in the damage response by targeting BRCA1/BRCA2 tumor suppressors to DNA damage foci through multivalent binding of Lys-63-linked polyubiquitin chains. Mutations within the high penetrance BRCA1/BRCA2 genes account for ∼20% of familial breast cancers. The genetic basis for the remaining cancers remains unknown, but may involve defects in binding partners for BRCA1 and BRCA2 that lead to impaired targeting to foci and a concomitant role in the pathogenesis of cancer. Recently, an in-frame deletion mutation (ΔE81) in a conserved region from the first ubiquitin interaction motif of RAP80 has been linked to an increase in chromosomal abnormalities. Using NMR spectroscopy, we demonstrate that the N-cap motif within the α-helix of the first ubiquitin interaction motif from ΔE81 undergoes a structural frameshift that leads to abolishment of multivalent binding of polyubiquitin chains. Loss of this single glutamate residue disrupts favorable electrostatic interactions between RAP80 and ubiquitin, establishing a plausible molecular basis for a potential predisposition to cancer unrelated to mutations within BRCA1/BRCA2 genes. PMID:24627472

  18. Rap as a roadway: creating creolized forms of science in an era of cultural globalization

    NASA Astrophysics Data System (ADS)

    Elmesky, Rowhea

    2011-03-01

    Even during an era of cultural globalization where diversity, hybridity, and heterogeneity prevail, educational institutions remain unchanged and economically and racially marginalized students continue to experience a sense of exclusion in school. Whereas the science education community often addresses such exclusion in terms of the achievement gap or the lack of materials and qualified teachers in urban schools, there are also more subtle ways in which these students remain as outsiders to the culture of science. The study highlights how the acceptance and affordance of students' cultural capital can encourage a sense of belonging with school science. Specifically, this paper contributes to the literature by sharing longitudinal findings that reveal students' skills of orality, in the form of rap practices, can be rich resources for developing creolized forms of school science, and how rap creates entryways for students to form and reform hybridized identities in which canonical science discourse and lyrics about non-science subjects can begin to emerge in integrated, fluid and seamless manners.

  19. An Interview with Cathy Fowler about Sharing a Love of Reading through Book Raps.

    ERIC Educational Resources Information Center

    Strangman, Nicole

    2002-01-01

    Includes an interview with Cathy Fowler, a Year 7 teacher at Kawungan State School in Queensland, Australia. Explains that Cathy is a participant and coordinator of the extremely popular Harry Potter Book Rap, a guided Internet book discussion among students all over the world. Discusses how this activity fueled her students' love for reading. (PM)

  20. From CNTNAP2 to Early Expressive Language in Infancy: The Mediation Role of Rapid Auditory Processing.

    PubMed

    Riva, Valentina; Cantiani, Chiara; Benasich, April A; Molteni, Massimo; Piazza, Caterina; Giorda, Roberto; Dionne, Ginette; Marino, Cecilia

    2018-06-01

    Although it is clear that early language acquisition can be a target of CNTNAP2, the pathway between gene and language is still largely unknown. This research focused on the mediation role of rapid auditory processing (RAP). We tested RAP at 6 months of age by the use of event-related potentials, as a mediator between common variants of the CNTNAP2 gene (rs7794745 and rs2710102) and 20-month-old language outcome in a prospective longitudinal study of 96 Italian infants. The mediation model examines the hypothesis that language outcome is explained by a sequence of effects involving RAP and CNTNAP2. The ability to discriminate spectrotemporally complex auditory frequency changes at 6 months of age mediates the contribution of rs2710102 to expressive vocabulary at 20 months. The indirect effect revealed that rs2710102 C/C was associated with lower P3 amplitude in the right hemisphere, which, in turn, predicted poorer expressive vocabulary at 20 months of age. These findings add to a growing body of literature implicating RAP as a viable marker in genetic studies of language development. The results demonstrate a potential developmental cascade of effects, whereby CNTNAP2 drives RAP functioning that, in turn, contributes to early expressive outcome.

  1. Evaluation of the combined effects of reclaimed asphalt pavement (RAP), reclaimed asphalt shingles (RAS), and different virgin binder sources on the performance of blended binders for mixes with higher percentages of RAP and RAS : a research report from t

    DOT National Transportation Integrated Search

    2015-11-01

    This report summarizes the main findings from a project funded by the National Center for : Sustainable Transportation (NCST) to investigate the use of higher percentages of reclaimed : asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) as a...

  2. Evaluation of the combined effects of reclaimed asphalt pavement (RAP), reclaimed asphalt shingles (RAS), and different virgin binder sources on the performance of blended binders for mixes with higher percentages of RAP and RAS : a national center for su

    DOT National Transportation Integrated Search

    2015-11-01

    This report summarizes the main findings from a project funded by the National Center for : Sustainable Transportation (NCST) to investigate the use of higher percentages of reclaimed : asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) as a...

  3. TRF2/RAP1 and DNA–PK mediate a double protection against joining at telomeric ends

    PubMed Central

    Bombarde, Oriane; Boby, Céline; Gomez, Dennis; Frit, Philippe; Giraud-Panis, Marie-Josèphe; Gilson, Eric; Salles, Bernard; Calsou, Patrick

    2010-01-01

    DNA-dependent protein kinase (DNA-PK) is a double-strand breaks repair complex, the subunits of which (KU and DNA-PKcs) are paradoxically present at mammalian telomeres. Telomere fusion has been reported in cells lacking these proteins, raising two questions: how is DNA–PK prevented from initiating classical ligase IV (LIG4)-dependent non-homologous end-joining (C-NHEJ) at telomeres and how is the backup end-joining (EJ) activity (B-NHEJ) that operates at telomeres under conditions of C-NHEJ deficiency controlled? To address these questions, we have investigated EJ using plasmid substrates bearing double-stranded telomeric tracks and human cell extracts with variable C-NHEJ or B-NHEJ activity. We found that (1) TRF2/RAP1 prevents C-NHEJ-mediated end fusion at the initial DNA–PK end binding and activation step and (2) DNA–PK counteracts a potent LIG4-independent EJ mechanism. Thus, telomeres are protected against EJ by a lock with two bolts. These results account for observations with mammalian models and underline the importance of alternative non-classical EJ pathways for telomere fusions in cells. PMID:20407424

  4. Reinforcing Alcohol Prevention (RAP) Program: A Secondary School Curriculum to Combat Underage Drinking and Impaired Driving

    ERIC Educational Resources Information Center

    Will, Kelli England; Sabo, Cynthia Shier

    2010-01-01

    The Reinforcing Alcohol Prevention (RAP) Program is an alcohol prevention curriculum developed in partnership with secondary schools to serve their need for a brief, evidence-based, and straightforward program that aligned with state learning objectives. Program components included an educational lesson, video, and interactive activities delivered…

  5. RapTOR: Automated Sequencing Library Preparation and Suppression for Rapid Pathogen Characterization (7th Annual SFAF Meeting, 2012)

    ScienceCinema

    Lane, Todd

    2018-05-18

    Todd Lane on "RapTOR: Automated sequencing library preparation and suppression for rapid pathogen characterization" at the 2012 Sequencing, Finishing, Analysis in the Future Meeting held June 5-7, 2012 in Santa Fe, New Mexico.

  6. RapTOR: Automated Sequencing Library Preparation and Suppression for Rapid Pathogen Characterization (7th Annual SFAF Meeting, 2012)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lane, Todd

    2012-06-01

    Todd Lane on "RapTOR: Automated sequencing library preparation and suppression for rapid pathogen characterization" at the 2012 Sequencing, Finishing, Analysis in the Future Meeting held June 5-7, 2012 in Santa Fe, New Mexico.

  7. Perform an investigation of the effects of increased reclaimed asphalt pavement (RAP) levels in dense graded friction courses.

    DOT National Transportation Integrated Search

    2015-04-01

    In this study, a total of 28 mixture combinations were designed and evaluated to : determine the maximum allowable amount of reclaimed asphalt pavement (RAP) : material in friction courses without jeopardizing pavement cracking performance. The : exp...

  8. University-Community Collaboration to Promote Healthy Mothers and Infants: The Relationships and Parenting Support (RAPS) Program

    ERIC Educational Resources Information Center

    Williams, Patricia Hrusa; Oravecz, Linda M.

    2016-01-01

    Research highlights the vulnerability of Black mothers and their infants, who experience higher rates of stress, preterm birth, low birth weight, and infant mortality than other racial groups. This article describes the development and implementation of the Relationships and Parenting Support (RAPS) Program, a community-based, family-focused…

  9. DLL4 overexpression increases gastric cancer stem/progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation.

    PubMed

    Miao, Zhi-Feng; Xu, Hao; Xu, Hui-Mian; Wang, Zhen-Ning; Zhao, Ting-Ting; Song, Yong-Xi; Xu, Ying-Ying

    2017-01-01

    Gastric cancer is one of the most common malignant diseases, and poses a serious threat to the quality of human life. Gastric cancer stem/progenitor cells (GCSPCs) have critical effects on tumor formation, affecting specific features of self-renewal and differentiation and playing a critical role in metastasis. The Notch-1 pathway is crucially important to GCSPCs and is regulated by DLL4. In this study, DLL4 and Nestin levels were measured in 383 gastric cancer tissue samples by immunohistochemistry, and the clinico-pathological features of patients assessed. After DLL4 silencing in selected gastric cancer cell lines, the expression of GCSPC markers and colony formation ability were analyzed and the self-renewal and differentiation capacities of the cells were evaluated. The relationship between DLL4 levels and Notch-1 signaling pathway effector amounts was assessed via Western blotting and immunofluorescence. Finally, the tumor formation ability of the gastric cancer cells was evaluated with different levels of DLL4 and multiple cell densities in vivo. Our results indicate that DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self-renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch-1 pathway, weakening invasion ability and resistance to 5-FU chemotherapy. In vivo, DLL4 silencing inhibited the tumor formation ability of GCSPCs. In conclusion, DLL4 affects GCSPC stemness, altering their pathological behavior. DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch-1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  10. Two biomarker-directed randomized trials in European and Chinese patients with nonsmall-cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies.

    PubMed

    Moran, T; Wei, J; Cobo, M; Qian, X; Domine, M; Zou, Z; Bover, I; Wang, L; Provencio, M; Yu, L; Chaib, I; You, C; Massuti, B; Song, Y; Vergnenegre, A; Lu, H; Lopez-Vivanco, G; Hu, W; Robinet, G; Yan, J; Insa, A; Xu, X; Majem, M; Chen, X; de Las Peñas, R; Karachaliou, N; Sala, M A; Wu, Q; Isla, D; Zhou, Y; Baize, N; Zhang, F; Garde, J; Germonpre, P; Rauh, S; ALHusaini, H; Sanchez-Ronco, M; Drozdowskyj, A; Sanchez, J J; Camps, C; Liu, B; Rosell, R

    2014-11-01

    In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients. Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS). Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82). Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to

  11. Pathway Distiller - multisource biological pathway consolidation.

    PubMed

    Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

    2012-01-01

    researchers access to the methods and example microarray data described in this manuscript, and the ability to analyze their own gene list by using our unique consolidation methods. By combining several pathway systems, implementing different, but complementary pathway consolidation methods, and providing a user-friendly web-accessible tool, we have enabled users the ability to extract functional explanations of their genome wide experiments.

  12. Evaluating the Effectiveness of GTM-1, Rapamycin, and Carbamazepine on Autophagy and Alzheimer Disease.

    PubMed

    Zhang, Lijuan; Wang, Lina; Wang, Run; Gao, Yuan; Che, Haoyue; Pan, Yonghua; Fu, Peng

    2017-02-14

    BACKGROUND This study was proposed to compare the efficacy and safety of GTM-1, Rapamycin (Rap), and Carbamazepine (CBZ) in managing Alzheimer disease (AD). The impact of the above mentioned therapeutic drugs on autophagy was also investigated in our study. MATERIAL AND METHODS Firstly, 3×Tg AD mice were randomly allocated into 4 groups (each group with 10 mice), in which AD mice were separately treated with dimethylsulfoxide (DMSO, vehicle group), GTM-1 (6 mg/kg), Rap (1 mg/kg), and CBZ (100 mg/kg). Then spatial memory and learning ability of mice was tested using the Morris water maze. Routine blood tests were performed to evaluate the toxicity of these drugs. Amyloid-β42 (Aβ42) concentration was detected by ELISA and immunohistochemistry. Proteins related to autophagy were detected by Western blot. RESULTS GTM-1, Rap, and CBZ significantly improved the spatial memory of 3×Tg AD mice compared to that in the vehicle group (all P<0.05). Moreover, this study revealed that CBZ dosage was related to toxicity in mice. All of the above drugs significantly increased the expression of LC3-II and reduced Aβ42 levels in hippocampi of 3×Tg AD mice (all P<0.05). On the other hand, neither GTM-1 nor CBZ had significant influence on the expression of proteins on the mTOR pathway. CONCLUSIONS GTM-1 can alleviate the AD syndrome by activating autophagy in a manner that is dependent on the mTOR pathway and it therefore can be considered as an alternative to Rap.

  13. Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion.

    PubMed

    Wise, Alexandria; Schatoff, Emma; Flores, Julian; Hua, Shao-Ying; Ueda, Atsushi; Wu, Chun-Fang; Venkatesh, Tadmiri

    2013-11-01

    The assembly of functional synapses requires the orchestration of the synthesis and degradation of a multitude of proteins. Protein degradation and modification by the conserved ubiquitination pathway has emerged as a key cellular regulatory mechanism during nervous system development and function (Kwabe and Brose, 2011). The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin ligase complex primarily characterized for its role in the regulation of mitosis (Peters, 2002). In recent years, a role for APC/C in nervous system development and function has been rapidly emerging (Stegmuller and Bonni, 2005; Li et al., 2008). In the mammalian central nervous system the activator subunit, APC/C-Cdh1, has been shown to be a regulator of axon growth and dendrite morphogenesis (Konishi et al., 2004). In the Drosophila peripheral nervous system (PNS), APC2, a ligase subunit of the APC/C complex has been shown to regulate synaptic bouton size and activity (van Roessel et al., 2004). To investigate the role of APC/C-Cdh1 at the synapse we examined loss-of-function mutants of Rap/Fzr (Retina aberrant in pattern/Fizzy related), a Drosophila homolog of the mammalian Cdh1 during the development of the larval neuromuscular junction in Drosophila. Our cell biological, ultrastructural, electrophysiological, and behavioral data showed that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function as well as locomotion defects. Data presented here show changes in size and morphology of synaptic boutons, and, muscle tissue organization. Electrophysiological experiments show that loss-of-function mutants exhibit increased frequency of spontaneous miniature synaptic potentials, indicating a higher rate of spontaneous synaptic vesicle fusion events. In addition, larval locomotion and peristaltic movement were also impaired. These findings suggest a role for Drosophila APC/C-Cdh1 mediated ubiquitination in regulating synaptic morphology

  14. Pathway Distiller - multisource biological pathway consolidation

    PubMed Central

    2012-01-01

    Distiller), is established to allow researchers access to the methods and example microarray data described in this manuscript, and the ability to analyze their own gene list by using our unique consolidation methods. Conclusions By combining several pathway systems, implementing different, but complementary pathway consolidation methods, and providing a user-friendly web-accessible tool, we have enabled users the ability to extract functional explanations of their genome wide experiments. PMID:23134636

  15. Efficient transcription of the glycolytic gene ADH1 and three translational component genes requires the GCR1 product, which can act through TUF/GRF/RAP binding sites.

    PubMed Central

    Santangelo, G M; Tornow, J

    1990-01-01

    Glycolytic gene expression in Saccharomyces cerevisiae is thought to be activated by the GCR and TUF proteins. We tested the hypothesis that GCR function is mediated by TUF/GRF/RAP binding sites (UASRPG elements). We found that UASRPG-dependent activation of a heterologous gene and transcription of ADH1, TEF1, TEF2, and RP59 were sensitive to GCR1 disruption. GCR is not required for TUF/GRF/RAP expression or in vitro DNA-binding activity. Images PMID:2405258

  16. Evaluation of field-produced hot mix asphalt (HMA) mixtures with fractionated recycled asphalt pavement (RAP) : 2007 Illinois tollway field mix trials.

    DOT National Transportation Integrated Search

    2008-10-01

    To test the fractionated recycled asphalt pavement (FRAP) materials, the Illinois Tollway, working through its : contractors and consultants, developed and conducted a project on the applicability and feasibility of using : increased RAP contents thr...

  17. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1.

    PubMed

    Nolz, Jeffrey C; Nacusi, Lucas P; Segovis, Colin M; Medeiros, Ricardo B; Mitchell, Jason S; Shimizu, Yoji; Billadeau, Daniel D

    2008-09-22

    WAVE2 regulates T cell receptor (TCR)-stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL-C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL-C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

  18. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL–C3G-mediated activation of Rap1

    PubMed Central

    Nolz, Jeffrey C.; Nacusi, Lucas P.; Segovis, Colin M.; Medeiros, Ricardo B.; Mitchell, Jason S.; Shimizu, Yoji; Billadeau, Daniel D.

    2008-01-01

    WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation. PMID:18809728

  19. Data-Rich Astronomy: Mining Sky Surveys with PhotoRApToR

    NASA Astrophysics Data System (ADS)

    Cavuoti, Stefano; Brescia, Massimo; Longo, Giuseppe

    2014-05-01

    In the last decade a new generation of telescopes and sensors has allowed the production of a very large amount of data and astronomy has become a data-rich science. New automatic methods largely based on machine learning are needed to cope with such data tsunami. We present some results in the fields of photometric redshifts and galaxy classification, obtained using the MLPQNA algorithm available in the DAMEWARE (Data Mining and Web Application Resource) for the SDSS galaxies (DR9 and DR10). We present PhotoRApToR (Photometric Research Application To Redshift): a Java based desktop application capable to solve regression and classification problems and specialized for photo-z estimation.

  20. Field performance of RAS test sections and laboratory investigation of impact of rejuvenators on engineering properties of RAP/RAS mixes.

    DOT National Transportation Integrated Search

    2014-04-01

    In the last several years, recycled asphalt shingles (RAS), in addition to reclaimed asphalt pavement (RAP), : have been widely used in Texas. The use of RAS can significantly reduce the cost of asphalt mixtures, conserve : energy, and protect the en...

  1. EVALUATION OF THE REAL-TIME AIR-QUALITY MODEL USING THE RAPS (REGIONAL AIR POLLUTION STUDY) DATA BASE. VOLUME 1. OVERVIEW

    EPA Science Inventory

    The theory and programming of statistical tests for evaluating the Real-Time Air-Quality Model (RAM) using the Regional Air Pollution Study (RAPS) data base are fully documented in four report volumes. Moreover, the tests are generally applicable to other model evaluation problem...

  2. EEG and MEG source localization using recursively applied (RAP) MUSIC

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mosher, J.C.; Leahy, R.M.

    1996-12-31

    The multiple signal characterization (MUSIC) algorithm locates multiple asynchronous dipolar sources from electroencephalography (EEG) and magnetoencephalography (MEG) data. A signal subspace is estimated from the data, then the algorithm scans a single dipole model through a three-dimensional head volume and computes projections onto this subspace. To locate the sources, the user must search the head volume for local peaks in the projection metric. Here we describe a novel extension of this approach which we refer to as RAP (Recursively APplied) MUSIC. This new procedure automatically extracts the locations of the sources through a recursive use of subspace projections, which usesmore » the metric of principal correlations as a multidimensional form of correlation analysis between the model subspace and the data subspace. The dipolar orientations, a form of `diverse polarization,` are easily extracted using the associated principal vectors.« less

  3. Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway.

    PubMed

    Rajagopal, Senthilkumar; Kumar, Divya P; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U; Bunnett, Nigel W; Grider, John R; Murthy, Karnam S

    2013-03-01

    The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5(-/-) mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2'-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser(188). TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids.

  4. Effects of Reclaimed Asphalt Pavement (RAP) Contents and Sources on Dynamic Modulus (|E*|) and Fatigue Performance of Asphalt Mixtures in Georgia

    DOT National Transportation Integrated Search

    2016-09-01

    This report presents the effect of RAP contents and sources on the dynamic modulus and the performance of Georgia asphalt concrete mixtures. Asphalt concrete mixtures were prepared based on two Job Mix Formulas from North and South with 12.5mm nomina...

  5. EVALUATION OF THE REAL-TIME AIR-QUALITY MODEL USING THE RAPS (REGIONAL AIR POLLUTION STUDY) DATA BASE. VOLUME 4. EVALUATION GUIDE

    EPA Science Inventory

    The theory and programming of statistical tests for evaluating the Real-Time Air-Quality Model (RAM) using the Regional Air Pollution Study (RAPS) data base are fully documented in four volumes. Moreover, the tests are generally applicable to other model evaluation problems. Volu...

  6. The Function of the Glutamate-Nitric Oxide-cGMP Pathway in Brain in Vivo and Learning Ability Decrease in Parallel in Mature Compared with Young Rats

    ERIC Educational Resources Information Center

    Piedrafita, Blanca; Cauli, Omar; Montoliu, Carmina; Felipo, Vicente

    2007-01-01

    Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. We have recently reported that the ability of rats to learn a Y-maze conditional discrimination task depends on the function of the glutamate-nitric oxide-cGMP pathway in brain. The aims of the present work were to assess whether the ability of rats to…

  7. 40 CFR 270.230 - May I perform remediation waste management activities under a RAP at a location removed from the...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... assumed to be in compliance with this requirement. (e) These alternative locations are remediation waste... 40 Protection of Environment 27 2011-07-01 2011-07-01 false May I perform remediation waste management activities under a RAP at a location removed from the area where the remediation wastes originated...

  8. 40 CFR 270.230 - May I perform remediation waste management activities under a RAP at a location removed from the...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... assumed to be in compliance with this requirement. (e) These alternative locations are remediation waste... 40 Protection of Environment 27 2014-07-01 2014-07-01 false May I perform remediation waste management activities under a RAP at a location removed from the area where the remediation wastes originated...

  9. Rock gabion, rip-rap, and culvert treatments: Successes and failures in post-fire erosion mitigation, Schultz Fire 2010

    Treesearch

    Daniel G. Neary; Karen A. Koestner

    2011-01-01

    Following the Schultz Fire in June of 2010, several erosion mitigation efforts were undertaken to reduce the impacts of post-fire flooding expected during the 2010 monsoon. One treatment consisted of the placement of large rock rip-rap on targeted fill slopes of a high elevation forest road that contains a buried pipeline supplying water to the city of Flagstaff....

  10. EVALUATION OF THE REAL-TIME AIR-QUALITY MODEL USING THE RAPS (REGIONAL AIR POLLUTION STUDY) DATA BASE. VOLUME 3. PROGRAM USER'S GUIDE

    EPA Science Inventory

    The theory and programming of statistical tests for evaluating the Real-Time Air-Quality Model (RAM) using the Regional Air Pollution Study (RAPS) data base are fully documented in four volumes. Moreover, the tests are generally applicable to other model evaluation problems. Volu...

  11. The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells

    PubMed Central

    Maymó, Julieta Lorena; Pérez Pérez, Antonio; Maskin, Bernardo; Dueñas, José Luis; Calvo, Juan Carlos; Sánchez Margalet, Víctor; Varone, Cecilia Laura

    2012-01-01

    Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)2cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the

  12. C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38α activation, while it impairs tumor growth through p38α-independent mechanisms

    PubMed Central

    Priego, Neibla; Arechederra, María; Sequera, Celia; Bragado, Paloma; Vázquez-Carballo, Ana; Gutiérrez-Uzquiza, Álvaro; Martín-Granado, Víctor; Ventura, Juan José; Kazanietz, Marcelo G.; Guerrero, Carmen; Porras, Almudena

    2016-01-01

    C3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38α MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38α hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38α collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38α individually or together promoted cell death in vitro, although only the double C3G-p38α silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38α or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis. PMID:27286263

  13. Mutational analysis of human RNA polymerase II subunit 5 (RPB5): the residues critical for interactions with TFIIF subunit RAP30 and hepatitis B virus X protein.

    PubMed

    Le, Thi Thu Thuy; Zhang, Shijun; Hayashi, Naoyuki; Yasukawa, Mami; Delgermaa, Luvsanjav; Murakami, Seishi

    2005-09-01

    RNA polymerase II (RNAPII) subunit 5 (RPB5) is positioned close to DNA downstream of the initiation site and is the site of interaction with several regulators. Hepatitis B virus X protein (HBx) binds the central part of RPB5 to modulate activated transcription, and TFIIF subunit RAP30 interacts with the same part of RPB5 that is critical for the association between TFIIF and RNAPII. However the residues necessary for these interactions remain unknown. Here we report systematic mutagenesis of the central part of RPB5 using two-step alanine scanning libraries to pinpoint critical residues for its binding to RAP30 in the TFIIF complex and/or to HBx, and identified these residues in both mammalian cells and in an in vitro binding assay. Four residues, F76, I104, T111 and S113, are critical for both TFIIF- and HBx-binding, indicating the overlapping nature of the sites of interaction. In addition, V74 and N98 are required for HBx-binding, and T56 and L58 are needed for RAP30-binding. Interestingly the residues exposed to solvent, T111 and S113, are very close to the DNA, implying that two factors may modulate the interaction between DNA and RPB5.

  14. Analysis of repeated signals during shell fights in the hermit crab Pagurus bernhardus

    PubMed Central

    Briffa, M.; Elwood, R. W.; Dick, J. T. A.

    1998-01-01

    Shell exchanges between hermit crabs may occur after a period of shell rapping, when the initiating or attacking crab brings its shell rapidly and repeatedly into contact with the shell of the non-initiator or defender, in a series of bouts. There are two opposing models of hermit crab shell exchange and the function of shell rapping. The negotiation model views shell exchange as a mutualistic activity, in which the initiator supplies information about the quality of its shell via the fundamental frequency of the rapping sound. The aggression model views shell rapping as either detrimental to the defending crab, or as providing it with information about the initiator's ability or motivation to continue, or both. The negotiation model makes no predictions about the temporal pattern of rapping, but under the aggression model it would be expected that crabs that rapped more vigorously would be more likely to effect an exchange. Repeating the signal could be expected under either model. Crabs that achieve an exchange rap more vigorously, rapping is more persistent when a clear gain in shell quality may be achieved, and the vigour is greater when the relative resource-holding potential (or 'fighting ability') is high. These findings support the aggression model rather than the negotiation model. Contrary to the predictions of game theory, crabs that do not effect an exchange appear to signal that they are about to give up. The data suggest that rapping is performed repeatedly because the accumulation of all of the performances acts as a signal of stamina.

  15. Neural correlates of lyrical improvisation: an FMRI study of freestyle rap.

    PubMed

    Liu, Siyuan; Chow, Ho Ming; Xu, Yisheng; Erkkinen, Michael G; Swett, Katherine E; Eagle, Michael W; Rizik-Baer, Daniel A; Braun, Allen R

    2012-01-01

    The neural correlates of creativity are poorly understood. Freestyle rap provides a unique opportunity to study spontaneous lyrical improvisation, a multidimensional form of creativity at the interface of music and language. Here we use functional magnetic resonance imaging to characterize this process. Task contrast analyses indicate that improvised performance is characterized by dissociated activity in medial and dorsolateral prefrontal cortices, providing a context in which stimulus-independent behaviors may unfold in the absence of conscious monitoring and volitional control. Connectivity analyses reveal widespread improvisation-related correlations between medial prefrontal, cingulate motor, perisylvian cortices and amygdala, suggesting the emergence of a network linking motivation, language, affect and movement. Lyrical improvisation appears to be characterized by altered relationships between regions coupling intention and action, in which conventional executive control may be bypassed and motor control directed by cingulate motor mechanisms. These functional reorganizations may facilitate the initial improvisatory phase of creative behavior.

  16. Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway

    PubMed Central

    Rajagopal, Senthilkumar; Kumar, Divya P.; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U.; Bunnett, Nigel W.; Grider, John R.

    2013-01-01

    The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5−/− mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2′-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser188. TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids. PMID:23275618

  17. Summary Report for the Environmental Protection Agency MERL/FRMAC/RAP Mission Alignment Exercise held at the Savannah River Site on June 9-13 2014

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Allen, Mark B.; Shanks, Sonoya Toyoko; Fournier, Sean Donovan

    From June 9th thru June 13th 2014, members of the Federal Radiological Monitoring and Assessment Center (FRMAC), the Environmental Protection Agency (EPA) and the Department of Energy Radiological Assistance Program (DOE RAP) Region-3 participated in a joint nuclear incident emergency response exercise at the Savannah River Site (SRS) near Aiken, South Carolina. The purpose of this exercise was to strengthen the interoperability relationship between the FRMAC, RAP, and the EPA Mobile Environmental Radiation Laboratory (MERL) stationed in Montgomery, Alabama. The exercise was designed to allowed members of the DOE RAP Region-3 team to collect soil, water, vegetation and air samplesmore » from SRS and submit them through an established FRMAC hotline. Once received and processed through the hotline, FRMAC delivered the samples to the EPA MERL for sample preparation and laboratory radiological analysis. Upon completion of laboratory analysis, data was reviewed and submitted back to FRMAC via an electronic data deliverable (EDD). As part of the exercise, an evaluation was conducted to identify gaps and potential improvements in each step of the processes. Additionally, noteworthy practices and potential future areas of interoperability between FRMAC and EPA were acknowledged. The exercise also provided a unique opportunity for FRMAC personnel to observe EPA sample receipt and sample preparation processes and to gain familiarity with the MERL laboratory instrumentation and radiation detection capabilities. The observations and lessons-learned from this exercise will be critical for developing a more efficient, integrated response for future interactions between the FRMAC and EPA assets.« less

  18. 40 CFR 270.140 - What else must the Director prepare in addition to the draft RAP or notice of intent to deny?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false What else must the Director prepare in... the Director prepare in addition to the draft RAP or notice of intent to deny? Once the Director has... Regional office or published material that is generally available need not be physically included with the...

  19. Who's Playin' Whom? Overwhelming Influence of Hip-Hop Culture, Rap Music on Historically Black College and University (HBCU) Campuses Concerns Students; Faculty

    ERIC Educational Resources Information Center

    Stewart, Pearl

    2004-01-01

    In December 2000, Dr. Thomas Earl Midgette had harsh words for the hip-hop movement that was sweeping his campus. When he was interviewed for an article in "Black Issues" titled "The Miseducation of Hip-Hop," Midgette didn't hold back: "You see students walking on campus reciting rap lyrics when they should be reciting…

  20. Vibrational Stark effect spectroscopy at the interface of Ras and Rap1A bound to the Ras binding domain of RalGDS reveals an electrostatic mechanism for protein-protein interaction.

    PubMed

    Stafford, Amy J; Ensign, Daniel L; Webb, Lauren J

    2010-11-25

    Electrostatic fields at the interface of the Ras binding domain of the protein Ral guanine nucleotide dissociation stimulator (RalGDS) with the structurally analogous GTPases Ras and Rap1A were measured with vibrational Stark effect (VSE) spectroscopy. Eleven residues on the surface of RalGDS that participate in this protein-protein interaction were systematically mutated to cysteine and subsequently converted to cyanocysteine in order to introduce a nitrile VSE probe in the form of the thiocyanate (SCN) functional group. The measured SCN absorption energy on the monomeric protein was compared with solvent-accessible surface area (SASA) calculations and solutions to the Poisson-Boltzmann equation using Boltzmann-weighted structural snapshots from molecular dynamics simulations. We found a weak negative correlation between SASA and measured absorption energy, indicating that water exposure of protein surface amino acids can be estimated from experimental measurement of the magnitude of the thiocyanate absorption energy. We found no correlation between calculated field and measured absorption energy. These results highlight the complex structural and electrostatic nature of the protein-water interface. The SCN-labeled RalGDS was incubated with either wild-type Ras or wild-type Rap1A, and the formation of the docked complex was confirmed by measurement of the dissociation constant of the interaction. The change in absorption energy of the thiocyanate functional group due to complex formation was related to the change in electrostatic field experienced by the nitrile functional group when the protein-protein interface forms. At some locations, the nitrile experiences the same shift in field when bound to Ras and Rap1A, but at others, the change in field is dramatically different. These differences identify residues on the surface of RalGDS that direct the specificity of RalGDS binding to its in vivo binding partner, Rap1A, through an electrostatic mechanism.

