CGK733-induced LC3 II formation is positively associated with the expression of cyclin-dependent kinase inhibitor p21Waf1/Cip1 through modulation of the AMPK and PERK/CHOP signaling pathways.

PubMed

Wang, Yufeng; Kuramitsu, Yasuhiro; Baron, Byron; Kitagawa, Takao; Tokuda, Kazuhiro; Akada, Junko; Nakamura, Kazuyuki

2015-11-24

Microtubule-associated protein 1A/1B-light chain 3 (LC3)-II is essential for autophagosome formation and is widely used to monitor autophagic activity. We show that CGK733 induces LC3 II and LC3-puncta accumulation, which are not involved in the activation of autophagy. The treatment of CGK733 did not alter the autophagic flux and was unrelated to p62 degradation. Treatment with CGK733 activated the AMP-activated protein kinase (AMPK) and protein kinase RNA-like endoplasmic reticulum kinase/CCAAT-enhancer-binding protein homologous protein (PERK/CHOP) pathways and elevated the expression of p21Waf1/Cip1. Inhibition of both AMPK and PERK/CHOP pathways by siRNA or chemical inhibitor could block CGK733-induced p21Waf1/Cip1 expression as well as caspase-3 cleavage. Knockdown of LC3 B (but not LC3 A) abolished CGK733-triggered LC3 II accumulation and consequently diminished AMPK and PERK/CHOP activity as well as p21Waf1/Cip1 expression. Our results demonstrate that CGK733-triggered LC3 II formation is an initial event upstream of the AMPK and PERK/CHOP pathways, both of which control p21Waf1/Cip1 expression.

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.

PubMed

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E; Seidman, J G; Pu, William T; Wang, Da-Zhi

2015-11-02

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

PubMed Central

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E.; Seidman, J.G.; Pu, William T.; Wang, Da-Zhi

2015-01-01

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression. PMID:26436652

Altered expression of key cell cycle regulators in renal cell carcinoma associated with Xp11.2 translocation.

PubMed

Barroca, H; Castedo, S; Vieira, J; Teixeira, M; Müller-Höcker, J

2009-01-01

Renal cell carcinoma (RCC) is a rare tumor in the pediatric population. Recently, a phenotypically and genetically distinct kidney carcinoma, mainly prevalent in children and associated with an Xp11.2 translocation or TFE3 gene fusion, has been described. It has been advanced that in this subtype of RCC, there is an accumulation of cyclin D1, cyclin D3, and p21 ((wafl/cip1)). The aim of the present study was to figure out in two pediatric RCC recently diagnosed in our department (one clear cell-type RCC and one TFE3-positive RCC) whether those features are indeed specific of the latter tumor or occur in pediatric RCC irrespective of the tumor type. The following immunostains were performed in both cases: Ki67, p16(ink4a), p21 ((wafl/cip1)), p27(kip1), p53, p63, mdm2, cyclin D1, cyclin D3, TFE3, CD10, vimentin, E-cadherin, and RCC-antigen. We observed in the TFE3-positive carcinoma an intense immunoreaction for p21 ((wafl/cip1)), cyclin D1, and cyclin D3, without expression for p53, p16, p27(kip1), and mdm2, whereas the immunoexpression profile observed in the classic RCC was similar to that of clear cell, adult-type RCC. Our study confirms that TFE3-positive RCC exhibits a deregulation of the cell cycle apparently unrelated to the young age of the patients.

CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine.

PubMed

Xu, Peng; Yao, Jie; He, Jin; Zhao, Long; Wang, Xiaodong; Li, Zhennan; Qian, Jianjun

2016-03-22

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein which participates in inhibiting tumor apoptosis in pancreatic cancer cells. Using immunohistochemical staining, we investigated the expression of CIP2A protein in 72 cases of human pancreatic ductal adenocarcinoma (PDAC) tissue and 27 cases of adjacent normal pancreatic tissue. The positive rate of CIP2A protein expression in pancreatic cancer tissue was70.83 %, which was significantly higher than that in adjacent non- cancerous pancreatic tissue (11.11%). The expression of CIP2A was found to be correlated with TNM stage, but not correlated with age, gender, tumor location, smoking status, alcohol consumption, diabetes, high blood pressure, BMI, tumor size, lymph node metastasis or distant metastases. Kaplan- Meier survival analysis showed that patients with positive CIP2A protein expression had a lower overall survival rate than patients without CIP2A expression. COX regression analysis indicated that expression of CIP2A was an independent prognostic factor for pancreatic ductal adenocarcinoma. In addition, down-regulation of CIP2A inhibited cell proliferation and increased sensitivity to gemcitabine in pancreatic cancer cells by decreasing AKT signaling pathway. Our results indicated that down-regulation of CIP2A could be a novel therapeutic strategy for pancreatic cancer.

Effects of sodium phenylbutyrate on differentiation and induction of the P21WAF1/CIP1 anti-oncogene in human liver carcinoma cell lines.

PubMed

Meng, Mei; Jiang, Jun Mei; Liu, Hui; In, Cheng Yong; Zhu, Ju Ren

2005-01-01

To explore the effects of sodium phenylbutyrate on the proliferation, differentiation, cell cycle arrest and induction of the P(21WAF1/CIP1) anti-oncogene in human liver carcinoma cell lines Bel-7402 and HepG2. Bel-7402 and HepG2 human liver carcinoma cells were treated with sodium phenylbutyrate at different concentrations. Light microscopy was used to observe morphological changes in the carcinoma cells. Effects on the cell cycle were detected by using flow cytometry. P(21WAF1/CIP1) expression was determined by both reverse transcription-polymerase chain reaction and western blotting. Statistical analysis was performed by using one-way anova and Student's t-test. Sodium phenylbutyrate treatment caused time- and dose-dependent growth inhibition of Bel-7402 and HepG2 cells. This treatment also caused a decline in the proportion of S-phase cells and an increase in the proportion of G(0)/G(1) cells. Sodium phenylbutyrate increased the expression of P(21WAF1/CIP1). Sodium phenylbutyrate inhibits the proliferation of human liver carcinoma cells Bel-7402 and HepG2, induces partial differentiation, and increases the expression of P(21WAF1/CIP1).

Characterization of the Akt2 Domain Essential for Binding Nuclear p21cip1 to Promote Cell Cycle Arrest during Myogenic Differentiation

PubMed Central

Heron-Milhavet, Lisa; Franckhauser, Celine; Fernandez, Anne; Lamb, Ned J.

2013-01-01

The binding of the cdk inhibitor p21cip1 to Akt2 in the nucleus is an essential component in determining the specific role of Akt2 in the cell cycle arrest that precedes myogenic differentiation. Here, through a combination of biochemical and cell biology approaches, we have addressed the molecular basis of this binding. Using amino-terminal truncation of Akt2, we show that p21cip1 binds at the carboxy terminal of Akt2 since deletion of the first 400 amino acids did not affect the interaction between Akt2 and p21cip1. Pull down using carboxy terminal-truncated Akt2 protein revealed the importance of the region between amino acids 400 and 445 for the binding to p21cip1. Since Akt2_400–445 and Akt2_420–445 peptides could both bind p21cip1, this refines the binding domain on Akt2 between amino acids 420 and 445. In order to confirm these data in living cells, we developed a protocol to synchronize myoblasts at the cell cycle exit point when p21cip1 expression is induced by MyoD before myogenic differentiation. When a synthetic Akt2 peptide spanning the region (410–437) was microinjected in p21-expressing myoblasts, p21cip1 no longer localized exclusively in the nucleus, instead being redistributed throughout the cell, thus showing that injected peptide 410–437 acts to compete with the binding of endogenous Akt2 to p21cip1. Taken together, our data suggest that this 27 amino acid sequence on Akt2 is necessary and sufficient to bind p21cip1 both in vitro and in living cells. PMID:24194853

Design of cellulose ether-based macromolecular prodrugs of ciprofloxacin for extended release and enhanced bioavailability.

PubMed

Amin, Muhammad; Abbas, Nazia Shahana; Hussain, Muhammad Ajaz; Sher, Muhammad; Edgar, Kevin J

2018-07-01

The present study reveals the syntheses of hydroxypropylcellulose‑(HPC) and hydroxyethylcellulose‑(HEC) based macromolecular prodrugs (MPDs) of ciprofloxacin (CIP) using homogeneous reaction methodology. Covalently loaded drug content (DC) of each prodrug was quantified using UV-Vis spectrophotometry to determine degree of substitution (DS). HPC-ciprofloxacin (HPC-CIP) conjugates showed DS of CIP in the range 0.87-1.15 whereas HEC-ciprofloxacin (HEC-CIP) conjugates showed DS range 0.51-0.75. Transmission electron microscopy revealed that HPC-CIP conjugate 2 and HEC-CIP conjugate 6 self-assembled into nanoparticles of 150-300 and 180-250nm, respectively. Size exclusion chromatography revealed HPC-CIP conjugate 2 and HEC-CIP conjugate 6 as monodisperse systems. In vitro drug release studies indicated 15 and 43% CIP release from HPC-CIP conjugate 2 after 6h in simulated gastric and simulated intestinal fluids (SGF and SIF), respectively. HEC-CIP conjugate 6 showed 16% and 46% release after 6h in SGF and SIF, respectively. HPC-CIP conjugate 2 and HEC-CIP conjugate 6 exhibited half-lives of 10.87 and 11.71h, respectively with area under the curve values of 164 and 175hμgmL -1 , respectively, indicating enhanced bioavailability and improved pharmacokinetic profiles in animal model. Equal antibacterial activities to that of unmodified CIP confirmed their competitive efficacies. Cytotoxicity studies supported their non-toxic nature and biocompatibility. Copyright © 2018 Elsevier B.V. All rights reserved.

Tocotrienol-rich fraction prevents cellular aging by modulating cell proliferation signaling pathways.

PubMed

Khor, S C; Mohd Yusof, Y A; Wan Ngah, W Z; Makpol, S

Vitamin E has been suggested as nutritional intervention for the prevention of degenerative and age-related diseases. In this study, we aimed to elucidate the underlying mechanism of tocotrienol-rich fraction (TRF) in delaying cellular aging by targeting the proliferation signaling pathways in human diploid fibroblasts (HDFs). Tocotrienol-rich fraction was used to treat different stages of cellular aging of primary human diploid fibroblasts viz. young (passage 6), pre-senescent (passage 15) and senescent (passage 30). Several selected targets involved in the downstream of PI3K/AKT and RAF/MEK/ERK pathways were compared in total RNA and protein. Different transcriptional profiles were observed in young, pre-senescent and senescent HDFs, in which cellular aging increased AKT, FOXO3, CDKN1A and RSK1 mRNA expression level, but decreased ELK1, FOS and SIRT1 mRNA expression level. With tocotrienol-rich fraction treatment, gene expression of AKT, FOXO3, ERK and RSK1 mRNA was decreased in senescent cells, but not in young cells. The three down-regulated mRNA in cellular aging, ELK1, FOS and SIRT1, were increased with tocotrienol-rich fraction treatment. Expression of FOXO3 and P21Cip1 proteins showed up-regulation in senescent cells but tocotrienol-rich fraction only decreased P21Cip1 protein expression in senescent cells. Tocotrienol-rich fraction exerts gene modulating properties that might be responsible in promoting cell cycle progression during cellular aging.

Studies of ciprofloxacin encapsulation on alginate/pectin matrixes and its relationship with biodisponibility.

PubMed

Islan, Germán A; de Verti, Ignacio Pérez; Marchetti, Sergio G; Castro, Guillermo R

2012-07-01

Screening of ciprofloxacin (Cip) with selected biopolymers brings about 90% antibiotic interactions with a coacervate composed of alginate/high metoxylated pectin in 2:1 ratio. Fourier transform infrared spectroscopy analysis provides information about the nature of this interaction, revealing ionic and hydrophobic patterns among the molecules. Alginate/high methoxylated pectin gel microspheres developed by ionic gelation encapsulates 46.8 ± 5.0% Cip. The gel matrix can release Cip in a sustained manner, releasing 42.7 ± 0.2% in 2 h under simulated stomach pH conditions, and 83.3 ± 1.1% Cip release in 80 mM phosphate at pH = 7.40 (intestinal). The increase of sodium chloride from 50 to 200 mM implies a Cip release from 69.0 ± 1.5% to 95.1 ± 3.6% respectively in 2 h. Scanning electron microscopy revealed the cohesive effect of HM pectin over alginate molecules on the microsphere surface. Those results guarantee all Cip contained in the alginate/HM pectin microspheres could be released in an established kinetic profile along the gastrointestinal tract, avoiding the Cip undesirable side effects during absorption.

The transcriptional co-activator p/CIP (NCoA-3) is up-regulated by STAT6 and serves as a positive regulator of transcriptional activation by STAT6.

PubMed

Arimura, Akinori; vn Peer, Maartje; Schröder, Andreas J; Rothman, Paul B

2004-07-23

Transcriptional activation by signal transducer and activator of transcription 6 (STAT6) has been shown to require the direct interaction not only with co-activators such as p300 and cAMP-responsive element-binding protein-binding protein (CBP) but also with nuclear co-activator 1, a member of the p160/steroid receptor co-activator family. Among the p160/steroid receptor co-activators, only p/CIP (nuclear co-activator 3) has been shown to be up-regulated by interleukin (IL)-4 in B cells through a STAT-6-dependent mechanism using Gene-Chip analysis. In this study, we have investigated the function of p/CIP in the transcriptional activation by STAT6. We found that p/CIP indirectly interacted with STAT6 via p300, and overexpression of the CBP-interacting domain of p/CIP (p/CIP(947-1084)) prevented the interaction of p/CIP with STAT6 by blocking the binding of p/CIP to p300. Whereas expression of p/CIP(947-1084) resulted in a marked reduction of STAT6-mediated transactivation, overexpression of wild type p/CIP resulted in significant enhancement of it. In addition, p/CIP(947-1084) markedly reduced CD23 expression on B cells stimulated with IL-4, whereas overexpression of wild type p/CIP enhanced it. Chromatin immunoprecipitations demonstrate that IL-4 increases the interaction of p/CIP with the murine immunoglobulin heavy chain germ line epsilon promoter in B cells. These results suggest that p/CIP positively regulates STAT6 transcriptional activation through formation of a STAT6, p300/CBP, and p/CIP complex.

Development of an abbreviated Career Indecision Profile-65 using item response theory: The CIP-Short.

PubMed

Xu, Hui; Tracey, Terence J G

2017-03-01

The current study developed an abbreviated version of the Career Indecision Profile-65 (CIP-65; Hacker, Carr, Abrams, & Brown, 2013) by using item response theory. In order to improve the efficiency of the CIP-65 in measuring career indecision, the individual item performance of the CIP-65 was examined with respect to the ordering of response occurrence and gender differential item functioning. The best 5 items of each scale of the CIP-65 (i.e., neuroticism/negative affectivity, choice/commitment anxiety, lack of readiness, and interpersonal conflicts) were retained in the CIP-Short using a sample of 588 college students. A validation sample (N = 174) supported the reliability and structural validity of the CIP-Short. The convergent and divergent validity of the CIP-Short was additionally supported in the findings of a hypothesized differential relational pattern in a separate sample (N = 360). While the current study supported the CIP-Short being a sound brief measure of career indecision, the limitations of this study and suggestions for future research were discussed as well. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

N1-acetyl substituted pyrrolidine derivative CIP-A5: a novel compound that could ameliorate liver cirrhosis through modulation of hepatic stellate cell activity.

PubMed

Wang, Xiao-Dan; Gao, Zu-Hua; Xue, Xia; Cheng, Yan-Na; Yue, Pan; Fang, Xu-Wen; Qu, Xian-Jun

2011-06-01

(2S,4R)-methyl 1-acetyl-4-(N-(4-bromophenyl)sulfamoyloxy)pyrrolidine-2-carboxylate (CIP-A5) is the N1-acetyl substituted pyrrolidine derivative which was designed against the structure of matrix metalloproteinase (MMP-2) and MMP-9. CIP-A5 has been considered as a candidate compound for treatment of liver cirrhosis. In this study, we evaluated the efficacy of CIP-A5 on the activity of hepatic stellate cells. CIP-A5 prevented the transforming growth factor β (TGF-β)-induced proliferation of hepatic stellate HSC-T6 cells as estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. CIP-A5 stimulated MMPs activity as evidenced by an increase of degradation of succinylated gelatin. Gelatin zymography analysis showed that CIP-A5 stimulated the secretion and activity of MMP-2 and MMP-9 in HSC-T6 cells. This stimulatory effect on MMPs was verified by the observation of increased expression of MMP-2 and MMP-9 as evaluated by Western blot assay. At the same time, a significant decrease of the expression of tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) was observed, suggesting a modulation of the balance of MMPs/TIMPs in hepatic stellate cells. CIP-A5 treatment also resulted in suppression of the profibrogenic cytokines, such as TGF-β, tumor necrosis factor alpha (TNF-α) and connective tissue growth factor (CTGF) in HSC-T6 cells. CIP-A5 did not have cytotoxicity to human normal hepatic cells. These results implied that CIP-A5 could selectively ameliorate the process of liver cirrhosis through modulation of activated hepatic stellate cell activity, which offers hope for prevention and treatment of this devastating end-stage liver disease. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors.

PubMed

Lu, Zhimin; Hunter, Tony

2010-06-15

The expression levels of the p21(Cip1) family CDK inhibitors (CKIs), p21(Cip1), p27(Kip1) and p57(Kip2), play a pivotal role in the precise regulation of cyclin-dependent kinase (CDK) activity, which is instrumental to proper cell cycle progression. The stabilities of p21(Cip1), p27(Kip1) and p57(Kip2) are all tightly and differentially regulated by ubiquitylation and proteasome-mediated degradation during various stages of the cell cycle, either in steady state or in response to extracellular stimuli, which often elicit site-specific phosphorylation of CKIs triggering their degradation.

Functional Heterologous Expression of an Engineered Full Length CipA from Clostridium thermocellum in Thermoanaerobacterium saccharolyticum

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

Currie, Devin; Herring, Christopher; Guss, Adam M

BACKGROUND: Cellulose is highly recalcitrant and thus requires a specialized suite of enzymes to solubilize it into fermentable sugars. In C. thermocellum, these extracellular enzymes are present as a highly active multi-component system known as the cellulosome. This study explores the expression of a critical C. thermocellum cellulosomal component in T. saccharolyticum as a step toward creating a thermophilic bacterium capable of consolidated bioprocessing by employing heterologously expressed cellulosomes. RESULTS: We developed an inducible promoter system based on the native T. saccharolyticum xynA promoter, which was shown to be induced by xylan and xylose. The promoter was used to expressmore » the cellulosomal component cipA*, an engineered form of the wild-type cipA from C. thermocellum. Expression and localization to the supernatant were both verified for CipA*. When a cipA mutant C. thermocellum strain was cultured with a CipA*-expressing T. saccharolyticum strain, hydrolysis and fermentation of 10 grams per liter SigmaCell 101, a highly crystalline cellulose, were observed. This trans-species complementation of a cipA deletion demonstrated the ability for CipA* to assemble a functional cellulosome. CONCLUSION: This study is the first example of an engineered thermophile heterologously expressing a structural component of a cellulosome. To achieve this goal we developed and tested an inducible promoter for controlled expression in T. saccharolyticum as well as a synthetic cipA. In addition, we demonstrate a high degree of hydrolysis (up to 93%) on microcrystalline cellulose.« less

Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth

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

Tane, Shoji; Okayama, Hitomi; Ikenishi, Aiko

Mammalian cardiomyocytes actively proliferate during embryonic stages, following which they exit their cell cycle after birth, and the exit is maintained. Previously, we showed that two inhibitory systems (the G1-phase inhibitory system: repression of cyclin D1 expression; the M-phase inhibitory system: inhibition of CDK1 activation) maintain the cell cycle exit of mouse adult cardiomyocytes. We also showed that two CDK inhibitors (CKIs), p21{sup Cip1} and p27{sup Kip1}, regulate the cell cycle exit in a portion of postnatal cardiomyocytes. It remains unknown whether the two inhibitory systems are involved in the cell cycle exit of postnatal cardiomyocytes and whether p21{sup Cip1}more » and p27{sup Kip1} also inhibit entry to M-phase. Here, we showed that more than 40% of cardiomyocytes entered an additional cell cycle by induction of cyclin D1 expression at postnatal stages, but M-phase entry was inhibited in the majority of cardiomyocytes. Marked cell cycle progression and endoreplication were observed in cardiomyocytes of p21{sup Cip1} knockout mice at 4 weeks of age. In addition, tri- and tetranucleated cardiomyocytes increased significantly in p21{sup Cip1} knockout mice. These data showed that the G1-phase inhibitory system and two CKIs (p21{sup Cip1} and p27{sup Kip1}) inhibit entry to an additional cell cycle in postnatal cardiomyocytes, and that the M-phase inhibitory system and p21{sup Cip1} inhibit M-phase entry of cardiomyocytes which have entered the additional cell cycle. - Highlights: • Many postnatal cardiomyocytes entered an additional cell cycle by cyclin D1 induction. • The majority of cardiomyocytes could not enter M-phase after cyclin D1 induction. • Cell cycle progressed markedly in p21{sup Cip1} knockout mice after postnatal day 14. • Tri- and tetranucleated cardiomyocytes increased in p21{sup Cip1} knockout mice.« less

IL-6 modulates hepatocyte proliferation via induction of HGF/p21{sup cip1}: Regulation by SOCS3

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

Sun Rui; Jaruga, Barbara; Kulkarni, Shailin

2005-12-30

The precise role of IL-6 in liver regeneration and hepatocyte proliferation is controversial and the role of SOCS3 in liver regeneration remains unknown. Here we show that in vitro treatment with IL-6 inhibited primary mouse hepatocyte proliferation. IL-6 induced p21{sup cip1} protein expression in primary mouse hepatocytes. Disruption of the p21{sup cip1} gene abolished the inhibitory effect of IL-6 on cell proliferation. Co-culture with nonparenchymal liver cells diminished IL-6 inhibition of hepatocyte proliferation, which was likely due to IL-6 stimulation of nonparenchymal cells to produce HGF. Finally, IL-6 induced higher levels of p21{sup cip1} protein expression and a slightly strongermore » inhibition of cell proliferation in SOCS3{sup +/-} mouse hepatocytes compared to wild-type hepatocytes, while liver regeneration was enhanced and prolonged in SOCS3{sup +/-} mice. Our findings suggest that IL-6 directly inhibits hepatocyte proliferation via a p21{sup cip1}-dependent mechanism and indirectly enhances hepatocyte proliferation via stimulating nonparenchymal cells to produce HGF. SOCS3 negatively regulates liver regeneration.« less

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer.

PubMed

Birkman, Eva-Maria; Elzagheid, Adam; Jokilehto, Terhi; Avoranta, Tuulia; Korkeila, Eija; Kulmala, Jarmo; Syrjänen, Kari; Westermarck, Jukka; Sundström, Jari

2018-03-01

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The maternal genes Ci-p53/p73-a and Ci-p53/p73-b regulate zygotic ZicL expression and notochord differentiation in Ciona intestinalis embryos.

PubMed

Noda, Takeshi

2011-12-01

I isolated a Ciona intestinalis homolog of p53, Ci-p53/p73-a, in a microarray screen of rapidly degraded maternal mRNA by comparing the transcriptomes of unfertilized eggs and 32-cell stage embryos. Higher expression of the gene in eggs and lower expression in later embryonic stages were confirmed by whole-mount in situ hybridization (WISH) and quantitative reverse transcription-PCR (qRT-PCR); expression was ubiquitous in eggs and early embryos. Knockdown of Ci-p53/p73-a by injection of antisense morpholino oligonucleotides (MOs) severely perturbed gastrulation cell movements and expression of notochord marker genes. A key regulator of notochord differentiation in Ciona embryos is Brachyury (Ci-Bra), which is directly activated by a zic-like gene (Ci-ZicL). The expression of Ci-ZicL and Ci-Bra in A-line notochord precursors was downregulated in Ci-p53/p73-a knockdown embryos. Maternal expression of Ci-p53/p73-b, a homolog of Ci-p53/p73-a, was also detected. In Ci-p53/p73-b knockdown embryos, gastrulation cell movements, expression of Ci-ZicL and Ci-Bra in A-line notochord precursors, and expression of notochord marker gene at later stages were perturbed. The upstream region of Ci-ZicL contains putative p53-binding sites. Cis-regulatory analysis of Ci-ZicL showed that these sites are involved in expression of Ci-ZicL in A-line notochord precursors at the 32-cell and early gastrula stages. These results suggest that p53 genes are maternal factors that play a crucial role in A-line notochord differentiation in C. intestinalis embryos by regulating Ci-ZicL expression. Copyright © 2011 Elsevier Inc. All rights reserved.

[Anti-MDR tumor mechanism of CIP-36, a podophyllotoxin derivative].

PubMed

Mei, Xin; Jiang, Yun-gen; Lü, Jing-jing; Wu, Ke-zhu; Cao, Bo; Chen, Hong

2011-10-01

This study is to investigate the antitumor activity of CIP-36 on multidrug resistant human oral squamous carcinoma cell line (KBV200 cells) in vitro and the possible anticancer mechanisms. MTT assay, Hoechst fluorescein stain, RT-PCR and immunohistochemistry were carried out on KBV200 and KB cells. The growth of many tumor cells was obviously inhibited by CIP-36, especially the multidrug resistant cells KBV200. Obvious apoptosis could be observed in the Hoechst 33342 staining experiments. The results of RT-PCR showed that the levels of p53, p21, caspase-3 and bax mRNA increased, and meanwhile the expression of mdr-1 and bcl-2 mRNA decreased in a dose-dependent manner. The data were significantly different from that of vehicle. The expression of P-gp significantly decreased with the increasing dosage of CIP-36 examined by immunohistochemistry. It can be concluded that CIP-36 could change resistance-related genes and proteins to overcome multidrug resistance in the KBV200 cell line.

The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models.

PubMed

Wang, Zhiyong; Shah, O Jameel; Hunter, Tony

2012-01-01

Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes.

The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models

PubMed Central

Wang, Zhiyong; Shah, O. Jameel; Hunter, Tony

2012-01-01

Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. PMID:22859932

Targeting aminopeptidase N (APN/CD13) with cyclic-imide peptidomimetics derivative CIP-13F inhibits the growth of human ovarian carcinoma cells.

PubMed

Cui, Shu-Xiang; Qu, Xian-Jun; Gao, Zu-Hua; Zhang, Yu-Sheng; Zhang, Xiao-Fan; Zhao, Cui-Rong; Xu, Wen-Fang; Li, Qian-Bin; Han, Jin-Xiang

2010-06-28

Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angiogenesis. Inhibition of APN/CD13 may be an effective strategy for cancer treatment. CIP-13F is a cyclic-imide peptidomimetics compound designed to fit the active pockets S1 and S'1 of APN/CD13 that act in tumor proliferation. Our aim in this study was to evaluate the efficacy of CIP-13F as a candidate compound for cancer treatment. The experiments were performed on the human ovarian carcinoma (OVCA) ES-2 and HRA cell lines, which have high and low levels of APN/CD13 respectively. CIP-13F significantly blocked APN/CD13 activity on the surface of ES-2 cells as measured by quantitating the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. CIP-13F effectively inhibited ES-2 cell growth and migration without significant cytotoxic effect. In contrast, CIP-13F did not significantly inhibit HRA cell growth, indicating that CIP-13F may inhibit ES-2 cell growth via suppression of APN/CD13. The suppression of APN/CD13 was also observed by using the assays of flow cytometry and Western blot analysis. Further, the inhibitory effects of CIP-13F on APN/CD13 and on ES-2 proliferation were supported by the induction of ES-2 apoptosis. CIP-13F-treated ES-2 cells resulted apoptotic characteristics, such as induction of externalization of phosphatidylserine and DNA laddering fragment. The activation of caspase-3 and poly ADP-ribose polymerase (PARP) was also enhanced. The inhibitory effects of CIP-13F on APN/CD13 expression and on ES-2 proliferation were confirmed in mice bearing ES-2 xenografts. CIP-13F delayed the growth of ES-2 xenografts in mice after 2 weeks of vena caudalis injection. These results suggest that CIP-13F has a high inhibitory effect on the growth of OVCA cells via decreasing the activity and expression of APN/CD13. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism.

PubMed

Su, W C; Kitagawa, M; Xue, N; Xie, B; Garofalo, S; Cho, J; Deng, C; Horton, W A; Fu, X Y

1997-03-20

The achondroplasia class of chondrodysplasias comprises the most common genetic forms of dwarfism in humans and includes achondroplasia, hypochondroplasia and thanatophoric dysplasia types I and II (TDI and TDII), which are caused by different mutations in a fibroblast growth-factor receptor FGFR3 (ref. 1). The molecular mechanism and the mediators of these FGFR3-related growth abnormalities are not known. Here we show that mutant TDII FGFR3 has a constitutive tyrosine kinase activity which can specifically activate the transcription factor Stat1 (for signal transducer and activator of transcription). Furthermore, expression of TDII FGFR3 induced nuclear translocation of Stat1, expression of the cell-cycle inhibitor p21(WAF1/CIP1), and growth arrest of the cell. Thus, TDII FGFR3 may use Stat1 as a mediator of growth retardation in bone development. Consistent with this, Stat1 activation and increased p21(WAF1/CIP1) expression was found in the cartilage cells from the TDII fetus, but not in those from the normal fetus. Thus, abnormal STAT activation and p21(WAF1/CIP1) expression by the TDII mutant receptor may be responsible for this FGFR3-related bone disease.

Recombinant adenovirus-p21 attenuates proliferative responses associated with excessive scarring.

PubMed

Gu, Danling; Atencio, Isabella; Kang, David W; Looper, L David; Ahmed, C M I; Levy, Alina; Maneval, Dan; Zepeda, Monica L

2005-01-01

Excessive cutaneous scarring is an important clinical disorder resulting in adverse tissue growth and function as well as undesirable cosmetic appearance. p21WAF-1/Cip-1 is a cyclin-dependent kinase inhibitor that blocks cell cycle progression and inhibits cell proliferation. We used a recombinant adenovirus containing the human p21WAF-1/Cip-1 cDNA (rAd-p21) to evaluate proliferative responses in skin models. In vitro dose-response studies using primary human dermal fibroblasts resulted in a dose-dependent expression of p21WAF-1/Cip-1 protein and a 3- to 80-fold reduction in cell proliferation as measured by 5-bromodeoxyuridine incorporation. Further, rAd-p21 reduced type I procollagen production when compared to control virus. A rat polyvinyl alcohol sponge model was used to determine rAd-p21 effects on granulation tissue formation in vivo. Sponges pretreated with a granulation tissue stimulator, rAd-PDGF-B and subsequently rAd-p21 on a second injection, showed a p21WAF-1/Cip-1 specific dose-dependent decrease in percent granulation fill as the rAd-p21 dose increased (p < 0.001). Immunohistochemistry identified human p21WAF-1/Cip-1 expression in sponges treated with rAd-p21 5 days postinjection. Additionally, 5-bromodeoxyuridine and Ki67 staining in sponges treated with rAd-p21 showed a significant decrease in proliferation when compared to rAd-platelet-derived growth factor-B alone or vehicle control groups (p < 0.01). These data support the utility of p21WAF-1/Cip-1 in targeting hyperproliferative disorders of the skin.

CDK inhibitors, p21{sup Cip1} and p27{sup Kip1}, participate in cell cycle exit of mammalian cardiomyocytes

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

Tane, Shoji; Ikenishi, Aiko; Okayama, Hitomi

2014-01-17

Highlights: •Expression of p21 and p27 in the hearts showed a peak during postnatal stages. •p21 and p27 bound to cyclin E, cyclin A and CDK2 in the hearts at postnatal stages. •Cardiomyocytes in both KO mice showed failure in the cell cycle exit at G1-phase. •These data show the first apparent phenotypes in the hearts of Cip/Kip KO mice. -- Abstract: Mammalian cardiomyocytes actively proliferate during embryonic stages, following which cardiomyocytes exit their cell cycle after birth. The irreversible cell cycle exit inhibits cardiac regeneration by the proliferation of pre-existing cardiomyocytes. Exactly how the cell cycle exit occurs remainsmore » largely unknown. Previously, we showed that cyclin E- and cyclin A-CDK activities are inhibited before the CDKs levels decrease in postnatal stages. This result suggests that factors such as CDK inhibitors (CKIs) inhibit CDK activities, and contribute to the cell cycle exit. In the present study, we focused on a Cip/Kip family, which can inhibit cyclin E- and cyclin A-CDK activities. Expression of p21{sup Cip1} and p27{sup Kip1} but not p57{sup Kip2} showed a peak around postnatal day 5, when cyclin E- and cyclin A-CDK activities start to decrease. p21{sup Cip1} and p27{sup Kip1} bound to cyclin E, cyclin A and CDK2 at postnatal stages. Cell cycle distribution patterns of postnatal cardiomyocytes in p21{sup Cip1} and p27{sup Kip1} knockout mice showed failure in the cell cycle exit at G1-phase, and endoreplication. These results indicate that p21{sup Cip1} and p27{sup Kip} play important roles in the cell cycle exit of postnatal cardiomyocytes.« less

β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1.

PubMed

Coughlan, N; Thillainadesan, G; Andrews, J; Isovic, M; Torchia, J

2013-06-01

The steroid receptor coactivator p/CIP, also known as SRC-3, is an oncogene commonly amplified in breast and ovarian cancers. p/CIP is known to associate with coactivator arginine methyltransferase 1 (CARM1) on select estrogen responsive genes. We have shown, using a ChIP-on-chip approach, that in response to stimulation with 17β-estradiol (E2), the p/CIP/CARM1 complex is recruited to 204 proximal promoters in MCF-7 cells. Many of the complex target genes have been previously implicated in signaling pathways related to oncogenesis. Jak2, a member of the Jak/Stat signaling cascade, is one of the direct E2-dependent targets of the p/CIP/CARM1 complex. Following E2-treatment, histone modifications at the Jak2 promoter are reflective of a transcriptionally permissive gene, and modest changes in RNA and protein expression lead us to suggest that an additional factor(s) may be required for a more notable transcriptional and functional response. Bioinformatic examination of the 204 proximal promoter sequences of p/CIP/CARM1 targets supports the idea that transcription factor crosstalk is likely the favored mechanism of E2-dependent p/CIP/CARM1 complex recruitment. This data may have implications towards understanding the oncogenic role of p/CIP in breast cancer and ultimately allow for the identification of new prognostic indicators and/or viable therapeutic targets. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Characterisation of cell cycle arrest and terminal differentiation in a maximally proliferative human epithelial tissue: Lessons from the human hair follicle matrix.

PubMed

Purba, Talveen S; Brunken, Lars; Peake, Michael; Shahmalak, Asim; Chaves, Asuncion; Poblet, Enrique; Ceballos, Laura; Gandarillas, Alberto; Paus, Ralf

2017-09-01

Human hair follicle (HF) growth and hair shaft formation require terminal differentiation-associated cell cycle arrest of highly proliferative matrix keratinocytes. However, the regulation of this complex event remains unknown. CIP/KIP family member proteins (p21 CIP1 , p27 KIP1 and p57 KIP2 ) regulate cell cycle progression/arrest, endoreplication, differentiation and apoptosis. Since they have not yet been adequately characterized in the human HF, we asked whether and where CIP/KIP proteins localise in the human hair matrix and pre-cortex in relation to cell cycle activity and HF-specific epithelial cell differentiation that is marked by keratin 85 (K85) protein expression. K85 expression coincided with loss or reduction in cell cycle activity markers, including in situ DNA synthesis (EdU incorporation), Ki-67, phospho-histone H3 and cyclins A and B1, affirming a post-mitotic state of pre-cortical HF keratinocytes. Expression of CIP/KIP proteins was found abundantly within the proliferative hair matrix, concomitant with a role in cell cycle checkpoint control. p21 CIP1 , p27 KIP1 and cyclin E persisted within post-mitotic keratinocytes of the pre-cortex, whereas p57 KIP2 protein decreased but became nuclear. These data imply a supportive role for CIP/KIP proteins in maintaining proliferative arrest, differentiation and anti-apoptotic pathways, promoting continuous hair bulb growth and hair shaft formation in anagen VI. Moreover, post-mitotic hair matrix regions contained cells with enlarged nuclei, and DNA in situ hybridisation showed cells that were >2N in the pre-cortex. This suggests that CIP/KIP proteins might counterbalance cyclin E to control further rounds of DNA replication in a cell population that has a propensity to become tetraploid. These data shed new light on the in situ-biography of human hair matrix keratinocytes on their path of active cell cycling, arrest and terminal differentiation, and showcase the human HF as an excellent, clinically relevant model system for cell cycle physiology research of human epithelial cells within their natural tissue habitat. Crown Copyright © 2017. Published by Elsevier GmbH. All rights reserved.

Correlation Among Six Biologic Factors (p53, p21{sup WAF1}, MIB-1, EGFR, HER2, and Bcl-2) and Clinical Outcomes After Curative Chemoradiation Therapy in Squamous Cell Cervical Cancer

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

Yamashita, Hideomi; Murakami, Naoya; Asari, Takao

Purpose: The expressions of six cell-cycle-associated proteins were analyzed in cervical squamous cell carcinomas in correlation in a search for prognostic correlations in tumors treated with concurrent chemoradiation therapy (cCRT). Methods and Materials: The expressions of p53, p21/waf1/cip1, molecular immunology borstel-1 (MIB-1), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor type 2 (HER2), and Bcl-2 were studied using an immunohistochemical method in 57 cases of cervical squamous cell carcinoma treated with cCRT. Patients received cCRT between 1998 and 2005. The mean patient age was 61 years (range, 27-82 years). The number of patients with Stage II, III, andmore » IVA disease was 18, 29, and 10, respectively. Results: The number of patients with tumors positive for p53, p21/waf1/cip1, MIB-1, EGFR, HER2, and Bcl-2 was 26, 24, 49, 26, 13, and 11, respectively; no significant correlation was noted. The 5-year overall survival rates of HER2-positive and -negative patients was 76% vs. 44%, which was of borderline significance (p = 0.0675). No significant correlation was noted between overall survival and expressions of p53, p21/waf1/cip1, MIB-1, EGFR, and Bcl-2. No correlation was observed between local control and expression of any of the proteins. Conclusion: Expression of HER2 protein had a weak impact of borderline significance on overall survival in squamous cell carcinoma of the uterine cervix treated with cCRT. However, no clinical associations could be established for p53, p21/waf1/cip1, MIB-1, EGFR, and Bcl-2 protein expressions.« less

Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells.

PubMed

Kim, Myeong-Ok; Choe, Min Ho; Yoon, Yi Na; Ahn, Jiyeon; Yoo, Minjin; Jung, Kwan-Young; An, Sungkwan; Hwang, Sang-Gu; Oh, Jeong Su; Kim, Jae-Sung

2017-11-15

Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. Copyright © 2017 Elsevier Inc. All rights reserved.

Modifications in cell cycle kinetics and in expression of G1 phase-regulating proteins in human amniotic cells after exposure to electromagnetic fields and ionizing radiation.

PubMed

Lange, S; Viergutz, T; Simkó, M

2004-10-01

Low-frequency electromagnetic fields are suspected of being involved in carcinogenesis, particularly in processes that could be related to cancer promotion. Because development of cancer is associated with deregulated cell growth and we previously observed a magnetic field-induced decrease in DNA synthesis [Lange et al. (2002) Alterations in the cell cycle and in the protein level of cyclin D1p, 21CIP1, and p16INK4a after exposure to 50 HZ. MF in human cells. Radiat. Environ. Biophys.41, 131], this study aims to document the influence of 50 Hz, 1 mT magnetic fields (MF), with or without initial gamma-ionizing radiation (IR), on the following cell proliferation-relevant parameters in human amniotic fluid cells (AFC): cell cycle distribution, expression of the G1 phase-regulating proteins Cdk4, cyclin D1, p21CIP1 and p16INK4a, and Cdk4 activity. While IR induced a G1 delay and a dose-dependent G2 arrest, no discernible changes in cell cycle kinetics were observed due to MF exposure. However, a significant decrease in the protein expression of cyclin D1 and an increase in p21CIP1- and p16INK4a-expression could be detected after exposure to MF alone. IR-exposure caused an augmentation of p21CIP1- and p16INK4a- levels as well, but did not alter cyclin D1 expression. A slight diminution of Cdk4 activity was noticed after MF exposure only, indicating that Cdk4 appears not to act as a mediator of MF- or IR-induced changes in the cell cycle of AFC cells. Co-exposure to MF/IR affected neither cell cycle distribution nor protein expression or kinase activity additionally or synergistically, and therefore MF seems not to modify the mutagenic potency of IR.

Delayed expression of hpS2 and prolonged expression of CIP1/WAF1/SDI1 in human tumour cells irradiated with X-rays, fission neutrons or 1 GeV/nucleon Fe ions

NASA Technical Reports Server (NTRS)

Balcer-Kubiczek, E. K.; Zhang, X. F.; Harrison, G. H.; Zhou, X. J.; Vigneulle, R. M.; Ove, R.; McCready, W. A.; Xu, J. F.

1999-01-01

PURPOSE: Differences in gene expression underlie the phenotypic differences between irradiated and unirradiated cells. The goal was to identify late-transcribed genes following irradiations differing in quality, and to determine the RBE of 1 GeV/n Fe ions. MATERIALS AND METHODS: Clonogenic assay was used to determine the RBE of Fe ions. Differential hybridization to cDNA target clones was used to detect differences in expression of corresponding genes in mRNA samples isolated from MCF7 cells irradiated with iso-survival doses of Fe ions (0 or 2.5 Gy) or fission neutrons (0 or 1.2 Gy) 7 days earlier. Northern analysis was used to confirm differential expression of cDNA-specific mRNA and to examine expression kinetics up to 2 weeks after irradiation. RESULTS: Fe ion RBE values were between 2.2 and 2.6 in the lines examined. Two of 17 differentially expressed cDNA clones were characterized. hpS2 mRNA was elevated from 1 to 14 days after irradiation, whereas CIP1/WAF1/SDI1 remained elevated from 3 h to 14 days after irradiation. Induction of hpS2 mRNA by irradiation was independent of p53, whereas induction of CIP1/WAF1/SDI1 was observed only in wild-type p53 lines. CONCLUSIONS: A set of coordinately regulated genes, some of which are independent of p53, is associated with change in gene expression during the first 2 weeks post-irradiation.

Aspirin reduces the apoptotic effect of etoposide via Akt activation and up-regulation of p21(cip).

PubMed

Feng, Xiaocheng; Lu, Bin; Xu, Yingying; Li, Qin; Zhou, Wenbai; Yang, Zhihong; Yang, Zeng; Zhao, Weiwei; Shen, Zonghou; Hu, Renming

2011-10-01

Previous studies on the apoptotic effect of aspirin mainly focus on colorectal cancer and breast carcinoma. Few studies have been designed to explore the effect of aspirin on hepatocellular carcinoma. In the present study, we observed that aspirin caused G0/G1 phase cell cycle arrest and reduced etoposide induced caspase-3 activation in hepatocellular carcinoma G2 (HepG2) cells. Further investigation demonstrated that aspirin notably enhanced the activity of Akt and ERK1/2. Blocking the activation of Akt by the PI3-K-selective inhibitor wortmannin abrogated the anti-apoptotic effect of aspirin while the MEK inhibitor U0126 did not. p21(cip), an important substrate of Akt, is involved in the regulation of cell cycle arrest and apoptosis. Our data showed that the protein expression and ser146 phosphorylation levels of p21(cip) were significantly increased after treatment with aspirin, whereas p53 or p27 showed no change. The increase of p21(cip) protein levels was also scavenged by wortmannin but not by U0126. Moreover, reduction of caspase-3 activity induced by aspirin was attenuated by silencing p21(cip) expression. These results indicated that the anti-apoptotic effect of aspirin was dependent on activation of Akt which inhibited cell apoptosis by up-regulating p21(cip) and blocking caspase-3 activation. These findings could have clinical relevance in anticancer therapy and aspirin co-treatment of human malignancies.

Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21WAF1/CIP1 expression.

PubMed

Tseng, Tsui-Hwa; Chien, Ming-Hsien; Lin, Wea-Lung; Wen, Yu-Ching; Chow, Jyh-Ming; Chen, Chi-Kuan; Kuo, Tsang-Chih; Lee, Wei-Jiunn

2017-02-01

Apigenin (4',5,7-trihydroxyflavone), a flavonoid commonly found in fruits and vegetables, has anticancer properties in various malignant cancer cells. However, the molecular basis of the anticancer effect remains to be elucidated. In this study, we investigated the cellular mechanisms underlying the induction of cell cycle arrest by apigenin. Our results showed that apigenin at the nonapoptotic induction concentration inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in the MDA-MB-231 breast cancer cell line. Immunoblot analysis indicated that apigenin suppressed the expression of cyclin A, cyclin B, and cyclin-dependent kinase-1 (CDK1), which control the G2-to-M phase transition in the cell cycle. In addition, apigenin upregulated p21 WAF1/CIP1 and increased the interaction of p21 WAF1/CIP1 with proliferating cell nuclear antigen (PCNA), which inhibits cell cycle progression. Furthermore, apigenin significantly inhibited histone deacetylase (HDAC) activity and induced histone H3 acetylation. The subsequent chromatin immunoprecipitation (ChIP) assay indicated that apigenin increased acetylation of histone H3 in the p21 WAF1/CIP1 promoter region, resulting in the increase of p21 WAF1/CIP1 transcription. In a tumor xenograft model, apigenin effectively delayed tumor growth. In these apigenin-treated tumors, we also observed reductions in the levels of cyclin A and cyclin B and increases in the levels of p21 WAF1/CIP1 and acetylated histone H3. These findings demonstrate for the first time that apigenin can be used in breast cancer prevention and treatment through epigenetic regulation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 434-444, 2017. © 2016 Wiley Periodicals, Inc.

Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells.

PubMed

Liu, Pei-Yao; Chan, James Yi-Hsin; Lin, Hsiu-Chen; Wang, Sung-Ling; Liu, Shu-Ting; Ho, Ching-Liang; Chang, Li-Chien; Huang, Shih-Ming

2008-07-01

Zac1 is a novel seven-zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21(WAF1/Cip1) promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21(WAF1/Cip1) gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A-induced p21(WAF1/Cip1) protein expression might be mediated through a p53-independent and HDAC deacetylase-independent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

Type I collagen aging impairs discoidin domain receptor 2-mediated tumor cell growth suppression

PubMed Central

Saby, Charles; Buache, Emilie; Brassart-Pasco, Sylvie; El Btaouri, Hassan; Courageot, Marie-Pierre; Van Gulick, Laurence; Garnotel, Roselyne; Jeannesson, Pierre; Morjani, Hamid

2016-01-01

Tumor cells are confronted to a type I collagen rich environment which regulates cell proliferation and invasion. Biological aging has been associated with structural changes of type I collagen. Here, we address the effect of collagen aging on cell proliferation in a three-dimensional context (3D). We provide evidence for an inhibitory effect of adult collagen, but not of the old one, on proliferation of human fibrosarcoma HT-1080 cells. This effect involves both the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP-2. DDR2 and SHP-2 were less activated in old collagen. DDR2 inhibition decreased SHP-2 phosphorylation in adult collagen and increased cell proliferation to a level similar to that observed in old collagen. In the presence of old collagen, a high level of JAK2 and ERK1/2 phosphorylation was observed while expression of the cell cycle negative regulator p21CIP1 was decreased. Inhibition of DDR2 kinase function also led to an increase in ERK1/2 phosphorylation and a decrease in p21CIP1 expression. Similar signaling profile was observed when DDR2 was inhibited in adult collagen. Altogether, these data suggest that biological collagen aging could increase tumor cell proliferation by reducingthe activation of the key matrix sensor DDR2. PMID:27121132

Pim-1 kinase expression during murine mammary development

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

Gapter, Leslie A.; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234; Magnuson, Nancy S.

2006-07-07

Pim-1 kinase phosphorylates substrates whose activities are linked to proliferation, survival, differentiation, and apoptosis. Although pim-1 is induced by hormones and cytokines, the hormonal control and contribution of Pim-1 to mammary gland development have not been evaluated. We examined Pim-1 expression in mammary cell lines, investigated whether Pim-1 levels could be altered in breast epithelia by mammogenic hormones, and evaluated Pim-1 expression during mammary development. We found that Pim-1 was elevated in most mammary carcinoma cell lines and progesterone increased Pim-1 protein to some extent in non-tumorigenic mammary epithelia. Pim-1 expression in situ was consistent with the documented profile ofmore » progesterone activity in mouse mammary glands. Pim-1 nuclear localization correlated with cytoplasmic distribution for its substrate, p21{sup CIP/Waf1}, and we found that Pim-1 and p21 associate in vitro. Our results suggest that Pim-1 expression may be regulated by progesterone during mammary development and Pim-1 associates with p21 in mammary epithelial cells.« less

Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.

PubMed

Narayanan, Bhagavathi A

2006-12-01

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer.

ROCK mediates phorbol ester-induced apoptosis in prostate cancer cells via p21Cip1 up-regulation and JNK.

PubMed

Xiao, Liqing; Eto, Masumi; Kazanietz, Marcelo G

2009-10-23

It is established that androgen-dependent prostate cancer cells undergo apoptosis upon treatment with phorbol esters and related analogs, an effect primarily mediated by PKCdelta. Treatment of LNCaP prostate cancer cells with phorbol 12-myristate 13-acetate (PMA) causes a strong and sustained activation of RhoA and its downstream effector ROCK (Rho kinase) as well as the formation of stress fibers. These effects are impaired in cells subjected to PKCdelta RNA interference depletion. Functional studies revealed that expression of a dominant negative RhoA mutant or treatment with the ROCK inhibitor Y-27632 inhibits the apoptotic effect of PMA in LNCaP cells. Remarkably, the cytoskeleton inhibitors cytochalasin B and blebbistatin blocked not only PMA-induced apoptosis but also the activation of JNK, a mediator of the cell death effect by the phorbol ester. In addition, we found that up-regulation of the cell cycle inhibitor p21(Cip1) is required for PMA-induced apoptosis and that inhibitors of ROCK or the cytoskeleton organization prevent p21(Cip1) induction. Real time PCR analysis and reporter gene assay revealed that PMA induces p21(Cip1) transcriptionally in a ROCK- and cytoskeleton-dependent manner. p21(Cip1) promoter analysis revealed that PMA induction is dependent on Sp1 elements in the p21(Cip1) promoter but independent of p53. Taken together, our studies implicate ROCK-mediated up-regulation of p21(Cip1) and the cytoskeleton in PKCdelta-dependent apoptosis in prostate cancer cells.

Role of the CipA Scaffoldin Protein in Cellulose Solubilization, as Determined by Targeted Gene Deletion and Complementation in Clostridium thermocellum

PubMed Central

Olson, Daniel G.; Giannone, Richard J.; Hettich, Robert L.

2013-01-01

The CipA scaffoldin protein plays a key role in the Clostridium thermocellum cellulosome. Previous studies have revealed that mutants deficient in binding or solubilizing cellulose also exhibit reduced expression of CipA. To confirm that CipA is, in fact, necessary for rapid solubilization of crystalline cellulose, the gene was deleted from the chromosome using targeted gene deletion technologies. The CipA deletion mutant exhibited a 100-fold reduction in cellulose solubilization rate, although it was eventually able to solubilize 80% of the 5 g/liter cellulose initially present. The deletion mutant was complemented by a copy of cipA expressed from a replicating plasmid. In this strain, Avicelase activity was restored, although the rate was 2-fold lower than that in the wild type and the duration of the lag phase was increased. The cipA coding sequence is located at the beginning of a gene cluster containing several other genes thought to be responsible for the structural organization of the cellulosome, including olpB, orf2p, and olpA. Tandem mass spectrometry revealed a 10-fold reduction in the expression of olpB, which may explain the lower growth rate. This deletion experiment adds further evidence that CipA plays a key role in cellulose solubilization by C. thermocellum, and it raises interesting questions about the differential roles of the anchor scaffoldin proteins OlpB, Orf2p, and SdbA. PMID:23204466

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients

PubMed Central

2014-01-01

Background Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. Methods In the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. Result The expressions of stathmin and EF1α gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P < 0.05). EF1α histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P < 0.05). Stathmin mRNA levels and histoscores, as well as EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P < 0.05). EF1α histoscores were also positively correlated with TIF (P < 0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P < 0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1α histoscore (all, P < 0.05). Conclusion Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1α levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients. PMID:24885363

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients.

PubMed

Ahn, Ei Yong; Yoo, Jeong Eun; Rhee, Hyungjin; Kim, Myung Soo; Choi, Junjeong; Ko, Jung Eun; Lee, Jee San; Park, Young Nyun

2014-05-31

Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. In the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. The expressions of stathmin and EF1α gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P<0.05). EF1α histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P<0.05). Stathmin mRNA levels and histoscores, as well as EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P<0.05). EF1α histoscores were also positively correlated with TIF (P<0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P<0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1α histoscore (all, P<0.05). Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1α levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients.

Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation

PubMed Central

Sørensen, Belinda Halling; Nielsen, Dorthe; Thorsteinsdottir, Unnur Arna; Hoffmann, Else Kay

2016-01-01

The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21Waf1/Cip1, Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21Waf1/Cip1 as well as Caspase-9/-3 activation in Cisplatin-sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFα-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin-induced increase in p53 protein level and its downstream signaling, i.e., Caspase-9/-3 activation, expression of p21Waf1/Cip1 and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A. PMID:26984736

Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells.

PubMed

Qu, Wei; Kang, Yin-Dong; Zhou, Mei-Sheng; Fu, Li-Li; Hua, Zhen-Hao; Wang, Li-Ming

2010-01-01

To investigate the inhibitory effect of histone deacetylase (HDAC) inhibitors (MS-275 and TSA) on T24 human bladder cancer cells in vitro, and explore the possible mechanism. The MTT assay was employed to evaluate the inhibitory effect of MS-275 and TSA on T24 cell growth. FCM was used to analyze the variation of T24 cell cycle distribution and the apoptotic ratio after T24 cells were treated with MS-275 and TSA. Histone acetylation level was detected by Western blot. mRNA expression of p21 WAF1/CIP1, cyclin A, and cyclin E was measured by FQ-PCR. Dynamic changes of Bcl-2 and bax expression were detected by FCM. MS-275 and TSA inhibited T24 cell growth in a concentration and time-dependent manner. Treatment with 4 μmol/l MS-275 or 0.4 μmol/l TSA blocked cell cycling in the G0/G1 phase and induced a significant increase in cell apoptosis. MS-275 and TSA significantly increased the level of histone acetylation, induced p21CIP1WAF1 mRNA expression, and inhibited cyclin A mRNA expression, though no significant effect was observed on cyclin E. Bcl-2 expression was down-regulated, while bax expression was up-regulated. HDAC inhibitors can block bladder cancer cell cycle in vitro and induce apoptosis. The molecular mechanism may be associated with increased level of histone acetylation, down-regulation of p21WAF1/CIP1 expression, up-regulation of cyclin A expression, and dynamic change of bcl-2 and bax expression. Copyright © 2010 Elsevier Inc. All rights reserved.

CIP-13F, a novel aminopeptidase N (APN/CD13) inhibitor, inhibits Lewis lung carcinoma growth and metastasis in mice.

PubMed

Pei, Ke-Ling; Yuan, Yi; Qin, San-Hai; Wang, Yan; Zhou, Ling; Zhang, Hou-Li; Qu, Xian-Jun; Cui, Shu-Xiang

2012-04-01

Aminopeptidase N (APN/CD13) is highly expressed on the surface of cancer cells and is thought to be involved in cancer growth and metastasis. The research of APN/CD13 inhibitors is considered as a strategy of cancer treatment. We aimed to evaluate the efficacy of CIP-13F, a novel APN/CD13 inhibitor, using a Lewis lung carcinoma (LLC) implantation mouse model. C57BL/6 mice were subcutaneously inoculated with LLC cells in anterior flank. Then, 0, 50 and 100 mg/kg of CIP-13F were injected via vena caudalis. Bestatin was used as the positive control. Administration of CIP-13F or bestatin was performed daily for 3 consecutive weeks. Mice were killed, and the tumors in anterior flank and metastasis nodules in lungs were examined. The assays of immunohistochemical staining, immunofluorescent flow cytometry and western blotting were performed to estimate the expression of APN/CD13 in LLC cells. We carried out the experiments of Annexin-V/PI staining, DNA fragmentation analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining to determine apoptotic cells in LLC tissues. Using immunohistochemical staining with CD34, the antiangiogenesis of CIP-13F was evaluated in LLC tissue sections. CIP-13F treatment resulted in a significant delay of LLC growth in anterior flank. Examination of lungs showed that the number of metastatic nodules of LLC was also markedly decreased. The inhibitory effect of CIP-13F on LLC growth was further evidenced by the induction of LLC apoptosis, showing the increases in Annexin-V/PI staining cells, DNA fragmentation and TUNEL staining cells. Molecular analyses of LLC tissues in CIP-13F-treated mice suggested that the decrease in APN/CD13 expression by CIP-13F might account for its actions of mechanism. Further, the inhibition of angiogenesis in LLC tissues was determined, showing the decreases in microvessel density (MVD) and angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF-α). Our results showed that CIP-13F effectively inhibited LLC growth and pulmonary metastasis in mice and suggested that CIP-13F is a potential drug for the treatment for cancers with positive APN/CD13 expression.

The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest.

PubMed

Gascoyne, Duncan M; Spearman, Hayley; Lyne, Linden; Puliyadi, Rathi; Perez-Alcantara, Marta; Coulton, Les; Fisher, Simon E; Croucher, Peter I; Banham, Alison H

2015-01-01

Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.

The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest

PubMed Central

Gascoyne, Duncan M.; Spearman, Hayley; Lyne, Linden; Puliyadi, Rathi; Perez-Alcantara, Marta; Coulton, Les; Fisher, Simon E.; Croucher, Peter I.; Banham, Alison H.

2015-01-01

Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology. PMID:26034982

Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

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

Bai, Lin; Shi, Guiying; Zhang, Xu

The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms ofmore » quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21{sup waf1}/cip1 and p57{sup kip2}, which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21{sup waf1}/cip1 and p57{sup kip2}. - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21{sup waf1/cip1} and p57{sup kip2}.« less

Risk Factors for Serious Prescription Opioid-Induced Respiratory Depression or Overdose: Comparison of Commercially Insured and Veterans Health Affairs Populations

PubMed Central

Nadpara, Pramit A; Joyce, Andrew R; Murrelle, E Lenn; Carroll, Nathan W; Carroll, Norman V; Barnard, Marie; Zedler, Barbara K

2018-01-01

Abstract Objective To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population. Subjects and Methods Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012. Results The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] = 10.20, 95% confidence interval [CI] = 9.06–11.40) and depression (OR = 3.12, 95% CI = 2.84–3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine; higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids. Conclusions Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices. PMID:28419384

Risk Factors for Serious Prescription Opioid-Induced Respiratory Depression or Overdose: Comparison of Commercially Insured and Veterans Health Affairs Populations.

PubMed

Nadpara, Pramit A; Joyce, Andrew R; Murrelle, E Lenn; Carroll, Nathan W; Carroll, Norman V; Barnard, Marie; Zedler, Barbara K

2018-01-01

To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population. Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012. The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] = 10.20, 95% confidence interval [CI] = 9.06-11.40) and depression (OR = 3.12, 95% CI = 2.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine; higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids. Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices. © 2017 American Academy of Pain Medicine.

CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations.

PubMed

Khanna, Anchit; Rane, Jayant K; Kivinummi, Kati K; Urbanucci, Alfonso; Helenius, Merja A; Tolonen, Teemu T; Saramäki, Outi R; Latonen, Leena; Manni, Visa; Pimanda, John E; Maitland, Norman J; Westermarck, Jukka; Visakorpi, Tapio

2015-08-14

Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.

DACH1 regulates cell cycle progression of myeloid cells through the control of cyclin D, Cdk 4/6 and p21{sup Cip1}

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

Lee, Jae-Woong; Kim, Hyeng-Soo; Kim, Seonggon

2012-03-30

Highlights: Black-Right-Pointing-Pointer DACH1 increases cyclin D, F and Cdk 1, 4, 6 in mouse myeloid progenitor cells. Black-Right-Pointing-Pointer The knockdown of DACH1 blocked the cell cycle progression of HL-60 cells. Black-Right-Pointing-Pointer The novel effect of DACH1 related with cell cycle regulation and leukemogenesis. -- Abstract: The cell-fate determination factor Dachshund, a component of the Retinal Determination Gene Network (RDGN), has a role in breast tumor proliferation through the repression of cyclin D1 and several key regulators of embryonic stem cell function, such as Nanog and Sox2. However, little is known about the role of DACH1 in a myeloid lineage asmore » a cell cycle regulator. Here, we identified the differential expression levels of extensive cell cycle regulators controlled by DACH1 in myeloid progenitor cells. The forced expression of DACH1 induced p27{sup Kip1} and repressed p21{sup Cip1}, which is a pivotal characteristic of the myeloid progenitor. Furthermore, DACH1 significantly increased the expression of cyclin D1, D3, F, and Cdk 1, 4, and 6 in myeloid progenitor cells. The knockdown of DACH1 blocked the cell cycle progression of HL-60 promyeloblastic cells through the decrease of cyclin D1, D3, F, and Cdk 1, 4, and 6 and increase in p21{sup Cip1}, which in turn decreased the phosphorylation of the Rb protein. The expression of Sox2, Oct4, and Klf4 was significantly up-regulated by the forced expression of DACH1 in mouse myeloid progenitor cells.« less

Regulation of Akt/FoxO3a/Skp2 Axis Is Critically Involved in Berberine-Induced Cell Cycle Arrest in Hepatocellular Carcinoma Cells

PubMed Central

Li, Fanni; Dong, Xiwen; Lin, Peng; Jiang, Jianli

2018-01-01

The maintenance of ordinal cell cycle phases is a critical biological process in cancer genesis, which is a crucial target for anti-cancer drugs. As an important natural isoquinoline alkaloid from Chinese herbal medicine, Berberine (BBR) has been reported to possess anti-cancer potentiality to induce cell cycle arrest in hepatocellular carcinoma cells (HCC). However, the underlying mechanism remains to be elucidated. In our present study, G0/G1 phase cell cycle arrest was observed in berberine-treated Huh-7 and HepG2 cells. Mechanically, we observed that BBR could deactivate the Akt pathway, which consequently suppressed the S-phase kinase-associated protein 2 (Skp2) expression and enhanced the expression and translocation of Forkhead box O3a (FoxO3a) into nucleus. The translocated FoxO3a on one hand could directly promote the transcription of cyclin-dependent kinase inhibitors (CDKIs) p21Cip1 and p27Kip1, on the other hand, it could repress Skp2 expression, both of which lead to up-regulation of p21Cip1 and p27Kip1, causing G0/G1 phase cell cycle arrest in HCC. In conclusion, BBR promotes the expression of CDKIs p21Cip1 and p27Kip1 via regulating the Akt/FoxO3a/Skp2 axis and further induces HCC G0/G1 phase cell cycle arrest. This research uncovered a new mechanism of an anti-cancer effect of BBR. PMID:29360760

Growth suppression of Leydig TM3 cells mediated by aryl hydrocarbon receptor

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

Iseki, Minoru; Department of Regulation Biology, Faculty of Science, Saitama University, Saitama; Ikuta, Togo

2005-06-17

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces developmental toxicity in reproductive organs. To elucidate the function of AhR, we generated stable transformants of TM3 cells overexpressing wild-type aryl hydrocarbon receptor (AhR) or its mutants which carried mutations in nuclear localization signal or nuclear export signal. In the presence of 3-methylcholanthrene (MC), proliferation of the cells transfected with wild-type AhR was completely suppressed, whereas cells expressing AhR mutants proliferated in a manner equivalent to control TM3 cells, suggesting AhR-dependent growth inhibition. The suppression was associated with up-regulation of cyclin-dependent kinase inhibitor p21{sup Cip1}, which was abolished by pretreatment with actinomycin D. A p38 MAPKmore » specific inhibitor, SB203580, blocked the increase of p21{sup Cip1} mRNA in response to MC. Treatment with indigo, another AhR ligand, failed to increase of p21{sup Cip1} mRNA, although up-regulation of mRNA for CYP1A1 was observed. These data suggest AhR in Leydig cells mediates growth inhibition by inducing p21{sup Cip1}.« less

Effects of Chrysanthemum indicum polysaccharide and its phosphate on anti-duck hepatitis a virus and alleviating hepatic injury.