  1. Phosphorylation of Synaptic GTPase-activating Protein (synGAP) by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and Cyclin-dependent Kinase 5 (CDK5) Alters the Ratio of Its GAP Activity toward Ras and Rap GTPases*

    PubMed Central

    Walkup, Ward G.; Washburn, Lorraine; Sweredoski, Michael J.; Carlisle, Holly J.; Graham, Robert L.; Hess, Sonja; Kennedy, Mary B.

    2015-01-01

    synGAP is a neuron-specific Ras and Rap GTPase-activating protein (GAP) found in high concentrations in the postsynaptic density (PSD) fraction from the mammalian forebrain. We have previously shown that, in situ in the PSD fraction or in recombinant form in Sf9 cell membranes, synGAP is phosphorylated by Ca2+/calmodulin-dependent protein kinase II (CaMKII), another prominent component of the PSD. Here, we show that recombinant synGAP (r-synGAP), lacking 102 residues at the N terminus, can be purified in soluble form and is phosphorylated by cyclin-dependent kinase 5 (CDK5) as well as by CaMKII. Phosphorylation of r-synGAP by CaMKII increases its HRas GAP activity by 25% and its Rap1 GAP activity by 76%. Conversely, phosphorylation by CDK5 increases r-synGAP's HRas GAP activity by 98% and its Rap1 GAP activity by 20%. Thus, phosphorylation by both kinases increases synGAP activity; CaMKII shifts the relative GAP activity toward inactivation of Rap1, and CDK5 shifts the relative activity toward inactivation of HRas. GAP activity toward Rap2 is not altered by phosphorylation by either kinase. CDK5 phosphorylates synGAP primarily at two sites, Ser-773 and Ser-802. Phosphorylation at Ser-773 inhibits r-synGAP activity, and phosphorylation at Ser-802 increases it. However, the net effect of concurrent phosphorylation of both sites, Ser-773 and Ser-802, is an increase in GAP activity. synGAP is phosphorylated at Ser-773 and Ser-802 in the PSD fraction, and its phosphorylation by CDK5 and CaMKII is differentially regulated by activation of NMDA-type glutamate receptors in cultured neurons. PMID:25533468

  2. Epac activation sensitizes rat sensory neurons through activation of Ras.

    PubMed

    Shariati, Behzad; Thompson, Eric L; Nicol, Grant D; Vasko, Michael R

    2016-01-01

    Guanine nucleotide exchange factors directly activated by cAMP (Epacs) have emerged as important signaling molecules mediating persistent hypersensitivity in animal models of inflammation, by augmenting the excitability of sensory neurons. Although Epacs activate numerous downstream signaling cascades, the intracellular signaling which mediates Epac-induced sensitization of capsaicin-sensitive sensory neurons remains unknown. Here, we demonstrate that selective activation of Epacs with 8-CPT-2'-O-Me-cAMP-AM (8CPT-AM) increases the number of action potentials (APs) generated by a ramp of depolarizing current and augments the evoked release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons. Internal perfusion of capsaicin-sensitive sensory neurons with GDP-βS, substituted for GTP, blocks the ability of 8CPT-AM to increase AP firing, demonstrating that Epac-induced sensitization is G-protein dependent. Treatment with 8CPT-AM activates the small G-proteins Rap1 and Ras in cultures of sensory neurons. Inhibition of Rap1, by internal perfusion of a Rap1-neutralizing antibody or through a reduction in the expression of the protein using shRNA does not alter the Epac-induced enhancement of AP generation or CGRP release, despite the fact that in most other cell types, Epacs act as Rap-GEFs. In contrast, inhibition of Ras through expression of a dominant negative Ras (DN-Ras) or through internal perfusion of a Ras-neutralizing antibody blocks the increase in AP firing and attenuates the increase in the evoked release of CGRP induced by Epac activation. Thus, in this subpopulation of nociceptive sensory neurons, it is the novel interplay between Epacs and Ras, rather than the canonical Epacs and Rap1 pathway, that is critical for mediating Epac-induced sensitization. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Epac activation sensitizes rat sensory neurons via activation of Ras

    PubMed Central

    Shariati, Behzad; Thompson, Eric L.; Nicol, Grant D.; Vasko, Michael R.

    2015-01-01

    Guanine nucleotide exchange factors directly activated by cAMP (Epacs) have emerged as important signaling molecules mediating persistent hypersensitivity in animal models of inflammation, by augmenting the excitability of sensory neurons. Although Epacs activate numerous downstream signaling cascades, the intracellular signaling which mediates Epac-induced sensitization of capsaicin-sensitive sensory neurons remains unknown. Here, we demonstrate that selective activation of Epacs with 8-CPT-2′-O-Me-cAMP-AM (8CPT-AM) increases the number of action potentials (APs) generated by a ramp of depolarizing current and augments the evoked release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons. Internal perfusion of capsaicin-sensitive sensory neurons with GDP-βS, substituted for GTP, blocks the ability of 8CPT-AM to increase AP firing, demonstrating that Epac-induced sensitization is G-protein dependent. Treatment with 8CPT-AM activates the small G-proteins Rap1 and Ras in cultures of sensory neurons. Inhibition of Rap1, by internal perfusion of a Rap1-neutralizing antibody or through a reduction in the expression of the protein using shRNA does not alter the Epac-induced enhancement of AP generation or CGRP release, despite the fact that in most other cell types, Epacs act as Rap-GEFs. In contrast, inhibition of Ras through expression of a dominant negative Ras (DN-Ras) or through internal perfusion of a Ras-neutralizing antibody blocks the increase in AP firing and attenuates the increase in the evoked release of CGRP induced by Epac activation. Thus, in this subpopulation of nociceptive sensory neurons, it is the novel interplay between Epacs and Ras, rather than the canonical Epacs and Rap1 pathway, that is critical for mediating Epac-induced sensitization. PMID:26596174

  4. Metabolic Pathways Visualization Skills Development by Undergraduate Students

    ERIC Educational Resources Information Center

    dos Santos, Vanessa J. S. V.; Galembeck, Eduardo

    2015-01-01

    We have developed a metabolic pathways visualization skill test (MPVST) to gain greater insight into our students' abilities to comprehend the visual information presented in metabolic pathways diagrams. The test is able to discriminate students' visualization ability with respect to six specific visualization skills that we identified as key to…

  5. The challenge of treating conduct disorder in low-resourced settings: rap music to the rescue.

    PubMed

    Evans, Dylan J

    2010-12-01

    Conduct disorder is one of the most frequent serious childhood problems that present for treatment in community clinic settings. Evidence-based treatments for conduct disorder are intensive and require considerable resources to implement. In low-resourced contexts it is often not feasible to implement evidence-based treatments in their current form, which poses significant challenges for clinicians attempting to treat children in these settings. This article explores these challenges using a case study of the treatment of a young adolescent boy with a short-term multisystem intervention where rap music was employed as a powerful tool to facilitate an empathic connection in therapy and as a projective technique to explore underlying emotional difficulties.

  6. Neural Correlates of Lyrical Improvisation: An fMRI Study of Freestyle Rap

    PubMed Central

    Liu, Siyuan; Chow, Ho Ming; Xu, Yisheng; Erkkinen, Michael G.; Swett, Katherine E.; Eagle, Michael W.; Rizik-Baer, Daniel A.; Braun, Allen R.

    2012-01-01

    The neural correlates of creativity are poorly understood. Freestyle rap provides a unique opportunity to study spontaneous lyrical improvisation, a multidimensional form of creativity at the interface of music and language. Here we use functional magnetic resonance imaging to characterize this process. Task contrast analyses indicate that improvised performance is characterized by dissociated activity in medial and dorsolateral prefrontal cortices, providing a context in which stimulus-independent behaviors may unfold in the absence of conscious monitoring and volitional control. Connectivity analyses reveal widespread improvisation-related correlations between medial prefrontal, cingulate motor, perisylvian cortices and amygdala, suggesting the emergence of a network linking motivation, language, affect and movement. Lyrical improvisation appears to be characterized by altered relationships between regions coupling intention and action, in which conventional executive control may be bypassed and motor control directed by cingulate motor mechanisms. These functional reorganizations may facilitate the initial improvisatory phase of creative behavior. PMID:23155479

  7. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial).

    PubMed

    Mandrioli, Jessica; D'Amico, Roberto; Zucchi, Elisabetta; Gessani, Annalisa; Fini, Nicola; Fasano, Antonio; Caponnetto, Claudia; Chiò, Adriano; Dalla Bella, Eleonora; Lunetta, Christian; Mazzini, Letizia; Marinou, Kalliopi; Sorarù, Gianni; de Biasi, Sara; Lo Tartaro, Domenico; Pinti, Marcello; Cossarizza, Andrea

    2018-06-01

    Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n

  8. Junction detection and pathway selection

    NASA Astrophysics Data System (ADS)

    Peck, Alex N.; Lim, Willie Y.; Breul, Harry T.

    1992-02-01

    The ability to detect junctions and make choices among the possible pathways is important for autonomous navigation. In our script-based navigation approach where a journey is specified as a script of high-level instructions, actions are frequently referenced to junctions, e.g., `turn left at the intersection.' In order for the robot to carry out these kind of instructions, it must be able (1) to detect an intersection (i.e., an intersection of pathways), (2) know that there are several possible pathways it can take, and (3) pick the pathway consistent with the high level instruction. In this paper we describe our implementation of the ability to detect junctions in an indoor environment, such as corners, T-junctions and intersections, using sonar. Our approach uses a combination of partial scan of the local environment and recognition of sonar signatures of certain features of the junctions. In the case where the environment is known, we use additional sensor information (such as compass bearings) to help recognize the specific junction. In general, once a junction is detected and its type known, the number of possible pathways can be deduced and the correct pathway selected. Then the appropriate behavior for negotiating the junction is activated.

  9. Telomere shortening triggers a feedback loop to enhance end protection

    PubMed Central

    Yang, Chia-Wei; Tseng, Shun-Fu; Yu, Chia-Jung; Chung, Chia-Yu; Chang, Cheng-Yen; Pobiega, Sabrina

    2017-01-01

    Abstract Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1–Rif1 association impairs telomere length regulation and increases telomere–telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1–Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis. PMID:28575419

  10. Telomere shortening triggers a feedback loop to enhance end protection.

    PubMed

    Yang, Chia-Wei; Tseng, Shun-Fu; Yu, Chia-Jung; Chung, Chia-Yu; Chang, Cheng-Yen; Pobiega, Sabrina; Teng, Shu-Chun

    2017-08-21

    Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1-Rif1 association impairs telomere length regulation and increases telomere-telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1-Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  11. Pathways from education to depression.

    PubMed

    Lee, Jinkook

    2011-06-01

    We examine educational gradients in depression and identify underlying mechanisms of how education might affect depression. We use a nationally representative sample of community-residing adults aged 45 and older from the 2006 Korean Longitudinal Study of Aging, which collected information about depressive symptoms and education. Using tobit regression, we estimate the effect of education on depression and examine what can explain the education gradients by controlling for proxy variables of different pathways linking education to depression. We found cognitive ability, economic resources, social status, social network, and health behavior explain all of the education gradients. Education affects depression through different underlying mechanisms, and the single most important pathway is through developing cognitive ability. Through these pathways, educational attainment influences not only depression for an individual but also for one's spouse, particularly for women, and parents.

  12. Plasma levels of soluble interleukin 1 receptor accessory protein are reduced in obesity.

    PubMed

    Bozaoglu, Kiymet; Attard, Chantal; Kulkarni, Hemant; Cummings, Nik; Diego, Vincent P; Carless, Melanie A; Shields, Katherine A; Johnson, Matthew P; Kowlessur, Sudhir; Dyer, Thomas D; Comuzzie, Anthony G; Almasy, Laura; Zimmet, Paul; Moses, Eric K; Göring, Harald H H; Curran, Joanne E; Blangero, John; Jowett, Jeremy B M

    2014-09-01

    Adipokines actuate chronic, low-grade inflammation through a complex network of immune markers, but the current understanding of these networks is incomplete. The soluble isoform of the IL-1 receptor accessory protein (sIL1RAP) occupies an important position in the inflammatory pathways involved in obesity. The pathogenetic and clinical influences of sIL1RAP are unknown. The objective of the study was to elucidate whether plasma levels of sIL1RAP are reduced in obesity, using affluent clinical, biochemical, and genetic data from two diverse cohorts. The study was conducted in two cohorts: the San Antonio Family Heart Study (n = 1397 individuals from 42 families) and South Asians living in Mauritius, n = 230). Plasma sIL1RAP levels were measured using an ELISA. The genetic basis of sIL1RAP levels were investigated using both a large-scale gene expression profiling study and a genome-wide association study. A significant decrease in plasma sIL1RAP levels were observed in obese subjects, even after adjustment for age and sex. The sIL1RAP levels demonstrated a strong inverse association with obesity measures in both populations. All associations were more significant in females. Plasma sIL1RAP levels were significantly heritable, correlated with IL1RAP transcript levels (NM_134470), showed evidence for shared genetic influences with obesity measures and were significantly associated with the rs2885373 single-nucleotide polymorphism (P = 6.7 × 10(-23)) within the IL1RAP gene. Plasma sIL1RAP levels are reduced in obesity and can potentially act as biomarkers of obesity. Mechanistic studies are required to understand the exact contribution of sIL1RAP to the pathogenesis of obesity.

  13. Plasma Levels of Soluble Interleukin 1 Receptor Accessory Protein Are Reduced in Obesity

    PubMed Central

    Attard, Chantal; Kulkarni, Hemant; Cummings, Nik; Diego, Vincent P.; Carless, Melanie A.; Shields, Katherine A.; Johnson, Matthew P.; Kowlessur, Sudhir; Dyer, Thomas D.; Comuzzie, Anthony G.; Almasy, Laura; Zimmet, Paul; Moses, Eric K.; Göring, Harald H. H.; Curran, Joanne E.; Blangero, John; Jowett, Jeremy B. M.

    2014-01-01

    Context: Adipokines actuate chronic, low-grade inflammation through a complex network of immune markers, but the current understanding of these networks is incomplete. The soluble isoform of the IL-1 receptor accessory protein (sIL1RAP) occupies an important position in the inflammatory pathways involved in obesity. The pathogenetic and clinical influences of sIL1RAP are unknown. Objective: The objective of the study was to elucidate whether plasma levels of sIL1RAP are reduced in obesity, using affluent clinical, biochemical, and genetic data from two diverse cohorts. Design, Setting, and Participants: The study was conducted in two cohorts: the San Antonio Family Heart Study (n = 1397 individuals from 42 families) and South Asians living in Mauritius, n = 230). Main Outcome Measures: Plasma sIL1RAP levels were measured using an ELISA. The genetic basis of sIL1RAP levels were investigated using both a large-scale gene expression profiling study and a genome-wide association study. Results: A significant decrease in plasma sIL1RAP levels were observed in obese subjects, even after adjustment for age and sex. The sIL1RAP levels demonstrated a strong inverse association with obesity measures in both populations. All associations were more significant in females. Plasma sIL1RAP levels were significantly heritable, correlated with IL1RAP transcript levels (NM_134470), showed evidence for shared genetic influences with obesity measures and were significantly associated with the rs2885373 single-nucleotide polymorphism (P = 6.7 × 10−23) within the IL1RAP gene. Conclusions: Plasma sIL1RAP levels are reduced in obesity and can potentially act as biomarkers of obesity. Mechanistic studies are required to understand the exact contribution of sIL1RAP to the pathogenesis of obesity. PMID:24915116

  14. An Automated Pipeline for Engineering Many-Enzyme Pathways: Computational Sequence Design, Pathway Expression-Flux Mapping, and Scalable Pathway Optimization.

    PubMed

    Halper, Sean M; Cetnar, Daniel P; Salis, Howard M

    2018-01-01

    Engineering many-enzyme metabolic pathways suffers from the design curse of dimensionality. There are an astronomical number of synonymous DNA sequence choices, though relatively few will express an evolutionary robust, maximally productive pathway without metabolic bottlenecks. To solve this challenge, we have developed an integrated, automated computational-experimental pipeline that identifies a pathway's optimal DNA sequence without high-throughput screening or many cycles of design-build-test. The first step applies our Operon Calculator algorithm to design a host-specific evolutionary robust bacterial operon sequence with maximally tunable enzyme expression levels. The second step applies our RBS Library Calculator algorithm to systematically vary enzyme expression levels with the smallest-sized library. After characterizing a small number of constructed pathway variants, measurements are supplied to our Pathway Map Calculator algorithm, which then parameterizes a kinetic metabolic model that ultimately predicts the pathway's optimal enzyme expression levels and DNA sequences. Altogether, our algorithms provide the ability to efficiently map the pathway's sequence-expression-activity space and predict DNA sequences with desired metabolic fluxes. Here, we provide a step-by-step guide to applying the Pathway Optimization Pipeline on a desired multi-enzyme pathway in a bacterial host.

  15. Utilization of recycled asphalt concrete with warm mix asphalt and cost-benefit analysis.

    PubMed

    Oner, Julide; Sengoz, Burak

    2015-01-01

    The asphalt paving industries are faced with two major problems. These two important challenges are generated with an increase in demand for environmentally friendly paving mixtures and the problem of rapidly rising raw materials. Recycling of reclaimed asphalt pavement (RAP) is a critical necessity to save precious aggregates and reduce the use of costly bitumen. Warm Mix Asphalt (WMA) technology provides not only the option of recycling asphalt pavement at a lower temperature than the temperature maintained in hot mixtures but also encourages the utilization of RAP and therefore saves energy and money. This paper describes the feasibility of utilizing three different WMA additives (organic, chemical and water containing) at recommended contents with different percentages of RAP. The mechanical properties and cost-benefit analysis of WMA containing RAP have been performed and compared with WMA without RAP. The results indicated that, 30%, 10% and 20% can be accepted as an optimum RAP addition related to organic, chemical and water containing additives respectively and organic additive with 30% RAP content has an appreciable increase in tensile strength over the control mix. It was also concluded that the RAP with WMA technology is the ability to reduce final cost compared to HMA and WMA mixtures.

  16. Utilization of Recycled Asphalt Concrete with Warm Mix Asphalt and Cost-Benefit Analysis

    PubMed Central

    Oner, Julide; Sengoz, Burak

    2015-01-01

    The asphalt paving industries are faced with two major problems. These two important challenges are generated with an increase in demand for environmentally friendly paving mixtures and the problem of rapidly rising raw materials. Recycling of reclaimed asphalt pavement (RAP) is a critical necessity to save precious aggregates and reduce the use of costly bitumen. Warm Mix Asphalt (WMA) technology provides not only the option of recycling asphalt pavement at a lower temperature than the temperature maintained in hot mixtures but also encourages the utilization of RAP and therefore saves energy and money. This paper describes the feasibility of utilizing three different WMA additives (organic, chemical and water containing) at recommended contents with different percentages of RAP. The mechanical properties and cost-benefit analysis of WMA containing RAP have been performed and compared with WMA without RAP. The results indicated that, 30%, 10% and 20% can be accepted as an optimum RAP addition related to organic, chemical and water containing additives respectively and organic additive with 30% RAP content has an appreciable increase in tensile strength over the control mix. It was also concluded that the RAP with WMA technology is the ability to reduce final cost compared to HMA and WMA mixtures. PMID:25574851

  17. Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis.

    PubMed

    Carrión, Ricardo E; Cornblatt, Barbara A; McLaughlin, Danielle; Chang, Jeremy; Auther, Andrea M; Olsen, Ruth H; Javitt, Daniel C

    2015-05-01

    There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. How CAGE, RAPS4-QF, and AUDIT Can Help Practitioners for Patients Admitted with Acute Alcohol Intoxication in Emergency Departments?

    PubMed

    Brousse, Georges; Arnaud, Benjamin; Geneste, Julie; Pereira, Bruno; De Chazeron, Ingrid; Teissedre, Frederique; Perrier, Christophe; Schwan, Raymund; Malet, Laurent; Schmidt, Jeannot; Llorca, Pierre Michel; Cherpitel, Cheryl J

    2014-01-01

    To help clinicians to identify the severity of alcohol use disorders (AUDs) from optimal thresholds found for recommended scales. Especially, taking account of the high prevalence of alcohol dependence among patients admitted to the emergency department (ED) for acute alcohol intoxication (AAI), we propose to define thresholds of severity of dependence based on the AUDIT score. All patients admitted to the ED with AAI (blood alcohol level >0.8 g/L), in a 2-month period, were assessed using the CAGE, RAPS-QF, and AUDIT, with the alcohol dependence/abuse section of the mini international neuropsychiatric interview (MINI) used as the gold standard. To explore the relation between the AUDIT and the MINI the sum of the positive items on the MINI (dependence) as a quantitative variable and as an ordinal parameter were analyzed. From the threshold score found for each scale we proposed intervals of severity of AUDs. The mean age of the sample (122 males, 42 females) was 46 years. Approximately 12% of the patients were identified with alcohol abuse and 78% with dependence (DSM-IV). Cut points were determined for the AUDIT in order to distinguish mild and moderate dependence from severe dependence. A strategy of intervention based on levels of severity of AUD was proposed. Different thresholds proposed for the CAGE, RAPS4-QF, and AUDIT could be used to guide the choice of intervention for a patient: brief intervention, brief negotiation interviewing, or longer more intensive motivational intervention.

  19. An optimization model for metabolic pathways.

    PubMed

    Planes, F J; Beasley, J E

    2009-10-15

    Different mathematical methods have emerged in the post-genomic era to determine metabolic pathways. These methods can be divided into stoichiometric methods and path finding methods. In this paper we detail a novel optimization model, based upon integer linear programming, to determine metabolic pathways. Our model links reaction stoichiometry with path finding in a single approach. We test the ability of our model to determine 40 annotated Escherichia coli metabolic pathways. We show that our model is able to determine 36 of these 40 pathways in a computationally effective manner.

  20. How CAGE, RAPS4-QF, and AUDIT Can Help Practitioners for Patients Admitted with Acute Alcohol Intoxication in Emergency Departments?

    PubMed Central

    Brousse, Georges; Arnaud, Benjamin; Geneste, Julie; Pereira, Bruno; De Chazeron, Ingrid; Teissedre, Frederique; Perrier, Christophe; Schwan, Raymund; Malet, Laurent; Schmidt, Jeannot; Llorca, Pierre Michel; Cherpitel, Cheryl J.

    2014-01-01

    Aims: To help clinicians to identify the severity of alcohol use disorders (AUDs) from optimal thresholds found for recommended scales. Especially, taking account of the high prevalence of alcohol dependence among patients admitted to the emergency department (ED) for acute alcohol intoxication (AAI), we propose to define thresholds of severity of dependence based on the AUDIT score. Methods: All patients admitted to the ED with AAI (blood alcohol level >0.8 g/L), in a 2-month period, were assessed using the CAGE, RAPS-QF, and AUDIT, with the alcohol dependence/abuse section of the mini international neuropsychiatric interview (MINI) used as the gold standard. To explore the relation between the AUDIT and the MINI the sum of the positive items on the MINI (dependence) as a quantitative variable and as an ordinal parameter were analyzed. From the threshold score found for each scale we proposed intervals of severity of AUDs. Results: The mean age of the sample (122 males, 42 females) was 46 years. Approximately 12% of the patients were identified with alcohol abuse and 78% with dependence (DSM-IV). Cut points were determined for the AUDIT in order to distinguish mild and moderate dependence from severe dependence. A strategy of intervention based on levels of severity of AUD was proposed. Conclusion: Different thresholds proposed for the CAGE, RAPS4-QF, and AUDIT could be used to guide the choice of intervention for a patient: brief intervention, brief negotiation interviewing, or longer more intensive motivational intervention. PMID:25009509

  1. Using rap music to promote adolescent health: pilot study of VoxBox.

    PubMed

    Paukste, Ernesta; Harris, Neil

    2015-04-01

    Alcohol, tobacco and other drugs (ATODs) usage among adolescents, particularly those living in lower socioeconomic communities, is a population health problem in Australia that requires innovative health promotion strategies. There is a growing recognition of the potential of arts-based approaches to engage youth in health promoting activities. This paper presents the process evaluation of the pilot VoxBox intervention that used rap to build adolescents' awareness of risks associated with ATODs. The VoxBox intervention was piloted in Logan, Queensland, at five high schools with 18 adolescents completing the intervention. Data collection methods included observation, focus groups, semi-structured interviews and a survey of adolescent participants. The intervention was well received by participants and stakeholders. Three factors characterising the project's successful engagement of adolescents were: participate - go with the flow, learning from the real deal and resourced to make some noise. In VoxBox, the emphasis on engaging adolescents in an activity of real interest that was appropriately resourced and delivered was central to credibility and success. SO WHAT?: The findings highlight the importance of interventions matching the interests of the targeted population group.

  2. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology

    PubMed Central

    Latendresse, Mario; Paley, Suzanne M.; Krummenacker, Markus; Ong, Quang D.; Billington, Richard; Kothari, Anamika; Weaver, Daniel; Lee, Thomas; Subhraveti, Pallavi; Spaulding, Aaron; Fulcher, Carol; Keseler, Ingrid M.; Caspi, Ron

    2016-01-01

    Pathway Tools is a bioinformatics software environment with a broad set of capabilities. The software provides genome-informatics tools such as a genome browser, sequence alignments, a genome-variant analyzer and comparative-genomics operations. It offers metabolic-informatics tools, such as metabolic reconstruction, quantitative metabolic modeling, prediction of reaction atom mappings and metabolic route search. Pathway Tools also provides regulatory-informatics tools, such as the ability to represent and visualize a wide range of regulatory interactions. This article outlines the advances in Pathway Tools in the past 5 years. Major additions include components for metabolic modeling, metabolic route search, computation of atom mappings and estimation of compound Gibbs free energies of formation; addition of editors for signaling pathways, for genome sequences and for cellular architecture; storage of gene essentiality data and phenotype data; display of multiple alignments, and of signaling and electron-transport pathways; and development of Python and web-services application programming interfaces. Scientists around the world have created more than 9800 Pathway/Genome Databases by using Pathway Tools, many of which are curated databases for important model organisms. PMID:26454094

  3. The amount of parenchyma and living fibers affects storage of nonstructural carbohydrates in young stems and roots of temperate trees.

    PubMed

    Plavcová, Lenka; Hoch, Günter; Morris, Hugh; Ghiasi, Sara; Jansen, Steven

    2016-04-01

    Concentrations of nonstructural carbohydrates (NSCs) are used as proxies for the net carbon balance of trees and as indicators of carbon starvation resulting from environmental stress. Woody organs are the largest NSC-storing compartments in forest ecosystems; therefore, it is essential to understand the factors that affect the size of this important storage pool. In wood, NSC are predominantly deposited in ray and axial parenchyma (RAP); however, direct links between nutrient storage and RAP anatomy have not yet been established. Here, we tested whether the NSC storage capacity of wood is influenced by the amount of RAP. We measured NSC concentrations and RAP fractions in root and stem sapwood of 12 temperate species sampled at the onset of winter dormancy and in stem sapwood of four tropical trees growing in an evergreen lowland rainforest. The patterns of starch distribution were visualized by staining with Lugol's solution. The concentration of NSCs in sapwood of temperate trees scales tightly with the amount of RAP and living fibers (LFs), with almost all RAP and LFs being densely packed with starch grains. In contrast, the tropical species had lower NSC concentrations despite their higher RAP and LFs fraction and had considerable interspecific differences in starch distribution. The differences in RAP and LFs abundance affect the ability of sapwood to store NSC in temperate trees, whereas a more diverse set of functions of RAP might be pronounced in species growing in a tropical environment with little seasonality. © 2016 Botanical Society of America.

  4. EGFR-L858R mutant enhances lung adenocarcinoma cell invasive ability and promotes malignant pleural effusion formation through activation of the CXCL12-CXCR4 pathway

    PubMed Central

    Tsai, Meng-Feng; Chang, Tzu-Hua; Wu, Shang-Gin; Yang, Hsiao-Yin; Hsu, Yi-Chiung; Yang, Pan-Chyr; Shih, Jin-Yuan

    2015-01-01

    Malignant pleural effusion (MPE) is a common clinical problem in non-small cell lung carcinoma (NSCLC) patients; however, the underlying mechanisms are still largely unknown. Recent studies indicate that the frequency of the L858R mutant form of the epidermal growth factor receptor (EGFR-L858R) is higher in lung adenocarcinoma with MPE than in surgically resected specimens, suggesting that lung adenocarcinoma cells harboring this mutation tend to invade the adjacent pleural cavity. The purpose of this study was to clarify the relationship between the EGFR-L858R mutation and cancer cell invasion ability and to investigate the molecular mechanisms involved in the formation of MPE. We found that expression of EGFR-L858R in lung cancer cells resulted in up-regulation of the CXCR4 in association with increased cancer cell invasive ability and MPE formation. Ectopic expression of EGFR-L858R in lung cancer cells acted through activation of ERK signaling pathways to induce the expression of CXCR4. We also indicated that Inhibition of CXCR4 with small interfering RNA, neutralizing antibody, or receptor antagonist significantly suppressed the EGFR-L858R–dependent cell invasion. These results suggest that targeting the production of CXCR4 and blocking the CXCL12-CXCR4 pathway might be effective strategies for treating NSCLCs harboring a specific type of EGFR mutation. PMID:26338423

  5. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ren, Jinqi; Cook, Aaron A.; Bergmeier, Wolfgang

    The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf–MEK–ERKmore » signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2. -- Highlights: •ERK2 phosphorylates the guanine nucleotide exchange factor RasGRP2 at Ser394. •Phosphorylated RasGRP2 has decreased capacity to active Rap1b in vitro and in cells. •Phosphorylation of RasGRP2 by ERK1/2 introduces a negative-feedback loop into the BRaf-MEK-ERK pathway.« less

  6. Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

    PubMed Central

    Cestari, Igor; Stuart, Ken

    2015-01-01

    African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing. PMID:25964327

  7. Pathway analysis with next-generation sequencing data.

    PubMed

    Zhao, Jinying; Zhu, Yun; Boerwinkle, Eric; Xiong, Momiao

    2015-04-01

    Although pathway analysis methods have been developed and successfully applied to association studies of common variants, the statistical methods for pathway-based association analysis of rare variants have not been well developed. Many investigators observed highly inflated false-positive rates and low power in pathway-based tests of association of rare variants. The inflated false-positive rates and low true-positive rates of the current methods are mainly due to their lack of ability to account for gametic phase disequilibrium. To overcome these serious limitations, we develop a novel statistic that is based on the smoothed functional principal component analysis (SFPCA) for pathway association tests with next-generation sequencing data. The developed statistic has the ability to capture position-level variant information and account for gametic phase disequilibrium. By intensive simulations, we demonstrate that the SFPCA-based statistic for testing pathway association with either rare or common or both rare and common variants has the correct type 1 error rates. Also the power of the SFPCA-based statistic and 22 additional existing statistics are evaluated. We found that the SFPCA-based statistic has a much higher power than other existing statistics in all the scenarios considered. To further evaluate its performance, the SFPCA-based statistic is applied to pathway analysis of exome sequencing data in the early-onset myocardial infarction (EOMI) project. We identify three pathways significantly associated with EOMI after the Bonferroni correction. In addition, our preliminary results show that the SFPCA-based statistic has much smaller P-values to identify pathway association than other existing methods.

  8. Characterization of local goat breeds using RAP-DNA markers

    NASA Astrophysics Data System (ADS)

    Al-Barzinji, Yousif M. S.; Hamad, Aram O.

    2017-09-01

    The present study was conducted on different colors of local goat breeds. A number of 216 does were sampled from the seven groups. Genomic DNA was extracted from the blood samples. From the twenty used RAPD primers 12 of them were amplified, and presence of bands. The total fragment number of 12 primers over all the goat breed samples was 485 fragments. Out of the 485 fragments, 90 of them were Polymorphic fragments numbers (PFN). From all bands obtained, 20 of them possessed unique bands. The highest unique band was found in locus RAP 6 which has 4 unique bands, three of them in the Maraz Brown and one in the local Koor. Nei's gene diversity and Shanon's information index in this study were averaged 0.38 and 0.60, respectively. The genetic distance among several goat breeds ranged from 9.11 to 43.33%. The highest genetic distance 43.33% recorded between Maraz goat and other goat breeds and between local Koor and other goat (except Maraz goats) breeds (37.79%). However, the lowest genetic distance recorded between local white and Pnok. The distance between (local Black and Pnok) and (local Black and local white) was 22.75%. In conclusions, the high distance among these goat breeds, polymorphism and high numbers of unique bands found in present study indicates that these goat breeds have the required amount of genetic variation to made genetic improvement. This study helps us to clarify the image of the genetic diversity of the local goat breeds and the breeders can used it for mating system when need to make the crossing among these goat breeds.