PubMed

Ming, Ke; Chen, Yun; Shi, Jintong; Yang, Jingjing; Yao, Fangke; Du, Hongu; Zhang, Wei; Bai, Jingying; Liu, Jiaguo; Wang, Deyun; Hu, Yuanliang; Wu, Yi

2017-09-01

To explore new effective anti-duck hepatitis A virus drugs, Chrysanthemum indicum polysaccharide (CIPS) was phosphorylation modified using STMP-STPP method, and phosphorylated Chrysanthemum indicum polysaccharide (pCIPS) was obtained. Characteristic absorption peaks were observed in pCIPS using IR spectrum, suggested that CIPS was successfully modified. In addition, field emission scanning electron micro-scope (FE-SEM) was used to observe the polysaccharides' surface features. In vitro, we found that the survival rate of DHAV-infected hepatocytes increased after the two drugs treatment, indicated that the two drugs possess good anti-DHAV activity. The results of real-time PCR showed that pCIPS inhibited the virus gene replication more effectively than CIPS. Reed-Muench assay was used to observe the changes of the virulence, and the expression level of IFN-β was observed to verify the changes of virulence. In vivo experiment, the blood virus content reduced after CIPS and pCIPS treatment. To evaluate the ducklings' hepatic injury, the serum ALT, AST, TP and ALB levels were detected. Results showed that both CIPS and pCIPS could alleviate the hepatic injury of ducklings infected DHAV, especially for pCIPS. All the results above mentioned demonstrated that the anti-DHAV activity of CIPS was enhanced after phosphorylation modification. Copyright © 2017 Elsevier B.V. All rights reserved.

[Inhibitory effect of exogenous insulin-like growth factor binding protein 7 on proliferation of human breast cancer cell line MDA-MB-453 and its mechanism].

PubMed

Yuan, Lei; Fan, Wen-Juan; Yang, Xu-Guang; Rao, Shu-Mei; Song, Jin-Ling; Song, Guo-Hua

2013-10-25

The present study was to investigate the effects of exogenous insulin-like growth factor binding protein 7 (IGFBP7) on the proliferation of human breast cancer cell line MDA-MB-453 and its possible mechanism. By means of MTT method in vitro, the results showed exogenous IGFBP7 inhibited the growth of MDA-MB-453 cells (IC50 of IGFBP7 = 8.49 μg/mL) in time- and concentration-dependent manner. SB203580, p38(MAPK) inhibitor, blocked the anti-proliferative effect of exogenous IGFBP7. The flow cytometry assay showed that exogenous IGFBP7 remarkably induced G0/G1 arrest in MDA-MB-453 cells. The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38(MAPK), up-regulated expression of p21(CIP1/WAF1), and inhibited phosphorylation of Rb. SB203580 restrained exogenous IGFBP7-induced regulation of p21(CIP1/WAF1) and p-Rb in MDA-MB-453 cells. In conclusion, the present study suggests that exogenous IGFBP7 could activate the p38(MAPK) signaling pathway, upregulate p21(CIP1/WAF1) expression, inhibit phosphorylation of Rb, and finally induce G0/G1 arrest in MDA-MB-453 cells.

RhoA influences the nuclear localization of extracellular signal-regulated kinases to modulate p21Waf/Cip1 expression.

PubMed

Zuckerbraun, Brian S; Shapiro, Richard A; Billiar, Timothy R; Tzeng, Edith

2003-08-19

The 42/44-kD mitogen-activated protein kinases (extracellular signal-regulated kinases, ERKs) regulate smooth muscle cell (SMC) cell-cycle progression and can either promote or inhibit proliferation depending on the activation status of the small GTPase RhoA. RhoA is involved in the regulation of the actin cytoskeleton and converges on multiple signaling pathways. However, the mechanism by which RhoA modulates ERK signaling is not well defined. The purpose of this investigation was to examine whether RhoA regulates ERK downstream signaling and cellular proliferation through its effects on the cytoskeleton and the nuclear localization of ERK. Treatment of SMCs with Clostridia botulinum C3 exoenzyme, which inhibits RhoA activation, decreased SMC proliferation to 24+/-7% of that of controls and increased p21Waf1/Cip1 transcription and protein levels. These effects of RhoA were reversed by inhibition of ERK phosphorylation. However, inactivation of RhoA did not alter levels of ERK phosphorylation but did increase nuclear localization of phosphorylated ERK. In addition, immunostaining demonstrated that phosphorylated ERK associated with the actin cytoskeleton, which was disrupted by C3 exoenzyme. Leptomycin B, an inhibitor of Crm1 that results in ERK nuclear accumulation, similarly increased p21Waf1/Cip1. RhoA inhibition increased levels of phosphorylated ERK in the cell nucleus. Inhibition of RhoA or pharmacological inhibition of nuclear export resulted in increased p21Waf1/Cip1 expression and decreased SMC proliferation, effects that were partially dependent on ERK. RhoA regulation of the actin cytoskeleton may determine ERK subcellular localization and its subsequent effects on SMC proliferation.

Dental pulp stem cell responses to novel antibiotic-containing scaffolds for regenerative endodontics

PubMed Central

Kamocki, K.; Nör, J. E.; Bottino, M. C.

2014-01-01

Aim To evaluate both the drug release profile and the effects on human dental pulp stem cells’ (hDPSC) proliferation and viability of novel bi-mix antibiotic-containing scaffolds intended for use as a drug-delivery system for root canal disinfection prior to regenerative endodontics. Methodology Polydioxanone (PDS)-based fibrous scaffolds containing both metronidazole (MET) and ciprofloxacin (CIP) at selected ratios were synthesized via electrospinning. Fibre diameter was evaluated based on scanning electron microscopy (SEM) images. Pure PDS scaffolds and a saturated CIP/MET solution (i.e. 50 mg of each antibiotic in 1 mL) (hereafter referred to as DAP) served as both negative (non-toxic) and positive (toxic) controls, respectively. High performance liquid chromatography (HPLC) was done to investigate the amount of drug(s) released from the scaffolds. WST-1® proliferation assay was used to evaluate the effect of the scaffolds on cell proliferation. LIVE/DEAD® assay was used to qualitatively assess cell viability. Data obtained from drug release and proliferation assays were statistically analysed at the 5% significance level. Results A burst release of CIP and MET was noted within the first 24 h, followed by a sustained maintenance of the drug(s) concentration for 14 days. A concentration-dependent trend was noticed upon hDPSCs’ exposure to all CIP-containing scaffolds, where increasing the CIP concentration resulted in reduced cell proliferation (P<0.05) and viability. In groups exposed to pure MET or pure PDS scaffolds, no changes in proliferation were observed. Conclusions Synthesized antibiotic-containing scaffolds had significantly lower effects on hDPSCs proliferation when compared to the saturated CIP/MET solution (DAP). PMID:25425048

Alteration of gene expression profiles in skeletal muscle of rats exposed to microgravity during a spaceflight

NASA Technical Reports Server (NTRS)

Taylor, Wayne E.; Bhasin, Shalender; Lalani, Rukhsana; Datta, Anuj; Gonzalez-Cadavid, Nestor F.

2002-01-01

To clarify the mechanism of skeletal muscle wasting during spaceflights, we investigated whether intramuscular gene expression profiles are affected, by using DNA microarray methods. Male rats sent on the 17-day NASA STS-90 Neurolab spaceflight were sacrificed 24 hours after return to earth (MG group). Ground control rats were maintained for 17 days in flight-simulated cages (CS group). Spaceflight induced a 19% and 23% loss of tibialis anterior and gastrocnemius muscle mass, respectively, as compared to ground controls. Muscle RNA was analyzed by the Clontech Atlas DNA expression array in four rats, with two MG/ CS pairs for the tibialis anterior, and one pair for the gastrocnemius. Alterations in gene expression were verified for selected genes by reverse-transcription PCR. In both muscles of MG rats, mRNAs for 12 genes were up-regulated by over 2-fold, and 38 were down-regulated compared to controls. There was inhibition of genes for cell proliferation and growth factor cascades, including cell cycle genes and signal transduction proteins, such as p21 Cip1, retinoblastoma (Rb), cyclins G1/S, -E and -D3, MAP kinase 3, MAD3, and ras related protein RAB2. These data indicate that following exposure to microgravity, there is downregulation of genes involved in regulation of muscle satellite cell replication.

Interaction between transposable phages: cip locus of prophage D3112, responsible for inhibition of integration and transposition of the related phage B39 of Pseudomonas aeruginosa

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

Gerasimov, V.A.; Yanenko, A.S.; Akhverdyan, V.Z.

1986-04-01

Bacteriophage D3112 forms two types of PA01 (D3112) lysogens: those that partially, or completely, limit the growth of the related heteroimmune phage B39. DNA/DNA hybridization has shown that the lysogens of the first type always contain one copy of prophage D3112 (monolysogens), and the lysogens of the second type contain two or more copies of prophage D3112. Limitation of the growth of phage B39 on PA01 (D3112) lysogens is associated with the functioning of the locus of prophage D3112, designated as cip (control of interaction of phages). Using deletion derivatives of plasmid RP4::D3112, the cip locus was mapped at anmore » interval of 1.3-2.45 kb of the D3112 genome. The expression of the cip locus occurs only if the D3112 genome is at the prophage state. The function of the Cip prophage of D3112 exerts an influence on early stages of development of phage B39, decreasing the efficiency of the integration and transposition processes of phage B39.« less

hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism.

PubMed

Perez-Neut, Mathew; Rao, Vidhya R; Gentile, Saverio

2016-09-13

The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers.The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21waf/cip and p16INK4A. In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators.

hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism

PubMed Central

Perez-Neut, Mathew; Rao, Vidhya R.; Gentile, Saverio

2016-01-01

The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers. The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21waf/cip and p16INK4A. In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators. PMID:25945833

Local epidemiology and resistance profiles in acute uncomplicated cystitis (AUC) in women: a prospective cohort study in an urban urological ambulatory setting.

PubMed

Seitz, Michael; Stief, Christian; Waidelich, Raphaela

2017-10-16

Acute uncomplicated cystitis (AUC) is a common ailment in the urological setting. Guidelines for urinary tract infections are based on large-scale multi-centre, epidemiological and international studies. The objective of this observational study was to establish whether the results of a multi-centre study on the resistance profile of Escherichia coli (E. coli) in patients with AUC could be directly applied to an urological practice in a major European city or whether there are divergences in the resistance profile. An observational study was applied prospectively to 502 patients with AUC between January 2015 and January 2017). Personal data were anonymised. Exclusion criteria were the patient's age (<18) and treatment with an antibiotic in the week preceding examination. The average age was 32 (range 18-56). The most commonly detected bacteria was E. coli with 86%, followed by Enterococcus faecalis with 10% and Klebsiella pneumoniae with 4%. Resistance tests showed E. coli to be highly sensitive to fosfomycin (99.2%), nitrofurantoin (98.1%) and cefpodoxime (92.9%). E. coli exhibited resistance to ciprofloxacin (CIP) in 15.1%, to trimethoprim/sulfamethoxazole (TRS) in 25.2% and to amoxicillin/clavulanic acid (AMC) in 34% of cases. The comparison between data from this study and data from a multi-centre European (ECO-SENSI, ECO-SENSII and the 2014 update) showed relatively good sensitivity rates for fosfomycin and nitrofurantoin but significant differences in respect of resistance levels to TRS, CIP and AMC. AUC should therefore only be treated with TRS, CIP and AMC after a susceptibility test has been carried out.

Ciprofloxacin Enhances Stress Erythropoiesis in Spleen and Increases Survival after Whole-Body Irradiation Combined with Skin-Wound Trauma

PubMed Central

Fukumoto, Risaku; Burns, True M.; Kiang, Juliann G.

2014-01-01

Severe hematopoietic loss is one of the major therapeutic targets after radiation-combined injury (CI), a kind of injury resulting from radiation exposure combined with other traumas. In this study, we tested the use of ciprofloxacin (CIP) as a treatment, because of recently reported immunomodulatory effects against CI that may improve hematopoiesis. The CIP regimen was a daily, oral dose for 3 weeks, with the first dose 2 h after CI. CIP treatment improved 30-day survival in mice at 80% compared to 35% for untreated controls. Study of early changes in hematological parameters identified CI-induced progressive anemia by 10 days that CIP significantly ameliorated. CI induced erythropoietin (EPO) mRNA in kidney and protein in kidney and serum; CIP stimulated EPO mRNA expression. In spleens of CI mice, CIP induced bone morphogenetic protein 4 (BMP4) in macrophages with EPO receptors. Splenocytes from CIP-treated CI mice formed CD71+ colony-forming unit-erythroid significantly better than those from controls. Thus, CIP-mediated BMP4-dependent stress erythropoiesis may play a role in improving survival after CI. PMID:24587369

CDC20 maintains tumor initiating cells

PubMed Central

Xie, Qi; Wu, Qiulian; Mack, Stephen C.; Yang, Kailin; Kim, Leo; Hubert, Christopher G.; Flavahan, William A.; Chu, Chengwei; Bao, Shideng; Rich, Jeremy N.

2015-01-01

Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes – FOXM1 and p21CIP1/WAF1 — elucidating a potential point for therapeutic intervention. PMID:25938542

75 FR 65618 - Commission Information Collection Activities (FERC-725B); Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-26

... requirements to safeguard critical cyber assets.\\4\\ These standards help protect the nation's Bulk-Power System against potential disruptions from cyber attacks.\\5\\ \\3\\ CIP-002-1, CIP-003-1, CIP-004-1, CIP-005-1, CIP... Cyber Asset Identification. Security Management Controls. Personnel and Training. Electronic Security...

Zac1, an Sp1-like protein, regulates human p21{sup WAF1/Cip1} gene expression in HeLa cells

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

Liu, Pei-Yao; Hsieh, Tsai-Yuan; Liu, Shu-Ting

2011-12-10

Zac1 functions as both a transcription factor and a transcriptional cofactor for p53, nuclear receptors (NRs) and NR coactivators. Zac1 might also act as a transcriptional repressor via the recruitment of histone deacetylase 1 (HDAC1). The ability of Zac1 to interact directly with GC-specific elements indicates that Zac1 possibly binds to Sp1-responsive elements. In the present study, our data show that Zac1 is able to interact directly with the Sp1-responsive element in the p21{sup WAF1/Cip1} gene promoter and enhance the transactivation activity of Sp1 through direct physical interaction. Our data further demonstrate that Zac1 might enhance Sp1-specific promoter activity bymore » interacting with the Sp1-responsive element, affecting the transactivation activity of Sp1 via a protein-protein interaction, or competing the HDAC1 protein away from the pre-existing Sp1/HDAC1 complex. Finally, the synergistic regulation of p21{sup WAF1/Cip1} gene expression by Zac1 and Sp1 is mediated by endogenous p53 protein and p53-responsive elements in HeLa cells. Our work suggests that Zac1 might serve as an Sp1-like protein that directly interacts with the Sp1-responsive element to oligomerize with and/or to coactivate Sp1.« less

NF-κB Hyper-Activation by HTLV-1 Tax Induces Cellular Senescence, but Can Be Alleviated by the Viral Anti-Sense Protein HBZ

PubMed Central

Zhi, Huijun; Yang, Liangpeng; Kuo, Yu-Liang; Ho, Yik-Khuan; Shih, Hsiu-Ming; Giam, Chou-Zen

2011-01-01

Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that down-regulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyper-activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis. PMID:21552325

Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF1/CIP1, expression in the absence of p53.

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

Jiang, H.; Lin, J.; Su, Z.-Z.

The melanoma differentiation associated gene, mda-6, which is identical to the P53-inducible gene WAF1/CIP1, encodes an M(r) 21,000 protein (p21) that can directly inhibit cell growth by repressing cyclin dependent kinases. mda-6 was identified using subtraction hybridization by virtue of its enhanced expression in human melanoma cells induced to terminally differentiate by treatment with human fibroblast interferon and the anti-leukemic compound mezerein (Jiang and Fisher, 1993). In the present study, we demonstrate that mda-6 (WAF1/CIP1) is an immediate early response gene induced during differentiation of the promyelocytic HL-60 leukemia cell line along the granulocytic or macrophage/monocyte pathway. mda-6 gene expressionmore » in HL-60 cells is induced within 1 to 3 h during differentiation along the macrophage/monocyte pathway evoked by 12-0-tetradecanoyl phorbol-13-acetate (TPA) or 1,25-dihydroxyvitamin D3 (Vit D3) or the granulocytic pathway produced by retinoic acid (RA) or dimethylsulfoxide (DMSO). Immunoprecipitation analyses using an anti-p21 antibody indicate a temporal induction of p21 protein following treatment with TPA, DMSO or RA. A relationship between rapid induction of mda-6 gene expression and differentiation is indicated by a delay in this expression in an HL-60 cell variant resistant to TPA-induced growth arrest and differentiation. A similar delay in mda-6 gene expression is not observed in Vit D3 treated TPA-resistant variant cells that are also sensitive to induction of monocytic differentiation. Since HL-60 cells have a null-p53 phenotype, these results demonstrate that p21 induction occurs during initiation of terminal differentiation in a p53-independent manner. In this context, p21 may play a more global role in growth control and differentiation than originally envisioned.« less

Montmorillonite enhanced ciprofloxacin transport in saturated porous media with sorbed ciprofloxacin showing antibiotic activity

NASA Astrophysics Data System (ADS)

Chen, Hao; Gao, Bin; Yang, Liu-Yan; Ma, Lena Q.

2015-02-01

Antibiotic ciprofloxacin (CIP) is immobile in the subsurface but it has been frequently detected in the aquatic system. Therefore it is important to investigate the factors impacting CIP's mobilization in aquifer. Laboratory columns packed with sand were used to test colloid-facilitated CIP transport by 1) using kaolinite or montmorillonite to mobilize presorbed-CIP in a column or 2) co-transporting with CIP by pre-mixing them before transport. The Langmuir model showed that CIP sorption by montmorillonite (23 g kg- 1) was 100 times more effective than sand or kaolinite. Even with strong CIP complexation ability to Fe/Al coating on sand surface, montmorillonite promoted CIP transport, but not kaolinite. All presorbed-CIP by sand was mobilized by montmorillonite after 3 pore volumes through co-transporting of CIP with montmorillonite. The majority of CIP was fixed onto the montmorillonite interlayer but still showed inhibition of bacteria growth. Our results suggested that montmorillonite with high CIP sorption ability can act as a carrier to enhance CIP's mobility in aquifer.

Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor.

PubMed

Zhang, Jingwei; Sun, Yuan; Wang, Yaoyao; Lu, Meng; He, Jichao; Liu, Jiali; Chen, Qianying; Zhang, Xiaoxuan; Zhou, Fang; Wang, Guangji; Sun, Xianqiang

2014-10-05

The aim of this study is to explore the potential enhancing effect of ginsenoside 20(S)-Rh2 (Rh2) towards ciprofloxacin (CIP) against Staphylococcus aureus (S. aureus) infection in vitro and in vivo, and analyze the possible mechanisms through NorA inhibition from a target cellular pharmacokinetic view. In combination with non-toxic dosage of Rh2, the susceptibilities of S. aureus strains to CIP were significantly augmented, and the antibacterial kinetics of CIP in the S. aureus strains were markedly promoted. This enhancing effect of Rh2 towards CIP was also observed in S. aureus infected peritonitis mice, with elevated survival rate and reduced bacteria counts in blood. However, Rh2 did not influence the plasma concentrations of CIP. Further analysis indicated that Rh2 significantly promoted the accumulations of CIP in S. aureus, and inhibited the NorA mediated efflux of pyronin Y. The expressions of NorA gene on S. aureus were positively correlated with the enhancing effect of Rh2 with CIP. This is the first report of the enhancing effect of Rh2 with CIP for S. aureus infection in vitro and in vivo, of which it is probably that Rh2 inhibited NorA-mediated efflux and promoted the accumulation of CIP in the bacteria. Copyright © 2014 Elsevier B.V. All rights reserved.

Cold Shock of a Hyperthermophilic Archaeon: Pyrococcus furiosus Exhibits Multiple Responses to a Suboptimal Growth Temperature with a Key Role for Membrane-Bound Glycoproteins

PubMed Central

Weinberg, Michael V.; Schut, Gerrit J.; Brehm, Scott; Datta, Susmita; Adams, Michael W. W.

2005-01-01

The hyperthermophilic archaeon, Pyrococcus furiosus, was grown on maltose near its optimal growth temperature, 95°C, and at the lower end of the temperature range for significant growth, 72°C. In addition, cultures were shocked by rapidly dropping the temperature from 95 to 72°C. This resulted in a 5-h lag phase, during which time little growth occurred. Transcriptional analyses using whole-genome DNA microarrays representing 2,065 open reading frames (ORFs) in the P. furiosus genome showed that cells undergo three very different responses at 72°C: an early shock (1 to 2 h), a late shock (5 h), and an adapted response (occurring after many generations at 72°C). Each response involved the up-regulation in the expression of more than 30 ORFs unique to that response. These included proteins involved in translation, solute transport, amino acid biosynthesis, and tungsten and intermediary carbon metabolism, as well as numerous conserved-hypothetical and/or membrane-associated proteins. Two major membrane proteins were evident after one-dimensional sodium dodecyl sulfate-gel analysis of cold-adapted cells, and staining revealed them to be glycoproteins. Their cold-induced expression evident from the DNA microarray analysis was confirmed by quantitative PCR. Termed CipA (PF0190) and CipB (PF1408), both appear to be solute-binding proteins. While the archaea do not contain members of the bacterial cold shock protein (Csp) family, they all contain homologs of CipA and CipB. These proteins are also related phylogenetically to some cold-responsive genes recently identified in certain bacteria. The Cip proteins may represent a general prokaryotic-type cold response mechanism that is present even in hyperthermophilic archaea. PMID:15601718

Mapping of CIP/KIP inhibitors, G1 cyclins D1, D3, E and p53 proteins in the rat term placenta.

PubMed

Korgun, Emin Turkay; Unek, Gozde; Herrera, Emilio; Jones, Carolyn J; Wadsack, Christian; Kipmen-Korgun, Dijle; Desoye, Gernot

2011-09-01

As cell cycle regulation is fundamental to the normal growth and development of the placenta, the aim of the present study was to determine the immunolocalizations of cell cycle related proteins, which have key roles in proliferation, differentiation and apoptosis during the development of the rat placenta. Here immunohistochemistry has been used to localize G1 cyclins (D1, D3, E), which are major determinants of proliferation, CIP/KIP inhibitors (p21, p27, p57), p53 as a master regulator and proliferating cell nuclear antigen in all cell types of the rat term placenta. The proportion of each cell type immunolabeled was counted. Cyclin D1 and cyclin D3 were present mostly in cells of the fetal aspect of the placenta, whereas the G1/S cyclin E was present only in the spongio- and labyrinthine trophoblast populations. Among the CIP/KIP inhibitors, p21 was present only in cells of the fetal aspect whereas p27 and p57 were found in all cell types studied. p53 was only found in a small proportion of cells with no co-localization of p53 and p21. The data suggest that the cells of the fetal side of the rat placenta still have some proliferation potential which is kept in check by expression of the CIP/KIP cell cycle inhibitors, whereas cells of the maternal aspect have lost this potential. Apoptosis is only marginal in the term rat placenta. In conclusion, proliferation and apoptosis in rat placental cells appears controlled mostly by the CIP/KIP inhibitors in late pregnancy.

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

Cheng, Jing; Du, Yi-Fang; Xiao, Zhi-Yi

KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the inhibitory activity test on Hep G{sub 2} growth. We found that KYKZL-1 inhibited the growth of Hep G{sub 2} cells via inducing apoptosis. Further studies showed that KYKZL-1 activated caspase-3 through cytochrome c release from mitochondria and down regulation of Bcl-2/Bax ratio and reduced the high level of COX-2 and 5-LOX. As shown in its anti-inflammatory effect, KYKZL-1 also exhibited inhibitory effect on the PGE{sub 2} and LTB{sub 4} production in Hep G{sub 2} cells. Accordingly, exogenous addition of PGE{sub 2} or LTB{sub 4} reversed the decreasesmore » in cell viability. In addition, KYKZL-1 caused cell cycle arrest at the S–G{sub 2} checkpoint via the activation of p21{sup CIP1} protein and down-regulation of cyclin A expression. These data indicate that the growth inhibitory effect of KYKZL-1 is associated with inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest. Combined with our previous findings, KYKZL-1 exhibiting COX/5-LOX inhibition may be a promising potential agent not only for inflammation control but also for cancer prevention/therapy with an enhanced gastric safety profile. - Highlights: • KYKZL-1 is designed to exhibit COX/5-LOX dual inhibition. • KYKZL-1 resulted in apoptosis of Hep G{sub 2} cells. • KYKZL-1 activated caspase-3 through cytochrome c and bcl-2/bax ratio. • KYKZL-1 caused cell cycle arrest via modulation of p21{sup CIP1} and cyclin A level.« less

Differential effects of cell cycle regulatory protein p21(WAF1/Cip1) on apoptosis and sensitivity to cancer chemotherapy.

PubMed

Liu, Suxing; Bishop, W Robert; Liu, Ming

2003-08-01

p21(WAF1/Cip1) was initially identified as a cell cycle regulatory protein that can cause cell cycle arrest. It is induced by both p53-dependent and p53-independent mechanisms. This mini-review briefly discusses its currently known functions in apoptosis and drug sensitivity. As an inhibitor of cell proliferation, p21(WAF1/Cip1) plays an important role in drug-induced tumor suppression. Nevertheless, a number of recent studies have shown that p21(WAF1/Cip1) can assume both pro- or anti-apoptotic functions in response to anti-tumor agents depending on cell type and cellular context. This dual role of p21(WAF1/Cip1) in cancer cells complicates using p21(WAF1/Cip1) status to predict response to anti-tumor agents. However, it is possible to develop p21(WAF1/Cip1)-targeted reagents or p21(WAF1/Cip1) gene transfer techniques to have a beneficial effect within a well-defined therapeutic context. Better understanding of the roles of p21(WAF1/Cip1) in tumors should enable a more rational approach to anti-tumor drug design and therapy.

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

PubMed

Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

2015-07-01

High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

Cytoplasmic localization and ubiquitination of p21{sup Cip1} by reactive oxygen species

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

Hwang, Chae Young; Kim, Ick Young; Kwon, Ki-Sun

2007-06-22

Reactive oxygen species were previously shown to trigger p21{sup Cip1} protein degradation through a proteasome-dependent pathway, however the detailed mechanism of degradation remains to be elucidated. In this report, we showed that p21{sup Cip1} was degraded at an early phase after low dose H{sub 2}O{sub 2} treatment of a variety of cell types and that preincubation of cells with the antioxidant, N-acetylcysteine, prolonged p21{sup Cip1} half-life. A mutant p21{sup Cip1} in which all six lysines were changed to arginines was protected against H{sub 2}O{sub 2} treatment. Direct interaction between p21{sup Cip1} and Skp2 was elevated in the H{sub 2}O{sub 2}-treatedmore » cells. Disruption of the two nuclear export signal (NES) sequences in p21{sup Cip1}, or treatment with leptomycin B blocked H{sub 2}O{sub 2}-induced p21{sup Cip1} degradation. Altogether, these results demonstrate that reactive oxygen species induce p21{sup Cip1} degradation through an NES-, Skp2-, and ubiquitin-dependent pathway.« less

Microbiological analysis of bile and its impact in critically ill patients with secondary sclerosing cholangitis.

PubMed

Voigtländer, Torsten; Leuchs, Ensieh; Vonberg, Ralf-Peter; Solbach, Philipp; Manns, Michael P; Suerbaum, Sebastian; Lankisch, Tim O

2015-05-01

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease entity with unfavourable outcome. Our aim was to analyze the microbial spectrum in bile of patients with SSC-CIP and to evaluate the potential impact on the empiric antibiotic treatment in these patients. 169 patients (72 patients with SSC-CIP and 97 patients with primary sclerosing cholangitis (PSC)) were included in a prospective observational study between 2010 and 2013. Bile was obtained during endoscopic retrograde cholangiography (ERC) and microbiologically analyzed. Patients with SSC displayed a significantly different microbiological profile in bile. Enterococcus faecium, Pseudomonas aeruginosa and non-albicans species of Candida were more frequent in SSC compared to patients with PSC (p < 0.05). Patients with SSC showed a higher incidence of drug or multi-drug resistant organisms in bile (p = 0.001). The antimicrobial therapy was adjusted in 64% of patients due to resistance or presence of microorganisms not covered by the initial therapy regimen. Patients with SSC-CIP have a distinct microbial profile in bile. Difficult to treat organisms are frequent and an ERC with bile fluid collection for microbiological analysis should be considered in case of insufficient antimicrobial treatment. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Cell Attachment to the Extracellular Matrix Induces Proteasomal Degradation of p21CIP1 via Cdc42/Rac1 Signaling

PubMed Central

Bao, Wenjie; Thullberg, Minna; Zhang, Hongquan; Onischenko, Anatoli; Strömblad, Staffan

2002-01-01

The cyclin-dependent kinase 2 (Cdk2) inhibitors p21CIP1 and p27KIP1 are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21CIP1 and p27KIP1 protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21CIP1 mRNA levels, while the protein stability of p21CIP1 was decreased. Importantly, the down-regulation of p21CIP1 and p27KIP1 was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21CIP1 mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21CIP1 was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21CIP1. However, dominant negative (dn) Cdc42 and dn Rac1 mutants blocked the anchorage-induced degradation of p21CIP1, suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21CIP1. Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control. PMID:12052868

Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability.

PubMed

Galanos, Panagiotis; Pappas, George; Polyzos, Alexander; Kotsinas, Athanassios; Svolaki, Ioanna; Giakoumakis, Nickolaos N; Glytsou, Christina; Pateras, Ioannis S; Swain, Umakanta; Souliotis, Vassilis L; Georgakilas, Alexandros G; Geacintov, Nicholas; Scorrano, Luca; Lukas, Claudia; Lukas, Jiri; Livneh, Zvi; Lygerou, Zoi; Chowdhury, Dipanjan; Sørensen, Claus Storgaard; Bartek, Jiri; Gorgoulis, Vassilis G

2018-03-16

Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21 WAF1/Cip1 , showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery. We now demonstrate that p21 WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities. Consequently, fewer single nucleotide substitutions (SNSs) occur, while formation of highly deleterious DNA double-strand breaks (DSBs) is enhanced, crafting a characteristic mutational signature landscape. Guided by the mutational signatures formed, we find that the DSBs are repaired by Rad52-dependent break-induced replication (BIR) and single-strand annealing (SSA) repair pathways. Conversely, the error-free synthesis-dependent strand annealing (SDSA) repair route is deficient. Surprisingly, Rad52 is activated transcriptionally in an E2F1-dependent manner, rather than post-translationally as is common for DNA repair factor activation. Our results signify the importance of mutational signatures as guides to disclose the repair history leading to genomic instability. We unveil how chronic p21 WAF1/Cip1 expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.

p21Waf1/Cip1/Sdi1 Prevents Apoptosis as Well as Stimulates Growth in Cells Transformed or Immortalized by Human T-Cell Leukemia Virus Type 1-Encoded Tax

PubMed Central

Kawata, Sanae; Ariumi, Yasuo; Shimotohno, Kunitada

2003-01-01

Human T-cell leukemia virus type 1 (HTLV-1) Tax regulates the expression of virally encoded genes, as well as various endogenous host genes in trans. Tax-mediated regulation of gene expression is important for the immortalization of normal human T lymphocytes and the transformation of fibroblast cells, such as Rat-1 cells. Tax has the ability to transactivate p21Waf1/Cip1/Sdi1, resulting in high expression levels in HTLV-1-immortalized cells. Since p21 expression is suppressed due to methylation of the promoter region in Rat-l cell line, p21 may not be critical for the transformation of this cell line by Tax. To further understand the role of p21 for the proliferation of Tax-transformed Rat-1 cells, we examined the effect of ectopic expression of p21 in these cells. Here, we observed that p21 expression enhanced the transformation of this cell line via at least two mechanisms: (i) the enhancement of NF-κB activation and/or CREB signaling and (ii) the excitation of antiapoptotic machinery. To analyze the role of p21 that is overexpressed in HTLV-1-immortalized lymphocytes, p21 expression was suppressed by using an antisense oligonucleotide specific for p21 mRNA; these cells then became sensitive to apoptotic induction. These results suggest that p21 plays an important role in the proliferation of Tax-expressing cells through the regulation of at least two independent mechanisms. PMID:12805427

Proteome analysis of the fungus Aspergillus carbonarius under ochratoxin A producing conditions.

PubMed

Crespo-Sempere, A; Gil, J V; Martínez-Culebras, P V

2011-06-30

Aspergillus carbonarius is an important ochratoxin A producing fungus that is responsible for mycotoxin contamination of grapes and wine. In this study, the proteomes of highly (W04-40) and weakly (W04-46) OTA-producing A. carbonarius strains were compared to identify proteins that may be involved in OTA biosynthesis. Protein samples were extracted from two biological replicates and subjected to two dimensional gel electrophoresis analysis and mass spectrometry. Expression profile comparison (PDQuest software), revealed 21 differential spots that were statistically significant and showed a two-fold change in expression, or greater. Among these, nine protein spots were identified by MALDI-MS/MS and MASCOT database and twelve remain unidentified. Of the identified proteins, seven showed a higher expression in strain W04-40 (high OTA producer) and two in strain W04-46 (low OTA producer). Some of the identified amino acid sequences shared homology with proteins involved in regulation, amino acid metabolism, oxidative stress and sporulation. It is worth noting the presence of a protein with 126.5 fold higher abundance in strain W04-40 showing homology with protein CipC, a protein with unknown function related with pathogenesis and mycotoxin production by some authors. Variations in protein expression were also further investigated at the mRNA level by real-time PCR analysis. The mRNA expression levels from three identified proteins including CipC showed correlation with protein expression levels. This study represents the first proteomic analysis for a comparison of two A. carbonarius strains with different OTA production and will contribute to a better understanding of the molecular events involved in OTA biosynthesis. Copyright © 2011 Elsevier B.V. All rights reserved.

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A.

PubMed

Huang, Qiuyue; Qin, Shanshan; Yuan, Xiaoning; Zhang, Liang; Ji, Juanli; Liu, Xuewen; Ma, Wenjing; Zhang, Yunfei; Liu, Pengfei; Sun, Zhiting; Zhang, Jingxuan; Liu, Ying

2017-07-01

We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage.

PubMed

Brun, Sonia; Abella, Neus; Berciano, Maria T; Tapia, Olga; Jaumot, Montserrat; Freire, Raimundo; Lafarga, Miguel; Agell, Neus

2017-01-01

We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO-conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus.

SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage

PubMed Central

Brun, Sonia; Abella, Neus; Berciano, Maria T.; Tapia, Olga; Jaumot, Montserrat; Freire, Raimundo; Lafarga, Miguel

2017-01-01

We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO-conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus. PMID:28582471

A phthalide derivative isolated from endophytic fungi Pestalotiopsis photiniae induces G1 cell cycle arrest and apoptosis in human HeLa cells.

PubMed

Chen, C; Yang, R L

2013-08-01

MP [4-(3',3'-dimethylallyloxy)-5-methyl-6-methoxyphthalide] was obtained from liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. MP significantly inhibited the proliferation of HeLa tumor cell lines. After treatment with MP, characteristic apoptotic features such as DNA fragmentation and chromatin condensation were observed in DAPI-stained HeLa cells. Flow cytometry showed that MP induced G1 cell cycle arrest and apoptosis in a dose-dependent manner. Western blotting and real-time reverse transcription-polymerase chain reaction were used to investigate protein and mRNA expression. MP caused significant cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27(KIP1) protein and p21(CIP1) mRNA levels in HeLa cells. The expression of p73 protein was increased after treatment with various MP concentrations. mRNA expression of the cell cycle-related genes, p21(CIP1), p16(INK4a) and Gadd45α, was significantly upregulated and mRNA levels demonstrated significantly increased translation of p73, JunB, FKHR, and Bim. The results indicate that MP may be a potential treatment for cervical cancer.

CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation

PubMed Central

Puustinen, Pietri; Rytter, Anna; Mortensen, Monika; Kohonen, Pekka; Moreira, José M.

2014-01-01

mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. This regulatory circuit is reversed by ubiquitination and p62/SQSTM1-dependent autophagic degradation of CIP2A and subsequent inhibition of mTORC1 activity. Consistent with CIP2A’s reported ability to protect c-Myc against proteasome-mediated degradation, autophagic degradation of CIP2A upon mTORC1 inhibition leads to destabilization of c-Myc. These data characterize CIP2A as a distinct regulator of mTORC1 and reveals mTORC1-dependent control of CIP2A degradation as a mechanism that links mTORC1 activity with c-Myc stability to coordinate cellular metabolism, growth, and proliferation. PMID:24590173

The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation.

PubMed

Naeem, Hina; Cheng, Donghang; Zhao, Qingshi; Underhill, Caroline; Tini, Marc; Bedford, Marc T; Torchia, Joseph

2007-01-01

The transcriptional coactivator p/CIP(SRC-3/AIB1/ACTR/RAC3) binds liganded nuclear hormone receptors and facilitates transcription by directly recruiting accessory factors such as acetyltransferase CBP/p300 and the coactivator arginine methyltransferase CARM1. In the present study, we have established that recombinant p/CIP (p300/CBP interacting protein) is robustly methylated by CARM1 in vitro but not by other protein arginine methyltransferase family members. Metabolic labeling of MCF-7 breast cancer cells with S-adenosyl-L-[methyl-(3)H]methionine and immunoblotting using dimethyl arginine-specific antibodies demonstrated that p/CIP is specifically methylated in intact cells. In addition, methylation of full-length p/CIP is not supported by extracts derived from CARM1(-/-) mouse embryo fibroblasts, indicating that CARM1 is required for p/CIP methylation. Using mass spectrometry, we have identified three CARM1-dependent methylation sites located in a glutamine-rich region within the carboxy terminus of p/CIP which are conserved among all steroid receptor coactivator proteins. These results were confirmed by in vitro methylation of p/CIP using carboxy-terminal truncation mutants and synthetic peptides as substrates for CARM1. Analysis of methylation site mutants revealed that arginine methylation causes an increase in full-length p/CIP turnover as a result of enhanced degradation. Additionally, methylation negatively impacts transcription via a second mechanism by impairing the ability of p/CIP to associate with CBP. Collectively, our data highlight coactivator methylation as an important regulatory mechanism in hormonal signaling.

Gene expression of the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in the regulation of hematopoietic stem cell aging by ginsenoside Rg1.

PubMed

Yue, Z; Rong, J; Ping, W; Bing, Y; Xin, Y; Feng, L D; Yaping, W

2014-12-04

The elucidation of the molecular mechanisms underlying the effects of traditional Chinese medicines in clinical practice is a key step toward their worldwide application, and this topic is currently a subject of intense research interest. Rg1, a component of ginsenoside, has recently been shown to perform several pharmacological functions; however, the underlying mechanisms of these effects remain unclear. In the present study, we investigated whether Rg1 has an anti-senescence effect on hematopoietic stem cells (HSCs) and the possible molecular mechanisms driving any effects. The results showed that Rg1 could effectively delay tert-butyl hydroperoxide (t-BHP)-induced senescence and inhibit gene expression in the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in HSCs. Our study suggested that these two signaling pathways might be potential targets for elucidating the molecular mechanisms of the Rg1 anti-senescence effect.

Overexpression of caspase 7 is ERα dependent to affect proliferation and cell growth in breast cancer cells by targeting p21(Cip).

PubMed

Chaudhary, S; Madhukrishna, B; Adhya, A K; Keshari, S; Mishra, S K

2016-04-18

Caspase 7 (CASP7) expression has important function during cell cycle progression and cell growth in certain cancer cells and is also involved in the development and differentiation of dental tissues. However, the function of CASP7 in breast cancer cells is unclear. The aim of this study was to analyze the expression of CASP7 in breast carcinoma patients and determine the role of CASP7 in regulating tumorigenicity in breast cancer cells. In this study, we show that the CASP7 expression is high in breast carcinoma tissues compared with normal counterpart. The ectopic expression of CASP7 is significantly associated with ERα expression status and persistently elevated in different stages of the breast tumor grades. High level of CASP7 expression showed better prognosis in breast cancer patients with systemic endocrine therapy as observed from Kaplan-Meier analysis. S3 and S4, estrogen responsive element (ERE) in the CASP7 promoter, is important for estrogen-ERα-mediated CASP7 overexpression. Increased recruitment of p300, acetylated H3 and pol II in the ERE region of CASP7 promoter is observed after hormone stimulation. Ectopic expression of CASP7 in breast cancer cells results in cell growth and proliferation inhibition via p21(Cip) reduction, whereas small interfering RNA (siRNA) mediated reduction of CASP7 rescued p21(Cip) levels. We also show that pro- and active forms of CASP7 is located in the nucleus apart from cytoplasmic region of breast cancer cells. The proliferation and growth of breast cancer cells is significantly reduced by broad-spectrum peptide inhibitors and siRNA of CASP7. Taken together, our findings show that CASP7 is aberrantly expressed in breast cancer and contributes to cell growth and proliferation by downregulating p21(Cip) protein, suggesting that targeting CASP7-positive breast cancer could be one of the potential therapeutic strategies.

Numerical study of dam-break induced tsunami-like bore with a hump of different slopes

NASA Astrophysics Data System (ADS)

Cheng, Du; Zhao, Xi-zeng; Zhang, Da-ke; Chen, Yong

2017-12-01

Numerical simulation of dam-break wave, as an imitation of tsunami hydraulic bore, with a hump of different slopes is performed in this paper using an in-house code, named a Constrained Interpolation Profile (CIP)-based model. The model is built on a Cartesian grid system with the Navier Stokes equations using a CIP method for the flow solver, and employs an immersed boundary method (IBM) for the treatment of solid body boundary. A more accurate interface capturing scheme, the Tangent of hyperbola for interface capturing/Slope weighting (THINC/SW) scheme, is adopted as the interface capturing method. Then, the CIP-based model is applied to simulate the dam break flow problem in a bumpy channel. Considerable attention is paid to the spilling type reflected bore, the following spilling type wave breaking, free surface profiles and water level variations over time. Computations are compared with available experimental data and other numerical results quantitatively and qualitatively. Further investigation is conducted to analyze the influence of variable slopes on the flow features of the tsunami-like bore.

Paris Saponin I Sensitizes Gastric Cancer Cell Lines to Cisplatin via Cell Cycle Arrest and Apoptosis.

PubMed

Song, Shuichuan; Du, Leiwen; Jiang, Hao; Zhu, Xinhai; Li, Jinhui; Xu, Ji

2016-10-18

BACKGROUND Dose-related toxicity is the major restriction of cisplatin and cisplatin-combination chemotherapy, and is a challenge for advanced gastric cancer treatment. We explored the possibility of using Paris saponin I as an agent to sensitize gastric cancer cells to cisplatin, and examined the underlying mechanism. MATERIAL AND METHODS Growth inhibition was detected by MTT assay. The cell cycle and apoptosis were detected using flow cytometry and Annexin V/PI staining. The P21waf1/cip1, Bcl-2, Bax, and caspase-3 protein expression were detected using Western blot analysis. RESULTS The results revealed that PSI sensitized gastric cancer cells to cisplatin, with low toxicity. The IC50 value of cisplatin in SGC-7901 cell lines was decreased when combined with PSI. PSI promoted cisplatin-induced G2/M phase arrest and apoptosis in a cisplatin concentration-dependent manner. Bcl-2 protein expression decreased, but Bax, caspase-3, and P21waf1/cip1 protein expression increased with PSI treatment. CONCLUSIONS The underlying mechanism of Paris saponin I may be related to targeting the apoptosis pathway and cell cycle blocking, which suggests that PSI is a potential therapeutic sensitizer for cisplatin in treating gastric cancer.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin.

PubMed

García, Mónica C; Aldana, Ana A; Tártara, Luis I; Alovero, Fabiana; Strumia, Miriam C; Manzo, Rubén H; Martinelli, Marisa; Jimenez-Kairuz, Alvaro F

2017-11-01

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films. Copyright © 2017 Elsevier Ltd. All rights reserved.

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress.

PubMed

Quereda, V; Porlan, E; Cañamero, M; Dubus, P; Malumbres, M

2016-03-01

Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21(Cip1) and p27(Kip1) proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21(Cip1) and p27(Kip1) in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism.

PubMed

Yao, Jun; Qian, Cui-Juan; Ye, Bei; Zhang, Xin; Liang, Yong

2012-09-04

To analyze the combined impact of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) and the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on gastric cancer (GC) cell line SGC7901 growth. SGC7901 cells were treated with TSA, PD98059 or with a TSA-PD98059 combination. Effects of drug treatment on tumor cell proliferation, apoptosis, cell cycle progression, and cell signaling pathways were investigated by MTS assay, flow cytometry, Western blotting, chromatin immunoprecipitation (ChIP) assay, electrophoretic mobility shift assay (EMSA), and luciferase reporter assay, respectively. PD98059 enhanced TSA-induced cell growth arrest, apoptosis and activation of p21(WAF1/CIP1), but reversed TSA-induced activation of ERK1/2 and nuclear factor-κB (NF-κB). TSA alone up-regulated Notch1 and Hes1, and down-regulated Notch2, but PD98059 did not affect the trends of Notch1 and Notch2 induced by TSA. Particularly, PD98059 did potentiate the ability of TSA to down-regulate phospho-histone H3 protein, but increased levels of the acetylated forms of histone H3 bound to the p21(WAF1/CIP1) promoter, leading to enhanced expression of p21(WAF1/CIP1) in SGC7901 cells. PD98059 synergistically potentiates TSA-induced GC growth arrest and apoptosis by manipulating NF-κB and p21(WAF1/CIP1) independent of Notch. Therefore, concomitant administration of HDACIs and ERK1/2 inhibitors may be a promising treatment strategy for individuals with GC. Copyright © 2012 Elsevier Inc. All rights reserved.

Urinary excretion of ciprofloxacin after administration of extended release tablets in healthy volunteers. Swellable drug-polyelectrolyte matrix versus bilayer tablets.

PubMed

Guzmán, M L; Romañuk, C B; Sanchez, M F; Luciani Giacobbe, L C; Alarcón-Ramirez, L P; Battistini, F D; Alovero, F L; Jimenez-Kairuz, A F; Manzo, R H; Olivera, María Eugenia

2018-02-01

This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR® bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, t max , area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications.

Neisseria meningitidis causes cell cycle arrest of human brain microvascular endothelial cells at S phase via p21 and cyclin G2.

PubMed

Oosthuysen, Wilhelm F; Mueller, Tobias; Dittrich, Marcus T; Schubert-Unkmeir, Alexandra

2016-01-01

Microbial pathogens have developed several mechanisms to modulate and interfere with host cell cycle progression. In this study, we analysed the effect of the human pathogen Neisseria meningitidis on cell cycle in a brain endothelial cell line as well as in primary brain endothelial cells. We found that N.  Meningitidis causes an accumulation of cells in the S phase early at 3 and at 24 h post-infection that was paralleled by a decrease of cells in G2/M phase. Importantly, the outer membrane proteins of the colony opacity-associated (Opa) protein family as well as the Opc protein proved to trigger the accumulation of cells in the S phase. A focused cell cycle reverse transcription quantitative polymerase chain reaction-based array and integrated network analysis revealed changes in the abundance of several cell cycle regulatory mRNAs, including the cell cycle inhibitors p21(WAF1/CIP1) and cyclin G2. These alterations were reflected in changes in protein expression levels and/or relocalization in N. meningitidis-infected cells. Moreover, an increase in p21(WAF1/CIP1) expression was found to be p53 independent. Genetic ablation of p21(WAF1/CIP1) and cyclin G2 abrogated N. meningitidis-induced S phase accumulation. Finally, by measuring the levels of the biomarker 8-hydroxydeoxyguanosine and phosphorylation of the histone variant H2AX, we provide evidence that N. meningitidis induces oxidative DNA damage in infected cells. © 2015 John Wiley & Sons Ltd.

Development of mice without Cip/Kip CDK inhibitors

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

Tateishi, Yuki; Matsumoto, Akinobu; Kanie, Tomoharu

2012-10-19

Highlights: Black-Right-Pointing-Pointer Mice lacking Cip/Kip CKIs (p21, p27, and p57) survive until embryonic day 13.5. Black-Right-Pointing-Pointer Proliferation of MEFs lacking all three Cip/Kip CKIs appears unexpectedly normal. Black-Right-Pointing-Pointer CDK2 kinase activity of the triple mutant MEFs is increased in G0 phase. -- Abstract: Timely exit of cells from the cell cycle is essential for proper cell differentiation during embryogenesis. Cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family (p21, p27, and p57) are negative regulators of cell cycle progression and are thought to be essential for development. However, the extent of functional redundancy among Cip/Kip family members has remained largelymore » unknown. We have now generated mice that lack all three Cip/Kip CKIs (TKO mice) and compared them with those lacking each possible pair of these proteins (DKO mice). We found that the TKO embryos develop normally until midgestation but die around embryonic day (E) 13.5, slightly earlier than p27/p57 DKO embryos. The TKO embryos manifested morphological abnormalities as well as increased rates of cell proliferation and apoptosis in the placenta and lens that were essentially indistinguishable from those of p27/p57 DKO mice. Unexpectedly, the proliferation rate and cell cycle profile of mouse embryonic fibroblasts (MEFs) lacking all three Cip/Kip CKIs did not differ substantially from those of control MEFs. The abundance and kinase activity of CDK2 were markedly increased, whereas CDK4 activity and cyclin D1 abundance were decreased, in both p27/p57 DKO and TKO MEFs during progression from G{sub 0} to S phase compared with those in control MEFs. The extents of the increase in CDK2 activity and the decrease in CDK4 activity and cyclin D1 abundance were greater in TKO MEFs than in p27/p57 DKO MEFs. These results suggest that p27 and p57 play an essential role in mouse development after midgestation, and that p21 plays only an auxiliary role in normal development (although it is thought to be a key player in the response to DNA damage).« less

Lack of a p21waf1/cip -dependent G1/S checkpoint in neural stem and progenitor cells after DNA damage in vivo.

PubMed

Roque, Telma; Haton, Céline; Etienne, Olivier; Chicheportiche, Alexandra; Rousseau, Laure; Martin, Ludovic; Mouthon, Marc-André; Boussin, François D

2012-03-01

The cyclin-dependent kinase inhibitor p21(waf1/cip) mediates the p53-dependent G1/S checkpoint, which is generally considered to be a critical requirement to maintain genomic stability after DNA damage. We used staggered 5-ethynyl-2'deoxyuridine/5-bromo-2'-deoxyuridine double-labeling in vivo to investigate the cell cycle progression and the role of p21(waf1/cip) in the DNA damage response of neural stem and progenitor cells (NSPCs) after exposure of the developing mouse cortex to ionizing radiation. We observed a radiation-induced p21-dependent apoptotic response in migrating postmitotic cortical cells. However, neural stem and progenitor cells (NSPCs) did not initiate a p21(waf1/cip1) -dependent G1/S block and continued to enter S-phase at a similar rate to the non-irradiated controls. The G1/S checkpoint is not involved in the mechanisms underlying the faithful transmission of the NSPC genome and/or the elimination of critically damaged cells. These processes typically involve intra-S and G2/M checkpoints that are rapidly activated after irradiation. p21 is normally repressed in neural cells during brain development except at the G1 to G0 transition. Lack of activation of a G1/S checkpoint and apoptosis of postmitotic migrating cells after DNA damage appear to depend on the expression of p21 in neural cells, since substantial cell-to-cell variations are found in the irradiated cortex. This suggests that repression of p21 during brain development prevents the induction of the G1/S checkpoint after DNA damage. Copyright © 2011 AlphaMed Press.

Regulation of p21/CIP1/WAF-1 mediated cell-cycle arrest by RNase L and tristetraprolin, and involvement of AU-rich elements

PubMed Central

Al-Haj, Latifa; Blackshear, Perry J.; Khabar, Khalid S.A.

2012-01-01

The p21Cip1/WAF1 plays an important role in cell-cycle arrest. Here, we find that RNase L regulates p21-mediated G1 growth arrest in AU-rich elements-dependent manner. We found a significant loss of p21 mRNA expression in RNASEL−/− MEFs and that the overexpression of RNase L in HeLa cells induces p21 mRNA expression. The p21 mRNA half-life significantly changes as a result of RNase L modulation, indicating a post-transcriptional effect. Indeed, we found that RNase L promotes tristetraprolin (TTP/ZFP36) mRNA decay. This activity was not seen with dimerization- and nuclease-deficient RNase L mutants. Deficiency in TTP led to increases in p21 mRNA and protein. With induced ablation of RNase L, TTP mRNA and protein expressions were higher, while p21 expression became reduced. We further establish that TTP, but not C124R TTP mutant, binds to, and accelerates the decay of p21 mRNA. The p21 mRNA half-life was prolonged in TTP−/− MEFs. The TTP regulation of p21 mRNA decay required functional AU-rich elements. Thus, we demonstrate a novel mechanism of regulating G1 growth arrest by an RNase L-TTP-p21 axis. PMID:22718976

Formation of high electrical-resistivity thin surface layer on carbonyl-iron powder (CIP) and thermal stability of nanocrystalline structure and vortex magnetic structure of CIP

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

Sugimura, K.; Miyajima, Y.; Sonehara, M.

2016-05-15

This study focuses on the carbonyl-iron powder (CIP) used in the metal composite bulk magnetic core for high-efficient/light-weight SiC/GaN power device MHz switching dc-dc converter, where the fine CIP with a mean diameter of 1.1 μm is used to suppress the MHz band eddy current inside the CIP body. When applying the CIP to composite core together with the resin matrix, high electrical resistivity layer must be formed on the CIP-surface in order to suppress the overlapped eddy current between adjacent CIPs. In this study, tens nm thick silica (SiO{sub 2}) was successfully deposited on the CIP-surface by using hydrolysismore » of TEOS (Si(OC{sub 2}H{sub 5}){sub 4}). Also tens nm thick oxidized layer of the CIP-surface was successfully formed by using CIP annealing in dry air. The SiC/GaN power device can operate at ambient temperature over 200 degree-C, and the composite magnetic core is required to operate at such ambient temperature. The as-made CIP had small coercivity below 800 A/m (10 Oe) due to its nanocrystalline-structure and had a single vortex magnetic structure. From the experimental results, both nanocrystalline and single vortex magnetic structure were maintained after heat-exposure of 250 degree-C, and the powder coercivity after same heat-exposure was nearly same as that of the as-made CIP. Therefore, the CIP with thermally stable nanocrystalline-structure and vortex magnetic state was considered to be heat-resistant magnetic powder used in the iron-based composite core for SiC/GaN power electronics.« less

Formation of high electrical-resistivity thin surface layer on carbonyl-iron powder (CIP) and thermal stability of nanocrystalline structure and vortex magnetic structure of CIP

NASA Astrophysics Data System (ADS)

Sugimura, K.; Miyajima, Y.; Sonehara, M.; Sato, T.; Hayashi, F.; Zettsu, N.; Teshima, K.; Mizusaki, H.

2016-05-01

This study focuses on the carbonyl-iron powder (CIP) used in the metal composite bulk magnetic core for high-efficient/light-weight SiC/GaN power device MHz switching dc-dc converter, where the fine CIP with a mean diameter of 1.1 μm is used to suppress the MHz band eddy current inside the CIP body. When applying the CIP to composite core together with the resin matrix, high electrical resistivity layer must be formed on the CIP-surface in order to suppress the overlapped eddy current between adjacent CIPs. In this study, tens nm thick silica (SiO2) was successfully deposited on the CIP-surface by using hydrolysis of TEOS (Si(OC2H5)4). Also tens nm thick oxidized layer of the CIP-surface was successfully formed by using CIP annealing in dry air. The SiC/GaN power device can operate at ambient temperature over 200 degree-C, and the composite magnetic core is required to operate at such ambient temperature. The as-made CIP had small coercivity below 800 A/m (10 Oe) due to its nanocrystalline-structure and had a single vortex magnetic structure. From the experimental results, both nanocrystalline and single vortex magnetic structure were maintained after heat-exposure of 250 degree-C, and the powder coercivity after same heat-exposure was nearly same as that of the as-made CIP. Therefore, the CIP with thermally stable nanocrystalline-structure and vortex magnetic state was considered to be heat-resistant magnetic powder used in the iron-based composite core for SiC/GaN power electronics.

Arsenic trioxide phosphorylates c-Fos to transactivate p21{sup WAF1/CIP1} expression

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

Liu Zimiao; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Huang, H.-S.

2008-12-01

An infamous poison, arsenic also has been used as a drug for nearly 2400 years; in recently years, arsenic has been effective in the treatment of acute promyelocytic leukemia. Increasing evidence suggests that opposite effects of arsenic trioxide (ATO) on tumors depend on its concentrations. For this reason, the mechanisms of action of the drug should be elucidated, and it should be used therapeutically only with extreme caution. Previously, we demonstrated the opposing effects of ERK1/2 and JNK on p21{sup WAF1/CIP1} (p21) expression in response to ATO in A431 cells. In addition, JNK phosphorylates c-Jun (Ser{sup 63/73}) to recruit TGIF/HDAC1more » to suppress p21 gene expression. Presently, we demonstrated that a high concentration of ATO sustains ERK1/2 phosphorylation, and increases c-Fos biosynthesis and stability, which enhances p21 gene expression. Using site-directed mutagenesis, a DNA affinity precipitation assay, and functional assays, we demonstrated that phosphorylation of the C-terminus of c-Fos (Thr{sup 232}, Thr{sup 325}, Thr{sup 331}, and Ser{sup 374}) plays an important role in its binding to the p21 promoter, and in conjunction with N-terminus phosphorylation of c-Fos (Ser{sup 70}) to transactivate p21 promoter expression. In conclusion, a high concentration of ATO can sustain ERK1/2 activation to enhance c-Fos expression, then dimerize with dephosphorylated c-Jun (Ser{sup 63/73}) and recruit p300/CBP to the Sp1 sites (- 84/- 64) to activate p21 gene expression in A431 cells.« less

The nuclear receptor NR2E1/TLX controls senescence.

PubMed

O'Loghlen, Ana; Martin, Nadine; Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

2015-07-30

The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.

A phthalide derivative isolated from endophytic fungi Pestalotiopsis photiniae induces G1 cell cycle arrest and apoptosis in human HeLa cells

PubMed Central

Chen, C.; Yang, R.L.

2013-01-01

MP [4-(3′,3′-dimethylallyloxy)-5-methyl-6-methoxyphthalide] was obtained from liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. MP significantly inhibited the proliferation of HeLa tumor cell lines. After treatment with MP, characteristic apoptotic features such as DNA fragmentation and chromatin condensation were observed in DAPI-stained HeLa cells. Flow cytometry showed that MP induced G1 cell cycle arrest and apoptosis in a dose-dependent manner. Western blotting and real-time reverse transcription-polymerase chain reaction were used to investigate protein and mRNA expression. MP caused significant cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27KIP1 protein and p21CIP1 mRNA levels in HeLa cells. The expression of p73 protein was increased after treatment with various MP concentrations. mRNA expression of the cell cycle-related genes, p21CIP1, p16INK4a and Gadd45α, was significantly upregulated and mRNA levels demonstrated significantly increased translation of p73, JunB, FKHR, and Bim. The results indicate that MP may be a potential treatment for cervical cancer. PMID:23903687

Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis.

PubMed

Lee, Yoon Hee; Oh, Bong-Kyeong; Yoo, Jeong Eun; Yoon, So-Mi; Choi, Jinsub; Kim, Kyung Sik; Park, Young Nyun

2009-08-01

Systemic analysis for chromosomal instability and inactivation of cell cycle checkpoints are scarce during hepatocarcinogenesis. We studied 24 patients with chronic B viral cirrhosis including 30 cirrhotic regenerative nodules, 35 low-grade dysplastic nodules, 15 high-grade dysplastic nodules, 7 dysplastic nodules with hepatocellular carcinoma foci, and 18 hepatocellular carcinomas. Eight normal livers were studied as the control group. Telomere length and micronuclei were detected by Southern blot and Feulgen-fast green dyeing technique, respectively, and p21(WAF1/CIP1) expression was studied by immunohistochemistry. Micronuclei >1 per 3000 hepatocytes were found in 17% of low-grade dysplastic nodules, 87% of high-grade dysplastic nodules, and 100% of high-grade dysplastic nodules with hepatocellular carcinoma foci and hepatocellular carcinomas in contrast to those of all normal livers, and 90% of cirrhosis showed no micronuclei. The micronuclei index showed a gradual increase during hepatocarcinogenesis and there was a significant increase between cirrhosis and low-grade dysplastic nodules, low-grade dysplastic nodules and high-grade dysplastic nodules, and high-grade dysplastic nodules and hepatocellular carcinomas. Telomere length showed a gradual shortening during hepatocarcinogenesis and a significant reduction was found in high-grade dysplastic nodules (P=0.024) and hepatocellular carcinomas (P=0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P=0.016). The p21(WAF1/CIP1) labeling index was significantly higher in cirrhosis than in normal livers (P=0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (P<0.05). The p21(WAF1/CIP1) labeling index was associated with telomere length (P<0.001) but not micronuclei index. This study shows that telomere shortening, chromosomal instability, and inactivation of p21(WAF1/CIP1) checkpoint function occur in low-grade dysplastic nodules as well as in high-grade dysplastic nodules, and their cooperation is considered to be critical for malignant transformation during hepatitis B virus associated-multistep hepatocarcinogenesis.

33 CFR Schedule III to Subpart A... - Calling-in Table

Code of Federal Regulations, 2010 CFR

2010-07-01

.... ETA C.I.P. 7. 4. Confirm pilot requirement—Snell Lock (inland vessels only). 4. C.I.P. 7—leaving... 12 1. Name of vessel.2. Location. 3. ETA Snell lock. 6. C.I.P. 8—order of passing through established... Eisenhower Lock ......do 1. Name of vessel.2. Location. 3. ETA C.I.P. 11. 4. Confirm pilot requirement—Lake...

Improved rheological properties of dimorphic magnetorheological gels based on flower-like carbonyl iron particles

NASA Astrophysics Data System (ADS)

Yang, Pingan; Yu, Miao; Luo, Hongping; Fu, Jie; Qu, Hang; Xie, Yuanpeng

2017-09-01

In this study, a new kind of dimorphic magnetorheological gels (MRGs) based on the conventional carbonyl iron particles (CIPs) and flower-like CIPs have been prepared for improving the yield stress and dynamic mechanical properties. The flower-like CIPs are synthesized by a simple and facile in situ reduction method. Characterization results indicate that the flower-like CIPs are synthesized successfully and a layer of uniform and continuous Fe nanosheets are grown on the surface of the raw microsphere CIPs. In addition, the flower-like CIPs exhibit excellent magnetic properties, which the saturated mass magnetization (Ms) can achieve 168.76 emu/g. In order to study the influence of mass fraction of flower-like CIPs on the rheological properties of this dimorphic MRGs, a series of polyurethane-based dimorphic MRGs are prepared by partial substitution of the CIPs with as-synthesized flower-like CIPs, and the MR properties of them are systematically investigated under both oscillatory and rotational shear modes. The experimental results indicate that, with 8 wt% flower-like CIPs, the maximum dynamic yield stresses and magneto-induced shear yield stress of dimorphic MRGs are 58.11 kPa and 54.53 kPa, ∼1.39 and ∼1.37 times of the MRG without flower-like CIPs at the same magnetic particle content. Moreover, the average loss factor and the loss factor under 1 T of the sample (flower-like CIPs weight content 8 wt%) are 0.36 and 0.07, which are approximately 1.71 and 2.71 times than that in the non-substitution sample. The increased loss factor is beneficial to improving the vibration reduction effect of MRGs of damping devices in the whole magnetic field region. Furthermore, the possible mechanism for the enhanced MR properties in dimorphic MRGs is proposed. In summary, this work is expected to promote the design and application of MRG devices.

Development of mice without Cip/Kip CDK inhibitors.

PubMed

Tateishi, Yuki; Matsumoto, Akinobu; Kanie, Tomoharu; Hara, Eiji; Nakayama, Keiko; Nakayama, Keiichi I

2012-10-19

Timely exit of cells from the cell cycle is essential for proper cell differentiation during embryogenesis. Cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family (p21, p27, and p57) are negative regulators of cell cycle progression and are thought to be essential for development. However, the extent of functional redundancy among Cip/Kip family members has remained largely unknown. We have now generated mice that lack all three Cip/Kip CKIs (TKO mice) and compared them with those lacking each possible pair of these proteins (DKO mice). We found that the TKO embryos develop normally until midgestation but die around embryonic day (E) 13.5, slightly earlier than p27/p57 DKO embryos. The TKO embryos manifested morphological abnormalities as well as increased rates of cell proliferation and apoptosis in the placenta and lens that were essentially indistinguishable from those of p27/p57 DKO mice. Unexpectedly, the proliferation rate and cell cycle profile of mouse embryonic fibroblasts (MEFs) lacking all three Cip/Kip CKIs did not differ substantially from those of control MEFs. The abundance and kinase activity of CDK2 were markedly increased, whereas CDK4 activity and cyclin D1 abundance were decreased, in both p27/p57 DKO and TKO MEFs during progression from G(0) to S phase compared with those in control MEFs. The extents of the increase in CDK2 activity and the decrease in CDK4 activity and cyclin D1 abundance were greater in TKO MEFs than in p27/p57 DKO MEFs. These results suggest that p27 and p57 play an essential role in mouse development after midgestation, and that p21 plays only an auxiliary role in normal development (although it is thought to be a key player in the response to DNA damage). Copyright © 2012 Elsevier Inc. All rights reserved.

Novel Insights into p63 Expression and Function in Prostate

DTIC Science & Technology

2004-07-15

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

123I-labeled HIV-1 tat peptide radioimmunoconjugates are imported into the nucleus of human breast cancer cells and functionally interact in vitro and in vivo with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1).

PubMed

Hu, Meiduo; Chen, Paul; Wang, Judy; Scollard, Deborah A; Vallis, Katherine A; Reilly, Raymond M

2007-03-01

To evaluate the internalization and nuclear translocation of (123)I-tat-peptide radioimmunoconjugates in MDA-MB-468 breast cancer cells and their ability to interact with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1). Peptides [GRKKRRQRRRPPQGYGC] harboring the nuclear-localizing sequence from HIV tat domain were conjugated to anti-p21(WAF-1/Cip-1) antibodies. Immunoreactivity was assessed by Western blot using lysate from MDA-MB-468 cells exposed to EGF to induce p21(WAF-1/Cip-1). Internalization and nuclear translocation were measured. The ability of tat-anti-p21(WAF-1/Cip-1) to block G(1)-S phase arrest in MDA-MB-468 cells caused by EGF-induced p21(WAF-1/Cip-1) was evaluated. Tumor and normal tissue uptake were determined at 48 h p.i. in athymic mice implanted s.c. with MDA-MB-468 xenografts injected intratumorally with EGF. There was 13.4+/-0.2% of radioactivity internalized by MDA-MB-468 cells incubated with (123)I-tat-anti-p21(WAF-1/Cip-1) and 34.6+/-3.1% imported into the nucleus. Tat-anti-p21(WAF-1/Cip-1)(8 muM) decreased the proportion of EGF-treated cells in G(1) phase from 81.9+/-0.7% to 46.1+/-0.7% (p<0.001), almost restoring the G(1) phase fraction to that of unexposed cells (25.8+/-0.2%). Non-specific tat-mouse IgG did not block EGF-induced G(1)-S phase arrest. Tumor uptake of radioactivity was higher in mice injected with EGF to induce p21(WAF-1/Cip-1) than in mice not receiving EGF (3.1+/-0.4% versus 1.8+/-0.2% ID/g; p=0.04). Western blot analysis of tumors revealed a threefold increase in the p21(WAF-1/Cip-1)/beta-actin ratio. We conclude that intracellular and nuclear epitopes in cancer cells can be functionally targeted with tat-radioimmunoconjugates to exploit many more epitopes for imaging and radiotherapeutic applications than have previously been accessible.

12 CFR 1292.1 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Investment Cash Advance program means: (1) A Bank's AHP; (2) A Bank's CIP; (3) A Bank's RDF program or UDF...) through (1)(iv), and (2)(i) and (2)(ii) of this definition are eligible for CIP advances. Targeted...; (3) For advances provided under CIP: (i) For economic development projects, incomes at or below 80...

12 CFR 952.1 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... CIP; (3) A Bank's RDF program or UDF program using any combination of the targeted beneficiaries and... paragraphs (1)(i) through (1)(iv), and (2)(i) and (2)(ii) of this definition are eligible for CIP advances..., for a family of four; (3) For advances provided under CIP: (i) For economic development projects...

12 CFR 952.1 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... CIP; (3) A Bank's RDF program or UDF program using any combination of the targeted beneficiaries and... paragraphs (1)(i) through (1)(iv), and (2)(i) and (2)(ii) of this definition are eligible for CIP advances..., for a family of four; (3) For advances provided under CIP: (i) For economic development projects...

12 CFR 952.1 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... CIP; (3) A Bank's RDF program or UDF program using any combination of the targeted beneficiaries and... paragraphs (1)(i) through (1)(iv), and (2)(i) and (2)(ii) of this definition are eligible for CIP advances..., for a family of four; (3) For advances provided under CIP: (i) For economic development projects...

Interspecies Interactions Reverse the Hazard of Antibiotics Exposure: A Plankton Community Study on Responses to Ciprofloxacin hydrochloride.

PubMed

Wang, Changyou; Wang, Ziyang; Zhang, Yong; Su, Rongguo

2017-05-24

The ecotoxicological effects of Ciprofloxacin hydrochloride (CIP) were tested on population densities of plankton assemblages consisting of two algae (Isochrysis galbana and Platymonas subcordiformis) and a rotifer (Brachionus plicatilis). The I. galbana showed a significant decrease in densities when concentrations of CIP were above 2.0 mg L -1 in single-species tests, while P. subcordiformis and B. plicatilis were stable in densities when CIP were less than10.0 mg L -1 . The equilibrium densities of I. galbana in community test increased with CIP concentrations after falling to a trough at 5.0 mg L -1 , showed a completely different pattern of P. subcordiformis which decreased with CIP concentrations after reaching a peak at 30.0 mg L -1 . The observed beneficial effect was a result of interspecies interactions of trophic cascade that buffered for more severe direct effects of toxicants. The community test-based NOEC of CIP (2.0 mg L -1 ), embodying the indirect effects, was different from the extrapolated one derived by single-species tests (0.5 mg L -1 ), but all lacked confidence interval. A CIP threshold concentration of obvious relevance to ecological interaction was calculated with a simplified plankton ecological model, achieving a value of 1.26 mg L -1 with a 95% bootstrapping confidence interval from 1.18 to 1.31 mg L -1 .

Increased expression of p53 and p21 (Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma.

PubMed

Yamamoto, Toshiyuki; Nishioka, Kiyoshi

2005-05-01

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive deposition of extracellular matrix in the affected skin as well as various internal organs, vascular injury and immune abnormality; however, the etiology of SSc remains still unknown. We previously established an experimental mouse model for scleroderma by repeated local injections of bleomycin, a DNA damaging agent. In this study, we examined the induction of apoptosis and the expression of p53, p21 (Waf1/Cip1), and proliferating cell nuclear antigen (PCNA) in the lesional skin following bleomycin exposure in this model. Dermal sclerosis was induced by alternate day's injections of bleomycin for 4 weeks. TUNEL assay showed that apoptotic cells began to appear at 1 week after bleomycin exposure, and were prominently detected at 3-4 weeks. Immunohistochemical examination showed increased expression of p53 and p21 mainly in the infiltrating mononuclear cells at 2 weeks after bleomycin treatment. Bleomycin treatment markedly enhanced PCNA expression at 1-2 weeks, mainly in mesenchyme, as compared with control phosphate buffered saline treatment. Reverse transcriptase-polymerase chain reaction analysis showed that the expression of p53 and p21 mRNA was concurrently upregulated at 1-2 weeks after bleomycin treatment. Taken together, coordinate increased levels of p53 and p21 preceded the maximal induction of apoptosis and dermal sclerosis. Our findings suggest that apoptotic processes are involved in the pathophysiology of bleomycin-induced scleroderma, which may be mediated, in part, by the upregulation of p53 and p21.

Overview of the development of quinolone resistance in Salmonella species in China, 2005–2016

PubMed Central

Song, Qifa; Xu, Zhaojun; Gao, Hong; Zhang, Danyang

2018-01-01

Purpose Several factors contribute to the complexity of quinolone resistance in Salmonella, including >2000 different Salmonella serotypes, a variety of hosts for Salmonella, and wide use of quinolones in human beings and animals. We thus aimed to obtain an overview of the development of quinolone resistance and relevant molecular mechanisms of such a resistance in Salmonella species. Materials and methods A total of 1,776 Salmonella isolates were collected in Ningbo, China, between 2005 and 2016. Antimicrobial susceptibility to quinolone and relevant genetic mechanisms in these isolates were retrospectively analyzed. Results The ratio for ciprofloxacin (CIP) resistant:reduced CIP susceptible:CIP susceptible was 26:522:1,228. CIP resistance was found in nine of 51 serotypes: Derby, London, Kentucky, Indiana, Corvallis, Rissen, Hadar, Typhimurium, and Agona. Of 26 CIP-resistant isolates, all were concurrently resistant to ampicillin and 21 were also concurrently resistant to cefotaxime and produced extended-spectrum β-lactamase (ESBL). The minimal inhibitory concentration values were at three levels: 2–4 μg/mL (serotypes except for Kentucky and Indiana), 16 μg/mL (one Kentucky isolate), and >32 μg/mL (Indiana isolates). As with the three most common serotypes, Salmonella Typhi showed quickly increased prevalence of reduced CIP susceptibility in recent years, Salmonella Enteritidis remained at a high prevalence of reduced CIP susceptibility throughout the study period, and several isolates of Salmonella Typhimurium were resistant to CIP. Transferable plasmid-mediated quinolone resistance gene qnrB was only found in all CIP-resistant isolates. In contrast, gyrA mutations were often found in reduced CIP-susceptible isolates and were not necessarily found in all CIP-resistant isolates. Conclusion We conclude that in Salmonella, there exists a high prevalence of reduced CIP susceptibility and a low prevalence of CIP resistance, which focuses on several serotypes. Our study also demonstrates that, rather than gyrA mutations, qnrB is the most common indicator for CIP resistance. PMID:29520157

Differential effects on apoptosis induction in hepatocyte lines by stable expression of hepatitis B virus X protein

PubMed Central

Fiedler, Nicola; Quant, Ellen; Fink, Ludger; Sun, Jianguang; Schuster, Ralph; Gerlich, Wolfram H; Schaefer, Stephan

2006-01-01

AIM: Hepatitis B virus protein X (HBx) has been shown to be weakly oncogenic in vitro. The transforming activities of HBx have been linked with the inhibition of several functions of the tumor suppressor p53. We have studied whether HBx may have different effects on p53 depending on the cell type. METHODS: We used the human hepatoma cell line HepG2 and the immortalized murine hepatocyte line AML12 and analyzed stably transfected clones which expressed physiological amounts of HBx. P53 was induced by UV irradiation. RESULTS: The p53 induction by UV irradiation was unaffected by stable expression of HBx. However, the expression of the cyclin kinase inhibitor p21waf/cip/sdi which gets activated by p53 was affected in the HBx transformed cell line AML12-HBx9, but not in HepG2. In AML-HBx9 cells, p21waf/cip/sdi-protein expression and p21waf/cip/sdi transcription were deregulated. Furthermore, the process of apoptosis was affected in opposite ways in the two cell lines investigated. While stable expression of HBx enhanced apoptosis induced by UV irradiation in HepG2-cells, apoptosis was decreased in HBx transformed AML12-HBx9. P53 repressed transcription from the HBV enhancer I, when expressed from expression vectors or after induction of endogenous p53 by UV irradiation. Repression by endogenous p53 was partially reversible by stably expressed HBx in both cell lines. CONCLUSION: Stable expression of HBx leads to deregulation of apoptosis induced by UV irradiation depending on the cell line used. In an immortalized hepatocyte line HBx acted anti-apoptotic whereas expression in a carcinoma derived hepatocyte line HBx enhanced apoptosis. PMID:16937438

Development of the Career Indecision Profile: Factor Structure, Reliability, and Validity

ERIC Educational Resources Information Center

Hacker, Jason; Carr, Andrea; Abrams, Matthew; Brown, Steven D.

2013-01-01

Prior research using a 167-item measure of career indecision (Career Indecision Profile-167 [CIP-167]) has suggested that career choice difficulties may be associated with four major sources of career indecision: neuroticism/negative affectivity, choice/commitment anxiety, lack of readiness, and interpersonal conflicts. The purpose of this study…

CIP Training Manual: Collaborative Information Portal Advance Training Information for Field Test Participants

NASA Technical Reports Server (NTRS)

Schreiner, John; Clancy, Daniel (Technical Monitor)

2002-01-01

The Collaborative Information Portal (CIP) is a web-based information management and retrieval system. Its purpose is to provide users at MER (Mars Exploration Rover) mission operations with easy access to a broad range of mission data and products and contextual information such as the current operations schedule. The CIP web-server provides this content in a user customizable web-portal environment. Since CIP is still under development, only a subset of the full feature set will be available for the EDO field test. The CIP web-portal will be accessed through a standard web browser. CIP is intended to be intuitive and simple to use, however, at the training session, users will receive a one to two page reference guide, which should aid them in using CIP. Users must provide their own computers for accessing CIP during the field test. These computers should be configured with Java 1.3 and a Java 2 enabled browser. Macintosh computers should be running OS 10.1.3 or later. Classic Mac OS (OS 9) is not supported. For more information please read section 7.3 in the FIASCO Rover Science Operations Test Mission Plan. Several screen shots of the Beta Release of CIP are shown on the following pages.

Novel Platinum (Pt)-Vandetanib Hybrid Compounds: Design, Synthesis and Investigation of Anti-cancer Activity and Mechanism of Action

NASA Astrophysics Data System (ADS)

Fei, Rong

Purpose: Lung cancer is one of the most common cancers and non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancers. 70% of individuals with NSCLC harboring somatic mutations in exons of the epidermal growth factor receptor (EGFR) gene that encode tyrosine kinase domain. EGFR tyrosine kinase inhibitors (TKIs) are promising molecular targeted therapy for NSCLC with sensitizing EGFR mutations. However, secondary mutation of EGFR after treatment of TKIs develops resistance. Vandetanib is introduced to overcome erlotinib resistance as a multi-targeted TKI. However, its anticancer effect is still compromised by EGFR T790M mutation. Therefore, new molecular anticancer strategies are necessarily needed. In this study, vandetanib is incorporated with Pt-based anticancer agents as hybrid compounds, aiming to circumvent TKI resistance. Furthermore, hybrid compounds are investigated in cisplatin resistant problem to expect to overcome resistance by introduction of vandetanib. Methods: Three novel Pt-vandetanib hybrid compounds were synthesized and its physicochemical properties were characterized. Anticancer activity and cytotoxicity were evaluated by sulforhodamine B assay and lactate dehydrogenase release. Docking simulation was performed to investigate the interaction of compounds with EGFR harboring different mutations. Inhibition efficacy of hybrids to kinases was evaluated by kinase inhibition profiling service and cell-free kinase inhibition assay. Mechanistic studies on cytotoxicity activity of the hybrid compounds were carried out. DNA damage response of hybrid compounds was further investigated in KB cells. The cytotoxicity of hybrids was tested in cisplatin resistant KB CP20 cells. Mechanistic of anticancer activity was studied to test inhibition on oncoprotein CIP2Aand DNA damage. Results: Platinum-vandetanib hybrid compounds were synthesized and test to be stable under extracellular condition. Hybrids reacted with 5'-GMP2- and glutathione, and both of them formed mono-dentate adducts. Moreover, hybrid compounds exhibited low toxicity in human normal kidney cells. Compounds maintained the inhibition selectivity towards EGFR from the results of kinase inhibition profiling and cell-free kinase inhibition assay. Hybrids formed strong H-bond at D800 on EGFR. Pt-vandetanib hybrids were highly effective against HCC827 cells harboring sensitizing EGFR mutation. Importantly, relative resistant rate of hybrids were much smaller than vandetanib in H1975 cells. Western blot analysis results revealed that the hybrid compounds could efficiently inhibit EGFR phosphorylation in a dose dependent manner in HCC827. While, inhibition of p-EGFR was not as good as the original TKI in H1975 cells. However, the hybrid compounds induced DNA damage and caused apoptosis of the NSCLC cells. Both of the two pathways were contributed to cancer cell death and overcome vandetanib resistance. Pt-vandetanib hybrids showed little resistance in cisplatin resistant cell line KB-CP20. Drug accumulation evaluation revealed that cisplatin accumulation in CP20 cells decreased to one eighth of that in the parental KB3.1 cells. While hybrids maintained similar drug accumulation extent in both cells lines. Mechanistic study showed that hybrid compounds could induce DNA damage and cause apoptosis, whereas cisplatin failed to cause DNA damage in KB-CP20 cells. Oncoprotein CIP2A was overexpressed in CP20 cell and was ascribed to CDDP resistance. The hybrids inhibited CIP2A expression and downstream AKT phosphorylation. It was hypothesized that downregulation of CIP2A contributed to circumvention platinum resistance. Conclusion: Novel Pt-vandetanib hybrid compounds were able to overcome vandetanib resistance in H1975 cells by maintaining inhibition to the EGFR and inducing DNA damage and apoptosis. Moreover, Pt-vandetanib hybrid compounds behaved low toxicity and overcome cisplatin resistance by being "non-substrate" to efflux transporter and successfully causing DNA damage. Hybrids were found to downregulate oncogene CIP2A expression level. The novel Pt-vandetanib hybrid compounds are potent for further development.

Molecular and phenotypic analyses reveal the non-identity of the Phaeobacter gallaeciensis type strain deposits CIP 105210T and DSM 17395.

PubMed

Buddruhs, Nora; Pradella, Silke; Göker, Markus; Päuker, Orsola; Pukall, Rüdiger; Spröer, Cathrin; Schumann, Peter; Petersen, Jörn; Brinkhoff, Thorsten

2013-11-01

The marine genus Phaeobacter currently comprises six species, some of which were intensively studied mainly due to their ability to produce secondary metabolites. The type strain of the type species, Phaeobacter gallaeciensis BS107(T), has been deposited at several public culture collections worldwide. Based on differences in plasmid profiles, we detected that the alleged P. gallaeciensis type strains deposited at the Collection Institute Pasteur (CIP; Paris, France) as CIP 105210 and at the German Collection of Microorganisms and Cell Cultures (DSMZ; Braunschweig, Germany) as DSM 17395 are not identical. To determine the identity of these strains, we conducted DNA-DNA hybridization, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), 16S rRNA gene and internal transcribed spacer (ITS) sequence analyses, as well as physiological experiments. Based on the detailed 16S rRNA gene reanalysis we showed that strain CIP 105210 most likely corresponds to the original P. gallaeciensis type strain BS107(T). In contrast, the Phaeobacter strain DSM 17395 exhibits a much closer affiliation to Phaeobacter inhibens DSM 16374(T) ( = T5(T)) and should thus be allocated to this species. The detection of the dissimilarity of strains CIP 105210(T) and DSM 17395 will influence future comparative studies within the genus Phaeobacter.

Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism.

PubMed

Phiboonchaiyanan, Preeyaporn Plaimee; Kiratipaiboon, Chayanin; Chanvorachote, Pithi

2016-04-25

Cancer stem cells (CSCs), a subpopulation of cancer cells with high aggressive behaviors, have been identified in many types of cancer including lung cancer as one of the key mediators driving cancer progression and metastasis. Here, we have reported for the first time that ciprofloxacin (CIP), a widely used anti-microbial drug, has a potentiating effect on CSC-like features in human non-small cell lung cancer (NSCLC) cells. CIP treatment promoted CSC-like phenotypes, including enhanced anchorage-independent growth and spheroid formation. The known lung CSC markers: CD133, CD44, ABCG2 and ALDH1A1 were found to be significantly increased, while the factors involving in epithelial to mesenchymal transition (EMT): Slug and Snail, were depleted. Also, self-renewal transcription factors Oct-4 and Nanog were found to be up-regulated in CIP-treated cells. The treatment of CIP on CSC-rich populations obtained from secondary spheroids resulted in the further increase of CSC markers. In addition, we have proven that the mechanistic insight of the CIP induced stemness is through Caveolin-1 (Cav-1)-dependent mechanism. The specific suppression of Cav-1 by stably transfected Cav-1 shRNA plasmid dramatically reduced the effect of CIP on CSC markers as well as the CIP-induced spheroid formation ability. Cav-1 was shown to activate protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways in CSC-rich population; however, such an effect was rarely found in the main lung cancer cells population. These findings reveal a novel effect of CIP in positively regulating CSCs in lung cancer cells via the activation of Cav-1, Akt and ERK, and may provoke the awareness of appropriate therapeutic strategy in cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Characterization of the Burkholderia thailandensis SOS Response by Using Whole-Transcriptome Shotgun Sequencing

PubMed Central

Ulrich, Ricky L.; DeShazer, David; Kenny, Tara A.; Ulrich, Melanie P.; Moravusova, Anna; Opperman, Timothy; Bavari, Sina; Bowlin, Terry L.; Moir, Donald T.

2013-01-01

The bacterial SOS response is a well-characterized regulatory network encoded by most prokaryotic bacterial species and is involved in DNA repair. In addition to nucleic acid repair, the SOS response is involved in pathogenicity, stress-induced mutagenesis, and the emergence and dissemination of antibiotic resistance. Using high-throughput sequencing technology (SOLiD RNA-Seq), we analyzed the Burkholderia thailandensis global SOS response to the fluoroquinolone antibiotic, ciprofloxacin (CIP), and the DNA-damaging chemical, mitomycin C (MMC). We demonstrate that a B. thailandensis recA mutant (RU0643) is ∼4-fold more sensitive to CIP in contrast to the parental strain B. thailandensis DW503. Our RNA-Seq results show that CIP and MMC treatment (P < 0.01) resulted in the differential expression of 344 genes in B. thailandensis and 210 genes in RU0643. Several genes associated with the SOS response were induced and include lexA, uvrA, dnaE, dinB, recX, and recA. At the genome-wide level, we found an overall decrease in gene expression, especially for genes involved in amino acid and carbohydrate transport and metabolism, following both CIP and MMC exposure. Interestingly, we observed the upregulation of several genes involved in bacterial motility and enhanced transcription of a B. thailandensis genomic island encoding a Siphoviridae bacteriophage designated ϕE264. Using B. thailandensis plaque assays and PCR with B. mallei ATCC 23344 as the host, we demonstrate that CIP and MMC exposure in B. thailandensis DW503 induces the transcription and translation of viable bacteriophage in a RecA-dependent manner. This is the first report of the SOS response in Burkholderia spp. to DNA-damaging agents. We have identified both common and unique adaptive responses of B. thailandensis to chemical stress and DNA damage. PMID:23872555

Characterization of the Burkholderia thailandensis SOS response by using whole-transcriptome shotgun sequencing.

PubMed

Ulrich, Ricky L; Deshazer, David; Kenny, Tara A; Ulrich, Melanie P; Moravusova, Anna; Opperman, Timothy; Bavari, Sina; Bowlin, Terry L; Moir, Donald T; Panchal, Rekha G

2013-10-01

The bacterial SOS response is a well-characterized regulatory network encoded by most prokaryotic bacterial species and is involved in DNA repair. In addition to nucleic acid repair, the SOS response is involved in pathogenicity, stress-induced mutagenesis, and the emergence and dissemination of antibiotic resistance. Using high-throughput sequencing technology (SOLiD RNA-Seq), we analyzed the Burkholderia thailandensis global SOS response to the fluoroquinolone antibiotic, ciprofloxacin (CIP), and the DNA-damaging chemical, mitomycin C (MMC). We demonstrate that a B. thailandensis recA mutant (RU0643) is ∼4-fold more sensitive to CIP in contrast to the parental strain B. thailandensis DW503. Our RNA-Seq results show that CIP and MMC treatment (P < 0.01) resulted in the differential expression of 344 genes in B. thailandensis and 210 genes in RU0643. Several genes associated with the SOS response were induced and include lexA, uvrA, dnaE, dinB, recX, and recA. At the genome-wide level, we found an overall decrease in gene expression, especially for genes involved in amino acid and carbohydrate transport and metabolism, following both CIP and MMC exposure. Interestingly, we observed the upregulation of several genes involved in bacterial motility and enhanced transcription of a B. thailandensis genomic island encoding a Siphoviridae bacteriophage designated E264. Using B. thailandensis plaque assays and PCR with B. mallei ATCC 23344 as the host, we demonstrate that CIP and MMC exposure in B. thailandensis DW503 induces the transcription and translation of viable bacteriophage in a RecA-dependent manner. This is the first report of the SOS response in Burkholderia spp. to DNA-damaging agents. We have identified both common and unique adaptive responses of B. thailandensis to chemical stress and DNA damage.

A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

PubMed Central

Yin, Bin; Delwel, Ruud; Valk, Peter J.; Wallace, Margaret R.; Loh, Mignon L.; Shannon, Kevin M.

2009-01-01

NF1 inactivation occurs in specific human cancers, including juvenile myelomonocytic leukemia, an aggressive myeloproliferative disorder of childhood. However, evidence suggests that Nf1 loss alone does not cause leukemia. We therefore hypothesized that inactivation of the Nf1 tumor suppressor gene requires cooperating mutations to cause acute leukemia. To search for candidate genes that cooperate with Nf1 deficiency in leukemogenesis, we performed a forward genetic screen using retroviral insertion mutagenesis in Nf1 mutant mice. We identified 43 common proviral insertion sites that contain candidate genes involved in leukemogenesis. One of these genes, Bcl11a, confers a growth advantage in cultured Nf1 mutant hematopoietic cells and causes early onset of leukemia of either myeloid or lymphoid lineage in mice when expressed in Nf1-deficient bone marrow. Bcl11a-expressing cells display compromised p21Cip1 induction, suggesting that Bcl11a's oncogenic effects are mediated, in part, through suppression of p21Cip1. Importantly, Bcl11a is expressed in human chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia samples. A subset of AML patients, who had poor outcomes, of 16 clusters, displayed high levels of BCL11A in leukemic cells. These findings suggest that deregulated Bcl11a cooperates with Nf1 in leukemogenesis, and a therapeutic strategy targeting the BCL11A pathway may prove beneficial in the treatment of leukemia. PMID:18948576

Thrombomodulin regulates monocye differentiation via PKCδ and ERK1/2 pathway in vitro and in atherosclerotic artery

PubMed Central

Tsai, Chien-Sung; Lin, Yi-Wen; Huang, Chun-Yao; Shih, Chun-Min; Tsai, Yi-Ting; Tsao, Nai-Wen; Lin, Chin-Sheng; Shih, Chun-Che; Jeng, Hellen; Lin, Feng-Yen

2016-01-01

Thrombomodulin (TM) modulates the activation of protein C and coagulation. Additionally, TM regulates monocyte migration and inflammation. However, its role on monocyte differentiation is still unknown. We investigated the effects of TM on monocyte differentiation. First, we found that TM was increased when THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA). Overexpression of TM enhanced the macrophage markers, CD14 and CD68 expression in PMA-induced THP-1. TM siRNA depressed the PMA-induced increase of p21Cip1/WAF1 via ERK1/2-NF-kB p65 signaling. TM regulated cytoskeletal reorganization via its interaction with paxillin, cofilin, LIMK1, and PYK2. In addition, PMA-induced p21Cip1/WAF1 expression, CD14-positive cell labeling intensity and ERK1/2 phosphorylation were markedly inhibited when protein kinase C-δ (PKCδ) was knocked down. We identified that TM directly interacts with PKCδ. PKCδ was highly expressed in human atherosclerotic arteries and colocalized with TM in CD68-positive infiltrated macrophages of plaques, indicating that the coordination between TM and PKCδ in macrophages participated in atherogenesis. TM may act as a scaffold for PKCδ docking, which keeps PKCδ in the region close to the monocyte membrane to promote the activation of ERK1/2. Taken together, our findings suggest that TM-PKCδ interaction may contribute to cardiovascular disorders by affecting monocye differentiation, which may develop future therapeutic applications. PMID:27910925

Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells.

PubMed

Shimizu, Masahito; Suzui, Masumi; Deguchi, Atsuko; Lim, Jin T E; Xiao, Danhua; Hayes, Julia H; Papadopoulos, Kyriakos P; Weinstein, I Bernard

2004-10-01

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

The MER/CIP Portal for Ground Operations

NASA Technical Reports Server (NTRS)

Chan, Louise; Desai, Sanjay; DOrtenzio, Matthew; Filman, Robtert E.; Heher, Dennis M.; Hubbard, Kim; Johan, Sandra; Keely, Leslie; Magapu, Vish; Mak, Ronald

2003-01-01

We developed the Mars Exploration Rover/Collaborative Information Portal (MER/CIP) to facilitate MER operations. MER/CIP provides a centralized, one-stop delivery platform integrating science and engineering data from several distributed heterogeneous data sources. Key issues for MER/CIP include: 1) Scheduling and schedule reminders; 2) Tracking the status of daily predicted outputs; 3) Finding and analyzing data products; 4) Collaboration; 5) Announcements; 6) Personalization.

33 CFR 401.79 - Advance notice of arrival, vessels requiring inspection.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Notice of Arrival (NOA) prior to entering at call in point 2 (CIP 2) as follows: (1) If your voyage time to CIP 2 is 96 hours or more, you must submit an electronic NOA 96 hours before entering the Seaway at CIP 2. (2) If your voyage time to CIP 2 is less than 96 hours, you must submit an electronic NOA...

33 CFR 401.79 - Advance notice of arrival, vessels requiring inspection.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Notice of Arrival (NOA) prior to entering at call in point 2 (CIP 2) as follows: (1) If your voyage time to CIP 2 is 96 hours or more, you must submit an electronic NOA 96 hours before entering the Seaway at CIP 2. (2) If your voyage time to CIP 2 is less than 96 hours, you must submit an electronic NOA...

The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway.

PubMed

Jia, Tao; Zhang, Li; Duan, Yale; Zhang, Min; Wang, Gang; Zhang, Jun; Zhao, Zheng

2014-01-01

The mechanism underlying the differential cytotoxicity of curcumin in various cancer types, however, remains largely unclear. The aims of this study is to examine the concentration- and time-related effects of curcumin on two different breast cancer cells, MCF-7 and MDA-MB-231, and investigated the functional changes induced by curcumin treatment, as well as their relationship to the PI3K/Akt-SKP2-Cip/Kips pathway. First, WST-1 and clonogenic assay were performed to determine the cytotoxicity of curcumin in MCF-7 and MDA-MB-231 cells. Then, the expression of CDK interacting protein/Kinase inhibitory protein (Cip/Kips) members (p27, p21 and p57) and S-phase kinase-associated protein-2 (SKP2) was investigated by QRT PCR and Western Blotting. Curcumin's effect on PI3K (phosphatidylinositol 3-kinase) /Akt and its substrates Foxo1 and Foxo3a were then studied by Western Blotting. Small interfering RNAs (siRNAs) targeting SKP2 was used to explore the relationship between SKP2 and Cip/Kips members. Finally, WST-1 assay was tested to explore the concomitant treatment with curcumin and the inhibition of PKB or SKP2 signaling on curcumin sensitivity in MCF-7 and MDA-MB-231 cells. We demonstrated MCF-7 and MDA-MB-231 cells exhibited differential responses to curcumin by WST-1 and clonogenic assay (MDA-MB-231 cells was sensitive, and MCF-7 cells was resistant), which were found to be related to the differential curcumin-mediated regulation of SKP2-Cip/Kips (p21 and p27 but not p57) signaling. The differential cellular responses were further linked to the converse effects of curcumin on PI3K/Akt and its substrates Foxo1 and Foxo3a. Importantly, PI3K inhibitor wortmannin could counteract both curcumin-induced phosphorylation of Akt and up-regulation of SKP2 in MCF-7 cells. Subsequent WST-1 assay demonstrated concomitant treatment with curcumin and wortmannin or SKP2 siRNA not only further augmented curcumin sensitivity in MDA-MB-231 cells but also overcame curcumin resistance in MCF-7 cells. Our study established PI3K/Akt-SKP2-Cip/Kips signaling pathway is involved in the mechanism of action of curcumin and revealed that the discrepant modulation of this pathway by curcumin is responsible for the differential susceptibilities of these two cell types to curcumin.

Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1α and HIF-2α

PubMed Central

Yoon, Donghoon; Okhotin, David V.; Kim, Bumjun; Okhotina, Yulia; Okhotin, Daniel J.; Miasnikova, Galina Y.; Sergueeva, Adelina I.; Polyakova, Lydia A.; Maslow, Alexei; Lee, Yonggu; Semenza, Gregg L.; Prchal, Josef T.

2010-01-01

Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen-sensing to be recognized, is characterized by a homozygous germ-line loss-of-function mutation of the VHL gene (VHLR200W) resulting in elevated hypoxia inducible factor (HIF)-1α and HIF-2α levels, increased red cell mass and propensity to thrombosis. Organ volume is determined by the size and number of cells, and the underlying molecular control mechanisms are not fully elucidated. Work from several groups has demonstrated that the proliferation of cells is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing MYC from the promoter of the gene encoding the cyclin-dependent kinase inhibitor, p21Cip1, thereby inducing its expression. In contrast, HIF-2α promotes MYC activity and cell proliferation. Here we report that the volumes of liver, spleen, and kidneys relative to body mass were larger in 30 individuals with Chuvash polycythemia than in 30 matched Chuvash controls. In Hif1a+/− mice, which are heterozygous for a null (knockout) allele at the locus encoding HIF-1α, hepatic HIF-2α mRNA was increased (2-fold) and the mass of the liver was increased, compared with wild-type littermates, without significant difference in cell volume. Hepatic p21Cip1 mRNA levels were 9.5-fold lower in Hif1a+/− mice compared with wild-type littermates. These data suggest that, in addition to increased red cell mass, the sizes of liver, spleen, and kidneys are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21Cip1 levels leading to increased hepatocyte proliferation. PMID:20140661

CIP1 polypeptides and their uses

DOEpatents

Foreman, Pamela [Los Altos, CA; Van Solingen, Pieter [Naaldwijk, NL; Goedegebuur, Frits [Vlaardingen, NL; Ward, Michael [San Francisco, CA

2011-04-12

Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts.

PubMed

Roninson, Igor B

2002-05-08

p21(Waf1/Cip1/Sdi1) is best known as a broad-specificity inhibitor of cyclin/cyclin-dependent kinase complexes, but p21 also interacts with many other regulators of transcription or signal transduction. p21 induction, which is mediated by p53 and by p53-independent mechanisms, is essential for the onset of cell cycle arrest in damage response and cell senescence. The effects of p21 knockout in mice and its expression patterns in human cancer are consistent with a role for p21 as both a tumour suppressor and an oncogene. Several functions of p21 are likely to promote carcinogenesis and tumour progression. These include endoreduplication and abnormal mitosis that develop in tumour cells after release from p21-induced growth arrest, the ability of p21 to inhibit apoptosis through several different mechanisms, and its ability to stimulate transcription of secreted factors with mitogenic and anti-apoptotic activities. The latter effects of p21 show close resemblance to paracrine activities of senescent cells and to tumour-promoting functions of stromal fibroblasts. Therapeutic strategies targeting the oncogenic consequences of p21 expression may provide a new approach to chemoprevention and treatment of cancer.

[CIP and CAP fragments of parathormone and selected parameters of calcium-phosphate balance in patients with chronic kidney disease treated with repeated haemodialysis].

PubMed

Polak-Jonkisz, Dorota; Zwolińska, Danuta; Nahaczewska, Wiesława

2010-01-01

Chronic kidney disease (CKD) leads to bone and mineral complications, which are manifested, among others, by hyperparathyroidism, calcium-phosphate and vitamin D balance disturbances. The results of investigation assessing the usefulness of CAP/CIP ratio, (cyclase activating PTH/cyclase inactive PTH) as a marker of bone turnover and bone disturbances in this group of patients are contradictory. was to estimate the concentration of CAP and CIP of parathormone, connection with selected calcium-phosphate balance parameters and usefulness of CAP/CIP ratio to differentiate bone mineral density in patients with CKD treated with repeated haemodialysis. The study included 31 children aged 5 to 18 years. Group I - 15 haemodialysed children. Group II - 16 healthy children. The patients underwent the following serum measurements: calcium concentration (Ca), inorganic phosphate (P), 1.25-dihydroxyvitamin D, parathormone (intact PTH), and CAP, CIP were evaluated with Scantibodies Laboratory Inc test. In group I the densitometric examination was done using the Lunar DPX-L system, performing the overall bone measurement. In children from group I the average values of iPTH concentration and both CIP and CAP components were significantly elevated (p<0.05) as compared to group II. CAP/CIP ratio in group I was <1; in healthy children >1. Average concentrations of Ca and 1.25(OH)2D in serum of group I were lowered, although without statistical significance in comparison with group II. CAP/CIP ratio does not differentiate the children with bone disturbances. Densitometric examination revealed osteopenic changes in 3 children and osteoporosis in 2 children. There were no statistically significant correlations between the examined parameters. 1. The CIP/CAP ratio does not differentiate the bone mineral density status and it is not associated with biochemical parameters of calcium-phosphate metabolism. 2. This indicates its poor diagnostic utility with reference to mineralization disturbances in children with chronic kidney disease.

Radiation dose effect of DNA repair-related gene expression in mouse white blood cells.

PubMed

Li, Ming-juan; Wang, Wei-wei; Chen, Shi-wei; Shen, Qian; Min, Rui

2011-10-01

The aim of this study was to screen molecular biomarkers for biodosimetry from DNA repair-related gene expression profiles. Mice were subjected to whole-body exposure with 60Co gamma rays with a dose range of 0-8 Gy at a dose rate of 0.80 Gy/min. RNA was extracted from the peripheral blood of irradiated mice at 4, 8, 12, 24 and 48hrs post-irradiation. The mRNA transcriptional changes of 11 genes related to DNA damage and repair were detected using real-time quantitative polymerase chain reaction (RT-PCR). Of the 11 genes examined, CDKN1A (cyclin-dependent kinase inhibitor 1A or p21, Cip1) and ATM (ataxia telangiectasia mutated) expression levels were found to be heavily up- and down-regulated, respectively, with exposure dose increasing at different post-irradiation times. RAD50 (RAD50 homolog), PLK3 (polo-like kinase 3), GADD45A (growth arrest and DNA damage-inducible, alpha), DDB2 (damage-specific DNA-binding protein 2), BBC3 (BCL2-binding component 3) and IER5 (immediate early response 5) gene expression levels were found to undergo significant oscillating changes over a broad dose range of 2-8 Gy at post-exposure time points observed. Three of the genes were found not to change within the observed exposure dose and post-radiation time ranges. The results of this study add to the biodosimetry with biomarker data pool and will be helpful for constructing appropriate gene expression biomarker systems to evaluate radiation exposure doses.

Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors.

PubMed

Cerqueira, Antonio; Martín, Alberto; Symonds, Catherine E; Odajima, Junko; Dubus, Pierre; Barbacid, Mariano; Santamaría, David

2014-04-01

The Cip/Kip family, namely, p21(Cip1), p27(Kip1), and p57(Kip2), are stoichiometric cyclin-dependent kinase inhibitors (CKIs). Paradoxically, they have been proposed to also act as positive regulators of Cdk4/6-cyclin D by stabilizing these heterodimers. Loss of p21(Cip1) and p27(Kip1) reduces Cdk4/6-cyclin D complexes, although with limited phenotypic consequences compared to the embryonic lethality of Cdk4/6 or triple cyclin D deficiency. This milder phenotype was attributed to Cdk2 compensatory mechanisms. To address this controversy using a genetic approach, we generated Cdk2(-/-) p21(-/-) p27(-/-) mice. Triple-knockout mouse embryonic fibroblasts (MEFs) displayed minimal levels of D-type cyclins and Cdk4/6-cyclin D complexes. p57(Kip2) downregulation in the absence of p21(Cip1) and p27(Kip1) aggravated this phenotype, yet MEFs lacking all Cip/Kip proteins exhibited increased retinoblastoma phosphorylation, together with enhanced proliferation and transformation capacity. In vivo, Cdk2 ablation induced partial perinatal lethality in p21(-/-) p27(-/-) mice, suggesting partial Cdk2-dependent compensation. However, Cdk2(-/-) p21(-/-) p27(-/-) survivors displayed all phenotypes described for p27(-/-) mice, including organomegalia and pituitary tumors. Thus, Cip/Kip deficiency does not impair interphasic Cdk activity even in the absence of Cdk2, suggesting that their Cdk-cyclin assembly function is dispensable for homeostatic control in most cell types.

Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells

PubMed Central

Swarbrick, Alexander; Lee, Christine S. L.; Sutherland, Robert L.; Musgrove, Elizabeth A.

2000-01-01

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1 among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27Kip1 and few were bound to p21Cip1. In vitro, recombinant His6-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His6-p27 in vitro or p27Kip1 in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18INK4c and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18INK4c led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27Kip1 and p18INK4c cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor β and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation. PMID:10713180

12 CFR 1292.5 - Community Investment Cash Advance Programs.

Code of Federal Regulations, 2014 CFR

2014-01-01

... shall offer a CIP to provide financing for housing projects and for eligible targeted community lending... projects. (1) For projects funded under CICA programs other than CIP, involving a combination of housing... under CIP, both the housing and economic development components of the project must meet the appropriate...

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

PubMed Central

Bobustuc, George C; Smith, Joshua S; Maddipatla, Sreeram; Jeudy, Sheila; Limaye, Arati; Isley, Beth; Caparas, Maria-Lourdes M; Constantino, Susan M; Shah, Nikita; Baker, Cheryl H; Srivenugopal, Kalkunte S; Baidas, Said; Konduri, Santhi D

2012-01-01

Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O6-benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21cip1/waf1. We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance. PMID:22549111

Measuring the Interactive Skills of Caregivers in Child Care Centers: Development and Validation of the Caregiver Interaction Profile Scales

ERIC Educational Resources Information Center

Helmerhorst, Katrien O. W.; Riksen-Walraven, J. Marianne; Vermeer, Harriet J.; Fukkink, Ruben G.; Tavecchio, Louis W. C.

2014-01-01

Research Findings: High-quality caregiver-child interactions constitute the core of high-quality child care for young children. This article describes the background and development of the Caregiver Interaction Profile (CIP) scales to rate 6 key skills of caregivers for interacting with 0-to 4-year-old children in child care centers: sensitive…

Theoretical understanding on the v(1)-SO4(2-) band perturbed by the formation of magnesium sulfate ion pairs.

PubMed

Zhang, Hao; Zhang, Yun-Hong; Wang, Feng

2009-02-01

The factors determining the spectroscopic characteristics of the v(1)-SO4(2-) band of the MgSO4 ion pairs are discussed via ab initio calculation, including coupling effect, hydrogen bonding effect, and direct contact effect of Mg2+ with SO4(2-). With the calculation of the heavy water hydrated contact ion pairs (CIP), the overlap between the librations of water and the v(1)-SO4(2-) band can be separated, and thus the coupling effect is abstracted, and this coupling effect leads to a blue shift for the v(1)-SO4(2-) band of 5.6 cm(-1) in the monodentate CIP and 3.6 cm(-1) in the bidentate CIP. The hydrogen bonding between each water molecule without relation to Mg2+ and the sulfate ion makes the v(1)-SO4(2-) band blue shift of 3.7 cm(-1). When the outer-sphere water around Mg2+ are hydrogen bonded between SO4(2-) and Mg2+, it will make the largest disturbance to the v(1)-SO4(2-) band. Moreover, the inner-sphere water can affect the v(1)-SO4(2-) band conjunct with the direct contact of Mg2+ with SO4(2-), showing a blue shift of 14.4 cm(-1) in the solvent-shared ion pair, 22.6 cm(-1) in the monodentate CIP, 4.3 cm(-1) in the bidentate CIP, and 21.4 cm(-1) in the tridentate CIP. At last, the Raman spectral evolution in the efflorescence production process is tried to be rationalized. The shoulder at 995 cm(-1) is attributed to the monodentate CIP with 2-3 outer-sphere water molecules, whereas the new peak at 1021 cm(-1) at high concentration is assigned to the formation of aqueous triple ion.

Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.

PubMed

Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Hayashi, Hitomi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2013-06-07

We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

PubMed Central

Drosten, Matthias; Sum, Eleanor Y. M.; Lechuga, Carmen G.; Simón-Carrasco, Lucía; Jacob, Harrys K. C.; García-Medina, Raquel; Huang, Sidong; Beijersbergen, Roderick L.; Bernards, Rene; Barbacid, Mariano

2014-01-01

The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N- and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism. PMID:25288756

The developmental expression of the CDK inhibitor p57(kip2) (Cdkn1c) in the early mouse placenta.

PubMed

Saunders, Ann Catherine Eugenia; McGonnigal, Bethany; Uzun, Alper; Padbury, James

2016-05-01

p57(kip2) (encoded by the Cdkn1c gene) is a member of the cip/kip family of cyclin-dependent kinase inhibitors that mediates cell cycle arrest in G1, allowing cells to differentiate. In the placenta, p57(kip2) is involved in endoreduplication, formation of trophoblast giant cells, trophoblast invasion, and expansion of placental cell layers. Here, we quantitatively and qualitatively define the cell- and region-specific expression of mouse placental p57(kip2) using laser-capture microdissection, in situ hybridization, and immunohistochemistry. Cdkn1c RNA was quantified by real-time quantitative PCR. Co-expression of Pl1 was used to identify trophoblast giant cells while Tbpba was used to identify spongiotrophoblast cells. Timed sacrifices were also carried out at embryonic days E7.5, E8.5, E9.5, and E12.5 to profile the expression in embryos and their placentas. At E8.5, intense expression of Cdkn1c was seen in invasive TGCs and the ectoplacental cone. Cdkn1c expression was more diffuse and more abundant in the labyrinth that in the junctional zone at both E9.5 and E12.5. Immunohistochemistry revealed robust p57(kip2) staining in trophoblast giant cells and in the ectoplacental cone at E8.5. p57(kip2) protein was seen in giant cells and throughout the labyrinth, although its abundance was reduced in the junctional zone at E9.5, and became more diffuse by E12.5. The early and intense expression in trophoblast giant cells is consistent with a role for p57(kip2) in the invasive phenotype of these cells. Mol. Reprod. Dev. 83: 405-412, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Ciprofloxacin-Eluting Nanofibers Inhibits Biofilm Formation by Pseudomonas aeruginosa and a Methicillin-Resistant Staphylococcus aureus

PubMed Central

Ahire, Jayesh J.; Neveling, Deon P.; Hattingh, Melanie; Dicks, Leon M. T.

2015-01-01

Pseudomonas aeruginosa and Staphylococcus aureus are commonly associated with hospital-acquired infections and are known to form biofilms. Ciprofloxacin (CIP), which is normally used to treat these infections, is seldom effective in killing cells in a biofilm. This is mostly due to slow or weak penetration of CIP to the core of biofilms. The problem is accentuated by the release of CIP below MIC (minimal inhibitory concentration) levels following a rapid (burst) release. The aim of this study was to develop a drug carrier that would keep CIP above MIC levels for an extended period. Ciprofloxacin was suspended into poly(D,L-lactide) (PDLLA) and poly(ethylene oxide) (PEO), and electrospun into nanofibers (CIP-F). All of the CIP was released from the nanofibers within 2 h, which is typical of a burst release. However, 99% of P. aeruginosa PA01 cells and 91% of S. aureus Xen 30 cells (a methicillin-resistant strain) in biofilms were killed when exposed to CIP-F. CIP levels remained above MIC for 5 days, as shown by growth inhibition of the cells in vitro. The nanofibers were smooth in texture with no bead formation, as revealed by scanning electron and atomic force microscopy. A single vibration peak at 1632 cm-1, recorded with Fourier transform infrared spectroscopy, indicated that CIP remained in crystal form when incorporated into PDLLA: PEO. No abnormalities in the histology of MCF-12A breast epithelial cells were observed when exposed to CIP-F. This is the first report of the inhibition of biofilm formation by CIP released from PDLLA: PEO nanofibers. PMID:25853255

Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

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

Yoon, Jeongyeon; Ryoo, Sungwoo, E-mail: ryoosw08@kangwon.ac.kr

2013-06-07

Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS)more » mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.« less

Cirrus cloud retrieval with MSG/SEVIRI using artificial neural networks

NASA Astrophysics Data System (ADS)

Strandgren, Johan; Bugliaro, Luca; Sehnke, Frank; Schröder, Leon

2017-09-01

Cirrus clouds play an important role in climate as they tend to warm the Earth-atmosphere system. Nevertheless their physical properties remain one of the largest sources of uncertainty in atmospheric research. To better understand the physical processes of cirrus clouds and their climate impact, enhanced satellite observations are necessary. In this paper we present a new algorithm, CiPS (Cirrus Properties from SEVIRI), that detects cirrus clouds and retrieves the corresponding cloud top height, ice optical thickness and ice water path using the SEVIRI imager aboard the geostationary Meteosat Second Generation satellites. CiPS utilises a set of artificial neural networks trained with SEVIRI thermal observations, CALIOP backscatter products, the ECMWF surface temperature and auxiliary data. CiPS detects 71 and 95 % of all cirrus clouds with an optical thickness of 0.1 and 1.0, respectively, that are retrieved by CALIOP. Among the cirrus-free pixels, CiPS classifies 96 % correctly. With respect to CALIOP, the cloud top height retrieved by CiPS has a mean absolute percentage error of 10 % or less for cirrus clouds with a top height greater than 8 km. For the ice optical thickness, CiPS has a mean absolute percentage error of 50 % or less for cirrus clouds with an optical thickness between 0.35 and 1.8 and of 100 % or less for cirrus clouds with an optical thickness down to 0.07 with respect to the optical thickness retrieved by CALIOP. The ice water path retrieved by CiPS shows a similar performance, with mean absolute percentage errors of 100 % or less for cirrus clouds with an ice water path down to 1.7 g m-2. Since the training reference data from CALIOP only include ice water path and optical thickness for comparably thin clouds, CiPS also retrieves an opacity flag, which tells us whether a retrieved cirrus is likely to be too thick for CiPS to accurately derive the ice water path and optical thickness. By retrieving CALIOP-like cirrus properties with the large spatial coverage and high temporal resolution of SEVIRI during both day and night, CiPS is a powerful tool for analysing the temporal evolution of cirrus clouds including their optical and physical properties. To demonstrate this, the life cycle of a thin cirrus cloud is analysed.

Biochemical effects of veterinary antibiotics on proliferation and cell cycle arrest of human HEK293 cells.

PubMed

Kim, Hyeon Young; Kim, Ki-Tae; Kim, Sang Don

2012-08-01

The purpose of this study was to examine the effects of veterinary antibiotics, including amoxicillin (AMX), chlortetracycline (CTC) and tylosin (TYL), on the biochemical mechanism of human embryonic kidney cells (HEK293). CTC and TYL inhibited HEK293 cell proliferation, in both time- and dose-dependent manners, and changed the cell morphology; whereas, AMX showed no cytotoxic effects. The cell cycle analysis of CTC and TYL revealed G1-arrest in HEK293 cells. Western blot analysis also showed that CTC and TYL affected the activation of DNA damage responsive proteins, as well as cell cycle regulatory proteins, such as p53, p21(Waf1/Cip1) and Rb protein, which are crucial in the G1-S transition. The activation of p21(Waf1/Cip1) was significantly up-regulated over time, but there was no change in the level of CDK2 expression. The results of this study suggest that veterinary antibiotics, even at low level concentrations on continuous exposure, can potentially risk the development of human cells.

77 FR 47831 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-10

... to Reliability Standard CIP-002-4--Critical Cyber Asset Identification. Filed Date: 8/1/12. Accession... Corporation for Approval of an Interpretation to Reliability Standard CIP-004-4--Personnel and Training. Filed...

A dimorphic magnetorheological elastomer incorporated with Fe nano-flakes modified carbonyl iron particles: preparation and characterization

NASA Astrophysics Data System (ADS)

Yu, M.; Zhu, M.; Fu, J.; Yang, P. A.; Qi, S.

2015-11-01

This paper describes a simple and convenient approach for the synthesis of Fe nano-flakes coated spherical carbonyl iron particles (CIP-Nano-Fe). The morphology and composition of CIP-Nano-Fe were characterized using electron scanning microscope and x-ray diffraction analysis. The results indicated that the CI particles were coated with uniform and continuous Fe nanostructures. Partial substitution of CI particles with CIP-Nano-Fe constituted a novel dimorphic magnetorheological elastomer (D-MRE), and the influence of the content of CIP-Nano-Fe on the viscoelastic performance of the magnetorheological elastomers (MREs) were systematically studied. The magnetorheological properties and the damping properties of the D-MRE samples were analyzed to evaluate their dynamic properties. The experimental results indicated that the MR effect, the max loss factor and the magneto-induced loss factor in the sample 3 (CIP-Nano-Fe weight content 6 wt%) were approximately 1.32, 1.45 and 1.56 times that in the sample 1 (non-doped MRE). The approach to synthesize CIP-Nano-Fe reported here can be readily explored for fabricating particles modified by other metal nanostructures, and the resulting D-MREs are expected to be applied in various applications, especially in the field of vibration and noise control, involving vibration isolators, tunable engine mounts, noise insulation devices, and so forth.

Graphene oxide-facilitated transport of levofloxacin and ciprofloxacin in saturated and unsaturated porous media.

PubMed

Sun, Kaixuan; Dong, Shunan; Sun, Yuanyuan; Gao, Bin; Du, Wenchao; Xu, Hongxia; Wu, Jichun

2018-04-15

In this work, effects of graphene oxide (GO) on the co-transport of the two typical Fluoroquinolones (FQs) - levofloxacin (LEV) and ciprofloxacin (CIP) in saturated and unsaturated quartz sand media were studied. The adsorption isotherms showed that GO had much larger sorption capacities to LEV and CIP than sand with the largest Langmuir adsorption capacity of 409 mg g -1 (CIP-GO); while the sorption affinity of the two FQs onto the two adsorbents might follow the order of CIP-sand > LEV-sand > LEV-GO > CIP-GO. GO promoted the mobility of the two FQs in both saturated and unsaturated porous media due to its strong mobility and sorption capacity. The GO-bound LEV/CIP was responsible for the LEV/CIP transport in the porous media, and transport of GO-bound FQs increased with the increasing of initial GO concentration. Under unsaturated conditions, moisture showed little effect on the transport of GO-bound CIP; however, the mobility of GO-bound LEV reduced with the decreasing of moisture content, suggesting the transport of adsorbed LEV from GO to air-water interface. GO sorption reduced the antibacterial ability of the two FQs, but they were still effective in inhibiting E. coli growth. Copyright © 2018 Elsevier B.V. All rights reserved.

The ethanol extract from Artemisia princeps Pampanini induces p53-mediated G1 phase arrest in A172 human neuroblastoma cells.

PubMed

Park, Eun Young; Lee, Kyung-Won; Lee, Heon-Woo; Cho, Young-Wuk; Baek, Nam-In; Chung, Hae-Gon; Jeong, Tae-Sook; Choi, Myung-Sook; Lee, Kyung-Tae

2008-06-01

In the present study, the antiproliferative effects of the ethanol extract of Artemisia princeps Pampanini (EAPP) and the mechanism involved were investigated. Of the various cancer cells examined, human neuroblastoma A172 cells were most sensitive to EAPP, and their proliferation was dose- and time-dependently inhibited by EAPP. DNA flow cytometry analysis indicated that EAPP notably induced the G(1) phase arrest in A172 cells. Of the G(1) phase cycle-related proteins examined, the expressions of cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 and of cyclin D(1), D(2), and D(3) were found to be markedly reduced by EAPP, whereas cyclin E was unaffected. Moreover, the protein and mRNA levels of the CDK inhibitors p16(INK4a), p21(CIP1/WAF1), and p27(KIP1) were increased, and the activities of CDK2, CDK4, and CDK6 were reduced. Furthermore, the expressions of E2F-1 and of phosphorylated pRb were also decreased, and the protein levels of p53 and pp53 (Ser15) were increased. Up-regulation of p21(CIP1/WAF1) was found to be mediated by a p53-dependent pathway in EAPP-induced G(1)-arrested A172 cells. When these data are taken together, the EAPP was found to potently inhibit the proliferation of human neuroblastoma A172 cells via G(1) phase cell cycle arrest.

Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1).

PubMed

Zu, Guo; Yao, Jihong; Ji, Anlong; Ning, Shili; Luo, Fuwen; Li, Zhenlu; Feng, Dongcheng; Rui, Yiqi; Li, Yang; Wang, Guangzhi; Tian, Xiaofeng

2017-01-01

Intestinal ischemia/reperfusion (I/R) injury is a potentially life-threatening condition that can cause injuries to remote organs at the end stage. The damage caused by intestinal I/R insult induces changes in the barrier functions of the intestine, and the intrinsic mechanism of regeneration is often insufficient to restore barrier functions, as indicated by the high mortality rate of patients experiencing intestinal I/R injury. However, little is known about the mechanisms of intestinal regeneration after I/R injury. Here, we reported that nuclear receptor-related protein 1 (Nurr1), a nuclear orphan receptor, was induced during intestinal regeneration after I/R. Our findings showed that Nurr1 expression was consistent with the expression of Ki-67 and phosphorylated histone H3 (pH 3) in the intestine after I/R injury. Nurr1 knockdown led to G1-phase arrest mediated by p21 (Waf1/Cip1) activation, but Nurr1 overexpression reduced the proportion of IEC-6 cells in G1 phase as a result of p21 inhibition in a p53-independent manner. Using chromatin immunoprecipitation assays, luciferase assays, and mutational analysis, we demonstrated that Nurr1 directly inhibited the transcription of p21. These results define a novel Nurr1/p21 pathway that is involved in intestinal regeneration after I/R injury. These findings provide novel molecular insights into the pathogenesis of intestinal regeneration after I/R and possibly support the development of new potential therapies for intestinal I/R injury. Nurr1 was induced during intestinal regeneration after I/R injury. Nurr1 promoted proliferation of intestinal epithelial cells after H/R injury. Nurr1 inhibited p21 expression in a p53-independent manner. Nurr1 inhibited p21 gene transcription by binding to p21 promoter directly.

Mitomycin C and decarbamoyl mitomycin C induce p53-independent p21WAF1/CIP1 activation

PubMed Central

Cheng, Shu-Yuan; Seo, Jiwon; Huang, Bik Tzu; Napolitano, Tanya; Champeil, Elise

2016-01-01

Mitomycin C (MC), a commonly used anticancer drug, induces DNA damage via DNA alkylation. Decarbamoyl mitomycin C (DMC), another mitomycin lacking the carbamate at C10, generates similar lesions as MC. Interstrand cross-links (ICLs) are believed to be the lesions primarily responsible for the cytotoxicity of MC and DMC. The major ICL generated by MC (α-ICL) has a trans stereochemistry at the guanine-drug linkage whereas the major ICL from DMC (β-ICL) has the opposite, cis, stereochemistry. In addition, DMC can provoke strong p53-independent cell death. Our hypothesis is that the stereochemistry of the major unique β-ICL generated by DMC is responsible for this p53-independent cell death signaling. p53 gene is inactively mutated in more than half of human cancers. p21WAF1/CIP1 known as a major effector of p53 is involved in p53-dependent and -independent control of cell proliferation and death. This study revealed the role of p21WAF1/CIP1 on MC and DMC triggered cell damage. MCF-7 (p53-proficient) and K562 (p53-deficient) cells were used. Cell cycle distributions were shifted to the G1/S phase in MCF-7 treated with MC and DMC, but were shifted to the S phase in K562. p21WAF1/CIP1 activation was observed in both cells treated with MC and DMC, and DMC triggered more significant activation. Knocking down p53 in MCF-7 did not attenuate MC and DMC induced p21WAF1/CIP1 activation. The α-ICL itself was enough to cause p21WAF1/CIP1 activation. PMID:27666201

78 FR 27113 - Version 5 Critical Infrastructure Protection Reliability Standards

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-09

... 119 and the table in P 124. Specifically, in P 119, the reference to ``CIP version 4'' in the fifth line is changed to ``CIP version 5.'' In addition, in the table in P 124, the ``Total Burden Hours in... Wednesday, April 24, 2013, the same corrections are made: 1. On page 24121, the reference to ``CIP version 4...

CrpP Is a Novel Ciprofloxacin-Modifying Enzyme Encoded by the Pseudomonas aeruginosa pUM505 Plasmid.

PubMed

Chávez-Jacobo, Víctor M; Hernández-Ramírez, Karen C; Romo-Rodríguez, Pamela; Pérez-Gallardo, Rocío Viridiana; Campos-García, Jesús; Gutiérrez-Corona, J Félix; García-Merinos, Juan Pablo; Meza-Carmen, Víctor; Silva-Sánchez, Jesús; Ramírez-Díaz, Martha I

2018-06-01

The pUM505 plasmid, isolated from a clinical Pseudomonas aeruginosa isolate, confers resistance to ciprofloxacin (CIP) when transferred into the standard P. aeruginosa strain PAO1. CIP is an antibiotic of the quinolone family that is used to treat P. aeruginosa infections. In silico analysis, performed to identify CIP resistance genes, revealed that the 65-amino-acid product encoded by the orf131 gene in pUM505 displays 40% amino acid identity to the Mycobacterium smegmatis aminoglycoside phosphotransferase (an enzyme that phosphorylates and inactivates aminoglycoside antibiotics). We cloned orf131 (renamed crpP , for c iprofloxacin r esistance p rotein, p lasmid encoded) into the pUCP20 shuttle vector. The resulting recombinant plasmid, pUC- crpP , conferred resistance to CIP on Escherichia coli strain J53-3, suggesting that this gene encodes a protein involved in CIP resistance. Using coupled enzymatic analysis, we determined that the activity of CrpP on CIP is ATP dependent, while little activity against norfloxacin was detected, suggesting that CIP may undergo phosphorylation. Using a recombinant His-tagged CrpP protein and liquid chromatography-tandem mass spectrometry, we also showed that CIP was phosphorylated prior to its degradation. Thus, our findings demonstrate that CrpP, encoded on the pUM505 plasmid, represents a new mechanism of CIP resistance in P. aeruginosa , which involves phosphorylation of the antibiotic. Copyright © 2018 American Society for Microbiology.

Lensing bias to CMB measurements of compensated isocurvature perturbations

NASA Astrophysics Data System (ADS)

Heinrich, Chen He; Grin, Daniel; Hu, Wayne

2016-08-01

Compensated isocurvature perturbations (CIPs) are modes in which the baryon and dark matter density fluctuations cancel. They arise in the curvaton scenario as well as some models of baryogenesis. While they leave no observable effects on the cosmic microwave background (CMB) at linear order, they do spatially modulate two-point CMB statistics and can be reconstructed in a manner similar to gravitational lensing. Due to the similarity between the effects of CMB lensing and CIPs, lensing contributes nearly Gaussian random noise to the CIP estimator that approximately doubles the reconstruction noise power. Additionally, the cross correlation between lensing and the integrated Sachs-Wolfe effect generates a correlation between the CIP estimator and the temperature field even in the absence of a correlated CIP signal. For cosmic-variance limited temperature measurements out to multipoles l ≤2500 , subtracting a fixed lensing bias degrades the detection threshold for CIPs by a factor of 1.3, whether or not they are correlated with the adiabatic mode.

Inhibition of Mdm2 Sensitizes Human Retinal Pigment Epithelial Cells to Apoptosis

PubMed Central

Ray, Ramesh M.; Chaum, Edward; Johnson, Dianna A.; Johnson, Leonard R.

2011-01-01

Purpose. Because recent studies indicate that blocking the interaction between p53 and Mdm2 results in the nongenotoxic activation of p53, the authors sought to investigate whether the inhibition of p53-Mdm2 binding activates p53 and sensitizes human retinal epithelial cells to apoptosis. Methods. Apoptosis was evaluated by the activation of caspases and DNA fragmentation assays. The Mdm2 antagonist Nutlin-3 was used to dissociate p53 from Mdm2 and, thus, to increase p53 activity. Knockdown of p53 expression was accomplished by using p53 siRNA. Results. ARPE-19 and primary RPE cells expressed high levels of the antiapoptotic proteins Bcl-2 and Bcl-xL. Exposure of these cells to camptothecin (CPT) or TNF-α/ cycloheximide (CHX) failed to induce apoptosis. In contrast, treatment with the Mdm2 antagonist Nutlin-3 in the absence of CPT or TNF-α/CHX increased apoptosis. Activation of p53 in response to Nutlin-3 also increased levels of Noxa, p53-upregulated modulator of apoptosis (PUMA), and Siva-1, decreased expression of Bcl-2 and Bcl-xL, and simultaneously increased caspases-9 and -3 activities and DNA fragmentation. Knockdown of p53 decreased the basal expression of p21Cip1 and Bcl-2, inhibited the Nutlin-3–induced upregulation of Siva-1 and PUMA expression, and consequently inhibited caspase-3 activation. Conclusions. These results indicate that the normally available pool of intracellular p53 is predominantly engaged in the regulation of cell cycle checkpoints by p21Cip1 and does not trigger apoptosis in response to DNA-damaging agents. However, the blockage of p53 binding to Mdm2 frees a pool of p53 that is sufficient, even in the absence of DNA-damaging agents, to increase the expression of proapoptotic targets and to override the resistance of RPE cells to apoptosis. PMID:21345989

Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors.

PubMed

Starostina, Natalia G; Kipreos, Edward T

2012-01-01

The mammalian CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors (CKIs) comprises three proteins--p21(Cip1/WAF1), p27(Kip1), and p57(Kip2)--that bind and inhibit cyclin-CDK complexes, which are key regulators of the cell cycle. CIP/KIP CKIs have additional independent functions in regulating transcription, apoptosis and actin cytoskeletal dynamics. These divergent functions are performed in distinct cellular compartments and contribute to the seemingly contradictory observation that the CKIs can both suppress and promote cancer. Multiple ubiquitin ligases (E3s) direct the proteasome-mediated degradation of p21, p27 and p57. This review analyzes recent data highlighting our current understanding of how distinct E3 pathways regulate subpopulations of the CKIs to control their diverse functions. Copyright © 2011 Elsevier Ltd. All rights reserved.