  9. Ready to learn physics: a team-based learning model for first year university

    NASA Astrophysics Data System (ADS)

    Parappilly, Maria; Schmidt, Lisa; De Ritter, Samantha

    2015-09-01

    Team-based learning (TBL) is an established model of group work which aims to improve students' ability to apply discipline-related content. TBL consists of a readiness assurance process (RAP), student groups and application activities. While TBL has not been implemented widely in science, technology, engineering and mathematics disciplines, it has been effective in improving student learning in other disciplines. This paper describes the incorporation of TBL activities into a non-calculus based introductory level physics topic—Physics for the Modern World. Students were given pre-class preparation materials and an individual RAP online test before the workshops. The pre-workshop individual RAP test ensured that all students were exposed to concept-based questions before their workshops and motivated them to use the preparatory materials in readiness for the workshop. The students were placed into random teams and during the first part of the workshop, the teams went through a subset of the quiz questions (team RAP test) and in the remaining time, teams completed an in-class assignment. After the workshop students were allowed another attempt at the individual RAP test to see if their knowledge had improved. The ability of TBL to promote student learning of key concepts was evaluated by experiment using pre- and post- testing. The students’ perception of TBL was monitored by discussion posts and survey responses. Finally, the ability of TBL to support peer-peer interaction was evaluated by video analysis of the class. We found that the TBL process improved student learning; students did interact with each other in class; and the students had a positive view of TBL. To assess the transferability of this model to other topics, we conducted a comparison study with an environmental science topic which produced similar results. Our study supports the use of this TBL model in science topics.

  10. PKA and Epac synergistically inhibit smooth muscle cell proliferation

    PubMed Central

    Hewer, Richard C.; Sala-Newby, Graciela B.; Wu, Yih-Jer; Newby, Andrew C.; Bond, Mark

    2011-01-01

    Cyclic AMP signalling promotes VSMC quiescence in healthy vessels and during vascular healing following injury. Cyclic AMP inhibits VSMC proliferation via mechanisms that are not fully understood. We investigated the role of PKA and Epac signalling on cAMP-induced inhibition of VSMC proliferation. cAMP-mediated growth arrest was PKA-dependent. However, selective PKA activation with 6-Benzoyl-cAMP did not inhibit VSMC proliferation, indicating a requirement for additional pathways. Epac activation using the selective cAMP analogue 8-CPT-2′-O-Me-cAMP, did not affect levels of hyperphosphorylated Retinoblastoma (Rb) protein, a marker of G1-S phase transition, or BrdU incorporation, despite activation of the Epac-effector Rap1. However, 6-Benzoyl-cAMP and 8-CPT-2′-O-Me-cAMP acted synergistically to inhibit Rb-hyperphosphorylation and BrdU incorporation, indicating that both pathways are required for growth inhibition. Consistent with this, constitutively active Epac increased Rap1 activity and synergised with 6-Benzoyl-cAMP to inhibit VSMC proliferation. PKA and Epac synergised to inhibit phosphorylation of ERK and JNK. Induction of stellate morphology, previously associated with cAMP-mediated growth arrest, was also dependent on activation of both PKA and Epac. Rap1 inhibition with Rap1GAP or siRNA silencing did not negate forskolin-induced inhibition of Rb-hyperphosphorylation, BrdU incorporation or stellate morphology. This data demonstrates for the first time that Epac synergises with PKA via a Rap1-independent mechanism to mediate cAMP-induced growth arrest in VSMC. This work highlights the role of Epac as a major player in cAMP-dependent growth arrest in VSMC. PMID:20971121

  11. Effects of Steaming Time and Frequency for Manufactured Red Liriope platyphylla on the Insulin Secretion Ability and Insulin Receptor Signaling Pathway.

    PubMed

    Choi, Sun Il; Lee, Hye Ryun; Goo, Jun Seo; Kim, Ji Eun; Nam, So Hee; Hwang, In Sik; Lee, Young Ju; Prak, So Hae; Lee, Hee Seob; Lee, Jong Sup; Jang, In Surk; Son, Hong Ju; Hwang, Dae Youn

    2011-06-01

    In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9-SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may

  12. Effects of Steaming Time and Frequency for Manufactured Red Liriope platyphylla on the Insulin Secretion Ability and Insulin Receptor Signaling Pathway

    PubMed Central

    Choi, Sun Il; Lee, Hye Ryun; Goo, Jun Seo; Kim, Ji Eun; Nam, So Hee; Hwang, In Sik; Lee, Young Ju; Prak, So Hae; Lee, Hee Seob; Lee, Jong Sup; Jang, In Surk; Son, Hong Ju

    2011-01-01

    In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9-SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may

  13. Differential effects of the steaming time and frequency for manufactured red Liriope platyphylla on nerve growth factor secretion ability, nerve growth factor receptor signaling pathway and regulation of calcium concentration.

    PubMed

    Choi, Sun Il; Goo, Jun Seo; Kim, Ji Eun; Nam, So Hee; Hwang, In Sik; Lee, Hye Ryun; Lee, Young Ju; Son, Hong Joo; Lee, Hee Seob; Lee, Jong Sup; Kim, Hak Jin; Hwang, Dae Youn

    2012-11-01

    The herb Liriope platyphylla (LP) has been considered to have curative properties for diabetes, asthma and neurodegenerative disorders. To examine the effects of steaming time and frequency of manufactured red LP (RLP) on the nerve growth factor (NGF) secretion ability and NGF receptor signaling pathway, the NGF concentration, cell differentiation, NGF signaling pathway and calcium concentration were analyzed in neuronal cells treated with several types of LPs manufactured under different conditions. The maximum NGF secretion was observed in B35 cells treated with 50 µg/ml LP extract steamed for 9 h (9-SLP) and with two repeated steps (3 h steaming and 24 h air-dried) carried out 7 times (7-SALP). No significant changes in viability were detected in any of the cells treated with the various LPs, with the exception of 0-SLP and 0-SALP. In addition, PC12 cell differentiation was induced by treatment with the NGF-containing conditional medium (CM) collected from the RLP-treated cells. The levels of TrkA and extracellular signal-regulated kinase (ERK) phosphorylation in the high affinity NGF receptor signaling pathway were significantly higher in the cells treated with 3-SLP or 1-SALP/3-SALP CM compared with those treated with the vehicle CM. In the low affinity NGF receptor pathway, the expression levels of most components were higher in the 9-, 15- and 24-SALP CM-treated cells compared with the vehicle CM-treated cells. However, this level was significantly altered in cells treated with 3-SALP CM. Furthermore, an examination of the RLP function on calcium regulation revealed that only the LP- or RLP-treated cells exhibited changes in intracellular and extracellular calcium levels. RLP induced a significant decrease in the intracellular calcium levels and an increase in the extracellular calcium levels. These results suggest the possibility that steaming-processed LP may aid in the relief of neurodegenerative diseases through the NGF secretion ability and NGF

  14. Sevoflurane represses the self-renewal ability by regulating miR-7a,7b/Klf4 signalling pathway in mouse embryonic stem cells.

    PubMed

    Wang, Qimin; Li, Guifeng; Li, Baolin; Chen, Qiu; Lv, Dongdong; Liu, Jiaying; Ma, Jieyu; Sun, Nai; Yang, Longqiu; Fei, Xuejie; Song, Qiong

    2016-10-01

    Sevoflurane is a frequently-used clinical inhalational anaesthetic and can cause toxicity to embryos during foetal development. Embryonic stem cells (ESCs) are derived from the inner cell mass of blastospheres and can be used as a useful model of early development. Here, we found that sevoflurane significantly influenced self-renewal ability of mESCs on stemness maintenance and cell proliferation. The cell cycle was arrested via G1 phase delay. We further found that sevoflurane upregulated expression of miR-7a,7b to repress self-renewal. Next we performed rescue experiments and found that after adding miR-7a,7b inhibitor into mESCs treated with sevoflurane, its influence on self-renewal could be blocked. Further we identified stemness factor Klf4 as the direct target of miR-7a,7b. Overexpression of Klf4 restored self-renewal ability repressed by miR-7a,7b or sevoflurane. In this work, we determined that sevoflurane repressed self-renewal ability by regulating the miR-7a,7b/Klf4 signalling pathway in mESCs. Our study demonstrated molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on safe usage of inhalational anaesthetic during non-obstetric surgery. © 2016 John Wiley & Sons Ltd.

  15. Representative Agricultural Pathways and Scenarios for Regional Integrated Assessment of Climate Change Impacts, Vulnerability, and Adaptation. 5; Chapter

    NASA Technical Reports Server (NTRS)

    Valdivia, Roberto O.; Antle, John M.; Rosenzweig, Cynthia; Ruane, Alexander C.; Vervoort, Joost; Ashfaq, Muhammad; Hathie, Ibrahima; Tui, Sabine Homann-Kee; Mulwa, Richard; Nhemachena, Charles; hide

    2015-01-01

    The global change research community has recognized that new pathway and scenario concepts are needed to implement impact and vulnerability assessment where precise prediction is not possible, and also that these scenarios need to be logically consistent across local, regional, and global scales. For global climate models, representative concentration pathways (RCPs) have been developed that provide a range of time-series of atmospheric greenhouse-gas concentrations into the future. For impact and vulnerability assessment, new socio-economic pathway and scenario concepts have also been developed, with leadership from the Integrated Assessment Modeling Consortium (IAMC).This chapter presents concepts and methods for development of regional representative agricultural pathways (RAOs) and scenarios that can be used for agricultural model intercomparison, improvement, and impact assessment in a manner consistent with the new global pathways and scenarios. The development of agriculture-specific pathways and scenarios is motivated by the need for a protocol-based approach to climate impact, vulnerability, and adaptation assessment. Until now, the various global and regional models used for agricultural-impact assessment have been implemented with individualized scenarios using various data and model structures, often without transparent documentation, public availability, and consistency across disciplines. These practices have reduced the credibility of assessments, and also hampered the advancement of the science through model intercomparison, improvement, and synthesis of model results across studies. The recognition of the need for better coordination among the agricultural modeling community, including the development of standard reference scenarios with adequate agriculture-specific detail led to the creation of the Agricultural Model Intercomparison and Improvement Project (AgMIP) in 2010. The development of RAPs is one of the cross-cutting themes in AgMIP's work

  16. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology.

    PubMed

    Karp, Peter D; Latendresse, Mario; Paley, Suzanne M; Krummenacker, Markus; Ong, Quang D; Billington, Richard; Kothari, Anamika; Weaver, Daniel; Lee, Thomas; Subhraveti, Pallavi; Spaulding, Aaron; Fulcher, Carol; Keseler, Ingrid M; Caspi, Ron

    2016-09-01

    Pathway Tools is a bioinformatics software environment with a broad set of capabilities. The software provides genome-informatics tools such as a genome browser, sequence alignments, a genome-variant analyzer and comparative-genomics operations. It offers metabolic-informatics tools, such as metabolic reconstruction, quantitative metabolic modeling, prediction of reaction atom mappings and metabolic route search. Pathway Tools also provides regulatory-informatics tools, such as the ability to represent and visualize a wide range of regulatory interactions. This article outlines the advances in Pathway Tools in the past 5 years. Major additions include components for metabolic modeling, metabolic route search, computation of atom mappings and estimation of compound Gibbs free energies of formation; addition of editors for signaling pathways, for genome sequences and for cellular architecture; storage of gene essentiality data and phenotype data; display of multiple alignments, and of signaling and electron-transport pathways; and development of Python and web-services application programming interfaces. Scientists around the world have created more than 9800 Pathway/Genome Databases by using Pathway Tools, many of which are curated databases for important model organisms. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  17. Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa is mandatory for TCR-mediated inside-out signaling, but dispensable for CXCR4-mediated LFA-1 activation, adhesion, and migration of T cells.

    PubMed

    Horn, Jessica; Wang, Xiaoqian; Reichardt, Peter; Stradal, Theresia E; Warnecke, Nicole; Simeoni, Luca; Gunzer, Matthias; Yablonski, Deborah; Schraven, Burkhart; Kliche, Stefanie

    2009-11-01

    Engagement of the TCR or of chemokine receptors such as CXCR4 induces adhesion and migration of T cells via so-called inside-out signaling pathways. The molecular processes underlying inside-out signaling events are as yet not completely understood. In this study, we show that TCR- and CXCR4-mediated activation of integrins critically depends on the membrane recruitment of the adhesion- and degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein of 55 kDa (SKAP55)/Rap1-interacting adapter protein (RIAM)/Rap1 module. We further demonstrate that the Src homology 2 domain containing leukocyte-specific phosphoprotein of 76 kDa (SLP76) is crucial for TCR-mediated inside-out signaling and T cell/APC interaction. Besides facilitating membrane recruitment of ADAP, SKAP55, and RIAM, SLP76 regulates TCR-mediated inside-out signaling by controlling the activation of Rap1 as well as Rac-mediated actin polymerization. Surprisingly, however, SLP76 is not mandatory for CXCR4-mediated inside-out signaling. Indeed, both CXCR4-induced T cell adhesion and migration are not affected by loss of SLP76. Moreover, after CXCR4 stimulation, the ADAP/SKAP55/RIAM/Rap1 module is recruited to the plasma membrane independently of SLP76. Collectively, our data indicate a differential requirement for SLP76 in TCR- vs CXCR4-mediated inside-out signaling pathways regulating T cell adhesion and migration.

  18. Momordin Ic couples apoptosis with autophagy in human hepatoblastoma cancer cells by reactive oxygen species (ROS)-mediated PI3K/Akt and MAPK signaling pathways.

    PubMed

    Mi, Yashi; Xiao, Chunxia; Du, Qingwei; Wu, Wanqiang; Qi, Guoyuan; Liu, Xuebo

    2016-01-01

    Momordin Ic is a principal saponin constituent of Fructus Kochiae, which acts as an edible and pharmaceutical product more than 2000 years in China. Our previous research found momordin Ic induced apoptosis by PI3K/Akt and MAPK signaling pathways in HepG2 cells. While the role of autophagy in momordin Ic induced cell death has not been discussed, and the connection between the apoptosis and autophagy is not clear yet. In this work, we reported momordin Ic promoted the formation of autophagic vacuole and expression of Beclin 1 and LC-3 in a dose- and time-dependent manner. Compared with momordin Ic treatment alone, the autophagy inhibitor 3-methyladenine (3-MA) also can inhibit apoptosis, while autophagy activator rapamycin (RAP) has the opposite effect, and the apoptosis inhibitor ZVAD-fmk also inhibited autophagy induced by momordin Ic. Momordin Ic simultaneously induces autophagy and apoptosis by suppressing the ROS-mediated PI3K/Akt and activating the ROS-related JNK and P38 pathways. Additionally, momordin Ic induces apoptosis by suppressing PI3K/Akt-dependent NF-κB pathways and promotes autophagy by ROS-mediated Erk signaling pathway. Those results suggest that momordin Ic has great potential as a nutritional preventive strategy in cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Index of cerebrospinal compensatory reserve in hydrocephalus.

    PubMed

    Kim, Dong-Joo; Czosnyka, Zofia; Keong, Nicole; Radolovich, Danila K; Smielewski, Peter; Sutcliffe, Michael P F; Pickard, John D; Czosnyka, Marek

    2009-03-01

    An index of cerebrospinal compensatory reserve (RAP) has been introduced as a potential descriptor of neurological deterioration after head trauma. It is numerically computed as a linear correlation coefficient between the mean intracranial pressure and the pulse amplitude of the pressure waveform. We explore how RAP varies with different forms of physiological or nonphysiological intracranial volume loads in adult hydrocephalus, with and without a functioning cerebrospinal fluid (CSF) shunt. A database of intracranial pressure recordings during CSF infusion studies and overnight monitoring in hydrocephalic patients was reviewed for clinical comparison of homogeneous subgroups of patients with hypothetical differences of pressure-volume compensatory reserve. The database includes 980 patients of mixed etiology: idiopathic normal pressure hydrocephalus (NPH), 47%; postsubarachnoid hemorrhage NPH, 12%; noncommunicating hydrocephalus, 22%; others, 19%. All CSF compensatory parameters were calculated by using intracranial pressure waveforms. In NPH, RAP correlated strongly with the resistance to CSF outflow (r(s) = 0.35; P = 0.045), but weakly correlated with ventriculomegaly (r(s) = 0.13; P = 0.41). In idiopathic nonshunted NPH patients, RAP did not correlate significantly with elasticity calculated from the CSF infusion test (r(s) = 0.11; P = 0.21). During infusion studies, RAP increased in comparison to values recorded at baseline (from a median of 0.45-0.86, P = 0.14 * 10(-8)), indicating a narrowing of the volume-pressure compensatory reserve. During B-waves associated with the REM (rapid eye movement) phase of sleep, RAP increased from a median of 0.53 to 0.89; P = 1.2 * 10(-5). After shunting, RAP decreased (median before shunting, 0.59; median after shunting, 0.34; P = 0.0001). RAP also showed the ability to reflect the functional state of the shunt (patent shunt median, 0.36; blocked shunt median, 0.84; P = 0.0002). RAP appears to characterize pressure

  20. End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1.

    PubMed

    Lescasse, Rachel; Pobiega, Sabrina; Callebaut, Isabelle; Marcand, Stéphane

    2013-03-20

    In eukaryotes, permanent inhibition of the non-homologous end joining (NHEJ) repair pathway at telomeres ensures that chromosome ends do not fuse. In budding yeast, binding of Rap1 to telomere repeats establishes NHEJ inhibition. Here, we show that the Uls1 protein is required for the maintenance of NHEJ inhibition at telomeres. Uls1 protein is a non-essential Swi2/Snf2-related translocase and a Small Ubiquitin-related Modifier (SUMO)-Targeted Ubiquitin Ligase (STUbL) with unknown targets. Loss of Uls1 results in telomere-telomere fusions. Uls1 requirement is alleviated by the absence of poly-SUMO chains and by rap1 alleles lacking SUMOylation sites. Furthermore, Uls1 limits the accumulation of Rap1 poly-SUMO conjugates. We propose that one of Uls1 functions is to clear non-functional poly-SUMOylated Rap1 molecules from telomeres to ensure the continuous efficiency of NHEJ inhibition. Since Uls1 is the only known STUbL with a translocase activity, it can be the general molecular sweeper for the clearance of poly-SUMOylated proteins on DNA in eukaryotes.

  1. Speech Perception Ability in Individuals with Friedreich Ataxia

    ERIC Educational Resources Information Center

    Rance, Gary; Fava, Rosanne; Baldock, Heath; Chong, April; Barker, Elizabeth; Corben, Louise; Delatycki

    2008-01-01

    The aim of this study was to investigate auditory pathway function and speech perception ability in individuals with Friedreich ataxia (FRDA). Ten subjects confirmed by genetic testing as being homozygous for a GAA expansion in intron 1 of the FXN gene were included. While each of the subjects demonstrated normal, or near normal sound detection, 3…

  2. The Ability of Different Imputation Methods to Preserve the Significant Genes and Pathways in Cancer.

    PubMed

    Aghdam, Rosa; Baghfalaki, Taban; Khosravi, Pegah; Saberi Ansari, Elnaz

    2017-12-01

    Deciphering important genes and pathways from incomplete gene expression data could facilitate a better understanding of cancer. Different imputation methods can be applied to estimate the missing values. In our study, we evaluated various imputation methods for their performance in preserving significant genes and pathways. In the first step, 5% genes are considered in random for two types of ignorable and non-ignorable missingness mechanisms with various missing rates. Next, 10 well-known imputation methods were applied to the complete datasets. The significance analysis of microarrays (SAM) method was applied to detect the significant genes in rectal and lung cancers to showcase the utility of imputation approaches in preserving significant genes. To determine the impact of different imputation methods on the identification of important genes, the chi-squared test was used to compare the proportions of overlaps between significant genes detected from original data and those detected from the imputed datasets. Additionally, the significant genes are tested for their enrichment in important pathways, using the ConsensusPathDB. Our results showed that almost all the significant genes and pathways of the original dataset can be detected in all imputed datasets, indicating that there is no significant difference in the performance of various imputation methods tested. The source code and selected datasets are available on http://profiles.bs.ipm.ir/softwares/imputation_methods/. Copyright © 2017. Production and hosting by Elsevier B.V.

  3. A novel artificial fish swarm algorithm for solving large-scale reliability-redundancy application problem.

    PubMed

    He, Qiang; Hu, Xiangtao; Ren, Hong; Zhang, Hongqi

    2015-11-01

    A novel artificial fish swarm algorithm (NAFSA) is proposed for solving large-scale reliability-redundancy allocation problem (RAP). In NAFSA, the social behaviors of fish swarm are classified in three ways: foraging behavior, reproductive behavior, and random behavior. The foraging behavior designs two position-updating strategies. And, the selection and crossover operators are applied to define the reproductive ability of an artificial fish. For the random behavior, which is essentially a mutation strategy, the basic cloud generator is used as the mutation operator. Finally, numerical results of four benchmark problems and a large-scale RAP are reported and compared. NAFSA shows good performance in terms of computational accuracy and computational efficiency for large scale RAP. Copyright © 2015 ISA. Published by Elsevier Ltd. All rights reserved.

  4. White matter microstructural properties correlate with sensorimotor synchronization abilities.

    PubMed

    Blecher, Tal; Tal, Idan; Ben-Shachar, Michal

    2016-09-01

    Sensorimotor synchronization (SMS) to an external auditory rhythm is a developed ability in humans, particularly evident in dancing and singing. This ability is typically measured in the lab via a simple task of finger tapping to an auditory beat. While simplistic, there is some evidence that poor performance on this task could be related to impaired phonological and reading abilities in children. Auditory-motor synchronization is hypothesized to rely on a tight coupling between auditory and motor neural systems, but the specific pathways that mediate this coupling have not been identified yet. In this study, we test this hypothesis and examine the contribution of fronto-temporal and callosal connections to specific measures of rhythmic synchronization. Twenty participants went through SMS and diffusion magnetic resonance imaging (dMRI) measurements. We quantified the mean asynchrony between an auditory beat and participants' finger taps, as well as the time to resynchronize (TTR) with an altered meter, and examined the correlations between these behavioral measures and diffusivity in a small set of predefined pathways. We found significant correlations between asynchrony and fractional anisotropy (FA) in the left (but not right) arcuate fasciculus and in the temporal segment of the corpus callosum. On the other hand, TTR correlated with FA in the precentral segment of the callosum. To our knowledge, this is the first demonstration that relates these particular white matter tracts with performance on an auditory-motor rhythmic synchronization task. We propose that left fronto-temporal and temporal-callosal fibers are involved in prediction and constant comparison between auditory inputs and motor commands, while inter-hemispheric connections between the motor/premotor cortices contribute to successful resynchronization of motor responses with a new external rhythm, perhaps via inhibition of tapping to the previous rhythm. Our results indicate that auditory

  5. [Activation of autophagy pathway in hippocampus and deterioration of learning and memory ability by intermittent hypoxia in rats after cerebral ischemia].

    PubMed

    Guo, Xiangfei; Zhao, Yaning; Li, Jianmin; Liu, Wenqian; Chen, Changxiang

    2016-09-01

    Objective To investigate the effects of different duration of intermittent hypoxia on the autophagy pathway in the hippocampus and the learning and memory ability after cerebral ischemia in rats. Methods 100 male Wistar rats were randomly divided into sham operation (SO) group, ischemia/reperfusion (I/R) group, intermittent hypoxia for 7 days combined with ischemia/reperfusion (IH7-I/R) group, intermittent hypoxia for 14 days combined with ischemia/reperfusion (IH14-I/R) group, intermittent hypoxia for 21 days combined with ischemia/reperfusion (IH21-I/R) group, n =20 in each group. The rats in IH7-I/R group, IH14-I/R group and IH21-I/R group were respectively subjected to intermittent hypoxia for 7, 14 and 21 days prior to I/R modeling by improved Pulsinelli four-vessel occlusion (4-VO). The morphological changes of nerve cells in the hippocampus of rat brain were detected by HE staining; the levels of mammalian target of rapamycin (mTOR) and beclin 1 mRNA in the hippocampus were determined by quantitative real-time PCR; the distribution of mTOR and beclin 1 in the hippocampus was observed by immunohistochemistry; the learning and memory ability of rats was assessed by the Morris water maze test. Results Compared with the SO group, the never cell morphology was damaged, the number of survival neurons in the hippocampus was reduced, the expressions of mTOR and beclin 1 in the hippocampus were strengthened, and the learning and memory ability declined in the I/R group. Compared with the I/R group, the never cell morphology was damaged seriously, the number of survival neurons in the hippocampus decreased, the expressions of mTOR and beclin 1 in the hippocampus increased, and the learning and memory ability dropped in the intermittent hypoxia groups. What's more, the above changes were dependent on the duration of intermittent hypoxia. Conclusion Intermittent hypoxia aggravates the dysfunction of learning and memory after cerebral ischemia and the damages increase

  6. Pathways to Improve Student Pharmacists’ Experience in Research

    PubMed Central

    McClendon, Katie S.; Bell, Allison M.; Ellis, Ashley; Adcock, Kim G.; Hogan, Shirley; Ross, Leigh Ann

    2015-01-01

    Objective. To describe the implementation of a student research program and to provide outcomes from the initial 4 years’ experience. Design. Students conducted individual research projects in a 4-year longitudinal program (known as Pathway), with faculty member advising and peer mentoring. A prospective assessment compared perceptions of those who completed the Pathway program with those of students who did not. Descriptive statistics, t tests, and analysis of variance (ANOVA) were used. Assessment. The class of 2013 was the first to complete the Pathway program. In the Pathway assessment project, 59% (n=47) of students who responded reached self-set goals. Pathway students agreed that this research experience improved their ability to work/think independently, evaluate literature, and distinguish themselves from other students. Conclusion. The Pathway program helped students understand the research process and reach other self-set goals. PMID:26089567

  7. A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

    PubMed Central

    Boucher, Gabrielle; Beauchamp, Claudine; Trynka, Gosia; Dubois, Patrick C.; Lagacé, Caroline; Stokkers, Pieter C. F.; Hommes, Daan W.; Barisani, Donatella; Palmieri, Orazio; Annese, Vito; van Heel, David A.; Weersma, Rinse K.; Daly, Mark J.; Wijmenga, Cisca; Rioux, John D.

    2011-01-01

    Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. PMID:21298027

  8. Enhanced leavening ability of baker's yeast by overexpression of SNR84 with PGM2 deletion.

    PubMed

    Lin, Xue; Zhang, Cui-Ying; Bai, Xiao-Wen; Xiao, Dong-Guang

    2015-06-01

    Dough-leavening ability is one of the main aspects considered when selecting a baker's yeast strain for baking industry. Generally, modification of maltose metabolic pathway and known regulatory networks of maltose metabolism were used to increase maltose metabolism to improve leavening ability in lean dough. In this study, we focus on the effects of PGM2 (encoding for the phosphoglucomutase) and SNR84 (encoding for the H/ACA snoRNA) that are not directly related to both the maltose metabolic pathway and known regulatory networks of maltose metabolism on the leavening ability of baker's yeast in lean dough. The results show that the modifications on PGM2 and/or SNR84 are effective ways in improving leavening ability of baker's yeast in lean dough. Deletion of PGM2 decreased cellular glucose-1-phosphate and overexpression of SNR84 increased the maltose permease activity. These changes resulted in 11, 19 and 21% increases of the leavening ability for PGM2 deletion, SNR84 overexpression and SNR84 overexpression combining deleted PGM2, respectively.

  9. Two Pathways to Stimulus Encoding in Category Learning?

    PubMed Central

    Davis, Tyler; Love, Bradley C.; Maddox, W. Todd

    2008-01-01

    Category learning theorists tacitly assume that stimuli are encoded by a single pathway. Motivated by theories of object recognition, we evaluate a dual-pathway account of stimulus encoding. The part-based pathway establishes mappings between sensory input and symbols that encode discrete stimulus features, whereas the image-based pathway applies holistic templates to sensory input. Our experiments use rule-plus-exception structures in which one exception item in each category violates a salient regularity and must be distinguished from other items. In Experiment 1, we find that discrete representations are crucial for recognition of exceptions following brief training. Experiments 2 and 3 involve multi-session training regimens designed to encourage either part or image-based encoding. We find that both pathways are able to support exception encoding, but have unique characteristics. We speculate that one advantage of the part-based pathway is the ability to generalize across domains, whereas the image-based pathway provides faster and more effortless recognition. PMID:19460948

  10. Geoscience Academic Provenance: A Comparison of Undergraduate Students' Pathways to Faculty Pathways

    NASA Astrophysics Data System (ADS)

    Houlton, H. R.; Keane, C. M.; Wilson, C. E.

    2012-12-01

    Most Science, Technology, Engineering and Mathematics (STEM) disciplines have a direct recruiting method of high school science courses to supply their undergraduate majors. However, recruitment and retention of students into geoscience academic programs, who will be the future workforce, remains an important issue. The geoscience community is reaching a critical point in its ability to supply enough geoscientists to meet the current and near-future demand. Previous work done by Houlton (2010) determined that undergraduate geoscience majors follow distinct pathways when pursuing their degree and career. These pathways are comprised of students' interests, experiences, goals and career aspirations, which are depicted in six pathway steps. Three population groups were determined from the original 17 participants, which exhibited differences in pathway trajectories. Continued data collection efforts developed and refined the pathway framework. As part of an informal workshop activity, data were collected from 27 participants who are underrepresented minority early-career and future faculty in the geosciences. In addition, 20 geoscience departments' Heads and Chairs participated in an online survey about their pathway trajectories. Pathways were determined from each of these new sample populations and compared against the original geoscience undergraduate student participants. Several pathway components consistently spanned across sample populations. Identification of these themes have illuminated broad geoscience-related interests, experiences and aspirations that can be used to broadly impact recruitment and retention initiatives for our discipline. Furthermore, fundamental differences between participants' ages, stages in career and racial/ethnic backgrounds have exhibited subtle nuances in their geoscience pathway trajectories. In particular, those who've had research experiences, who think "creativity" is an important aspect of a geoscience career and those who

  11. Multiscale imaging and characterization of the effect of mixing temperature on asphalt concrete containing recycled components.

    PubMed

    Cavalli, M C; Griffa, M; Bressi, S; Partl, M N; Tebaldi, G; Poulikakos, L D

    2016-10-01

    When producing asphalt concrete mixture with high amounts of reclaimed asphalt pavement (RAP), the mixing temperature plays a significant role in the resulting spatial distribution of the components as well as on the quality of the resulting mixture, in terms of workability during mixing and compaction as well as in service mechanical properties. Asphalt concrete containing 50% RAP was investigated at mixing temperatures of 140, 160 and 180°C, using a multiscale approach. At the microscale, using energy dispersive X-ray spectroscopy the RAP binder film thickness was visualized and measured. It was shown that at higher mixing temperatures this film thickness was reduced. The reduction in film thickness can be attributed to the loss of volatiles as well as the mixing of RAP binder with virgin binder at higher temperatures. X-ray computer tomography was used to characterize statistically the distribution of the RAP and virgin aggregates geometric features: volume, width and shape anisotropy. In addition using X-ray computer tomography, the packing and spatial distribution of the RAP and virgin aggregates was characterized using the nearest neighbour metric. It was shown that mixing temperature may have a positive effect on the spatial distribution of the aggregates but did not affect the packing. The study shows a tendency for the RAP aggregates to be more likely distributed in clusters at lower mixing temperatures. At higher temperatures, they were more homogeneously distributed. This indicates a higher degree of blending both at microscale (binder film) and macroscale (spatial distribution) between RAP and virgin aggregates as a result of increasing mixing temperatures and the ability to quantify this using various imaging techniques. © 2016 The Authors Journal of Microscopy © 2016 Royal Microscopical Society.

  12. Problem-solving by traumatically brain injured and neurologically intact subjects on an adaptation of the twenty questions test.