31 CFR 1020.220 - Customer identification programs for banks, savings associations, credit unions, and certain non...

Code of Federal Regulations, 2011 CFR

2011-07-01

... written Customer Identification Program (CIP) appropriate for its size and type of business that, at a.... 5318(h), 12 U.S.C. 1818(s), or 12 U.S.C. 1786(q)(1), then the CIP must be a part of the anti-money... directors. (2) Identity verification procedures. The CIP must include risk-based procedures for verifying...

31 CFR 1020.220 - Customer identification programs for banks, savings associations, credit unions, and certain non...

Code of Federal Regulations, 2013 CFR

2013-07-01

... written Customer Identification Program (CIP) appropriate for its size and type of business that, at a.... 5318(h), 12 U.S.C. 1818(s), or 12 U.S.C. 1786(q)(1), then the CIP must be a part of the anti-money... directors. (2) Identity verification procedures. The CIP must include risk-based procedures for verifying...

31 CFR 1020.220 - Customer identification programs for banks, savings associations, credit unions, and certain non...

Code of Federal Regulations, 2012 CFR

2012-07-01

... written Customer Identification Program (CIP) appropriate for its size and type of business that, at a.... 5318(h), 12 U.S.C. 1818(s), or 12 U.S.C. 1786(q)(1), then the CIP must be a part of the anti-money... directors. (2) Identity verification procedures. The CIP must include risk-based procedures for verifying...

34 CFR 668.6 - Reporting and disclosure requirements for programs that prepare students for gainful employment...

Code of Federal Regulations, 2013 CFR

2013-07-01

... Classification of Instructional Program (CIP) code of that program; and (C) If the student completed a program during the award year— (1) The name and CIP code of that program, and the date the student completed the... program, by name and CIP code, offered by the institution under § 668.8(c)(3) or (d), the total number of...

34 CFR 668.6 - Reporting and disclosure requirements for programs that prepare students for gainful employment...

Code of Federal Regulations, 2014 CFR

2014-07-01

... Classification of Instructional Program (CIP) code of that program; and (C) If the student completed a program during the award year— (1) The name and CIP code of that program, and the date the student completed the... program, by name and CIP code, offered by the institution under § 668.8(c)(3) or (d), the total number of...

31 CFR 1020.220 - Customer identification programs for banks, savings associations, credit unions, and certain non...

Code of Federal Regulations, 2014 CFR

2014-07-01

... written Customer Identification Program (CIP) appropriate for its size and type of business that, at a.... 5318(h), 12 U.S.C. 1818(s), or 12 U.S.C. 1786(q)(1), then the CIP must be a part of the anti-money... directors. (2) Identity verification procedures. The CIP must include risk-based procedures for verifying...

34 CFR 668.6 - Reporting and disclosure requirements for programs that prepare students for gainful employment...

Code of Federal Regulations, 2011 CFR

2011-07-01

... Classification of Instructional Program (CIP) code of that program; and (C) If the student completed a program during the award year— (1) The name and CIP code of that program, and the date the student completed the... program, by name and CIP code, offered by the institution under § 668.8(c)(3) or (d), the total number of...

34 CFR 668.6 - Reporting and disclosure requirements for programs that prepare students for gainful employment...

Code of Federal Regulations, 2012 CFR

2012-07-01

... Classification of Instructional Program (CIP) code of that program; and (C) If the student completed a program during the award year— (1) The name and CIP code of that program, and the date the student completed the... program, by name and CIP code, offered by the institution under § 668.8(c)(3) or (d), the total number of...

Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress

PubMed Central

Lehman, Stacey L.; Cerniglia, George J.; Johannes, Gregg J.; Ye, Jiangbin; Ryeom, Sandra; Koumenis, Constantinos

2015-01-01

Multiple transcripts encode for the cell cycle inhibitor p21Cip1. These transcripts produce identical proteins but differ in their 5’ untranslated regions (UTRs). Although several stresses that induce p21 have been characterized, the mechanisms regulating the individual transcript variants and their functional significance are unknown. Here we demonstrate through 35S labeling, luciferase reporter assays, and polysome transcript profiling that activation of the Integrated Stress Response (ISR) kinase GCN2 selectively upregulates the translation of a p21 transcript variant containing 5’ upstream open reading frames (uORFs) through phosphorylation of the eukaryotic translation initiation factor eIF2α. Mutational analysis reveals that the uORFs suppress translation under basal conditions, but promote translation under stress. Functionally, ablation of p21 ameliorates G1/S arrest and reduces cell survival in response to GCN2 activation. These findings uncover a novel mechanism of p21 post-transcriptional regulation, offer functional significance for the existence of multiple p21 transcripts, and support a key role for GCN2 in regulating the cell cycle under stress. PMID:26102367

TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex

PubMed Central

Koch, Giacomo; Ruge, Diane; Cheeran, Binith; Fernandez Del Olmo, Miguel; Pecchioli, Cristiano; Marconi, Barbara; Versace, Viviana; Lo Gerfo, Emanuele; Torriero, Sara; Oliveri, Massimiliano; Caltagirone, Carlo; Rothwell, John C

2009-01-01

Using a twin coil transcranial magnetic stimulation (tc-TMS) approach we have previously demonstrated that facilitation may be detected in the primary motor cortex (M1) following stimulation over the ipsilateral caudal intraparietal sulcus (cIPS). Here we tested the interhemispheric interactions between the IPS and the contralateral motor cortex (M1). We found that conditioning the right cIPS facilitated contralateral M1 when the conditioning stimulus had an intensity of 90% resting motor threshold (RMT) but not at 70% or 110% RMT. Facilitation was maximal when the interstimulus interval (ISI) between cIPS and M1 was 6 or 12 ms. These facilitatory effects were mediated by interactions with specific groups of interneurons in the contralateral M1. In fact, short intracortical inhibition (SICI) was reduced following cIPS stimulation. Moreover, additional comparison of facilitation of responses evoked by anterior–posterior versus posterior–anterior stimulation of M1 suggested that facilitation was more effective on early I1/I2 circuits than on I3 circuits. In contrast to these effects, stimulation of anterior IPS (aIPS) at 90% RMT induced inhibition, instead of facilitation, of contralateral M1 at ISIs of 10–12 ms. Finally, we found similar facilitation between left cIPS and right M1 although the conditioning stimuli had to have a higher intensity compared with stimulation of right cIPS (110% instead of 90% RMT). These findings demonstrate that different subregions of the posterior parietal cortex (PPC) in humans exert both facilitatory and inhibitory effects towards the contralateral primary motor cortex. These corticocortical projections could contribute to a variety of motor tasks such as bilateral manual coordination, movement planning in space and grasping. PMID:19622612

Interactions of ciprofloxacin (CIP), titanium dioxide (TiO2) nanoparticles and natural organic matter (NOM) in aqueous suspensions.

PubMed

Fries, Elke; Crouzet, Catherine; Michel, Caroline; Togola, Anne

2016-09-01

The aim of the present study was to investigate interactions of the antibiotic ciprofloxacin (CIP), titanium dioxide nanoparticles (TiO2 NP) and natural organic matter (NOM) in aqueous suspensions. The mean hydrodynamic diameter of particles of TiO2 NP and NOM in the suspensions ranged from 113 to 255nm. During batch experiments the radioactivity resulting from (14)CIP was determined in the filtrate (filter pore size 100nm) by scintillation measurements. Up to 72h, no significant sorption of NOM to TiO2 NP was observed at a TiO2 NP concentration of 5mg/L. When the concentration of TiO2 NP was increased to 500mg/L, a small amount of NOM of 9.5%±0.6% was sorbed at 72h. The low sorption affinity of NOM on TiO2 NP surfaces could be explained by the negative charge of both components in alkaline media or by the low hydrophobicity of the NOM contents. At a TiO2 NP concentration of 5mgL(-1), the sorption of CIP on TiO2 NP was insignificant (TiO2 NP/CIP ratio: 10). When the TiO2 NP/CIP ratio was increased to 1000, a significant amount of 53.6%±7.2% of CIP was sorbed on TiO2 NP under equilibrium conditions at 64h. In alkaline media, CIP is present mainly as zwitterions which have an affinity to sorb on negatively charged TiO2 NP surfaces. The sorption of CIP on TiO2 NP in the range of TiO2 NP concentrations currently estimated for municipal wastewater treatment plants is estimated to be rather low. The Freundlich sorption coefficients (KF) in the presence of NOM of 2167L(n)mgmg(-n)kg(-1) was about 10 times lower than in the absence of NOM. This is an indication that the particle fraction of NOM<100nm could play a role as a carrier for ionic organic micro-pollutants as CIP. Copyright © 2015 Elsevier B.V. All rights reserved.

cDNA Microarray Gene Expression Profiling of Hedgehog Signaling Pathway Inhibition in Human Colon Cancer Cells

PubMed Central

Shi, Ting; Mazumdar, Tapati; DeVecchio, Jennifer; Duan, Zhong-Hui; Agyeman, Akwasi; Aziz, Mohammad; Houghton, Janet A.

2010-01-01

Background Hedgehog (HH) signaling plays a critical role in normal cellular processes, in normal mammalian gastrointestinal development and differentiation, and in oncogenesis and maintenance of the malignant phenotype in a variety of human cancers. Increasing evidence further implicates the involvement of HH signaling in oncogenesis and metastatic behavior of colon cancers. However, genomic approaches to elucidate the role of HH signaling in cancers in general are lacking, and data derived on HH signaling in colon cancer is extremely limited. Methodology/Principal Findings To identify unique downstream targets of the GLI genes, the transcriptional regulators of HH signaling, in the context of colon carcinoma, we employed a small molecule inhibitor of both GLI1 and GLI2, GANT61, in two human colon cancer cell lines, HT29 and GC3/c1. Cell cycle analysis demonstrated accumulation of GANT61-treated cells at the G1/S boundary. cDNA microarray gene expression profiling of 18,401 genes identified Differentially Expressed Genes (DEGs) both common and unique to HT29 and GC3/c1. Analyses using GenomeStudio (statistics), Matlab (heat map), Ingenuity (canonical pathway analysis), or by qRT-PCR, identified p21Cip1 (CDKN1A) and p15Ink4b (CDKN2B), which play a role in the G1/S checkpoint, as up-regulated genes at the G1/S boundary. Genes that determine further cell cycle progression at G1/S including E2F2, CYCLIN E2 (CCNE2), CDC25A and CDK2, and genes that regulate passage of cells through G2/M (CYCLIN A2 [CCNA2], CDC25C, CYCLIN B2 [CCNB2], CDC20 and CDC2 [CDK1], were down-regulated. In addition, novel genes involved in stress response, DNA damage response, DNA replication and DNA repair were identified following inhibition of HH signaling. Conclusions/Significance This study identifies genes that are involved in HH-dependent cellular proliferation in colon cancer cells, and following its inhibition, genes that regulate cell cycle progression and events downstream of the G1/S boundary. PMID:20957031

Effects of dietary supplementation with an expressed fusion peptide bovine lactoferricin-lactoferrampin on performance, immune function and intestinal mucosal morphology in piglets weaned at age 21 d.

PubMed

Tang, Zhiru; Yin, Yulong; Zhang, Youming; Huang, Ruilin; Sun, Zhihong; Li, Tiejun; Chu, Wuying; Kong, Xiangfeng; Li, Lili; Geng, Meimei; Tu, Qiang

2009-04-01

Lactoferrin has antimicrobial activity associated with peptide fragments lactoferricin (LFC) and lactoferrampin (LFA) released on digestion. These two fragments have been expressed in Photorhabdus luminescens as a fusion peptide linked to protein cipB. The construct cipB-LFC-LFA was tested as an alternative to antimicrobial growth promoters in pig production. Sixty piglets with an average live body weight of 5.42 (sem 0.59) kg were challenged with enterotoxigenic Escherichia coli and randomly assigned to four treatment groups fed a maize-soyabean meal diet containing either no addition (C), cipB at 100 mg/kg (C+B), cipB-LFC-LFA at 100 mg/kg (C+L) or colistin sulfate at 100 mg/kg (C+CS) for 3 weeks. Compared with C, dietary supplementation with C+L for 3 weeks increased daily weight gain by 21 %, increased recovery from diarrhoea, enhanced serum glutathione peroxidase (GPx), peroxidase (POD) and total antioxidant content (T-AOC), liver GPx, POD, superoxide dismutase and T-AOC, Fe, total Fe-binding capacity, IgA, IgG and IgM levels (P < 0.05), decreased the concentration of E. coli in the ileum, caecum and colon (P < 0.05), increased the concentration of lactobacilli and bifidobacteria in the ileum, caecum and colon (P < 0.05), and promoted development of the villus-crypt architecture of the small intestine. Growth performance was similar between C+L- and C+CS-supplemented pigs. The present results indicate that LFC-LFA is an effective alternative to the feed antibiotic CS for enhancing growth performance in piglets weaned at age 21 d.

Chromosome-Encoded Broad-Spectrum Ambler Class A β-Lactamase RUB-1 from Serratia rubidaea

PubMed Central

Didi, Jennifer; Ergani, Ayla; Lima, Sandra

2016-01-01

ABSTRACT Whole-genome sequencing of Serratia rubidaea CIP 103234T revealed a chromosomally located Ambler class A β-lactamase gene. The gene was cloned, and the β-lactamase, RUB-1, was characterized. RUB-1 displayed 74% and 73% amino acid sequence identity with the GIL-1 and TEM-1 penicillinases, respectively, and its substrate profile was similar to that of the latter β-lactamases. Analysis by 5′ rapid amplification of cDNA ends revealed promoter sequences highly divergent from the Escherichia coli σ70 consensus sequence. This work further illustrates the heterogeneity of β-lactamases among Serratia spp. PMID:27956418

Chromosome-Encoded Broad-Spectrum Ambler Class A β-Lactamase RUB-1 from Serratia rubidaea.

PubMed

Bonnin, Rémy A; Didi, Jennifer; Ergani, Ayla; Lima, Sandra; Naas, Thierry

2017-02-01

Whole-genome sequencing of Serratia rubidaea CIP 103234 T revealed a chromosomally located Ambler class A β-lactamase gene. The gene was cloned, and the β-lactamase, RUB-1, was characterized. RUB-1 displayed 74% and 73% amino acid sequence identity with the GIL-1 and TEM-1 penicillinases, respectively, and its substrate profile was similar to that of the latter β-lactamases. Analysis by 5' rapid amplification of cDNA ends revealed promoter sequences highly divergent from the Escherichia coli σ 70 consensus sequence. This work further illustrates the heterogeneity of β-lactamases among Serratia spp. Copyright © 2017 American Society for Microbiology.

FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells.

PubMed

Martin, Bernd T; Kleiber, Kai; Wixler, Viktor; Raab, Monika; Zimmer, Brigitte; Kaufmann, Manfred; Strebhardt, Klaus

2007-07-15

The transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G2/M in MDA-MB 231 cells and an accelerated G2/M transition when FHL2 expression was suppressed in these cells. In search for G2/M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

Mitigation of a nitrate reducing Pseudomonas aeruginosa biofilm and anaerobic biocorrosion using ciprofloxacin enhanced by D-tyrosine.

PubMed

Jia, Ru; Yang, Dongqing; Xu, Dake; Gu, Tingyue

2017-07-31

Pseudomonas aeruginosa (PA) is a ubiquitous microbe. It can form recalcitrant biofilms in clinical and industrial settings. PA biofilms cause infections in patients. They also cause biocorrosion of medical implants. In this work, D-tyrosine (D-tyr) was investigated as an antimicrobial enhancer for ciprofloxacin (CIP) against a wild-type PA biofilm (strain PAO1) on C1018 carbon steel in a strictly anaerobic condition. Seven-day biofilm prevention test results demonstrated that 2 ppm (w/w) D-tyr enhanced 30 ppm CIP by achieving extra 2-log sessile cell reduction compared with the 30 ppm CIP alone treatment. The cocktail of 30 ppm CIP + 2 ppm D-tyr achieved similar efficacy as the 80 ppm CIP alone treatment in the biofilm prevention test. Results also indicated that the enhanced antimicrobial treatment reduced weight loss and pitting corrosion. In the 3-hour biofilm removal test, the cocktail of 80 ppm CIP + 5 ppm D-tyr achieved extra 1.5-log reduction in sessile cell count compared with the 80 ppm CIP alone treatment. The cocktail of 80 ppm CIP + 5 ppm D-tyr achieved better efficacy than the 150 ppm CIP alone treatment in the biofilm removal test.

Desorption kinetics of ciprofloxacin in municipal biosolids determined by diffusion gradient in thin films.

PubMed

D'Angelo, E; Starnes, D

2016-12-01

Ciprofloxacin (CIP) is a commonly-prescribed antibiotic that is largely excreted by the body, and is often found at elevated concentrations in treated sewage sludge (biosolids) at municipal wastewater treatment plants. When biosolids are applied to soils, they could release CIP to surface runoff, which could adversely affect growth of aquatic organisms that inhabit receiving water bodies. The hazard risk largely depends on the amount of antibiotic in the solid phase that can be released to solution (labile CIP), its diffusion coefficient, and sorption/desorption exchange rates in biosolids particles. In this study, these processes were evaluated in a Class A Exceptional Quality Biosolids using a diffusion gradient in thin films (DGT) sampler that continuously removed CIP from solution, which induced desorption and diffusion in biosolids. Mass accumulation of antibiotic in the sampler over time was fit by a diffusion transport and exchange model available in the software tool 2D-DIFS to derive the distribution coefficient of labile CIP (K dl ) and sorption/desorption rate constants in the biosolids. The K dl was 13 mL g -1 , which equated to 16% of total CIP in the labile pool. Although the proportion of labile CIP was considerable, release rates to solution were constrained by slow desorption kinetics (desorption rate constant = 4 × 10 -6 s -1 ) and diffusion rate (effective diffusion coefficient = 6 × 10 -9  cm 2  s -1 . Studies are needed to investigate how changes in temperature, water content, pH and other physical and chemical characteristics can influence antibiotic release kinetics and availability and mobility in biosolid-amended soils. Copyright © 2016 Elsevier Ltd. All rights reserved.

The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function.

PubMed

Gu, Yue; Jones, Amanda E; Yang, Wei; Liu, Shanrun; Dai, Qian; Liu, Yudong; Swindle, C Scott; Zhou, Dewang; Zhang, Zhuo; Ryan, Thomas M; Townes, Tim M; Klug, Christopher A; Chen, Dongquan; Wang, Hengbin

2016-01-05

Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.

A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture.

PubMed

Sierralta, Walter D; Epuñan, Maria J; Reyes, José M; Valladares, Luis E; Andersen, Thomas T; Bennett, James A; Jacobson, Herbert I; Pino, Ana M

2008-01-01

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 microg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.

Pancreatic intraepithelial neoplasia in association with intraductal papillary mucinous neoplasms of the pancreas: implications for disease progression and recurrence.

PubMed

Biankin, Andrew V; Kench, James G; Biankin, Sandra A; Lee, C-Soon; Morey, Adrienne L; Dijkman, Floriaan P; Coleman, Maxwell J; Sutherland, Robert L; Henshall, Susan M

2004-09-01

The development of pancreatic cancer (PC) several years after curative resection for noninvasive intraductal papillary mucinous neoplasm (IPMN) and the presence of PC distant from IPMN suggest that PC may develop independently of the IPMN. Here, we identified pancreatic intraepithelial neoplasia (PanIN) lesions, the putative precursors of PC, in the ducts of pancreata resected for IPMN and assessed the frequency of molecular aberrations common to PanIN and PC, within these lesions. The protein expression of p53, p21(WAF1/CIP1), cyclin D1, p16(INK4A) and DPC4/Smad4 were examined by immunohistochemistry in 267 PanIN lesions from a cohort of 23 patients with IPMN. Overexpression of p21(WAF1/CIP1) was present in PanIN-1A and -1B lesions and increased in frequency in PanIN-2 and PanIN-3. Overexpression of p53 and cyclin D1, and loss of p16(INK4A) expression were detected in PanIN-2 and PanIN-3 lesions. Loss of DPC4/Smad4 expression occurred only in the PanIN-3 lesions. PanIN lesions that were more dysplastic than the coincident IPMN were identified in 5 of 12 patients, and 2 of these contained a greater number of aberrations in protein expression than the IPMN. PanIN lesions seen in association with IPMN demonstrate molecular and histologic changes identical to PanIN lesions found in association with PC and, in some cases, are more advanced than the associated IPMN. These data suggest that PanIN lesions found in the ducts of a pancreas with IPMN may be relevant to the development of PC either coincident with IPMN or in the remnant pancreas after curative resection of IPMN.

Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer

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

Li, Wenjuan; Zhao, Li; Zang, Wen

2011-12-16

Highlights: Black-Right-Pointing-Pointer JMJD2B is required for cell proliferation and in vivo tumorigenesis. Black-Right-Pointing-Pointer JMJD2B depletion induces apoptosis and/or cell cycle arrest. Black-Right-Pointing-Pointer JMJD2B depletion activates DNA damage response and enhances p53 stabilization. Black-Right-Pointing-Pointer JMJD2B is overexpressed in human primary gastric cancer. -- Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Jumonji domain containing 2B (JMJD2B) is a newly identified histone demethylase that regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 9 on histone H3. Recent observations have shown oncogenic activity of JMJD2B. We explored the functional role ofmore » JMJD2B in cancer cell proliferation, survival and tumorigenesis, and determined its expression profile in gastric cancer. Knocking down JMJD2B expression by small interfering RNA (siRNA) in gastric and other cancer cells inhibited cell proliferation and/or induced apoptosis and elevated the expression of p53 and p21{sup CIP1} proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. JMJD2B knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, JMJD2B expression was increased in primary gastric-cancer tissues of humans. Thus, JMJD2B is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of gastric cancer.« less

Low-molecular-weight organic acids correlate with cultivar variation in ciprofloxacin accumulation in Brassica parachinensis L.

PubMed

Zhao, Hai-Ming; Xiang, Lei; Wu, Xiao-Lian; Jiang, Yuan-Neng; Li, Hui; Li, Yan-Wen; Cai, Quan-Ying; Mo, Ce-Hui; Liu, Jie-Sheng; Wong, Ming-Hung

2017-08-31

To understand the mechanism controlling cultivar differences in the accumulation of ciprofloxacin (CIP) in Chinese flowering cabbage (Brassica parachinensis L.), low-molecular-weight organic acids (LMWOAs) secreted from the roots of high- and low-CIP cultivars (Sijiu and Cutai, respectively) and their effects on the bioavailability of CIP in soil were investigated. Significant differences in the content of LMWOAs (especially maleic acid) between the two cultivars played a key role in the variation in CIP accumulation. Based on the Freundlich sorption coefficient (K f ) and distribution coefficient (K d ), the presence of LMWOAs reduced the CIP sorption onto soil particles, and higher concentrations of LMWOAs led to less CIP sorption onto soil. On the other hand, LMWOAs enhanced CIP desorption by lowering the solution pH, which changed the surface charge of soil particles and the degree of CIP ionization. LMWOAs promoted CIP desorption from soil by breaking cation bridges and dissolving metal cations, particularly Cu 2+ . These results implied that the LMWOAs (mainly maleic acid) secreted from Sijiu inhibited CIP sorption onto soil and improved CIP desorption from soil to a greater extent than those secreted from Cutai, resulting in higher bioavailability of CIP and more uptake and accumulation of CIP in the former.

Semi-analytical integration of the Earth's precession-nutation based on the GCRS coordinates of the CIP unit vector

NASA Astrophysics Data System (ADS)

Capitaine, N.; Folgueira, M.

2012-12-01

In a previous paper (Capitaine et al. 2006), referred here as Paper I, we demonstrated the possibility of integrating the Earth's rotational motion in terms of the coordinates (X, Y ) of the celestial intermediate pole (CIP) unit vector in the Geocentric celestial reference system (GCRS). Here, we report on the approach that has been followed for solving the equations in the case of an axially symmetric rigid Earth and the semi-analytical (X, Y ) solution obtained from the expression of the external torque acting on the Earth derived from the most complete semi-analytical solutions for the Earth, Moon and planets.

Clinical review: Critical illness polyneuropathy and myopathy

PubMed Central

Hermans, Greet; De Jonghe, Bernard; Bruyninckx, Frans; Berghe, Greet Van den

2008-01-01

Critical illness polyneuropathy (CIP) and myopathy (CIM) are major complications of severe critical illness and its management. CIP/CIM prolongs weaning from mechanical ventilation and physical rehabilitation since both limb and respiratory muscles can be affected. Among many risk factors implicated, sepsis, systemic inflammatory response syndrome, and multiple organ failure appear to play a crucial role in CIP/CIM. This review focuses on epidemiology, diagnostic challenges, the current understanding of pathophysiology, risk factors, important clinical consequences, and potential interventions to reduce the incidence of CIP/CIM. CIP/CIM is associated with increased hospital and intensive care unit (ICU) stays and increased mortality rates. Recently, it was shown in a single centre that intensive insulin therapy significantly reduced the electrophysiological incidence of CIP/CIM and the need for prolonged mechanical ventilation in patients in a medical or surgical ICU for at least 1 week. The electrophysiological diagnosis was limited by the fact that muscle membrane inexcitability was not detected. These results have yet to be confirmed in a larger patient population. One of the main risks of this therapy is hypoglycemia. Also, conflicting evidence concerning the neuromuscular effects of corticosteroids exists. A systematic review of the available literature on the optimal approach for preventing CIP/CIM seems warranted. PMID:19040777

Development of CIP/graphite composite additives for electromagnetic wave absorption applications

NASA Astrophysics Data System (ADS)

Woo, Soobin; Yoo, Chan-Sei; Kim, Hwijun; Lee, Mijung; Quevedo-Lopez, Manuel; Choi, Hyunjoo

2017-09-01

In this study, the electromagnetic (EM) wave absorption ability of carbonyl iron powder (CIP)/graphite composites produced by ball milling were studied in a range of 28.5 GHz to examine the effects of the morphology and volume fraction of graphite on EM wave absorption ability. The results indicated that a ball milling technique was effective in exfoliating the graphite and covering it with CIP, thereby markedly increasing the specific surface area of the hybrid powder. The increase in the surface area and hybridization with dielectric loss materials (i.e., graphite) improved EM absorbing properties of CIP in the range of S and X bands. Specifically, the CIP/graphite composite containing 3 wt% graphite exhibited electromagnetic wave absorption of -13 dB at 7 GHz, -21 dB at 5.8 GHz, and -29 dB at 4.3 GHz after 1 h, 8 h, and 16 h of milling, respectively. [Figure not available: see fulltext.

78 FR 76112 - 36(b)(1) Arms Sales Notification

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-16

...: participation in the F/A-18 Engine Component Improvement Program (CIP), spare and repair parts, system...: participation in the F/A-18 Engine Component Improvement Program (CIP), spare and repair parts, system...

12 CFR 1201.1 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... U.S.C. 1426(b)). CIP means the Community Investment Program, an advance program under CICA required...)); a Bank's Community Investment Program (CIP), offered under section 10(i) of the Bank Act (12 U.S.C...

Enhanced and broadband microwave absorption of flake-shaped Fe and FeNi composite with Ba ferrites

NASA Astrophysics Data System (ADS)

Li, Wangchang; Lv, Junjun; Zhou, Xiang; Zheng, Jingwu; Ying, Yao; Qiao, Liang; Yu, Jing; Che, Shenglei

2017-03-01

In order to achieve a broad bandwidth absorber at high frequency, the composites of M-type ferrite BaCo1.0Ti1.0Fe10O19 (BaM) with flaked carbonyl iron powders (CIP) and flaked Fe50Ni50 were prepared to optimize the surface impedance in broadband frequency, respectively. The diameter of the flaked carbonyl iron powders (CIP) and Fe50Ni50 is in the range of 5-10 μm and 10-20 μm and the thickness of the CIP and Fe50Ni50 is close to 200 nm and 400 nm, respectively. The complex permeability and permittivity show that the addition of BaM obviously reduces the values of real part of permittivity and imaginary part of the permeability which can enhance the matched-wave-impedance. The absorption bands less than -10 dB of CIP-BaM and FeNi-BaM absorber approach to 5.5 GHz (5.7-11.2 GHz) and 7 GHz (11-18 GHz) at 1.5 mm. However, the bands of CIP and FeNi are only 1.9 GHz (4.7-6.6 GHz) and 2.1 GHz (4.0-6.1 GHz). Hence, the electromagnetic match property is greatly improved by BaM ferrites, and this composite shows a broaden absorption band.

Evolution of antibiotic resistance in biofilm and planktonic P. aeruginosa populations exposed to sub-inhibitory levels of ciprofloxacin.

PubMed

Ahmed, Marwa N; Porse, Andreas; Sommer, Morten Otto Alexander; Høiby, Niels; Ciofu, Oana

2018-05-14

The opportunistic Gram-negative pathogen Pseudomonas aeruginosa , known for its intrinsic and acquired antibiotic resistance, has a notorious ability to form biofilms, which often facilitate chronic infections. The evolutionary paths to antibiotic resistance have mainly been investigated in planktonic cultures and are less studied in biofilms. We experimentally evolved P. aeruginosa PAO1 colony-biofilms and stationary-phase planktonic cultures for seven passages in the presence of sub-inhibitory levels (0.1 mg/L) of ciprofloxacin (CIP) and performed a genotypic (whole bacterial population sequencing) and phenotypic assessment of the populations. We observed a higher proportion of CIP resistance in the CIP-evolved biofilm populations compared to planktonic populations exposed to the same drug concentrations. However, the minimal inhibitory concentrations (MICs) of ciprofloxacin were lower in CIP-resistant isolates selected from biofilm population compared to the MICs of CIP-resistant isolates from the planktonic cultures. We found common evolutionary trajectories between the different lineages, with mutations in known CIP resistance determinants as well as growth condition-dependent adaptations. A general trend towards a reduction in type IV-pili dependent motility (twitching) in CIP-evolved populations, and towards loss of virulence associated traits in the populations evolved in the absence of antibiotic, was observed. In conclusion, our data indicate that biofilms facilitate the development of low-level mutational resistance, probably due to the lower effective drug exposure compared to planktonic cultures. These results provide a framework for the selection process of resistant variants and the evolutionary mechanisms in the two different growth conditions. Copyright © 2018 American Society for Microbiology.

Ciprofloxacin degradation in anaerobic sulfate-reducing bacteria (SRB) sludge system: Mechanism and pathways.

PubMed

Jia, Yanyan; Khanal, Samir Kumar; Shu, Haoyue; Zhang, Huiqun; Chen, Guang-Hao; Lu, Hui

2018-06-01

Ciprofloxacin (CIP), a fluoroquinolone antibiotic, removal was examined for the first time, in an anaerobic sulfate-reducing bacteria (SRB) sludge system. About 28.0% of CIP was biodegraded by SRB sludge when the influent CIP concentration was 5000 μg/L. Some SRB genera with high tolerance to CIP (i.e. Desulfobacter), were enriched at CIP concentration of 5000 μg/L. The changes in antibiotic resistance genes (ARGs) of SRB sludge coupled with CIP biodegradation intermediates were used to understand the mechanism of CIP biodegradation for the first time. The percentage of efflux pump genes associated with ARGs increased, while the percentage of fluoroquinolone resistance genes that inhibit the DNA copy of bacteria decreased during prolonged exposure to CIP. It implies that some intracellular CIP was extruded into extracellular environment of microbial cells via efflux pump genes to reduce fluoroquinolone resistance genes accumulation caused by exposure to CIP. Additionally, the degradation products and the possible pathways of CIP biodegradation were also examined using the new method developed in this study. The results suggest that CIP was biodegraded intracellularly via desethylation reaction in piperazinyl ring and hydroxylation reaction catalyzed by cytochrome P450 enzymes. This study provides an insight into the mechanism and pathways of CIP biodegradation by SRB sludge, and opens-up a new opportunity for the treatment of CIP-containing wastewater using sulfur-mediated biological process. Copyright © 2018 Elsevier Ltd. All rights reserved.

Electronic Structure and Transport in Magnetic Multilayers

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

None

2008-02-18

ORNL assisted Seagate Recording Heads Operations in the development of CIPS pin Valves for application as read sensors in hard disk drives. Personnel at ORNL were W. H. Butler and Xiaoguang Zhang. Dr. Olle Heinonen from Seagate RHO also participated. ORNL provided codes and materials parameters that were used by Seagate to model CIP GMR in their heads. The objectives were to: (1) develop a linearized Boltzmann transport code for describing CIP GMR based on realistic models of the band structure and interfaces in materials in CIP spin valves in disk drive heads; (2) calculate the materials parameters needed asmore » inputs to the Boltzmann code; and (3) transfer the technology to Seagate Recording Heads.« less

Targeting p35/Cdk5 signalling via CIP-peptide promotes angiogenesis in hypoxia.

PubMed

Bosutti, Alessandra; Qi, Jie; Pennucci, Roberta; Bolton, David; Matou, Sabine; Ali, Kamela; Tsai, Li-Huei; Krupinski, Jerzy; Petcu, Eugene B; Montaner, Joan; Al Baradie, Raid; Caccuri, Francesca; Caruso, Arnaldo; Alessandri, Giulio; Kumar, Shant; Rodriguez, Cristina; Martinez-Gonzalez, Jose; Slevin, Mark

2013-01-01

Cyclin-dependent kinase-5 (Cdk5) is over-expressed in both neurons and microvessels in hypoxic regions of stroke tissue and has a significant pathological role following hyper-phosphorylation leading to calpain-induced cell death. Here, we have identified a critical role of Cdk5 in cytoskeleton/focal dynamics, wherein its activator, p35, redistributes along actin microfilaments of spreading cells co-localising with p(Tyr15)Cdk5, talin/integrin beta-1 at the lamellipodia in polarising cells. Cdk5 inhibition (roscovitine) resulted in actin-cytoskeleton disorganisation, prevention of protein co-localization and inhibition of movement. Cells expressing Cdk5 (D144N) kinase mutant, were unable to spread, migrate and form tube-like structures or sprouts, while Cdk5 wild-type over-expression showed enhanced motility and angiogenesis in vitro, which was maintained during hypoxia. Gene microarray studies demonstrated myocyte enhancer factor (MEF2C) as a substrate for Cdk5-mediated angiogenesis in vitro. MEF2C showed nuclear co-immunoprecipitation with Cdk5 and almost complete inhibition of differentiation and sprout formation following siRNA knock-down. In hypoxia, insertion of Cdk5/p25-inhibitory peptide (CIP) vector preserved and enhanced in vitro angiogenesis. These results demonstrate the existence of critical and complementary signalling pathways through Cdk5 and p35, and through which coordination is a required factor for successful angiogenesis in sustained hypoxic condition.

75 FR 29336 - North American Electric Reliability Corporation; Notice of Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-25

... (VSL) assignments for Version 1 of the Critical Infrastructure Protection (CIP) Reliability Standards... Infrastructure Protection Reliability Standards, 130 FERC ] 61,211 at PP 23, 28, 31-33 (2010) (March 18 CIP VSL...

Reaction kinetics and oxidation products formation in the degradation of ciprofloxacin and ibuprofen by ferrate(VI).

PubMed

Zhou, Zhengwei; Jiang, Jia-Qian

2015-01-01

The treatment of ciprofloxacin (CIP) and ibuprofen (IBU) in test solutions by ferrate(VI) was investigated in this study. A series of jar test was performed in bench-scale at pH 6-9 and ferrate(VI) dose of 1-5 mg L(-1). Results demonstrated that ferrate(VI) removed CIP from test solutions efficiently, with above 70% of reduction under study conditions. In contrary, the removal rates of IBU were very low, less than 25% in all conditions. Raising ferrate(VI) dose improved the treatment performance, while the influence of solution pH was not significant at pH 6-9 compared with that of ferrate(VI) dose. In addition, kinetic studies of ferrate(VI) with both compounds were carried out at pH 8 and pH 9 (20 °C). Ferrate(VI) had a much higher reactivity with CIP than IBU at pH 8 and pH 9, with CIP's apparent second-order rate constants of 113.7±6.3 M(-1) s(-1) and 64.1±1.0 M(-1) s(-1), respectively. The rate constants of ferrate(VI) with IBU were less than 0.2 M(-1) s(-1) at pH 8 and pH 9. Furthermore, seven oxidation products (OPs) were formed during CIP degradation by ferrate(VI). The attack on the piperazinyl ring of the CIP by ferrate(VI) appeared to lead to the cleavage or hydroxylation of the rings, and the attack on the quinolone moiety by ferrate(VI) might lead to the cleavage of the double bond at the six-member heterocyclic ring. No OPs of IBU were detected during ferrate(VI) oxidation due to very small part of IBU was degraded by ferrate(VI). Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterization of the Novel DNA-Binding Activity of p270, a hSWI/SNF Protein Frequently Downregulated in Breast Cancer

DTIC Science & Technology

2005-07-01

M62324), MRF2 (M73837), RRPe (P24374), RBP1L1 (NP 057458), Jumonji (92833), SMoX (L25270), SMCY (Nok004644), RBP2 (S66431), and PLU-1 (CAB43532). Aoic...associated with specific aspects of cell cycle 2 regulation. Expression of the cell cycle inhibitor p21 CIP1/WAF1 has been repeatedly identified as 3 BRG1...Histone H1, Ascorbic acid, P-glycerol phosphate, and protease inhibitors were obtained from 6 Sigma Chemical Co. (St. Louis, MO), and G418 from Gibco

Carfilzomib induces leukaemia cell apoptosis via inhibiting ELK1/KIAA1524 (Elk-1/CIP2A) and activating PP2A not related to proteasome inhibition.

PubMed

Liu, Chun-Yu; Hsieh, Feng-Shu; Chu, Pei-Yi; Tsai, Wen-Chun; Huang, Chun-Teng; Yu, Yuan-Bin; Huang, Tzu-Ting; Ko, Po-Shen; Hung, Man-Hsin; Wang, Wan-Lun; Shiau, Chung-Wai; Chen, Kuen-Feng

2017-06-01

Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment. © 2017 John Wiley & Sons Ltd.

Microarsecond models for the celestial motions of the CIP and CEO

NASA Astrophysics Data System (ADS)

Capitaine, N.

2004-09-01

The Celestial intermediate pole (CIP) and Celestial ephemeris (orintermediate) origin (CEO/CIO) have been adopted by the IAU (c.f. IAU2000 Resolution B1.8) as the celestial pole and origin, respectively,to be used for realizing the intermediate celestial system between theInternational Terrestrial System (ITRS) and Geocentric CelestialReference System (GCRS). Resolution B1.8 has also recommended that theInternational Earth Rotation and Reference Systems Service (IERS)continue to provide users with data and algorithms for the conventionaltransformation. The IAU 2000 Resolutions have been implemented in theIERS 2003 Conventions including Tables and routines that provide thecelestial motions of the CIP and the CEO with a theoretical accuracy ofone microarcsecond after one century using either the classical or thenew transformation. This paper reports on the method used for achievingthis accuracy in the positions of the CIP and CIO and on the differencebetween this rigorous procedure and the pre-2003 classical one.

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation*

PubMed Central

Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

2009-01-01

High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERRα-dependent manner. XCT790 induces, in a p53-independent manner, the expression of the cell cycle inhibitor p21waf/cip1 at the protein, mRNA, and promoter level, leading to an accumulation of hypophosphorylated Rb. Finally, XCT790 reduces cell tumorigenicity in Nude mice. PMID:19546226

Concentrations of indoor pollutants (CIP) database user's manual (Version 4. 0)

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

Apte, M.G.; Brown, S.R.; Corradi, C.A.

1990-10-01

This is the latest release of the database and the user manual. The user manual is a tutorial and reference for utilizing the CIP Database system. An installation guide is included to cover various hardware configurations. Numerous examples and explanations of the dialogue between the user and the database program are provided. It is hoped that this resource will, along with on-line help and the menu-driven software, make for a quick and easy learning curve. For the purposes of this manual, it is assumed that the user is acquainted with the goals of the CIP Database, which are: (1) tomore » collect existing measurements of concentrations of indoor air pollutants in a user-oriented database and (2) to provide a repository of references citing measured field results openly accessible to a wide audience of researchers, policy makers, and others interested in the issues of indoor air quality. The database software, as distinct from the data, is contained in two files, CIP. EXE and PFIL.COM. CIP.EXE is made up of a number of programs written in dBase III command code and compiled using Clipper into a single, executable file. PFIL.COM is a program written in Turbo Pascal that handles the output of summary text files and is called from CIP.EXE. Version 4.0 of the CIP Database is current through March 1990.« less

Deficiency of cyclin-dependent kinase inhibitors p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apolipoprotein E-deficient mice

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

Akyuerek, Levent M.; Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Goeteborg, SE-405 30; Boehm, Manfred

2010-05-28

Cyclin-dependent kinase inhibitors, p21{sup Cip1} and p27{sup Kip1}, are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21{sup Cip1} or p27{sup Kip1} in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE{sup -/-} aortae, both apoE{sup -/-}/p21{sup -/-} and apoE{sup -/-}/p27{sup -/-} aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27{sup Kip1} accelerated plaque formation significantly more than p21{sup -/-} in apoE{sup -/-} mice. This increased plaque formation was in parallel with increased intima/mediamore » area ratios. Deficiency of p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apoE{sup -/-} mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells.« less

Lensing bias to CMB polarization measurements of compensated isocurvature perturbations

NASA Astrophysics Data System (ADS)

Heinrich, Chen

2018-01-01

Compensated isocurvature perturbations (CIPs) are opposite spatial fluctuations in the baryon and dark matter (DM) densities. They arise in the curvaton model and some models of baryogenesis. While the gravitational effects of baryon fluctuations are compensated by those of DM, leaving no observable impacts on the cosmic microwave background (CMB) at first order, they modulate the sound horizon at recombination, thereby correlating CMB anisotropies at different multipoles. As a result, CIPs can be reconstructed using quadratic estimators similarly to CMB detection of gravitational lensing. Because of these similarities, however, the CIP estimators are biased with lensing contributions that must be subtracted. These lensing contributions for CMB polarization measurement of CIPs are found to roughly triple the noise power of the total CIP estimator on large scales. In addition, the cross power with temperature and E -mode polarization are contaminated by lensing-ISW (integrated Sachs-Wolfe) correlations and reionization-lensing correlations respectively. For a cosmic-variance-limited temperature and polarization experiment measuring out to multipoles lmax=2500 , the lensing noise raises the detection threshold by a factor of 1.5, leaving a 2.7 σ detection possible for the maximal CIP signal in the curvaton model.

Comparison of PMC measurements from AIM and SBUV/2

NASA Astrophysics Data System (ADS)

Benze, S.; Randall, C.; Deland, M.; Thomas, G.; Rusch, D.; Bailey, S.; Russell, J.; McClintock, W.; Merkel, A.; Jeppesen, C.

2007-12-01

The Aeronomy of Ice in the Mesosphere (AIM) spacecraft, launched on April 25 from Vandenberg Air Force Base, is a satellite mission that explores Polar Mesospheric Clouds (PMCs) in order to find out why they form and why they are changing. Results of this mission will provide new knowledge about the connection between PMCs and the meteorology of the polar mesosphere. The Cloud Imaging and Particle Size (CIPS) instrument is a nadir- viewing instrument from which PMC frequency and brightness can be inferred. It produces panoramic images of scattered radiation at 265 nm with a field of view of 1800 x 800 km and high spatial resolution. This work provides a first comparison of CIPS PMC morphology to concurrent results from the Solar Backscatter Ultraviolet (SBUV/2) instrument, which has provided a 28-year climatology of PMC brightness and frequency. CIPS and SBUV/2 PMC detections are compared for selected days in the 2007 northern hemispheric season. To facilitate comparison, the CIPS footprint of 1x2 km is binned to match the SBUV/2 footprint of 150x150 km at the PMC altitude of 80 km. Because CIPS measures only one wavelength at 265 nm, the SBUV PMC detection algorithm, which normally uses data at five wavelengths between 252-292 nm, is simplified to an algorithm applying just one wavelength. It will be shown that the single wavelength SBUV/2 algorithm gives similar results to the original algorithm. PMC frequency and brightness derived from both CIPS and SBUV/2 using the common algorithm will be compared. Cloud brightness for all latitudes agrees to within 1 percent over the season. In addition, a coincidence analysis of CIPS and all three operational SBUV/2 instruments for the summer 2007 season will be shown.

Examination of the expanding pathways for the regulation of p21 expression and activity.

PubMed

Jung, Yong-Sam; Qian, Yingjuan; Chen, Xinbin

2010-07-01

p21(Waf1/Cip1/Sdi1) was originally identified as an inhibitor of cyclin-dependent kinases, a mediator of p53 in growth suppression and a marker of cellular senescence. p21 is required for proper cell cycle progression and plays a role in cell death, DNA repair, senescence and aging, and induced pluripotent stem cell reprogramming. Although transcriptional regulation is considered to be the initial control point for p21 expression, there is growing evidence that post-transcriptional and post-translational regulations play a critical role in p21 expression and activity. This review will briefly discuss the activity of p21 and focus on current knowledge of the determinants that control p21 transcription, mRNA stability and translation, and protein stability and activity. (c) 2010 Elsevier Inc. All rights reserved.

Evaluation Manual for CIP Courses: Objectives and Implementation Procedures.

ERIC Educational Resources Information Center

Siri, Carmen

This manual has been designed to guide courses on potato production sponsored by the International Potato Center (CIP) in Lima (Peru). It describes the CIP Course Evaluation System that is presently used and provides guidelines on how to use feedback more effectively for improving training. CIP evaluations are largely formative. The CIP focuses on…

Genotypic Characterization of Egypt Enterotoxigenic Escherichia coli Isolates Expressing Coli Surface Antigen 6

DTIC Science & Technology

2013-02-01

47%) of these isolates were resistant to ampicillin, a third (37%) of the isolates were resistant to trimethoprim -sulfamethoxazole, and 24% of the...isolates were tetracycline-resistant. A blaTEM gene was detected in 24 (83%) ampicillin-resistant isolates. Trimethoprim -sulfamethoxazole-resistant...ciprofloxacin (CIP) 5 μg, amikacin (AN) 30 μg, gentamicin (GEN) 10 μg, tetracycline (TET) 30 μg, trimethoprim 1.25 μg / sulfamethoxazole 23.75 μg (SXT

The anchorage function of CipA (CelL), a scaffolding protein of the Clostridium thermocellum cellulosome

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

Kruus, K.; Wu, J.H.D.; Lua, A.C.

1995-09-26

Enzymatic cellulose degradation is a heterogeneous reaction requiring binding of soluble cellulase molecules to the solid substrate. Based on our studies of the cellulase complex of Clostridium thermocellum (the cellulosome), we have previously proposed that such binding can be brought about by a special {open_quotes}anchorage subunit.{close_quotes} In this {open_quotes}anchor-enzyme{close_quotes} model, CipA (a major subunit of the cellulosome) enhances the activity of CelS (the most abundant catalytic subunit of the cellulosome) by anchoring it to the cellulose surface. We have subsequently reported that CelS contains a conserved duplicated sequence at its C terminus and the CipA contains nine repeated sequences withmore » a cellulose binding domain (CBD) in between the second and third repeats. In this work, we reexamined the anchor-enzyme mechanism by using recombinant CelS (rCelS) and various CipA domains, CBD, R3 (the repeat next to CBD), and CBD/R3, expressed in Escherichia coli. As analyzed by non-denaturing gel electrophoresis, rCelS, through its conserved duplicated sequence, formed a stable complex with R3 or CBD/R3 but not with CBD. Although R3 or CBD alone did not affect the binding of rCelS to cellulose, such binding was dependent on CBD/R3, indicating the anchorage role of CBD/R3. Such anchorage apparently increased the rCelS activity toward crystalline cellulose. These results substantiate the proposed anchor-enzyme model and the expected roles of individual CipA domains and the conserved duplicated sequence of CelS.« less

Child Care Quality in the Netherlands over the Years: A Closer Look

ERIC Educational Resources Information Center

Helmerhorst, Katrien O. W.; Riksen-Walraven, J. Marianne A.; Gevers Deynoot-Schaub, Mirjam J. J. M.; Tavecchio, Louis W. C.; Fukkink, Ruben G.

2015-01-01

Research Findings: We assessed the quality of child care in a nationally representative sample of 200 Dutch child care centers using the Infant/Toddler Environment Rating Scale-Revised and/or Early Childhood Environment Rating Scale-Revised and compared it with a previous assessment in 2005. The Caregiver Interaction Profile (CIP) scales were used…

Bioaerosols from a food waste composting plant affect human airway epithelial cell remodeling genes.

PubMed

Chang, Min-Wei; Lee, Chung-Ru; Hung, Hsueh-Fen; Teng, Kuo-Sheng; Huang, Hsin; Chuang, Chun-Yu

2013-12-24

The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 10(2) conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5-10 μm) having higher endotoxin levels than did fine particles (0.5-2.5 μm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1 (p21 WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers.

Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma

PubMed Central

Cheng, Zhixiang; Gong, Yuanying; Ma, Yufang; Lu, Kaihua; Lu, Xiang; Pierce, Larry A.; Thompson, Reid C.; Muller, Susanne; Knapp, Stefan; Wang, Jialiang

2014-01-01

Purpose Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples. Experimental Design The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors. Results We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors. Conclusion Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. PMID:23403638

Transcriptomic Analysis of the Adaptation of Listeria monocytogenes to Lagoon and Soil Matrices Associated with a Piggery Environment: Comparison of Expression Profiles

PubMed Central

Vivant, Anne-Laure; Desneux, Jeremy; Pourcher, Anne-Marie; Piveteau, Pascal

2017-01-01

Understanding how Listeria monocytogenes, the causative agent of listeriosis, adapts to the environment is crucial. Adaptation to new matrices requires regulation of gene expression. To determine how the pathogen adapts to lagoon effluent and soil, two matrices where L. monocytogenes has been isolated, we compared the transcriptomes of L. monocytogenes CIP 110868 20 min and 24 h after its transfer to effluent and soil extract. Results showed major variations in the transcriptome of L. monocytogenes in the lagoon effluent but only minor modifications in the soil. In both the lagoon effluent and in the soil, genes involved in mobility and chemotaxis and in the transport of carbohydrates were the most frequently represented in the set of genes with higher transcript levels, and genes with phage-related functions were the most represented in the set of genes with lower transcript levels. A modification of the cell envelop was only found in the lagoon environment. Finally, the differential analysis included a large proportion of regulators, regulons, and ncRNAs. PMID:29018416

Transcriptomic Analysis of the Adaptation of Listeria monocytogenes to Lagoon and Soil Matrices Associated with a Piggery Environment: Comparison of Expression Profiles.

PubMed

Vivant, Anne-Laure; Desneux, Jeremy; Pourcher, Anne-Marie; Piveteau, Pascal

2017-01-01

Understanding how Listeria monocytogenes , the causative agent of listeriosis, adapts to the environment is crucial. Adaptation to new matrices requires regulation of gene expression. To determine how the pathogen adapts to lagoon effluent and soil, two matrices where L. monocytogenes has been isolated, we compared the transcriptomes of L. monocytogenes CIP 110868 20 min and 24 h after its transfer to effluent and soil extract. Results showed major variations in the transcriptome of L. monocytogenes in the lagoon effluent but only minor modifications in the soil. In both the lagoon effluent and in the soil, genes involved in mobility and chemotaxis and in the transport of carbohydrates were the most frequently represented in the set of genes with higher transcript levels, and genes with phage-related functions were the most represented in the set of genes with lower transcript levels. A modification of the cell envelop was only found in the lagoon environment. Finally, the differential analysis included a large proportion of regulators, regulons, and ncRNAs.

Neural representations of the sense of self

PubMed Central

Klemm, William R.

2011-01-01

The brain constructs representations of what is sensed and thought about in the form of nerve impulses that propagate in circuits and network assemblies (Circuit Impulse Patterns, CIPs). CIP representations of which humans are consciously aware occur in the context of a sense of self. Thus, research on mechanisms of consciousness might benefit from a focus on how a conscious sense of self is represented in brain. Like all senses, the sense of self must be contained in patterns of nerve impulses. Unlike the traditional senses that are registered by impulse flow in relatively simple, pauci-synaptic projection pathways, the sense of self is a system- level phenomenon that may be generated by impulse patterns in widely distributed complex and interacting circuits. The problem for researchers then is to identify the CIPs that are unique to conscious experience. Also likely to be of great relevance to constructing the representation of self are the coherence shifts in activity timing relations among the circuits. Consider that an embodied sense of self is generated and contained as unique combinatorial temporal patterns across multiple neurons in each circuit that contributes to constructing the sense of self. As with other kinds of CIPs, those representing the sense of self can be learned from experience, stored in memory, modified by subsequent experiences, and expressed in the form of decisions, choices, and commands. These CIPs are proposed here to be the actual physical basis for conscious thought and the sense of self. When active in wakefulness or dream states, the CIP representations of self act as an agent of the brain, metaphorically as an avatar. Because the selfhood CIP patterns may only have to represent the self and not directly represent the inner and outer worlds of embodied brain, the self representation should have more degrees of freedom than subconscious mind and may therefore have some capacity for a free-will mind of its own. S everal lines of evidence for this theory are reviewed. Suggested new research includes identifying distinct combinatorially coded impulse patterns and their temporal coherence shifts in defined circuitry, such as neocortical microcolumns. This task might be facilitated by identifying the micro-topography of field-potential oscillatory coherences among various regions and between different frequencies associated with specific conscious mentation. Other approaches can include identifying the changes in discrete conscious operations produced by focal trans-cranial magnetic stimulation. PMID:21826192

Cornmeal-induced resistance to ciprofloxacin and erythromycin in enterococci.

PubMed

Yu, Dao-Jin; Lai, Bao-Se; Li, Jian; Ma, Yu-Fang; Yang, Fan; Li, Zhou; Luo, Xiao-Qing; Chen, Xia; Huang, Yi-Fan

2012-09-01

To establish a model ecosystem to study the impact of cornmeal on the appearance and persistence of the erythromycin (ERY)- and ciprofloxacin (CIP)-resistant phenotypes in waterborne enterococci. After the model ecosystem was established, the system was divided into six dose groups, with the addition of 8, 4, 1, 0.25, 0.05, and 0 g L(-1) sterilized cornmeal. System mud samples were collected at 0, 1, 3, 7, 14, 30, 40, 61, and 130 d, and enterococci present in the mud samples were evaluated for their sensitivities to CIP and ERY. PCR was employed to detect genes such as gyrA and ermB. The gyrA gene was sequenced, and codons 83 and 87 were analyzed for mutations. (1) The addition of 0.05-8 g L(-1) cornmeal had an impact on CIP resistance. The higher the dose of cornmeal added, the larger the impact it generated. Furthermore, the earlier the emergence of CIP-resistant strains, the greater the incidence of drug resistance. The impact of cornmeal on resistance to ERY was less consistent, and the degree of the impact was not in proportion to the dose of cornmeal added. (2) There were no mutations at codons 83 and 87 in the gyrA genes from 102 strains isolated from the model ecosystem. The incidence of ermB-positive strains of ERY-resistant enterococci (28 strains) was 78.6%, and the incidence of ermB-positive strains of ERY-sensitive enterococci (16 strains) was 0%. (1) Adding different doses of cornmeal can facilitate resistance to CIP and ERY in waterborne enterococci. In this study, the degree of resistance was related to the cornmeal dose. (2) In the model ecosystem, enterococcal CIP resistance was not caused by a gyrA gene mutation; however, in the vast majority of cases, resistance to ERY was related to the ermB resistance gene. Copyright © 2012 Elsevier Ltd. All rights reserved.

Degradation of Ciprofloxacin by Basidiomycetes and Identification of Metabolites Generated by the Brown Rot Fungus Gloeophyllum striatum

PubMed Central

Wetzstein, Heinz-Georg; Stadler, Marc; Tichy, Hans-Volker; Dalhoff, Axel; Karl, Wolfgang

1999-01-01

Ciprofloxacin (CIP), a fluoroquinolone antibacterial drug, is widely used in the treatment of serious infections in humans. Its degradation by basidiomycetous fungi was studied by monitoring 14CO2 production from [14C]CIP in liquid cultures. Sixteen species inhabiting wood, soil, humus, or animal dung produced up to 35% 14CO2 during 8 weeks of incubation. Despite some low rates of 14CO2 formation, all species tested had reduced the antibacterial activity of CIP in supernatants to between 0 and 33% after 13 weeks. Gloeophyllum striatum was used to identify the metabolites formed from CIP. After 8 weeks, mycelia had produced 17 and 10% 14CO2 from C-4 and the piperazinyl moiety, respectively, although more than half of CIP (applied at 10 ppm) had been transformed into metabolites already after 90 h. The structures of 11 metabolites were elucidated by high-performance liquid chromatography combined with electrospray ionization mass spectrometry and 1H nuclear magnetic resonance spectroscopy. They fell into four categories as follows: (i) monohydroxylated congeners, (ii) dihydroxylated congeners, (iii) an isatin-type compound, proving elimination of C-2, and (iv) metabolites indicating both elimination and degradation of the piperazinyl moiety. A metabolic scheme previously described for enrofloxacin degradation could be confirmed and extended. A new type of metabolite, 6-defluoro-6-hydroxy-deethylene-CIP, provided confirmatory evidence for the proposed network of congeners. This may result from sequential hydroxylation of CIP and its congeners by hydroxyl radicals. Our findings reveal for the first time the widespread potential for CIP degradation among basidiomycetes inhabiting various environments, including agricultural soils and animal dung. PMID:10103250

Assessing your competitors' application of CIM/CIP. [Computer Integrated Manufacturing/Processing

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

King, M.J.; Evans, H.N.

1993-07-01

As part of the authors consulting assignments, they are frequently asked to describe what is best industry practice in the area of computer integrated manufacturing/processing (CIM/CIP). This might be specific to a particular piece, such as advanced controls or a laboratory system. Often it is in response to the enormous publicity given to CIM/CIP--begging the question, Who in the hydrocarbon industry is actually doing it '' Although much of this information is available to consultants, client confidentiality precludes its release. Instead, included is a questionnaire intended to be completed by representatives of manufacturing sites. The data gathered will be analyzedmore » and reported in a future issue. The intent is to give anyone who has completed the questionnaire the opportunity to assess the position of his or her site with respect to the competition. To show how this might work a prototype study was completed. This included an estimate of the advanced control benefits achieved in 68 refineries in Western Europe. So that sites could be compared, these were expressed as a percentage of the maximum economically achievable.« less

MiR-135 post-transcriptionally regulates FOXO1 expression and promotes cell proliferation in human malignant melanoma cells.

PubMed

Ren, Jian-Wen; Li, Zhang-Jun; Tu, Chen

2015-01-01

Malignant melanoma is the deadliest form of all skin cancers. Recently, microRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeted repression of transcription and translation and play essential roles during cancer development. Our study showed that miR-135a is upregulated in malignant melanoma tissues and cell lines by using Real-time PCR assay. Enforced expression of miR-135a in malignant melanoma cells promotes cell proliferation, tumorigenicity, and cell cycle progression, whereas inhibition of miR-135a reverses the function. Additionally, we demonstrated FOXO1 is a direct target of miR-135a and transcriptionally down-regulated by miR-135a. Ectopic expression of miR-135a led to downregulation of the FOXO1 protein, resulting in upregulation of Cyclin D1, and downregulation of P21(Cip1) and P27(Kip1) through AKT pathway. Our findings suggested that miR-135a represents a potential onco-miRNA and plays an important role in malignant melanoma progression by suppressing FOXO1 expression.

A spatial approach for the epidemiology of antibiotic use and resistance in community-based studies: the emergence of urban clusters of Escherichia coli quinolone resistance in Sao Paulo, Brasil

PubMed Central

2011-01-01

Background Population antimicrobial use may influence resistance emergence. Resistance is an ecological phenomenon due to potential transmissibility. We investigated spatial and temporal patterns of ciprofloxacin (CIP) population consumption related to E. coli resistance emergence and dissemination in a major Brazilian city. A total of 4,372 urinary tract infection E. coli cases, with 723 CIP resistant, were identified in 2002 from two outpatient centres. Cases were address geocoded in a digital map. Raw CIP consumption data was transformed into usage density in DDDs by CIP selling points influence zones determination. A stochastic model coupled with a Geographical Information System was applied for relating resistance and usage density and for detecting city areas of high/low resistance risk. Results E. coli CIP resistant cluster emergence was detected and significantly related to usage density at a level of 5 to 9 CIP DDDs. There were clustered hot-spots and a significant global spatial variation in the residual resistance risk after allowing for usage density. Conclusions There were clustered hot-spots and a significant global spatial variation in the residual resistance risk after allowing for usage density. The usage density of 5-9 CIP DDDs per 1,000 inhabitants within the same influence zone was the resistance triggering level. This level led to E. coli resistance clustering, proving that individual resistance emergence and dissemination was affected by antimicrobial population consumption. PMID:21356088

Analysis of extracellular polymeric substances (EPS) and ciprofloxacin-degrading microbial community in the combined Fe-C micro-electrolysis-UBAF process for the elimination of high-level ciprofloxacin.

PubMed

Zhang, Longlong; Yue, Qinyan; Yang, Kunlun; Zhao, Pin; Gao, Baoyu

2018-02-01

Extracellular polymeric substances (EPS) and ciprofloxacin-degrading microbial community in the combined Fe-C micro-electrolysis and up-flow biological aerated filter (UBAF) process for the treatment of high-level ciprofloxacin (CIP) were analyzed. The research demonstrated a great potential of Fe-C micro-electrolysis-UBAF for the elimination of high-level CIP. Above 90% of CIP removal was achieved through the combined process at 100 mg L -1 of CIP loading. In UBAF, the pollutants were mainly removed at 0-70 cm heights. Three-dimensional fluorescence spectrum (3D-EEM) was used to characterize the chemical structural of loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) extracted from biofilm sample in UBAF. The results showed that the protein-like substances in LB-EPS and TB-EPS had no clear change in the study. Nevertheless, an obvious release of polysaccharides in EPSs was observed during long-term exposure to CIP, which was considered as a protective response of microbial to CIP toxic. The high-throughput sequencing results revealed that the biodiversity of bacteria community became increasingly rich with gradual ciprofloxacin biodegradation in UBAF. The ciprofloxacin-degrading microbial community was mainly dominated by Proteobacteria and Bacteroidetes. Microorganisms from genera Dechloromonas, Brevundimonas, Flavobacterium, Sphingopyxis and Bosea might take a major role in ciprofloxacin degradation. This study provides deep theoretical guidance for real CIP wastewater treatment. Copyright © 2017. Published by Elsevier Ltd.

Cation-Pi Interaction: A Key Force for Sorption of Fluoroquinolone Antibiotics on Pyrogenic Carbonaceous Materials.

PubMed

Zhao, Qing; Zhang, Siyu; Zhang, Xuejiao; Lei, Lei; Ma, Wei; Ma, Chuanxin; Song, Lei; Chen, Jingwen; Pan, Bo; Xing, Baoshan

2017-12-05

Cation-pi attraction is a major force that determines macromolecular structures and drug-receptor interactions. However, the role of the cation-pi interaction in sorption of fluoroquinolone antibiotics by pyrogenic carbonaceous materials (PCMs) has not been addressed. We studied sorption of ciprofloxacin (CIP) on graphite to quantify the contribution of the cation-pi interaction. Through competition experiments, the decreased amount of sorbed CIP by sequential treatment with hexadecane, phenanthrene and benzylamine represents the contribution of hydrophobic, pi-pi and cation-pi interactions, respectively. Benzylamine competed more strongly with CIP than n-hexadecane and phenanthrene, indicating that cation-pi is a major force. Cation-pi interactions accounted for up to 72.6% of the total sorption at an initial CIP concentration of 0.000015 mmol/L. Importantly, species transformation (CIP(0) captures H + from water to form CIP(+1)) induced by cation-pi interactions was verified both experimentally and theoretically and can be used to explain the environmental behavior of other fluoroquinolone antibiotics and biochemical processes of amino acids that interact with aromatic moieties. Because of the significant role of cation-pi interactions, CIP desorption increased up to 2.32 times when Na + increased from 0.01 mM to 0.45 mM, which is an environmentally relevant scenario at river estuaries. Hence, behaviors of fluoroquinolone antibiotics that are affected by ionic strength changes need to be carefully evaluated, especially in river estuaries.

Mississippi Curriculum Framework for Business and Office and Related Technology Cluster. Office Systems Technology (CIP: 52.0401--Administrative Assistant/Secretarial). Accounting Technology (CIP: 52.0302). Medical Office Technology (CIP: 52.0404--Medical Admin. Asst./Secretarial). Microcomputer Technology (CIP: 52.0490). Court Reporting Technology (CIP: 52.0405). Paralegal Technology (CIP: Paralegal/Legal Assistant).

ERIC Educational Resources Information Center

Mississippi Research and Curriculum Unit for Vocational and Technical Education, State College.

This document, which is intended for use by community and junior colleges throughout Mississippi, contains curriculum frameworks for four programs in the postsecondary-level business and office cluster (office systems, accounting, medical office, and microcomputer technologies) and two programs in the legal cluster (court reporting and paralegal…

Cirrus cloud retrieval from MSG/SEVIRI during day and night using artificial neural networks

NASA Astrophysics Data System (ADS)

Strandgren, Johan; Bugliaro, Luca

2017-04-01

By covering a large part of the Earth, cirrus clouds play an important role in climate as they reflect incoming solar radiation and absorb outgoing thermal radiation. Nevertheless, the cirrus clouds remain one of the largest uncertainties in atmospheric research and the understanding of the physical processes that govern their life cycle is still poorly understood, as is their representation in climate models. To monitor and better understand the properties and physical processes of cirrus clouds, it's essential that those tenuous clouds can be observed from geostationary spaceborne imagers like SEVIRI (Spinning Enhanced Visible and InfraRed Imager), that possess a high temporal resolution together with a large field of view and play an important role besides in-situ observations for the investigation of cirrus cloud processes. CiPS (Cirrus Properties from Seviri) is a new algorithm targeting thin cirrus clouds. CiPS is an artificial neural network trained with coincident SEVIRI and CALIOP (Cloud-Aerosol Lidar with Orthogonal Polarization) observations in order to retrieve a cirrus cloud mask along with the cloud top height (CTH), ice optical thickness (IOT) and ice water path (IWP) from SEVIRI. By utilizing only the thermal/IR channels of SEVIRI, CiPS can be used during day and night making it a powerful tool for the cirrus life cycle analysis. Despite the great challenge of detecting thin cirrus clouds and retrieving their properties from a geostationary imager using only the thermal/IR wavelengths, CiPS performs well. Among the cirrus clouds detected by CALIOP, CiPS detects 70 and 95 % of the clouds with an optical thickness of 0.1 and 1.0 respectively. Among the cirrus free pixels, CiPS classify 96 % correctly. For the CTH retrieval, CiPS has a mean absolute percentage error of 10 % or less with respect to CALIOP for cirrus clouds with a CTH greater than 8 km. For the IOT retrieval, CiPS has a mean absolute percentage error of 100 % or less with respect to CALIOP for cirrus clouds with an optical thickness down to 0.07. For such thin cirrus clouds an error of 100 % should be regarded as low from a geostationary imager like SEVIRI. The IWP retrieved by CiPS shows a similar performance, but has larger deviations for the thinner cirrus clouds.

Clinically significant borderline resistance of sequential clinical isolates of Klebsiella pneumoniae.

PubMed

Wagenlehner, F M E; Heisig, P; Irtenkauf, C; Notka, F; Decker, J; Lehn, N; Linde, H

2003-10-01

Two sequential clinical isolates of Klebsiella pneumoniae (Kpn) were isolated from bronchoalveolar lavage fluid (Kpn#1) and sputum (Kpn#2) of a patient with pneumonia, complicated by anatomical and immunosuppressive problems due to Wegener's granulomatosis. Despite 4 weeks of systemic treatment with ciprofloxacin (CIP) Kpn#2 was isolated thereafter. A fluoroquinolone-resistant mutant (Kpn#1-SEL) was derived from Kpn#1 in vitro by selecting on agar plates supplemented with ofloxacin. Kpn#1, Kpn#1-SEL and Kpn#2 had an identical pattern in PFGE. CIP MICs were 0.25, 2 and 4 mg/l for Kpn#1, Kpn#2 and Kpn#1-SEL, respectively. Kpn ATCC 10031 (CIP MIC 0.002 mg/l) served as control. We analyzed mechanisms of fluoroquinolone resistance by determining antibiotic susceptibility, organic solvent tolerance, accumulation of fluoroquinolones, dominance testing with wild-type topoisomerase genes (gyrA/B, parC/E), sequencing of the quinolone resistance determining regions of gyrA/B, parC/E and marR and Northern blotting of marR and acrAB genes. Compared with Kpn ATCC 10031, elevated MICs to fluoroquinolones and unrelated antibiotics in Kpn#1 was presumably due to a primary efflux pump other than AcrAB and increased the CIP MIC 125-fold. Although Kpn#1 tested sensitive according to NCCLS breakpoints, the elevated CIP MIC of 0.25 mg/l presumably rendered this isolate clinically resistant and lead to therapeutic failure in this case. Further increase of MIC to fluoroquinolones in vivo and in vitro was distinct. Kpn#1-SEL, selected in vitro, acquired a GyrA target mutation, whereas in Kpn#2 no known resistance mechanism could be detected.

Characterization of extracellular polymeric substances in biofilms under long-term exposure to ciprofloxacin antibiotic using fluorescence excitation-emission matrix and parallel factor analysis.

PubMed

Gu, Chaochao; Gao, Pin; Yang, Fan; An, Dongxuan; Munir, Mariya; Jia, Hanzhong; Xue, Gang; Ma, Chunyan

2017-05-01

The presence of antibiotic residues in the environment has been regarded as an emerging concern due to their potential adverse environmental consequences such as antibiotic resistance. However, the interaction between antibiotics and extracellular polymeric substances (EPSs) of biofilms in wastewater treatment systems is not entirely clear. In this study, the effect of ciprofloxacin (CIP) antibiotic on biofilm EPS matrix was investigated and characterized using fluorescence excitation-emission matrix (EEM) and parallel factor (PARAFAC) analysis. Physicochemical analysis showed that the proteins were the major EPS fraction, and their contents increased gradually with an increase in CIP concentration (0-300 μg/L). Based on the characterization of biofilm tightly bound EPS (TB-EPS) by EEM, three fluorescent components were identified by PARAFAC analysis. Component C1 was associated with protein-like substances, and components C2 and C3 belonged to humic-like substances. Component C1 exhibited an increasing trend as the CIP addition increased. Pearson's correlation results showed that CIP correlated significantly with the protein contents and component C1, while strong correlations were also found among UV 254 , dissolved organic carbon, humic acids, and component C3. A combined use of EEM-PARAFAC analysis and chemical measurements was demonstrated as a favorable approach for the characterization of variations in biofilm EPS in the presence of CIP antibiotic.

Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated ARser81

PubMed Central

Mehraein-Ghomi, Farideh; Church, Dawn R.; Schreiber, Cynthia L.; Weichmann, Ashley M.; Basu, Hirak S.; Wilding, George

2015-01-01

Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration-resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF-κB subunit, and/or an increase in its stability by phosphorylation that delays its degradation. Here we identified a specific inhibitor of AR/p52 interaction, AR/p52-02, via a high throughput screen based on the reconstitution of Gaussia Luciferase. We found that AR/p52-02 markedly inhibited growth of both castration-resistant C4-2 (IC50 ∼6 μM) and parental androgen-dependent LNCaP (IC50 ∼4 μM) human prostate cancer cells under low androgen conditions. Growth inhibition was associated with significantly reduced nuclear p52 levels and DNA binding activity, as well as decreased phosphorylation of AR at serine 81, increased AR ubiquitination, and decreased AR transcriptional activity as indicated by decreased prostate-specific antigen (PSA) mRNA levels in both cell lines. AR/p52-02 also caused a reduction in levels of p21WAF/CIP1, which is a direct AR targeted gene in that its expression correlates with androgen stimulation and mitogenic proliferation in prostate cancer under physiologic levels of androgen, likely by disrupting the AR signaling axis. The reduced level of cyclinD1 reported previously for this compound may be due to the reduction in nuclear presence and activity of p52, which directly regulates cyclinD1 expression, as well as the reduction in p21WAF/CIP1, since p21WAF/CIP1 is reported to stabilize nuclear cyclinD1 in prostate cancer. Overall, the data suggest that specifically inhibiting the interaction of AR with p52 and blocking activity of p52 and pARser81 may be an effective means of reducing castration-resistant prostate cancer cell growth. PMID:26622945

Vacuum-and-solvent-free fabrication of organic semiconductor layers for field-effect transistors

PubMed Central

Matsushima, Toshinori; Sandanayaka, Atula S. D.; Esaki, Yu; Adachi, Chihaya

2015-01-01

We demonstrate that cold and hot isostatic pressing (CIP and HIP) is a novel, alternative method for organic semiconductor layer fabrication, where organic powder is compressed into a layer shape directly on a substrate with 200 MPa pressure. Spatial gaps between powder particles and the other particles, substrates, or electrodes are crushed after CIP and HIP, making it possible to operate organic field-effect transistors (OFETs) containing the compressed powder as the semiconductor. The CIP-compressed powder of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) had a hole mobility of (1.6 ± 0.4) × 10–2 cm2/Vs. HIP of C8-BTBT powder increased the hole mobility to an amorphous silicon-like value (0.22 ± 0.07 cm2/Vs) because of the growth of the C8-BTBT crystallites and the improved continuity between the powder particles. The vacuum and solution processes are not involved in our CIP and HIP techniques, offering a possibility of manufacturing OFETs at low cost. PMID:26416434

Compaction and sintering behaviors of a Nd-Fe-B permanent magnet alloy

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

Chin, T.; Hung, M.; Tsai, D.

1988-11-15

Extensive x-ray diffraction (XRD) and magnetic measurements were done on Nd/sub 15/ Fe/sub 77/ B/sub 8/ magnet alloy green compacts after cold isostatic pressing following a pulsed 2-T field (CIP) and die-pressing under a static 1.2-T perpendicular field (DP1) or parallel field (DP2), and on those after sintering. An alignment factor F, through the calculation of the integrated diffraction intensity ratio of the XRD patterns, was adopted as the effectiveness of magnetic alignment. At the green compact state, DP1 has the best alignment while CIP the worst. However, after sintering the alignment factor was such that CIP>DPI>DP2, the same ordermore » as the magnetic properties. Three mechanisms were proposed for the evolution of the alignment factor at different stages of sintering, i.e., that both the appearance of a liquid phase at low temperatures and preferred grain growth at high temperatures enhance F, while recrystallization at intermediate temperatures deteriorates F. CIP results in less-defect green compact, hence less recrystallization, leading to better resultant alignment« less

Vacuum-and-solvent-free fabrication of organic semiconductor layers for field-effect transistors.

PubMed

Matsushima, Toshinori; Sandanayaka, Atula S D; Esaki, Yu; Adachi, Chihaya

2015-09-29

We demonstrate that cold and hot isostatic pressing (CIP and HIP) is a novel, alternative method for organic semiconductor layer fabrication, where organic powder is compressed into a layer shape directly on a substrate with 200 MPa pressure. Spatial gaps between powder particles and the other particles, substrates, or electrodes are crushed after CIP and HIP, making it possible to operate organic field-effect transistors (OFETs) containing the compressed powder as the semiconductor. The CIP-compressed powder of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) had a hole mobility of (1.6 ± 0.4) × 10(-2) cm(2)/Vs. HIP of C8-BTBT powder increased the hole mobility to an amorphous silicon-like value (0.22 ± 0.07 cm(2)/Vs) because of the growth of the C8-BTBT crystallites and the improved continuity between the powder particles. The vacuum and solution processes are not involved in our CIP and HIP techniques, offering a possibility of manufacturing OFETs at low cost.

Vacuum-and-solvent-free fabrication of organic semiconductor layers for field-effect transistors

NASA Astrophysics Data System (ADS)

Matsushima, Toshinori; Sandanayaka, Atula S. D.; Esaki, Yu; Adachi, Chihaya

2015-09-01

We demonstrate that cold and hot isostatic pressing (CIP and HIP) is a novel, alternative method for organic semiconductor layer fabrication, where organic powder is compressed into a layer shape directly on a substrate with 200 MPa pressure. Spatial gaps between powder particles and the other particles, substrates, or electrodes are crushed after CIP and HIP, making it possible to operate organic field-effect transistors (OFETs) containing the compressed powder as the semiconductor. The CIP-compressed powder of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) had a hole mobility of (1.6 ± 0.4) × 10-2 cm2/Vs. HIP of C8-BTBT powder increased the hole mobility to an amorphous silicon-like value (0.22 ± 0.07 cm2/Vs) because of the growth of the C8-BTBT crystallites and the improved continuity between the powder particles. The vacuum and solution processes are not involved in our CIP and HIP techniques, offering a possibility of manufacturing OFETs at low cost.

The activity and stability of the intrinsically disordered Cip/Kip protein family are regulated by non-receptor tyrosine kinases

PubMed Central

Otieno, Steve; Lelli, Moreno; Kriwacki, Richard W.

2014-01-01

The Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors includes p21Cip1, p27Kip1 and p57Kip2. Their kinase inhibitory activities are mediated by a homologous N-terminal kinase-inhibitory domain (KID). The Cdk inhibitory activity and stability of p27 have been shown to be regulated by a two-step phosphorylation mechanism involving a tyrosine residue within the KID and a threonine residue within the flexible C-terminus. We show that these residues are conserved in p21 and p57, suggesting that a similar phosphorylation cascade regulates these Cdk inhibitors. However, the presence of a cyclin binding motif within its C-terminus alters the regulatory interplay between p21 and Cdk2/cyclin A, and its responses to tyrosine phosphorylation and altered p21:Cdk2/cyclin A stoichiometry. We also show that the Cip/Kip proteins can be phosphorylated in vitro by representatives of many non-receptor tyrosine kinase (NRTK) sub-families, suggesting that NRTKs may generally regulate the activity and stability of these Cdk inhibitors. Our results further suggest that the Cip/Kip proteins integrate signals from various NRTK pathways and cell cycle regulation. PMID:25463440

The activity and stability of the intrinsically disordered Cip/Kip protein family are regulated by non-receptor tyrosine kinases.

PubMed

Huang, Yongqi; Yoon, Mi-Kyung; Otieno, Steve; Lelli, Moreno; Kriwacki, Richard W

2015-01-30

The Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors includes p21(Cip1), p27(Kip1) and p57(Kip2). Their kinase inhibitory activities are mediated by a homologous N-terminal kinase inhibitory domain. The Cdk inhibitory activity and stability of p27 have been shown to be regulated by a two-step phosphorylation mechanism involving a tyrosine residue within the kinase inhibitory domain and a threonine residue within the flexible C-terminus. We show that these residues are conserved in p21 and p57, suggesting that a similar phosphorylation cascade regulates these Cdk inhibitors. However, the presence of a cyclin binding motif within its C-terminus alters the regulatory interplay between p21 and Cdk2/cyclin A, as well as its responses to tyrosine phosphorylation and altered p21:Cdk2/cyclin A stoichiometry. We also show that the Cip/Kip proteins can be phosphorylated in vitro by representatives of many non-receptor tyrosine kinase (NRTK) sub-families, suggesting that NRTKs may generally regulate the activity and stability of these Cdk inhibitors. Our results further suggest that the Cip/Kip proteins integrate signals from various NRTK pathways and cell cycle regulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells

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

Kim, Han-Soo; Kim, Ju Won; Gang, Jingu

2006-09-15

LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s). Growth inhibition by these two FTIs was accompanied by G1 and G2/M cell cycle arrests in H-ras and K-ras-transformed RIE cells, respectively. We identified three key markers, p21{sup CIP1/WAF1}, RhoB and EGFR, that can explain themore » differences in the molecular mechanism of action between two FTIs. Only LB7 induced the upregulation of p21{sup CIP1/WAF1} and RhoB above the basal level that led to the cell cycle arrest and to distinct morphological alterations of ras-transformed RIE cells. Both FTIs successfully inhibited the ERK and activated JNK in RIE/K-ras cells. While the addition of conditioned medium from RIE/K-ras reversed the growth inhibition of ras-transformed RIE cells by LB9, it failed to overcome the growth inhibitory effect of LB7 in both H-ras- and K-ras-transformed RIE cells. We found that LB7, but not LB9, decreased the expression of EGFRs that confers the cellular unresponsiveness to EGFR ligands. These results suggest that LB7 causes the induction of p21{sup CIP1/WAF1} and RhoB and downregulation of EGFR that may serve as critical steps in the mechanism by which FTIs trigger irreversible inhibitions on the cell growth and apoptosis in ras-transformed cells.« less

Simulation of Pellet Ablation

NASA Astrophysics Data System (ADS)

Parks, P. B.; Ishizaki, Ryuichi

2000-10-01

In order to clarify the structure of the ablation flow, 2D simulation is carried out with a fluid code solving temporal evolution of MHD equations. The code includes electrostatic sheath effect at the cloud interface.(P.B. Parks et al.), Plasma Phys. Contr. Fusion 38, 571 (1996). An Eulerian cylindrical coordinate system (r,z) is used with z in a spherical pellet. The code uses the Cubic-Interpolated Psudoparticle (CIP) method(H. Takewaki and T. Yabe, J. Comput. Phys. 70), 355 (1987). that divides the fluid equations into non-advection and advection phases. The most essential element of the CIP method is in calculation of the advection phase. In this phase, a cubic interpolated spatial profile is shifted in space according to the total derivative equations, similarly to a particle scheme. Since the profile is interpolated by using the value and the spatial derivative value at each grid point, there is no numerical oscillation in space, that often appears in conventional spline interpolation. A free boundary condition is used in the code. The possibility of a stationary shock will also be shown in the presentation because the supersonic ablation flow across the magnetic field is impeded.

Rating the severity and character of transient cocaine-induced delusions and hallucinations with a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP).

PubMed

Cubells, Joseph F; Feinn, Richard; Pearson, Deborah; Burda, Jeffrey; Tang, Yilang; Farrer, Lindsay A; Gelernter, Joel; Kranzler, Henry R

2005-10-01

Cocaine can induce transient psychotic symptoms. We examined the phenomenology of such cocaine-induced psychosis (CIP) using a modified version of the Scale for Assessment of Positive Symptoms (SAPS), a well-validated instrument for the assessment of schizophrenic psychosis. We developed a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP), based on the well-validated SAPS. We interviewed 243 unrelated cocaine-dependent adults using both the SAPS-CIP and an instrument for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ). One hundred and eighty-one (75%) of the subjects endorsed CIP using the CEQ. With the SAPS-CIP, hallucination (HAL) and delusion (DEL) scores correlated strongly, and the DEL domain showed excellent concurrent validity with the CEQ. We observed significant positive correlations, respectively, between severity of HAL and DEL, and lifetime number of episodes of cocaine use, and negative correlations with age at onset of cocaine use. The results suggest that CIP consists of transient delusional and hallucinatory symptoms, which tend to occur together and co-vary in severity. It appears that rating cocaine-induced paranoia alone (e.g., with the CEQ) can identify most subjects experiencing CIP. However, the SAPS-CIP is useful for quantifying the severity of CIP according to operational criteria. Our data provide additional evidence that CIP is a sensitizing response.

Ratio of cyclase activating and cyclase inactive parathormone (CAP/CIP) in dialysis patients: correlations with other markers of bone disease.

PubMed

Grzegorzewska, A E; Młot, M

2004-01-01

We checked correlation of CAP/CIP with osteoprotegrin (OPG), its soluble ligand (OPGL) and routinely measured parameters of bone turnover in patients treated with peritoneal dialysis (PD) and hemodialysis (HD). In 30 patients (22 HD, 8 PD) we determined serum concentrations of intact parathormone (iPTH), CAP, OPG, OPGL, total Ca, inorganic phosphates (Pi), creatinine, urea, total alkaline phosphatase (AP) and blood pH. CIP was calculated by subtraction of CAP from iPTH. Controls (Cs) included 9 healthy persons in whom iPTH, CAP, OPG and OPGL were measured as well as CIP, CAP/CIP and OPGL/OPG were calculated. Differences between HD and PD patients included dialysis duration, OPGL, OPGL/OPG, AP, Pi, Ca and pH. After adjustment to dialysis duration differences in OPGL/OPG, Pi, Ca and pH remained significant. HD patients differed from Cs in terms of iPTH, CAP, CIP, OPGL, OPG and OPGL/OPG. In whole group of patients iPTH, CAP, CIP but not CAP/CIP correlated negatively with OPGL and OPGL/OPG as well as positively with dialysis duration, OPG and AP. Despite more advanced uremic bone disease in longer dialyzed HD patients than in shorter dialyzed PD ones, CAP/CIP is not different neither between these groups nor Cs persons. CAP/CIP does not seem to be more powerful tool in noninvasive diagnosis of bone disease than iPTH or CAP and CIP alone.

Laboratory scale Clean-In-Place (CIP) studies on the effectiveness of different caustic and acid wash steps on the removal of dairy biofilms.

PubMed

Bremer, Philip J; Fillery, Suzanne; McQuillan, A James

2006-02-15

A laboratory scale, bench top flow system was used to partially reproduce dairy plant conditions under which biofilms form and to quantify the effectiveness of caustic and acid wash steps in reducing the number of viable bacteria attached to stainless steel (SS) surfaces. Once bacteria attached to surfaces, a standard clean-in-place (CIP) regime (water rinse, 1% sodium hydroxide at 65 degrees C for 10 min, water rinse, 1.0% nitric acid at 65 degrees C for 10 min, water rinse) did not reproducibly ensure their removal. Standard CIP effectiveness was compared to alternative cleaning chemicals such as: caustic blends (Alkazolv 48, Ultrazolv 700, Concept C20, and Reflex B165); a caustic additive (Eliminator); acid blends (Nitroplus and Nitrobrite); and sanitizer (Perform). The addition of a caustic additive, Eliminator, enhanced biofilm removal compared to the standard CIP regime and further increases in cleaning efficiency occurred when nitric acid was substituted with Nitroplus. The combination of NaOH plus Eliminator and Nitroplus achieved a 3.8 log reduction in the number of cells recovered from the stainless steel surface. The incorporation of a sanitizer step into the CIP did not appear to enhance biofilm removal. This study has shown that the effectiveness of a "standard" CIP can possibly be enhanced through the testing and use of caustic and acid blends. There are many implications of these findings, including: the development of improved cleaning regimes and improved product quality, plant performance, and economic returns.

Comparison of In-Situ, Model and Ground Based In-Flight Icing Severity

NASA Technical Reports Server (NTRS)

Johnston, Christopher J.; Serke, David J.; Adriaansen, Daniel R.; Reehorst, Andrew L.; Politovich, Marica K.; Wolff, Cory A.; McDonough, Frank

2011-01-01

As an aircraft flies through supercooled liquid water, the liquid freezes instantaneously to the airframe thus altering its lift, drag, and weight characteristics. In-flight icing is a contributing factor to many aviation accidents, and the reliable detection of this hazard is a fundamental concern to aviation safety. The scientific community has recently developed products to provide in-flight icing warnings. NASA's Icing Remote Sensing System (NIRSS) deploys a vertically--pointing Ka--band radar, a laser ceilometer, and a profiling multi-channel microwave radiometer for the diagnosis of terminal area in-flight icing hazards with high spatial and temporal resolution. NCAR s Current Icing Product (CIP) combines several meteorological inputs to produce a gridded, three-dimensional depiction of icing severity on an hourly basis. Pilot reports are the best and only source of information on in-situ icing conditions encountered by an aircraft. The goal of this analysis was to ascertain how the testbed NIRSS icing severity product and the operational CIP severity product compare to pilot reports of icing severity, and how NIRSS and CIP compare to each other. This study revealed that the icing severity product from the ground-based NASA testbed system compared very favorably with the operational model-based product and pilot reported in-situ icing.

Power spectra based Planck constraints on compensated isocurvature, and forecasts for LiteBIRD and CORE space missions

NASA Astrophysics Data System (ADS)

Väliviita, Jussi

2017-04-01

Compensated isocurvature perturbations (CIP), where the primordial baryon and cold dark matter density perturbations cancel, do not cause total matter isocurvature perturbation. Consequently, at the linear order in the baryon density contrast Δ, a mixture of CIP and the adiabatic mode leads to the same CMB spectra as the pure adiabatic mode. Only recently, Muñoz et al. showed that at the second order CIP leaves an imprint in the observable CMB by smoothing the power spectra in a similar manner as lensing. This causes a strong degeneracy between the CIP variance Δrms2 ≡ langleΔ2rangle and the phenomenological lensing parameter AL. We study several combinations of the Planck 2015 data and show that the measured lensing potential power spectrum Clphiphi breaks the degeneracy. Nested sampling of the ΛCDM+Δrms2(+AL) model using the Planck 2015 temperature, polarization, and lensing data gives Δrms2 = (6.9+3.0-3.1) × 10-3 at 68% CL. A non-zero value is favoured at 2.3σ (or without the polarization data at 2.8σ). CIP with Δrms2 ≈ 7 × 10-3 improves the bestfit χ2 by 3.6 compared to the adiabatic ΛCDM model. In contrast, although the temperature data favour AL simeq 1.22, allowing AL ≠ 1 does not improve the joint fit at all, since the lensing data disfavour AL ≠ 1. Indeed, CIP provides a rare example of a simple model, which is capable of reducing the Planck lensing anomaly significantly and fitting well simultaneously the high (and low) multipole temperature and lensing data, as well as the polarization data. Finally, we derive forecasts for two future satellite missions (LiteBIRD proposal to JAXA/NASA and Exploring Cosmic Origins with CORE proposal to ESA's M5 call) and compare these to simulated Planck data. Due to its coarse angular resolution, LiteBIRD is not able to improve the constraints on Δrms2 or AL, but CORE-M5 (almost) reaches the cosmic variance limit and improves the CIP constraint to Δrms2 < 0.6 (1.4) × 10-3 at 68 (95)% CL, which is nine times better than the current trispectrum based upper bound and six times better than obtained from the simulated Planck data. In addition, CORE-M5 will exquisitely distinguish between Δrms2 and AL. No matter whether CIP is allowed for or not, the uncertainty of the lensing parameter will be σ(AL) ≈ 0.012, in the case where the simulated data are based on the adiabatic ΛCDM model with AL = 1.

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs.

PubMed

Stanley-Hasnain, Shanna; Hauck, Ludger; Grothe, Daniela; Aschar-Sobbi, Roozbeh; Beca, Sanja; Butany, Jagdish; Backx, Peter H; Mak, Tak W; Billia, Filio

2017-01-01

Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21 Cip1 and p27 Kip1 . Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.

Thermal characterization of magnetically aligned carbonyl iron/agar composites.

PubMed

Diaz-Bleis, D; Vales-Pinzón, C; Freile-Pelegrín, Y; Alvarado-Gil, J J

2014-01-01

Composites of magnetic particles into polymeric matrices have received increasing research interest due to their capacity to respond to external magnetic or electromagnetic fields. In this study, agar from Gelidium robustum has been chosen as natural biocompatible polymer to build the matrix of the magnetic carbonyl iron particles (CIP) for their uses in biomedical fields. Heat transfer behavior of the CIP-agar composites containing different concentrations (5, 10, 15, 20, 25 and 30% w/w) of magnetically aligned and non-aligned CIP in the agar matrix was studied using photothermal radiometry (PTR) in the back-propagation emission configuration. The morphology of the CIP-agar composites with aligned and non-aligned CIP under magnetic field was also evaluated by scanning electron microscopy (SEM). The results revealed a dominant effect of CIP concentration over the alignment patterns induced by the magnetic field, which agrees with the behavior of the thermal diffusivity and thermal conductivity. Agar served as a perfect matrix to be used with CIP, and CIP-agar composites magnetically aligned at 20% CIP concentration can be considered as promising 'smart' material for hyperthermia treatments in the biomedical field. Copyright © 2013 Elsevier Ltd. All rights reserved.

76 FR 29720 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-23

..., ``Customer Initiated Payments (CIP)'' and RD 1951-66, ``Fedwire Worksheet''. OMB Control Number: 0575-0184... Preauthorized Debits (PAD), Customer Initiated Payments (CIP), and FedWire. These electronic collection methods..., is prepared by the borrower to enroll in CIP. CIP is an electronic collection method that enables...

Effects of the morphology of CIPs on microwave absorption behaviors

NASA Astrophysics Data System (ADS)

Woo, Soobin; Yoo, Chan-Sei; Kim, Hwijun; Lee, Mijung; Quevedo-Lopez, Manuel; Choi, Hyunjoo

2017-11-01

Electromagnetic (EM) wave absorption properties are affected by the thickness and surface area of absorbing materials. In this study, a facile ball-milling process was introduced to effectively reduce the diameter and increase the aspect ratio of carbonyl iron powder (CIP), which is one of the most commercially available EM-absorbing materials. The size, aspect ratio, and consequent surface area of CIP were manipulated by controlling the milling parameters to investigate their effects on EM absorption properties. The results indicated that ball-milled CIPs exhibited better EM wave absorption ability when compared with that of pristine CIPs. However, significant differences in minimum reflection loss values were not observed between CIPs with different morphologies and similar specific surface areas. Hence, both fine and flaky CIPs were considered as beneficial for EM wave absorption.[Figure not available: see fulltext.

Suppression of ciprofloxacin-induced resistant Pseudomonas aeruginosa in a dynamic kill curve system.

PubMed

Wu, Benjamin M; Sabarinath, Sreedharan N; Rand, Kenneth; Johnson, Judith; Derendorf, Hartmut

2011-06-01

Current dosing approaches for treating microbial infections ignore resistant subpopulations. A clinical isolate of Pseudomonas aeruginosa was cultured in a dynamic in vitro kill curve system designed to simulate the half-lives of drugs in order to evaluate the drug-microbial response relationship. The first dose of ciprofloxacin (CIP) uses a concentration equivalent to the unbound fraction of a 200mg clinical dose. A second dose of 200mg or 600 mg CIP, or ceftriaxone (CFX) or gentamicin (GEN) was administered at 12h. Dynamics of the minimum inhibitory concentration (MIC) were assessed using Etest strips before and throughout the CIP treatment period. In addition, the microbroth dilution method was used to evaluate drug susceptibility across a wide range of antibiotics using samples from before and after CIP exposure. A significant loss of CIP effects was observed at the second dose. Cross-resistance to many antibiotics (cefoxitin, cefuroxime, cefotetan, ampicillin and ertapenem) was observed. GEN, but not CFX or high-dose CIP, was sufficient to suppress the developed resistant subpopulation following the initial CIP exposure. The CIP MIC increased substantially from 0.13 μg/mL pre dose to 4 μg/mL at 12h after a CIP dose. In addition, aztreonam induced a similar resistance pattern as CIP, indicating that induction of resistance was not limited to fluoroquinolones. In conclusion, the in vitro dynamic kill curve system revealed that aminoglycosides, more than other classes of antibiotics, were effective against the CIP-induced resistant subpopulations. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Identification of "Haematobacter," a new genus of aerobic Gram-negative rods isolated from clinical specimens, and reclassification of Rhodobacter massiliensis as "Haematobacter massiliensis comb. nov.".

PubMed

Helsel, Leta O; Hollis, Dannie; Steigerwalt, Arnold G; Morey, Roger E; Jordan, Jean; Aye, Tin; Radosevic, Jon; Jannat-Khah, Deanna; Thiry, Dorothy; Lonsway, David R; Patel, Jean B; Daneshvar, Maryam I; Levett, Paul N

2007-04-01

Twelve strains of gram-negative, nonfermenting rods recovered mainly from septicemic patients were studied using conventional and molecular methods. The phenotypic profiles of these strains most closely resembled Psychrobacter phenylpyruvicus. They produced catalase, oxidase, urease, and H(2)S (lead acetate paper) but did not produce indole, reduce nitrate or nitrite, or hydrolyze gelatin or esculin. No acid production was observed in a King's oxidation-fermentation base containing d-glucose, d-xylose, d-mannitol, sucrose, lactose, or maltose. All strains were nonmotile and nonpigmented. Most strains produced green discoloration on blood agar. All strains grew at 25 degrees C and 35 degrees C and most grew on MacConkey agar. They shared a common cellular fatty acid (CFA) profile characterized by large amounts (56% to 90%) of 18:1omega7c and the presence of 3-OH-10:0, 16:1omega7c, 16:0, and 19:0cycomega8c that overall was most similar to that of Rhodobacter species but was quite distinct from that of P. phenylpyruvicus. The MICs for most beta-lactams, fluoroquinolones, aminoglycosides, and carbapenems were low. MICs for aztreonam and piperacillin were higher, with MICs for some strains of > 64 mg/liter and > 128 mg/liter, respectively. Polyphasic analysis of these strains, including morphological, biochemical, CFA composition, DNA-DNA hybridization, 16S rRNA gene sequencing, and percent guanine-plus-cytosine (G+C) content analysis, demonstrated that these strains and Rhodobacter massiliensis represent a new genus, "Haematobacter" (proposed name), with the species H. missouriensis (type strain H1892(T) = CCUG 52307(T) = CIP 109176(T)) and H. massiliensis comb. nov. (type strain Framboise(T) = CCUG 47968(T) = CIP 107725(T)) and an unnamed genomospecies.

Color intensity projections: A rapid approach for evaluating four-dimensional CT scans in treatment planning

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

Cover, Keith S.; Lagerwaard, Frank J.; Senan, Suresh

2006-03-01

Purpose: Four-dimensional computerized tomography scans (4DCT) enable intrafractional motion to be determined. Because more than 1500 images can be generated with each 4DCT study, tools for efficient data visualization and evaluation are needed. We describe the use of color intensity projections (CIP) for visualizing mobility. Methods: Four-dimensional computerized tomography images of each patient slice were combined into a CIP composite image. Pixels largely unchanged over the component images appear unchanged in the CIP image. However, pixels whose intensity changes over the phases of the 4DCT appear in the CIP image as colored pixels, and the hue encodes the percentage ofmore » time the tissue was in each location. CIPs of 18 patients were used to study tumor and surrogate markers, namely the diaphragm and an abdominal marker block. Results: Color intensity projections permitted mobility of high-contrast features to be quickly visualized and measured. In three selected expiratory phases ('gating phases') that were reviewed in the sagittal plane, gating would have reduced mean tumor mobility from 6.3 {+-} 2.0 mm to 1.4 {+-} 0.5 mm. Residual tumor mobility in gating phases better correlated with residual mobility of the marker block than that of the diaphragm. Conclusion: CIPs permit immediate visualization of mobility in 4DCT images and simplify the selection of appropriate surrogates for gated radiotherapy.« less

Sodium valproate, a histone deacetylase inhibitor, enhances the efficacy of vinorelbine-cisplatin-based chemoradiation in non-small cell lung cancer cells.

PubMed

Gavrilov, Vladimir; Lavrenkov, Konstantin; Ariad, Samuel; Shany, Shraga

2014-11-01

To enhance the anticancer activity of vinorelbine, cisplatin and ionizing radiation (IR) combination against non-small cell lung cancer (NSCLC) cells by co-administration of sodium valproate (VPA), a histone deacetylase inhibitor, and to elucidate molecular events underpinning treatment efficacy. The NSCLC A549 cell line was treated with cisplatin (0.2 μg/ml), vinorelbine (2 nM), VPA (1 mM) and IR (2.5 Gy) alone, or in combination. Cell proliferation, cell-cycle distribution, apoptosis, and levels of DNA double-strand breaks, activated DNA damage checkpoint kinases pCHK1, pCHK2, cell-cycle inhibitors p21CIP1/WAF1 and p27KIP1 were assessed. VPA markedly enhanced the DNA-damaging effect of the cisplatin-vinorelbine-IR combination and induced increased DSBs, and expression of pCHK2, pCHK1, p21CIP1/WAF1 and p27KIP1. These molecular changes led to cell-cycle arrest and increased apoptosis and consequently markedly curtailed cancer cell growth. VPA markedly enhances the anticancer activity of cisplatin-vinorelbine-IR combination. This finding has translational implications for enhancing the efficacy of anticancer treatment and for reducing side-effects by reducing doses of radiation and drugs. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Concise CIO based precession-nutation formulations

NASA Astrophysics Data System (ADS)

Capitaine, N.; Wallace, P. T.

2008-01-01

Context: The IAU 2000/2006 precession-nutation models have precision goals measured in microarcseconds. To reach this level of performance has required series containing terms at over 1300 frequencies and involving several thousand amplitude coefficients. There are many astronomical applications for which such precision is not required and the associated heavy computations are wasteful. This justifies developing smaller models that achieve adequate precision with greatly reduced computing costs. Aims: We discuss strategies for developing simplified IAU 2000/2006 precession-nutation procedures that offer a range of compromises between accuracy and computing costs. Methods: The chain of transformations linking celestial and terrestrial coordinates comprises frame bias, precession-nutation, Earth rotation and polar motion. We address the bias and precession-nutation (NPB) portion of the chain, linking the Geocentric Celestial Reference System (GCRS) with the Celestial Intermediate Reference System (CIRS), the latter based on the Celestial Intermediate Pole (CIP) and Celestial Intermediate Origin (CIO). Starting from direct series that deliver the CIP coordinates X,Y and (via the quantity s + XY/2) the CIO locator s, we look at the opportunities for simplification. Results: The biggest reductions come from truncating the series, but some additional gains can be made in the areas of the matrix formulation, the expressions for the nutation arguments and by subsuming long period effects into the bias quantities. Three example models are demonstrated that approximate the IAU 2000/2006 CIP to accuracies of 1 mas, 16 mas and 0.4 arcsec throughout 1995-2050 but with computation costs reduced by 1, 2 and 3 orders of magnitude compared with the full model. Appendices A to G are only available in electronic form at http://www.aanda.org

Constraining compensated isocurvature perturbations using the CMB

NASA Astrophysics Data System (ADS)

Smith, Tristan L.; Rhiannon Smith, Kyle Yee, Julian Munoz, Daniel Grin

2017-01-01

Compensated isocurvature perturbations (CIPs) are variations in the cosmic baryon fraction which leave the total non-relativistic matter (and radiation) density unchanged. They are predicted by models of inflation which involve more than one scalar field, such as the curvaton scenario. At linear order, they leave the CMB two-point correlation function nearly unchanged: this is why existing constraints to CIPs are so much more permissive than constraints to typical isocurvature perturbations. Recent work articulated an efficient way to calculate the second order CIP effects on the CMB two-point correlation. We have implemented this method in order to explore constraints to the CIP amplitude using current Planck temperature and polarization data. In addition, we have computed the contribution of CIPs to the CMB lensing estimator which provides us with a novel method to use CMB data to place constraints on CIPs. We find that Planck data places a constraint to the CIP amplitude which is competitive with other methods.

Electromagnetic and Microwave Absorption Properties of Carbonyl Tetrapod-Shaped Zno Nanostructures Composite Coatings

NASA Astrophysics Data System (ADS)

Yu, Haibo; Qin, Hui; Huang, Yunhua

2012-08-01

CIP/T-ZnO/EP composite coatings with carbonyl iron powders (CIP) and tetrapodshaped ZnO (T-ZnO) nanostructures as absorbers, and epoxy resin (EP) as matrix were prepared. The complex permittivity, permeability and microwave absorption properties of the coatings were investigated in the frequency range of 2-18 GHz. The effects of the weight ratio (CIP/T-ZnO/EP), the thickness and the solidification temperature on microwave absorption properties were discussed. When the weight ratio (CIP/TZnO/ EP), the thickness and the solidification temperature is 28:2:22, 1.8 mm, and 10°C, respectively, the optimal wave absorption with the minimum reflection loss (RL) value of -22.38 dB at 15.67 GHz and the bandwidth (RL<-10 dB) of 5.74 GHz was obtained, indicating that the composite coatings may have a promising application in Ku-band (12-18 GHz).

Critical illness polyneuropathy (CIP) in neurological early rehabilitation: clinical and neurophysiological features.

PubMed

Schmidt, Simone B; Rollnik, Jens D

2016-12-15

Critical illness polyneuropathy (CIP) is a complex disease affecting 30-70% of critically ill patients. Clinical (Barthel index, length of stay (LOS), morbidity, duration of mechanical ventilation, routine lab results) and neurophysiological (neurography) data of 191 patients admitted to neurological early rehabilitation and diagnosed with CIP have been analyzed retrospectively. CIP diagnosis was correct in 159 cases (83%). In this study, systemic inflammation, sepsis, systemic inflammatory response syndrome (SIRS), multiple organic failure (MOF), chronic renal failure, liver dysfunction, mechanical ventilation, diabetes, dyslipidemia and impaired ion homeostasis (hypocalcaemia, hypokalemia) were associated with CIP. Neurography, in particular of the peroneal, sural, tibial and median nerves, helped to identify CIP patients. Compound muscle action potential amplitude (r = -0.324, p < 0.05), as well as sensory (r = -0.389, p < 0.05) and motor conduction velocity (r = -0.347, p < 0.05) of the median nerve correlated with LOS in neurological early rehabilitation but not with outcome measures. In most cases, diagnosis of CIP among neurological early rehabilitation patients seems to be correct. Neurography may help to verify the diagnosis and to learn more about CIP pathophysiology, but it does not allow outcome prediction. Further studies on CIP are strongly encouraged.

Solid-phase partitioning of mercury in artisanal gold mine tailings from selected key areas in Mindanao, Philippines, and its implications for mercury detoxification.

PubMed

Opiso, Einstine M; Aseneiro, John Paul J; Banda, Marybeth Hope T; Tabelin, Carlito B

2018-03-01

The solid-phase partitioning of mercury could provide necessary data in the identification of remediation techniques in contaminated artisanal gold mine tailings. This study was conducted to determine the total mercury content of mine wastes and identify its solid-phase partitioning through selective sequential extraction coupled with cold vapour atomic absorption spectroscopy. Samples from mine tailings and the carbon-in-pulp (CIP) process were obtained from selected key areas in Mindanao, Philippines. The results showed that mercury use is still prevalent among small-scale gold miners in the Philippines. Tailings after ball mill-gravity concentration (W-BM and Li-BM samples) from Mt Diwata and Libona contained high levels of mercury amounting to 25.024 and 6.5 mg kg -1 , respectively. The most prevalent form of mercury in the mine tailings was elemental/amalgamated mercury, followed by water soluble, exchangeable, organic and strongly bound phases, respectively. In contrast, mercury content of carbon-in-pulp residues were significantly lower at only 0.3 and 0.06 mg kg -1 for P-CIP (Del Pilar) and W-CIP (Mt Diwata), respectively. The bulk of mercury in P-CIP samples was partitioned in residual fraction while in W-CIP samples, water soluble mercury predominated. Overall, this study has several important implications with regards to mercury detoxification of contaminated mine tailings from Mindanao, Philippines.

Alignment of carbon iron into polydimethylsiloxane to create conductive composite with low percolation threshold and high piezoresistivity: experiment and simulation

NASA Astrophysics Data System (ADS)

Dong, Shuai; Wang, Xiaojie

2017-04-01

In this study, various amounts of carbonyl iron particles (CIPs) were cured into polydimethylsiloxane (PDMS) matrix under a magnetic field up to 1.0 T to create anisotropy of conductive composite materials. The electrical resistivity for the longitudinal direction was measured as a function of filler volume fraction to understand the electrical percolation behavior. The electrical percolation threshold (EPT) of CIPs-PDMS composite cured under a magnetic field can be as low as 0.1 vol%, which is much less than most of those studies in particulate composites. Meanwhile, the effects of compressive strain on the electrical properties of CIPs-PDMS composites were also investigated. The strain sensitivity depends on filler volume fraction and decreases with the increasing of compressive strain. It has been found that the composites containing a small amount of CI particles curing under a magnetic field exhibit a high strain sensitivity of over 150. Based on the morphological observation of the composite structures, a two-dimensional stick percolation model for the CIPs-PDMS composites has been established. The Monte Carlo simulation is performed to obtain the percolation probability. The simulation results in prediction of the values of EPTs are close to that of experimental measurements. It demonstrates that the low percolation behavior of CIPs-PDMS composites is due to the average length of particle chains forming by external magnetic field.

Comparison of Intravenous/Oral Ciprofloxacin Plus Metronidazole Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections

PubMed Central

Cohn, Stephen M.; Lipsett, Pamela A.; Buchman, Timothy G.; Cheadle, William G.; Milsom, Jeffery W.; O’Marro, Steven; Yellin, Albert E.; Jungerwirth, Steven; Rochefort, Estela V.; Haverstock, Daniel C.; Kowalsky, Steven F.

2000-01-01

Objective To compare the safety and efficacy of intravenous (IV) ciprofloxacin plus IV metronidazole (CIP+MET) with that of IV piperacillin/tazobactam (PIP/TAZO) in adults with complicated intraabdominal infections, and to compare the efficacy of sequential IV-to-oral CIP+MET therapy with that of the IV CIP-only regimen. Summary Background Data Treatment of intraabdominal infections remains a challenge, mainly because of their polymicrobial etiology and attendant death and complications. Antimicrobial regimens using sequential IV-to-oral therapy may reduce the length of hospital stay. Methods In this multicenter, randomized, double-blind trial involving 459 patients, clinically improved IV-treated patients were switched to oral therapy after 48 hours. Overall clinical response was the primary efficacy measurement. Results A total of 282 patients (151 CIP+MET, 131 PIP/TAZO) were valid for efficacy. Of these patients, 64% CIP+MET and 57% PIP/TAZO patients were considered candidates for oral therapy. Patients had a mean APACHE II score of 9.6. The most common diagnoses were appendicitis (33%), other intraabdominal infection (29%), and abscess (25%). Overall clinical resolution rates were statistically superior for CIP+MET (74%) compared with PIP/TAZO (63%). Corresponding rates in the subgroup suitable for oral therapy were 85% for CIP+MET and 70% for PIP/TAZO. Postsurgical wound infection rates were significantly lower in CIP+MET (11%) versus PIP/TAZO patients (19%). Mean length of stay was 14 days for CIP+MET and 17 days for PIP/TAZO patients. Conclusion CIP+MET, initially administered IV and followed by CIP+MET oral therapy, was clinically more effective than IV PIP/TAZO for the treatment of patients with complicated intraabdominal infections. PMID:10903605

Partnerships for Policy Development: A Case Study From Uganda’s Costed Implementation Plan for Family Planning

PubMed Central

Lipsky, Alyson B; Gribble, James N; Cahaelen, Linda; Sharma, Suneeta

2016-01-01

ABSTRACT In global health, partnerships between practitioners and policy makers facilitate stakeholders in jointly addressing those issues that require multiple perspectives for developing, implementing, and evaluating plans, strategies, and programs. For family planning, costed implementation plans (CIPs) are developed through a strategic government-led consultative process that results in a detailed plan for program activities and an estimate of the funding required to achieve an established set of goals. Since 2009, many countries have developed CIPs. Conventionally, the CIP approach has not been defined with partnerships as a focal point; nevertheless, cooperation between key stakeholders is vital to CIP development and execution. Uganda launched a CIP in November 2014, thus providing an opportunity to examine the process through a partnership lens. This article describes Uganda’s CIP development process in detail, grounded in a framework for assessing partnerships, and provides the findings from 22 key informant interviews. Findings reveal strengths in Uganda’s CIP development process, such as willingness to adapt and strong senior management support. However, the evaluation also highlighted challenges, including district health officers (DHOs), who are a key group of implementers, feeling excluded from the development process. There was also a lack of planning around long-term partnership practices that could help address anticipated execution challenges. The authors recommend that future CIP development efforts use a long-term partnership strategy that fosters accountability by encompassing both the short-term goal of developing the CIP and the longer-term goal of achieving the CIP objectives. Although this study focused on Uganda’s CIP for family planning, its lessons have implications for any policy or strategy development efforts that require multiple stakeholders to ensure successful execution. PMID:27353621

A Reliable Service-Oriented Architecture for NASA's Mars Exploration Rover Mission

NASA Technical Reports Server (NTRS)

Mak, Ronald; Walton, Joan; Keely, Leslie; Hehner, Dennis; Chan, Louise

2005-01-01

The Collaborative Information Portal (CIP) was enterprise software developed jointly by the NASA Ames Research Center and the Jet Propulsion Laboratory (JPL) for NASA's highly successful Mars Exploration Rover (MER) mission. Both MER and CIP have performed far beyond their original expectations. Mission managers and engineers ran CIP inside the mission control room at JPL, and the scientists ran CIP in their laboratories, homes, and offices. All the users connected securely over the Internet. Since the mission ran on Mars time, CIP displayed the current time in various Mars and Earth time zones, and it presented staffing and event schedules with Martian time scales. Users could send and receive broadcast messages, and they could view and download data and image files generated by the rovers' instruments. CIP had a three-tiered, service-oriented architecture (SOA) based on industry standards, including J2EE and web services, and it integrated commercial off-the-shelf software. A user's interactions with the graphical interface of the CIP client application generated web services requests to the CIP middleware. The middleware accessed the back-end data repositories if necessary and returned results for these requests. The client application could make multiple service requests for a single user action and then present a composition of the results. This happened transparently, and many users did not even realize that they were connecting to a server. CIP performed well and was extremely reliable; it attained better than 99% uptime during the course of the mission. In this paper, we present overviews of the MER mission and of CIP. We show how CIP helped to fulfill some of the mission needs and how people used it. We discuss the criteria for choosing its architecture, and we describe how the developers made the software so reliable. CIP's reliability did not come about by chance, but was the result of several key design decisions. We conclude with some of the important lessons we learned form developing, deploying, and supporting the software.

31 CFR 1024.220 - Customer identification programs for mutual funds.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Identification Program (“CIP”) appropriate for its size and type of business that, at a minimum, includes each of the requirements of paragraphs (a)(1) through (5) of this section. The CIP must be a part of the...). (2) Identity verification procedures. The CIP must include risk-based procedures for verifying the...

31 CFR 1024.220 - Customer identification programs for mutual funds.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Identification Program (“CIP”) appropriate for its size and type of business that, at a minimum, includes each of the requirements of paragraphs (a)(1) through (5) of this section. The CIP must be a part of the...). (2) Identity verification procedures. The CIP must include risk-based procedures for verifying the...

31 CFR 1024.220 - Customer identification programs for mutual funds.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Identification Program (“CIP”) appropriate for its size and type of business that, at a minimum, includes each of the requirements of paragraphs (a)(1) through (5) of this section. The CIP must be a part of the...). (2) Identity verification procedures. The CIP must include risk-based procedures for verifying the...

Trichoderma genes

DOEpatents

Foreman, Pamela [Los Altos, CA; Goedegebuur, Frits [Vlaardingen, NL; Van Solingen, Pieter [Naaldwijk, NL; Ward, Michael [San Francisco, CA

2012-06-19

Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

Ciprofloxacin adsorption on graphene and granular activated carbon: kinetics, isotherms, and effects of solution chemistry.

PubMed

Zhu, Xuan; Tsang, Daniel C W; Chen, Feng; Li, Shiyu; Yang, Xin

2015-01-01

Ciprofloxacin (CIP) is a commonly used antibiotic and widely detected in wastewaters and farmlands nowadays. This study evaluated the efficacy of next-generation adsorbent (graphene) and conventional adsorbent (granular activated carbon, GAC) for CIP removal. Batch experiments and characterization tests were conducted to investigate the adsorption kinetics, equilibrium isotherms, thermodynamic properties, and the influences of solution chemistry (pH, ionic strength, natural organic matter (NOM), and water sources). Compared to GAC, graphene showed significantly faster adsorption and reached equilibrium within 3 min, confirming the rapid access of CIP into the macroporous network of high surface area of graphene as revealed by the Brunner-Emmet-Teller measurements analysis. The kinetics was better described by a pseudo-second-order model, suggesting the importance of the initial CIP concentration related to surface site availability of graphene. The adsorption isotherm on graphene followed Langmuir model with a maximum adsorption capacity of 323 mg/g, which was higher than other reported carbonaceous adsorbents. The CIP adsorption was thermodynamically favourable on graphene and primarily occurred through π - π interaction, according to the FTIR spectroscopy. While the adsorption capacity of graphene decreased with increasing solution pH due to the speciation change of CIP, the adverse effects of ionic strength (0.01-0.5 mol L(-1)), presence of NOM (5 mg L⁻¹), and different water sources (river water or drinking water) were less significant on graphene than GAC. These results indicated that graphene can serve as an alternative adsorbent for CIP removal in commonly encountered field conditions, if proper separation and recovery is available in place.

High fat diet triggers cell cycle arrest and excessive apoptosis of granulosa cells during the follicular development

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

Wu, Yanqing; Zhang, Zhenghong; Liao, Xinghui

The regulatory mechanism of granulosa cells (GCs) proliferation during the follicular development is complicated and multifactorial, which is essential for the oocyte growth and normal ovarian functions. To investigate the role of high fat diet (HFD) on the proliferation of GCs, 4-week old female mice were fed with HFD or normal control diet (NC) for 15 weeks or 20 weeks and then detected the expression level of some regulatory molecules of cell cycle and apoptosis. The abnormal ovarian morphology was observed at 20 weeks. Further mechanistic studies indicated that HFD induced-obesity caused elevated apoptotic levels in GCs of the ovariesmore » in a time-dependent manner. Moreover, cell cycle progress was also impacted after HFD fed. The cell cycle inhibitors, p27{sup Kip1} and p21{sup Cip1}, were significantly induced in the ovaries from the mice in HFD group when compared with that in the ovaries from the mice in NC group. Subsequently, the expression levels of Cyclin D1, D3 and CDK4 were also significantly influenced in the ovaries from the mice fed with HFD in a time-dependent manner. The present results suggested that HFD induced-obesity may trigger cell cycle arrest and excessive apoptosis of GCs, causing the abnormal follicular development and ovarian function failure. - Highlights: • HFD induced-obesity leads to abnormal ovarian morphology. • HFD induced-obesity triggers excessive apoptosis in the ovary. • HFD induced-obesity up-regulates cell cycle inhibitors p21{sup Cip1} and p27{sup Kip1} in the ovary. • HFD induced-obesity causes cell cycle arrest in the ovary.« less

Irradiation With Carbon Ion Beams Induces Apoptosis, Autophagy, and Cellular Senescence in a Human Glioma-Derived Cell Line

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

Jinno-Oue, Atsushi; Shimizu, Nobuaki; 21st Century Center of Excellence Program for Biomedical Research Using Accelerator Technology, Maebashi, Gunma

2010-01-15

Purpose: We examined biological responses of human glioma cells to irradiation with carbon ion beams (C-ions). Methods and Materials: A human glioma-derived cell line, NP-2, was irradiated with C-ions. Apoptotic cell nuclei were stained with Hoechst 33342. Induction of autophagy was examined either by staining cells with monodansylcadaverine (MDC) or by Western blotting to detect conversion of microtuble-associated protein light chain 3 (MAP-LC3) (LC3-I) to the membrane-bound form (LC3-II). Cellular senescence markers including induction of senescence-associated beta-galactosidase (SA-beta-gal) were examined. The mean telomere length of irradiated cells was determined by Southern blot hybridization. Expression of tumor suppressor p53 and cyclin/cyclin-dependentmore » kinase inhibitor p21{sup WAF1/CIP1} in the irradiated cells was analyzed by Western blotting. Results: When NP-2 cells were irradiated with C-ions at 6 Gy, the major population of the cells died of apoptosis and autophagy. The residual fraction of attached cells (<1% of initially irradiated cells) could not form a colony: however, they showed a morphological phenotype consistent with cellular senescence, that is, enlarged and flattened appearance. The senescent nature of these attached cells was further indicated by staining for SA-beta-gal. The mean telomere length was not changed after irradiation with C-ions. Phosphorylation of p53 at serine 15 as well as the expression of p21{sup WAF1/CIP1} was induced in NP-2 cells after irradiation. Furthermore, we found that irradiation with C-ions induced cellular senescence in a human glioma cell line lacking functional p53. Conclusions: Irradiation with C-ions induced apoptosis, autophagy, and cellular senescence in human glioma cells.« less

78 FR 44597 - Notice of Approval of Record of Decision for Stehekin River Corridor Implementation Plan, Lake...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-24

... Environmental Impact Statement (Final EIS) for the Stehekin River Corridor Implementation Plan (CIP). The... River CIP. The CIP will allow water from large floods to occupy more of the floodplain (within the... approved CIP is the relocation of approximately two miles of the Stehekin Valley Road, removal of park...

Fabrication, characterization and comparison of composite magnetic materials for high efficiency integrated voltage regulators with embedded magnetic core micro-inductors

NASA Astrophysics Data System (ADS)

Bellaredj, Mohamed L. F.; Mueller, Sebastian; Davis, Anto K.; Mano, Yasuhiko; Kohl, Paul A.; Swaminathan, Madhavan

2017-11-01

High-efficiency integrated voltage regulators (IVRs) require the integration of power inductors, which have low loss and reduced size at very high frequency. The use of a magnetic material core can reduce significantly the inductor area and simultaneously increase the inductance. This paper focuses on the fabrication, characterization and modeling of nickel zinc (NiZn) ferrite and carbonyl iron powder (CIP)-epoxy magnetic composite materials, which are used as the magnetic core materials of embedded inductors in a printed wiring board (PWB) for a system in package (SIP) based buck type IVR. The fabricated composite materials and process are fully compatible with FR4 epoxy resin prepreg and laminate. For 85% weight loading of the magnetic powder (around 100 MHz at room temperature), the composite materials show a relative permeability of 7.5-8.1 for the NiZn ferrite composite and 5.2-5.6 for the CIP composite and a loss tangent value of 0.24-0.28 for the NiZn ferrite composite and 0.09-0.1 for the CIP-composite. The room temperature saturation flux density values are 0.1351 T and 0.5280 T for the NiZn ferrite and the CIP composites, respectively. The frequency dispersion parameters of the magnetic composites are modeled using a simplified Lorentz and Landau-Lifshitz-Gilbert equation for a Debye type relaxation. Embedded magnetic core solenoid inductors were designed based on the composite materials for the output filter of a high-efficiency SIP based buck type IVR. Evaluation of a SIP based buck type IVR with the designed inductors shows that it can reach peak efficiencies of 91.7% at 11 MHz for the NiZn ferrite-composite, 91.6% at 14 MHz for CIP-composite and 87.5% (NiZn ferrite-composite) and 87.3% (CIP-composite) efficiency at 100 MHz for a 1.7 V:1.05 V conversion. For a direct 5 V:1 V conversion using a stacked topology, a peak efficiency of 82% at 10 MHz and 72% efficiency at 100 MHz can be achieved for both materials.

Methylation of eukaryotic elongation factor 2 induced by basic fibroblast growth factor via mitogen-activated protein kinase.

PubMed

Jung, Gyung Ah; Shin, Bong Shik; Jang, Yeon Sue; Sohn, Jae Bum; Woo, Seon Rang; Kim, Jung Eun; Choi, Go; Lee, Kyung Mi; Min, Bon Hong; Lee, Kee Ho; Park, Gil Hong

2011-10-31

Protein arginine methylation is important for a variety of cellular processes including transcriptional regulation, mRNA splicing, DNA repair, nuclear/cytoplasmic shuttling and various signal transduction pathways. However, the role of arginine methylation in protein biosynthesis and the extracellular signals that control arginine methylation are not fully understood. Basic fibroblast growth factor (bFGF) has been identified as a potent stimulator of myofibroblast dedifferentiation into fibroblasts. We demonstrated that symmetric arginine dimethylation of eukaryotic elongation factor 2 (eEF2) is induced by bFGF without the change in the expression level of eEF2 in mouse embryo fibroblast NIH3T3 cells. The eEF2 methylation is preceded by ras-raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2)- p21Cip/WAF1 activation, and suppressed by the mitogenactivated protein kinase (MAPK) inhibitor PD98059 and p21Cip/WAF1 short interfering RNA (siRNA). We determined that protein arginine methyltransferase 7 (PRMT7) is responsible for the methylation, and that PRMT5 acts as a coordinator. Collectively, we demonstrated that eEF2, a key factor involved in protein translational elongation is symmetrically arginine-methylated in a reversible manner, being regulated by bFGF through MAPK signaling pathway.

Methylation of eukaryotic elongation factor 2 induced by basic fibroblast growth factor via mitogen-activated protein kinase

PubMed Central

Jung, Gyung Ah; Shin, Bong Shik; Jang, Yeon Sue; Sohn, Jae Bum; Woo, Seon Rang; Kim, Jung Eun; Choi, Go; Lee, Kyung-Mi; Min, Bon Hong

2011-01-01

Protein arginine methylation is important for a variety of cellular processes including transcriptional regulation, mRNA splicing, DNA repair, nuclear/cytoplasmic shuttling and various signal transduction pathways. However, the role of arginine methylation in protein biosynthesis and the extracellular signals that control arginine methylation are not fully understood. Basic fibroblast growth factor (bFGF) has been identified as a potent stimulator of myofibroblast dedifferentiation into fibroblasts. We demonstrated that symmetric arginine dimethylation of eukaryotic elongation factor 2 (eEF2) is induced by bFGF without the change in the expression level of eEF2 in mouse embryo fibroblast NIH3T3 cells. The eEF2 methylation is preceded by ras-raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2)-p21Cip/WAF1 activation, and suppressed by the mitogen-activated protein kinase (MAPK) inhibitor PD98059 and p21Cip/WAF1 short interfering RNA (siRNA). We determined that protein arginine methyltransferase 7 (PRMT7) is responsible for the methylation, and that PRMT5 acts as a coordinator. Collectively, we demonstrated that eEF2, a key factor involved in protein translational elongation is symmetrically arginine-methylated in a reversible manner, being regulated by bFGF through MAPK signaling pathway. PMID:21778808

Serratia marcescens resistance profile and its susceptibility to photodynamic antimicrobial chemotherapy.

PubMed

Parente, Ticiana Mont Alverne Lopes; Rebouças, Emanuela de Lima; Santos, Vitor Coutinho Vieira Dos; Barbosa, Francisco Cesar Barroso; Zanin, Iriana Carla Junqueira

2016-06-01

Some authors have reported the antimicrobial action of photodynamic antimicrobial chemotherapy (PACT) on bacteria related to nosocomial infections but there are few studies evaluating PACT on Serratia marcescens grown as planktonic cultures or as biofilms. The purpose of this study was to analyze the S. marcescens resistance profile and its susceptibility to PACT. Initially, 55 S. marcescens strains isolated from environmental, oral and extra-oral infections were tested by antimicrobial resistance to cefotaxime (CTX), imipenem (IPM), ciprofloxacin (CIP), tobramycin (TOB) and doxycycline (DOX) using E-test(®). Following, isolates grown as planktonic cultures or biofilms were submitted to PACT using the association of a light-emitting diode and toluidine blue (TBO). The E-test(®) results demonstrated intermediated sensitive strains to CTX, IMP, TOB, and DOX; and resistant strains to CTX, TOB, DOX and CIP. Also, CTX and IMP demonstrated variation when CLSI 2007 and CLSI 2015 were compared. Planktonic cultures and biofilms submitted to PACT demonstrated counts varying from 10(11) to 10(7) for planktonic cultures and 10(10) to 10(7) for biofilms. There were no statistical differences in the results when planktonic cultures and biofilms were compared. Increase in the profile of S. marcescens resistance was observed when CLSI 2007 and CLSI 2015 were compared. Also, IMP remains as the drug with lower rate of resistance. Additionally, both S. marcescens planktonic cultures and early biofilms are susceptible to PACT under tested conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

New directions in photonics simulation: Lanczos recursion and finite-difference time-domain

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

Hawkins, R.J.; McLeod, R.R.; Kallman, J.S.

1992-06-01

Computational Integrated Photonics (CIP) is the area of computational physics that treats the propagation of light in optical fibers and in integrated optical circuits. The purpose of integrated photonics simulation is to develop the computational tools that will support the design of photonic and optoelectronic integrated devices. CIP has, in general, two thrusts: (1) predictive models of photonic device behavior that can be used reliably to enhance significantly the speed with which designs axe optimized for development applications, and (2) to further our ability to describe the linear and nonlinear processes that occur - and can be exploited - inmore » real photonic devices. Experimental integrated optics has been around for over a decade with much of the work during this period. centered on proof-of-principle devices that could be described using simple analytic and numerical models. Recent advances in material growths, photolithography, and device complexity have conspired to reduce significantly the number of devices that can be designed with simple models and to increase dramatically the interest in CIP. In the area of device design, CIP is viewed as critical to understanding device behavior and to optimization. In the area of propagation physics, CIP is an important tool in the study of nonlinear processes in integrated optical devices and fibers. In this talk I will discuss two of the new directions we have been investigating in CIP: Lanczos recursion and finite-difference time-domain.« less

Absorption property of C@CIPs composites by the mechanical milling process

NASA Astrophysics Data System (ADS)

Liu, Ting; Zhou, Li; Zheng, Dianliang; Xu, Yonggang

2017-09-01

The C@CIPs absorbents were fabricated by the mechanical milling method. The particle morphology and crystal grain structure were characterized by the scanning electron microscopy and the X-ray diffraction patterns, respectively. The complex permittivity and permeability of the absorbing composites added the hybrid particles were tested in 2-18 GHz. The reflection loss (RL) and shielding effectiveness were calculated using the tested parameters. It was found that the MWCNTs were bonded to the CIPs surface. The permittivity and permeability of the C@CIPs were increased as the MWCNTs coated on the CIPs. It was attributed to the dielectric property of MWCNTs, particle shape and the interactions of the two particles according to the Debye equation and the Maxwell-Garnett mixing rule. The C@CIPs composites had a better absorbing property as RL < -4 dB in 4.6-17 GHz with thickness 0.6 mm as well as shielding property (maximum 12.7 dB) in 2-18 GHz. It indicated that C@CIPs might be an effective absorbing/shielding absorbent.

cipC is important for Aspergillus fumigatus virulence.