    PubMed

    Marshall, Robert C; Karow, Colleen M; Morelli, Claudia A; Iden, Kristin K; Dixon, Judith

    2003-07-01

    RAPS (Rapid Assessment of Problem-Solving) is a clinical measure for assessing verbal problem-solving in hard-to-test patients or those that may not be able to tolerate a longer, more detailed assessment. The design of the test is based on Mosher and Hornsby's Twenty Question test, but RAPS contains several modifications to facilitate its use with brain-injured individuals. This study used RAPS to compare the verbal problem-solving ability of subjects that were neurologically intact and subjects that had chronic traumatic brain injuries. Twenty-one adults that were neurologically intact (NI) and 21 adults that had incurred a traumatic brain injury (TBI) matched for age, gender and education took part in the study. Before being tested with RAPS, participants signed an IRB-approved consent form and completed a battery of neurocognitive measures. RAPS entailed the solving of three verbal problems. Each problem involved an array of 32 pictures of common objects (e.g. football) arranged in a 4x 8 grid. The subjects were instructed to ask yes/no questions to determine which picture the examiner was 'thinking of '. Three scores were computed for each problem solved: number of questions asked, percentage of constraint-seeking questions, and question-asking efficiency scores for the first four questions. No learning effects across the problems were found for any of the RAPS measures. Scores were averaged across the three problems to determine group effects. Groups of TBI and NI subjects did not differ significantly in the number of questions asked in solving RAPS problems. Members of the NI group asked significantly more constraint-seeking questions (e.g. Is it an animal?) than those in the TBI group, and the subjects that had incurred brain injuries did more guessing than the NI group. Over 70% of the time, guessing took place after the semantic category containing the target picture was known to the subject. Guesses took the form of pseudo-constraint questions (e.g. Is it

  13. Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.

    PubMed

    Segura-Ibarra, Victor; Amione-Guerra, Javier; Cruz-Solbes, Ana S; Cara, Francisca E; Iruegas-Nunez, David A; Wu, Suhong; Youker, Keith A; Bhimaraj, Arvind; Torre-Amione, Guillermo; Ferrari, Mauro; Karmouty-Quintana, Harry; Guha, Ashrith; Blanco, Elvin

    2017-05-30

    Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Reading acceleration training changes brain circuitry in children with reading difficulties

    PubMed Central

    Horowitz-Kraus, Tzipi; Vannest, Jennifer J; Kadis, Darren; Cicchino, Nicole; Wang, Yingying Y; Holland, Scott K

    2014-01-01

    Introduction Dyslexia is characterized by slow, inaccurate reading. Previous studies have shown that the Reading Acceleration Program (RAP) improves reading speed and accuracy in children and adults with dyslexia and in typical readers across different orthographies. However, the effect of the RAP on the neural circuitry of reading has not been established. In the current study, we examined the effect of the RAP training on regions of interest in the neural circuitry for reading using a lexical decision task during fMRI in children with reading difficulties and typical readers. Methods Children (8–12 years old) with reading difficulties and typical readers were studied before and after 4 weeks of training with the RAP in both groups. Results In addition to improvements in oral and silent contextual reading speed, training-related gains were associated with increased activation of the left hemisphere in both children with reading difficulties and typical readers. However, only children with reading difficulties showed improvements in reading comprehension, which were associated with significant increases in right frontal lobe activation. Conclusions Our results demonstrate differential effects of the RAP on neural circuits supporting reading in both children with reading difficulties and typical readers and suggest that the intervention may stimulate use of typical neural circuits for reading and engage compensatory pathways to support reading in the developing brain of children with reading difficulties. PMID:25365797

  15. Are genetic variants in the platelet-derived growth factor [beta] gene associated with chronic pancreatitis?

    PubMed

    Muddana, Venkata; Park, James; Lamb, Janette; Yadav, Dhiraj; Papachristou, Georgios I; Hawes, Robert H; Brand, Randall; Slivka, Adam; Whitcomb, David C

    2010-11-01

    Platelet-derived growth factor [beta] (PDGF-[beta]) is a major signal in proliferation and matrix synthesis through activated pancreatic stellate cells, leading to fibrosis of the pancreas. Recurrent acute pancreatitis (RAP) seems to predispose to chronic pancreatitis (CP) in some patients but not others. We tested the hypothesis that 2 known PDGF-[beta] polymorphisms are associated with progression from RAP to CP. We also tested the hypothesis that PDGF-[beta] polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP. Three hundred eighty-two patients with CP (n = 176) and RAP (n = 206) and 251 controls were evaluated. Platelet-derived growth factor [beta] polymorphisms +286 A/G (rs#1800818) seen in 5'-UTR and +1135 A/C (rs#1800817) in first intron were genotyped using single-nucleotide polymorphism polymerase chain reaction approach and confirmed by DNA sequencing. The genotypic frequencies for PDGF-[beta] polymorphisms in positions +286 and +1135 were found to be similar in controls and patients with RAP and CP. There was no difference in genotypic frequencies among RAP, CP, and controls in subjects in the alcohol and smoking subgroups. Known variations in the PDGF-[beta] gene do not have a significant effect on promoting or preventing fibrogenesis in pancreatitis. Further evaluation of this important pathway is warranted.

  16. Comments on Awad El Karim M. Ibrahim's "Becoming Black: Rap and Hip-Hop, Race, Gender, and Identity and the Politics of ESL Learning" [and] A Reader Reacts . . . [and] Identity or Identification? A Response to Some Objections.

    ERIC Educational Resources Information Center

    Goldstein, Lynn; Ibrahim, Awad El Karim M.

    2000-01-01

    Goldstein questions the way Awad El Karim M. Ibrahim portrayed her research on the language and identity of Hispanic English-as-a-Second-Language learners in his article, "Becoming Black: Rap and Hip-Hop, Race, Gender, and Identity and the Politics of ESL Learning." Ibrahim responds to these comments. (Author/VWL)

  17. Assessing the Ability of Vegetation Indices to Identify Shallow Subsurface Water Flow Pathways from Hyperspectral Imagery Using Machine Learning: Application

    NASA Astrophysics Data System (ADS)

    Doctor, K.; Byers, J. M.

    2017-12-01

    Shallow underground water flow pathways expressed as slight depressions are common in the land surface. Under conditions of saturated overland flow, such as during heavy rain or snow melt, these areas of preferential flow might appear on the surface as very shallow flowing streams. When there is no water flowing in these ephemeral channels it can be difficult to identify them. It is especially difficult to discern the slight depressions above the subsurface water flow pathways (SWFP) when the area is covered by vegetation. Since the soil moisture content in these SWFP is often greater than the surrounding area, the vegetation growing on top of these channels shows different vigor and moisture content than the vegetation growing above the non-SWFP area. Vegetation indices (VI) are used in visible and near infrared (VNIR) hyperspectral imagery to enhance biophysical properties of vegetation, and so the brightness values between vegetation atop SWFP and the surrounding vegetation were highlighted. We performed supervised machine learning using ground-truth class labels to determine the conditional probability of a SWFP at a given pixel given either the spectral distribution or VI at that pixel. The training data estimates the probability distributions to a determined finite sampling accuracy for a binary Naïve Bayes classifier between SWFP and non-SWFP. The ground-truth data provides a test bed for understanding the ability to build SWFP classifiers using hyperspectral imagery. SWFP were distinguishable in the imagery within corn and grass fields and in areas with low-lying vegetation. However, the training data is limited to particular types of terrain and vegetation cover in the Shenandoah Valley, Virginia and this would limit the resulting classifier. Further training data could extend its use to other environments.

  18. An Enhanced Concept Map Approach to Improving Children's Storytelling Ability

    ERIC Educational Resources Information Center

    Liu, Chen-Chung; Chen, Holly S. L.; Shih, Ju-Ling; Huang, Guo-Ting; Liu, Baw-Jhiune

    2011-01-01

    Storytelling is an imperative and innovative pathway to enhance learning due to the fact that such activity prompts learners to reflect to construct meaning based on their observations and knowledge. Therefore, to develop and enhance students' storytelling ability has become an important issue for both educators and researchers. Since storytelling…

  19. How Many Pathways Underlie Socioeconomic Differences in the Development of Cognition and Achievement?

    PubMed

    Tucker-Drob, Elliot M

    2013-06-01

    Children whose parents have higher education enjoy greater age-linked gains in cognitive abilities and academic achievement. Different researchers have typically focused on different outcomes, and the extent to which parental education relates to multiple child outcomes via a single developmental pathway has received little empirical attention. This issue was examined by applying common factor structural equation models to a large (N = 4,810) nationally representative sample of kindergarten through 12 th grade children, who were measured on 6 distinct cognitive abilities and 5 distinct forms of knowledge and academic achievement. Results indicated that a single pathway accounted for the relations between parental education and age differences in children's cognitive abilities. However, additional unique pathways were necessary to account for the relations between parental education and age differences in academic knowledge and mathematics. These results suggest that while socioeconomic differences are largely manifest in global aspects of cognitive development, they have incremental relations with some forms of academic achievement.

  20. Alternative Pathways to Apprenticeships. Good Practice Guide

    ERIC Educational Resources Information Center

    National Centre for Vocational Education Research (NCVER), 2015

    2015-01-01

    Apprenticeships are changing. The increasing proportions of people entering apprenticeships at various levels of ability and backgrounds are stimulating demand for alternative pathways to completions. This good practice guide assembles the key findings for education practitioners and workplace supervisors from three related research reports on…

  1. Stress signaling pathways for the pathogenicity of Cryptococcus.

    PubMed

    Bahn, Yong-Sun; Jung, Kwang-Woo

    2013-12-01

    Sensing, responding, and adapting to the surrounding environment are crucial for all living organisms to survive, proliferate, and differentiate in their biological niches. This ability is also essential for Cryptococcus neoformans and its sibling species Cryptococcus gattii, as these pathogens have saprobic and parasitic life cycles in natural and animal host environments. The ability of Cryptococcus to cause fatal meningoencephalitis is highly related to its capability to remodel and optimize its metabolic and physiological status according to external cues. These cues act through multiple stress signaling pathways through a panoply of signaling components, including receptors/sensors, small GTPases, secondary messengers, kinases, transcription factors, and other miscellaneous adaptors or regulators. In this minireview, we summarize and highlight the importance of several stress signaling pathways that influence the pathogenicity of Cryptococcus and discuss future challenges in these areas.

  2. Stress Signaling Pathways for the Pathogenicity of Cryptococcus

    PubMed Central

    Jung, Kwang-Woo

    2013-01-01

    Sensing, responding, and adapting to the surrounding environment are crucial for all living organisms to survive, proliferate, and differentiate in their biological niches. This ability is also essential for Cryptococcus neoformans and its sibling species Cryptococcus gattii, as these pathogens have saprobic and parasitic life cycles in natural and animal host environments. The ability of Cryptococcus to cause fatal meningoencephalitis is highly related to its capability to remodel and optimize its metabolic and physiological status according to external cues. These cues act through multiple stress signaling pathways through a panoply of signaling components, including receptors/sensors, small GTPases, secondary messengers, kinases, transcription factors, and other miscellaneous adaptors or regulators. In this minireview, we summarize and highlight the importance of several stress signaling pathways that influence the pathogenicity of Cryptococcus and discuss future challenges in these areas. PMID:24078305

  3. White matter pathways for prosodic structure building: A case study.

    PubMed

    Sammler, Daniela; Cunitz, Katrin; Gierhan, Sarah M E; Anwander, Alfred; Adermann, Jens; Meixensberger, Jürgen; Friederici, Angela D

    2018-05-11

    The relevance of left dorsal and ventral fiber pathways for syntactic and semantic comprehension is well established, while pathways for prosody are little explored. The present study examined linguistic prosodic structure building in a patient whose right arcuate/superior longitudinal fascicles and posterior corpus callosum were transiently compromised by a vasogenic peritumoral edema. Compared to ten matched healthy controls, the patient's ability to detect irregular prosodic structure significantly improved between pre- and post-surgical assessment. This recovery was accompanied by an increase in average fractional anisotropy (FA) in right dorsal and posterior transcallosal fiber tracts. Neither general cognitive abilities nor (non-prosodic) syntactic comprehension nor FA in right ventral and left dorsal fiber tracts showed a similar pre-post increase. Together, these findings suggest a contribution of right dorsal and inter-hemispheric pathways to prosody perception, including the right-dorsal tracking and structuring of prosodic pitch contours that is transcallosally informed by concurrent syntactic information. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. The Diversity of Romantic Pathways during Emerging Adulthood and Their Developmental Antecedents

    ERIC Educational Resources Information Center

    Shulman, Shmuel; Seiffge-Krenke, Inge; Scharf, Miri; Boiangiu, Shira Bezalel; Tregubenko, Valerya

    2018-01-01

    The present study examined patterns of romantic pathways in 100 Israeli emerging adults (54 males) who were followed from age 22 to 29 years. Analyses of interviews at age 29 yielded four distinctive romantic pathways differing in stability and ability to learn from romantic experiences: "Sporadic," "Lengthy Relationships but…

  5. Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast

    PubMed Central

    2012-01-01

    plays an important role in baking-associated stress tolerance. Conclusions In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains. PMID:22462683

  6. Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast.

    PubMed

    Sasano, Yu; Haitani, Yutaka; Hashida, Keisuke; Ohtsu, Iwao; Shima, Jun; Takagi, Hiroshi

    2012-04-01

    role in baking-associated stress tolerance. In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains.

  7. Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX-Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model.

    PubMed

    Zareba, Ilona; Surazynski, Arkadiusz; Chrusciel, Marcin; Miltyk, Wojciech; Doroszko, Milena; Rahman, Nafis; Palka, Jerzy

    2017-01-01

    The effect of impaired intracellular proline availability for proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied. We generated a constitutively knocked-down PRODH/POX MCF-7 breast cancer cell line (MCF-7shPRODH/POX) as a model to analyze the functional consequences of impaired intracellular proline levels. We have used inhibitor of proline utilization in collagen biosynthesis, 2-metoxyestradiol (MOE), inhibitor of prolidase that generate proline, rapamycin (Rap) and glycyl-proline (GlyPro), substrate for prolidase. Collagen and DNA biosynthesis were evaluated by radiometric assays. Cell viability was determined using Nucleo-Counter NC-3000. The activity of prolidase was determined by colorimetric assay. Expression of proteins was assessed by Western blot and immunofluorescence bioimaging. Concentration of proline was analyzed by liquid chromatography with mass spectrometry. PRODH/POX knockdown decreased DNA and collagen biosynthesis, whereas increased prolidase activity and intracellular proline level in MCF-7shPRODH/POX cells. All studied compounds decreased cell viability in MCF-7 and MCF-7shPRODH/POX cells. DNA biosynthesis was similarly inhibited by Rap and MOE in both cell lines, but GlyPro inhibited the process only in MCF-7shPRODH/POX and MOE+GlyPro only in MCF-7 cells. All the compounds inhibited collagen biosynthesis, increased prolidase activity and cytoplasmic proline level in MCF-7shPRODH/POX cells and contributed to the induction of pro-survival mode only in MCF-7shPRODH/POX cells. In contrast, all studied compounds upregulated expression of pro-apoptotic protein only in MCF-7 cells. PRODH/POX was confirmed as a driver of apoptosis and proved the eligibility of MCF-7shPRODH/POX cell line as a highly effective model to elucidate the different mechanisms underlying proline utilization or generation in PRODH/POX-dependent pro-apoptotic pathways. © 2017 The Author(s). Published by S. Karger AG, Basel.

  8. Perspectives on the Use of Clinical Pathways in Oncology Care.

    PubMed

    Chiang, Anne C; Ellis, Peter; Zon, Robin

    2017-01-01

    Pathways and guidelines are valuable tools to provide evidence-based care in oncology. Pathways may be more restrictive than guidelines because they attempt (where possible) to reduce cost, add efficiency, and remove unwarranted variability. Pathways offer an opportunity to measure, report, and improve quality of care; they can drive to evidence-based targeted therapy where appropriate; they can enhance efficiency through standardization; and, finally, they can be a vehicle to enhance participation in clinical trials. Pathway implementation requires understanding and commitment on the part of the physician and leadership as they may initially disrupt workflow, but ultimately have the ability to enhance patient care. ASCO criteria have been published for the development and implementation of high-quality oncology pathway programs. Future challenges for pathways include incorporation of molecular testing and appropriate targeted care in a real-time precision oncology approach.

  9. Electrostatic precipitator rapping with sonic horns at Atlantic Electric`s B.L. England Generating Station

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Maziarz, M.; Gallo, F.

    1995-12-31

    B.L. England Generating Station (BLE) is located in Beesleys Point, NJ. Beesleys Point is on Great Egg Bay, which is 20 minutes south of Atlantic City and one hour east of Philadelphia. BLE has three generating units: No. 1 is a 120 Megawatt (MW) B&W cyclone boiler; No. 2 is a 160 MW B&W cyclone boiler; & No. 3 is a tangential fired Combustion Engineering boiler. Units 1 & 2 burn medium sulfur eastern bituminous coal. Unit 3 burns No. 6 oil. Units 1&2 are equipped with precipitators (ESPs). The two ESPs were manufactured by Environmental Elements Corp. (EEC) andmore » were placed in service in 1980. Units are dual chamber with each having four mechanical fields and eight electrical fields. Each field has two Transformer/Rectifier (T/R) sets for a total of sixteen per ESP. The ESPs are rigid frame design (Rigitrode by EEC) with hammer & anvil rapping. Ash reinjection systems permit direct or cross reinjection of fly ash. Both ESPs have perforated plates for inlet & outlet gas flow distribution. There are three inlet plates and one outlet plate. The first inlet plates and the outlets are cleaned via electric reciprocating vibrators. There was no means of cleaning the remaining plates provided.« less

  10. Age-dependent regulation of ERF-VII transcription factor activity in Arabidopsis thaliana.

    PubMed

    Giuntoli, Beatrice; Shukla, Vinay; Maggiorelli, Federica; Giorgi, Federico M; Lombardi, Lara; Perata, Pierdomenico; Licausi, Francesco

    2017-10-01

    The Group VII Ethylene Responsive Factors (ERFs-VII) RAP2.2 and RAP2.12 have been mainly characterized with regard to their contribution as activators of fermentation in plants. However, transcriptional changes measured in conditions that stabilize these transcription factors exceed the mere activation of this biochemical pathway, implying additional roles performed by the ERF-VIIs in other processes. We evaluated gene expression in transgenic Arabidopsis lines expressing a stabilized form of RAP2.12, or hampered in ERF-VII activity, and identified genes affected by this transcriptional regulator and its homologs, including some involved in oxidative stress response, which are not universally induced under anaerobic conditions. The contribution of the ERF-VIIs in regulating this set of genes in response to chemically induced or submergence-stimulated mitochondria malfunctioning was found to depend on the plant developmental stage. A similar age-dependent mechanism also restrained ERF-VII activity upon the core-hypoxic genes, independently of the N-end rule pathway, which is accounted for the control of the anaerobic response. To conclude, this study shed new light on a dual role of ERF-VII proteins under submergence: as positive regulators of the hypoxic response and as repressors of oxidative-stress related genes, depending on the developmental stage at which plants are challenged by stress conditions. © 2017 John Wiley & Sons Ltd.

  11. PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

    PubMed Central

    Strazza, Marianne; Azoulay-Alfaguter, Inbar; Peled, Michael; Smrcka, Alan V.; Skolnik, Edward Y.; Srivastava, Shekhar; Mor, Adam

    2017-01-01

    Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)–expressing cells. Structure–function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs. PMID:28213494

  12. Vitamins and aging: pathways to NAD+ synthesis.

    PubMed

    Denu, John M

    2007-05-04

    Recent genetic evidence reveals additional salvage pathways for NAD(+) synthesis. In this issue, Belenky et al. (2007) report that nicotinamide riboside, a new NAD(+) precursor, regulates Sir2 deacetylase activity and life span in yeast. The ability of nicotinamide riboside to enhance life span does not depend on calorie restriction.

  13. The PhoBR two-component system regulates antibiotic biosynthesis in Serratia in response to phosphate

    PubMed Central

    2009-01-01

    Background Secondary metabolism in Serratia sp. ATCC 39006 (Serratia 39006) is controlled via a complex network of regulators, including a LuxIR-type (SmaIR) quorum sensing (QS) system. Here we investigate the molecular mechanism by which phosphate limitation controls biosynthesis of two antibiotic secondary metabolites, prodigiosin and carbapenem, in Serratia 39006. Results We demonstrate that a mutation in the high affinity phosphate transporter pstSCAB-phoU, believed to mimic low phosphate conditions, causes upregulation of secondary metabolism and QS in Serratia 39006, via the PhoBR two-component system. Phosphate limitation also activated secondary metabolism and QS in Serratia 39006. In addition, a pstS mutation resulted in upregulation of rap. Rap, a putative SlyA/MarR-family transcriptional regulator, shares similarity with the global regulator RovA (regulator of virulence) from Yersina spp. and is an activator of secondary metabolism in Serratia 39006. We demonstrate that expression of rap, pigA-O (encoding the prodigiosin biosynthetic operon) and smaI are controlled via PhoBR in Serratia 39006. Conclusion Phosphate limitation regulates secondary metabolism in Serratia 39006 via multiple inter-linked pathways, incorporating transcriptional control mediated by three important global regulators, PhoB, SmaR and Rap. PMID:19476633

  14. Comparison of Three Commercial Systems for Identification of Yeasts Commonly Isolated in the Clinical Microbiology Laboratory

    PubMed Central

    Wadlin, Jill K.; Hanko, Gayle; Stewart, Rebecca; Pape, John; Nachamkin, Irving

    1999-01-01

    We evaluated three commercial systems (RapID Yeast Plus System; Innovative Diagnostic Systems, Norcross, Ga.; API 20C Aux; bioMerieux-Vitek, Hazelwood, Mo.; and Vitek Yeast Biochemical Card, bioMerieux-Vitek) against an auxinographic and microscopic morphologic reference method for the ability to identify yeasts commonly isolated in our clinical microbiology laboratory. Two-hundred one yeast isolates were compared in the study. The RapID Yeast Plus System was significantly better than either API 20C Aux (193 versus 167 correct identifications; P < 0.0001) or the Vitek Yeast Biochemical Card (193 versus 173 correct identifications; P = 0.003) for obtaining correct identifications to the species level without additional testing. There was no significant difference between results obtained with API 20C Aux and the Vitek Yeast Biochemical Card system (P = 0.39). The API 20C Aux system did not correctly identify any of the Candida krusei isolates (n = 23) without supplemental testing and accounted for the major differences between the API 20C Aux and RapID Yeast Plus systems. Overall, the RapID Yeast Plus System was easy to use and is a good system for the routine identification of clinically relevant yeasts. PMID:10325356

  15. Reciprocal regulation of YAP/TAZ by the Hippo pathway and the Small GTPase pathway.

    PubMed

    Jang, Ju-Won; Kim, Min-Kyu; Bae, Suk-Chul

    2018-04-20

    Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) (YAP/TAZ) are transcriptional coactivators that regulate genes involved in proliferation and transformation by interacting with DNA-binding transcription factors. Remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, and metastasis. The oncogenic activity of YAP/TAZ is inhibited by the Hippo cascade, an evolutionarily conserved pathway that is governed by two kinases, mammalian Ste20-like kinases 1/2 (MST1/2) and Large tumor suppressor kinase 1/2 (LATS1/2), corresponding to Drosophila's Hippo (Hpo) and Warts (Wts), respectively. One of the most influential aspects of YAP/TAZ biology is that these factors are transducers of cell structural features, including polarity, shape, and cytoskeletal organization. In turn, these features are intimately related to the cell's ability to attach to other cells and to the surrounding extracellular matrix (ECM), and are also influenced by the cell's microenvironment. Thus, YAP/TAZ respond to changes that occur at the level of whole tissues. Notably, small GTPases act as master organizers of the actin cytoskeleton. Recent studies provided convincing genetic evidence that small GTPase signaling pathways activate YAP/TAZ, while the Hippo pathway inhibits them. Biochemical studies showed that small GTPases facilitate the YAP-Tea domain transcription factor (TEAD) interaction by inhibiting YAP phosphorylation in response to serum stimulation, while the Hippo pathway facilitates the YAP-RUNX3 interaction by increasing YAP phosphorylation. Therefore, small GTPase pathways activate YAP/TAZ by switching its DNA-binding transcription factors. In this review, we summarize the relationship between the Hippo pathway and small GTPase pathways in the regulation of YAP/TAZ.

  16. Astaxanthin induces angiogenesis through Wnt/β-catenin signaling pathway.

    PubMed

    Xu, Yangyang; Zhang, Jie; Jiang, Wanglin; Zhang, Shuping

    2015-07-15

    In the present study, we sought to elucidate whether astaxanthin contributes to induce angiogenesis and its mechanisms. To this end, we examined the role of astaxanthin on human brain microvascular endothelial cell line (HBMEC) and rat aortic smooth muscle cell (RASMC) proliferation, invasion and tube formation in vitro. For study of mechanism, the Wnt/β-catenin signaling pathway inhibitor IWR-1-endo was used. HMBECs and RASMCs proliferation were tested by cell counting. Scratch adhesion test was used to assess the ability of invasion. A matrigel tube formation assay was performed to test capillary tube formation ability. The Wnt/β-catenin pathway activation in HMBECs and RASMCs were tested by Western blot. Our data suggested that astaxanthin induces angiogenesis by increasing proliferation, invasion and tube formation in vitro. Wnt and β-catenin expression were increased by astaxanthin and counteracted by IWR-1-endo in HMBECs and RASMCs. Tube formation was increased by astaxanthin and counteracted by IWR-1-endo. It may be suggested that astaxanthin induces angiogenesis in vitro via a programmed Wnt/β-catenin signaling pathway. Copyright © 2015 Elsevier GmbH. All rights reserved.

  17. Selectins and chemokines use shared and distinct signals to activate β2 integrins in neutrophils

    PubMed Central

    Yago, Tadayuki; Zhang, Nan; Zhao, Liang; Abrams, Charles S.

    2018-01-01

    Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates β2 integrins to slow rolling velocities. Chemokine signaling activates β2 integrins to cause arrest. Despite extensive study, key aspects of these signaling cascades remain unresolved. Using complementary in vitro and in vivo assays, we found that selectin and chemokine signals in neutrophils triggered Rap1a-dependent and phosphatidylinositol-4-phosphate 5-kinase γ (PIP5Kγ90)–dependent pathways that induce integrin-dependent slow rolling and arrest. Interruption of both pathways, but not either pathway alone, blocked talin-1 recruitment to and activation of integrins. An isoform of PIP5Kγ90 lacking the talin-binding domain (PIP5Kγ87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase γ (PI3Kγ) in cooperation with Rap1a to mediate integrin-dependent slow rolling (at low chemokine concentrations), as well as arrest (at high chemokine concentrations). High levels of chemokines activated β2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate β2 integrins. PMID:29592875

  18. Selectins and chemokines use shared and distinct signals to activate β2 integrins in neutrophils.

    PubMed

    Yago, Tadayuki; Zhang, Nan; Zhao, Liang; Abrams, Charles S; McEver, Rodger P

    2018-04-10

    Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates β2 integrins to slow rolling velocities. Chemokine signaling activates β2 integrins to cause arrest. Despite extensive study, key aspects of these signaling cascades remain unresolved. Using complementary in vitro and in vivo assays, we found that selectin and chemokine signals in neutrophils triggered Rap1a-dependent and phosphatidylinositol-4-phosphate 5-kinase γ (PIP5Kγ90)-dependent pathways that induce integrin-dependent slow rolling and arrest. Interruption of both pathways, but not either pathway alone, blocked talin-1 recruitment to and activation of integrins. An isoform of PIP5Kγ90 lacking the talin-binding domain (PIP5Kγ87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase γ (PI3Kγ) in cooperation with Rap1a to mediate integrin-dependent slow rolling (at low chemokine concentrations), as well as arrest (at high chemokine concentrations). High levels of chemokines activated β2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate β2 integrins. © 2018 by The American Society of Hematology.

  19. The Hippo pathway in intestinal regeneration and disease.

    PubMed

    Hong, Audrey W; Meng, Zhipeng; Guan, Kun-Liang

    2016-06-01

    The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.

  20. The Hippo pathway in intestinal regeneration and disease

    PubMed Central

    Hong, Audrey W.; Meng, Zhipeng; Guan, Kun-Liang

    2017-01-01

    The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease. PMID:27147489

  1. Are teachers' judgements of pupils' ability influenced by body shape?

    PubMed

    Shackleton, N L; Campbell, T

    2014-04-01

    Evidence indicates that teachers can judge pupils on the basis of their physical appearance, including their body shape. Teacher bias towards obese pupils has been suggested as a potential pathway through which obese children attain relatively lower academic levels. The aim of this study was to investigate whether teachers' judgements of pupils' ability are influenced by the body shape of the child. The sample includes English, singleton children in state schools from the Millennium Cohort Study. The data were taken from the fourth wave of data collection, when the children were approximately 7 years old. In all, 5086/5072 children had teacher ability ratings of reading and maths. Logistic regression analyses were used to test whether teachers' perceptions of the child's reading and mathematics ability were influenced by the pupil's waist circumference, conditional upon cognitive test scores of reading and maths ability. After adjustment for cognitive test scores, no significant overall relationship was found between the pupil's waist circumference and the teacher's judgements of ability. No statistically significant differences were observed in the probability of being judged as above average after further adjustments were made for potential confounders. There is little evidence that teachers' judgements of pupils' ability are influenced by obesity.

  2. GWAS-based pathway analysis differentiates between fluid and crystallized intelligence.

    PubMed

    Christoforou, A; Espeseth, T; Davies, G; Fernandes, C P D; Giddaluru, S; Mattheisen, M; Tenesa, A; Harris, S E; Liewald, D C; Payton, A; Ollier, W; Horan, M; Pendleton, N; Haggarty, P; Djurovic, S; Herms, S; Hoffman, P; Cichon, S; Starr, J M; Lundervold, A; Reinvang, I; Steen, V M; Deary, I J; Le Hellard, S

    2014-09-01

    Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation. © 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

  3. FNV: light-weight flash-based network and pathway viewer.

    PubMed

    Dannenfelser, Ruth; Lachmann, Alexander; Szenk, Mariola; Ma'ayan, Avi

    2011-04-15

    Network diagrams are commonly used to visualize biochemical pathways by displaying the relationships between genes, proteins, mRNAs, microRNAs, metabolites, regulatory DNA elements, diseases, viruses and drugs. While there are several currently available web-based pathway viewers, there is still room for improvement. To this end, we have developed a flash-based network viewer (FNV) for the visualization of small to moderately sized biological networks and pathways. Written in Adobe ActionScript 3.0, the viewer accepts simple Extensible Markup Language (XML) formatted input files to display pathways in vector graphics on any web-page providing flexible layout options, interactivity with the user through tool tips, hyperlinks and the ability to rearrange nodes on the screen. FNV was utilized as a component in several web-based systems, namely Genes2Networks, Lists2Networks, KEA, ChEA and PathwayGenerator. In addition, FVN can be used to embed pathways inside pdf files for the communication of pathways in soft publication materials. FNV is available for use and download along with the supporting documentation and sample networks at http://www.maayanlab.net/FNV. avi.maayan@mssm.edu.

  4. MDMA (ecstasy/molly) use among African Americans: The perceived influence of hip-hop/rap music.

    PubMed

    Rigg, Khary K; Estreet, Anthony T

    2018-02-12

    Over the past two decades, the demographic profile of MDMA (ecstasy/molly) users has changed. In particular, African American MDMA use has risen in some cities. One explanation of this new trend is the drug's recent popularity (as molly) in hip-hop/rap (HHR) music. Several top rappers endorse the drug as a way to have fun or get women "loose." There are currently no studies, however, that investigate the extent to which African American MDMA users listen to HHR music or the influence that these pro-MDMA messages have on their use of the drug. To address this gap, the current study used survey data to (a) identify the extent to which HHR music is listened to by African American MDMA users and (b) assess the perceived influence of HHR music on their decision to begin using. Qualitative interview data are also presented to contextualize the influence of these messages on their use of MDMA. The findings of this study suggest that African American MDMA users are high consumers of HHR music and that pro-MDMA messages in HHR music are influencing their expectations of the drug and their decision to initiate use. These findings add to the limited amount of research on African American MDMA use and have the potential to inform future interventions.

  5. Enzymology of the Wood–Ljungdahl Pathway of Acetogenesis

    PubMed Central

    Ragsdale, Stephen W.