PubMed

Canela, Heliara Maria Spina; Takami, Luciano Akira; da Silva Ferreira, Márcia Eliana

2017-02-01

Aspergillus fumigatus is the main causative agent of invasive aspergillosis, a disease that affects immunocompromised patients and has a high mortality rate. We previously observed that the transcription of a cipC-like gene was increased when A. fumigatus encountered an increased CO 2 concentration, as occurs during the infection process. CipC is a protein of unknown function that might be associated with fungal pathogenicity. In this study, the cipC gene was disrupted in A. fumigatus to evaluate its importance for fungal pathogenicity. The gene was replaced, and the germination, growth phenotype, stress responses, and virulence of the resultant mutant were assessed. Although cipC was not essential, its deletion attenuated A. fumigatus virulence in a low-dose murine infection model, suggesting the involvement of the cipC gene in the virulence of this fungus. This study is the first to disrupt the cipC gene in A. fumigatus. © 2017 APMIS. Published by John Wiley & Sons Ltd.

New AIM/CIPS global observations of gravity waves near 50-55 km

NASA Astrophysics Data System (ADS)

Randall, C. E.; Carstens, J.; France, J. A.; Harvey, V. L.; Hoffmann, L.; Bailey, S. M.; Alexander, M. J.; Lumpe, J. D.; Yue, J.; Thurairajah, B.; Siskind, D. E.; Zhao, Y.; Taylor, M. J.; Russell, J. M.

2017-07-01

This paper describes a new data set from the Aeronomy of Ice in the Mesosphere (AIM) Cloud Imaging and Particle Size (CIPS) instrument, from which gravity waves (GWs) at an altitude of 50-55 km can be inferred. CIPS is sensitive to GWs with horizontal wavelengths from 15 to 600 km and vertical wavelengths longer than 15 km. Several examples of GWs in CIPS observations are shown, including waves associated with the Andes Mountains, island topography, convection, the polar night jet, and the tropospheric jet stream. GW signatures in the CIPS data are shown to agree well with near-coincident but lower altitude measurements from the Atmospheric Infrared Sounder (AIRS) in June of 2016. Results suggest the power of combining CIPS measurements with those from other instruments to investigate GW filtering and propagation. The CIPS data set opens new areas of inquiry, enabling comprehensive investigations of GWs in the middle atmosphere on a near-global scale.

Ecological risk assessment of the antibiotic enrofloxacin applied to Pangasius catfish farms in the Mekong Delta, Vietnam.

PubMed

Andrieu, Margot; Rico, Andreu; Phu, Tran Minh; Huong, Do Thi Thanh; Phuong, Nguyen Thanh; Van den Brink, Paul J

2015-01-01

Antibiotics applied in aquaculture production may be released into the environment and contribute to the deterioration of surrounding aquatic ecosystems. In the present study, we assessed the ecological risks posed by the use of the antibiotic enrofloxacin (ENR), and its main metabolite ciprofloxacin (CIP), in a Pangasius catfish farm in the Mekong Delta region, Vietnam. Water and sediment samples were collected in a stream receiving effluents from a Pangasius catfish farm that had applied ENR. The toxicity of ENR and CIP was assessed on three tropical aquatic species: the green-algae Chlorella sp. (72 h - growth inhibition test), the micro-invertebrate Moina macrocopa (48 h - immobilization test), and the Nile tilapia (Oreochromis niloticus). The toxic effects on O. niloticus were evaluated by measuring the cholinesterase (ChE) and catalase (CAT) activities in the fish brain and muscles, respectively, and by considering feed exposure and water exposure separately. Ecological risks were assessed by comparing maximum exposure concentrations with predicted no effect concentrations for cyanobacteria, green algae, invertebrates and fish derived with available toxicity data. The results of this study showed that maximum antibiotic concentrations in Pangasius catfish farm effluents were 0.68 μg L(-1) for ENR and 0.25 μg L(-1) for CIP (dissolved water concentrations). Antibiotics accumulated in sediments down-stream the effluent discharge point at concentrations up to 2590 μg kg(-1) d.w. and 592 μg kg(-1) d.w. for ENR and CIP, respectively. The calculated EC50 values for ENR and CIP were 111000 and 23000 μg L(-1) for Chlorella sp., and 69000 and 71000 μg L(-1) for M. macrocopa, respectively. Significant effects on the ChE and CAT enzymatic activities of O. niloticus were observed at 5 g kg(-1) feed and 400-50000 μg L(-1), for both antibiotics. The results of the ecological risk assessment performed in this study indicated only minor risks for cyanobacteria communities, suggesting that residual concentrations of ENR and CIP after medication are not likely to result in severe toxic effects on exposed aquatic ecosystems. However, more studies should be performed by considering other antibiotic treatments used in Pangasius catfish production and the potential ecotoxicological effects of relevant antibiotic mixtures on sediment communities. Copyright © 2014 Elsevier Ltd. All rights reserved.

BOK promotes chemical-induced hepatocarcinogenesis in mice.

PubMed

Rabachini, Tatiana; Fernandez-Marrero, Yuniel; Montani, Matteo; Loforese, Giulio; Sladky, Valentina; He, Zhaoyue; Bachmann, Daniel; Wicki, Simone; Villunger, Andreas; Stroka, Deborah; Kaufmann, Thomas

2018-03-01

BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver. Of note, induction of CHOP and the pro-apoptotic BH3-only proteins PUMA and BIM by DEN was strongly reduced in the absence of BOK. Accordingly, Bok -/- mice were significantly protected from DEN-induced acute hepatocellular apoptosis and associated inflammation. As a consequence, Bok -/- animals were partially protected against chemical-induced hepatocarcinogenesis showing fewer and, surprisingly, also smaller tumors than WT controls. Gene expression profiling revealed that downregulation of BOK results in upregulation of genes involved in cell cycle arrest. Bok -/- hepatocellular carcinoma (HCC) displayed higher expression levels of the cyclin kinase inhibitors p19 INK4d and p21 cip1 . Accordingly, hepatocellular carcinoma in Bok -/- animals, BOK-deficient human HCC cell lines, as well as non-transformed cells, showed significantly less proliferation than BOK-proficient controls. We conclude that BOK is induced by DEN, contributes to DEN-induced hepatocellular apoptosis and resulting hepatocarcinogenesis. In line with its previously reported predominant localization at the endoplasmic reticulum, our findings support a role of BOK that links the cell cycle and cell death machineries upstream of mitochondrial damage.

Protein Kinase CK2 Regulates Cytoskeletal Reorganization during Ionizing Radiation-Induced Senescence of Human Mesenchymal Stem Cells

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

Wang, Daojing; Jang, Deok-Jin

2009-08-21

Human mesenchymal stem cells (hMSC) are critical for tissue regeneration. How hMSC respond to genotoxic stresses and potentially contribute to aging and cancer remain underexplored. We demonstrated that ionizing radiation induced cellular senescence of hMSC over a period of 10 days, showing a critical transition between day 3 and day 6. This was confirmed by senescence-associated beta-galactosidase (SA-{beta}-gal) staining, protein expression profiles of key cell cycle regulators (retinoblastoma (Rb) protein, p53, p21{sup waf1/Cip1}, and p16{sup INK4A}), and senescence-associated secretory phenotypes (SASPs) (IL-8, IL-12, GRO, and MDC). We observed dramatic cytoskeletal reorganization of hMSC through reduction of myosin-10, redistribution of myosin-9,more » and secretion of profilin-1. Using a SILAC-based phosphoproteomics method, we detected significant reduction of myosin-9 phosphorylation at Ser1943, coinciding with its redistribution. Importantly, through treatment with cell permeable inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT)), and gene knockdown using RNA interference, we identified CK2, a kinase responsible for myosin-9 phosphorylation at Ser1943, as a key factor contributing to the radiation-induced senescence of hMSC. We showed that individual knockdown of CK2 catalytic subunits CK2{alpha} and CK2{alpha}{prime} induced hMSC senescence. However, only knockdown of CK2{alpha} resulted in morphological phenotypes resembling those of radiation-induced senescence. These results suggest that CK2{alpha} and CK2{alpha}{prime} play differential roles in hMSC senescence progression, and their relative expression might represent a novel regulatory mechanism for CK2 activity.« less

Structure of the catalytic domain of glucuronoyl esterase Cip2 from Hypocrea jecorina

USDA-ARS?s Scientific Manuscript database

The structure of the catalytic domain of glucuronoyl esterase Cip2 from the fungus Hypocrea jecorina was determined at a resolution of 1.9 Angstroms. This is the first structure of the newly established carbohydrate esterase family 15. The structure has revealed the residues Ser278–His411–Glu301 pre...

Composition Instruction and Cognitive Performance: Results of a Pilot Study

ERIC Educational Resources Information Center

Bugos, Jennifer; Jacobs, Edward

2012-01-01

The purpose of this study was to evaluate the effects of a composition program, Composers in Public Schools (CiPS), on cognitive skills essential for academic success. The underlying hypothesis is that composition instruction will promote creative expression and increase performance on music-specific skills such as music reading, as well as foster…

[Effect of shikonin, a phytocompound from Lithospermum erythrorhizon, on rat vascular smooth muscle cells proliferation and apoptosis in vitro].

PubMed

Zhang, Zhuo-qi; Cao, Xi-chuan; Zhang, Ling; Zhu, Wen-ling

2005-06-08

To study the anti-proliferation, pro-apoptosis and cell cycle blocking effects of shikonin on rat vascular smooth muscle cell (VSMC) in vitro. VSMCs were primarily cultured by explant method from the thoracic aorta of male SD rats. Shikonin of different concentration, 4, 2, 1, 0.5, 0.25, and 0 micromol/L was added. The cell viability was detected by MTT method. Cell growth curve was drawn by trypan blue exclusion method. (3)H-thymidine incorporation was used to calculate the inhibition rate of DNA synthesis. Flow cytometry was used to detect the cell cycle. Cell apoptosis was observed by fluorescence microscopy. Western blotting was performed to detect the expression of different cell apoptosis and cell cycle regulatory proteins, such as cyclin D(1) and E, proliferating cell nuclear antigen (PCNA), p21(waf1/cip1), p27(kip1), and p53. Compared with control group, shikonin had no obvious cytotoxic effect on cell viability at the concentration of 0.25-1 micromol/L (P > 0.05). While it could inhibit, both time- and dose-dependently, the growth of VSMC, which was predominant of 1 micromol/L at 72 h (1.9 x 10(5)/well vs 5.8 x 10(5)/well, P < 0.05), and DNA synthesis was also significantly inhibited in a time- and dose-dependent manner with inhibition rate varied from 33 to 98% (P < 0.05 or P < 0.01). 1 micromol/L shikonin significantly blocked the cell cycle progression in proliferative VSMC, decreased S, G(2)/M phase (P < 0.05) and increased G(0)/G(1) phase (P < 0.05) to quiescent level with sub-G(1) apoptotic distribution at 48 h (10.9% +/- 0.3%). Shikohin at the concentration of 1-2 micromol/L significantly increased the percentage of apoptotic cells in a time- and dose-dependent manner compared with control group (2.8%-23.7% vs 0.2%-0.4%, P < 0.05), and typical apoptotic nuclear morphological changes were observed. 1 micromol/L shikonin significantly down-regulated cyclin D(1), E and PCNA expression, up-regulated p21(wif1/cip1) expression, and did not obviously influence the p27(kip1) and p53 expression. Shikonin inhibits the proliferation, promotes the apoptosis and blocks cell cycle progression of VSMC. These effects are associated with the expression changes of cell cycle regulatory proteins.

Application of the 3D slicer chest imaging platform segmentation algorithm for large lung nodule delineation

PubMed Central

Parmar, Chintan; Blezek, Daniel; Estepar, Raul San Jose; Pieper, Steve; Kim, John; Aerts, Hugo J. W. L.

2017-01-01

Purpose Accurate segmentation of lung nodules is crucial in the development of imaging biomarkers for predicting malignancy of the nodules. Manual segmentation is time consuming and affected by inter-observer variability. We evaluated the robustness and accuracy of a publically available semiautomatic segmentation algorithm that is implemented in the 3D Slicer Chest Imaging Platform (CIP) and compared it with the performance of manual segmentation. Methods CT images of 354 manually segmented nodules were downloaded from the LIDC database. Four radiologists performed the manual segmentation and assessed various nodule characteristics. The semiautomatic CIP segmentation was initialized using the centroid of the manual segmentations, thereby generating four contours for each nodule. The robustness of both segmentation methods was assessed using the region of uncertainty (δ) and Dice similarity index (DSI). The robustness of the segmentation methods was compared using the Wilcoxon-signed rank test (pWilcoxon<0.05). The Dice similarity index (DSIAgree) between the manual and CIP segmentations was computed to estimate the accuracy of the semiautomatic contours. Results The median computational time of the CIP segmentation was 10 s. The median CIP and manually segmented volumes were 477 ml and 309 ml, respectively. CIP segmentations were significantly more robust than manual segmentations (median δCIP = 14ml, median dsiCIP = 99% vs. median δmanual = 222ml, median dsimanual = 82%) with pWilcoxon~10−16. The agreement between CIP and manual segmentations had a median DSIAgree of 60%. While 13% (47/354) of the nodules did not require any manual adjustment, minor to substantial manual adjustments were needed for 87% (305/354) of the nodules. CIP segmentations were observed to perform poorly (median DSIAgree≈50%) for non-/sub-solid nodules with subtle appearances and poorly defined boundaries. Conclusion Semi-automatic CIP segmentation can potentially reduce the physician workload for 13% of nodules owing to its computational efficiency and superior stability compared to manual segmentation. Although manual adjustment is needed for many cases, CIP segmentation provides a preliminary contour for physicians as a starting point. PMID:28594880

3D model for Cancerous Inhibitor of Protein Phosphatase 2A armadillo domain unveils highly conserved protein-protein interaction characteristics.

PubMed

Dahlström, Käthe M; Salminen, Tiina A

2015-12-07

Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is a human oncoprotein, which exerts its cancer-promoting function through interaction with other proteins, for example Protein Phosphatase 2A (PP2A) and MYC. The lack of structural information for CIP2A significantly prevents the design of anti-cancer therapeutics targeting this protein. In an attempt to counteract this fact, we modeled the three-dimensional structure of the N-terminal domain (CIP2A-ArmRP), analyzed key areas and amino acids, and coupled the results to the existing literature. The model reliably shows a stable armadillo repeat fold with a positively charged groove. The fact that this conserved groove highly likely binds peptides is corroborated by the presence of a conserved polar ladder, which is essential for the proper peptide-binding mode of armadillo repeat proteins and, according to our results, several known CIP2A interaction partners appropriately possess an ArmRP-binding consensus motif. Moreover, we show that Arg229Gln, which has been linked to the development of cancer, causes a significant change in charge and surface properties of CIP2A-ArmRP. In conclusion, our results reveal that CIP2A-ArmRP shares the typical fold, protein-protein interaction site and interaction patterns with other natural armadillo proteins and that, presumably, several interaction partners bind into the central groove of the modeled CIP2A-ArmRP. By providing essential structural characteristics of CIP2A, the present study significantly increases our knowledge on how CIP2A interacts with other proteins in cancer progression and how to develop new therapeutics targeting CIP2A. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Enterolactone induces G1-phase cell cycle arrest in non-small cell lung cancer cells by down-regulating cyclins and cyclin-dependent kinases

PubMed Central

Chikara, Shireen; Lindsey, Kaitlin; Dhillon, Harsharan; Mamidi, Sujan; Kittilson, Jeffrey; Christofidou-Solomidou, Melpo; Reindl, Katie M.

2017-01-01

Flaxseed is a rich source of the plant lignan secoisolariciresinol diglucoside (SDG) which is metabolized into mammalian lignans enterodiol (ED) and enterolactone (EL) in the digestive tract. The anti-cancer properties of these lignans have been demonstrated for various cancer types, but have not been studied for lung cancer. In this study we investigated the anti-cancer effects of EL for several non-small cell lung cancer (NSCLC) cell lines of various genetic backgrounds. EL inhibited the growth of A549, H441, and H520 lung cancer cells in concentration- and time-dependent manners. The anti-proliferative effects of EL for lung cancer cells were not due to enhanced cell death, but rather due to G1-phase cell cycle arrest. Molecular studies revealed that EL- decreased mRNA or protein expression levels of the G1-phase promoters cyclin D1, cyclin E, cyclin-dependent kinases (CDK)-2, -4, and -6, and p-cdc25A; decreased phosphorylated retinoblastoma (p-pRb) protein levels; and simultaneously increased levels of p21WAF1/CIP1, a negative regulator of the G1-phase. The results suggest that EL inhibits the growth of NSCLC cell lines by down-regulating G1-phase cyclins and CDKs, and up-regulating p21WAF1/CIP1, which leads to G1-phase cell cycle arrest. Therefore, EL may hold promise as an adjuvant treatment for lung cancer therapy. PMID:28323486

Enterolactone Induces G1-phase Cell Cycle Arrest in Nonsmall Cell Lung Cancer Cells by Downregulating Cyclins and Cyclin-dependent Kinases.

PubMed

Chikara, Shireen; Lindsey, Kaitlin; Dhillon, Harsharan; Mamidi, Sujan; Kittilson, Jeffrey; Christofidou-Solomidou, Melpo; Reindl, Katie M

2017-01-01

Flaxseed is a rich source of the plant lignan secoisolariciresinol diglucoside (SDG), which is metabolized into mammalian lignans enterodiol (ED) and enterolactone (EL) in the digestive tract. The anticancer properties of these lignans have been demonstrated for various cancer types, but have not been studied for lung cancer. In this study, we investigated the anticancer effects of EL for several nonsmall cell lung cancer (NSCLC) cell lines of various genetic backgrounds. EL inhibited the growth of A549, H441, and H520 lung cancer cells in concentration- and time-dependent manners. The antiproliferative effects of EL for lung cancer cells were not due to enhanced cell death, but rather due to G 1 -phase cell cycle arrest. Molecular studies revealed that EL decreased mRNA or protein expression levels of the G 1 -phase promoters cyclin D1, cyclin E, cyclin-dependent kinases (CDK)-2, -4, and -6, and p-cdc25A; decreased phosphorylated retinoblastoma (p-pRb) protein levels; and simultaneously increased levels of p21 WAF1/CIP1 , a negative regulator of the G 1 phase. The results suggest that EL inhibits the growth of NSCLC cell lines by downregulating G 1 -phase cyclins and CDKs, and upregulating p21 WAF1/CIP1 , which leads to G 1 -phase cell cycle arrest. Therefore, EL may hold promise as an adjuvant treatment for lung cancer therapy.

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro.

PubMed

Lin, Qing-Huan; Que, Fu-Chang; Gu, Chun-Ping; Zhong, De-Sheng; Zhou, Dan; Kong, Yi; Yu, Le; Liu, Shu-Wen

2017-12-01

Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC 50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G 1 /G 0 -phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21 Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G 1 /G 0 -phase arrest. Knockdown of p21 Waf1/Cip1 attenuated ABT-263-induced G 1 /G 0 -phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.

Femtosecond-picosecond laser photolysis studies on the dynamics of excited charge-transfer complexes: Aromatic hydrocarbon-acid anhydride, -tetracyanoethylene, and -tetracyanoquinodimethane systems in acetonitrile solutions

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

Asahi, Tsuyoshi; Mataga, Noboru

1991-03-07

Formation processes of contact ion pairs (CIP) from the excited Franck-Condon (FC) state of charge-transfer (CT) complexes of aromatic hydrocarbons with acid anhydride as well as cyano compound acceptors in acetonitrile solution and charge recombination (CR) rates (k{sub CR}{sup CIP}) of produced CIP states have been investigated by femtosecond and picosecond laser phototlysis and time-resolved absorption spectral measurements covering a wide range of free energy gap-{Delta}G{degree}{sub ip} between the ion pair and the ground state. It has been confirmed that the CIP formation becomes faster and k{sub CR}{sup CIP} of the produced CIP increases with increase of the strengths ofmore » the electron donor (D) and acceptor (A) in the complex, i.e., with decrease of the {minus}{Delta}G{degree}{sub ip} value. This peculiar energy gap dependence of k{sub CR}{sup CIP}, quite different from the bell-shaped one observed in the case of the solvent-separated ion pairs (SSIP) or loose ion pairs (LIP) formed by encounter between fluorescer and quencher in the fluoresence quenching reaction, has been interpreted by assuming the change of electronic and geometrical structures of CIP depending on the strengths of D and A.« less

Inactivation of EGFR/AKT signaling enhances TSA-induced ovarian cancer cell differentiation.

PubMed

Shao, Genbao; Lai, Wensheng; Wan, Xiaolei; Xue, Jing; Wei, Ye; Jin, Jie; Zhang, Liuping; Lin, Qiong; Shao, Qixiang; Zou, Shengqiang

2017-05-01

Ovarian tumor is one of the most lethal gynecologic cancers, but differentiation therapy for this cancer is poorly characterized. Here, we show that thrichostatin A (TSA), the well known inhibitor of histone deacetylases (HDACs), can induce cell differentiation in HO8910 ovarian cancer cells. TSA-induced cell differentiation is characterized by typical morphological change, increased expression of the differentiation marker FOXA2, decreased expression of the pluripotency markers SOX2 and OCT4, suppressing cell proliferation, and cell cycle arrest in the G1 phase. TSA also induces an elevated expression of cell cycle inhibitory protein p21Cip1 along with a decrease in cell cycle regulatory protein cyclin D1. Significantly, blockage of epidermal growth factor receptor (EGFR) signaling pathway with specific inhibitors of this signaling cascade promotes the TSA-induced differentiation of HO8910 cells. These results imply that the EGFR cascade inhibitors in combination with TSA may represent a promising differentiation therapy strategy for ovarian cancer.

Properties of plate-like carbonyl iron particle for magnetorheological fluid

NASA Astrophysics Data System (ADS)

Shilan, S. T.; Mazlan, S. A.; Khairi, M. H. A.; Ubaidillah

2016-11-01

This work experimentally discussed the characterization, magnetic, and rheological properties of plate-like carbonyl iron particle (CIP) in comparison with conventional spherical CIP. Plate-like CIP was produced by using ball milling method. The effect of plate-like shape on the magnetic behavior of CIP was firstly investigated by vibrating sample magnetometer (VSM). The results indicated that the plate-like CIP obtained higher saturation magnetization (about 8%) than that of the spherical particles. In addition, the field-dependent rheological properties such as yield stress were investigated and the results are compared between two particles as a function of the magnetic field intensity.

Overcoming the Law of the Hidden in Cyberinfrastructures.

PubMed

Bucksch, Alexander; Das, Abhiram; Schneider, Hannah; Merchant, Nirav; Weitz, Joshua S

2017-02-01

Cyberinfrastructure projects (CIPs) are complex, integrated systems that require interaction and organization amongst user, developer, hardware, technical infrastructure, and funding resources. Nevertheless, CIP usability, functionality, and growth do not scale with the sum of these resources. Instead, growth and efficient usage of CIPs require access to 'hidden' resources. These include technical resources within CIPs as well as social and functional interactions among stakeholders. We identify approaches to overcome resource limitations following the conceptual basis of Liebig's Law of the Minimum. In so doing, we recommend practical steps towards efficient and scaleable resource use, taking the iPlant/CyVerse CIP as an example. Copyright © 2016 Elsevier Ltd. All rights reserved.

Efficient mineralization of antibiotic ciprofloxacin in acid aqueous medium by a novel photoelectro-Fenton process using a microwave discharge electrodeless lamp irradiation.

PubMed

Wang, Aimin; Zhang, Yanyu; Zhong, Huihui; Chen, Yu; Tian, Xiujun; Li, Desheng; Li, Jiuyi

2018-01-15

In this study, a novel photoelectro-Fenton (PEF) process using microwave discharge electrodeless lamp (MDEL) as a UV irradiation source was developed for the removal of antibiotic ciprofloxacin (CIP) in water. Comparative degradation of 200mgL -1 CIP was studied by direct MDEL photolysis, anodic oxidation (AO), AO in presence of electrogenerated H 2 O 2 (AO-H 2 O 2 ), AO-H 2 O 2 under MDEL irradiation (MDEL-AO-H 2 O 2 ), electro-Fenton (EF) and MDEL-PEF processes. Higher oxidation power was found in the sequence: MDEL photolysis < AO < AO-H 2 O 2 < MDEL-AO-H 2 O 2 < EF < MDEL-PEF. Effects of current density, pH, initial Fe 2+ concentration and initial CIP concentration on TOC removal in MDEL-PEF process were examined, and the optimal conditions were ascertained. The releases of three inorganic ions (F - , NH 4 + and NO 3 - ) and two carboxylic acids (oxalic and formic acids) were qualified. Seven aromatic intermediates mainly generated from hydroxylation, dealkylation and defluorination of CIP were detected by UPLC-QTOF-MS/MS technology. Therefore, plausible degradation sequences for CIP degradation in MDEL-PEF process including all detected products were proposed. Copyright © 2017 Elsevier B.V. All rights reserved.

What Can the Community Involvement Program Tell Us about Alumni Giving at the University of the Pacific

ERIC Educational Resources Information Center

Ruiz-Huston, Ines Marta

2010-01-01

The purpose of this research is to analyze characteristics and motivators among alumni of the Community Involvement Program (CIP) for donating to the University of the Pacific. The research questions were: (1) what are the characteristics and motivators of CIP alumni for donating to the University of the Pacific? (2) do the characteristics and…

CASL L1 Milestone report : CASL.P4.01, sensitivity and uncertainty analysis for CIPS with VIPRE-W and BOA.

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

Sung, Yixing; Adams, Brian M.; Secker, Jeffrey R.

2011-12-01

The CASL Level 1 Milestone CASL.P4.01, successfully completed in December 2011, aimed to 'conduct, using methodologies integrated into VERA, a detailed sensitivity analysis and uncertainty quantification of a crud-relevant problem with baseline VERA capabilities (ANC/VIPRE-W/BOA).' The VUQ focus area led this effort, in partnership with AMA, and with support from VRI. DAKOTA was coupled to existing VIPRE-W thermal-hydraulics and BOA crud/boron deposit simulations representing a pressurized water reactor (PWR) that previously experienced crud-induced power shift (CIPS). This work supports understanding of CIPS by exploring the sensitivity and uncertainty in BOA outputs with respect to uncertain operating and model parameters. Thismore » report summarizes work coupling the software tools, characterizing uncertainties, and analyzing the results of iterative sensitivity and uncertainty studies. These studies focused on sensitivity and uncertainty of CIPS indicators calculated by the current version of the BOA code used in the industry. Challenges with this kind of analysis are identified to inform follow-on research goals and VERA development targeting crud-related challenge problems.« less

Inactivation of p16INK4a, with retention of pRB and p53/p21cip1 function, in human MRC5 fibroblasts that overcome a telomere-independent crisis during immortalization.

PubMed

Taylor, Lisa M; James, Alexander; Schuller, Christine E; Brce, Jesena; Lock, Richard B; Mackenzie, Karen L

2004-10-15

Recent investigations, including our own, have shown that specific strains of fibroblasts expressing telomerase reverse transcriptase (hTERT) have an extended lifespan, but are not immortal. We previously demonstrated that hTERT-transduced MRC5 fetal lung fibroblasts (MRC5hTERTs) bypassed senescence but eventually succumbed to a second mortality barrier (crisis). In the present study, 67 MRC5hTERT clones were established by limiting dilution of a mass culture. Whereas 39/67 clones had an extended lifespan, all 39 extended lifespan clones underwent crisis. 11 of 39 clones escaped crisis and were immortalized. There was no apparent relationship between the fate of clones at crisis and the level of telomerase activity. Telomeres were hyperextended in the majority of the clones analyzed. There was no difference in telomere length of pre-crisis compared with post-crisis and immortal clones, indicating that hyperextended telomeres were conducive for immortalization and confirming that crisis was independent of telomere length. Immortalization of MRC5hTERT cells was associated with repression of the cyclin-dependent kinase inhibitor p16INK4a and up-regulation of pRB. However, the regulation of pRB phosphorylation and the response of the p53/p21cip1/waf1 pathway were normal in immortal cells subject to genotoxic stress. Overexpression of oncogenic ras failed to de-repress p16INK4a in immortal cells. Furthermore, expression of ras enforced senescent-like growth arrest in p16INK4a-positive, but not p16INK4a-negative MRC5hTERT cells. Immortal cells expressing ras formed small, infrequent colonies in soft agarose, but were non-tumorigenic. Overall, these results implicate the inactivation of p16INK4a as a critical event for overcoming telomere-independent crisis, immortalizing MRC5 fibroblasts and overcoming ras-induced premature senescence.

Less understood issues: p21(Cip1) in mitosis and its therapeutic potential.

PubMed

Kreis, N-N; Louwen, F; Yuan, J

2015-04-02

p21(Cip1) is a multifunctional protein and a key player in regulating different cellular processes. The transcription of p21 is regulated by p53-dependent and -independent pathways. The expression of p21 is increased in response to various cellular stresses to arrest the cell cycle and ensure genomic stability. p21 has been shown to be a tumor suppressor and an oncogene as well. The function of p21 in mitosis has been proposed but not systematically studied. We have recently shown that p21 binds to and inhibits the activity of Cdk1/cyclin B1, and is important for a fine-tuned mitotic progression. Loss of p21 prolongs the duration of mitosis and results in severe mitotic defects like chromosome segregation and cytokinesis failures promoting consequently genomic instability. Moreover, p21 is dramatically stabilized in mitotic tumor cells upon treatment with mitotic agents like paclitaxel or mitotic kinase inhibitors. Increased p21 is mainly localized in the cytoplasm and associates with cell survival indicating a crucial role of p21 in susceptibility to mitotic agents in tumor cells. In this review we will briefly summarize the structure and general physiological functions as well as regulation of p21, discuss in detail its role in mitosis and its potential to serve as a therapeutic target.

Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest.

PubMed

Zalc, Antoine; Hayashi, Shinichiro; Auradé, Frédéric; Bröhl, Dominique; Chang, Ted; Mademtzoglou, Despoina; Mourikis, Philippos; Yao, Zizhen; Cao, Yi; Birchmeier, Carmen; Relaix, Frédéric

2014-07-01

A central question in development is to define how the equilibrium between cell proliferation and differentiation is temporally and spatially regulated during tissue formation. Here, we address how interactions between cyclin-dependent kinase inhibitors essential for myogenic growth arrest (p21(cip1) and p57(kip2)), the Notch pathway and myogenic regulatory factors (MRFs) orchestrate the proliferation, specification and differentiation of muscle progenitor cells. We first show that cell cycle exit and myogenic differentiation can be uncoupled. In addition, we establish that skeletal muscle progenitor cells require Notch signaling to maintain their cycling status. Using several mouse models combined with ex vivo studies, we demonstrate that Notch signaling is required to repress p21(cip1) and p57(kip2) expression in muscle progenitor cells. Finally, we identify a muscle-specific regulatory element of p57(kip2) directly activated by MRFs in myoblasts but repressed by the Notch targets Hes1/Hey1 in progenitor cells. We propose a molecular mechanism whereby information provided by Hes/Hey downstream of Notch as well as MRF activities are integrated at the level of the p57(kip2) enhancer to regulate the decision between progenitor cell maintenance and muscle differentiation. © 2014. Published by The Company of Biologists Ltd.

Microcontact imprinted quartz crystal microbalance nanosensor for protein C recognition.

PubMed

Bakhshpour, Monireh; Özgür, Erdoğan; Bereli, Nilay; Denizli, Adil

2017-03-01

Detection of protein C (PC) in human serum was performed by quartz crystal microbalance (QCM) based on molecular imprinting technique (MIP). The high-resolution and mass-sensitive QCM based sensor was integrated with high sensitivity and selectivity of the MIP technique. The PC microcontact imprinted (PC-μCIP) nanofilm was prepared on the glass surface. Then, the PC-μCIP/QCM sensor was prepared with 2-hydroxyethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EGDMA) and N-methacryloyl l-histidine methylester (MAH) as the functional monomer with copper(II) ions. The polymerization was performed under UV light (100W and 365nm) for 20-25min under nitrogen atmosphere. The characterization studies of QCM sensor were done by observation using atomic force microscopy (AFM), contact angle measurements, ellipsometry and fourier transform infrared spectroscopy (FTIR). Detection of PC was investigated in a concentration range of 0.1-30μg/mL. Selectivity of PC-μCIP and PC non-imprinted/QCM (PC-non-μCIP) sensors for PC determination was investigated by using proteins namely hemoglobin (Hb), human serum albumin (HSA) and fibrinogen solutions. QCM sensor was also used for detection of PC molecules in aqueous solutions and human plasma. The detection limit was determined as 0.01μg/mL for PC analysis. The PC-μCIP/QCM sensor was used for five consecutive adsorption-desorption cycles. According to the results, the PC-μCIP/QCM sensor had obtained high selectivity and sensitivity for detection of PC molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion

PubMed Central

Kandhaya-Pillai, Renuka; Miro-Mur, Francesc; Alijotas-Reig, Jaume; Tchkonia, Tamara; Kirkland, James L.; Schwartz, Simo

2017-01-01

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence. PMID:29176033

Complete Genome Sequence of Rahnella aquatilis CIP 78.65

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

Martinez, Robert J; Bruce, David; Detter, J C

2012-01-01

Rahnella aquatilis CIP 78.65 is a gammaproteobacterium isolated from a drinking water source in Lille, France. Here we report the complete genome sequence of Rahnella aquatilis CIP 78.65, the type strain of R. aquatilis.

Complete genome sequence of Rahnella aquatilis CIP 78.65.

PubMed

Martinez, Robert J; Bruce, David; Detter, Chris; Goodwin, Lynne A; Han, James; Han, Cliff S; Held, Brittany; Land, Miriam L; Mikhailova, Natalia; Nolan, Matt; Pennacchio, Len; Pitluck, Sam; Tapia, Roxanne; Woyke, Tanja; Sobecky, Patricia A

2012-06-01

Rahnella aquatilis CIP 78.65 is a gammaproteobacterium isolated from a drinking water source in Lille, France. Here we report the complete genome sequence of Rahnella aquatilis CIP 78.65, the type strain of R. aquatilis.

Power spectra based Planck constraints on compensated isocurvature, and forecasts for LiteBIRD and CORE space missions

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

Väliviita, Jussi, E-mail: jussi.valiviita@helsinki.fi

Compensated isocurvature perturbations (CIP), where the primordial baryon and cold dark matter density perturbations cancel, do not cause total matter isocurvature perturbation. Consequently, at the linear order in the baryon density contrast Δ, a mixture of CIP and the adiabatic mode leads to the same CMB spectra as the pure adiabatic mode. Only recently, Muñoz et al. showed that at the second order CIP leaves an imprint in the observable CMB by smoothing the power spectra in a similar manner as lensing. This causes a strong degeneracy between the CIP variance Δ{sub rms}{sup 2} ≡ (Δ{sup 2}) and the phenomenologicalmore » lensing parameter A {sub L}. We study several combinations of the Planck 2015 data and show that the measured lensing potential power spectrum C {sub ℓ}{sup φφ} breaks the degeneracy. Nested sampling of the ΛCDM+Δ{sub rms}{sup 2}(+ A {sub L}) model using the Planck 2015 temperature, polarization, and lensing data gives Δ{sub rms}{sup 2} = (6.9{sup +3.0}{sub −3.1}) × 10{sup −3} at 68% CL. A non-zero value is favoured at 2.3σ (or without the polarization data at 2.8σ). CIP with Δ{sub rms}{sup 2} ≈ 7 × 10{sup −3} improves the bestfit χ{sup 2} by 3.6 compared to the adiabatic ΛCDM model. In contrast, although the temperature data favour A {sub L} ≅ 1.22, allowing A {sub L} ≠ 1 does not improve the joint fit at all, since the lensing data disfavour A {sub L} ≠ 1. Indeed, CIP provides a rare example of a simple model, which is capable of reducing the Planck lensing anomaly significantly and fitting well simultaneously the high (and low) multipole temperature and lensing data, as well as the polarization data. Finally, we derive forecasts for two future satellite missions (LiteBIRD proposal to JAXA/NASA and Exploring Cosmic Origins with CORE proposal to ESA's M5 call) and compare these to simulated Planck data. Due to its coarse angular resolution, LiteBIRD is not able to improve the constraints on Δ{sub rms}{sup 2} or A {sub L}, but CORE-M5 (almost) reaches the cosmic variance limit and improves the CIP constraint to Δ{sub rms}{sup 2} < 0.6 (1.4) × 10{sup −3} at 68 (95)% CL, which is nine times better than the current trispectrum based upper bound and six times better than obtained from the simulated Planck data. In addition, CORE-M5 will exquisitely distinguish between Δ{sub rms}{sup 2} and A {sub L}. No matter whether CIP is allowed for or not, the uncertainty of the lensing parameter will be σ( A {sub L}) ≈ 0.012, in the case where the simulated data are based on the adiabatic ΛCDM model with A {sub L} = 1.« less

Preparation of methoxyl poly(ethylene glycol) (MPEG)-coated carbonyl iron particles (CIPs) and their application in potassium dihydrogen phosphate (KDP) magnetorheological finishing (MRF)

NASA Astrophysics Data System (ADS)

Ji, Fang; Xu, Min; Wang, Baorui; Wang, Chao; Li, Xiaoyuan; Zhang, Yunfei; Zhou, Ming; Huang, Wen; Wei, Qilong; Tang, Guangping; He, Jianguo

2015-10-01

KDP is a common type of optics that is extremely difficult to polish by the conventional route. MRF is a local polishing technology based on material removal via shearing with minimal normal load and sub-surface damage. In contrast to traditional emendation on an abrasive, the MPEG soft coating is designed and prepared to modify the CIP surface to achieve a hardness matched with that of KDP because CIP inevitably takes part in the material removal during finishing. Morphology and infrared spectra are explored to prove the existence of homogeneous coating, and the improvement of MPEG for the polishing quality is validated by the analysis of roughness, turning grooves, and stress. The synthesized MPEG-coated CIP (MPEG-CIP) is chemically and physically compatible with KDP, which can be removed after cleaning. Our research exhibits the promising prospects of MPEG-CIP in KDP MRF.

The electrical resistivity and percolation threshold of MWCNTs/polymer composites filled with a few aligned carbonyl iron particles

NASA Astrophysics Data System (ADS)

Dong, Shuai; Wang, Xiaojie

2018-03-01

Conductive polymer composites (CPCs) consist of multi-walled carbon nanotubes (MWCNTs), a few carbonyl iron particles (CIPs) and polydimethylsiloxane (PDMS) are fabricated under a moderate magnetic field. The alignment of CIPs will change the structure of MWCNT network, and consequently the electrical properties of CPCs. The volume fraction of CIPs is fixed at 0.08 vol% at which CIPs will not directly participate in electric conduction. The electrical resistivity of CPCs and the changes of resistance versus strain are evaluated at various MWCNT volume fractions. The testing results show that a percolation threshold as low as 0.19 vol% is obtained due to the effect of aligned CIPs, comparing with 0.39 vol% of isotropic MWCNT/CIP/PDMS (prepared without magnetic field). Meanwhile, the anisotropic structure reduces the electrical resistivity by more than 80% when the MWCNT volume fractions is over the percolation threshold.

Surface plasmon resonance sensor for antibiotics detection based on photo-initiated polymerization molecularly imprinted array.

PubMed

Luo, Qiaohui; Yu, Neng; Shi, Chunfei; Wang, Xiaoping; Wu, Jianmin

2016-12-01

A surface plasmon resonance (SPR) sensor combined with nanoscale molecularly imprinted polymer (MIP) film as recognition element was developed for selective detection of the antibiotic ciprofloxacin (CIP). The MIP film on SPR sensor chip was prepared by in situ photo-initiated polymerization method which has the advantages of short polymerization time, controllable thickness and good uniformity. The surface wettability and thickness of MIP film on SPR sensor chip were characterized by static contact angle measurement and stylus profiler. The MIP-SPR sensor exhibited high selectivity, sensitivity and good stability for ciprofloxacin. The imprinting factors of the MIP-SPR sensor to ciprofloxacin and its structural analogue ofloxacin were 2.63 and 3.80, which is much higher than those to azithromycin, dopamine and penicillin. The SPR response had good linear relation with CIP concentration over the range 10 -11 -10 -7 molL -1 . The MIP-SPR sensor also showed good repeatability and stability during cyclic detections. On the basis of the photo-initiated polymerization method, a surface plasmon resonance imaging (SPRi) chip modified with three types of MIP sensing spots was fabricated. The MIPs-SPRi sensor shows different response patterns to ciprofloxacin and azithromycin, revealing the ability to recognize different antibiotic molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

Real-Time Monitoring of nfxB Mutant Occurrence and Dynamics in Pseudomonas aeruginosa Biofilm Exposed to Subinhibitory Concentrations of Ciprofloxacin

PubMed Central

Zaborskyte, Greta; Andersen, Jens Bo; Kragh, Kasper Nørskov

2016-01-01

ABSTRACT Biofilm infections caused by Pseudomonas aeruginosa are frequently treated with ciprofloxacin (CIP); however, resistance rapidly develops. One of the primary resistance mechanisms is the overexpression of the MexCD-OprJ pump due to a mutation in nfxB, encoding the transcriptional repressor of this pump. The aim of this study was to investigate the effect of subinhibitory concentrations of CIP on the occurrence of nfxB mutants in the wild-type PAO1 flow cell biofilm model. For this purpose, we constructed fluorescent reporter strains (PAO1 background) with an mCherry tag for constitutive red fluorescence and chromosomal transcriptional fusion between the PmexCD promoter and gfp leading to green fluorescence upon mutation of nfxB. We observed a rapid development of nfxB mutants by live confocal laser scanning microscopy (CLSM) imaging of the flow cell biofilm (reaching 80 to 90% of the whole population) when treated with 1/10 minimal biofilm inhibitory concentration of CIP for 24 h and 96 h. Based on the observed developmental stages, we propose that nfxB mutants emerged de novo in the biofilm during CIP treatment from filamentous cells, which might have arisen due to the stress responses induced by CIP. Identical nfxB mutations were found in fluorescent colonies from the same flow cell biofilm, especially in 24-h biofilms, suggesting selection and clonal expansion of the mutants during biofilm growth. Our findings point at the significant role of high-enough antibiotic dosages or appropriate combination therapy to avoid the emergence of resistant mutants in biofilms. PMID:27993856

P21 cip-Overexpression in the Mouse β Cells Leads to the Improved Recovery from Streptozotocin-Induced Diabetes

PubMed Central

Jiang, Wei; Sun, Xiaoning; Han, Yuhua; Ding, Mingxiao; Shi, Yan; Deng, Hongkui

2009-01-01

Under normal conditions, the regeneration of mouse β cells is mainly dependent on their own duplication. Although there is evidence that pancreatic progenitor cells exist around duct, whether non-β cells in the islet could also potentially contribute to β cell regeneration in vivo is still controversial. Here, we developed a novel transgenic mouse model to study the pancreatic β cell regeneration, which could specifically inhibit β cell proliferation by overexpressing p21 cip in β cells via regulation of the Tet-on system. We discovered that p21 overexpression could inhibit β-cell duplication in the transgenic mice and these mice would gradually suffer from hyperglycemia. Importantly, the recovery efficiency of the p21-overexpressing mice from streptozotocin-induced diabetes was significantly higher than control mice, which is embodied by better physiological quality and earlier emergence of insulin expressing cells. Furthermore, in the islets of these streptozotocin-treated transgenic mice, we found a large population of proliferating cells which expressed pancreatic duodenal homeobox 1 (PDX1) but not markers of terminally differentiated cells. Transcription factors characteristic of early pancreatic development, such as Nkx2.2 and NeuroD1, and pancreatic progenitor markers, such as Ngn3 and c-Met, could also be detected in these islets. Thus, our work showed for the first time that when β cell self-duplication is repressed by p21 overexpression, the markers for embryonic pancreatic progenitor cells could be detected in islets, which might contribute to the recovery of these transgenic mice from streptozotocin-induced diabetes. These discoveries could be important for exploring new diabetes therapies that directly promote the regeneration of pancreatic progenitors to differentiate into islet β cells in vivo. PMID:20020058

Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.

PubMed

Vendetti, Frank P; Leibowitz, Brian J; Barnes, Jennifer; Schamus, Sandy; Kiesel, Brian F; Abberbock, Shira; Conrads, Thomas; Clump, David Andy; Cadogan, Elaine; O'Connor, Mark J; Yu, Jian; Beumer, Jan H; Bakkenist, Christopher J

2017-02-01

We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21 CIP/WAF1 )-/- mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21 CIP/WAF1 )-/- mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21 CIP/WAF1 )-/-, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21 CIP/WAF1 )-/- mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.

IR, 1H NMR, mass, XRD and TGA/DTA investigations on the ciprofloxacin/iodine charge-transfer complex.

PubMed

Refat, Moamen S; El-Hawary, W F; Moussa, Mohamed A A

2011-05-01

The charge-transfer complex (CTC) of ciprofloxacin drug (CIP) as a donor with iodine (I(2)) as a sigma acceptor has been studied spectrophotometrically in CHCl(3). At maximum absorption bands, the stoichiometry of CIP:iodine system was found to be 1:1 ratio according to molar ratio method. The essential spectroscopic data like formation constant (K(CT)), molar extinction coefficient (ɛ(CT)), standard free energy (ΔG°), oscillator strength (f), transition dipole moment (μ), resonance energy (R(N)) and ionization potential (I(D)) were estimated. The spectroscopic techniques such as IR, (1)H NMR, mass and UV-vis spectra and elemental analyses (CHN) as well as TG-DTG and DTA investigations were used to characterize the chelating behavior of CIP/iodine charge-transfer complex. The iodine CT interaction was associated with a presence of intermolecular hydrogen bond. The X-ray investigation was carried out to investigate the iodine doping in the synthetic CT complex. Copyright © 2011 Elsevier B.V. All rights reserved.

Phlebotomine Sand Fly Fauna and Leishmania Infection in the Vicinity of the Serra do Cipó National Park, a Natural Brazilian Heritage Site

PubMed Central

Lana, Rosana Silva; Michalsky, Érika Monteiro; Fortes-Dias, Consuelo Latorre; França-Silva, João Carlos; Lara-Silva, Fabiana de Oliveira; Lima, Ana Cristina Vianna Mariano da Rocha; Moreira de Avelar, Daniel; Martins, Juliana Cristina Dias; Dias, Edelberto Santos

2015-01-01

In the New World, the leishmaniases are primarily transmitted to humans through the bites of Leishmania-infected Lutzomyia (Diptera: Psychodidae) phlebotomine sand flies. Any or both of two basic clinical forms of these diseases are endemic to several cities in Brazil—the American cutaneous leishmaniasis (ACL) and the American visceral leishmaniasis (AVL). The present study was conducted in the urban area of a small-sized Brazilian municipality (Jaboticatubas), in which three cases of AVL and nine of ACL have been reported in the last five years. Jaboticatubas is an important tourism hub, as it includes a major part of the Serra do Cipó National Park. Currently, no local data is available on the entomological fauna or circulating Leishmania. During the one-year period of this study, we captured 3,104 phlebotomine sand flies belonging to sixteen Lutzomyia species. In addition to identifying incriminated or suspected vectors of ACL with DNA of the etiological agent of AVL and vice versa, we also detected Leishmania DNA in unexpected Lutzomyia species. The expressive presence of vectors and natural Leishmania infection indicates favorable conditions for the spreading of leishmaniases in the vicinity of the Serra do Cipó National Park. PMID:25793193

Phlebotomine sand fly fauna and leishmania infection in the vicinity of the Serra do Cipó National Park, a natural Brazilian heritage site.

PubMed

Lana, Rosana Silva; Michalsky, Érika Monteiro; Fortes-Dias, Consuelo Latorre; França-Silva, João Carlos; Lara-Silva, Fabiana de Oliveira; Lima, Ana Cristina Vianna Mariano da Rocha; Moreira de Avelar, Daniel; Martins, Juliana Cristina Dias; Dias, Edelberto Santos

2015-01-01

In the New World, the leishmaniases are primarily transmitted to humans through the bites of Leishmania-infected Lutzomyia (Diptera: Psychodidae) phlebotomine sand flies. Any or both of two basic clinical forms of these diseases are endemic to several cities in Brazil--the American cutaneous leishmaniasis (ACL) and the American visceral leishmaniasis (AVL). The present study was conducted in the urban area of a small-sized Brazilian municipality (Jaboticatubas), in which three cases of AVL and nine of ACL have been reported in the last five years. Jaboticatubas is an important tourism hub, as it includes a major part of the Serra do Cipó National Park. Currently, no local data is available on the entomological fauna or circulating Leishmania. During the one-year period of this study, we captured 3,104 phlebotomine sand flies belonging to sixteen Lutzomyia species. In addition to identifying incriminated or suspected vectors of ACL with DNA of the etiological agent of AVL and vice versa, we also detected Leishmania DNA in unexpected Lutzomyia species. The expressive presence of vectors and natural Leishmania infection indicates favorable conditions for the spreading of leishmaniases in the vicinity of the Serra do Cipó National Park.

Bioaerosols from a Food Waste Composting Plant Affect Human Airway Epithelial Cell Remodeling Genes

PubMed Central

Chang, Ming-Wei; Lee, Chung-Ru; Hung, Hsueh-Fen; Teng, Kuo-Sheng; Huang, Hsin; Chuang, Chun-Yu

2013-01-01

The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 102 conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5–10 μm) having higher endotoxin levels than did fine particles (0.5–2.5 μm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1 (p21WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers. PMID:24368426

Adding Only One Priority Rule Allows Extending CIP Rules to Supramolecular Systems.

PubMed

Alkorta, Ibon; Elguero, José; Cintas, Pedro

2015-05-01

There are frequent situations both in supramolecular chemistry and in crystallography that result in stereogenic centers, whose absolute configuration needs to be specified. With this aim we propose the inclusion of one simple additional rule to the Cahn-Ingold-Prelog (CIP) system of priority rules stating that noncovalent interactions have a fictitious number between 0 and 1. © 2015 Wiley Periodicals, Inc.

33 CFR 401.19 - Disposal and discharge systems.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., including overboard discharge pipes. (d) Burning of shipboard garbage is prohibited between CIP 2 & Cardinal and between CIP 15 and CIP 16. (68 Stat. 93-96, 33 U.S.C. 981-990, as amended and secs. 4, 5, 6, 7, 8...

33 CFR 401.19 - Disposal and discharge systems.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., including overboard discharge pipes. (d) Burning of shipboard garbage is prohibited between CIP 2 & Cardinal and between CIP 15 and CIP 16. (68 Stat. 93-96, 33 U.S.C. 981-990, as amended and secs. 4, 5, 6, 7, 8...

33 CFR 401.19 - Disposal and discharge systems.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., including overboard discharge pipes. (d) Burning of shipboard garbage is prohibited between CIP 2 & Cardinal and between CIP 15 and CIP 16. (68 Stat. 93-96, 33 U.S.C. 981-990, as amended and secs. 4, 5, 6, 7, 8...

33 CFR 401.19 - Disposal and discharge systems.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., including overboard discharge pipes. (d) Burning of shipboard garbage is prohibited between CIP 2 & Cardinal and between CIP 15 and CIP 16. (68 Stat. 93-96, 33 U.S.C. 981-990, as amended and secs. 4, 5, 6, 7, 8...

[Diagnostic value of PTH total kit for estimation of bone turnover in children with chronic renal failure].

PubMed

Ziółkowska, Helena; Roszkowska-Blaim, Maria

2006-01-01

The aim of the study was to estimate the usefulness of total PTH and 1-84 molecule (CAP) assay in clinical practice. 118 children with chronic renal failure aged 13.8 +/- 4.5 years were examined: 69 on conservative treatment with creatinine clearance 40.7 +/- 20 ml/min/1.73 m2, 31 on peritoneal dialysis and 16 on hemodialysis. In all patients the following parameters were assessed: serum levels of calcium (sCa), phosphorus (sP), PTH intact (PTHs) by chemiluminescence method (Immulite analyzer), total PTH (PTHc) and CAP with Duo PTH Assay (Scantibodies Laboratories, USA). The value of CIP as the difference between total PTH and CAP was calculated. For the evaluation of bone turnover the serum level of osteocalcin (OC) with IRMA, (OsteoRiact, CIS, F) and activity of serum alkaline phosphatase (AP) were determined. The correlations between parameters were calculated by Pearson's correlation coefficient (r). Significant correlation were found between PTHs and PTHc (r=0.84, p=0.0000), CAP (r=0.79, p=0.0000) and CIP. The increase of PTHs, PTHc, CAP, CIP, sP, OC and percentage of CIP were noticed, when parallel increase of creatinine level was found. The negative correlation between creatinine level and CAP/CIP was observed. The similar correlations between level of PTHs, PTHc, CAP and OC level were observed (r=0.55, 0.49 and 0.50 respectively). The assay of total PTH and CAP fragment is not usefull in clinical practice for estimation of bone turnover in children with chronic renal failure.

A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release.

PubMed

García, Mónica C; Cuggino, Julio C; Rosset, Clarisa I; Páez, Paulina L; Strumia, Miriam C; Manzo, Ruben H; Alovero, Fabiana L; Alvarez Igarzabal, Cecilia I; Jimenez-Kairuz, Alvaro F

2016-12-01

The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of cold isostatic pressing in the formation of the properties of ZrO{sub 2}-base ceramics obtained from ultradisperse powders

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

Akimov, G.Y.; Prokhorov, I.Y.; Gorelik, I.V.

1995-09-01

The physicomechanical properties of ceramics obtained from plasmachemical and sol-gel powders of partially stabilized (3% Y{sub 2}O{sub 3}) zirconia (PSZ) and its compositions with 20% Al{sub 2}O{sub 3} by cold isostatic pressing (CIP) at a pressure of at most 2 GPa and sintering at 1300-1650{degrees}C are investigated. It is established that plasmachemical PSZ exhibits its best properties (K{sub 1c} = 7.8 MPa {center_dot} m{sup 1/2}, a strength of 650 MPa) only after complete disintegration at a CIP of 0.1 GPa and a sintering temperature of 1650{degrees}C, when the material is sintered to a density of 5.5 g/cm{sup 3}. After partialmore » stabilization and CIP at 0.1 GPa the plasmachemical composition of PSZ + 20% Al{sub 2}O{sub 3} is sintered at 1650{degrees}C to a density of 4.7 g/cm{sup 3}, but has K{sub 1c} = 8.5 MPa {center_dot} m{sup 1/2} and a strength of 700 MPa. The deagglomerated sol-gel powder exhibits properties at a level of K{sub 1c} = 12.4 MPa {center_dot} m{sup 1/2} and a strength of 950 MPa at a density above 6.0 g/cm{sup 3} after CIP at 0.3 GPa and sintering at 1450{degrees}C. The latter obviously has the best mechanical properties of all the investigated materials.« less

Biodegradation of ciprofloxacin by white rot fungus Pleurotus ostreatus.

PubMed

Singh, Sushil Kumar; Khajuria, Robinka; Kaur, Loveleen

2017-05-01

Unrestricted and reckless use of antibiotics has resulted in their accumulation in environment. This, in turn, has led to the emergence of multiple drug-resistant microbes. The present study focuses on degradation of ciprofloxacin (CIP) by an edible white rot fungus Pleurotus ostreatus. Effect of CIP was determined on radial growth and biomass of P. ostreatus. Titrimetric and spectrophotometric assays were carried out to assess the degrading potential of P. ostreatus towards CIP. It was found that CIP has a stimulatory effect on growth and enzyme activity of P. ostreatus. Maximum enzyme (glucanase, ligninases, laccase) production was observed at the highest concentration of CIP (500 ppm). Antibiotic degradation of about 68.8, 94.25 and 91.34% was estimated after 14 days of incubation at 500 ppm CIP using Titrimetric, Indigo carmine and Methyl orange assay, respectively. Degradation of CIP was further validated by high performance liquid chromatography (HPLC) and microbiological analysis. HPLC analysis revealed 95.07% degradation while microbiological test also exhibited a decreased antimicrobial activity of degraded products against Escherichia coli, Staphylococcus aureus and Streptococcus pyogenes. To the best of our knowledge, this is the first study wherein P. ostreatus was used for the degradation of ciprofloxacin.

CIP-36, a novel topoisomerase II-targeting agent, induces the apoptosis of multidrug-resistant cancer cells in vitro.

PubMed

Cao, Bo; Chen, Hong; Gao, Ying; Niu, Cong; Zhang, Yuan; Li, Ling

2015-03-01

The need to overcome cancer multidrug resistance (MDR) has fueled considerable interest in the development of novel synthetic antitumor agents with cytotoxicity against cancer cell lines with MDR. In this study, we aimed to investigate CIP-36, a novel podophyllotoxin derivative, for its inhibitory effects on human cancer cells from multiple sources, particularly cells with MDR in vitro. The human leukemia cell line, K562, and the adriamycin-resistant subline, K562/A02, were exposed to CIP-36 or anticancer agents, and various morphological and biochemical properties were assessed by Hoechst 33342 staining under a fluorescence microscope. Subsequently, cytotoxicity, cell growth curves and the cell cycle were analyzed. Finally, the effects of CIP-36 on topoisomerase IIα (Topo IIα) activity were determined. Treatment with CIP-36 significantly inhibited the growth of the K562 and MDR K562/A02 cells. Our data demonstrated that CIP-36 induced apoptosis, inhibited cell cycle progression and inhibited Topo IIα activity. These findings suggest that CIP-36 has the potential to overcome the multidrug resistance of K562/A02 cells by mediating Topo IIα activity.

Do clinical safety charts improve paramedic key performance indicator results? (A clinical improvement programme evaluation).

PubMed

Ebbs, Phillip; Middleton, Paul M; Bonner, Ann; Loudfoot, Allan; Elliott, Peter

2012-07-01

Is the Clinical Safety Chart clinical improvement programme (CIP) effective at improving paramedic key performance indicator (KPI) results within the Ambulance Service of New South Wales? The CIP intervention area was compared with the non-intervention area in order to determine whether there was a statistically significant improvement in KPI results. The CIP was associated with a statistically significant improvement in paramedic KPI results within the intervention area. The strategies used within this CIP are recommended for further consideration.

Formation of core-shell structured complex microparticles during fabrication of magnetorheological elastomers and their magnetorheological behavior

NASA Astrophysics Data System (ADS)

Wang, Yonghong; Zhang, Xinru; Chung, Kyungho; Liu, Chengcen; Choi, Seung-Bok; Choi, Hyoung Jin

2016-11-01

To improve mechanical and magnetorheological properties of magnetorheological elastomers (MREs), a facile method was used to fabricate high-performance MREs which consisted of the core-shell complex microparticles with an organic-inorganic network structure dispersed in an ethylene propylene diene rubber. In this work, the proposed magnetic complex microparticles were in situ formed during MREs fabrication as a result of strong interaction between matrix and CIPs using carbon black as a connecting point. The morphology of both isotropic (i-MREs) and anisotropic MREs (a-MREs) was observed by scanning electron microscope (SEM). The effects of carbonyl iron particle (CIP) volume content on mechanical properties and hysteresis loss of MREs were investigated. The effects of CIP volume content on the shear storage modulus, MR effect and loss tangent were studied using a modified dynamic mechanical analyzer under applied magnetic field strengths. The results showed that the orientation effect became more pronounced with increasing CIPs in the a-MREs, whereas CIPs distributed uniformly in the i-MREs. The tensile strength, tear strength and elongation at break decreased with increasing CIP content up to 40 vol.%, while the hardness increased. It is worth noting that the tensile strength of i-MREs and a-MREs containing 40 vol.% CIPs still had high mechanical properties as a result of good compatibility between complex microparticles and rubber matrix. The MR performance of shear storage modulus and damping properties of MREs increased remarkably with CIP content due to strong dipole-dipole interaction of complex microparticles. Besides, the hysteresis loss increased with increasing CIP content as a result of magnetic field induced interfacial sliding between complex microparticles.

p21{sup WAF1/CIP1} deficiency induces mitochondrial dysfunction in HCT116 colon cancer cells

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

Kim, Ae Jeong; Jee, Hye Jin; Song, Naree

2013-01-11

Highlights: Black-Right-Pointing-Pointer p21{sup -/-} HCT116 cells exhibited an increase in mitochondrial mass. Black-Right-Pointing-Pointer The expression levels of PGC-1{alpha} and AMPK were upregulated in p21{sup -/-} HCT116 cells. Black-Right-Pointing-Pointer The proliferation of p21{sup -/-} HCT116 cells in galactose medium was significantly impaired. Black-Right-Pointing-Pointer p21 may play a role in maintaining proper mitochondrial mass and respiratory function. -- Abstract: p21{sup WAF1/CIP1} is a critical regulator of cell cycle progression. However, the role of p21 in mitochondrial function remains poorly understood. In this study, we examined the effect of p21 deficiency on mitochondrial function in HCT116 human colon cancer cells. We found thatmore » there was a significant increase in the mitochondrial mass of p21{sup -/-} HCT116 cells, as measured by 10-N-nonyl-acridine orange staining, as well as an increase in the mitochondrial DNA content. In contrast, p53{sup -/-} cells had a mitochondrial mass comparable to that of wild-type HCT116 cells. In addition, the expression levels of the mitochondrial biogenesis regulators PGC-1{alpha} and TFAM and AMPK activity were also elevated in p21{sup -/-} cells, indicating that p21 deficiency induces the rate of mitochondrial biogenesis through the AMPK-PGC-1{alpha} axis. However, the increase in mitochondrial biogenesis in p21{sup -/-} cells did not accompany an increase in the cellular steady-state level of ATP. Furthermore, p21{sup -/-} cells exhibited significant proliferation impairment in galactose medium, suggesting that p21 deficiency induces a defect in the mitochondrial respiratory chain in HCT116 cells. Taken together, our results suggest that the loss of p21 results in an aberrant increase in the mitochondrial mass and in mitochondrial dysfunction in HCT116 cells, indicating that p21 is required to maintain proper mitochondrial mass and respiratory function.« less

33 CFR 401.19 - Disposal and discharge systems.

Code of Federal Regulations, 2014 CFR

2014-07-01

... discharge pipes. (d) Burning of shipboard garbage is prohibited between CIP 2 & Cardinal and between CIP 15 and CIP 16. (68 Stat. 93-96, 33 U.S.C. 981-990, as amended and secs. 4, 5, 6, 7, 8, 12 and 13 of sec...

Microwave absorption properties of a wave-absorbing coating employing carbonyl-iron powder and carbon black

NASA Astrophysics Data System (ADS)

Liu, Lidong; Duan, Yuping; Ma, Lixin; Liu, Shunhua; Yu, Zhen

2010-11-01

To prevent serious electromagnetic interference, a single-layer wave-absorbing coating employing complex absorbents composed of carbonyl-iron powder (CIP) and carbon black (CB) with epoxy resin as matrix was prepared. The morphologies of CIP and CB were characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM), respectively. The electromagnetic parameters of CIP and CB were measured in the frequency range of 2-18 GHz by transmission/reflection technology, and the electromagnetic loss mechanisms of the two particles were discussed, respectively. The microwave absorption properties of the coatings were investigated by measuring reflection loss (RL) using arch method. The effects of CIP ratio, CB content and thickness on the microwave absorption properties were discussed, respectively. The results showed that the higher thickness, CIP or CB content could make the absorption band shift towards the lower frequency range. Significantly, the wave-absorbing coating could be applied in different frequency ranges according to actual demand by controlling the content of CIP or CB in composites.

Effects of ischemic preconditioning and iloprost on myocardial ischemia-reperfusion damage in rats.

PubMed

Ay, Yasin; Kara, Ibrahim; Aydin, Cemalettin; Ay, Nuray Kahraman; Teker, Melike Elif; Senol, Serkan; Inan, Bekir; Basel, Halil; Uysal, Omer; Zeybek, Rahmi

2013-01-01

This study investigates the effects of cardiac ischemic preconditioning and iloprost on reperfusion damage in rats with myocardial ischemia/reperfusion. 38 male Wistar Albino rats used in this study were divided into 5 groups. The control group (Group 1) (n=6), ischemia/reperfusion (IR) group (Group 2) (n=8), cardiac ischemic preconditioning (CIP) group (Group 3) (n=8), iloprost (ILO) group (Group 4) (n=8), and cardiac ischemic preconditioning + iloprost (CIP+ILO) group (Group 5) (n=8). Pre-ischemia, 15 minutes post-ischemia, 45 minutes post-reperfusion, mean blood pressure (MBP), and heart rates (HR) were recorded. The rate-pressure product (RPP) was calculated. Post-reperfusion plasma creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin (cTn) vlaues, and infarct size/area at risk (IS/AAR) were calculated from myocardial tissue samples. Arrhythmia and ST segment elevations were evaluated during the ischemia and reperfusion stages. Although the MBP, HR, RPP values, biochemical parameters of CK-MB and LDH levels, IS/AAR rates, ST segment elevation values were found to be similar in CIP and CIP+ILO groups and the IR and ILO groups (p>0.05), CIP-containing group values had a positively meaningful difference (p<0.05) compared with the IR and ILO group. While mild-moderate findings of damage were observed in Group 3 and Group 5, severely findings of damage were releaved in Group 2 and Group 4. The arrhythmia score of the ILO group was meaningfully lower (F: 41.4, p<0.001) than the IR group. We can conclude that the effects of myocardial reperfusion damage can be reduced by cardiac ischemic preconditioning, intravenous iloprost reduced the incidence of ventricular arrhythmia associated with reperfusion, and its use with CIP caused no additional changes.