    2011-01-01

    The biochemistry of acetogenesis is reviewed. The microbes that catalyze the reactions that are central to acetogenesis are described and the focus is on the enzymology of the process. These microbes play a key role in the global carbon cycle, producing over 10 trillion kilograms of acetic acid annually. Acetogens have the ability to anaerobically convert carbon dioxide and CO into acetyl-CoA by the Wood–Ljungdahl pathway, which is linked to energy conservation. They also can convert the six carbons of glucose stoichiometrically into 3 mol of acetate using this pathway. Acetogens and other anaerobic microbes (e.g., sulfate reducers and methanogens) use the Wood–Ljungdahl pathway for cell carbon synthesis. Important enzymes in this pathway that are covered in this review are pyruvate ferredoxin oxidoreductase, CO dehydrogenase/acetyl-CoA synthase, a corrinoid iron-sulfur protein, a methyltransferase, and the enzymes involved in the conversion of carbon dioxide to methyl-tetrahydrofolate. PMID:18378591

  6. AOP-DB: A database resource for the exploration of Adverse Outcome Pathways through integrated association networks.

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability t...

  7. Pathway collages: personalized multi-pathway diagrams.

    PubMed

    Paley, Suzanne; O'Maille, Paul E; Weaver, Daniel; Karp, Peter D

    2016-12-13

    Metabolic pathway diagrams are a classical way of visualizing a linked cascade of biochemical reactions. However, to understand some biochemical situations, viewing a single pathway is insufficient, whereas viewing the entire metabolic network results in information overload. How do we enable scientists to rapidly construct personalized multi-pathway diagrams that depict a desired collection of interacting pathways that emphasize particular pathway interactions? We define software for constructing personalized multi-pathway diagrams called pathway-collages using a combination of manual and automatic layouts. The user specifies a set of pathways of interest for the collage from a Pathway/Genome Database. Layouts for the individual pathways are generated by the Pathway Tools software, and are sent to a Javascript Pathway Collage application implemented using Cytoscape.js. That application allows the user to re-position pathways; define connections between pathways; change visual style parameters; and paint metabolomics, gene expression, and reaction flux data onto the collage to obtain a desired multi-pathway diagram. We demonstrate the use of pathway collages in two application areas: a metabolomics study of pathogen drug response, and an Escherichia coli metabolic model. Pathway collages enable facile construction of personalized multi-pathway diagrams.

  8. Perceived mathematical ability under challenge: a longitudinal perspective on sex segregation among STEM degree fields.

    PubMed

    Nix, Samantha; Perez-Felkner, Lara; Thomas, Kirby

    2015-01-01

    Students' perceptions of their mathematics ability vary by gender and seem to influence science, technology, engineering, and mathematics (STEM) degree choice. Related, students' perceptions during academic difficulty are increasingly studied in educational psychology, suggesting a link between such perceptions and task persistence. Despite interest in examining the gender disparities in STEM, these concepts have not been considered in tandem. In this manuscript, we investigate how perceived ability under challenge-in particular in mathematics domains-influences entry into the most sex-segregated and mathematics-intensive undergraduate degrees: physics, engineering, mathematics, and computer science (PEMC). Using nationally representative Education Longitudinal Study of 2002 (ELS) data, we estimate the influence of perceived ability under challenging conditions on advanced high school science course taking, selection of an intended STEM major, and specific major type 2 years after high school. Demonstrating the importance of specificity when discussing how gender influences STEM career pathways, the intersecting effects of gender and perceived ability under mathematics challenge were distinct for each scientific major category. Perceived ability under challenge in secondary school varied by gender, and was highly predictive of selecting PEMC and health sciences majors. Notably, women's 12th grade perceptions of their ability under mathematics challenge increased their probability of selecting PEMC majors over and above biology. In addition, gender moderated the effect of growth mindset on students' selection of health science majors. Perceptions of ability under challenge in general and verbal domains also influenced retention in and declaration of certain STEM majors. The implications of these results are discussed, with particular attention to access to advanced scientific coursework in high school and interventions aimed at enhancing young women's perceptions of

  9. Perceived mathematical ability under challenge: a longitudinal perspective on sex segregation among STEM degree fields

    PubMed Central

    Nix, Samantha; Perez-Felkner, Lara; Thomas, Kirby

    2015-01-01

    Students' perceptions of their mathematics ability vary by gender and seem to influence science, technology, engineering, and mathematics (STEM) degree choice. Related, students' perceptions during academic difficulty are increasingly studied in educational psychology, suggesting a link between such perceptions and task persistence. Despite interest in examining the gender disparities in STEM, these concepts have not been considered in tandem. In this manuscript, we investigate how perceived ability under challenge—in particular in mathematics domains—influences entry into the most sex-segregated and mathematics-intensive undergraduate degrees: physics, engineering, mathematics, and computer science (PEMC). Using nationally representative Education Longitudinal Study of 2002 (ELS) data, we estimate the influence of perceived ability under challenging conditions on advanced high school science course taking, selection of an intended STEM major, and specific major type 2 years after high school. Demonstrating the importance of specificity when discussing how gender influences STEM career pathways, the intersecting effects of gender and perceived ability under mathematics challenge were distinct for each scientific major category. Perceived ability under challenge in secondary school varied by gender, and was highly predictive of selecting PEMC and health sciences majors. Notably, women's 12th grade perceptions of their ability under mathematics challenge increased their probability of selecting PEMC majors over and above biology. In addition, gender moderated the effect of growth mindset on students' selection of health science majors. Perceptions of ability under challenge in general and verbal domains also influenced retention in and declaration of certain STEM majors. The implications of these results are discussed, with particular attention to access to advanced scientific coursework in high school and interventions aimed at enhancing young women

  10. Neural pathways for visual speech perception

    PubMed Central

    Bernstein, Lynne E.; Liebenthal, Einat

    2014-01-01

    This paper examines the questions, what levels of speech can be perceived visually, and how is visual speech represented by the brain? Review of the literature leads to the conclusions that every level of psycholinguistic speech structure (i.e., phonetic features, phonemes, syllables, words, and prosody) can be perceived visually, although individuals differ in their abilities to do so; and that there are visual modality-specific representations of speech qua speech in higher-level vision brain areas. That is, the visual system represents the modal patterns of visual speech. The suggestion that the auditory speech pathway receives and represents visual speech is examined in light of neuroimaging evidence on the auditory speech pathways. We outline the generally agreed-upon organization of the visual ventral and dorsal pathways and examine several types of visual processing that might be related to speech through those pathways, specifically, face and body, orthography, and sign language processing. In this context, we examine the visual speech processing literature, which reveals widespread diverse patterns of activity in posterior temporal cortices in response to visual speech stimuli. We outline a model of the visual and auditory speech pathways and make several suggestions: (1) The visual perception of speech relies on visual pathway representations of speech qua speech. (2) A proposed site of these representations, the temporal visual speech area (TVSA) has been demonstrated in posterior temporal cortex, ventral and posterior to multisensory posterior superior temporal sulcus (pSTS). (3) Given that visual speech has dynamic and configural features, its representations in feedforward visual pathways are expected to integrate these features, possibly in TVSA. PMID:25520611

  11. C/EBPα induces adipogenesis through PPARγ: a unified pathway

    PubMed Central

    Rosen, Evan D.; Hsu, Chung-Hsin; Wang, Xinzhong; Sakai, Shuichi; Freeman, Mason W.; Gonzalez, Frank J.; Spiegelman, Bruce M.

    2002-01-01

    PPARγ and C/EBPα are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain about whether these factors operate independently in separate, parallel pathways of differentiation, or whether a single pathway exists. PPARγ can promote adipogenesis in C/EBPα-deficient cells, but the converse has not been tested. We have created an immortalized line of fibroblasts lacking PPARγ, which we use to show that C/EBPα has no ability to promote adipogenesis in the absence of PPARγ. These results indicate that C/EBPα and PPARγ participate in a single pathway of fat cell development with PPARγ being the proximal effector of adipogenesis. PMID:11782441

  12. Allorecognition pathways in transplant rejection and tolerance.

    PubMed

    Ali, Jason M; Bolton, Eleanor M; Bradley, J Andrew; Pettigrew, Gavin J

    2013-10-27

    With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

  13. Gait Speed rather than Dynapenia Is a Simple Indicator for Complex Care Needs: A Cross-sectional Study Using Minimum Data Set.

    PubMed

    Huang, Tzu-Ya; Liang, Chih-Kuang; Shen, Hsiu-Chu; Chen, Hon-I; Liao, Mei-Chen; Chou, Ming-Yueh; Lin, Yu-Te; Chen, Liang-Kung

    2017-08-21

    The impact of dynapenia on the complexity of care for residents of long-term care facilities (LTCF) remains unclear. The present study evaluated associations between dynapenia, care problems and care complexity in 504 residents of Veterans Care Homes (VCHs) in Taiwan. Subjects with dynapenia, defined as low muscle strength (handgrip strength <26 kg), were older adults with lower body mass index (BMI), slow gait speed, and higher numbers of Resident Assessment Protocol (RAP) triggers. After adjusting for age, education, BMI, and Charlson's comorbidity index (CCI), only age, education, BMI and gait speed were independently associated with higher numbers of RAP triggers, but not dynapenia or handgrip strength (kg). Dividing subjects into groups based on quartiles of gait speed, those with gait speed ≤0.803 m/s were significantly associated with higher complexity of care needs (defined as ≥4 RAP triggers) compared to the reference group (gait speed >1 m/s). Significantly slow gait speed was associated with RAP triggers, including cognitive loss, poor communication ability, rehabilitation needs, urinary incontinence, depressed mood, falls, pressure ulcers, and use of psychotropic drugs. In conclusion, slow gait speed rather than dynapenia is a simple indicator for higher complexity of care needs of older male LTCF residents.

  14. Biosensor-based engineering of biosynthetic pathways

    DOE PAGES

    Rogers, Jameson K.; Taylor, Noah D.; Church, George M.

    2016-03-18

    Biosynthetic pathways provide an enzymatic route from inexpensive renewable resources to valuable metabolic products such as pharmaceuticals and plastics. However, designing these pathways is challenging due to the complexities of biology. Advances in the design and construction of genetic variants has enabled billions of cells, each possessing a slightly different metabolic design, to be rapidly generated. However, our ability to measure the quality of these designs lags by several orders of magnitude. Recent research has enabled cells to report their own success in chemical production through the use of genetically encoded biosensors. A new engineering discipline is emerging around themore » creation and application of biosensors. Biosensors, implemented in selections and screens to identify productive cells, are paving the way for a new era of biotechnological progress.« less

  15. PACAP signaling to DREAM: a cAMP-dependent pathway that regulates cortical astrogliogenesis.

    PubMed

    Vallejo, Mario

    2009-04-01

    Astrocytes constitute a very abundant cell type in the mammalian central nervous system and play critical roles in brain function. During development, astrocytes are generated from neural progenitor cells only after these cells have generated neurons. This so called gliogenic switch is tightly regulated by intrinsic factors that inhibit the generation of astrocytes during the neurogenic period. Once neural progenitors acquire gliogenic competence, they differentiate into astrocytes in response to specific extracellular signals. Some of these signals are delivered by neurotrophic cytokines via activation of the gp130-JAK-signal transducer and activator of transcription system, whereas others depend on the activity of pituitary adenylate cyclase-activating polypeptide (PACAP) on specific PAC1 receptors that stimulate the production of cAMP. This results in the activation of the small GTPases Rap1 and Ras, and in the cAMP-dependent entry of extracellular calcium into the cell. Calcium, in turn, stimulates the transcription factor downstream regulatory element antagonist modulator (DREAM), which is bound to specific sites of the promoter of the glial fibrillary acidic protein gene, stimulating its expression during astrocyte differentiation. Lack of DREAM in vivo results in alterations in the number of neurons and astrocytes generated during development. Thus, the PACAP-cAMP-Ca(2+)-DREAM signaling cascade constitutes an important pathway to activate glial-specific gene expression during astrocyte differentiation.

  16. An integrated pathway system modeling of Saccharomyces cerevisiae HOG pathway: a Petri net based approach.

    PubMed

    Tomar, Namrata; Choudhury, Olivia; Chakrabarty, Ankush; De, Rajat K

    2013-02-01

    Biochemical networks comprise many diverse components and interactions between them. It has intracellular signaling, metabolic and gene regulatory pathways which are highly integrated and whose responses are elicited by extracellular actions. Previous modeling techniques mostly consider each pathway independently without focusing on the interrelation of these which actually functions as a single system. In this paper, we propose an approach of modeling an integrated pathway using an event-driven modeling tool, i.e., Petri nets (PNs). PNs have the ability to simulate the dynamics of the system with high levels of accuracy. The integrated set of signaling, regulatory and metabolic reactions involved in Saccharomyces cerevisiae's HOG pathway has been collected from the literature. The kinetic parameter values have been used for transition firings. The dynamics of the system has been simulated and the concentrations of major biological species over time have been observed. The phenotypic characteristics of the integrated system have been investigated under two conditions, viz., under the absence and presence of osmotic pressure. The results have been validated favorably with the existing experimental results. We have also compared our study with the study of idFBA (Lee et al., PLoS Comput Biol 4:e1000-e1086, 2008) and pointed out the differences between both studies. We have simulated and monitored concentrations of multiple biological entities over time and also incorporated feedback inhibition by Ptp2 which has not been included in the idFBA study. We have concluded that our study is the first to the best of our knowledge to model signaling, metabolic and regulatory events in an integrated form through PN model framework. This study is useful in computational simulation of system dynamics for integrated pathways as there are growing evidences that the malfunctioning of the interplay among these pathways is associated with disease.

  17. Adaptable Learning Pathway Generation with Ant Colony Optimization

    ERIC Educational Resources Information Center

    Wong, Lung-Hsiang; Looi, Chee-Kit

    2009-01-01

    One of the new major directions in research on web-based educational systems is the notion of adaptability: the educational system adapts itself to the learning profile, preferences and ability of the student. In this paper, we look into the issues of providing adaptability with respect to learning pathways. We explore the state of the art with…

  18. Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ovacik, Meric A.; Sen, Banalata; Euling, Susan Y.

    Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significancemore » analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.« less

  19. Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation.

    PubMed

    Galvin, Jason; Eyermann, Christopher; Colognato, Holly

    2010-11-15

    The adhesion receptor dystroglycan positively regulates terminal differentiation of oligodendrocytes, but the mechanism by which this occurs remains unclear. Using primary oligodendrocyte cultures, we identified and examined a connection between dystroglycan and the ability of insulin-like growth factor-1 (IGF-1) to promote oligodendrocyte differentiation. Consistent with previous reports, treatment with exogenous IGF-1 caused an increase in MBP protein that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways. The extracellular matrix protein laminin was further shown to potentiate the effect of IGF-1 on oligodendrocyte differentiation. Depletion of the laminin receptor dystroglycan using siRNA, however, blocked the ability of IGF-1 to promote oligodendrocyte differentiation of cells grown on laminin, suggesting a role for dystroglycan in IGF-1-mediated differentiation. Indeed, loss of dystroglycan led to a reduction in the ability of IGF-1 to activate MAPK, but not PI3K, signaling pathways. Pharmacological inhibition of MAPK signaling also prevented IGF-1-induced increases in myelin basic protein (MBP), indicating that MAPK signaling was necessary to drive IGF-1-mediated enhancement of oligodendrocyte differentiation. Using immunoprecipitation, we found that dystroglycan, the adaptor protein Grb2, and insulin receptor substrate-1 (IRS-1), were associated in a protein complex. Taken together, our results suggest that the positive regulatory effect of laminin on oligodendrocyte differentiation may be attributed, at least in part, to dystroglycan's ability to promote IGF-1-induced differentiation.

  20. An Integrative Data Mining Approach to Identify Adverse Outcome Pathway Signatures

    EPA Science Inventory

    Adverse Outcome Pathways (AOPs) provide a formal framework for describing the mechanisms underlying the toxicity of chemicals in our environment. This process improves our ability to incorporate high-throughput toxicity testing (HTT) results and biomarker information on early key...

  1. Entourage: Visualizing Relationships between Biological Pathways using Contextual Subsets

    PubMed Central

    Lex, Alexander; Partl, Christian; Kalkofen, Denis; Streit, Marc; Gratzl, Samuel; Wassermann, Anne Mai; Schmalstieg, Dieter; Pfister, Hanspeter

    2014-01-01

    Biological pathway maps are highly relevant tools for many tasks in molecular biology. They reduce the complexity of the overall biological network by partitioning it into smaller manageable parts. While this reduction of complexity is their biggest strength, it is, at the same time, their biggest weakness. By removing what is deemed not important for the primary function of the pathway, biologists lose the ability to follow and understand cross-talks between pathways. Considering these cross-talks is, however, critical in many analysis scenarios, such as judging effects of drugs. In this paper we introduce Entourage, a novel visualization technique that provides contextual information lost due to the artificial partitioning of the biological network, but at the same time limits the presented information to what is relevant to the analyst’s task. We use one pathway map as the focus of an analysis and allow a larger set of contextual pathways. For these context pathways we only show the contextual subsets, i.e., the parts of the graph that are relevant to a selection. Entourage suggests related pathways based on similarities and highlights parts of a pathway that are interesting in terms of mapped experimental data. We visualize interdependencies between pathways using stubs of visual links, which we found effective yet not obtrusive. By combining this approach with visualization of experimental data, we can provide domain experts with a highly valuable tool. We demonstrate the utility of Entourage with case studies conducted with a biochemist who researches the effects of drugs on pathways. We show that the technique is well suited to investigate interdependencies between pathways and to analyze, understand, and predict the effect that drugs have on different cell types. Fig. 1Entourage showing the Glioma pathway in detail and contextual information of multiple related pathways. PMID:24051820

  2. Phospholipase C-ε links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans

    PubMed Central

    Dzhura, Igor; Chepurny, Oleg G; Leech, Colin A; Roe, Michael W; Dzhura, Elvira; Xu, Xin; Lu, Youming; Schwede, Frank; Genieser, Hans-G; Smrcka, Alan V

    2011-01-01

    Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is potentiated by cAMP-elevating agents, such as the incretin hormone glucagon-like peptide-1 (GLP-1) and cAMP exerts its insulin secretagogue action by activating both protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Although prior studies of mouse islets demonstrated that Epac2 acts via Rap1 GTPase to potentiate GSIS, it is not understood which downstream targets of Rap1 promote the exocytosis of insulin. Here, we measured insulin secretion stimulated by a cAMP analog that is a selective activator of Epac proteins in order to demonstrate that a Rap1-regulated phospholipase C-epsilon (PLC-ε) links Epac2 activation to the potentiation of GSIS. Our analysis demonstrates that the Epac activator 8-pCPT-2′-O-Me-cAMP-AM potentiates GSIS from the islets of wild-type (WT) mice, whereas it has a greatly reduced insulin secretagogue action in the islets of Epac2 (−/−) and PLC-ε (−/−) knockout (KO) mice. Importantly, the insulin secretagogue action of 8-pCPT-2′-O-Me-cAMP-AM in WT mouse islets cannot be explained by an unexpected action of this cAMP analog to activate PKA, as verified through the use of a FRET-based A-kinase activity reporter (AKAR3) that reports PKA activation. Since the KO of PLC-ε disrupts the ability of 8-pCPT-2′-O-Me-cAMP-AM to potentiate GSIS, while also disrupting its ability to stimulate an increase of β-cell [Ca2+]i, the available evidence indicates that it is a Rap1-regulated PLC-ε that links Epac2 activation to Ca2+-dependent exocytosis of insulin. PMID:21478675

  3. miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-{beta}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Song, Libing, E-mail: lb.song1@gmail.com; Huang, Quan; Chen, Kun

    2010-11-05

    Research highlights: {yields} miR-218 is markedly downregulated in glioma cell lines and in primary glioma tissues. {yields} Upregulation of miR-218 dramatically reduces the invasive ability of glioma cells. {yields} Ectopic expression of miR-218 inactivates IKK-{beta}/NF-{kappa}B signaling pathway. {yields} miR-218 directly targets the 3'-untranslated region (3'-UTR) of IKK-{beta}. -- Abstract: Aberrant activation of nuclear factor-kappa B (NF-{kappa}B) pathway has been proven to play important roles in the development and progression of cancers. Activation of NF-{kappa}B via the classical pathway is modulated by I{kappa}Bs kinase (IKK-{beta}). However, the mechanism underlying the epigenetic regulation of IKK-{beta}/NF-{kappa}B pathway remains largely unknown. In this study,more » we found that the expression level of miR-218 was markedly downregulated in glioma cell lines and in human primary glioma tissues. Upregulation of miR-218 dramatically reduced the migratory speed and invasive ability of glioma cells. Furthermore, we showed that ectopically expressing miR-218 in glioma cells resulted in downregulation of matrix metalloproteinase-9 (MMP-9) and reduction in NF-{kappa}B transactivity at a transcriptional level, but inhibition of miR-218 enhanced the expression of MMP-9 and transcriptional activity of NF-{kappa}B. Moreover, we showed that miR-218 inactivated the NF-{kappa}B pathway through downregulating IKK-{beta} expression by directly targeting the 3'-untranslated region (3'-UTR) of IKK-{beta}. Taken together, our results suggest that miR-218 plays an important role in preventing the invasiveness of glioma cells, and our results present a novel mechanism of miRNA-mediated direct suppression of IKK-{beta}/NF-{kappa}B pathway in gliomas.« less

  4. The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair

    PubMed Central

    Fallahi, Emma; O’Driscoll, Niamh A.; Matallanas, David

    2016-01-01

    The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. PMID:27322327

  5. Transcriptional activation of peroxisome proliferator-activated receptor-{gamma} requires activation of both protein kinase A and Akt during adipocyte differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Sang-pil; Ha, Jung Min; Yun, Sung Ji

    2010-08-13

    Research highlights: {yields} Elevated cAMP activates both PKA and Epac. {yields} PKA activates CREB transcriptional factor and Epac activates PI3K/Akt pathway via Rap1. {yields} Akt modulates PPAR-{gamma} transcriptional activity in concert with CREB. -- Abstract: Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-{gamma} is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-{gamma}. Hormonal induction of adipogenesis was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), by a protein kinase A (PKA) inhibitor (H89), and by amore » Rap1 inhibitor (GGTI-298). Transcriptional activity of PPAR-{gamma} was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-{gamma} transcriptional activity was blocked by PI3K/Akt, PKA, or Rap1 inhibitors. 8-(4-Chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT-2'-O-Me-cAMP) which is a specific agonist for exchanger protein directly activated by cAMP (Epac) significantly induced the activation of Akt. Furthermore, knock-down of Akt1 markedly attenuated PPAR-{gamma} transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-{gamma}, suggesting post-translational activation of PPAR-{gamma} might be critical step for adipogenic gene expression.« less

  6. The bright side of plasmonic gold nanoparticles; activation of Nrf2, the cellular protective pathway

    NASA Astrophysics Data System (ADS)

    Goldstein, Alona; Soroka, Yoram; Frušić-Zlotkin, Marina; Lewis, Aaron; Kohen, Ron

    2016-06-01

    Plasmonic gold nanoparticles (AuNPs) are widely investigated for cancer therapy, due to their ability to strongly absorb light and convert it to heat and thus selectively destroy tumor cells. In this study we shed light on a new aspect of AuNPs and their plasmonic excitation, wherein they can provide anti-oxidant and anti-inflammatory protection by stimulating the cellular protective Nrf2 pathway. Our study was carried out on cells of the immune system, macrophages, and on skin cells, keratinocytes. A different response to AuNPs was noted in the two types of cells, explained by their distinct uptake profiles. In keratinocytes, the exposure to AuNPs, even at low concentrations, was sufficient to activate the Nrf2 pathway, without any irradiation, due to the presence of free AuNPs inside the cytosol. In contrast, in macrophages, the plasmonic excitation of the AuNPs by a low, non-lethal irradiation dose was required for their release from the constraining vesicles. The mechanism by which AuNPs activate the Nrf2 pathway was studied. Direct and indirect activation were suggested, based on the inherent ability of the AuNPs to react with thiol groups and to generate reactive oxygen species, in particular, under plasmonic excitation. The ability of AuNPs to directly activate the Nrf2 pathway renders them good candidates for treatment of disorders in which the up-regulation of Nrf2 is beneficial, specifically for topical treatment of inflammatory skin diseases.

  7. Molecular analysis of Phr peptide processing in Bacillus subtilis.

    PubMed

    Stephenson, Sophie; Mueller, Christian; Jiang, Min; Perego, Marta

    2003-08-01

    In Bacillus subtilis, an export-import pathway regulates production of the Phr pentapeptide inhibitors of Rap proteins. Processing of the Phr precursor proteins into the active pentapeptide form is a key event in the initiation of sporulation and competence development. The PhrA (ARNQT) and PhrE (SRNVT) peptides inhibit the RapA and RapE phosphatases, respectively, whose activity is directed toward the Spo0F approximately P intermediate response regulator of the sporulation phosphorelay. The PhrC (ERGMT) peptide inhibits the RapC protein acting on the ComA response regulator for competence with regard to DNA transformation. The structural organization of PhrA, PhrE, and PhrC suggested a role for type I signal peptidases in the processing of the Phr preinhibitor, encoded by the phr genes, into the proinhibitor form. The proinhibitor was then postulated to be cleaved to the active pentapeptide inhibitor by an additional enzyme. In this report, we provide evidence that Phr preinhibitor proteins are subject to only one processing event at the peptide bond on the amino-terminal end of the pentapeptide. This processing event is most likely independent of type I signal peptidase activity. In vivo and in vitro analyses indicate that none of the five signal peptidases of B. subtilis (SipS, SipT, SipU, SipV, and SipW) are indispensable for Phr processing. However, we show that SipV and SipT have a previously undescribed role in sporulation, competence, and cell growth.

  8. Direct and indirect effects of organizational justice on work ability.

    PubMed

    Spanier, K; Radoschewski, F M; Gutenbrunner, C; Bethge, M

    2014-12-01

    Organizational justice (OJ), involving transparent workplace procedures and treating staff members with respect, has been of growing concern in recent epidemiological research as a determinant of health-related outcomes. To examine the factorial validity of the German version of Moorman's Organizational Justice Questionnaire (OJQ), to investigate the direct cross-sectional effect of OJ on self-rated work ability and to analyse if there is an additional indirect effect of OJ on work ability mediated by effort-reward imbalance. An analysis of cross-sectional data from the Second German Sociomedical Panel of Employees, involving white-collar workers employed at least half time. We performed confirmatory factor analyses to test the factorial validity of the OJQ and analysed the direct and indirect associations of OJ and self-rated work ability by path model analysis. Of the 1217 participants (47% female; mean age: 51) 36% had poor work ability. Factor analyses confirmed the two-factor structure of the German OJQ. Work ability was explained directly by OJ (β = 0.30) and effort-reward imbalance (β = -0.27). Additionally, we identified an indirect effect of OJ that was mediated by effort-reward imbalance (β = 0.14). The total effect of OJ on work ability was remarkably strong (β = 0.44). Associations remained unchanged after adjustment for socio-demographic parameters. This study showed the importance of considering additional indirect pathways when examining the impact of OJ on the work ability of employees. © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. The Pathway Coexpression Network: Revealing pathway relationships

    PubMed Central

    Tanzi, Rudolph E.

    2018-01-01

    A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of

  10. Rapid Auditory Processing and Learning Deficits in Rats With P1 versus P7 Neonatal Hypoxic-Ischemic Injury

    PubMed Central

    McClure, Melissa M.; Threlkeld, Steven W.; Rosen, Glenn D.; Fitch, R. Holly

    2014-01-01

    Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits, or impairments in the ability to discriminate rapidly changing acoustic signals, play a causal role in emergent language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal day 1, 7, or 10 (P1, P7, or P10; 23). While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide us with sufficient power to detect Age-at-injury differences within HI groups. The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury in P1 vs. P7 pups. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but the deficit in the P1 HI group resolved with repeated testing (compared to shams). However, P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (Age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 vs. P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan. PMID:16765458

  11. Comparative study on gene set and pathway topology-based enrichment methods.

    PubMed

    Bayerlová, Michaela; Jung, Klaus; Kramer, Frank; Klemm, Florian; Bleckmann, Annalen; Beißbarth, Tim

    2015-10-22

    Enrichment analysis is a popular approach to identify pathways or sets of genes which are significantly enriched in the context of differentially expressed genes. The traditional gene set enrichment approach considers a pathway as a simple gene list disregarding any knowledge of gene or protein interactions. In contrast, the new group of so called pathway topology-based methods integrates the topological structure of a pathway into the analysis. We comparatively investigated gene set and pathway topology-based enrichment approaches, considering three gene set and four topological methods. These methods were compared in two extensive simulation studies and on a benchmark of 36 real datasets, providing the same pathway input data for all methods. In the benchmark data analysis both types of methods showed a comparable ability to detect enriched pathways. The first simulation study was conducted with KEGG pathways, which showed considerable gene overlaps between each other. In this study with original KEGG pathways, none of the topology-based methods outperformed the gene set approach. Therefore, a second simulation study was performed on non-overlapping pathways created by unique gene IDs. Here, methods accounting for pathway topology reached higher accuracy than the gene set methods, however their sensitivity was lower. We conducted one of the first comprehensive comparative works on evaluating gene set against pathway topology-based enrichment methods. The topological methods showed better performance in the simulation scenarios with non-overlapping pathways, however, they were not conclusively better in the other scenarios. This suggests that simple gene set approach might be sufficient to detect an enriched pathway under realistic circumstances. Nevertheless, more extensive studies and further benchmark data are needed to systematically evaluate these methods and to assess what gain and cost pathway topology information introduces into enrichment analysis. Both

  12. The Retinoblastoma Tumor Suppressor Regulates a Xenobiotic Detoxification Pathway

    PubMed Central

    Sáenz Robles, Maria Teresa; Case, Ashley; Chong, Jean-Leon; Leone, Gustavo; Pipas, James M.

    2011-01-01

    The retinoblastoma tumor suppressor (pRb) regulates cell cycle entry, progression and exit by controlling the activity of the E2F-family of transcription factors. During cell cycle exit pRb acts as a transcriptional repressor by associating with E2F proteins and thereby inhibiting their ability to stimulate the expression of genes required for S phase. Indeed, many tumors harbor mutations in the RB gene and the pRb-E2F pathway is compromised in nearly all types of cancers. In this report we show that both pRb and its interacting partners, the transcriptional factors E2F1-2-3, act as positive modulators of detoxification pathways important for metabolizing and clearing xenobiotics—such as toxins and drugs—from the body. Using a combination of conventional molecular biology techniques and microarray analysis of specific cell populations, we have analyzed the detoxification pathway in murine samples in the presence or absence of pRb and/or E2F1-2-3. In this report, we show that both pRb and E2F1-2-3 act as positive modulators of detoxification pathways in mice, challenging the conventional view of E2F1-2-3 as transcriptional repressors negatively regulated by pRb. These results suggest that mutations altering the pRb-E2F axis may have consequences beyond loss of cell cycle control by altering the ability of tissues to remove toxins and to properly metabolize anticancer drugs, and might help to understand the formation and progression rates of different types of cancer, as well as to better design appropriate therapies based on the particular genetic composition of the tumors. PMID:22022495

  13. The Intracellular Trafficking Pathway of Transferrin

    PubMed Central

    Mayle, Kristine M.; Le, Alexander M.; Kamei, Daniel T.