Cytoplasmic p21(CIP1/WAF1), ERK1/2 activation, and cytoskeletal remodeling are associated with the senescence-like phenotype after airborne particulate matter (PM(10)) exposure in lung cells.

PubMed

Sánchez-Pérez, Yesennia; Chirino, Yolanda I; Osornio-Vargas, Álvaro Román; Herrera, Luis A; Morales-Bárcenas, Rocío; López-Saavedra, Alejandro; González-Ramírez, Imelda; Miranda, Javier; García-Cuellar, Claudia María

2014-02-10

The exposure to particulate matter with a mean aerodynamic diameter ≤10 μm (PM10) from urban zones is considered to be a risk factor in the development of cancer. The aim of this work was to determine if PM10 exposure induces factors related to the acquisition of a neoplastic phenotype, such as cytoskeletal remodeling, changes in the subcellular localization of p21(CIP1/WAF1), an increase in β-galactosidase activity and changes in cell cycle. To test our hypothesis, PM10 from an industrial zone (IZ) and a commercial zone (CZ) were collected, and human adenocarcinoma lung cell cultures (A549) were exposed to a sublethal PM10 concentration (10 μg/cm(2)) for 24 h and 48 h. The results showed that PM10 exposure induced an increase in F-actin stress fibers and caused the cytoplasmic stabilization of p21(CIP1/WAF1) via phosphorylation at Thr(145) and Ser(146) and the phosphorylation of ERK1/2 on Thr(202). Changes in the cell cycle or apoptosis were not observed, but an increase in β-galactosidase activity was detected. The PM10 from CZ caused more dramatic effects in lung cells. We conclude that PM10 exposure induced cytoplasmic p21(CIP1/WAF1) retention, ERK1/2 activation, cytoskeleton remodeling and the acquisition of a senescence-like phenotype in lung cells. These alterations could have mechanistic implications regarding the carcinogenic potential of PM10. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Reversible tetraplegia after percutaneous nephrostolithotomy and septic shock: a case of critical illness polyneuropathy and myopathy with acute onset and complete recovery

PubMed Central

2013-01-01

Background Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are complications causing weakness of respiratory and limb muscles in critically ill patients. As an important differential diagnosis of Guillain-Barré syndrome (GBS), CIP and CIM should be diagnosed with caution, after a complete clinical and laboratory examination. Although not uncommon in ICU, CIP and CIM as severe complications of percutaneous nephrostolithotomy (PNL) have not been documented in literature. Case presentation A 48-year-old Chinese woman was referred to our hospital, complaining of occasional pain in the right lower back for one month. Lithiasis was diagnosed by ultrasonographical and radiological examinations on the urinary system. PNL was indicated and performed. The patient developed CIP and CIM on the fourth day after PNL. Early recognition and treatment of the severe complications contributed to a satisfactory recovery of the patient. Conclusion This case expands our understanding of the complications of PNL and underscores the importance of differentiating CIP/CIM from GBS in case of such patients developing weakness after the treatment. Clinical characteristics and examination results should be carefully evaluated to make the diagnosis of CIP or CIM. Both anti-septic prophylaxis and control of hyperglycemia might be effective for the prevention of CIP or CIM; aggressive treatment on sepsis and multiple organ failure is considered to be the most effective measure to reduce the incidence of CIP/CIM. PMID:23409743

The susceptibility of Staphylococcus aureus CIP 65.8 and Pseudomonas aeruginosa ATCC 9721 cells to the bactericidal action of nanostructured Calopteryx haemorrhoidalis damselfly wing surfaces.

PubMed

Truong, Vi Khanh; Geeganagamage, Nipuni Mahanamanam; Baulin, Vladimir A; Vongsvivut, Jitraporn; Tobin, Mark J; Luque, Pere; Crawford, Russell J; Ivanova, Elena P

2017-06-01

Nanostructured insect wing surfaces have been reported to possess the ability to resist bacterial colonization through the mechanical rupture of bacterial cells coming into contact with the surface. In this work, the susceptibility of physiologically young, mature and old Staphylococcus aureus CIP 65.8 and Pseudomonas aeruginosa ATCC 9721 bacterial cells, to the action of the bactericidal nano-pattern of damselfly Calopteryx haemorrhoidalis wing surfaces, was investigated. The results were obtained using several surface characterization techniques including optical profilometry, scanning electron microscopy, synchrotron-sourced Fourier transform infrared microspectroscopy, water contact angle measurements and antibacterial assays. The data indicated that the attachment propensity of physiologically young S. aureus CIP 65.8 T and mature P. aeruginosa ATCC 9721 bacterial cells was greater than that of the cells at other stages of growth. Both the S. aureus CIP 65.8 T and P. aeruginosa ATCC 9721 cells, grown at the early (1 h) and late stationary phase (24 h), were found to be most susceptible to the action of the wings, with up to 89.7 and 61.3% as well as 97.9 and 97.1% dead cells resulting from contact with the wing surface, respectively.

Robust Synthesis of Ciprofloxacin-Capped Metallic Nanoparticles and Their Urease Inhibitory Assay.

PubMed

Nisar, Muhammad; Khan, Shujaat Ali; Qayum, Mughal; Khan, Ajmal; Farooq, Umar; Jaafar, Hawa Z E; Zia-Ul-Haq, Muhammad; Ali, Rashid

2016-03-25

The fluoroquinolone antibacterial drug ciprofloxacin (cip) has been used to cap metallic (silver and gold) nanoparticles by a robust one pot synthetic method under optimized conditions, using NaBH₄ as a mild reducing agent. Metallic nanoparticles (MNPs) showed constancy against variations in pH, table salt (NaCl) solution, and heat. Capping with metal ions (Ag/Au-cip) has significant implications for the solubility, pharmacokinetics and bioavailability of fluoroquinolone molecules. The metallic nanoparticles were characterized by several techniques such as ultraviolet visible spectroscopy (UV), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) methods. The nanoparticles synthesized using silver and gold were subjected to energy dispersive X-ray tests in order to show their metallic composition. The NH moiety of the piperazine group capped the Ag/Au surfaces, as revealed by spectroscopic studies. The synthesized nanoparticles were also assessed for urease inhibition potential. Fascinatingly, both Ag-cip and Au-cip NPs exhibited significant urease enzyme inhibitory potential, with IC50 = 1.181 ± 0.02 µg/mL and 52.55 ± 2.3 µg/mL, compared to ciprofloxacin (IC50 = 82.95 ± 1.62 µg/mL). MNPs also exhibited significant antibacterial activity against selected bacterial strains.

Ion-pairing dynamics of Li{sup +} and SCN{sup -} in dimethylformamide solution: Chemical exchange two-dimensional infrared spectroscopy

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

Lee, Kyung-Koo; Park, Kwang-Hee; Kwon, Donghyun

2011-02-14

Ultrafast two-dimensional infrared (2DIR) spectroscopy has been proven to be an exceptionally useful method to study chemical exchange processes between different vibrational chromophores under thermal equilibria. Here, we present experimental results on the thermal equilibrium ion pairing dynamics of Li{sup +} and SCN{sup -} ions in N,N-dimethylformamide. Li{sup +} and SCN{sup -} ions can form a contact ion pair (CIP). Varying the relative concentration of Li{sup +} in solution, we could control the equilibrium CIP and free SCN{sup -} concentrations. Since the CN stretch frequency of Li-SCN CIP is blue-shifted by about 16 cm{sup -1} from that of free SCN{supmore » -} ion, the CN stretch IR spectrum is a doublet. The temperature-dependent IR absorption spectra reveal that the CIP formation is an endothermic (0.57 kJ/mol) process and the CIP state has larger entropy by 3.12 J/(K mol) than the free ion states. Since the two ionic configurations are spectrally distinguishable, this salt solution is ideally suited for nonlinear IR spectroscopic investigations to study ion pair association and dissociation dynamics. Using polarization-controlled IR pump-probe methods, we first measured the lifetimes and orientational relaxation times of these two forms of ionic configurations. The vibrational population relaxation times of both the free ion and CIP are about 32 ps. However, the orientational relaxation time of the CIP, which is {approx}47 ps, is significantly longer than that of the free SCN{sup -}, which is {approx}7.7 ps. This clearly indicates that the effective moment of inertia of the CIP is much larger than that of the free SCN{sup -}. Then, using chemical exchange 2DIR spectroscopy and analyzing the diagonal peak and cross-peak amplitude changes with increasing the waiting time, we determined the contact ion pair association and dissociation time constants that are found to be 165 and 190 ps, respectively. The results presented and discussed in this paper are believed to be important, not only because the ion-pairing dynamics is one of the most fundamental physical chemistry problems but also because such molecular ion-ion interactions are of critical importance in understanding Hofmeister effects on protein stability.« less

12 CFR 952.5 - Community Investment Cash Advance Programs.

Code of Federal Regulations, 2010 CFR

2010-01-01

... chapter. (2) Each Bank shall offer a CIP to provide financing for housing projects and for eligible... than CIP, involving a combination of housing projects and economic development projects, only the... respective CICA program. (2) For projects funded under CIP, both the housing and economic development...

12 CFR 952.5 - Community Investment Cash Advance Programs.

Code of Federal Regulations, 2012 CFR

2012-01-01

... chapter. (2) Each Bank shall offer a CIP to provide financing for housing projects and for eligible... than CIP, involving a combination of housing projects and economic development projects, only the... respective CICA program. (2) For projects funded under CIP, both the housing and economic development...

12 CFR 952.5 - Community Investment Cash Advance Programs.

Code of Federal Regulations, 2011 CFR

2011-01-01

... chapter. (2) Each Bank shall offer a CIP to provide financing for housing projects and for eligible... than CIP, involving a combination of housing projects and economic development projects, only the... respective CICA program. (2) For projects funded under CIP, both the housing and economic development...

12 CFR 952.5 - Community Investment Cash Advance Programs.

Code of Federal Regulations, 2013 CFR

2013-01-01

... chapter. (2) Each Bank shall offer a CIP to provide financing for housing projects and for eligible... than CIP, involving a combination of housing projects and economic development projects, only the... respective CICA program. (2) For projects funded under CIP, both the housing and economic development...

DNA damage-inducible genes as biomarkers for exposures to environmental agents

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

Johnson, N.F.; Carpenter, T.R.; Jaramillo, R.J.

1997-06-01

A biodosimetric approach to determine alpha-particle dose to the respiratory tract epithelium from known exposures to radon has been developed in the rat. Cytotoxicity assays have been used to obtain dose-conversion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive enough to derive close-conversion factors for indoor radon exposures. The expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 cells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip 1,more » and Gadd45. These protein changes were associated with a transient arrest of cells passing through the cell cycle. This arrest was typified by an increase in the number of cells in the G{sub 1} and G{sub 2} phases and a decrease in the number of cells in the S phase. The effect of inhaled alpha particles (radon progeny) in rats was examined in the epithelial cells of the lateral wall of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G{sub 1} phase and a decrease in the number of cells in the S phase. These cell-cycle changes were concomitant with an increase in the number of cells containing DNA strand breaks. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbestos, and glass microfiber. These studies showed that physical and chemical agents induce different expression patterns of p53, Cip 1, and Gadd153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measurement of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical toxicants encountered in the environment. 9 figs., 42 refs.« less

Congenital Insensitivity to Pain: Novel SCN9A Missense and In-Frame Deletion Mutations

PubMed Central

Cox, James J; Sheynin, Jony; Shorer, Zamir; Reimann, Frank; Nicholas, Adeline K; Zubovic, Lorena; Baralle, Marco; Wraige, Elizabeth; Manor, Esther; Levy, Jacov; Woods, C Geoffery; Parvari, Ruti

2010-01-01

SCN9A encodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc. PMID:20635406

Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations.

PubMed

Cox, James J; Sheynin, Jony; Shorer, Zamir; Reimann, Frank; Nicholas, Adeline K; Zubovic, Lorena; Baralle, Marco; Wraige, Elizabeth; Manor, Esther; Levy, Jacov; Woods, C Geoffery; Parvari, Ruti

2010-09-01

SCN9Aencodes the voltage-gated sodium channel Na(v)1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Na(v)1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Na(v)1.7-DeltaR1370-L1374). Both of these mutations map to the pore region of the Na(v)1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Na(v)1.7. Copyright 2010 Wiley-Liss, Inc.

p21{sup WAF1/Cip1/Sdi1} knockout mice respond to doxorubicin with reduced cardiotoxicity

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

Terrand, Jerome; Xu, Beibei; Morrissy, Steve

2011-11-15

Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21{sup WAF1/Cip1/Sdi1} (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significantmore » changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFN{gamma} and TNF{alpha} in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice. -- Highlights: Black-Right-Pointing-Pointer Doxorubicin induces p21 elevation in the myocardium. Black-Right-Pointing-Pointer Doxorubicin causes dilated cardiomyopathy in wild type mice. Black-Right-Pointing-Pointer p21 Knockout mice are resistant against doxorubicin induced cardiomyopathy. Black-Right-Pointing-Pointer Lack of inflammatory response correlates with the resistance in p21 knockout mice.« less

76 FR 13976 - Notice of Request for Revision of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-15

.... SUPPLEMENTARY INFORMATION: Title: Form RD 1951-65, Customer Initiated Payments (CIP) Enrollment Form; Form RD... Initiated Payments [CIP], FedWire, and Preauthorized Debits [PAD]) for receiving and processing loan... approved forms for collecting bank routing information for CIP, FedWire, and PAD. Estimate of Burden...

Guidelines for Cataloguing-in-Publication.

ERIC Educational Resources Information Center

Anderson, Dorothy, Comp.

The guidelines provide the criteria for the design of a national cataloguing-in-publication (CIP) program which will both be a component part of the international CIP network and fit the requirements of a specific library and publishing environment. Cataloguing-in-publication is defined, its development is traced, and current CIP programs in nine…

Alliances in Human Biology: The Harvard Committee on Industrial Physiology, 1929-1939.

PubMed

Oakes, Jason

2015-08-01

In 1929 the newly-reorganized Rockefeller Foundation funded the work of a cross-disciplinary group at Harvard University called the Committee on Industrial Physiology (CIP). The committee's research and pedagogical work was oriented towards different things for different members of the alliance. The CIP program included a research component in the Harvard Fatigue Laboratory and Elton May's interpretation of the Hawthorne Studies; a pedagogical aspect as part of Wallace Donham's curriculum for Harvard Business School; and Lawrence Henderson's work with the Harvard Pareto Circle, his course Sociology 23, and the Harvard Society of Fellows. The key actors within the CIP alliance shared a concern with training men for elite careers in government service, business leadership, and academic prominence. But the first communications between the CIP and the Rockefeller Foundation did not emphasize training in human biology. Instead, the CIP presented itself as a coordinating body that would be able to organize all the varied work going on at Harvard that did not fit easily into one department, and it was on this basis that the CIP became legible to the President of Harvard, A. Lawrence Lowell, and to Rockefeller's Division of Social Sciences. The members of the CIP alliance used the term human biology for this project of research, training and institutional coordination.

Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK

PubMed Central

Wang, Jieqiong; Hu, Kewen; Guo, Jiawei; Cheng, Feixiong; Lv, Jing; Jiang, Wenhao; Lu, Weiqiang; Liu, Jinsong; Pang, Xiufeng; Liu, Mingyao

2016-01-01

No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21WAF1/CIP1, leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21WAF1/CIP1, either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21WAF1/CIP1. Co-administration of BI-2536 and fasudil either in the LSL-KRASG12D mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers. PMID:27193833

p21WAF1/CIP1 Upregulation through the Stress Granule-Associated Protein CUGBP1 Confers Resistance to Bortezomib-Mediated Apoptosis

PubMed Central

Gareau, Cristina; Fournier, Marie-Josée; Filion, Christine; Coudert, Laetitia; Martel, David; Labelle, Yves; Mazroui, Rachid

2011-01-01

Background p21WAF1/CIP1 is a well known cyclin-dependent kinase inhibitor induced by various stress stimuli. Depending on the stress applied, p21 upregulation can either promote apoptosis or prevent against apoptotic injury. The stress-mediated induction of p21 involves not only its transcriptional activation but also its posttranscriptional regulation, mainly through stabilization of p21 mRNA levels. We have previously reported that the proteasome inhibitor MG132 induces the stabilization of p21 mRNA, which correlates with the formation of cytoplasmic RNA stress granules. The mechanism underlying p21 mRNA stabilization, however, remains unknown. Methodology/Principal Findings We identified the stress granules component CUGBP1 as a factor required for p21 mRNA stabilization following treatment with bortezomib ( =  PS-341/Velcade). This peptide boronate inhibitor of the 26S proteasome is very efficient for the treatment of myelomas and other hematological tumors. However, solid tumors are sometimes refractory to bortezomib treatment. We found that depleting CUGBP1 in cancer cells prevents bortezomib-mediated p21 upregulation. FISH experiments combined to mRNA stability assays show that this effect is largely due to a mistargeting of p21 mRNA in stress granules leading to its degradation. Altering the expression of p21 itself, either by depleting CUGBP1 or p21, promotes bortezomib-mediated apoptosis. Conclusions/Significance We propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1. PMID:21637851

Making limb and nadir measurements comparable: A common volume study of PMC brightness observed by Odin OSIRIS and AIM CIPS

NASA Astrophysics Data System (ADS)

Benze, Susanne; Gumbel, Jörg; Randall, Cora E.; Karlsson, Bodil; Hultgren, Kristoffer; Lumpe, Jerry D.; Baumgarten, Gerd

2018-01-01

Combining limb and nadir satellite observations of Polar Mesospheric Clouds (PMCs) has long been recognized as problematic due to differences in observation geometry, scattering conditions, and retrieval approaches. This study offers a method of comparing PMC brightness observations from the nadir-viewing Aeronomy of Ice in the Mesosphere (AIM) Cloud Imaging and Particle Size (CIPS) instrument and the limb-viewing Odin Optical Spectrograph and InfraRed Imaging System (OSIRIS). OSIRIS and CIPS measurements are made comparable by defining a common volume for overlapping OSIRIS and CIPS observations for two northern hemisphere (NH) PMC seasons: NH08 and NH09. We define a scattering intensity quantity that is suitable for either nadir or limb observations and for different scattering conditions. A known CIPS bias is applied, differences in instrument sensitivity are analyzed and taken into account, and effects of cloud inhomogeneity and common volume definition on the comparison are discussed. Not accounting for instrument sensitivity differences or inhomogeneities in the PMC field, the mean relative difference in cloud brightness (CIPS - OSIRIS) is -102 ± 55%. The differences are largest for coincidences with very inhomogeneous clouds that are dominated by pixels that CIPS reports as non-cloud points. Removing these coincidences, the mean relative difference in cloud brightness reduces to -6 ± 14%. The correlation coefficient between the CIPS and OSIRIS measurements of PMC brightness variations in space and time is remarkably high, at 0.94. Overall, the comparison shows excellent agreement despite different retrieval approaches and observation geometries.

Whole-Genome Sequence of Corynebacterium auriscanis Strain CIP 106629 Isolated from a Dog with Bilateral Otitis from the United Kingdom.

PubMed

Tiwari, Sandeep; Jamal, Syed Babar; Oliveira, Leticia Castro; Clermont, Dominique; Bizet, Chantal; Mariano, Diego; de Carvalho, Paulo Vinicius Sanches Daltro; Souza, Flavia; Pereira, Felipe Luiz; de Castro Soares, Siomar; Guimarães, Luis C; Dorella, Fernanda; Carvalho, Alex; Leal, Carlos; Barh, Debmalya; Figueiredo, Henrique; Hassan, Syed Shah; Azevedo, Vasco; Silva, Artur

2016-08-11

In this work, we describe a set of features of Corynebacterium auriscanis CIP 106629 and details of the draft genome sequence and annotation. The genome comprises a 2.5-Mbp-long single circular genome with 1,797 protein-coding genes, 5 rRNA, 50 tRNA, and 403 pseudogenes, with a G+C content of 58.50%. Copyright © 2016 Tiwari et al.

L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.

PubMed

Huang, Hongbiao; Liu, Ningning; Guo, Haiping; Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q Ping; Liu, Jinbao

2012-01-01

L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21(cip1) gene, mRNA and protein in cancer cells but not p27(kip1); (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21(cip1) gene but not p27(kip1) detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.

L-Carnitine Is an Endogenous HDAC Inhibitor Selectively Inhibiting Cancer Cell Growth In Vivo and In Vitro

PubMed Central

Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

2012-01-01

L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21cip1 gene, mRNA and protein in cancer cells but not p27kip1; (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21cip1 gene but not p27kip1 detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance. PMID:23139833

Comprehensive mutation analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 genes is suggestive of a non- neoplastic nature of phenytoin induced gingival overgrowth.

PubMed

Swamikannu, Bhuminathan; Kumar, Kishore S; Jayesh, Raghavendra S; Rajendran, Senthilnathan; Muthupalani, Rajendran Shanmugam; Ramanathan, Arvind

2013-01-01

Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1, are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons 1α, 1β and 2 of p16INK4a and p14ARF, and exon 2 of p21Waf1/Cip1, in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1. The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1 that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non-neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes.

Protein-protein interaction specificity is captured by contact preferences and interface composition.

PubMed

Nadalin, Francesca; Carbone, Alessandra

2018-02-01

Large-scale computational docking will be increasingly used in future years to discriminate protein-protein interactions at the residue resolution. Complete cross-docking experiments make in silico reconstruction of protein-protein interaction networks a feasible goal. They ask for efficient and accurate screening of the millions structural conformations issued by the calculations. We propose CIPS (Combined Interface Propensity for decoy Scoring), a new pair potential combining interface composition with residue-residue contact preference. CIPS outperforms several other methods on screening docking solutions obtained either with all-atom or with coarse-grain rigid docking. Further testing on 28 CAPRI targets corroborates CIPS predictive power over existing methods. By combining CIPS with atomic potentials, discrimination of correct conformations in all-atom structures reaches optimal accuracy. The drastic reduction of candidate solutions produced by thousands of proteins docked against each other makes large-scale docking accessible to analysis. CIPS source code is freely available at http://www.lcqb.upmc.fr/CIPS. alessandra.carbone@lip6.fr. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Distributed Wind Competitiveness Improvement Project

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

The Competitiveness Improvement Project (CIP) is a periodic solicitation through the U.S. Department of Energy and its National Renewable Energy Laboratory. The Competitiveness Improvement Project (CIP) is a periodic solicitation through the U.S. Department of Energy and its National Renewable Energy Laboratory. Manufacturers of small and medium wind turbines are awarded cost-shared grants via a competitive process to optimize their designs, develop advanced manufacturing processes, and perform turbine testing. The goals of the CIP are to make wind energy cost competitive with other distributed generation technology and increase the number of wind turbine designs certified to national testing standards. Thismore » fact sheet describes the CIP and funding awarded as part of the project.ufacturers of small and medium wind turbines are awarded cost-shared grants via a competitive process to optimize their designs, develop advanced manufacturing processes, and perform turbine testing. The goals of the CIP are to make wind energy cost competitive with other distributed generation technology and increase the number of wind turbine designs certified to national testing standards. This fact sheet describes the CIP and funding awarded as part of the project.« less

CIP (cleaning-in-place) stability of AlGaN/GaN pH sensors.

PubMed

Linkohr, St; Pletschen, W; Schwarz, S U; Anzt, J; Cimalla, V; Ambacher, O

2013-02-20

The CIP stability of pH sensitive ion-sensitive field-effect transistors based on AlGaN/GaN heterostructures was investigated. For epitaxial AlGaN/GaN films with high structural quality, CIP tests did not degrade the sensor surface and pH sensitivities of 55-58 mV/pH were achieved. Several different passivation schemes based on SiO(x), SiN(x), AlN, and nanocrystalline diamond were compared with special attention given to compatibility to standard microelectronic device technologies as well as biocompatibility of the passivation films. The CIP stability was evaluated with a main focus on the morphological stability. All stacks containing a SiO₂ or an AlN layer were etched by the NaOH solution in the CIP process. Reliable passivations withstanding the NaOH solution were provided by stacks of ICP-CVD grown and sputtered SiN(x) as well as diamond reinforced passivations. Drift levels about 0.001 pH/h and stable sensitivity over several CIP cycles were achieved for optimized sensor structures. Copyright © 2012 Elsevier B.V. All rights reserved.

The impact of p53 on the early stage replication of retrovirus.

PubMed

Kinnetz, Michaela; Alghamdi, Faris; Racz, Michael; Hu, Wenwei; Shi, Binshan

2017-08-09

The function of p53 in cancer biology has been studied extensively, but its role in anti-retrovirus infection has been elusive for many years. The restriction of retrovirus early stage replication by p53 was investigated in this study. VSV-G pseudotyped retrovirus with GFP reporter gene was used to infect both HCT116 p53 +/+ cells and its isogenic p53 knockout HCT116 p53 -/- cells. The infection was detected by flow cytometry. Reverse transcription products were quantified by real time PCR. Mutation analysis was performed after 1-LTR cycle and 2-LTR cycle DNA were amplified and PCR products were sequenced. Transcription and translation of cyclin-dependent kinase inhibitor 1 (p21 Cip1 ) and SAM domain and HD domain-containing protein 1 (SAMHD1) were analyzed by TaqMan PCR and Western blot experiments. siRNA experiment was applied to study the role of p53 downstream gene p21 Cip1 in the restriction of retrovirus infection. It was found that the block of retrovirus infection in non-cycling cells was significantly attenuated in HCT116 p53 -/- cells when compared to HCT116 p53 +/+ cells. It was found that both late reverse transcription products and viral 2-LTR cycle DNA were significantly increased in infected non-cycling HCT116 p53 -/- cells. Furthermore, the mutation frequency detected in 1-LTR DNA from HCT116 p53 +/+ cells were significantly decreased in comparison to HCT116 p53 -/- cells. A higher number of insertion and deletion mutations were detected in the joint region of 2-LTR cycle DNA in infected p53 +/+ cells. Cell cycle analysis showed retrovirus infection promoted host cell replication. Higher levels of mRNA and protein of p21 Cip1 were found in HCT116 p53 +/+ cells in comparison to the HCT116 p53 -/- cells. Furthermore, knockdown of p21 Cip1 in non-cycling HCT116 p53 +/+ cells significantly increased the infection. The results of this study showed that p53 is an important restriction factor that interferes with retrovirus infection in its early stage of replication. Our results suggested that p53 mediates the inhibition of retrovirus infection in non-cycling cells through it downstream gene p21 Cip1 , and p53 also functions to influence formation of 1-LTR cycle and 2-LTR cycle DNA.

Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections.

PubMed

Walters, D J; Solomkin, J S; Paladino, J A

1999-11-01

To compare the cost effectiveness of sequential intravenous (i.v.) to oral ciprofloxacin plus metronidazole (CIP/MTZ i.v./PO) with that of i.v. ciprofloxacin plus i.v. metronidazole (CIP/MTZ i.v.) and i.v. imipenem-cilastatin (IMI i.v.) in patients with intra-abdominal infections. Patients enrolled in a double-blind randomised clinical trial were eligible for inclusion into this cost-effectiveness analysis. Decision analysis was used to characterise the economic outcomes between groups and provide a structure upon which to base the sensitivity analyses. 1996 cost values were used throughout. The economic perspective of the analysis was that of a hospital provider. Among 446 economically evaluable patients, 176 could be switched from i.v. to oral administration. The 51 patients randomised to CIP/MTZ i.v./PO who received active oral therapy had a success rate of 98%, mean duration of therapy of 9.1 days and mean cost of $US7678. There were 125 patients randomized to either CIP/MTZ i.v. or IMI i.v. who received oral placebo while continuing on active i.v. antibacterials; their success rate was 94%, mean duration of therapy was 10.1 days and mean cost was $US8774 (p = 0.029 vs CIP/MTZ i.v./PO). Of the 270 patients who were unable to receive oral administration, 97 received IMI i.v. and had a success rate of 75%, mean duration of therapy of 13.8 days and a mean cost of $US12,418, and 173 received CIP/MTZ i.v. and had a success rate of 77%, mean duration of therapy of 13.4 days and mean cost of $US12,219 (p = 0.26 vs IMI i.v.). In patients able to receive oral therapy, sequential i.v. to oral treatment with ciprofloxacin plus metronidazole was cost effective compared with full i.v. courses of ciprofloxacin plus metronidazole or imipenem-cilastatin. In patients unable to receive oral therapy, no difference in mean cost was found between i.v. imipenem-cilastatin or i.v. ciprofloxacin plus i.v. metronidazole.

Spin-pumping and spin-Hall magnetoresistance (SMR) at transition metal interfaces: case of (Co/Pt) (Conference Presentation)

NASA Astrophysics Data System (ADS)

Jaffres, Henri; George, Jean-Marie; Laczowski, Piotr; Reyren, Nicolas; Vila, Laurent

2016-10-01

Spintronic phenomena are made possible via the diffusion of spin-currents or the generation of spin-accumulation. Spinorbitronics uses the electronic spin-orbit coupling (SOC) and emerges as a new route to create spin-currents in the transverse direction of the charge flow. This is made possible via the intrinsic spin Hall conduction (SHE) of heavy metals or extrinsic spin-Hall effect of metallic alloys. SHE borrows its concept from the anomalous Hall effect (AHE) where the relativistic spin-orbit coupling (SOC) promotes an asymmetric deflection of the spin-current. SHE is now at the base of magnetization commutation and domain wall moving via spin-orbit torque (SOT) and spin-transfer torque operations in the FMR regime. However, the exact anatomy of SOT at spin-orbit active interfaces like Co/Pt is still missing. In the case of Pt, recent studies have put forward the major role played by i) the spin-memory loss (SML) and the electronic transparency at 3d/5d interfaces and ii) the inhomogeneity of the conductivity in the current-in-plane (CIP) geometry to explain the discrepancy in the SHE. Ingredients to consider then are the profiles of both the conductivity and spin-current across the multilayers and spin-transmission. In this talk, we will present robust SMR measurements observed on NiCo/Pt multilayer stacks characterized by a perpendicular magnetic anisotropy (PMA). The SMR occurs for both in-plane magnetization rotation or from nominal out-of-plane to the in-plane direction transverse to the current flow. This clearly departs from standard AMR or pure interfacial anisotropic-AMR symmetries. We analyze in large details our SMR signals for the whole series of samples owing to two main guidelines: i) we consider the exact conductivity profile across the multilayers, in particular near the Co/Pt interface, via the Camley-Barnas approach and ii) we derive the spin current profile generated by SHE along the perpendicular direction responsible for SMR. We consider pure interfacial spin dissipation by SML (decoherence, interfacial enhanced scattering) and give out a general analytical expression for SMR. Our conclusions go towards a robust value of the spin-Hall conductivity and SML like previously published. The CIP spin-Hall angle, of the order of 0.10 is larger than the one found in spin-pumping experiments (CPP geometry) owing to the smaller conductivity at the Co/Pt interface, in agreement with the results of STT-FMR experiments.

Run Clever – No difference in risk of injury when comparing progression in running volume and running intensity in recreational runners: A randomised trial

PubMed Central

Rasmussen, Sten; Sørensen, Henrik; Parner, Erik Thorlund; Lind, Martin; Nielsen, Rasmus Oestergaard

2018-01-01

Background/aim The Run Clever trial investigated if there was a difference in injury occurrence across two running schedules, focusing on progression in volume of running intensity (Sch-I) or in total running volume (Sch-V). It was hypothesised that 15% more runners with a focus on progression in volume of running intensity would sustain an injury compared with runners with a focus on progression in total running volume. Methods Healthy recreational runners were included and randomly allocated to Sch-I or Sch-V. In the first eight weeks of the 24-week follow-up, all participants (n=839) followed the same running schedule (preconditioning). Participants (n=447) not censored during the first eight weeks entered the 16-week training period with a focus on either progression in intensity (Sch-I) or volume (Sch-V). A global positioning system collected all data on running. During running, all participants received real-time, individualised feedback on running intensity and running volume. The primary outcome was running-related injury (RRI). Results After preconditioning a total of 80 runners sustained an RRI (Sch-I n=36/Sch-V n=44). The cumulative incidence proportion (CIP) in Sch-V (reference group) were CIP2 weeks 4.6%; CIP4 weeks 8.2%; CIP8 weeks 13.2%; CIP16 weeks 28.0%. The risk differences (RD) and 95% CI between the two schedules were RD2 weeks=2.9%(−5.7% to 11.6%); RD4 weeks=1.8%(−9.1% to 12.8%); RD8 weeks=−4.7%(−17.5% to 8.1%); RD16 weeks=−14.0% (−36.9% to 8.9%). Conclusion A similar proportion of runners sustained injuries in the two running schedules. PMID:29527322

Derivative Quotient Spectrophotometry and an Eco-Friendly Micellar Chromatographic Approach with Time-Programmed UV-Detection for the Separation of Two Fluoroquinolones and Phenazopyridine

PubMed Central

Tolba, Manar M.; Salim, Mohamed M.

2016-01-01

In this study, two analytical approaches were exploited for the resolution of binary mixtures of ciprofloxacin HCl (CIP) or norfloxacin (NOR) and phenazopyridine HCl (PHZ). In the first approach, the amplitudes of the first derivative of the ratio spectra were measured at 267 or 287 nm for CIP and at 268 or 291 nm for NOR. PHZ could be directly determined in the presence of CIP or NOR at 405 nm. The calibration graphs were rectilinear over the ranges of 1.0–16.0 µg/mL for CIP or NOR and 1.0–10.0 µg/mL for PHZ. In the second approach, an accurate, reliable and environmentally nontoxic micellar liquid chromatographic (MLC) method was developed. A good chromatographic separation was achieved using a 150 mm × 4.6 mm i.d., 5 µm particle size Spherisorb ODS-2 column. Eco-friendly mobile phase containing 0.12 M sodium dodecyl sulphate, 0.3% triethylamine and 6% n-butanol in 0.02 M orthophosphoric acid of pH 3.0 was pumped at a flow rate of 1 mL/min. Time programmed UV-detection was applied to allow sensitive determination of the studied drugs. The analytes were eluted without interferences in <10 min. Methocarbamol was used as an internal standard. The MLC method was found to be rectilinear over the concentration range of 0.5–20.0 μg/mL for CIP, NOR or PHZ. These optimized and validated methods were successfully applied for the simultaneous analysis of the studied drugs in their synthetic mixtures and co-formulated tablets. Moreover, the second method was further extended to the determination of these drugs in human urine with direct injection and without any pretreatment. PMID:26867555

Optimization of the electrochemical degradation process of the antibiotic ciprofloxacin using a double-sided β-PbO2 anode in a flow reactor: kinetics, identification of oxidation intermediates and toxicity evaluation.

PubMed

Wachter, Naihara; Aquino, José M; Denadai, Marina; Barreiro, Juliana C; Silva, Adilson J; Cass, Quezia B; Rocha-Filho, Romeu C; Bocchi, Nerilso

2018-06-06

The electrochemical degradation of ciprofloxacin-CIP (50 mg L -1 in 0.10 mol L -1 Na 2 SO 4 ) was investigated using a double-sided Ti-Pt/β-PbO 2 anode in a filter-press flow reactor, with identification of oxidation intermediates and follow-up of antimicrobial activity against Escherichia coli. The effect of solution pH, flow rate, current density, and temperature on the CIP removal rate was evaluated. All of these parameters did affect the CIP removal performance; thus, optimized electrolysis conditions were further explored: pH = 10, q V  = 6.5 L min -1 , j = 30 mA cm -2 , and θ = 25 °C. Therefore, CIP was removed within 2 h, whereas ~75% of the total organic carbon concentration (TOC) was removed after 5 h and then, the solution no longer presented antimicrobial activity. When the electrochemical degradation of CIP was investigated using a single-sided boron-doped diamond (BDD) anode, its performance in TOC removal was similar to that of the Ti-Pt/β-PbO 2 anode; considering the higher oxidation power of BDD, the surprisingly good comparative performance of the Ti-Pt/β-PbO 2 anode was ascribed to significantly better hydrodynamic conditions attained in the filter-press reactor used with this electrode. Five initial oxidation intermediates were identified by LC-MS/MS and completely removed after 4 h of electrolysis; since they have also been determined in other degradation processes, there must be similarities in the involved oxidation mechanisms. Five terminal oxidation intermediates (acetic, formic, oxamic, propionic, and succinic acids) were identified by LC-UV and all of them (except acetic acid) were removed after 10 h of electrolysis.

Baryons still trace dark matter: Probing CMB lensing maps for hidden isocurvature

NASA Astrophysics Data System (ADS)

Smith, Tristan L.; Muñoz, Julian B.; Smith, Rhiannon; Yee, Kyle; Grin, Daniel

2017-10-01

Compensated isocurvature perturbations (CIPs) are primordial fluctuations that balance baryon and dark-matter isocurvature to leave the total matter density unperturbed. The effects of CIPs on the cosmic microwave background (CMB) anisotropies are similar to those produced by weak lensing of the CMB: smoothing of the power spectrum and generation of non-Gaussian features. Here, an entirely new CIP contribution to the standard estimator for the lensing-potential power spectrum is derived. Planck measurements of the temperature and polarization power spectrum, as well as estimates of CMB lensing, are used to place limits on the variance of the CIP fluctuations on CMB scales, Δrms2(RCMB). The resulting constraint of Δrms2(RCMB)<4.3 ×10-3 at 95% confidence level (CL) using this new technique improves on past work by a factor of ˜3 . We find that for Planck data our constraints almost reach the sensitivity of the optimal CIP estimator. The method presented here is currently the most sensitive probe of the amplitude of a scale-invariant CIP power spectrum, ACIP, placing an upper limit of ACIP<0.017 at 95% CL. Future measurements of the large-scale CMB lensing-potential power spectrum could probe CIP amplitudes as low as Δrms2(RCMB)=8 ×10-5 at 95% CL (corresponding to ACIP=3.2 ×10-4).

FY 2011 Educational Facilities Master Plan & the FY 2011-2016 Capital Improvements Program

ERIC Educational Resources Information Center

Montgomery County Public Schools, 2010

2010-01-01

The FY 2011 Educational Facilities Master Plan (Master Plan) and FY 2011-2016 Capital Improvements Program (CIP) reflect the adopted actions of the Montgomery County (Maryland) Council and integrate the facilities planning process with the annual capital budget and the six-year CIP. The CIP is developed in accordance with the Board of Education…

76 FR 7810 - Certain Hot-Rolled Carbon Steel Flat Products From India: Notice of Court Decision Not in Harmony...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-11

... Policy (``CIP''). See Final Results, and accompanying I&D Memorandum at ``SGOC's Industrial Policy...'' or ``fourth administrative review''), which found that Essar did not benefit from the CIP, cast ``grave doubt'' upon the Department's findings that Essar benefited from the CIP during the fifth POR. See...

Approach to critical illness polyneuropathy and myopathy.

PubMed

Pati, S; Goodfellow, J A; Iyadurai, S; Hilton-Jones, D

2008-07-01

A newly acquired neuromuscular cause of weakness has been found in 25-85% of critically ill patients. Three distinct entities have been identified: (1) critical illness polyneuropathy (CIP); (2) acute myopathy of intensive care (itself with three subtypes); and (3) a syndrome with features of both 1 and 2 (called critical illness myopathy and/or neuropathy or CRIMYNE). CIP is primarily a distal axonopathy involving both sensory and motor nerves. Electroneurography and electromyography (ENG-EMG) is the gold standard for diagnosis. CIM is a proximal as well as distal muscle weakness affecting both types of muscle fibres. It is associated with high use of non-depolarising muscle blockers and corticosteroids. Avoidance of systemic inflammatory response syndrome (SIRS) is the most effective way to reduce the likelihood of developing CIP or CIM. Outcome is variable and depends largely on the underlying illness. Detailed history, careful physical examination, review of medication chart and analysis of initial investigations provides invaluable clues towards the diagnosis.

Prevalence of quinolone resistance genes, copper resistance genes, and the bacterial communities in a soil-ryegrass system co-polluted with copper and ciprofloxacin.

PubMed

Tuo, Xiaxia; Gu, Jie; Wang, Xiaojuan; Sun, YiXin; Duan, Manli; Sun, Wei; Yin, Yanan; Guo, Aiyun; Zhang, Li

2018-04-01

The presence of high concentrations of residual antibiotics and antibiotic resistance genes (ARGs) in soil may pose potential health and environmental risks. This study investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) genes, copper resistance genes (CRGs), and the bacterial communities in a soil-ryegrass pot system co-polluted with copper and ciprofloxacin (CIP; 0, 20, or 80 mg kg -1 dry soil). Compared with the samples on day 0, the total relative abundances of the PMQR genes and mobile genetic elements (MGEs) were reduced significantly by 80-89% in the ryegrass and soil by the cutting stage (after 75 days). The abundances of PMQR genes and MGEs were reduced by 63-81% in soil treated with 20 mg kg -1 CIP compared with the other treatments, but the abundances of CRGs increased by 18-42%. The presence of 80 mg kg -1 CIP affected the microbial community structure in the soil by increasing the abundances of Acidobacteria and Thaumarchaeota, but decreasing those of Firmicutes. Redundancy analysis indicated that the pH and microbial composition were the main factors that affected the variations in PMQR genes, MGEs, and CRGs, where they could explain 42.2% and 33.3% of the variation, respectively. Furthermore, intI2 may play an important role in the transfer of ARGs. We found that 80 mg kg -1 CIP could increase the abundances of ARGs and CRGs in a soil-ryegrass pot system. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Potato Cryobank at The International Potato Center (Cip): A Model for Long Term Conservation of Clonal Plant Genetic Resources Collections of the Future.

PubMed

Vollmer, R; Villagaray, R; Egusquiza, V; Espirilla, J; García, M; Torres, A; Rojas, E; Panta, A; Barkley, N A; Ellis, D

Cryobanks are a secure, efficient and low cost method for the long-term conservation of plant genetic resources for theoretically centuries or millennia with minimal maintenance. The present manuscript describes CIP's modified protocol for potato cryopreservation, its large-scale application, and the establishment of quality and operational standards, which included a viability reassessment of material entering the cryobank. In 2013, CIP established stricter quality and operational standards under which 1,028 potato accessions were cryopreserved with an improved PVS2-droplet protocol. In 2014 the viability of 114 accessions cryopreserved in 2013 accessions were reassessed. The average recovery rate (full plant recovery after LN exposure) of 1028 cryopreserved Solanum species ranged from 34 to 59%, and 70% of the processed accessions showed a minimum recovery rate of ≥20% and were considered as successfully cryopreserved. CIP has established a new high quality management system for cryobanking. Periodic viability reassessment, strict and clear recovery criteria and the monitoring of the percent of successful accessions meeting the criteria as well as contamination rates are metrics that need to be considered in cryobanks.

MOOSE Implementation of MAMBA

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

Galloway, Jack; Matthews, Topher

The development of MAMBA is targeted at capturing both core wide CRUD induced power shifts (CIPS) as well as pin-­level CRUD induced localized corrosion (CILC). Both CIPS and CILC require some sort of information from thermal-­hydraulic, neutronics, and fuel performance codes, although the degree of coupling is different for the two effects. Since CIPS necessarily requires a core-­wide power distribution solve, it requires tight coupling with a neutronics code. Conversely, CIPS tends to be an individual pin phenomenon, requiring tight coupling a fuel performance code. As efforts are now focused on coupling MAMBA within the VERA suite, a natural separationmore » has surfaced in which a FORTRAN rewrite of MAMBA is optimal for VERA integration to capture CIPS behavior, while a CILC focused calculation would benefit from a tight coupling with BISON, motivating a MOOSE version of MAMBA.« less

Epidermal growth factor treatment decreases mortality and is associated with improved gut integrity in sepsis.

PubMed

Clark, Jessica A; Clark, Andrew T; Hotchkiss, Richard S; Buchman, Timothy G; Coopersmith, Craig M

2008-07-01

Epidermal growth factor (EGF) is a cytoprotective peptide that has healing effects on the intestinal mucosa. We sought to determine whether systemic administration of EGF after the onset of sepsis improved intestinal integrity and decreased mortality. FVB/N mice were subjected to either sham laparotomy or 2 x 23 cecal ligation and puncture (CLP). Septic mice were further randomized to receive injection of either 150 microg kg(-1) d(-1) (i.p.) EGF or 0.9% saline (i.p.). Circulating EGF levels were decreased after CLP compared with sham animals but were unaffected by giving exogenous EGF treatment. In contrast, intestinal EGF levels increased after CLP and were further augmented by exogenous EGF treatment. Intestinal EGF receptor was increased after CLP, whether assayed by immunohistochemistry, real-time polymerase chain reaction, or Western blot, and exogenous EGF treatment decreased intestinal EGF receptor. Villus length decreased 2-fold between sham and septic animals, and EGF treatment resulted in near total restitution of villus length. Sepsis decreased intestinal proliferation and increased intestinal apoptosis. This was accompanied by increased expression of the proapoptotic proteins Bid and Fas-associated death domain, as well as the cyclin-dependent kinase inhibitor p21 cip1/waf Epidermal growth factor treatment after the onset of sepsis restored both proliferation and apoptosis to levels seen in sham animals and normalized expression of Bid, Fas-associated death domain, and p21 cip1/waf . To determine whether improvements in gut homeostasis were associated with a decrease in sepsis-induced mortality, septic mice with or without EGF treatment after CLP were followed 7 days for survival. Mortality decreased from 60% to 30% in mice treated with EGF after the onset of sepsis (P < 0.05). Thus, EGF may be a potential therapeutic agent for the treatment of sepsis in part due to its ability to protect intestinal integrity.

Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3.

PubMed

Shi, Z; Li, Z; Li, Z J; Cheng, K; Du, Y; Fu, H; Khuri, F R

2015-05-07

The cyclin-dependent kinase (CDK) inhibitor 1A, p21/Cip1, is a vital cell cycle regulator, dysregulation of which has been associated with a large number of human malignancies. One critical mechanism that controls p21 function is through its degradation, which allows the activation of its associated cell cycle-promoting kinases, CDK2 and CDK4. Thus delineating how p21 is stabilized and degraded will enhance our understanding of cell growth control and offer a basis for potential therapeutic interventions. Here we report a novel regulatory mechanism that controls the dynamic status of p21 through its interaction with Cdk5 and Abl enzyme substrate 1 (Cables1). Cables1 has a proposed role as a tumor suppressor. We found that upregulation of Cables1 protein was correlated with increased half-life of p21 protein, which was attributed to Cables1/p21 complex formation and supported by their co-localization in the nucleus. Mechanistically, Cables1 interferes with the proteasome (Prosome, Macropain) subunit alpha type 3 (PSMA3) binding to p21 and protects p21 from PSMA3-mediated proteasomal degradation. Moreover, silencing of p21 partially reverses the ability of Cables1 to induce cell death and inhibit cell proliferation. In further support of a potential pathophysiological role of Cables1, the expression level of Cables1 is tightly associated with p21 in both cancer cell lines and human lung cancer patient tumor samples. Together, these results suggest Cables1 as a novel p21 regulator through maintaining p21 stability and support the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21.

A numerical study of tsunami wave impact and run-up on coastal cliffs using a CIP-based model

NASA Astrophysics Data System (ADS)

Zhao, Xizeng; Chen, Yong; Huang, Zhenhua; Hu, Zijun; Gao, Yangyang

2017-05-01

There is a general lack of understanding of tsunami wave interaction with complex geographies, especially the process of inundation. Numerical simulations are performed to understand the effects of several factors on tsunami wave impact and run-up in the presence of gentle submarine slopes and coastal cliffs, using an in-house code, a constrained interpolation profile (CIP)-based model. The model employs a high-order finite difference method, the CIP method, as the flow solver; utilizes a VOF-type method, the tangent of hyperbola for interface capturing/slope weighting (THINC/SW) scheme, to capture the free surface; and treats the solid boundary by an immersed boundary method. A series of incident waves are arranged to interact with varying coastal geographies. Numerical results are compared with experimental data and good agreement is obtained. The influences of gentle submarine slope, coastal cliff and incident wave height are discussed. It is found that the tsunami amplification factor varying with incident wave is affected by gradient of cliff slope, and the critical value is about 45°. The run-up on a toe-erosion cliff is smaller than that on a normal cliff. The run-up is also related to the length of a gentle submarine slope with a critical value of about 2.292 m in the present model for most cases. The impact pressure on the cliff is extremely large and concentrated, and the backflow effect is non-negligible. Results of our work are highly precise and helpful in inverting tsunami source and forecasting disaster.

Optimization of consolidation parameters of 18Cr-ODS ferritic steel through microstructural and microtexture characterization

NASA Astrophysics Data System (ADS)

Dash, Manmath Kumar; Mythili, R.; Dasgupta, Arup; Saroja, S.

2018-04-01

This paper reports the optimization of consolidation process based on the evolution of microstructure, microtexture and densification in 18%-Cr Oxide Dispersion Strengthened steel. The steel powder of composition Fe-18Cr-0.01C-2W-0.25Ti-0.35Y2O3 has been consolidated by cold isostatic pressing (CIP) for green compaction after mechanical milling. Sintering (1000-1250 °C) and hot isostatic pressing (HIP) at 1150 °C has been employed to achieve good densification on compacted CIP specimen. The effect of sintering temperatures on densification behavior was evaluated and sintering at 1150°C was identified to be optimum for achieving good compaction (92% density) and homogeneous polygonal microstructure with a uniform distribution of fine pores. In addition, HIP of CIP product at 1150°C was found to yield a more homogeneous microstructure as compared to sintered product with 97% density. A static/dynamic recrystallization associated with (1 1 1) texture is observed during consolidation process. A statistical comparison has been made based on frequency of grain boundary distribution and associated texture with its theoretical attributes.

Effects of histone acetylation and DNA methylation on p21( WAF1) regulation.

PubMed

Fang, Jing-Yuan; Lu, You-Yong

2002-06-01

Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.

FY 2013 Educational Facilities Master Plan and the FY 2013-2018 Capital Improvements Program

ERIC Educational Resources Information Center

Montgomery County Public Schools, 2012

2012-01-01

The FY 2013 Educational Facilities Master Plan (Master Plan) and the FY 2013-2018 Capital Improvements Program (CIP) reflect the adopted actions of the Montgomery County (Maryland) Council and integrate the facilities planning process with the annual capital budget and the six-year CIP. The CIP is developed in accordance with the Board of…

FY 2012 Educational Facilities Master Plan and the Amended FY 2011-2016 Capital Improvements Program

ERIC Educational Resources Information Center

Montgomery County Public Schools, 2011

2011-01-01

The FY 2012 Educational Facilities Master Plan (Master Plan) and Amendments to the FY 2011-2016 Capital Improvements Program (CIP) reflect the adopted actions of the Montgomery County (Maryland) Council and integrate the facilities planning process with the annual capital budget and the six-year CIP. The CIP is developed in accordance with the…

FY 2007 Educational Facilities Master Plan and the FY 2007-2012 Capital Improvements Program

ERIC Educational Resources Information Center

Montgomery County Public Schools, 2006

2006-01-01

The FY 2007 Educational Facilities Master Plan (Master Plan) and FY 2007-2012 Capital Improvements Program (CIP) reflect the adopted actions of the Montgomery County (Maryland) Council and integrate the facilities planning process with the annual capital budget and the six-year CIP. The CIP is developed in accordance with the Board of Education…

Social Validity of the Social Skills Improvement System--Classwide Intervention Program (SSIS-CIP) in the Primary Grades

ERIC Educational Resources Information Center

Wollersheim Shervey, Sarah; Sandilos, Lia E.; DiPerna, James C.; Lei, Pui-Wa

2017-01-01

The purpose of this study was to examine the social validity of the Social Skills Improvement System--Classwide Intervention Program (SSIS-CIP) for teachers in the primary grades. Participants included 45 first and second grade teachers who completed a 16-item social validity questionnaire during each year of the SSIS-CIP efficacy trial. Findings…

Walking the Razor's Edge: Risks and Rewards for Students and Faculty Adopting Case in Point Teaching and Learning Approaches

ERIC Educational Resources Information Center

Wildermuth, Cristina de-Mello-e-Souza; Smith-Bright, Elaine; Noll-Wilson, Sarah; Fink, Alex

2015-01-01

Case in Point (CIP) is an interactive leadership development method pioneered by Ronald Heifetz. CIP instructors follow a fluid class structure, in which group dynamics and student concerns become catalysts for learning. CIP proponents defend the method's potential to help students experience real life leadership challenges. To date, however, very…

Social Validity of the Social Skills Improvement System--Classwide Intervention Program (SSIS-CIP) in the Primary Grades

ERIC Educational Resources Information Center

Wollersheim Shervey, Sarah; Sandilos, Lia E.; DiPerna, James C.; Lei, Pui-Wa

2017-01-01

The purpose of this study was to examine the social validity of the Social Skills Improvement System-Classwide Intervention Program (SSIS-CIP) for teachers in the primary grades. Participants included 45 first and second grade teachers who completed a 16-item social validity questionnaire during each year of the SSIS-CIP efficacy trial. Findings…

The reference strain Aeromonas hydrophicla CIP 57.50 should be reclassified as Aeromonas salmonicida CIP 57.50.

PubMed

Miñana-Galbis, David; Farfàn, Maribel; Lorén, J Gaspar; Fusté, M Carmen

2010-03-01

The use of reference strains is a critical element for the quality control of different assays, from the development of molecular methods to the evaluation of antimicrobial activities. Most of the strains used in these assays are not type strains and some of them are cited erroneously because of subsequent reclassifications and descriptions of novel species. In this study, we propose that the reference strain Aeromonas hydrophila CIP 57.50 be reclassified as Aeromonas salmonicida CIP 57.50 based on phenotypic characterization and sequence analyses of the cpn60, dnaJ, gyrB and rpoD genes.

A TMS Investigation on the Role of Lateral Occipital Complex and Caudal Intraparietal Sulcus in the Perception of Object Form and Orientation.

PubMed

Chouinard, Philippe A; Meena, Deiter K; Whitwell, Robert L; Hilchey, Matthew D; Goodale, Melvyn A

2017-05-01

We used TMS to assess the causal roles of the lateral occipital (LO) and caudal intraparietal sulcus (cIPS) areas in the perceptual discrimination of object features. All participants underwent fMRI to localize these areas using a protocol in which they passively viewed images of objects that varied in both form and orientation. fMRI identified six significant brain regions: LO, cIPS, and the fusiform gyrus, bilaterally. In a separate experimental session, we applied TMS to LO or cIPS while the same participants performed match-to-sample form or orientation discrimination tasks. Compared with sham stimulation, TMS to either the left or right LO increased RTs for form but not orientation discrimination, supporting a critical role for LO in form processing for perception- and judgment-based tasks. In contrast, we did not observe any effects when we applied TMS to cIPS. Thus, despite the clear functional evidence of engagement for both LO and cIPS during the passive viewing of objects in the fMRI experiment, the TMS experiment revealed that cIPS is not critical for making perceptual judgments about their form or orientation.

The excretion and environmental effects of amoxicillin, ciprofloxacin, and doxycycline residues in layer chicken manure.

PubMed

Peng, Ping-cai; Wang, Yan; Liu, Long-yong; Zou, Yong-de; Liao, Xin-di; Liang, Juan-boo; Wu, Yin-bao

2016-05-01

The excretion rates and ecological risk to the environment of three commonly used veterinary antibiotics (VAs), amoxicillin, ciprofloxacin, and doxycycline, in layer hen manure during the application and withdrawal periods were investigated in a study consisting of a control group fed with VA-free basal diet and nine treatment groups consisted of three levels (200 mg/kg, 100 mg/kg, and 50 mg/kg) of amoxicillin (AMX), ciprofloxacin (CIP), or doxycycline (DOC). Each treatment group was replicated seven times with three layer hens per replication. Results of the study showed that the average excretion rates of AMX in the 200, 100, and 50 mg/kg groups were 67.88, 55.82, and 66.15%, respectively, while those for CIP and DOC were 47.84, 51.85, and 44.87% and 82.67, 94.39, and 95.72%, respectively. The concentrations of the above veterinary drugs in manure decreased sharply in the withdrawal period (7, 28, and 10 d, respectively), for AMX, DOC, and CIP. Neither AMX nor DOC was detected in the manure after the withdrawal period. In contrast to AMX and DOC, the excretion rate of CIP was significantly lower and thus had a longer residence time. Ecological risk study, estimated using hazard quotient values, showed that AMX in the 100 and 50 mg/kg groups posed no risk to the environment after d 1 of withdrawal, while CIP in the 50 mg/kg group posed no risk to the environment from d 5 of withdrawal. CIP in the 200 and 100 mg/kg groups required 10 d withdrawal in order to pose no risk to the environment. In contrast, DOC residue during withdrawal in the manure posed no risk to the environment, thus making it more environmentally safe. © 2016 Poultry Science Association Inc.

Sequence Analysis of Scaffolding Protein CipC and ORFXp, a New Cohesin-Containing Protein in Clostridium cellulolyticum: Comparison of Various Cohesin Domains and Subcellular Localization of ORFXp

PubMed Central

Pagès, Sandrine; Bélaïch, Anne; Fierobe, Henri-Pierre; Tardif, Chantal; Gaudin, Christian; Bélaïch, Jean-Pierre

1999-01-01

The gene encoding the scaffolding protein of the cellulosome from Clostridium cellulolyticum, whose partial sequence was published earlier (S. Pagès, A. Bélaïch, C. Tardif, C. Reverbel-Leroy, C. Gaudin, and J.-P. Bélaïch, J. Bacteriol. 178:2279–2286, 1996; C. Reverbel-Leroy, A. Bélaïch, A. Bernadac, C. Gaudin, J. P. Bélaïch, and C. Tardif, Microbiology 142:1013–1023, 1996), was completely sequenced. The corresponding protein, CipC, is composed of a cellulose binding domain at the N terminus followed by one hydrophilic domain (HD1), seven highly homologous cohesin domains (cohesin domains 1 to 7), a second hydrophilic domain, and a final cohesin domain (cohesin domain 8) which is only 57 to 60% identical to the seven other cohesin domains. In addition, a second gene located 8.89 kb downstream of cipC was found to encode a three-domain protein, called ORFXp, which includes a cohesin domain. By using antiserum raised against the latter, it was observed that ORFXp is associated with the membrane of C. cellulolyticum and is not detected in the cellulosome fraction. Western blot and BIAcore experiments indicate that cohesin domains 1 and 8 from CipC recognize the same dockerins and have similar affinity for CelA (Ka = 4.8 × 109 M−1) whereas the cohesin from ORFXp, although it is also able to bind all cellulosome components containing a dockerin, has a 19-fold lower Ka for CelA (2.6 × 108 M−1). Taken together, these data suggest that ORFXp may play a role in cellulosome assembly. PMID:10074072

Sequence analysis of scaffolding protein CipC and ORFXp, a new cohesin-containing protein in Clostridium cellulolyticum: comparison of various cohesin domains and subcellular localization of ORFXp.

PubMed

Pagès, S; Bélaïch, A; Fierobe, H P; Tardif, C; Gaudin, C; Bélaïch, J P

1999-03-01

The gene encoding the scaffolding protein of the cellulosome from Clostridium cellulolyticum, whose partial sequence was published earlier (S. Pagès, A. Bélaïch, C. Tardif, C. Reverbel-Leroy, C. Gaudin, and J.-P. Bélaïch, J. Bacteriol. 178:2279-2286, 1996; C. Reverbel-Leroy, A. Bélaïch, A. Bernadac, C. Gaudin, J. P. Bélaïch, and C. Tardif, Microbiology 142:1013-1023, 1996), was completely sequenced. The corresponding protein, CipC, is composed of a cellulose binding domain at the N terminus followed by one hydrophilic domain (HD1), seven highly homologous cohesin domains (cohesin domains 1 to 7), a second hydrophilic domain, and a final cohesin domain (cohesin domain 8) which is only 57 to 60% identical to the seven other cohesin domains. In addition, a second gene located 8.89 kb downstream of cipC was found to encode a three-domain protein, called ORFXp, which includes a cohesin domain. By using antiserum raised against the latter, it was observed that ORFXp is associated with the membrane of C. cellulolyticum and is not detected in the cellulosome fraction. Western blot and BIAcore experiments indicate that cohesin domains 1 and 8 from CipC recognize the same dockerins and have similar affinity for CelA (Ka = 4.8 x 10(9) M-1) whereas the cohesin from ORFXp, although it is also able to bind all cellulosome components containing a dockerin, has a 19-fold lower Ka for CelA (2.6 x 10(8) M-1). Taken together, these data suggest that ORFXp may play a role in cellulosome assembly.

Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways

PubMed Central

Mitsui, Yozo; Hirata, Hiroshi; Arichi, Naoko; Hiraki, Miho; Yasumoto, Hiroaki; Chang, Inik; Fukuhara, Shinichiro; Yamamura, Soichiro; Shahryari, Varahram; Deng, Guoren; Saini, Sharanjot; Majid, Shahana; Dahiya, Rajvir; Tanaka, Yuichiro; Shiina, Hiroaki

2015-01-01

We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2′-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC. PMID:25797254

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

Svensson, Emelie; Eriksson, Helena; Gekas, Christos

The Wilms tumor gene 1 (WT1) encodes a zinc-finger-containing transcription factor highly expressed in immature hematopoietic progenitor cells. Overexpression and presence of somatic mutations in acute leukemia indicate a role for WT1 in the pathogenesis of leukemia. CD34{sup +} progenitor cells were transduced with one splice variant of human WT1 without the KTS insert in the zinc-finger domain, WT1(+/-), and with a deleted mutant of WT1 lacking the entire zinc-finger region, WT1(delZ), thus incapable of binding DNA. We show that inhibition of erythroid colony formation and differentiation is absolutely dependent on the DNA-binding zinc-finger domain of WT1. Unexpectedly, however, WT1(delZ)more » was equally effective as wild type protein in the reduction of myeloid clonogenic growth as well as in stimulation of myeloid differentiation, as judged by the expression of cell surface CD11b. Expression of neither WT1(+/-) nor WT1(delZ) upregulated mRNA for the cdk inhibitor p21{sup Waf1/Cip1} or p27{sup Kip1}. Our results demonstrate that WT1 affects proliferation and differentiation in erythroid and myeloid cells by different molecular mechanisms, and suggest that mutations affecting the zinc-finger domain of WT1 could interfere with normal differentiation in the pathogenesis of leukemia.« less

76 FR 14793 - Procedures for Monitoring Bank Secrecy Act Compliance and Fair Credit Reporting: Technical...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-18

... regulations in 12 CFR 326.8, and specific cross- references to the Customer Identification Program (``CIP''), 31 CFR 103.121, in 12 CFR 326.8, 12 CFR 334.82, and Appendix J to Part 334. The CIP regulation, which... of the Customer Identification Program (CIP) rules implementing 31 U.S.C. 5318(l) (31 CFR 1020.220...

p21(WAF1/CIP1) and cancer: a shifting paradigm?

PubMed

Gartel, Andrei L

2009-01-01

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) is a key mediator of p53-dependent cell cycle arrest and may play the role of a tumor suppressor in cancer. However, it has been shown that p21 may also act as an oncogene, because it inhibits apoptosis and may promote cell proliferation in some tumors. These data point out to "antagonistic duality" of p21, because it possesses anticancer and procancer properties at the same time. New data suggest that more and more proteins also may play contradictory roles in cancer thus challenging current paradigm of established oncogenes and tumor suppressors. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Magnetic copper-based metal organic framework as an effective and recyclable adsorbent for removal of two fluoroquinolone antibiotics from aqueous solutions.

PubMed

Wu, Gege; Ma, Jiping; Li, Shuang; Guan, Jing; Jiang, Bo; Wang, Liyan; Li, Jinhua; Wang, Xiaoyan; Chen, Lingxin

2018-05-30

Fe 3 O 4 /HKUST-1 magnetic copper based metal-organic frameworks (MOF) were synthesized by a simple and facile method and applied as an effective and recyclable adsorbent for the adsorptive removal of two widely used ciprofloxacin (CIP) and norfloxacin (NOR) fluoroquinolone antibiotics (FQAs) from aqueous solutions. Fe 3 O 4 /HKUST-1 was thoroughly characterized, and the major influence factors including solution pH, adsorbent amount and salt concentration were investigated. Compared to the reported adsorbents, Fe 3 O 4 /HKUST-1 has a very high adsorption rate, and it is found that CIP and NOR could be removed within 30 min. Moreover, the maximum adsorption capacities of the magnetic composites toward CIP and NOR reached as high as 538 mg g -1 and 513 mg g -1 , respectively, much higher than those of most of the reported adsorbents for these two FQAs. The saturation magnetization value of Fe 3 O 4 /HKUST-1 was 44 emu g -1 , which was sufficient for the separation of the Fe 3 O 4 /HKUST-1adsorbent from the aqueous solution by the application of an external magnetic field. Additionally, this magnetic material showed a good reusability with the adsorption capability decreasing only slightly after reuse for ten cycles. These results indicated that the magnetic composites Fe 3 O 4 /HKUST-1 may be a promising adsorbent in the decontamination of FQAs from wastewater due to its high adsorption capability, fast kinetics, easy separation from water, and excellent recyclability. The adsorption mechanism was proposed based on the effects of pH on adsorption and on the zeta potential of the adsorbent. For the adsorption of CIP and NOR by Fe 3 O 4 /HKUST-1, both electrostatic and π-π interactions may be important. Copyright © 2018 Elsevier Inc. All rights reserved.