    2011-01-01

    Background Transferrin (Tf) is an iron-binding protein that facilitates iron-uptake in cells. Iron-loaded Tf first binds to the Tf receptor (TfR) and enters the cell through clathrin-mediated endocytosis. Inside the cell, Tf is trafficked to early endosomes, delivers iron, and then is subsequently directed to recycling endosomes to be taken back to the cell surface. Scope of Review We aim to review the various methods and techniques that researchers have employed for elucidating the Tf trafficking pathway and the cell-machinery components involved. These experimental methods can be categorized as microscopy, radioactivity, and surface plasmon resonance (SPR). Major Conclusions Qualitative experiments, such as total internal reflectance fluorescence (TIRF), electron, laser-scanning confocal, and spinning-disk confocal microscopy, have been utilized to determine the roles of key components in the Tf trafficking pathway. These techniques allow temporal resolution and are useful for imaging Tf endocytosis and recycling, which occur on the order of seconds to minutes. Additionally, radiolabeling and SPR methods, when combined with mathematical modeling, have enabled researchers to estimate quantitative kinetic parameters and equilibrium constants associated with Tf binding and trafficking. General Significance Both qualitative and quantitative data can be used to analyze the Tf trafficking pathway. The valuable information that is obtained about the Tf trafficking pathway can then be combined with mathematical models to identify design criteria to improve the ability of Tf to deliver anticancer drugs. PMID:21968002

  14. Graphite Web: web tool for gene set analysis exploiting pathway topology

    PubMed Central

    Sales, Gabriele; Calura, Enrica; Martini, Paolo; Romualdi, Chiara

    2013-01-01

    Graphite web is a novel web tool for pathway analyses and network visualization for gene expression data of both microarray and RNA-seq experiments. Several pathway analyses have been proposed either in the univariate or in the global and multivariate context to tackle the complexity and the interpretation of expression results. These methods can be further divided into ‘topological’ and ‘non-topological’ methods according to their ability to gain power from pathway topology. Biological pathways are, in fact, not only gene lists but can be represented through a network where genes and connections are, respectively, nodes and edges. To this day, the most used approaches are non-topological and univariate although they miss the relationship among genes. On the contrary, topological and multivariate approaches are more powerful, but difficult to be used by researchers without bioinformatic skills. Here we present Graphite web, the first public web server for pathway analysis on gene expression data that combines topological and multivariate pathway analyses with an efficient system of interactive network visualizations for easy results interpretation. Specifically, Graphite web implements five different gene set analyses on three model organisms and two pathway databases. Graphite Web is freely available at http://graphiteweb.bio.unipd.it/. PMID:23666626

  15. Mycobacterium avium Genes Associated with the Ability To Form a Biofilm

    PubMed Central

    Yamazaki, Yoshitaka; Danelishvili, Lia; Wu, Martin; MacNab, Molly; Bermudez, Luiz E.

    2006-01-01

    Mycobacterium avium is widely distributed in the environment, and it is chiefly found in water and soil. M. avium, as well as Mycobacterium smegmatis, has been recognized to produce a biofilm or biofilm-like structure. We screened an M. avium green fluorescent protein (GFP) promoter library in M. smegmatis for genes involved in biofilm formation on polyvinyl chloride (PVC) plates. Clones associated with increased GFP expression ≥2.0-fold over the baseline were sequenced. Seventeen genes, most encoding proteins of the tricarboxylic acid (TCA) cycle and GDP-mannose and fatty acid biosynthesis, were identified. Their regulation in M. avium was confirmed by examining the expression of a set of genes by real-time PCR after incubation on PVC plates. In addition, screening of 2,000 clones of a transposon mutant bank constructed using M. avium strain A5, a mycobacterial strain with the ability to produce large amounts of biofilm, revealed four mutants with an impaired ability to form biofilm. Genes interrupted by transposons were homologues of M. tuberculosis 6-oxodehydrogenase (sucA), enzymes of the TCA cycle, protein synthetase (pstB), enzymes of glycopeptidolipid (GPL) synthesis, and Rv1565c (a hypothetical membrane protein). In conclusion, it appears that GPL biosynthesis, including the GDP-mannose biosynthesis pathway, is the most important pathway involved in the production of M. avium biofilm. PMID:16391123

  16. PathwayAccess: CellDesigner plugins for pathway databases.

    PubMed

    Van Hemert, John L; Dickerson, Julie A

    2010-09-15

    CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

  17. Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

    PubMed Central

    Wallin, Jeffrey J.; Guan, Jane; Edgar, Kyle A.; Zhou, Wei; Francis, Ross; Torres, Anthony C.; Haverty, Peter M.; Eastham-Anderson, Jeffrey; Arena, Sabrina; Bardelli, Alberto; Griffin, Sue; Goodall, John E.; Grimshaw, Kyla M.; Hoeflich, Klaus P.; Torrance, Christopher; Belvin, Marcia; Friedman, Lori S.

    2012-01-01

    The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP3 production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis. PMID:22570710

  18. Tissue Inhibitor of Metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal

    PubMed Central

    Pérez-Martínez, Leonor; Jaworski, Diane M.

    2005-01-01

    Although traditionally recognized for maintaining extracellular matrix integrity during morphogenesis, the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), in the mature nervous system is largely unknown. Here, we report that TIMP-2 induces PC12 cell cycle arrest via regulation of cell cycle regulatory proteins resulting in differentiation and neurite outgrowth. TIMP-2 decreases cyclin B and D expression and increases p21Cip expression. Furthermore, TIMP-2 promotes cell differentiation via activation of the cAMP/Rap1/ERK pathway. Expression of dominant negative Rap1 blocks TIMP-2 mediated neurite outgrowth. Both the cell cycle arrest and neurite outgrowth induced by TIMP-2 was independent of MMP inhibitory activity. Consistent with the PC12 cell data, primary cultures of TIMP-2 knockout cerebral cortical neurons exhibit significantly reduced neurite length, which is rescued by TIMP-2. These in vitro results were corroborated in vivo. TIMP-2 deletion causes a delay in neuronal differentiation as demonstrated by the persistence of nestin-positive progenitors in the neocortical ventricular zone. The interaction of TIMP-2 with α3β1 integrin in the cerebral cortex suggests that TIMP-2 promotes neuronal differentiation and maintains mitotic quiescence in an MMP independent manner through integrin activation. The identification of molecules responsible for neuronal quiescence has significant implications for the adult brain’s ability to generate new neurons in response to injury and neurological disorders such as Alzheimer’s and Parkinson’s disease. PMID:15901773

  19. Survey of owner motivations and veterinary input of owners feeding diets containing raw animal products

    PubMed Central

    Willis, Susan; Shepherd, Megan L.

    2017-01-01

    Background The practice of feeding of diets containing raw animal products (RAP) to pets (dogs and cats) is discouraged by veterinary organizations and governmental public health organizations. Nevertheless, the practice of feeding RAP to pets is increasing in popularity. Pet owner motivations for feeding RAP diets to pets have not been explored and the benefits of RAP diets remain largely anecdotal. We hypothesized that pet owners feeding RAP diets would not rely on veterinary advice in choosing their pet’s diet. We also hypothesized that these owners would have lower levels of trust in veterinary advice with respect to nutrition relative to pet owners not feeding RAP. Methods An anonymous web-based survey was developed to identify pet owner motivations for feeding RAP diets, and to characterize the veterinarian-client relationships of individuals feeding RAP diets. Results There were 2,337 respondents and 2,171 completed surveys. Of survey respondents, 804 reported feeding RAP at the time of the survey. While 20% of pet owners feeding RAP relied on online resources to determine what or how much RAP to feed, only 9% reported consulting with a veterinarian in making decisions about feeding RAP. Pet owners feeding RAP reported lower levels of trust in veterinary advice both ‘in general’ and ‘with respect to nutrition’ than pet owners not feeding RAP. Most pet owners reported that a discussion regarding their pet’s nutrition does not occur at every veterinary appointment. Discussion Pet owners feeding a RAP diet have lower trust in veterinary advice than pet owners not feeding a RAP diet. Owners feeding RAP are more reliant on online resources than their own veterinarian in deciding what and how much RAP to feed. Pet owners perceive that nutrition is not discussed at most veterinary appointments. Therefore, there is room for improvement in the veterinarian-client communication with regards to nutrition. PMID:28265510

  20. Engineering Sialic Acid Synthesis Ability in Insect Cells.

    PubMed

    Viswanathan, Karthik; Narang, Someet; Betenbaugh, Michael J

    2015-01-01

    Insect cells lack the ability to synthesize the sialic acid donor molecule CMP-sialic acid or its precursor, sialic acid. In this chapter, we describe a method to engineer CMP-sialic acid synthesis capability into Spodoptera frugiperda (Sf9) cells, a prototypical insect cell line, by recombinant expression of sialic acid synthesis pathway genes using baculovirus technology. Co-expression of a sialuria mutant UDP-GlcNAc-2-epimerase/ManNAc kinase (EKR263L), wild-type sialic acid 9-phosphate synthase (SAS), and wild-type CMP-sialic acid synthetase (CSAS) in the presence of GlcNAc leads to synthesis of CMP-sialic acids synthesis to support sialylation of N-glycans on glycoproteins.

  1. Molecular Analysis of Phr Peptide Processing in Bacillus subtilis†

    PubMed Central

    Stephenson, Sophie; Mueller, Christian; Jiang, Min; Perego, Marta

    2003-01-01

    In Bacillus subtilis, an export-import pathway regulates production of the Phr pentapeptide inhibitors of Rap proteins. Processing of the Phr precursor proteins into the active pentapeptide form is a key event in the initiation of sporulation and competence development. The PhrA (ARNQT) and PhrE (SRNVT) peptides inhibit the RapA and RapE phosphatases, respectively, whose activity is directed toward the Spo0F∼P intermediate response regulator of the sporulation phosphorelay. The PhrC (ERGMT) peptide inhibits the RapC protein acting on the ComA response regulator for competence with regard to DNA transformation. The structural organization of PhrA, PhrE, and PhrC suggested a role for type I signal peptidases in the processing of the Phr preinhibitor, encoded by the phr genes, into the proinhibitor form. The proinhibitor was then postulated to be cleaved to the active pentapeptide inhibitor by an additional enzyme. In this report, we provide evidence that Phr preinhibitor proteins are subject to only one processing event at the peptide bond on the amino-terminal end of the pentapeptide. This processing event is most likely independent of type I signal peptidase activity. In vivo and in vitro analyses indicate that none of the five signal peptidases of B. subtilis (SipS, SipT, SipU, SipV, and SipW) are indispensable for Phr processing. However, we show that SipV and SipT have a previously undescribed role in sporulation, competence, and cell growth. PMID:12897006

  2. Do early life cognitive ability and self-regulation skills explain socio-economic inequalities in academic achievement? An effect decomposition analysis in UK and Australian cohorts.

    PubMed

    Pearce, Anna; Sawyer, Alyssa C P; Chittleborough, Catherine R; Mittinty, Murthy N; Law, Catherine; Lynch, John W

    2016-09-01

    Socio-economic inequalities in academic achievement emerge early in life and are observed across the globe. Cognitive ability and "non-cognitive" attributes (such as self-regulation) are the focus of many early years' interventions. Despite this, little research has compared the contributions of early cognitive and self-regulation abilities as separate pathways to inequalities in academic achievement. We examined this in two nationally representative cohorts in the UK (Millennium Cohort Study, n = 11,168; 61% original cohort) and Australia (LSAC, n = 3028; 59% original cohort). An effect decomposition method was used to examine the pathways from socio-economic disadvantage (in infancy) to two academic outcomes: 'low' maths and literacy scores (based on bottom quintile) at age 7-9 years. Risk ratios (RRs, and bootstrap 95% confidence intervals) were estimated with binary regression for each pathway of interest: the 'direct effect' of socio-economic disadvantage on academic achievement (not acting through self-regulation and cognitive ability in early childhood), and the 'indirect effects' of socio-economic disadvantage acting via self-regulation and cognitive ability (separately). Analyses were adjusted for baseline and intermediate confounding. Children from less advantaged families were up to twice as likely to be in the lowest quintile of maths and literacy scores. Around two-thirds of this elevated risk was 'direct' and the majority of the remainder was mediated by early cognitive ability and not self-regulation. For example in LSAC: the RR for the direct pathway from socio-economic disadvantage to poor maths scores was 1.46 (95% CI: 1.17-1.79). The indirect effect of socio-economic disadvantage through cognitive ability (RR = 1.13 [1.06-1.22]) was larger than the indirect effect through self-regulation (1.05 [1.01-1.11]). Similar patterns were observed for both outcomes and in both cohorts. Policies to alleviate social inequality (e.g. child poverty

  3. New Hydrocarbon Degradation Pathways in the Microbial Metagenome from Brazilian Petroleum Reservoirs

    PubMed Central

    Sierra-García, Isabel Natalia; Correa Alvarez, Javier; Pantaroto de Vasconcellos, Suzan; Pereira de Souza, Anete; dos Santos Neto, Eugenio Vaz; de Oliveira, Valéria Maia

    2014-01-01

    Current knowledge of the microbial diversity and metabolic pathways involved in hydrocarbon degradation in petroleum reservoirs is still limited, mostly due to the difficulty in recovering the complex community from such an extreme environment. Metagenomics is a valuable tool to investigate the genetic and functional diversity of previously uncultured microorganisms in natural environments. Using a function-driven metagenomic approach, we investigated the metabolic abilities of microbial communities in oil reservoirs. Here, we describe novel functional metabolic pathways involved in the biodegradation of aromatic compounds in a metagenomic library obtained from an oil reservoir. Although many of the deduced proteins shared homology with known enzymes of different well-described aerobic and anaerobic catabolic pathways, the metagenomic fragments did not contain the complete clusters known to be involved in hydrocarbon degradation. Instead, the metagenomic fragments comprised genes belonging to different pathways, showing novel gene arrangements. These results reinforce the potential of the metagenomic approach for the identification and elucidation of new genes and pathways in poorly studied environments and contribute to a broader perspective on the hydrocarbon degradation processes in petroleum reservoirs. PMID:24587220

  4. Effects of Acanthopanax senticosus on Brain Injury Induced by Simulated Spatial Radiation in Mouse Model Based on Pharmacokinetics and Comparative Proteomics

    PubMed Central

    Cheng, Cuilin; Baranenko, Denis; Wang, Jiaping; Li, Yongzhi; Lu, Weihong

    2018-01-01

    The active compounds in Acanthopanax senticosus (AS) have different pharmacokinetic characteristics in mouse models. Cmax and AUC of Acanthopanax senticosus polysaccharides (ASPS) were significantly reduced in radiation-injured mice, suggesting that the blood flow of mouse was blocked or slowed, due to the pathological state of ischemia and hypoxia, which are caused by radiation. In contrast, the ability of various metabolizing enzymes to inactivate, capacity of biofilm transport decrease, and lessening of renal blood flow accounts for radiation, resulting in the accumulation of syringin and eleutheroside E in the irradiated mouse. Therefore, there were higher pharmacokinetic parameters—AUC, MRT, and t1/2 of the two compounds in radiation-injured mouse, when compared with normal mouse. In order to investigate the intrinsic mechanism of AS on radiation injury, AS extract’s protective effects on brain, the main part of mouse that suffered from radiation, were explored. The function of AS extract in repressing expression changes of radiation response proteins in prefrontal cortex (PFC) of mouse brain included tubulin protein family (α-, β-tubulin subunits), dihydropyrimidinase-related protein 2 (CRMP2), γ-actin, 14-3-3 protein family (14-3-3ζ, ε), heat shock protein 90β (HSP90β), and enolase 2. The results demonstrated the AS extract had positive effects on nerve cells’ structure, adhesion, locomotion, fission, and phagocytosis, through regulating various action pathways, such as Hippo, phagosome, PI3K/Akt (phosphatidylinositol 3 kinase/protein kinase B), Neurotrophin, Rap1 (Ras-related protein RAP-1A), gap junction glycolysis/gluconeogenesis, and HIF-1 (Hypoxia-inducible factor 1) signaling pathways to maintain normal mouse neurological activity. All of the results indicated that AS may be a promising alternative medicine for the treatment of radiation injury in mouse brain. It would be tested that whether the bioactive ingredients of AS could be

  5. What Can Causal Networks Tell Us about Metabolic Pathways?

    PubMed Central

    Blair, Rachael Hageman; Kliebenstein, Daniel J.; Churchill, Gary A.

    2012-01-01

    Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. The extent to which graphical models can recapitulate the architecture of an underlying biological processes is not well understood. We consider metabolic networks with known stoichiometry to address the fundamental question: “What can causal networks tell us about metabolic pathways?”. Using data from an Arabidopsis BaySha population and simulated data from dynamic models of pathway motifs, we assess our ability to reconstruct metabolic pathways using graphical models. Our results highlight the necessity of non-genetic residual biological variation for reliable inference. Recovery of the ordering within a pathway is possible, but should not be expected. Causal inference is sensitive to subtle patterns in the correlation structure that may be driven by a variety of factors, which may not emphasize the substrate-product relationship. We illustrate the effects of metabolic pathway architecture, epistasis and stochastic variation on correlation structure and graphical model-derived networks. We conclude that graphical models should be interpreted cautiously, especially if the implied causal relationships are to be used in the design of intervention strategies. PMID:22496633

  6. TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

    PubMed Central

    Cammareri, Patrizia; Vincent, David F; Hodder, Michael C; Ridgway, Rachel A; Murgia, Claudio; Nobis, Max; Campbell, Andrew D; Varga, Julia; Huels, David J; Subramani, Chithra; Prescott, Katie L H; Nixon, Colin; Hedley, Ann; Barry, Simon T; Greten, Florian R; Inman, Gareth J; Sansom, Owen J

    2017-01-01

    Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment. PMID:28622298

  7. Motor pathway convergence predicts syllable repertoire size in oscine birds

    PubMed Central

    Moore, Jordan M.; Székely, Tamás; Büki, József; DeVoogd, Timothy J.

    2011-01-01

    Behavioral specializations are frequently associated with expansions of the brain regions controlling them. This principle of proper mass spans sensory, motor, and cognitive abilities and has been observed in a wide variety of vertebrate species. Yet, it is unknown if this concept extrapolates to entire neural pathways or how selection on a behavioral capacity might otherwise shape circuit structure. We investigate these questions by comparing the songs and neuroanatomy of 49 species from 17 families of songbirds, which vary immensely in the number of unique song components they produce and possess a conserved neural network dedicated to this behavior. We find that syllable repertoire size is strongly related to the degree of song motor pathway convergence. Repertoire size is more accurately predicted by the number of neurons in higher motor areas relative to that in their downstream targets than by the overall number of neurons in the song motor pathway. Additionally, the convergence values along serial premotor and primary motor projections account for distinct portions of the behavioral variation. These findings suggest that selection on song has independently shaped different components of this hierarchical pathway, and they elucidate how changes in pathway structure could have underlain elaborations of this learned motor behavior. PMID:21918109

  8. Relative size of auditory pathways in symmetrically and asymmetrically eared owls.

    PubMed

    Gutiérrez-Ibáñez, Cristián; Iwaniuk, Andrew N; Wylie, Douglas R

    2011-01-01

    Owls are highly efficient predators with a specialized auditory system designed to aid in the localization of prey. One of the most unique anatomical features of the owl auditory system is the evolution of vertically asymmetrical ears in some species, which improves their ability to localize the elevational component of a sound stimulus. In the asymmetrically eared barn owl, interaural time differences (ITD) are used to localize sounds in azimuth, whereas interaural level differences (ILD) are used to localize sounds in elevation. These two features are processed independently in two separate neural pathways that converge in the external nucleus of the inferior colliculus to form an auditory map of space. Here, we present a comparison of the relative volume of 11 auditory nuclei in both the ITD and the ILD pathways of 8 species of symmetrically and asymmetrically eared owls in order to investigate evolutionary changes in the auditory pathways in relation to ear asymmetry. Overall, our results indicate that asymmetrically eared owls have much larger auditory nuclei than owls with symmetrical ears. In asymmetrically eared owls we found that both the ITD and ILD pathways are equally enlarged, and other auditory nuclei, not directly involved in binaural comparisons, are also enlarged. We suggest that the hypertrophy of auditory nuclei in asymmetrically eared owls likely reflects both an improved ability to precisely locate sounds in space and an expansion of the hearing range. Additionally, our results suggest that the hypertrophy of nuclei that compute space may have preceded that of the expansion of the hearing range and evolutionary changes in the size of the auditory system occurred independently of phylogeny. Copyright © 2011 S. Karger AG, Basel.

  9. Computational identification of signalling pathways in Plasmodium falciparum.

    PubMed

    Oyelade, Jelili; Ewejobi, Itunu; Brors, Benedikt; Eils, Roland; Adebiyi, Ezekiel

    2011-06-01

    Malaria is one of the world's most common and serious diseases causing death of about 3 million people each year. Its most severe occurrence is caused by the protozoan Plasmodium falciparum. Reports have shown that the resistance of the parasite to existing drugs is increasing. Therefore, there is a huge and urgent need to discover and validate new drug or vaccine targets to enable the development of new treatments for malaria. The ability to discover these drug or vaccine targets can only be enhanced from our deep understanding of the detailed biology of the parasite, for example how cells function and how proteins organize into modules such as metabolic, regulatory and signal transduction pathways. It has been noted that the knowledge of signalling transduction pathways in Plasmodium is fundamental to aid the design of new strategies against malaria. This work uses a linear-time algorithm for finding paths in a network under modified biologically motivated constraints. We predicted several important signalling transduction pathways in Plasmodium falciparum. We have predicted a viable signalling pathway characterized in terms of the genes responsible that may be the PfPKB pathway recently elucidated in Plasmodium falciparum. We obtained from the FIKK family, a signal transduction pathway that ends up on a chloroquine resistance marker protein, which indicates that interference with FIKK proteins might reverse Plasmodium falciparum from resistant to sensitive phenotype. We also proposed a hypothesis that showed the FIKK proteins in this pathway as enabling the resistance parasite to have a mechanism for releasing chloroquine (via an efflux process). Furthermore, we also predicted a signalling pathway that may have been responsible for signalling the start of the invasion process of Red Blood Cell (RBC) by the merozoites. It has been noted that the understanding of this pathway will give insight into the parasite virulence and will facilitate rational vaccine design

  10. The function of BTG3 in colorectal cancer cells and its possible signaling pathway.

    PubMed

    Lv, Chi; Wang, Heling; Tong, Yuxin; Yin, Hongzhuan; Wang, Dalu; Yan, Zhaopeng; Liang, Yichao; Wu, Di; Su, Qi

    2018-02-01

    B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior. BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression. BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data. BTG3 expression might

  11. Reaction mechanism studies towards effective fabrication of lithium-rich anti-perovskites Li 3OX (X=Cl, Br)

    DOE PAGES

    Li, Shuai; Zhu, Jinlong; Wang, Yonggang; ...

    2015-12-10

    Lithium-rich Anti-perovskite (LiRAP), with general formula Li 3OX (X = Cl, Br, I), and recently reported as superionic conductors with 3-dimensional Li + migrating channels, is emerging as a promising candidate for solid electrolyte of all-solid-state LIBs. But, it is still difficult to fabricate pure LiRAP due to the difficulty of the phase formation and moisture-sensitive nature of the products. In this work, we thoroughly studied the formation mechanism of Li 3OCl and Li 3OBr in various solid state reaction routes. We developed different experimental strategies in order to improve the syntheses, in purposes of improved phase stability and large-scalemore » production of LiRAP. One feasible method is to use strongly reductive agents Li metal or LiH to eliminate OH species. The results show that LiH is more effective than Li metal because of negatively charged H - and uniform reaction. The other well-established method is using Li 2O and LiX mixture as reagents to preventing OH phase at the beginning, and using protected ball milling to make fine powders and hence active the reaction. Finally, IR spectroscopy, thermal analyses and first-principle calculation were performed to give indications on the reaction pathway.« less

  12. Childhood Cognitive Ability and Age-Related Changes in Physical Capability From Midlife: Findings From a British Birth Cohort Study.

    PubMed

    Cooper, Rachel; Richards, Marcus; Kuh, Diana

    2017-09-01

    The aim of the study was to test the hypothesis that higher childhood cognitive ability is associated with reduced risk of decline in physical capability in late midlife. Participants were 1954 men and women from the Medical Research Council National Survey of Health and Development with complete data on cognitive ability at age of 15 years and measures of grip strength and chair rise speed at ages of 53 and 60 to 64 years. Using multinomial logistic regression, associations of childhood cognitive ability with categories of change in grip strength and chair rise speed (i.e., decline, stable high, stable low, reference) were investigated. Adjustments were made for potential confounders from early life and adult mediators including health behaviors, educational level, and cognitive ability at age of 53 years. Higher childhood cognitive scores were associated with reduced risks of decline in grip strength and chair rise speed, for example, the sex-adjusted relative-risk ratio of decline (versus reference) in grip strength per 1SD increase in childhood cognitive score was 0.82 (95% confidence interval = 0.73-0.92). Higher childhood cognitive scores were also associated with reduced risk of stable low and increased likelihood of stable high chair rise speed. These findings suggest that childhood cognitive ability may be related to decline in physical capability in late midlife. A number of life course pathways are implicated, including those linking childhood and adult cognitive ability. Future research aiming to identify new opportunities to prevent or minimize age-related declines in physical capability may benefit from considering the potential role of neurodevelopmental as well as neurodegenerative pathways.

  13. [Visual perceptual abilities of children with low motor abilities--a pilot study].

    PubMed

    Werpup-Stüwe, Lina; Petermann, Franz

    2015-01-01

    The results of many studies show visual perceptual deficits in children with low motor abilities. This study aims to indicate the correlation between visual-perceptual and motor abilities. The correlation of visual-perceptual and motor abilities of 41 children is measured by using the German versions of the Developmental Test of Visual Perception--Adolescent and Adult (DTVP-A) and the Movement Assessment Battery for Children--Second Edition (M-ABC-2). The visual-perceptual abilities of children with low motor abilities (n=21) are also compared to the visual-perceptual abilities of children with normal motor abilities (the control group, n=20). High correlations between the visual-perceptual and motor abilities are found. The perceptual abilities of the groups differ significantly. Nearly half of the children with low motor abilities show visual-perceptual deficits. Visual perceptual abilities of children suffering coordination disorders should always be assessed. The DTVP-A is useful, because it provides the possibilities to compare motor-reduced visual-perceptual abilities and visualmotor integration abilities and to estimate the deficit's degree.

  14. Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.

    PubMed

    Su, Ting; Ludwig, Michael Z; Xu, Jiajie; Fehon, Richard G

    2017-03-13

    The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. MinePath: Mining for Phenotype Differential Sub-paths in Molecular Pathways

    PubMed Central

    Koumakis, Lefteris; Kartsaki, Evgenia; Chatzimina, Maria; Zervakis, Michalis; Vassou, Despoina; Marias, Kostas; Moustakis, Vassilis; Potamias, George

    2016-01-01

    Pathway analysis methodologies couple traditional gene expression analysis with knowledge encoded in established molecular pathway networks, offering a promising approach towards the biological interpretation of phenotype differentiating genes. Early pathway analysis methodologies, named as gene set analysis (GSA), view pathways just as plain lists of genes without taking into account either the underlying pathway network topology or the involved gene regulatory relations. These approaches, even if they achieve computational efficiency and simplicity, consider pathways that involve the same genes as equivalent in terms of their gene enrichment characteristics. Most recent pathway analysis approaches take into account the underlying gene regulatory relations by examining their consistency with gene expression profiles and computing a score for each profile. Even with this approach, assessing and scoring single-relations limits the ability to reveal key gene regulation mechanisms hidden in longer pathway sub-paths. We introduce MinePath, a pathway analysis methodology that addresses and overcomes the aforementioned problems. MinePath facilitates the decomposition of pathways into their constituent sub-paths. Decomposition leads to the transformation of single-relations to complex regulation sub-paths. Regulation sub-paths are then matched with gene expression sample profiles in order to evaluate their functional status and to assess phenotype differential power. Assessment of differential power supports the identification of the most discriminant profiles. In addition, MinePath assess the significance of the pathways as a whole, ranking them by their p-values. Comparison results with state-of-the-art pathway analysis systems are indicative for the soundness and reliability of the MinePath approach. In contrast with many pathway analysis tools, MinePath is a web-based system (www.minepath.org) offering dynamic and rich pathway visualization functionality, with the

  16. MinePath: Mining for Phenotype Differential Sub-paths in Molecular Pathways.

    PubMed

    Koumakis, Lefteris; Kanterakis, Alexandros; Kartsaki, Evgenia; Chatzimina, Maria; Zervakis, Michalis; Tsiknakis, Manolis; Vassou, Despoina; Kafetzopoulos, Dimitris; Marias, Kostas; Moustakis, Vassilis; Potamias, George

    2016-11-01

    Pathway analysis methodologies couple traditional gene expression analysis with knowledge encoded in established molecular pathway networks, offering a promising approach towards the biological interpretation of phenotype differentiating genes. Early pathway analysis methodologies, named as gene set analysis (GSA), view pathways just as plain lists of genes without taking into account either the underlying pathway network topology or the involved gene regulatory relations. These approaches, even if they achieve computational efficiency and simplicity, consider pathways that involve the same genes as equivalent in terms of their gene enrichment characteristics. Most recent pathway analysis approaches take into account the underlying gene regulatory relations by examining their consistency with gene expression profiles and computing a score for each profile. Even with this approach, assessing and scoring single-relations limits the ability to reveal key gene regulation mechanisms hidden in longer pathway sub-paths. We introduce MinePath, a pathway analysis methodology that addresses and overcomes the aforementioned problems. MinePath facilitates the decomposition of pathways into their constituent sub-paths. Decomposition leads to the transformation of single-relations to complex regulation sub-paths. Regulation sub-paths are then matched with gene expression sample profiles in order to evaluate their functional status and to assess phenotype differential power. Assessment of differential power supports the identification of the most discriminant profiles. In addition, MinePath assess the significance of the pathways as a whole, ranking them by their p-values. Comparison results with state-of-the-art pathway analysis systems are indicative for the soundness and reliability of the MinePath approach. In contrast with many pathway analysis tools, MinePath is a web-based system (www.minepath.org) offering dynamic and rich pathway visualization functionality, with the

  17. Fluorescent nanocolloids for differential labeling of the endocytic pathway and drug delivery applications

    NASA Astrophysics Data System (ADS)

    Delehanty, James B.; Spillmann, Christopher M.; Naciri, Jawad; Algar, W. Russ; Ratna, Banahalli R.; Medintz, Igor L.

    2013-02-01

    The demonstration of fine control over nanomaterials within biological systems, particularly in live cells, is integral for the successful implementation of nanoparticles (NPs) in biomedical applications. Here, we show the ability to differentially label the endocytic pathway of mammalian cells in a spatiotemporal manner utilizing fluorescent nanocolloids (NCs) doped with a perylene-based dye. EDC-based conjugation of green- and red-emitting NCs to the iron transport protein transferrin resulted in stable bioconjugates that were efficiently endocytosed by HEK 293T/17 cells. The staggered delivery of the bioconjugates allowed for the time-resolved, differential labeling of distinct vesicular compartments along the endocytic pathway in a nontoxic manner. We further demonstrated the ability of the NCs to be impregnated with the anticancer therapeutic, doxorubicin. Delivery of the drug-doped nanoconjugates resulted in the intracellular release and nuclear accumulation of doxorubicin in a time- and dose-dependent manner. We discuss our results in the context of the utility of such materials for NP-mediated drug delivery applications.

  18. Pancreatic Cancer Cells Enhance the Ability of Collagen Internalization during Epithelial–Mesenchymal Transition

    PubMed Central

    Ikenaga, Naoki; Ohuchida, Kenoki; Mizumoto, Kazuhiro; Akagawa, Shin; Fujiwara, Kenji; Eguchi, Daiki; Kozono, Shingo; Ohtsuka, Takao; Takahata, Shunichi; Tanaka, Masao

    2012-01-01

    Background Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial–mesenchymal transition (EMT). Methodology/Principal Findings We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P<0.05). Expression of Endo180, a collagen uptake receptor, was high in mesenchymal pancreatic cancer cell lines, as determined by EMT marker expression (P<0.01). Quantitative RT-PCR and western blot analyses showed that Endo180 expression was also increased by EMT induction in SUIT-2 and KP-2 cells. Endo180 knockdown by RNA interference attenuated the collagen uptake (P<0.01) and invasive abilities (P<0.05) of SUIT-2 and KP-2 cells. Conclusions/Significance Pancreatic cancer cells are capable of collagen internalization, which is enhanced by EMT. This ECM clearance system may be a novel mechanism for cellular invasion and a potential therapeutic target in pancreatic cancer. PMID:22792318

  19. Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model.

    PubMed

    Ham, Sangwoo; Lee, Yun-Il; Jo, Minkyung; Kim, Hyojung; Kang, Hojin; Jo, Areum; Lee, Gum Hwa; Mo, Yun Jeong; Park, Sang Chul; Lee, Yun Song; Shin, Joo-Ho; Lee, Yunjong

    2017-04-03

    Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.

  20. Use of reclaimed asphalt pavement in concrete pavement slabs.

    DOT National Transportation Integrated Search

    2012-10-01

    This study evaluated the feasibiltiy of using RAP as aggregate replacement in concrete for use in pavement. Four different RAPs from FDOT approved RAP sources were used. Concrete mixtures with 0%, 20%, 40%, 70%, and 100% aggregate replacement by RAP ...

  1. Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies

    PubMed Central

    Manitz, Juliane; Burger, Patricia; Amos, Christopher I.; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike

    2017-01-01

    The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility. PMID:28785300

  2. Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies.

    PubMed

    Friedrichs, Stefanie; Manitz, Juliane; Burger, Patricia; Amos, Christopher I; Risch, Angela; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike; Hofner, Benjamin

    2017-01-01

    The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility.

  3. Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways.

    PubMed

    Wang, Q; Shi, C-J; Lv, S-H

    2017-03-30

    Different pathways act synergistically to participate in many biological processes. Thus, the purpose of our study was to extract dysregulated pathways to investigate the pathogenesis of colorectal cancer (CRC) based on the functional dependency among pathways. Protein-protein interaction (PPI) information and pathway data were retrieved from STRING and Reactome databases, respectively. After genes were aligned to the pathways, each pathway activity was calculated using the principal component analysis (PCA) method, and the seed pathway was discovered. Subsequently, we constructed the pathway interaction network (PIN), where each node represented a biological pathway based on gene expression profile, PPI data, as well as pathways. Dysregulated pathways were then selected from the PIN according to classification performance and seed pathway. A PIN including 11,960 interactions was constructed to identify dysregulated pathways. Interestingly, the interaction of mRNA splicing and mRNA splicing-major pathway had the highest score of 719.8167. Maximum change of the activity score between CRC and normal samples appeared in the pathway of DNA replication, which was selected as the seed pathway. Starting with this seed pathway, a pathway set containing 30 dysregulated pathways was obtained with an area under the curve score of 0.8598. The pathway of mRNA splicing, mRNA splicing-major pathway, and RNA polymerase I had the maximum genes of 107. Moreover, we found that these 30 pathways had crosstalks with each other. The results suggest that these dysregulated pathways might be used as biomarkers to diagnose CRC.

  4. Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1.

    PubMed

    Parmo-Cabañas, Marisa; García-Bernal, David; García-Verdugo, Rosa; Kremer, Leonor; Márquez, Gabriel; Teixidó, Joaquin

    2007-08-01

    The alpha4beta1 integrin is expressed on thymocytes and mediates cell attachment to its ligands CS-1/fibronectin (CS-1/FN) and VCAM-1 in the thymus. The chemokine CCL25 is highly expressed in the thymus, where it binds to its receptor CCR9 on thymocytes promoting migration and activation. We show here that alpha4beta1 and CCR9 are coexpressed mainly on double- and single-positive thymocytes and that CCL25 strongly stimulates CD4(+)CD8(+) and CD4(+)CD8(-) adhesion to CS-1/FN and VCAM-1. CCL25 rapidly activated the GTPases Rac and Rap1 on thymocytes, and this activation was required for stimulation of adhesion, as detected using the CCR9(+)/alpha4beta1(+) human T cell line Molt-4. To study the role on CCL25-stimulated adhesion of the Rac downstream effector Wiskott-Aldrich syndrome protein family verproline-homologous protein 2 (WAVE2) as well as of Rap1-GTP-interacting proteins, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP-interacting adapter molecule (RIAM), we knocked down their expression and tested transfectant attachment to alpha4beta1 ligands. We found that WAVE2 and RAPL but not RIAM were required for efficient triggering by CCL25 of T cell adhesion to CS-1/FN and VCAM-1. Although Rac and Rap1 activation was required during early steps of T cell adhesion stimulated by CCL25, WAVE2 was needed for the development of actin-dependent T cell spreading subsequent to adhesion strengthening but not during initial alpha4beta1-ligand interactions. These results suggest that regulation by CCL25 of adhesion of thymocyte subpopulations mediated by alpha4beta1 could contribute to control their trafficking in the thymus during maturation, and identify Rac-WAVE2 and Rap1-RAPL as pathways whose activation is required in inside-out signaling, leading to stimulated adhesion.

  5. Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning.

    PubMed

    Dunovan, Kyle; Verstynen, Timothy

    2016-01-01

    The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning.

  6. Graphic Abilities in Relation to Mathematical and Scientific Ability in Adolescents

    ERIC Educational Resources Information Center

    Stavridou, Fotini; Kakana, Domna

    2008-01-01

    Background: The study investigated a small range of cognitive abilities, related to visual-spatial intelligence, in adolescents. This specific range of cognitive abilities was termed "graphic abilities" and defined as a range of abilities to visualise and think in three dimensions, originating in the domain of visual-spatial…

  7. Epigenetic Telomere Protection by Drosophila DNA Damage Response Pathways

    PubMed Central

    Oikemus, Sarah R; Queiroz-Machado, Joana; Lai, KuanJu; McGinnis, Nadine; Sunkel, Claudio; Brodsky, Michael H

    2006-01-01

    Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms

  8. Epigenetic telomere protection by Drosophila DNA damage response pathways.

    PubMed

    Oikemus, Sarah R; Queiroz-Machado, Joana; Lai, KuanJu; McGinnis, Nadine; Sunkel, Claudio; Brodsky, Michael H

    2006-05-01

    Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms.

  9. Recycled asphalt pavement - fly ash geopolymers as a sustainable pavement base material: Strength and toxic leaching investigations.

    PubMed

    Hoy, Menglim; Horpibulsuk, Suksun; Rachan, Runglawan; Chinkulkijniwat, Avirut; Arulrajah, Arul

    2016-12-15

    In this research, a low-carbon stabilization method was studied using Recycled Asphalt Pavement (RAP) and Fly Ash (FA) geopolymers as a sustainable pavement material. The liquid alkaline activator (L) is a mixture of sodium silicate (Na 2 SiO 3 ) and sodium hydroxide (NaOH), and high calcium FA is used as a precursor to synthesize the FA-RAP geopolymers. Unconfined Compressive Strength (UCS) of RAP-FA blend and RAP-FA geopolymer are investigated and compared with the requirement of the national road authorities of Thailand. The leachability of the heavy metals is measured by Toxicity Characteristic Leaching Procedure (TCLP) and compared with international standards. The Scanning Electron Microscopy (SEM) analysis of RAP-FA blend indicates the Calcium Aluminate (Silicate) Hydrate (C-A-S-H) formation, which is due to a reaction between the high calcium in RAP and high silica and alumina in FA. The low geopolymerization products (N-A-S-H) of RAP-FA geopolymer at NaOH/Na 2 SiO 3 =100:0 are detected at the early 7days of curing, hence its UCS is lower than that of RAP-FA blend. The 28-day UCS of RAP-FA geopolymers at various NaOH/Na 2 SiO 3 ratios are significantly higher than that of the RAP-FA blend, which can be attributed to the development of geopolymerization reactions. With the input of Na 2 SiO 3 , the highly soluble silica from Na 2 SiO 3 reacted with leached silica and alumina from FA and RAP and with free calcium from FA and RAP; hence the coexistence of N-A-S-H gel and C-A-S-H products. Therefore, the 7-day UCS values of RAP-FA geopolymers increase with decreasing NaOH/Na 2 SiO 3 ratio. TCLP results demonstrated that there is no environmental risk for both RAP-FA blends and RAP-FA geopolymers in road construction. The geopolymer binder reduces the leaching of heavy metal in RAP-FA mixture. The outcomes from this research will promote the move toward increased applications of recycled materials in a sustainable manner in road construction. Copyright © 2016

  10. Work ability assessment in a worker population: comparison and determinants of Work Ability Index and Work Ability score.

    PubMed

    El Fassi, Mehdi; Bocquet, Valery; Majery, Nicole; Lair, Marie Lise; Couffignal, Sophie; Mairiaux, Philippe

    2013-04-08

    Public authorities in European countries are paying increasing attention to the promotion of work ability throughout working life and the best method to monitor work ability in populations of workers is becoming a significant question. The present study aims to compare the assessment of work ability based on the use of the Work Ability Index (WAI), a 7-item questionnaire, with another one based on the use of WAI's first item, which consists in the worker's self-assessment of his/her current work ability level as opposed to his/her lifetime best, this single question being termed "Work Ability score" (WAS). Using a database created by an occupational health service, the study intends to answer the following questions: could the assessment of work ability be based on a single-item measure and which are the variables significantly associated with self-reported work ability among those systematically recorded by the occupational physician during health examinations? A logistic regression model was used in order to estimate the probability of observing "poor" or "moderate" WAI levels depending on age, gender, body mass index, smoking status, position held, firm size and diseases reported by the worker in a population of workers aged 40 to 65 and examined between January 2006 and June 2010 (n=12389). The convergent validity between WAS and WAI was statistically significant (rs=0.63). In the multivariable model, age (p<0.001), reported diseases (OR=1.13, 95%CI [1.11-1.15]) and holding a position mostly characterized by physical activity (OR=1.67, 95%CI [1.49-1.87]) increased the probability of reporting moderate or poor work ability. A work position characterized by the predominance of mental activity (OR=0.71, 95%CI [0.61-0.84]) had a favourable impact on work ability. These relations were observed regardless of the work ability measurement tool used. The convergent validity and the similarity in results between WAI and WAS observed in a large population of employed

  11. Methotrexate Is a JAK/STAT Pathway Inhibitor

    PubMed Central

    Thomas, Sally; Fisher, Katherine H.; Snowden, John A.; Danson, Sarah J.; Brown, Stephen; Zeidler, Martin P.

    2015-01-01

    Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low

  12. Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

    PubMed Central

    Hebert, Mark; Licursi, Maria; Jensen, Brittany; Baker, Ashley; Milway, Steve; Malsbury, Charles; Grant, Virginia L.; Adamec, Robert; Hirasawa, Michiru; Blundell, Jacqueline

    2014-01-01

    Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy. PMID:24787262

  13. Autophagy modulates endoplasmic reticulum stress-induced cell death in podocytes: A protective role

    PubMed Central

    Cheng, Yu-Chi; Chang, Jer-Ming; Chen, Chien-An

    2015-01-01

    Endoplasmic reticulum stress occurs in a variety of patho-physiological mechanisms and there has been great interest in managing this pathway for the treatment of clinical diseases. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In this study, podocytes were exposed to tunicamycin and thapsigargin to induce endoplasmic reticulum stress. Thapsigargin/tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansylcadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on endoplasmic reticulum stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic reticulum stress-induced cell death was decreased at 6 h, but was not reduced at 24 h after Rap+TG or Rap+TM treatment. In contrast, endoplasmic reticulum stress-induced cell death increased at 6 and 24 h after 3-MA+TG or 3-MA+TM treatment. Our study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. In summary, autophagy helps the podocytes from cell death and may contribute to sustain the longevity as a highly differentiated cell lineage. PMID:25322957

  14. Differential Effect of Zoledronic Acid on Human Vascular Smooth Muscle Cells

    PubMed Central

    Albadawi, Hassan; Haurani, Mounir J.; Oklu, Rahmi; Trubiano, Jordan P.; Laub, Peter J.; Yoo, Hyung-Jin; Watkins, Michael T.

    2012-01-01

    Introduction The activation of human vascular smooth muscle cell proliferation, adhesion and migration is essential for intimal hyperplasia formation. These experiments were designed to test whether Zoledronic Acid (ZA) would modulate indices of human smooth muscle cell activation, exert differential effects on proliferating vs. quiescent cells and determine whether these effects were dependent on GTPase binding proteins prenylation. ZA was chosen for testing in these experiments because it is clinically used in humans with cancer, and has been shown to modulate rat smooth muscle cell proliferation and migration. Methods Human aortic smooth muscle cells (HASMC) were cultured under either proliferating or growth arrest (quiescent) conditions in the presence or absence of ZA for 48 hours, whereupon the effect of ZA on HASMC proliferation, cellular viability, metabolic activity and membrane integrity were compared. In addition, the effect of ZA on adhesion and migration were assessed in proliferating cells. The effect of increased concentration of ZA on the mevalonate pathway and genomic/cellular stress related poly ADP Ribose polymerase (PARP) enzyme activity were assessed using the relative prenylation of Rap-1A/B protein and the formation of poly ADP- ribosylated proteins (PAR) respectively. Results There was a dose dependent inhibition of cellular proliferation, adhesion and migration following ZA treatment. ZA treatment decreased indices of cellular viability and significantly increased membrane injury in proliferating vs. quiescent cells. This was correlated with the appearance of unprenylated Rap-1A protein and dose dependent down regulation of PARP activity. Conclusions These data suggest that ZA is effective in inhibiting HASMC proliferation, adhesion and migration which coincide with the appearance of unprenylated RAP-1A/B protein, thereby suggesting that the mevalonate pathway may play a role in the inhibition of HASMC activation. PMID:23164362

  15. Strength of Temporal White Matter Pathways Predicts Semantic Learning.

    PubMed

    Ripollés, Pablo; Biel, Davina; Peñaloza, Claudia; Kaufmann, Jörn; Marco-Pallarés, Josep; Noesselt, Toemme; Rodríguez-Fornells, Antoni

    2017-11-15

    Learning the associations between words and meanings is a fundamental human ability. Although the language network is cortically well defined, the role of the white matter pathways supporting novel word-to-meaning mappings remains unclear. Here, by using contextual and cross-situational word learning, we tested whether learning the meaning of a new word is related to the integrity of the language-related white matter pathways in 40 adults (18 women). The arcuate, uncinate, inferior-fronto-occipital and inferior-longitudinal fasciculi were virtually dissected using manual and automatic deterministic fiber tracking. Critically, the automatic method allowed assessing the white matter microstructure along the tract. Results demonstrate that the microstructural properties of the left inferior-longitudinal fasciculus predict contextual learning, whereas the left uncinate was associated with cross-situational learning. In addition, we identified regions of special importance within these pathways: the posterior middle temporal gyrus, thought to serve as a lexical interface and specifically related to contextual learning; the anterior temporal lobe, known to be an amodal hub for semantic processing and related to cross-situational learning; and the white matter near the hippocampus, a structure fundamental for the initial stages of new-word learning and, remarkably, related to both types of word learning. No significant associations were found for the inferior-fronto-occipital fasciculus or the arcuate. While previous results suggest that learning new phonological word forms is mediated by the arcuate fasciculus, these findings show that the temporal pathways are the crucial neural substrate supporting one of the most striking human abilities: our capacity to identify correct associations between words and meanings under referential indeterminacy. SIGNIFICANCE STATEMENT The language-processing network is cortically (i.e., gray matter) well defined. However, the role of the

  16. d-Xylose Degradation Pathway in the Halophilic Archaeon Haloferax volcanii

    PubMed Central

    Johnsen, Ulrike; Dambeck, Michael; Zaiss, Henning; Fuhrer, Tobias; Soppa, Jörg; Sauer, Uwe; Schönheit, Peter

    2009-01-01

    The pathway of d-xylose degradation in archaea is unknown. In a previous study we identified in Haloarcula marismortui the first enzyme of xylose degradation, an inducible xylose dehydrogenase (Johnsen, U., and Schönheit, P. (2004) J. Bacteriol. 186, 6198–6207). Here we report a comprehensive study of the complete d-xylose degradation pathway in the halophilic archaeon Haloferax volcanii. The analyses include the following: (i) identification of the degradation pathway in vivo following 13C-labeling patterns of proteinogenic amino acids after growth on [13C]xylose; (ii) identification of xylose-induced genes by DNA microarray experiments; (iii) characterization of enzymes; and (iv) construction of in-frame deletion mutants and their functional analyses in growth experiments. Together, the data indicate that d-xylose is oxidized exclusively to the tricarboxylic acid cycle intermediate α-ketoglutarate, involving d-xylose dehydrogenase (HVO_B0028), a novel xylonate dehydratase (HVO_B0038A), 2-keto-3-deoxyxylonate dehydratase (HVO_B0027), and α-ketoglutarate semialdehyde dehydrogenase (HVO_B0039). The functional involvement of these enzymes in xylose degradation was proven by growth studies of the corresponding in-frame deletion mutants, which all lost the ability to grow on d-xylose, but growth on glucose was not significantly affected. This is the first report of an archaeal d-xylose degradation pathway that differs from the classical d-xylose pathway in most bacteria involving the formation of xylulose 5-phosphate as an intermediate. However, the pathway shows similarities to proposed oxidative pentose degradation pathways to α-ketoglutarate in few bacteria, e.g. Azospirillum brasilense and Caulobacter crescentus, and in the archaeon Sulfolobus solfataricus. PMID:19584053

  17. Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

    PubMed Central

    Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

    2016-01-01

    The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

  18. Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

    PubMed

    Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

    2017-06-01

    Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RP<0.01 were defined as critical pathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RP<0.01, and the top 10 pathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing

  19. "Rap Universal": Using Multimodal Media Production to Develop ICT Literacies

    ERIC Educational Resources Information Center

    Turner, K. C. Nat

    2011-01-01

    Through a multimodal media production literacy intervention in an extended-day program, culturally and linguistically diverse youth developed valuable information and communication technology literacies, including: (1) Specific how-to skills useful in future academic, professional, social, and civic contexts; (2) Abilities to critically interpret…

  20. Dependence of prevalence of contiguous pathways in proteins on structural complexity.

    PubMed

    Thayer, Kelly M; Galganov, Jesse C; Stein, Avram J

    2017-01-01

    Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible. A major difficulty for testing the two methods is the ability to definitively determine that a residue is directly involved in allosteric signal transduction. Statistical Coupling Analysis (SCA) is a method that has been successful at predicting pathways, and experimental tests involving mutagenesis or domain substitution provide the best available evidence of signaling pathways. However, ascertaining energetic pathways which need not be contiguous is far more difficult. To date, simple estimates of the statistical significance of a pathway in a protein remain to be established. The focus of this work is to estimate such benchmarks for the statistical significance of contiguous pathways for the null model of selecting residues at random. We found that when 20% of residues in proteins are randomly selected, contiguous pathways at the 6 Å cutoff level were found with success rates of 51% in PDZ, 30% in p53, and 3% in MutS. The results suggest that the significance of pathways may have system specific factors involved. Furthermore, the possible existence of false positives for contiguous pathways implies that signaling could be occurring via alternate routes including those consistent with the energetic landscape model.

  1. Auditory agnosia due to long-term severe hydrocephalus caused by spina bifida - specific auditory pathway versus nonspecific auditory pathway.

    PubMed

    Zhang, Qing; Kaga, Kimitaka; Hayashi, Akimasa

    2011-07-01

    A 27-year-old female showed auditory agnosia after long-term severe hydrocephalus due to congenital spina bifida. After years of hydrocephalus, she gradually suffered from hearing loss in her right ear at 19 years of age, followed by her left ear. During the time when she retained some ability to hear, she experienced severe difficulty in distinguishing verbal, environmental, and musical instrumental sounds. However, her auditory brainstem response and distortion product otoacoustic emissions were largely intact in the left ear. Her bilateral auditory cortices were preserved, as shown by neuroimaging, whereas her auditory radiations were severely damaged owing to progressive hydrocephalus. Although she had a complete bilateral hearing loss, she felt great pleasure when exposed to music. After years of self-training to read lips, she regained fluent ability to communicate. Clinical manifestations of this patient indicate that auditory agnosia can occur after long-term hydrocephalus due to spina bifida; the secondary auditory pathway may play a role in both auditory perception and hearing rehabilitation.

  2. Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy.

    PubMed

    Wang, Huiqiang; Li, Ke; Ma, Linlin; Wu, Shuo; Hu, Jin; Yan, Haiyan; Jiang, Jiandong; Li, Yuhuan

    2017-01-11

    The MEK-ERK signaling pathway and autophagy play an important role for enterovirus71(EV71) replication. Inhibition of MEK-ERK signaling pathway and autophagy is shown to impair EV71 replication. Berberine (BBR), an isoquinoline alkaloid isolated from Berberis vulgaris L., has been reported to have ability to regulate this signaling pathway and autophagy. Herein, we want to determine whether berberine can inhibit EV71 infection by downregulating the MEK/ERK signaling pathway and autophagy. The antiviral effect of berberine was determined by cytopathic effect (CPE) assay, western blotting assay and qRT-PCR assay. The mechanism of BBR anti-virus was determined by western blotting assay and immunofluorescence assay. We showed that berberine does-dependently reduced EV71 RNA and protein synthesis, which was, at least in part, the result of inhibition of activation of MEK/ERK signaling pathway. Furthermore, we found that berberine suppressed the EV71-induced autophagy by activating AKT protein and inhibiting the phosphorylation of JNK and PI3KIII. BBR inhibited EV71 replication by downregulating autophagy and MEK/ERK signaling pathway. These findings suggest that BBR may be a potential agent or supplement against EV71 infection.

  3. Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning

    PubMed Central

    Dunovan, Kyle; Verstynen, Timothy

    2016-01-01

    The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning. PMID:27047328

  4. Cognitive abilities and motivational processes in high school students' science achievement and engagement

    NASA Astrophysics Data System (ADS)

    Lau, Shun

    The dissertation presents two analytic approaches, a variable-centered and person-centered approach, to investigating holistic patterns of the cognitive, motivational, and affective correlates of science achievement and engagement in a sample of 491 10th and 11th grade high-school students. Building on Snow's (1989) idea of two pathways to achievement outcomes, Study 1 adopted a variable-centered approach to examining how cognitive and motivational factors associated with the performance and commitment pathways, respectively, contributed to the prediction of achievement outcomes in science. Results of hierarchical regression analyses showed that (a) students' cognitive abilities were the strongest predictors of their performance in science as measured by standardized test scores; (b) motivational processes enhanced the predictive validity for science test scores and grades beyond the variance accounted for by ability and demography; (c) motivational processes were the strongest predictors of students' commitment to science in the form of situational engagement and anticipated choices of science-related college majors and careers; and (d) competence beliefs served as a point of contact between the performance and commitment pathways. These results are consistent with Snow's (1989) conjecture that both performance and commitment pathway-related factors are necessary for understanding the full range of person-level inputs to achievement outcomes. Study 2 adopted a person-centered approach to examining holistic organizations of psychological factors within individuals and their relations to science achievement and engagement. Four types of students characterized by unique configurations of cognitive, motivational, and affective attributes were identified in both the male and female subsamples using inverse factor analysis. Type membership was found to distinguish students in various indicators of science achievement and engagement. Two of the four types were also found

  5. Descending pathways controlling visually guided updating of reaching in cats.

    PubMed

    Pettersson, L-G; Perfiliev, S

    2002-10-01

    This study uses a previously described paradigm (Pettersson et al., 1997) to investigate the ability of cats to change the direction of ongoing reaching when the target is shifted sideways; the effect on the switching latency of spinal cord lesions was investigated. Large ventral lesions transecting the ventral funicle and the ventral half of the lateral funicle gave a 20-30 ms latency prolongation of switching in the medial (right) direction, but less prolongation of switching directed laterally (left), and in one cat the latencies of switching directed laterally were unchanged. It may be inferred that the command for switching in the lateral direction can be mediated by the dorsally located cortico- and rubrospinal tracts whereas the command for short-latency switching in the medial direction is mediated by ventral pathways. A restricted ventral lesion transecting the tectospinal pathway did not change the switching latency. Comparison of different ventral lesions revealed prolongation of the latency if the lesion included a region extending dorsally along the ventral horn and from there ventrally as a vertical strip, so it may be postulated that the command for fast switching, directed medially, is mediated by a reticulospinal pathway within this location. A hypothesis is forwarded suggesting that the visual control is exerted via ponto-cerebellar pathways.

  6. MiR-9-5p promotes MSC migration by activating β-catenin signaling pathway.

    PubMed

    Li, Xianyang; He, Lihong; Yue, Qing; Lu, Junhou; Kang, Naixin; Xu, Xiaojing; Wang, Huihui; Zhang, Huanxiang

    2017-07-01

    Mesenchymal stem cells (MSCs) have the potential to treat various tissue damages, but the very limited number of cells that migrate to the damaged region strongly restricts their therapeutic applications. Full understanding of mechanisms regulating MSC migration will help to improve their migration ability and therapeutic effects. Increasing evidence shows that microRNAs play important roles in the regulation of MSC migration. In the present study, we reported that miR-9-5p was upregulated in hepatocyte growth factor -treated MSCs and in MSCs with high migration ability. Overexpression of miR-9-5p promoted MSC migration, whereas inhibition of endogenous miR-9-5p decreased MSC migration. To elucidate the underlying mechanism, we screened the target genes of miR-9-5p and report for the first time that CK1α and GSK3β, two inhibitors of β-catenin signaling pathway, were direct targets of miR-9-5p in MSCs and that overexpression of miR-9-5p upregulated β-catenin signaling pathway. In line with these data, inhibition of β-catenin signaling pathway by FH535 decreased the miR-9-5p-promoted migration of MSCs, while activation of β-catenin signaling pathway by LiCl rescued the impaired migration of MSCs triggered by miR-9-5p inhibitor. Furthermore, the formation and distribution of focal adhesions as well as the reorganization of F-actin were affected by the expression of miR-9-5p. Collectively, these results demonstrate that miR-9-5p promotes MSC migration by upregulating β-catenin signaling pathway, shedding light on the optimization of MSCs for cell replacement therapy through manipulating the expression level of miR-9-5p. Copyright © 2017 the American Physiological Society.

  7. PATHWAYS - ELECTRON TUNNELING PATHWAYS IN PROTEINS

    NASA Technical Reports Server (NTRS)

    Beratan, D. N.

    1994-01-01

    The key to understanding the mechanisms of many important biological processes such as photosynthesis and respiration is a better understanding of the electron transfer processes which take place between metal atoms (and other groups) fixed within large protein molecules. Research is currently focused on the rate of electron transfer and the factors that influence it, such as protein composition and the distance between metal atoms. Current models explain the swift transfer of electrons over considerable distances by postulating bridge-mediated tunneling, or physical tunneling pathways, made up of interacting bonds in the medium around and between donor and acceptor sites. The program PATHWAYS is designed to predict the route along which electrons travel in the transfer processes. The basic strategy of PATHWAYS is to begin by recording each possible path element on a connectivity list, including in each entry which two atoms are connected and what contribution the connection would make to the overall rate if it were included in a pathway. The list begins with the bonded molecular structure (including the backbone sequence and side chain connectivity), and then adds probable hydrogen bond links and through-space contacts. Once this list is completed, the program runs a tree search from the donor to the acceptor site to find the dominant pathways. The speed and efficiency of the computer search offers an improvement over manual techniques. PATHWAYS is written in FORTRAN 77 for execution on DEC VAX series computers running VMS. The program inputs data from four data sets and one structure file. The software was written to input BIOGRAF (old format) structure files based on x-ray crystal structures and outputs ASCII files listing the best pathways and BIOGRAF vector files containing the paths. Relatively minor changes could be made in the input format statements for compatibility with other graphics software. The executable and source code are included with the

  8. Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

    PubMed

    Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

    2018-03-01

    The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

  9. Recycled asphalt pavement - fly ash geopolymer as a sustainable stabilized pavement material

    NASA Astrophysics Data System (ADS)

    Horpibulsuk, S.; Hoy, M.; Witchayaphong, P.; Rachan, R.; Arulrajah, A.

    2017-11-01

    Strength, durability, microstructure and leachate characteristics of Recycled Asphalt Pavement and Fly Ash (RAP-FA) geopolymers and RAP-FA blends as a sustainable pavement material are evaluated in this paper. The strength development of the stabilized materials with and without effect wetting-drying (w-d) cycles was determined by Unconfined Compression Strength (UCS) test. The mineralogical and microstructural changes of the stabilized material were analyzed by X-Ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). The leachability of the heavy metals were measured by Toxicity Characteristic Leaching Procedure (TCLP) and compared with international standard. The results show that both RAP-FA blend and RAP-FA geopolymer increase with increasing the number of w-d cycles (C), reaching its peak at 6 w-d cycles. The XRD and SEM analyses indicate that the strength development of RAP-FA blend occurs due to stimulation of the chemical reaction between the high amount to Calcium in RAP and the high amount of Silica and Alumina in FA leaching to production of Calcium Aluminium (Silicate) Hydrate, while the geopolymerization reaction is observed in RAP-FA geopolymer. For C> 6, the significant macro- and micro-cracks developed during w-d cycles cause strength reduction for both RAP-FA blend and geopolymer. The TCLP results demonstrate that there is no environmental risk for these stabilized materials. Furthermore, FA-geopolymer can reduce the leachability of heavy metal in RAP-FA blend. The outcome from this research confirms the viability of using RAP-FA blend and RAP-FA geopolymer as alternative sustainable pavement materials.

  10. Prediction of enzymatic pathways by integrative pathway mapping

    PubMed Central

    Wichelecki, Daniel J; San Francisco, Brian; Zhao, Suwen; Rodionov, Dmitry A; Vetting, Matthew W; Al-Obaidi, Nawar F; Lin, Henry; O'Meara, Matthew J; Scott, David A; Morris, John H; Russel, Daniel; Almo, Steven C; Osterman, Andrei L

    2018-01-01

    The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology. PMID:29377793

  11. Thrombin Promotes Sustained Signaling and Inflammatory Gene Expression through the CDC25 and Ras-associating Domains of Phospholipase Cϵ*

    PubMed Central

    Dusaban, Stephanie S.; Kunkel, Maya T.; Smrcka, Alan V.; Brown, Joan Heller

    2015-01-01

    Phospholipase C-epsilon (PLCϵ) plays a critical role in G-protein-coupled receptor-mediated inflammation. In addition to its ability to generate the second messengers inositol 1,4,5-trisphosphate and diacylglycerol, PLCϵ, unlike the other phospholipase C family members, is activated in a sustained manner. We hypothesized that the ability of PLCϵ to function as a guanine nucleotide exchange factor (GEF) for Rap1 supports sustained downstream signaling via feedback of Rap1 to the enzyme Ras-associating (RA2) domain. Using gene deletion and adenoviral rescue, we demonstrate that both the GEF (CDC25 homology domain) and RA2 domains of PLCϵ are required for long term protein kinase D (PKD) activation and subsequent induction of inflammatory genes. PLCϵ localization is largely intracellular and its compartmentalization could contribute to its sustained activation. Here we show that localization of PLCϵ to the Golgi is required for activation of PKD in this compartment as well as for subsequent induction of inflammatory genes. These data provide a molecular mechanism by which PLCϵ mediates sustained signaling and by which astrocytes mediate pathophysiological inflammatory responses. PMID:26350460

  12. Policy-into-practice for rheumatoid arthritis: randomized controlled trial and cohort study of e-learning targeting improved physiotherapy management.

    PubMed

    Fary, Robyn E; Slater, Helen; Chua, Jason; Ranelli, Sonia; Chan, Madelynn; Briggs, Andrew M

    2015-07-01

    To examine the effectiveness of a physiotherapy-specific, web-based e-learning platform, "RAP-el," in best-practice management of rheumatoid arthritis (RA) using a single-blind, randomized controlled trial (RCT) and prospective cohort study. Australian-registered physiotherapists were electronically randomized into intervention and control groups. The intervention group accessed RAP-eL over 4 weeks. Change in self-reported confidence in knowledge and skills was compared between groups at the end of the RCT using linear regression conditioned for baseline scores by a blinded assessor, using intent-to-treat analysis. Secondary outcomes included physiotherapists' satisfaction with RA management and responses to RA-relevant clinical statements and practice-relevant vignettes. Retention was evaluated in a cohort study 8 weeks after the RCT. Eighty physiotherapists were randomized into the intervention and 79 into the control groups. Fifty-six and 48, respectively, provided baseline data. Significant between-group differences were observed for change in confidence in knowledge (mean difference 8.51; 95% confidence interval [95% CI] 6.29, 10.73; effect size 1.62) and skills (mean difference 7.26; 95% CI 5.1, 9.4; effect size 1.54), with the intervention group performing better. Satisfaction in ability to manage RA, 4 of the 6 clinical statements, and responses to vignettes demonstrated significant improvement in the intervention group. Although 8-week scores showed declines in most outcomes, their clinical significance remains uncertain. RAP-eL can improve self-reported confidence, likely practice behaviors and satisfaction in physiotherapists' ability to manage people with RA, and improve their clinical knowledge in several areas of best-practice RA management in the short term. © 2015, American College of Rheumatology.

  13. Quantification of small GTPase glucosylation by clostridial glucosylating toxins using multiplexed MRM analysis.

    PubMed

    Junemann, Johannes; Lämmerhirt, Chantal M; Polten, Felix; Just, Ingo; Gerhard, Ralf; Genth, Harald; Pich, Andreas

    2017-05-01

    Large clostridial toxins mono-O-glucosylate small GTPases of the Rho and Ras subfamily. As a result of glucosylation, the GTPases are inhibited and thereby corresponding downstream signaling pathways are disturbed. Current methods for quantifying the extent of glucosylation include sequential [ 14 C]glucosylation, sequential [ 32 P]ADP-ribosylation, and Western Blot detection of nonglucosylated GTPases, with neither method allowing the quantification of the extent of glucosylation of an individual GTPase. Here, we describe a novel MS-based multiplexed MRM assay to specifically quantify the glucosylation degree of small GTPases. This targeted proteomics approach achieves a high selectivity and reproducibility, which allows determination of the in vivo substrate pattern of glucosylating toxins. As proof of principle, GTPase glucosylation was analyzed in CaCo-2 cells treated with TcdA, and glucosylation kinetics were determined for RhoA/B, RhoC, RhoG, Ral, Rap1, Rap2, (H/K/N)Ras, and R-Ras2. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. The PDZ domain of the guanine nucleotide exchange factor PDZGEF directs binding to phosphatidic acid during brush border formation.

    PubMed

    Consonni, Sarah V; Brouwer, Patricia M; van Slobbe, Eleonora S; Bos, Johannes L

    2014-01-01

    PDZGEF is a guanine nucleotide exchange factor for the small G protein Rap. It was recently found that PDZGEF contributes to establishment of intestinal epithelial polarity downstream of the kinase Lkb1. By binding to phosphatidic acid enriched at the apical membrane, PDZGEF locally activates Rap2a resulting in induction of brush border formation via a pathway that includes the polarity players TNIK, Mst4 and Ezrin. Here we show that the PDZ domain of PDZGEF is essential and sufficient for targeting PDZGEF to the apical membrane of polarized intestinal epithelial cells. Inhibition of PLD and consequently production of phosphatidic acid inhibitis targeting of PDZGEF to the plasma membrane. Furthermore, localization requires specific positively charged residues within the PDZ domain. We conclude that local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid.

  15. The PDZ Domain of the Guanine Nucleotide Exchange Factor PDZGEF Directs Binding to Phosphatidic Acid during Brush Border Formation

    PubMed Central

    Consonni, Sarah V.; Brouwer, Patricia M.; van Slobbe, Eleonora S.; Bos, Johannes L.

    2014-01-01

    PDZGEF is a guanine nucleotide exchange factor for the small G protein Rap. It was recently found that PDZGEF contributes to establishment of intestinal epithelial polarity downstream of the kinase Lkb1. By binding to phosphatidic acid enriched at the apical membrane, PDZGEF locally activates Rap2a resulting in induction of brush border formation via a pathway that includes the polarity players TNIK, Mst4 and Ezrin. Here we show that the PDZ domain of PDZGEF is essential and sufficient for targeting PDZGEF to the apical membrane of polarized intestinal epithelial cells. Inhibition of PLD and consequently production of phosphatidic acid inhibitis targeting of PDZGEF to the plasma membrane. Furthermore, localization requires specific positively charged residues within the PDZ domain. We conclude that local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid. PMID:24858808

  16. Uncovering the pathways underlying whole body regeneration in a chordate model, Botrylloides leachi using de novo transcriptome analysis.

    PubMed

    Zondag, Lisa E; Rutherford, Kim; Gemmell, Neil J; Wilson, Megan J

    2016-02-16

    Regenerative capacity differs greatly between animals. In vertebrates regenerative abilities are highly limited and tissue or organ specific. However the closest related chordate to the vertebrate clade, Botrylloides leachi, can undergo whole body regeneration (WBR). Therefore, research on WBR in B. leachi has focused on pathways known to be important for regeneration in vertebrates. To obtain a comprehensive vision of this unique process we have carried out the first de novo transcriptome sequencing for multiple stages of WBR occurring in B. leachi. The identified changes in gene expression during B. leachi WBR offer novel insights into this remarkable ability to regenerate. The transcriptome of B. leachi tissue undergoing WBR were analysed using differential gene expression, gene ontology and pathway analyses. We observed up-regulation in the expression of genes involved in wound healing and known developmental pathways including WNT, TGF-β and Notch, during the earliest stages of WBR. Later in WBR, the expression patterns in several pathways required for protein synthesis, biogenesis and the organisation of cellular components were up-regulated. While the genes expressed early on are characteristic of a necessary wound healing response to an otherwise lethal injury, the subsequent vast increase in protein synthesis conceivably sustains the reestablishment of the tissue complexity and body axis polarity within the regenerating zooid. We have, for the first time, provided a global overview of the genes and their corresponding pathways that are modulated during WBR in B. leachi.

  17. Protein kinase A and fungal virulence: a sinister side to a conserved nutrient sensing pathway.

    PubMed

    Fuller, Kevin K; Rhodes, Judith C

    2012-01-01

    Diverse fungal species are the cause of devastating agricultural and human diseases. As successful pathogenesis is dependent upon the ability of the fungus to adapt to the nutritional and chemical environment of the host, the understanding of signaling pathways required for such adaptation will provide insights into the virulence of these pathogens and the potential identification of novel targets for antifungal intervention. The cAMP-PKA signaling pathway is well conserved across eukaryotes. In the nonpathogenic yeast, S. cerevisiae, PKA is activated in response to extracellular nutrients and subsequently regulates metabolism and growth. Importantly, this pathway is also a regulator of pathogenesis, as defects in PKA signaling lead to an attenuation of virulence in diverse plant and human pathogenic fungi. This review will compare and contrast PKA signaling in S. cerevisiae vs. various pathogenic species and provide a framework for the role of this pathway in regulating fungal virulence.

  18. Ratio of Systolic Blood Pressure to Right Atrial Pressure, a Novel Marker to Predict Morbidity and Mortality in Acute Systolic Heart Failure.

    PubMed

    Omar, Hesham R; Charnigo, Richard; Guglin, Maya

    2017-04-01

    Congestion is the main contributor to heart failure (HF) morbidity and mortality. We assessed the combined role of congestion and decreased forward flow in predicting morbidity and mortality in acute systolic HF. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial data set was used to determine if the ratio of simultaneously measured systolic blood pressure (SBP)/right atrial pressure (RAP) on admission predicted HF rehospitalization and 6-month mortality. One hundred ninety-five patients (mean age 56.5 years, 75% men) who received pulmonary artery catheterization were studied. The RAP, SBP, and SBP/RAP had an area under the curve (AUC) of 0.593 (p = 0.0205), 0.585 (p = 0.0359), and 0.621 (p = 0.0026), respectively, in predicting HF rehospitalization. The SBP/RAP was a superior marker of HF rehospitalization compared with RAP alone (difference in AUC 0.0289, p = 0.0385). The optimal criterion of SBP/RAP <11 provided the highest combined sensitivity (77.1%) and specificity (50.9%) in predicting HF rehospitalization. The SBP/RAP had an AUC 0.622, p = 0.0108, and a cut-off value of SBP/RAP <8 had a sensitivity of 61.9% and specificity 64.1% in predicting mortality. Multivariate analysis showed that an SBP/RAP <11 independently predicted rehospitalization for HF (estimated odds ratio 3.318, 95% confidence interval 1.692 to 6.506, p = 0.0005) and an SBP/RAP <8 independently predicted mortality (estimated hazard ratio 2.025, 95% confidence interval 1.069 to 3.833, p = 0.030). In conclusion, SBP/RAP ratio is a marker that identifies a spectrum of complications after hospitalization of patients with decompensated systolic HF, starting with increased incidence of HF rehospitalization at SBP/RAP <11 to increased mortality with SBP/RAP <8. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. p38 MAPK pathway is essential for self-renewal of mouse male germline stem cells (mGSCs).

    PubMed

    Niu, Zhiwei; Mu, Hailong; Zhu, Haijing; Wu, Jiang; Hua, Jinlian

    2017-02-01

    Male germline stem cells (mGSCs), also called spermatogonial stem cells (SSCs), constantly generate spermatozoa in male animals. A number of preliminary studies on mechanisms of mGSC self-renewal have previously been conducted, revealing that several factors are involved in this regulated process. The p38 MAPK pathway is widely conserved in multiple cell types in vivo, and plays an important role in cell proliferation, differentiation, inflammation and apoptosis. However, its role in self-renewal of mGSCs has not hitherto been determined. Here, the mouse mGSCs were cultured and their identity was verified by semi-RT-PCR, alkaline phosphatase (AP) staining and immunofluorescence staining. Then, the p38 MAPK pathway was blocked by p38 MAPK-specific inhibitor SB202190. mGSC self-renewal ability was then analysed by observation of morphology, cell number, cell growth analysis, TUNEL incorporation assay and cell cycle analysis. Results showed that mouse mGSC self-renewal ability was significantly inhibited by SB202190. This study showed for the first time that the p38 MAPK pathway plays a key role in maintaining self-renewal capacity of mouse mGSCs, which offers a new self-renewal pathway for these cells and contributes to overall knowledge of the mechanisms of mGSC self-renewal. © 2016 John Wiley & Sons Ltd.

  20. Pathway Pathology

    PubMed Central

    Rosner, Andrea; Miyoshi, Keiko; Landesman-Bollag, Esther; Xu, Xin; Seldin, David C.; Moser, Amy R.; MacLeod, Carol L.; Shyamala, G.; Gillgrass, Amy E.; Cardiff, Robert D.

    2002-01-01

    To study phenotype-genotype correlations, ErbB/Ras pathway tumors (transgenic for ErbB2, c-Neu, mutants of c-Neu, polyomavirus middle T antigene (PyV-mT), Ras, and bi-transgenic for ErbB2/Neu with ErbB3 and with progesterone receptor) from four different institutions were histopathologically compared with Wnt pathway tumors [transgenes Wnt1, Wnt10b, dominant-negative glycogen synthase kinase 3-β, β-Catenin, and spontaneous mutants of adenomatous polyposis coli gene (Apc)]. ErbB/Ras pathway tumors tend to form solid nodules consisting of poorly differentiated cells with abundant cytoplasm. ErbB/Ras pathway tumors also have scanty stroma and lack myoepithelial or squamous differentiation. In contrast, Wnt pathway tumors exhibit myoepithelial, acinar, or glandular differentiation, and, frequently, combinations of these. Squamous metaplasia is frequent and may include transdifferentiation to epidermal and pilar structures. Most Wnt pathway tumors form caricatures of elongated, branched ductules, and have well-developed stroma, inflammatory infiltrates, and pushing margins. Tumors transgenic for interacting genes such as protein kinase CK2α (casein kinase IIα), and the fibroblast growth factors (Fgf) Int2/Fgf3 or keratinocyte growth factor (Kgf/Fgf7) also have the Wnt pathway phenotype. Because the tumors from the ErbB/Ras and the Wnt pathway are so distinct and can be readily identified using routine hematoxylin and eosin sections, we suggest that pathway pathology is applicable in both basic and clinical cancer research. PMID:12213737

  1. Specific Abilities May Increment Psychometric g for High Ability Populations

    DTIC Science & Technology

    2016-04-14

    tend to sort themselves into jobs that are commensurate with their ability level ( McCormick , DeNisi, & Staw, 1979; McCormick , Jeanneret, & Mecham...of Genetic Psychology, 153, 229-230. Specific abilities, g, & high ability populations 14 McCormick , E. J., DeNisi, A. S., & Shaw, J. B... McCormick , E. J., Jeanneret, P. R., & Mecham, R. C. (1972). A study of job characteristics and job dimensions as based on the Position Analysis Questionnaire

  2. Bioreactors to Influence Stem Cell Fate: Augmentation of Mesenchymal Stem Cell Signaling Pathways via Dynamic Culture Systems

    PubMed Central

    Yeatts, Andrew B.; Choquette, Daniel T.; Fisher, John P.

    2012-01-01

    Background Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro. Scope of Review This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems. Major Conclusions The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased. General Significance Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. PMID:22705676

  3. A novel dysregulated pathway-identification analysis based on global influence of within-pathway effects and crosstalk between pathways

    PubMed Central

    Han, Junwei; Li, Chunquan; Yang, Haixiu; Xu, Yanjun; Zhang, Chunlong; Ma, Jiquan; Shi, Xinrui; Liu, Wei; Shang, Desi; Yao, Qianlan; Zhang, Yunpeng; Su, Fei; Feng, Li; Li, Xia

    2015-01-01

    Identifying dysregulated pathways from high-throughput experimental data in order to infer underlying biological insights is an important task. Current pathway-identification methods focus on single pathways in isolation; however, consideration of crosstalk between pathways could improve our understanding of alterations in biological states. We propose a novel method of pathway analysis based on global influence (PAGI) to identify dysregulated pathways, by considering both within-pathway effects and crosstalk between pathways. We constructed a global gene–gene network based on the relationships among genes extracted from a pathway database. We then evaluated the extent of differential expression for each gene, and mapped them to the global network. The random walk with restart algorithm was used to calculate the extent of genes affected by global influence. Finally, we used cumulative distribution functions to determine the significance values of the dysregulated pathways. We applied the PAGI method to five cancer microarray datasets, and compared our results with gene set enrichment analysis and five other methods. Based on these analyses, we demonstrated that PAGI can effectively identify dysregulated pathways associated with cancer, with strong reproducibility and robustness. We implemented PAGI using the freely available R-based and Web-based tools (http://bioinfo.hrbmu.edu.cn/PAGI). PMID:25551156

  4. Prefrontal-Hippocampal Pathways Underlying Inhibitory Control Over Memory

    PubMed Central

    Anderson, Michael C.; Bunce, Jamie G.; Barbas, Helen

    2016-01-01

    A key function of the prefrontal cortex is to support inhibitory control over behavior. It is widely believed that this function extends to stopping cognitive processes as well. Consistent with this, mounting evidence establishes the role of the right lateral prefrontal cortex in a clear case of cognitive control: retrieval suppression. Retrieval suppression refers to the ability to intentionally stop the retrieval process that arises when a reminder to a memory appears. Functional imaging data indicates that retrieval suppression involves top-down modulation of hippocampal activity by the dorsolateral prefrontal cortex, but the anatomical pathways supporting this inhibitory modulation remain unclear. Here we bridge this gap by integrating key findings about retrieval suppression observed through functional imaging with a detailed consideration of relevant anatomical pathways observed in non-human primates. Focusing selectively on the potential role of the anterior cingulate cortex, we develop two hypotheses about the pathways mediating interactions between lateral prefrontal cortex and the medial temporal lobes during suppression, and their cellular targets: the entorhinal gating hypothesis, and thalamo-hippocampal modulation via the nucleus reuniens. We hypothesize that whereas entorhinal gating is well situated to stop retrieval proactively, thalamo-hippocampal modulation may interrupt an ongoing act of retrieval reactively. Isolating the pathways that underlie retrieval suppression holds the potential to advance our understanding of a range of psychiatric disorders characterized by persistent intrusive thoughts. More broadly, an anatomical account of retrieval suppression would provide a key model system for understanding inhibitory control over cognition. PMID:26642918

  5. Electropysiologic evaluation of the visual pathway in patients with multiple sclerosis.

    PubMed

    Rodriguez-Mena, Diego; Almarcegui, Carmen; Dolz, Isabel; Herrero, Raquel; Bambo, Maria P; Fernandez, Javier; Pablo, Luis E; Garcia-Martin, Elena

    2013-08-01

    To evaluate the ability of visual evoked potentials and pattern electroretinograms (PERG) to detect subclinical axonal damage in patients during the early diagnostic stage of multiple sclerosis (MS). The authors also compared the ability of optical coherence tomography (OCT), PERG, and visual evoked potentials to detect axonal loss in MS patients and correlated the functional and structural properties of the retinal nerve fiber layer. Two hundred twenty-eight eyes of 114 subjects (57 MS patients and 57 age- and sex-matched healthy controls) were included. The visual pathway was evaluated based on functional and structural assessments. All patients underwent a complete ophthalmic examination that included assessment of visual acuity, ocular motility, intraocular pressure, visual field, papillary morphology, OCT, visual evoked potentials, and PERG. Visual evoked potentials (P100 latency and amplitude), PERG (N95 amplitude and N95/P50 ratio), and OCT parameters differed significantly between MS patients and healthy subjects. Moderate significant correlations were found between visual evoked potentials or PERG parameters and OCT measurements. Axonal damage in ganglion cells of the visual pathway can be detected based on structural measures provided by OCT in MS patients and by the N95 component and N95/P50 index of PERG, thus providing good correlation between function and structure.

  6. A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis.

    PubMed

    Voyle, Nicola; Keohane, Aoife; Newhouse, Stephen; Lunnon, Katie; Johnston, Caroline; Soininen, Hilkka; Kloszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Hodges, Angela; Kiddle, Steven; Dobson, Richard Jb

    2016-01-01

    Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis. Gene and pathway level models performed similarly to each other and to a model based on demographic information only. Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.

  7. Using the Semantic Web for Rapid Integration of WikiPathways with Other Biological Online Data Resources

    PubMed Central

    Waagmeester, Andra; Pico, Alexander R.

    2016-01-01

    The diversity of online resources storing biological data in different formats provides a challenge for bioinformaticians to integrate and analyse their biological data. The semantic web provides a standard to facilitate knowledge integration using statements built as triples describing a relation between two objects. WikiPathways, an online collaborative pathway resource, is now available in the semantic web through a SPARQL endpoint at http://sparql.wikipathways.org. Having biological pathways in the semantic web allows rapid integration with data from other resources that contain information about elements present in pathways using SPARQL queries. In order to convert WikiPathways content into meaningful triples we developed two new vocabularies that capture the graphical representation and the pathway logic, respectively. Each gene, protein, and metabolite in a given pathway is defined with a standard set of identifiers to support linking to several other biological resources in the semantic web. WikiPathways triples were loaded into the Open PHACTS discovery platform and are available through its Web API (https://dev.openphacts.org/docs) to be used in various tools for drug development. We combined various semantic web resources with the newly converted WikiPathways content using a variety of SPARQL query types and third-party resources, such as the Open PHACTS API. The ability to use pathway information to form new links across diverse biological data highlights the utility of integrating WikiPathways in the semantic web. PMID:27336457

  8. Using the Semantic Web for Rapid Integration of WikiPathways with Other Biological Online Data Resources.

    PubMed

    Waagmeester, Andra; Kutmon, Martina; Riutta, Anders; Miller, Ryan; Willighagen, Egon L; Evelo, Chris T; Pico, Alexander R

    2016-06-01

    The diversity of online resources storing biological data in different formats provides a challenge for bioinformaticians to integrate and analyse their biological data. The semantic web provides a standard to facilitate knowledge integration using statements built as triples describing a relation between two objects. WikiPathways, an online collaborative pathway resource, is now available in the semantic web through a SPARQL endpoint at http://sparql.wikipathways.org. Having biological pathways in the semantic web allows rapid integration with data from other resources that contain information about elements present in pathways using SPARQL queries. In order to convert WikiPathways content into meaningful triples we developed two new vocabularies that capture the graphical representation and the pathway logic, respectively. Each gene, protein, and metabolite in a given pathway is defined with a standard set of identifiers to support linking to several other biological resources in the semantic web. WikiPathways triples were loaded into the Open PHACTS discovery platform and are available through its Web API (https://dev.openphacts.org/docs) to be used in various tools for drug development. We combined various semantic web resources with the newly converted WikiPathways content using a variety of SPARQL query types and third-party resources, such as the Open PHACTS API. The ability to use pathway information to form new links across diverse biological data highlights the utility of integrating WikiPathways in the semantic web.

  9. Effect of Mixing Ability Groups on Ability Levels Attained.

    ERIC Educational Resources Information Center

    de Jong, John H. A. L.

    In 1983, in the Netherlands' highly differentiated school system, two types of curriculum representing different ability levels were combined as a first step towards a more heterogeneous grouping of student abilities. A study of one aspect of the results of this change compared over 1000 samples of English and German second language listening…

  10. The Role of Habitus and Reflexivity in Young People Managing Pathways out of Crime

    ERIC Educational Resources Information Center

    France, Alan; Bottrell, Dorothy; Haddon, Edward

    2013-01-01

    This article draws on material from the ESRC funded "Pathways into and out of crime" research programme (Grant number L330253001) to explore how a group of educationally disaffected young people negotiate and try to manage their desistance from offending. We argue that the ability to be reflexive represents a form of embodied cultural…

  11. Neurophysiological Pathways to Obesity: Below Awareness and Beyond Individual Control

    PubMed Central

    Cohen, Deborah A.

    2008-01-01

    A global obesity epidemic is occurring simultaneously with ongoing increases in the availability and salience of food in the environment. Obesity is increasing across all socioeconomic groups and educational levels and occurs even among individuals with the highest levels of education and expertise in nutrition and related fields. Given these circumstances, it is plausible that excessive food consumption occurs in ways that defy personal insight or are below individual awareness. The current food environment stimulates automatic reflexive responses that enhance the desire to eat and increase caloric intake, making it exceedingly difficult for individuals to resist, especially because they may not be aware of these influences. This article identifies 10 neurophysiological pathways that can lead people to make food choices subconsciously or, in some cases, automatically. These pathways include reflexive and uncontrollable neurohormonal responses to food images, cues, and smells; mirror neurons that cause people to imitate the eating behavior of others without awareness; and limited cognitive capacity to make informed decisions about food. Given that people have limited ability to shape the food environment individually and no ability to control automatic responses to food-related cues that are unconsciously perceived, it is incumbent upon society as a whole to regulate the food environment, including the number and types of food-related cues, portion sizes, food availability, and food advertising. PMID:18586908

  12. Pathway activity inference for multiclass disease classification through a mathematical programming optimisation framework.

    PubMed

    Yang, Lingjian; Ainali, Chrysanthi; Tsoka, Sophia; Papageorgiou, Lazaros G

    2014-12-05

    Applying machine learning methods on microarray gene expression profiles for disease classification problems is a popular method to derive biomarkers, i.e. sets of genes that can predict disease state or outcome. Traditional approaches where expression of genes were treated independently suffer from low prediction accuracy and difficulty of biological interpretation. Current research efforts focus on integrating information on protein interactions through biochemical pathway datasets with expression profiles to propose pathway-based classifiers that can enhance disease diagnosis and prognosis. As most of the pathway activity inference methods in literature are either unsupervised or applied on two-class datasets, there is good scope to address such limitations by proposing novel methodologies. A supervised multiclass pathway activity inference method using optimisation techniques is reported. For each pathway expression dataset, patterns of its constituent genes are summarised into one composite feature, termed pathway activity, and a novel mathematical programming model is proposed to infer this feature as a weighted linear summation of expression of its constituent genes. Gene weights are determined by the optimisation model, in a way that the resulting pathway activity has the optimal discriminative power with regards to disease phenotypes. Classification is then performed on the resulting low-dimensional pathway activity profile. The model was evaluated through a variety of published gene expression profiles that cover different types of disease. We show that not only does it improve classification accuracy, but it can also perform well in multiclass disease datasets, a limitation of other approaches from the literature. Desirable features of the model include the ability to control the maximum number of genes that may participate in determining pathway activity, which may be pre-specified by the user. Overall, this work highlights the potential of building

  13. Laboratory and field evaluation of hot mix asphalt with high contents of reclaimed asphalt pavement

    NASA Astrophysics Data System (ADS)

    Van Winkle, Clinton Isaac

    Currently in Iowa, the amount of RAP materials allowed for the surface layer is limited to 15% by weight. The objective of this project was to develop quality standards for inclusion of RAP content higher than 15% in asphalt mixtures. To meet Superpave mix design requirements, it was necessary to fractionate the RAP materials. Based on the extensive sieve-by-sieve analysis of RAP materials, the optimum sieve size to fractionate RAP materials was identified. To determine if the higher percentage of RAP materials than 15% can be used in Iowa's state highway, three test sections with 30.0%, 35.5% and 39.2% of RAP materials were constructed on Highway 6 in Iowa City. The construction of the field test sections was monitored and the cores were obtained to measure field densities of test sections. Field mixtures collected from test sections were compacted in the laboratory in order to test the moisture sensitivity using a Hamburg Wheel Tracking Device. The binder was extracted from the field mixtures with varying amounts of RAP materials and tested to determine the effects of RAP materials on the PG grade of a virgin binder. Field cores were taken from the various mix designs to determine the percent density of each test section. A condition survey of the test sections was then performed to evaluate the short-term performance.

  14. Identification of the key pathway of oxazolinoanthracyclines mechanism of action in cells derived from human solid tumors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Denel-Bobrowska, Marta, E-mail: mdenel@biol.uni.lo

    Oxazolinodoxorubicin (O-DOX) and oxazolinodaunorubicin (O-DAU) are novel anthracycline derivatives with a modified daunosamine moiety. In the present study, we evaluated the cytotoxicities, genotoxicities and abilities of O-DOX and O-DAU to induce apoptosis in cancer cell lines (SKOV-3; A549; HepG2), and compared the results with their parent drugs. We assessed antiproliferative activity by MTT assay. We evaluated apoptosis-inducing ability by double-staining with fluorescent probes (Hoechst 33258/propidium iodide), and by determining expression levels of genes involved in programmed cell death by reverse transcription-polymerase chain reaction. Genotoxicities of the compounds were tested by comet assays. Oxazolinoanthracyclines demonstrated high anti-tumor activity. O-DOX had significantlymore » higher cytotoxicity, apoptosis-inducing ability, and genotoxicity compared with parental doxorubicin (DOX) in all tested conditions, while O-DAU activity differed among cell lines. The mechanism of oxazoline analog action appeared to involve the mitochondrial pathway of programmed cell death. These results provide further information about oxazoline derivatives of commonly used anthracycline chemotherapy agents. O-DOX and O-DAU have the ability to induce apoptosis in tumor cells. - Highlights: • Substituted amino group increased the anticancer activity of anthracyclines. • Mitochondrial apoptotic pathway seems to be involved in the mechanism of action. • Favorable biological properties of oxazoline derivatives were confirmed.« less

  15. Effects of Germline Mutations in the Ras/MAPK Signaling Pathway on Adaptive Behavior: Cardiofaciocutaneous Syndrome and Noonan Syndrome

    PubMed Central

    Pierpont, Elizabeth I.; Pierpont, Mary Ella; Mendelsohn, Nancy J.; Roberts, Amy E.; Tworog-Dube, Erica; Rauen, Katherine A.; Seidenberg, Mark S.

    2011-01-01

    Cardiofaciocutaneous syndrome (CFC) and Noonan syndrome (NS) are two phenotypically overlapping genetic disorders whose underlying molecular etiologies affect a common signaling pathway. Mutations in the BRAF, MEK1 and MEK2 genes cause most cases of CFC and mutations in PTPN11, SOS1, KRAS and RAF1 typically cause NS. Although both syndromes are associated with developmental delays of varying severity, the extent to which the behavioral profiles differ may shed light on the different roles these respective genes play in development of skills necessary for everyday functioning. In this study, profiles of adaptive behavior of individuals with CFC and NS who had confirmed pathogenic mutations in Ras/MAPK pathway genes were investigated. Patterns of strengths and weaknesses, age-related differences, and risk factors for difficulties in adaptive skills were assessed. Although genes acting more downstream in the Ras/MAPK pathway were associated with more difficulties in adaptive functioning than genes more upstream in the pathway, several inconsistencies highlight the wide spectrum of possible developmental courses in CFC and NS. Along with clinical and genetic factors, variables such as chronological age, gestational age at birth and parental education levels accounted for significant variance in adaptive skills. Results indicate that there is wide heterogeneity in adaptive ability in CFC and NS, but that these abilities are correlated to some extent with the specific disease-causing genes. PMID:20186801

  16. Local cost structures and the economics of robot assisted radical prostatectomy.

    PubMed

    Scales, Charles D; Jones, Peter J; Eisenstein, Eric L; Preminger, Glenn M; Albala, David M

    2005-12-01

    Robot assisted prostatectomy (RAP) is more costly than traditional radical retropubic prostatectomy (RRP) under the cost structures at certain hospitals. However, this finding may not be the case in all care settings. We investigated the sensitivity of RAP and RRP inpatient costs to variations in length of stay (LOS), local hospitalization costs and robotic case volume in the specialist and generalist settings. We developed a model of RAP vs RRP costs in the specialist and generalist settings using published data on operative time and LOS, and cost data from our academic medical center. All inpatient cost centers were included, namely surgery costs, professional fees, postoperative care, robotic equipment and service. Extensive 1 and 2-way sensitivity analyses were performed. Our base case model demonstrated a cost premium for RAP vs RRP of USD $783 and $195 in the specialist and generalist settings, respectively. Sensitivity analysis of our model assumptions demonstrated that RAP could achieve cost equivalence with RRP at a surgical volume of 10 cases weekly. If case volume increased to 14 cases weekly, RAP would be less expensive than RRP in some practice settings in which RAP LOS was less than 1.5 days. The inpatient costs of robotic assisted prostatectomy are volume dependent and cost equivalence with generalist radical retropubic prostatectomy is possible at higher volume RAP specialty centers. While RAP may be cost competitive with RRP at high cost hospitals or high volume RAP specialist centers, this procedure would exist at a cost premium to RRP in other practice settings.

  17. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

    PubMed Central

    Popovich, Irina G; Anisimov, Vladimir N; Zabezhinski, Mark A; Semenchenko, Anna V; Tyndyk, Margarita L; Yurova, Maria N; Blagosklonny, Mikhail V

    2014-01-01

    Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break (1.5 × 6/bi-weekly schedule: total of 6 injections during a 4-week period). This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice. Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention. The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice. PMID:24556924

  18. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin.

    PubMed

    Popovich, Irina G; Anisimov, Vladimir N; Zabezhinski, Mark A; Semenchenko, Anna V; Tyndyk, Margarita L; Yurova, Maria N; Blagosklonny, Mikhail V

    2014-05-01

    Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break (1.5 × 6/bi-weekly schedule: total of 6 injections during a 4-week period). This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice. Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention. The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice.

  19. ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway

    PubMed Central

    Ogawa, Tadashi; Hirohashi, Yoshihiko; Murai, Aiko; Nishidate, Toshihiko; Okita, Kenji; Wang, Liming; Ikehara, Yuzuru; Satoyoshi, Tetsuta; Usui, Akihiro; Kubo, Terufumi; Nakastugawa, Munehide; Kanaseki, Takayuki; Tsukahara, Tomohide; Kutomi, Goro; Furuhata, Tomohisa; Hirata, Koichi; Sato, Noriyuki; Mizuguchi, Toru; Takemasa, Ichiro; Torigoe, Toshihiko

    2017-01-01

    Colorectal cancer (CRC) is a mortal disease due to treatment resistance, recurrence and distant metastasis. Emerging evidence has revealed that a small sub-population of cancer cells termed cancer stem cells (CSCs)/ cancer-initiating cells (CICs) is endowed with high levels of tumor-initiating ability, self-renewal ability and differentiation ability and is responsible for treatment resistance, recurrence and distant metastasis. Eradication of CSCs/CICs is essential to improve current treatments. However, the molecular mechanisms by which CSCs/CICs are maintained are still elusive. In this study, we aimed to determine the molecular mechanisms by which colorectal (CR)-CSCs/CICs in are maintained human primary CRC cells. CR-CSCs/CICs were isolated by sphere-culture and the ALDEFLUOR assay, and transcriptome analysis revealed that the gene ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) was expressed at high levels in CR-CSCs/CICs. Overexpression of ST6GALNAC1 enhanced the expression of sialyl-Tn (STn) antigen, which is carried by the CSC marker CD44, and increased the sphere-forming ability and resistance to a chemotherapeutic reagent. The opposite phenomena were observed by gene knockdown using siRNA. Furthermore, the Akt pathway was activated in ST6GANAC1-overexpressed cells, and activation of the pathway was cancelled by gene knockdown of galectin-3. The results indicate that ST6GALNAC1 has a role in the maintenance of CR-CSCs/CICs by activating the Akt pathway in cooperation with galectin-3 and that ST6GalNAC1 (or STn antigen) might be a reasonable molecule for CSC/CIC-targeting therapy. PMID:29348846

  20. Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway.

    PubMed

    Jelínková, Iva; Šafaříková, Barbora; Vondálová Blanářová, Olga; Skender, Belma; Hofmanová, Jiřina; Sova, Petr; Moyer, Mary Pat; Kozubík, Alois; Kolář, Zdeněk; Ehrmann, Jiří; Hyršlová Vaculová, Alena

    2014-12-01

    In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action. Copyright © 2014 Elsevier Inc. All rights reserved.