Down-regulation of p21 (CDKN1A/CIP1) is inversely associated with microsatellite instability and CpG island methylator phenotype (CIMP) in colorectal cancer.

PubMed

Ogino, S; Kawasaki, T; Kirkner, G J; Ogawa, A; Dorfman, I; Loda, M; Fuchs, C S

2006-10-01

p21 (CDKN1A/CIP1/WAF1), one of the cyclin-dependent kinase inhibitors, plays a key role in regulating the cell cycle and is transcriptionally regulated by p53. Down-regulation of p21 is caused by TP53 mutations in colorectal cancer. CpG island methylator phenotype (CIMP) appears to be a distinct subtype of colorectal cancer with concordant methylation of multiple gene promoters and is associated with a high degree of microsatellite instability (MSI-H) and BRAF mutations. However, no study to date has evaluated the relationship between p21 expression and CIMP in colorectal cancer. The purpose of this study was to examine the inter-relationships between p21, p53, CIMP, MSI and KRAS/BRAF status in colorectal cancer. We utilized 737 relatively unbiased samples of colorectal cancers from two large prospective cohort studies. Using quantitative real-time PCR (MethyLight), we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1 and NEUROG1]. CIMP-high (>or=4/5 methylated promoters) was diagnosed in 118 (16%) of the 737 tumours. We also assessed expression of p21 and p53 by immunohistochemistry. Among the 737 tumours, 371 (50%) showed p21 loss. Both p21 loss and p53 positivity were inversely associated with CIMP-high, MSI-H and BRAF mutations. The associations of p21 with these molecular features were still present after tumours were stratified by p53 status. In contrast, the associations of p53 positivity with the molecular features were no longer present after tumours were stratified by p21 status. When CIMP-high and non-CIMP-high tumours were stratified by MSI or KRAS/BRAF status, CIMP-high and MSI-H (but not BRAF mutations) were still inversely associated with p21 loss. In conclusion, down-regulation of p21 is inversely correlated with CIMP-high and MSI-H in colorectal cancer, independent of TP53 and BRAF status.

Senior Computational Scientist | Center for Cancer Research

Cancer.gov

The Basic Science Program (BSP) pursues independent, multidisciplinary research in basic and applied molecular biology, immunology, retrovirology, cancer biology, and human genetics. Research efforts and support are an integral part of the Center for Cancer Research (CCR) at the Frederick National Laboratory for Cancer Research (FNLCR). The Cancer & Inflammation Program (CIP), Basic Science Program, HLA Immunogenetics Section, under the leadership of Dr. Mary Carrington, studies the influence of human leukocyte antigens (HLA) and specific KIR/HLA genotypes on risk of and outcomes to infection, cancer, autoimmune disease, and maternal-fetal disease. Recent studies have focused on the impact of HLA gene expression in disease, the molecular mechanism regulating expression levels, and the functional basis for the effect of differential expression on disease outcome. The lab’s further focus is on the genetic basis for resistance/susceptibility to disease conferred by immunogenetic variation. KEY ROLES/RESPONSIBILITIES The Senior Computational Scientist will provide research support to the CIP-BSP-HLA Immunogenetics Section performing bio-statistical design, analysis and reporting of research projects conducted in the lab. This individual will be involved in the implementation of statistical models and data preparation. Successful candidate should have 5 or more years of competent, innovative biostatistics/bioinformatics research experience, beyond doctoral training Considerable experience with statistical software, such as SAS, R and S-Plus Sound knowledge, and demonstrated experience of theoretical and applied statistics Write program code to analyze data using statistical analysis software Contribute to the interpretation and publication of research results

Incorporation of ciprofloxacin/laponite in polycaprolactone electrospun nanofibers: drug release and antibacterial studies

NASA Astrophysics Data System (ADS)

Kalwar, Kaleemullah; Zhang, Xuan; Aqeel Bhutto, Muhammad; Dali, Li; Shan, Dan

2017-12-01

Electrospun nanofibers with sustained drug release are a challenge but it can be improved by using hydrophobic polymer. Polycaprolactone (PCL) is a hydrophobic and biocompatible polymer. In this work, we have proposed a drug release mechanism by preparation of ciprofloxacin (Cip)/Laponite (LAP) complex and then incorporation in PCL nanofibers through electrospinning technique. In addition, drug incorporation was confirmed by FTIR and morphology of electrospun nanofibers was revealed by SEM. Drug loading was measured by using spectrophotometer. PCL/LAP/Cip NFs proved sustained drug release as compared to PCL NFs and PCL/Cip NFs. Furthermore, PCL/LAP/Cip NFs were used as antimicrobial agent and higher effect measured.

Social validity of the Social Skills Improvement System-Classwide Intervention Program (SSIS-CIP) in the primary grades.

PubMed

Wollersheim Shervey, Sarah; Sandilos, Lia E; DiPerna, James C; Lei, Pui-Wa

2017-09-01

The purpose of this study was to examine the social validity of the Social Skills Improvement System-Classwide Intervention Program (SSIS-CIP) for teachers in the primary grades. Participants included 45 first and second grade teachers who completed a 16-item social validity questionnaire during each year of the SSIS-CIP efficacy trial. Findings indicated that teachers generally perceived the SSIS-CIP as a socially valid and feasible intervention for primary grades; however, teachers' ratings regarding ease of implementation and relevance and sequence demonstrated differences across grade levels in the second year of implementation. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

A High Precision Survey of the Molecular Dynamics of Mammalian Clathrin-Mediated Endocytosis

PubMed Central

Taylor, Marcus J.; Perrais, David; Merrifield, Christien J.

2011-01-01

Dual colour total internal reflection fluorescence microscopy is a powerful tool for decoding the molecular dynamics of clathrin-mediated endocytosis (CME). Typically, the recruitment of a fluorescent protein–tagged endocytic protein was referenced to the disappearance of spot-like clathrin-coated structure (CCS), but the precision of spot-like CCS disappearance as a marker for canonical CME remained unknown. Here we have used an imaging assay based on total internal reflection fluorescence microscopy to detect scission events with a resolution of ∼2 s. We found that scission events engulfed comparable amounts of transferrin receptor cargo at CCSs of different sizes and CCS did not always disappear following scission. We measured the recruitment dynamics of 34 types of endocytic protein to scission events: Abp1, ACK1, amphiphysin1, APPL1, Arp3, BIN1, CALM, CIP4, clathrin light chain (Clc), cofilin, coronin1B, cortactin, dynamin1/2, endophilin2, Eps15, Eps8, epsin2, FBP17, FCHo1/2, GAK, Hip1R, lifeAct, mu2 subunit of the AP2 complex, myosin1E, myosin6, NECAP, N-WASP, OCRL1, Rab5, SNX9, synaptojanin2β1, and syndapin2. For each protein we aligned ∼1,000 recruitment profiles to their respective scission events and constructed characteristic “recruitment signatures” that were grouped, as for yeast, to reveal the modular organization of mammalian CME. A detailed analysis revealed the unanticipated recruitment dynamics of SNX9, FBP17, and CIP4 and showed that the same set of proteins was recruited, in the same order, to scission events at CCSs of different sizes and lifetimes. Collectively these data reveal the fine-grained temporal structure of CME and suggest a simplified canonical model of mammalian CME in which the same core mechanism of CME, involving actin, operates at CCSs of diverse sizes and lifetimes. PMID:21445324

Hemorrhage Control for Major Traumatic Vascular Injuries

DTIC Science & Technology

2015-10-01

Human Subjects Protection Scientist, at 301-619-9268/karen.m.eaton.ctr@mail.mil. SHARON A. EVANS, PhD, CIP Deputy Director, Human Research... CIP Deputy Director, Human Research Protection Office Office of Research Protections US Army Medical Research and Materiel Command Note: The...debra.depaul.ctr@mail.mil; the POC for the USAMRMC ORP HRPO review is the undersigned at 301-619-7801. 25 ANDREA J. KLINE, MS, CIP Director

A new magnetic compound fluid slurry and its performance in magnetic field-assisted polishing of oxygen-free copper

NASA Astrophysics Data System (ADS)

Wang, Youliang; Wu, Yongbo; Guo, Huiru; Fujimoto, Masakazu; Nomura, Mitsuyoshi; Shimada, Kunio

2015-05-01

In nano-precision surface finishing of engineering materials using MCF (magnetic compound fluid) slurry, the water-based MCF slurry is preferable from the viewpoint of the environmental issue and the running cost of cleaning workpiece and equipment. However, the uncoated-CIPs (carbonyl-iron-powders) within the conventional MCF slurry have low ability against aqueous corrosion, leading to the performance deterioration and working life shortening of the conventional MCF slurry. This study proposed a new MCF slurry containing ZrO2-coated CIPs instead of the uncoated CIPs. Its performance in the polishing of oxygen-free copper was compared experimentally with that of the conventional one. The results showed that the work-surface finish polished with the new slurry was in the same level as that with the conventional one when the slurry was used soon after prepared, i.e., the settling time was 0 min; however, as the settling time increased the uncoated-CIPs got rusty, leading to a deterioration in the slurry performance. By contrast, no rust was observed on ZrO2-coated CIPs even the settling time reached several days, indicating the employment of ZrO2-coated CIPs prolonged the working-life of the MCF slurry greatly.

[Influence of Four Kinds of PPCPs on Micronucleus Rate of the Root-Tip Cells of Vicia-faba and Garlic].

PubMed

Wang, Lan-jun; Wang, Jin-hua; Zhu, Lu-sheng; Wang, Jun; Zhao, Xiang

2016-04-15

In order to determine the degree of biological genetic injury induced by PPCPs, the genotoxic effects of the doxycycline (DOX), ciprofloxacin (CIP), triclocarban (TCC) and carbamazepine (CBZ) in the concentration range of 12.5-100 mg · L⁻¹ were studied using micronucleus rate and micronucleus index of Vicia-fabe and garlic. The results showed that: (1) When the Vicia-faba root- tip cells were exposed to DOX, CIP, TCC and CBZ, micronucleus rates were higher than 1.67 ‰ (CK₁), it was significantly different from that of the control group (P < 0.05), and the micronucleus index was even greater than 3.5; With the increasing concentrations of the PPCPs, the micronucleus rates first increased and then decreased. (2) When the garlic root tip cells were exposed to DOX, CIP, TCC and CBZ respectively, the micronucleus rates were less than those of the Vicia-faba, while in most treatments significantly higher than that of the control group (0.67‰). The micronucleus index was higher than 3.5 in the groups exposed to CIP with concentrations of 25, 50, 100 mg · L⁻¹ and TCC and CBZ with concentrations of 25 mg · L⁻¹; With the increase of exposure concentrations, the micronucleus rate showed a trend of first increasing and then decreasing as well. (3) Under the same experimental conditions, the cells micronucleus rates of the garlic cells caused by the four tested compounds were significantly lower than those of Vicia-faba. (4) The micronucleus index of the root tip cells of Vicia-faba and garlic treated with the four kinds of compounds followed the order of CIP > CBZ > TCC > DOX. These results demonstrated that the four compounds caused biological genetic injury to root-tip cells of Vicia-faba and garlic, and the genetic damage caused to garlic was significantly lower than that to Vicia-faba. The damages caused by the four kinds of different compounds were also different.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

PubMed Central

Torres, Bruna G. S.; Helfer, Victória E.; Bernardes, Priscila M.; Macedo, Alexandre José; Nielsen, Elisabet I.; Friberg, Lena E.

2017-01-01

ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations. PMID:28461311

Epidemiological Characteristics and Clinical Treatment Outcome of Typhoid Fever in Ningbo, China, 2005-2014: Pulsed-Field Gel Electorophoresis Results Revealing Great Proportion of Common Transmission Sources.

PubMed

Song, Qifa; Yang, Yuanbin; Lin, Wenping; Yi, Bo; Xu, Guozhang

2017-09-25

We aimed to describe the molecular epidemiological characteristics and clinical treatment outcome of typhoid fever in Ningbo, China during 2005-2014. Eighty-eight Salmonella Typhi isolates were obtained from 307 hospitalized patients. Three prevalent pulsed-field gel electrophoresis (PFGE) patterns of 54 isolates from 3 outbreaks were identified. Overall, there were 64 (72.7%) isolates from clustered cases and 24 (27.3%) isolates from sporadic cases. Resistance to nalidixic acid (NAL) (n = 47; 53.4%) and ampicillin (AMP) (n = 40; 45.4%) and rare resistance to tetracycline (TET) (n = 2; 2.3%) and gentamicin (GEN) (n = 2; 2.3%) were observed. No isolates resistant to cefotaxime (CTX), chloramphenicol (CL), ciprofloxacin (CIP), and trimethoprim-sulfamethoxazole (SXT) were found. The occurrence of reduced sensitivity to CIP was 52.3% (n = 46). The medians of fever clearance time in cases with and without complications were 7 (interquartile range (IQR): 4-10) and 5 (IQR: 3-7) days (P = 0.001), respectively, when patients were treated with CIP or levofloxacin (LEV) and/or third-generation cephalosporins (CEP). Rates of serious complications were at low levels: peritonitis (2.3%), intestinal hemorrhage (6.8%), and intestinal perforation (1.1%). The present study revealed a long-term clustering trend with respect to PFGE patterns, occasional outbreaks, and the rapid spread of AMP resistance and decreased CIP susceptibility among S. Typhi isolates in recent years.

HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility

PubMed Central

LI, YUCHUN; WANG, KAIJUAN; DAI, LIPING; WANG, PENG; SONG, CHUNHUA; SHI, JIANXIANG; REN, PENGFEI; YE, HUA; ZHANG, JIANYING

2012-01-01

CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-myc in human malignancies. Autoantibodies to CIP2A protein have been reported to be present in higher levels in sera from patients with hepatocellular carcinoma (HCC) than in sera of healthy individuals. The CIP2A gene has been demonstrated as a potential cancer susceptibility gene. To elucidate whether common CIP2A variants are associated with HCC susceptibility, we conducted a case-control study comprising 233 cases of HCC and 280 controls matched on age, gender and ethnicity in the Chinese Han population. Two haplotype-tagging single nucleotide polymorphisms (htSNPs) (rs2278911 and rs4855656) from the HapMap database were analyzed, which provide an almost complete coverage of the genetic variations in the CIP2A gene. We found that neither of these htSNPs and haplotypes were associated with the risk of HCC. However, an interaction was observed between hepatitis virus B and C infection (HBV and HCV) and the C carriers (TC or CC) of rs2278911 on HCC risk (OR=12.35; 95% CI, 4.93–19.87). No such association was found for rs4855656. Our study also demonstrated that two htSNPs (rs2278911 and rs4855656) in the CIP2A gene are not associated with the risk of HCC. HBV and HCV infection was found to exert a synergistic effect on the risk of HCC in individuals with the C carriers (TC or CC) of rs2278911 in the Chinese Han population. PMID:22844383

Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

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

Huang, H.-S., E-mail: huanghs@mail.ncku.edu.t; Liu, Z.-M.; Hong, D.-Y.

2010-04-15

Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21{sup WAF1/CIP1} (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells couldmore » inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.« less

Restrictions in Cell Cycle Progression of Adult Vestibular Supporting Cells in Response to Ectopic Cyclin D1 Expression

PubMed Central

Loponen, Heidi; Ylikoski, Jukka; Albrecht, Jeffrey H.; Pirvola, Ulla

2011-01-01

Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27Kip1 and p21Cip1 expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells. PMID:22073316

Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression.

PubMed

Loponen, Heidi; Ylikoski, Jukka; Albrecht, Jeffrey H; Pirvola, Ulla

2011-01-01

Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27(Kip1) and p21(Cip1) expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells.

Novel anticancer agent, benzyldihydroxyoctenone, isolated from Streptomyces sp. causes G1 cell cycle arrest and induces apoptosis of HeLa cells.

PubMed

Lee, Chul-Hoon; Lim, Haeyoung; Moon, Sangik; Shin, Choonshik; Kim, Seunghyun; Kim, Bum-Joon; Lim, Yoongho

2007-06-01

In the course of screening for anticancer agents, a novel active compound, F3-2-5, was isolated from culture broth of Streptomyces sp., KACC91015. Its structure was identified using nuclear magnetic resonance, mass spectrometry, and molecular modeling experiments, and confirmed by total synthesis. The growth of various human cancer cell lines was inhibited in a dose-dependent manner by 0.06-0.48 mM F3-2-5 over 24 h. Its IC(50) values were estimated at 37 microM on HeLa, 72 microM on A549, and 190 microM on HT-29 cells. However, F3-2-5 had no antiproliferative effect on normal lymphocytes and normal fibroblasts used as controls. Moreover, it affected cell cycle regulation and caused apoptosis of the HeLa cells; chromatin condensation and DNA fragmentation were observed in cells exposed to 80 microM F3-2-5. Western blot analysis revealed that F3-2-5 inhibited phosphorylation of retinoblastoma protein (pRb) and reduced expression of cyclin-dependent kinase-4 and -6, and cyclin D1 and E, while levels of p53 and p21(WAF1/CIP1) increased. Taken together, these findings show that F3-2-5 inhibits proliferation of HeLa cells by inducing G(1) phase arrest as a consequence of inhibition of pRb phosphorylation following up-regulation of p21(WAF1/CIP1) and p53. Furthermore, apoptosis in HeLa cells treated with F3-2-5 was associated with an increase in Bax and p53, leading to release of cytochrome c, activation of caspase-3, and -8, and cleavage of poly (ADP-ribose) polymerase.

Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.

PubMed

Sleiman, Sama F; Langley, Brett C; Basso, Manuela; Berlin, Jill; Xia, Li; Payappilly, Jimmy B; Kharel, Madan K; Guo, Hengchang; Marsh, J Lawrence; Thompson, Leslie Michels; Mahishi, Lata; Ahuja, Preeti; MacLellan, W Robb; Geschwind, Daniel H; Coppola, Giovanni; Rohr, Jürgen; Ratan, Rajiv R

2011-05-04

Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration.

Financing future power generation in Italy

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

Esposito, P.

1998-07-01

Under Italian law, independent power generation fueled by renewable and so-called ``assimilated'' sources must be given incentives. To implement this provision, a resolution known as ``CIP 6'' and a decree setting forth the procedure to sell such electricity to ENEL were issued. CIP 6 has recently been revoked and new incentives have been announced. In the meantime, CIP 6 continues to apply to various projects which have been approved but not yet constructed.

A spontaneous mutation in kdsD, a biosynthesis gene for 3 Deoxy-D-manno-Octulosonic Acid, occurred in a ciprofloxacin resistant strain of Francisella tularensis and caused a high level of attenuation in murine models of tularemia

PubMed Central

Chance, Taylor; Toothman, Ronald G.; Nuss, Jonathan E.; Raymond, Jo Lynne; Biot, Fabrice V.; Demons, Samandra; Miller, Lynda; Halasohoris, Stephanie; Mou, Sherry; Koroleva, Galina; Lovett, Sean; Palacios, Gustavo; Vietri, Nicholas J.; Worsham, Patricia L.; Cote, Christopher K.; Kijek, Todd M.; Bozue, Joel A.

2017-01-01

Francisella tularensis, a gram–negative facultative intracellular bacterial pathogen, is the causative agent of tularemia and able to infect many mammalian species, including humans. Because of its ability to cause a lethal infection, low infectious dose, and aerosolizable nature, F. tularensis subspecies tularensis is considered a potential biowarfare agent. Due to its in vitro efficacy, ciprofloxacin is one of the antibiotics recommended for post-exposure prophylaxis of tularemia. In order to identify therapeutics that will be efficacious against infections caused by drug resistant select-agents and to better understand the threat, we sought to characterize an existing ciprofloxacin resistant (CipR) mutant in the Schu S4 strain of F. tularensis by determining its phenotypic characteristics and sequencing the chromosome to identify additional genetic alterations that may have occurred during the selection process. In addition to the previously described genetic alterations, the sequence of the CipR mutant strain revealed several additional mutations. Of particular interest was a frameshift mutation within kdsD which encodes for an enzyme necessary for the production of 3-Deoxy-D-manno-Octulosonic Acid (KDO), an integral component of the lipopolysaccharide (LPS). A kdsD mutant was constructed in the Schu S4 strain. Although it was not resistant to ciprofloxacin, the kdsD mutant shared many phenotypic characteristics with the CipR mutant, including growth defects under different conditions, sensitivity to hydrophobic agents, altered LPS profiles, and attenuation in multiple models of murine tularemia. This study demonstrates that the KdsD enzyme is essential for Francisella virulence and may be an attractive therapeutic target for developing novel medical countermeasures. PMID:28328947

Rho-associated kinase (ROCK) inhibition reverses low cell activity on hydrophobic surfaces.

PubMed

Tian, Yu Shun; Kim, Hyun Jung; Kim, Hyun-Man

2009-08-28

Hydrophobic polymers do not offer an adequate scaffold surface for cells to attach, migrate, proliferate, and differentiate. Thus, hydrophobic scaffolds for tissue engineering have traditionally been physicochemically modified to enhance cellular activity. However, modifying the surface by chemical or physical treatment requires supplementary engineering procedures. In the present study, regulation of a cell signal transduction pathway reversed the low cellular activity on a hydrophobic surface without surface modification. Inhibition of Rho-associated kinase (ROCK) by Y-27632 markedly enhanced adhesion, migration, and proliferation of osteoblastic cells cultured on a hydrophobic polystyrene surface. ROCK inhibition regulated cell-cycle-related molecules on the hydrophobic surface. This inhibition also decreased expression of the inhibitors of cyclin-dependent kinases such as p21(cip1) and p27(kip1) and increased expression of cyclin A and D. These results indicate that defective cellular activity on the hydrophobic surface can be reversed by the control of a cell signal transduction pathway without physicochemical surface modification.

Increased p50/p50 NF-κB Activation in Human Papillomavirus Type 6- or Type 11-Induced Laryngeal Papilloma Tissue

PubMed Central

Vancurova, Ivana; Wu, Rong; Miskolci, Veronika; Sun, Shishinn

2002-01-01

We have observed elevated NF-κB DNA-binding activity in nuclear extracts from human papillomavirus type 6- and 11-infected laryngeal papilloma tissues. The predominant DNA-binding species is the p50/p50 homodimer. The elevated NF-κB activity could be correlated with a reduced level of cytoplasmic IκBβ and could be associated with the overexpression of p21CIP1/WAF1 in papilloma cells. Increased NF-κB activity and cytoplasmic accumulation of p21CIP1/WAF1 might counteract death-promoting effects elicited by overexpressed PTEN and reduced activation of Akt and STAT3 previously noted in these tissues. PMID:11773428

Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

PubMed Central

Liu, Chun-Yu; Shiau, Chung-Wai; Kuo, Hsin-Yu; Huang, Hsiang-Po; Chen, Ming-Huang; Tzeng, Cheng-Hwai; Chen, Kuen-Feng

2013-01-01

The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies. Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells. Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Bortezomib increased protein phosphatase 2A activity in sensitive leukemia cells (HL-60 and KG-1), but not in resistant cells (MOLT-3 and K562). Bortezomib’s downregulation of cancerous inhibitor of protein phosphatase 2A and phospho-Akt correlated with its drug sensitivity. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity. Ectopic expression of CIP2A up-regulated phospho-Akt and protected HL-60 cells from bortezomib-induced apoptosis, whereas silencing CIP2A overcame the resistance to bortezomib-induced apoptosis in MOLT3 and K562 cells. Importantly, bortezomib exerted in vivo antitumor activity in HL-60 xenografted tumors and induced cell death in some primary leukemic cells. Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib-induced apoptosis in leukemia cells. PMID:22983581

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

PubMed Central

Naudin, Cécile; Hattabi, Aurore; Michelet, Fabio; Miri-Nezhad, Ayda; Benyoucef, Aissa; Pflumio, Françoise; Guillonneau, François; Fichelson, Serge; Vigon, Isabelle; Dusanter-Fourt, Isabelle

2017-01-01

RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-3′ untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p21−CIP1 and p27−KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth. PMID:28232582

[Characterization and determination of antibiotic resistance profiles of a single clone Acinetobacter baumannii strains isolated from blood cultures].

PubMed

Karagöz, Alper; Baran, Irmak; Aksu, Neriman; Acar, Sümeyra; Durmaz, Rıza

2014-10-01

Acinetobacter baumannii which is a significant cause of nosocomial infections, increases the rate of morbidity and mortality in health care settings especially in intensive care units (ICUs). The aim of this study was to determine the antibiotic resistance profiles of A.baumannii strains isolated from blood cultures of inpatients from different ICUs, wards and hospital environment and evaluate their clonal relationships and epidemiologic features. A total of 54 A.baumannii strains (47 from the blood cultures and 7 from the hospital environment), identified between 01 January 2012-28 December 2012 at the Clinical Microbiology Laboratory of Ankara Numune Training and Research Hospital, Turkey, were included in the study. Identification of A.baumannii isolates and their antimicrobial [sulbactam-ampicillin (SAM), piperacillin (PIP), piperacillin-tazobactam (TZP), ceftazidime (CFZ), cefoperazone-sulbactam (SCF), cefepime (CEF), imipenem (IMP), meropenem (MER), amikacin (AMK), gentamicin (GEN), netilmicin (NT), ciprofloxacin (CIP), levofloxacin (LVF), tetracycline (TET), tigecycline (TG), colistin (COL), trimethoprim-sulfamethoxazole (SXT)] susceptibility testing were performed by Vitek 2 (bioMérieux, France) system. The clonal relationship between the A.baumannii isolates was analysed by pulsed-field gel electrophoresis (PFGE). In our study colistin, tigecycline and netilmicin were found to be the most effective agents against A.baumannii isolates. All of the clinical isolates (n= 47) were found susceptible to COL, however all were resistant to SAM, PIP, TZP, CEF, IPM, CFZ, MER and CIP. While 1.85%, 14.8%, 14.8%, 16.6%, 59.2% and 22.2% of the isolates were susceptible to SCF, AMK, NT, GEN, TG and SXT, respectively; 1.85%, 1.85%, 9.2%, 16.6%, 38.8% and 27.7% of the isolates were intermediate to SCF, TET, AMK, NT, LVF and TG, respectively. Similarly, all of the environmental A.baumannii isolates (n= 7) were resistant to SAM, PIP, TZP, CFZ, CEF, IPM, MER and CIP, and all were susceptible to TG and COL. The resistance rates of the environmental isolates to SCF, AMK, GEN, NT, LVF, TET and SXT were determined as 57.1%, 85.7%, 85.7%, 28.8%, 28.6%, 85.7% and 57.1%, respectively. PFGE analysis done by the use of ApaI enzyme revealed the presence of one major clone. Dendogram analysis indicated that environmental and clinical isolates were in the same clone indicating that the outbreak was possibly originated from the same internal ICUs. Our data emphasized that multidrug resistant A.baumannii isolates were quite common in our hospital, and enviromental cross-contamination throughout the year was confirmed by molecular methods. Despite the precautions such as continous education on effective hand washing, use of gloves and hospital cleaning, established in our hospital, this single clonal spread was attributed to staff shortage and poor adherence to infection control rules. In conclusion, for the prevention of dissemination of multidrug resistant A.baumannii strains and control of nosocomial infections, infection control strategies should be established and strict compliance to these rules should be provided.

TGF-beta3 is expressed in taste buds and inhibits proliferation of primary cultured taste epithelial cells.

PubMed

Nakamura, Shin-ichi; Kawai, Takayuki; Kamakura, Takashi; Ookura, Tetsuya

2010-01-01

Transforming growth factor-betas (TGF-betas), expressed in various tissues, play important roles in embryonic development and adult tissue homeostasis through their effects on cell proliferation, cell differentiation, cell death, and cell motility. However, expression of TGF-beta signaling components and their biological effect on taste epithelia has not been elucidated. We performed expression analysis of TGF-beta signaling components in taste epithelia and found that the TGF-beta3 mRNA was specifically expressed in taste buds. Type II TGF-betas receptor (TbetaR-II) mRNA was specifically expressed in the tongue epithelia including the taste epithelia. To elucidate the biological function of TGF-beta3 in taste epithelia, we performed proliferation assay with primary cultured taste epithelial cells. In the presence of TGF-beta3, percentage of BrdU-labeled cells decreased significantly, suggesting that the TGF-beta3 inhibited the proliferation of cultured taste epithelial cells through inhibiting cell-cycle entry into S phase. By quantitative reverse transcription-polymerase chain reaction assay, we found that the TGF-beta3 resulted in an increased level of expression of p15Ink4b and p21Cip1, suggesting that the TGF-beta3 inhibited the taste epithelial cell proliferation through inhibiting G1cyclin-Cdk complexes. Taken together, these results suggested that the TGF-beta3 may regulate taste epithelial cell homeostasis through controlling cell proliferation.

Inhibition of histone deacetylase for the treatment of biliary tract cancer: A new effective pharmacological approach

PubMed Central

Bluethner, Thilo; Niederhagen, Manuel; Caca, Karel; Serr, Frederik; Witzigmann, Helmut; Moebius, Christian; Mossner, Joachim; Wiedmann, Marcus

2007-01-01

AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21WAF-1/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 (3 d) 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1/CIP-1, induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVP-LBH589 significantly reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation (MIB-1). CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended. PMID:17729398

Comparison of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia.

PubMed

Mayer, Karin; Hahn-Ast, Corinna; Mückter, Sara; Schmitz, Andrea; Krause, Simon; Felder, Linda; Bekeredjian-Ding, Isabelle; Molitor, Ernst; Brossart, Peter; von Lilienfeld-Toal, Marie

2015-05-01

Recent meta-analyses showed that antibiotic prophylaxis in patients with neutropenia after chemotherapy reduced the incidence of fever and mortality rate. Fluoroquinolones appear to be most effective and well tolerated. Thus, in April 2008, we changed our antibiotic prophylaxis regimen from cotrimoxazole/colistin (COT/COL) to the fluoroquinolone ciprofloxacin (CIP) in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to compare efficacy and development of bacterial resistance with two different prophylaxis regimens over a time period of more than 4 years. Induction chemotherapy courses given for AML during the antibiotic prophylaxis period with COT/COL (01/2006-04/2008) and CIP (04/2008-06/2010) were retrospectively analyzed with a standard questionnaire. Eighty-five courses in the COT/COL group and 105 in the CIP group were analyzed. The incidence of fever was not significantly different (COT/COL 80 % vs CIP 77 %; p = 0.724). Also, the rate of microbiologically documented infections was nearly the same (29 vs 26 %; p = 0.625). In addition, there was no significant difference in the incidence of clinically documented infections (11 vs 19 %; p = 0.155) or in the rates of detected gram-positive and gram-negative bacteria. Of note, there was no increase in resistance rates or cases with Clostridium difficile-associated diarrhea in the CIP group. The antibiotic prophylaxis with CIP compared to COT/COL in AML was similarly effective with no increase in bacterial resistance. COT/COL may have the advantages of providing additional prophylaxis against Pneumocystis jirovecii pneumonia and leaving fluoroquinolones as an additional option for treatment of febrile neutropenia.

The National Plan for Research and Development In Support of Critical Infrastructure Protection

DTIC Science & Technology

2004-01-01

vulnerabilities and highlight areas for improvement. As part of this effort, CIP &CP has cre- ated a research and development agenda aimed at improving...Infrastructure Protection Research and Development Plan 13 LONG-TERM DIRECTION PROVIDED BY THE CIP R&D PLAN The creation of a national critical...Research and Development Plan 20 Mapping to Other National R&D Plans The many R&D plans outside the direct context of CIP underway within DHS, other

Integrating Intelligence and Acquisition to Meet Evolving Threats: Interview With Dr. Sean Kirkpatrick of the Defense Intelligence Agency

DTIC Science & Technology

2015-06-01

CIPs ) We have drafted policy language that Defense Acquisition, Technology, and Logistics now is coordinating that will make it a requirement for at...least Acquisition Category I programs to identify CIPs early and for the intelligence community to monitor those and report breaches throughout the...are coming. Two important ones are the Critical Intelligence Parameters ( CIPs ) policy and the change to the System Threat Assessment Re- port (STAR

Mississippi Curriculum Framework for Computer Information Systems Technology. Computer Information Systems Technology (Program CIP: 52.1201--Management Information Systems & Business Data). Computer Programming (Program CIP: 52.1201). Network Support (Program CIP: 52.1290--Computer Network Support Technology). Postsecondary Programs.

ERIC Educational Resources Information Center

Mississippi Research and Curriculum Unit for Vocational and Technical Education, State College.

This document, which is intended for use by community and junior colleges throughout Mississippi, contains curriculum frameworks for two programs in the state's postsecondary-level computer information systems technology cluster: computer programming and network support. Presented in the introduction are program descriptions and suggested course…

Chronic intestinal pseudo-obstruction.

PubMed

Gabbard, Scott L; Lacy, Brian E

2013-06-01

Chronic intestinal pseudo-obstruction (CIP) is a rare and serious disorder of the gastrointestinal (GI) tract characterized as a motility disorder with the primary defect of impaired peristalsis; symptoms are consistent with a bowel obstruction, although mechanical obstruction cannot be identified. CIP is classified as a neuropathy, myopathy, or mesenchymopathy; it is a neuropathic process in the majority of patients. The natural history of CIP is generally that of a progressive disorder, although occasional patients with secondary CIP note significant symptomatic improvement when the underlying disorder is identified and treated. Symptoms vary from patient to patient depending on the location of the luminal GI tract involved and the degree of involvement; however, the small intestine is nearly always involved. Common symptoms include dysphagia, gastroesophageal reflux, abdominal pain, nausea, vomiting, bloating, abdominal distension, constipation or diarrhea, and involuntary weight loss. Unfortunately, these symptoms are nonspecific, which can contribute to misdiagnosis or a delay in diagnosis and treatment. Since many of the symptoms and signs suggest a mechanical bowel obstruction, diagnostic tests typically focus on uncovering a mechanical obstruction, although routine tests do not identify an obstructive process. Nutrition supplementation is required for many patients with CIP due to symptoms of dysphagia, nausea, vomiting, and weight loss. This review discusses the epidemiology, etiology, pathogenesis, diagnosis, and treatment of patients with CIP, with an emphasis on nutrition assessment and treatment options for patients with nutrition compromise.

Development of sensitive and reliable LC-MS/MS methods for the determination of three fluoroquinolones in water and fish tissue samples and preliminary environmental risk assessment of their presence in two rivers in northern Poland.

PubMed

Wagil, Marta; Kumirska, Jolanta; Stolte, Stefan; Puckowski, Alan; Maszkowska, Joanna; Stepnowski, Piotr; Białk-Bielińska, Anna

2014-09-15

Antibiotic consumption (e.g. fluoroquinolones (FQs)) and, as a consequence, their presence in the environment, have received a lot of attention in the last several years due to increasing numbers of diseases and infections that are becoming resistant to traditional treatments for both humans and animals. In addition, even though antibiotics are safe for human and veterinary usage, ecosystems may be exposed to these substances. In this study, analytical methods for determining enrofloxacin (ENR), norfloxacin (NOR) and ciprofloxacin (CIP) in water samples and fish tissue based on the LC-MS/MS technique were developed and validated. As there is no data available concerning the risks posed by antibiotics in Poland, the proposed methods were applied for monitoring drug presence in environmental samples collected from two rivers in northern Poland. Evaluations of the ecotoxicity of ENR, NOR and CIP towards four different species of aquatic organisms: marine bacteria (Vibrio fischeri), green algae (Scenedesmus vacuolatus), duckweed (Lemna minor) and crustacean (Daphnia magna), were also carried out. All the investigated compounds were detected at least once in the survey. NOR was found to be the most ubiquitous drug with concentrations of up to 442.8 ng L(-1). Moreover, it was established that L. minor is the most sensitive species to the investigated drugs (EC50NOR = 0.13 mg L(-1), EC50ENR = 0.22 mg L(-1) and EC50CIP = 0.34 mg L(-1)). The calculated risk quotient (RQ) values confirmed that the concentrations of the investigated FQs in the environmental samples were at a level of moderate environmental risk (1

Fundamental properties of monolithic bentonite buffer material formed by cold isostatic pressing for high-level radioactive waste repository

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

Kawakami, S.; Yamanaka, Y.; Kato, K.

1999-07-01

The methods of fabrication, handling, and emplacement of engineered barriers used in a deep geological repository for high level radioactive waste should be planned as simply as possible from the engineering and economic viewpoints. Therefore, a new concept of a monolithic buffer material around a waste package have been proposed instead of the conventional concept with the use of small blocks, which would decrease the cost for buffer material. The monolithic buffer material is composed of two parts of highly compacted bentonite, a cup type body and a cover. As the forming method of the monolithic buffer material, compaction bymore » the cold isostatic pressing process (CIP) has been employed. In this study, monolithic bentonite bodies with the diameter of about 333 mm and the height of about 455 mm (corresponding to the approx. 1/5 scale for the Japanese reference concept) were made by the CIP of bentonite powder. The dry densities: {rho}d of the bodies as a whole were measured and the small samples were cut from several locations to investigate the density distribution. The swelling pressure and hydraulic conductivity as function of the monolithic body density for CIP-formed specimens were also measured. High density ({rho}d: 1.4--2.0 Mg/m{sup 3}) and homogeneous monolithic bodies were formed by the CIP. The measured results of the swelling pressure (3--15 MPa) and hydraulic conductivity (0.5--1.4 x 10{sup {minus}13} m/s) of the specimens were almost the same as those for the uniaxial compacted bentonite in the literature. It is shown that the vacuum hoist system is an applicable handling method for emplacement of the monolithic bentonite.« less

The Visual Representation of 3D Object Orientation in Parietal Cortex

PubMed Central

Cowan, Noah J.; Angelaki, Dora E.

2013-01-01

An accurate representation of three-dimensional (3D) object orientation is essential for interacting with the environment. Where and how the brain visually encodes 3D object orientation remains unknown, but prior studies suggest the caudal intraparietal area (CIP) may be involved. Here, we develop rigorous analytical methods for quantifying 3D orientation tuning curves, and use these tools to the study the neural coding of surface orientation. Specifically, we show that single neurons in area CIP of the rhesus macaque jointly encode the slant and tilt of a planar surface, and that across the population, the distribution of preferred slant-tilts is not statistically different from uniform. This suggests that all slant-tilt combinations are equally represented in area CIP. Furthermore, some CIP neurons are found to also represent the third rotational degree of freedom that determines the orientation of the image pattern on the planar surface. Together, the present results suggest that CIP is a critical neural locus for the encoding of all three rotational degrees of freedom specifying an object's 3D spatial orientation. PMID:24305830

The Group B Streptococcus–Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways

PubMed Central

Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla

2016-01-01

The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. PMID:26608922

A Curved Image-Plate Detector System for High-Resolution Synchrotron X-ray Diffraction

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

Sarin, P.; Haggerty, R; Yoon, W

2009-01-01

The developed curved image plate (CIP) is a one-dimensional detector which simultaneously records high-resolution X-ray diffraction (XRD) patterns over a 38.7 2{theta} range. In addition, an on-site reader enables rapid extraction, transfer and storage of X-ray intensity information in {le}30 s, and further qualifies this detector to study kinetic processes in materials science. The CIP detector can detect and store X-ray intensity information linearly proportional to the incident photon flux over a dynamical range of about five orders of magnitude. The linearity and uniformity of the CIP detector response is not compromised in the unsaturated regions of the image plate,more » regardless of saturation in another region. The speed of XRD data acquisition together with excellent resolution afforded by the CIP detector is unique and opens up wide possibilities in materials research accessible through X-ray diffraction. This article presents details of the basic features, operation and performance of the CIP detector along with some examples of applications, including high-temperature XRD.« less

Evaluation of the interaction of cyclin-dependent kinase 5 with activator p25 and with p25-derived inhibitor CIP.

PubMed

Cardone, Antonio; Albers, R Wayne; Sriram, Ram D; Pant, Harish C

2010-05-01

A high-affinity inhibitor protein called CIP, produced by small truncations of p35, was experimentally identified. P35 is a physiological activator of the cyclin-dependent kinase cdk5. P25 is derived from proteolytic truncation of p35 within "stressed" neurons, and it is associated with the hyperphosphorylation of specific neuronal proteins, typically occurring in neurodegenerative diseases such as Alzheimer's. Here, we report a study of the binding mechanisms of the cdk5-p25 and cdk5-CIP complexes. This provides a better understanding of the source of the inhibitory activity of the protein CIP. We use a geometry-based technique to test the hypothesis that p25's truncation increases the flexibility of CIP and thus prevents cdk5 from reaching its active conformation. Our study is based on a geometry-based alignment algorithm, which aligns two given protein conformations with respect to their interfaces. Our results support the flexibility hypothesis and will be used as a basis for targeted molecular dynamics simulations.

A method to determine the protection zone of chemical industrial park considering air quality, health risk and environmental risk: a case study.

PubMed

Shi, Jingang; Zhang, Mingbo; Li, Dong; Liu, Jia

2018-04-01

In China, chemical enterprises are required to cluster into a large number of chemical industrial parks (CIPs), which increase risks and threats to the environment and human being's health due to aggregation of the complicated chemical process and huge unit scale. Setting a scientific and reasonable protection zone around CIP is a very efficient way to protect surrounding people's health. A method was designed to determine the comprehensive protection zone of CIP, taking into account multiple factors: air quality, health risk and environmental risk. By establishing a comprehensive and multi-levels index system, the protection zone and the corresponding environmental risk management countermeasures can be proposed hierarchically, which are very important to the development and environmental risk management of CIP. A CIP located in coastal area of Shandong Province was studied, and it is turned out that the method to determine the protection zone of chemical industrial park considering air quality, health risk and environmental risk has great advantages compared with other methods.

The Bmi-1 helix–turn and ring finger domains are required for Bmi-1 antagonism of (–) epigallocatechin-3-gallate suppression of skin cancer cell survival

PubMed Central

Balasubramanian, Sivaprakasam; Scharadin, Tiffany M.; Han, Bingshe; Xu, Wen; Eckert, Richard L.

2016-01-01

The Bmi-1 Polycomb group (PcG) protein is an important epigenetic regulator of chromatin status. Elevated Bmi-1 expression is observed in skin cancer and contributes to cancer cell survival. (–) Epigallocatechin-3-gallate (EGCG), an important green tea-derived cancer prevention agent, reduces Bmi-1 level resulting in reduced skin cancer cell survival. This is associated with increased p21Cip1 and p27Kip1 expression, reduced cyclin, and cyclin dependent kinase expression, and increased cleavage of apoptotic markers. These EGCG-dependent changes are attenuated by vector-mediated maintenance of Bmi-1 expression. In the present study, we identify Bmi-1 functional domains that are required for this response. Bmi-1 expression reverses the EGCG-dependent reduction in SCC-13 cell survival, but Bmi-1 mutants lacking the helix–turn–helix–turn–helix–turn (Bmi-1ΔHT) or ring finger (Bmi-1ΔRF) domains do not reverse the EGCG impact. The reduction in Ring1B ubiquitin ligase activity, observed in the presence of mutant Bmi-1, is associated with reduced ability of these mutants to interact with and activate Ring1B ubiquitin ligase, the major ligase responsible for the ubiquitination of histone H2A during chromatin condensation. This results in less chromatin condensation leading to increased tumor suppressor gene expression and reduced cell survival; thereby making the cells more susceptible to the anti-survival action of EGCG. We further show that these mutants act in a dominant-negative manner to inhibit the action of endogenous Bmi-1. Our results suggest that the HT and RF domains are required for Bmi-1 ability to maintain skin cancer cell survival in response to cancer preventive agents. PMID:25843776

Rapid alterations of cell cycle control proteins in human T lymphocytes in microgravity

PubMed Central

2012-01-01

In our study we aimed to identify rapidly reacting gravity-responsive mechanisms in mammalian cells in order to understand if and how altered gravity is translated into a cellular response. In a combination of experiments using "functional weightlessness" provided by 2D-clinostats and real microgravity provided by several parabolic flight campaigns and compared to in-flight-1g-controls, we identified rapid gravity-responsive reactions inside the cell cycle regulatory machinery of human T lymphocytes. In response to 2D clinorotation, we detected an enhanced expression of p21 Waf1/Cip1 protein within minutes, less cdc25C protein expression and enhanced Ser147-phosphorylation of cyclinB1 after CD3/CD28 stimulation. Additionally, during 2D clinorotation, Tyr-15-phosphorylation occurred later and was shorter than in the 1 g controls. In CD3/CD28-stimulated primary human T cells, mRNA expression of the cell cycle arrest protein p21 increased 4.1-fold after 20s real microgravity in primary CD4+ T cells and 2.9-fold in Jurkat T cells, compared to 1 g in-flight controls after CD3/CD28 stimulation. The histone acetyltransferase (HAT) inhibitor curcumin was able to abrogate microgravity-induced p21 mRNA expression, whereas expression was enhanced by a histone deacetylase (HDAC) inhibitor. Therefore, we suppose that cell cycle progression in human T lymphocytes requires Earth gravity and that the disturbed expression of cell cycle regulatory proteins could contribute to the breakdown of the human immune system in space. PMID:22273506

Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI.

PubMed

Guerard, Marie; Robin, Thomas; Perron, Pascal; Hatat, Anne-Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoit; Coll, Jean-Luc; Lantuejoul, Sylvie; Eymin, Beatrice; Hurbin, Amandine; Gazzeri, Sylvie

2018-04-28

Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-β1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

12 CFR 222.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2011 CFR

2011-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

12 CFR 222.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2014 CFR

2014-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

12 CFR 222.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2013 CFR

2013-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

12 CFR 571.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2014 CFR

2014-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

12 CFR 222.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2012 CFR

2012-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

12 CFR 571.82 - Duties of users regarding address discrepancies.

Code of Federal Regulations, 2013 CFR

2013-01-01

... consumer's identity in accordance with the requirements of the Customer Identification Program (CIP) rules... of address notifications, other customer account records, or retained CIP documentation; or (C...

Effects of the Caregiver Interaction Profile Training on Caregiver-Child Interactions in Dutch Child Care Centers: A Randomized Controlled Trial.

PubMed

Helmerhorst, Katrien O W; Riksen-Walraven, J Marianne A; Fukkink, Ruben G; Tavecchio, Louis W C; Gevers Deynoot-Schaub, Mirjam J J M

2017-01-01

Previous studies underscore the need to improve caregiver-child interactions in early child care centers. In this study we used a randomized controlled trial to examine whether a 5-week video feedback training can improve six key interactive skills of caregivers in early child care centers: Sensitive responsiveness, respect for autonomy, structuring and limit setting, verbal communication, developmental stimulation, and fostering positive peer interactions. A total of 139 caregivers from 68 early child care groups for 0- to 4-year-old children in Dutch child care centers participated in this RCT, 69 in the intervention condition and 70 in the control condition. Caregiver interactive skills during everyday interactions with the children were rated from videotape using the Caregiver Interaction Profile (CIP) scales at pretest, posttest, and follow-up 3 months after the posttest. Results at posttest indicate a significant positive training effect on all six caregiver interactive skills. Effect sizes of the CIP training range between d  = 0.35 and d  = 0.79. Three months after the posttest, caregivers in the intervention group still scored significantly higher on sensitive responsiveness, respect for autonomy, verbal communication, and fostering positive peer interactions than caregivers in the control group with effect sizes ranging between d  = 0.47 and d  = 0.70. This study shows that the quality of caregiver-child interactions can be improved for all six important caregiver skills, with a relatively short training program. Possible ways to further improve the training and to implement it in practice and education are discussed.

p21, an important mediator of quiescence during pituitary tumor formation, is dispensable for normal pituitary development during embryogenesis.

PubMed Central

Monahan, Pamela; Himes, Ashley D.; Parfieniuk, Agata; Raetzman, Lori T.

2011-01-01

A delicate balance between proliferation and differentiation must be maintained in the developing pituitary to ensure the formation of the appropriate number of hormone producing cells. In the adult, proliferation is actively restrained to prevent tumor formation. The cyclin dependent kinase inhibitors (CDKIs) of the CIP/KIP family, p21, p27 and p57, mediate cell cycle inhibition. Although p21 is induced in the pituitary upon loss of Notch signaling or initiation of tumor formation to halt cell cycle progression, its role in normal pituitary organogenesis has not been explored. In wildtype pituitaries, expression of p21 is limited to a subset of cells embryonically as well as during the postnatal proliferative phase. Mice lacking p21 do not have altered cell proliferation during early embryogenesis, but do show a slight delay in separation of proliferating progenitors from the oral ectoderm. By embryonic day 16.5, p21 mutants have an alteration in the spatial distribution of proliferating pituitary progenitors, however there is no overall change in proliferation. At postnatal day 21, there appears to be no change in proliferation, as assessed by cells expressing Ki67 protein. However, p21 mutant pituitaries have significantly less mRNA of Myc and the cyclins Ccnb1, Ccnd1, Ccnd2 and Ccne1 than wildtype pituitaries. Interestingly, unlike the redundant role in cell cycle inhibition uncovered in p27/p57 double mutants, the pituitary of p21/p27 double mutants has a similar proliferation profile to p27 single mutants at the time points examined. Taken together, these studies demonstrate that unlike p27 or p57, p21 does not play a major role in control of progenitor proliferation in the developing pituitary. However, p21 may be required to maintain normal levels of cell cycle components. PMID:22154697

A reference model for model-based design of critical infrastructure protection systems

NASA Astrophysics Data System (ADS)

Shin, Young Don; Park, Cheol Young; Lee, Jae-Chon

2015-05-01

Today's war field environment is getting versatile as the activities of unconventional wars such as terrorist attacks and cyber-attacks have noticeably increased lately. The damage caused by such unconventional wars has also turned out to be serious particularly if targets are critical infrastructures that are constructed in support of banking and finance, transportation, power, information and communication, government, and so on. The critical infrastructures are usually interconnected to each other and thus are very vulnerable to attack. As such, to ensure the security of critical infrastructures is very important and thus the concept of critical infrastructure protection (CIP) has come. The program to realize the CIP at national level becomes the form of statute in each country. On the other hand, it is also needed to protect each individual critical infrastructure. The objective of this paper is to study on an effort to do so, which can be called the CIP system (CIPS). There could be a variety of ways to design CIPS's. Instead of considering the design of each individual CIPS, a reference model-based approach is taken in this paper. The reference model represents the design of all the CIPS's that have many design elements in common. In addition, the development of the reference model is also carried out using a variety of model diagrams. The modeling language used therein is the systems modeling language (SysML), which was developed and is managed by Object Management Group (OMG) and a de facto standard. Using SysML, the structure and operational concept of the reference model are designed to fulfil the goal of CIPS's, resulting in the block definition and activity diagrams. As a case study, the operational scenario of the nuclear power plant while being attacked by terrorists is studied using the reference model. The effectiveness of the results is also analyzed using multiple analysis models. It is thus expected that the approach taken here has some merits over the traditional design methodology of repeating requirements analysis and system design.

Ciprofloxacin-lidocaine-based hydrogel: development, characterization, and in vivo evaluation in a second-degree burn model.

PubMed

Sanchez, María Florencia; Breda, Susana Andrea; Soria, Elio Andrés; Tártara, Luis Ignacio; Manzo, Rubén Hilario; Olivera, María Eugenia

2018-04-13

The purpose of this work was to develop an effective carbomer hydrogel to be used to treat second-degree burns that combined ciprofloxacin and lidocaine (CbCipLid hydrogel). Its antibiotic and anesthetic efficacy and the physical and chemical properties of the CbCipLid hydrogel (release rate and kinetics, rheology, appearance, and drug content) were evaluated both before and after a sterilization cycle and also after 6 months of storage. For the in vivo studies, second-degree burns were developed in a rat model. Animals were divided into three groups: CbCipLid hydrogel, silver sulfadiazine cream (reference), and carbomer hydrogel (as control). The treatments were applied daily for 21 days, and the healing was monitored by macroscopic observation and histologic evaluation. The anesthetic effect was evaluated through the corneal touch threshold in a rabbit eye model. The CbCipLid hydrogel obtained is transparent and allows the loading of ciprofloxacin above its solubility at a neutral pH, with a rheology which is convenient for topical administration. Its physical and chemical properties remained unchanged after sterilization and for at least six additional months. Both ciprofloxacin and lidocaine are reversibly released from the CbCipLid hydrogel with a kinetics fitting the Higuchi model. The presence of a biologic-like fluid increased the rate of drug delivery through an ionic exchange mechanism. Treatment with the CbCipLid hydrogel decreased the wound-healing period, compared with the reference, and was associated with a greater number of fibroblasts and a faster rate of epithelialization and dermis reconstruction. These differences were assigned to the moist environment provided by the hydrogel and also to the presence of a therapeutic concentration of ciprofloxacin. Moreover, CbCipLid hydrogel provides an immediate anesthetic effect, which is significantly more intense than that of the reference. Based on these results, it is believed that the CbCipLid hydrogel could be a potential candidate in the prophylaxis/treatment of second-degree burns.

Enantioselective extraction of (+)-(S)-citalopram and its main metabolites using a tailor-made stir bar chiral imprinted polymer for their LC-ESI-MS/MS quantitation in urine samples.

PubMed

Unceta, Nora; Gómez-Caballero, Alberto; García, Deiene; Díaz, Goretti; Guerreiro, Antonio; Piletsky, Sergey; Goicolea, M Aránzazu; Barrio, Ramón J

2013-11-15

This paper reports the application of a chiral imprinted polymer (CIP)-coated stir bar for the selective extraction of (+)-(S)-citalopram (SCIT) and its main metabolites, (+)-(S)-desmethylcitalopram (SDCIT) and (+)-(S)-didesmethylcitalopram (SDDCIT), from urine samples. The developed device has been demonstrated to be capable of selectively extracting the three target analytes from urine samples without saturating the imprinted sites. A CIP-coated stir bar sorptive extraction procedure (CIP-SBSE) is proposed for the isolation of SCIT, SDCIT and SDDCIT followed by their subsequent analysis using liquid chromatography ion trap mass spectrometry (LC-ITMS). Deuterated SCIT-d6 was used as an internal standard. The method was validated using a standard procedure, which revealed that a quantification of 5 ng mL(-1) was obtained in urine samples and that the accuracy and precision were within the established values while no matrix effect was observed. Copyright © 2013 Elsevier B.V. All rights reserved.

Epidermal growth factor treatment decreases mortality and is associated with improved gut integrity in sepsis

PubMed Central

Clark, Jessica A.; Clark, Andrew T.; Hotchkiss, Richard S.; Buchman, Timothy G.; Coopersmith, Craig M.

2007-01-01

Epidermal growth factor (EGF) is a cytoprotective peptide that has healing effects on the intestinal mucosa. We sought to determine whether systemic administration of EGF following the onset of sepsis improved intestinal integrity and decreased mortality. FVB/N mice were subjected to either sham laparotomy or 2×23 cecal ligation and puncture (CLP). Septic mice were further randomized to receive intraperitoneal injection of either 150 μg/kg/day EGF or 0.9% saline. Circulating EGF levels were decreased following CLP compared to sham animals but were unaffected by giving exogenous EGF treatment. In contrast, intestinal EGF levels increased following CLP, and were further augmented by exogenous EGF treatment. Intestinal EGF-receptor (EGF-R) was increased following CLP whether assayed by immunohistochemistry, real-time PCR or western blot, and exogenous EGF treatment decreased intestinal EGF-R. Villus length decreased 2-fold between sham and septic animals, and EGF treatment resulted in near total restitution of villus length. Sepsis decreased intestinal proliferation and increased intestinal apoptosis. This was accompanied by increased expression of the pro-apoptotic proteins Bid and FADD, as well as the cyclin-dependent kinase inhibitor p21cip1/waf. EGF treatment after the onset of sepsis restored both proliferation and apoptosis to levels seen in sham animals and normalized expression of Bid, FADD, and p21cip1/waf. To determine whether improvements in gut homeostasis were associated with a decrease in sepsis-induced mortality, septic mice with or without EGF treatment after CLP were followed seven days for survival. Mortality decreased from 60% to 30% in mice treated with EGF after the onset of sepsis (p<0.05). EGF may thus be a potential therapeutic agent for the treatment of sepsis, in part due to its ability to protect intestinal integrity. PMID:18004230

Characterization of photo-transformation products of the antibiotic drug Ciprofloxacin with liquid chromatography-tandem mass spectrometry in combination with accurate mass determination using an LTQ-Orbitrap.

PubMed

Haddad, Tarek; Kümmerer, Klaus

2014-11-01

The presence of pharmaceuticals, especially antibiotics, in the aquatic environment is of growing concern. Several studies have been carried out on the occurrence and environmental risk of these compounds. Ciprofloxacin (CIP), a broad-spectrum anti-microbial second-generation fluoroquinolone, is widely used in human and veterinary medicine. In this work, photo-degradation of CIP in aqueous solution using UV and xenon lamps was studied. The transformation products (TPs), created from CIP, were initially analyzed by an ion trap in the MS, MS/MS and MS(3) modes. These data were used to clarify the structures of the degradation products. Furthermore, the proposed products were confirmed by accurate mass measurement and empirical formula calculation for the molecular ions of TPs using LTQ-Orbitrap XL mass spectrometer. The degree of mineralization, the abundance of detected TPs and degradation pathways were determined. Eleven TPs were detected in the present study. TP1, which was never detected before, was structurally characterized in this work. All TPs still retained the core quinolone structure, which is responsible for the biological activity. As mineralization of CIP and its transformation products did not happen, the formation of stable TPs can be expected in waste water treatment and in surface water with further follow-up problems. Copyright © 2014 Elsevier Ltd. All rights reserved.

RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC

PubMed Central

Majumder, Mrinmoyee; House, Reniqua; Palanisamy, Nallasivam; Qie, Shuo; Day, Terrence A.; Neskey, David; Diehl, J. Alan

2016-01-01

RNA-binding proteins (RBP) regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1), plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck squamous cell carcinoma targets (G-quadruplex (G4) RNA structure within) both mRNA encoding p21 (Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A, Cip1) and the non-coding RNA Telomerase RNA Component (TERC), and regulates their turnover to avoid senescence. Silencing of FXR1 in cancer cells triggers the activation of Cyclin-Dependent Kinase Inhibitors, p53, increases DNA damage, and ultimately, cellular senescence. Overexpressed FXR1 binds and destabilizes p21 mRNA, subsequently reduces p21 protein expression in oral cancer cells. In addition, FXR1 also binds and stabilizes TERC RNA and suppresses the cellular senescence possibly through telomerase activity. Finally, we report that FXR1-regulated senescence is irreversible and FXR1-depleted cells fail to form colonies to re-enter cellular proliferation. Collectively, FXR1 displays a novel mechanism of controlling the expression of p21 through p53-dependent manner to bypass cellular senescence in oral cancer cells. PMID:27606879

34 CFR 600.10 - Date, extent, duration, and consequence of eligibility.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Classification of Instructional Programs (CIP) code under the taxonomy of instructional program classifications... same CIP code as another program offered by the institution but leads to a different degree or...

34 CFR 600.10 - Date, extent, duration, and consequence of eligibility.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Classification of Instructional Programs (CIP) code under the taxonomy of instructional program classifications... same CIP code as another program offered by the institution but leads to a different degree or...

34 CFR 600.10 - Date, extent, duration, and consequence of eligibility.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Classification of Instructional Programs (CIP) code under the taxonomy of instructional program classifications... same CIP code as another program offered by the institution but leads to a different degree or...

34 CFR 600.10 - Date, extent, duration, and consequence of eligibility.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Classification of Instructional Programs (CIP) code under the taxonomy of instructional program classifications... same CIP code as another program offered by the institution but leads to a different degree or...

Theoretical surface core-level shifts for Be(0001)

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

Feibelman, P.J.

1994-05-15

Core-ionization potentials (CIP's) are computed for Be(0001). Three core features are observed in corresponding photoelectron spectra, with CIP's shifted relative to the bulk core level by [minus]0.825, [minus]0.570, and [minus]0.265 eV. The computed CIP shifts for the outer and subsurface layers, [minus]0.60 and [minus]0.29 eV, respectively, agree with the latter two of these. It is surmised that the [minus]0.825-eV shift is associated with a surface defect. The negative signs of the Be(0001) surface core-level shifts do not fit into the thermochemical picture widely used to explain CIP shifts. The reason is that a core-ionized Be atom is too small tomore » bond effectively to the remainder of the unrelaxed Be lattice.« less

Pyramiding of insecticidal compounds for control of the cowpea bruchid (Callosobruchus maculatus F.).

PubMed

Tarver, Matthew R; Shade, Richard E; Shukle, Richard H; Moar, William J; Muir, William M; Murdock, Larry M; Pittendrigh, Barry R

2007-05-01

The cowpea bruchid (Callosobruchus maculatus F.) (Chrysomelidae: Bruchini) is a major pest of stored cowpea grain. With limited available technologies for controlling the bruchid, transgenic cowpeas with bruchid resistance genes engineered into them could become the next management tools. An investigation was made of two different sets of potential transgenic insecticidal compounds using an artificial seed system: (i) CIP-PH-BT-J and recombinant egg white avidin, and (ii) avidin and wheat alpha-amylase inhibitor. CIP-PH-BT-J (0.1%; 1000 mg kg(-1)) and recombinant egg white avidin (0.006%; 60 mg kg(-1)) incorporated separately into artificial seeds caused 98.2 and 99% larval mortality rates respectively. Combining CIP-PH-BT-J and avidin in the same artificial seed provided additional mortality compared with each factor incorporated singly; no insects survived in seeds with the combined toxins. Similarly, when avidin and wheat alpha-amylase inhibitor (alphaAI) (1%; 10 g kg(-1)) were incorporated separately into artificial seeds, this caused 99.8 and 98% mortality respectively. However, in combination, avidin and alphaAI did not increase mortality, but they did cause a significant increase in developmental time of the cowpea bruchids. These results emphasize that the joint action of potential insecticidal compounds cannot be predicted from results obtained separately for each compound, and they suggest potential transgenes for further consideration.

Microencapsulation of Lactobacillus plantarum spp in an alginate matrix coated with whey proteins.

PubMed

Gbassi, Gildas Komenan; Vandamme, Thierry; Ennahar, Saïd; Marchioni, Eric

2009-01-31

Whey proteins were used as a coating material to improve encapsulation of Lactobacillus plantarum strains in calcium alginate beads. L. plantarum 299v, L. plantarum 800 and L. plantarum CIP A159 were used in this study. Inactivation experiments were carried out in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Cross-sections of freeze-dried beads revealed the random distribution of bacteria throughout the alginate network. From an initial count of 10.04+/-0.01 log(10) CFU g(-1) for L. plantarum 299v, 10.12+/-0.04 for L. plantarum CIP A159 and 10.03+/-0.01 for L. plantarum 800, bacteria in coated beads and incubated in SGF (37 degrees C, 60 min) showed a better survival for L. plantarum 299v, L. plantarum CIP A159 and L. plantarum 800 (respectively 7.76+/-0.12, 6.67+/-0.08 and 5.81+/-0.25 log(10) CFU g(-1)) when compared to uncoated beads (2.19+/-0.09, 1.89+/-0.09 and 1.65+/-0.10 log(10) CFU g(-1)) (p<0.05). Only bacteria in the coated beads survived in the SIF medium (37 degrees C, 180 min) after SGF treatment. This preliminary work showed that whey proteins are a convenient, cheap and efficient material for coating alginate beads loaded with bacteria.

Investigation of residual fluoroquinolones in a soil-vegetable system in an intensive vegetable cultivation area in Northern China.

PubMed

Li, Xue-Wen; Xie, Yun-Feng; Li, Cang-Lin; Zhao, Hui-Nan; Zhao, Hui; Wang, Ning; Wang, Jin-Feng

2014-01-15

One of the largest vegetable cultivation field sites in Northeast China was selected to investigate the occurrence and distribution pattern of fluoroquinolones (FQs) in the soil-vegetable system. A total of 100 surface soil samples and 68 vegetable samples were collected from this study area. The antibiotic concentration was analyzed using high-performance liquid chromatography tandem mass spectrometry. Results indicated the presence of FQs in all soil samples. Ciprofloxacin (CIP) had the highest mean concentration, at 104.4 μg · kg(-1) in the soil, a level that represents a relatively high risk to the environment and to human health. However, in the vegetable samples, norfloxacin (NOR) was significantly higher than CIP and enrofloxacin (ENR), ranging from 18.2 to 658.3 μg · kg(-1). The transfer ability of NOR in soil-vegetables is greater than that of CIP and ENR. Moreover, we found that the solanaceous fruits had a higher antibiotic accumulation ability than the leafy vegetables. Taken together, these data indicate that greater attention should be paid to the region in which vegetables with higher accumulation ability are grown. © 2013.

Posterior Parietal Cortex Drives Inferotemporal Activations During Three-Dimensional Object Vision.

PubMed

Van Dromme, Ilse C; Premereur, Elsie; Verhoef, Bram-Ernst; Vanduffel, Wim; Janssen, Peter

2016-04-01

The primate visual system consists of a ventral stream, specialized for object recognition, and a dorsal visual stream, which is crucial for spatial vision and actions. However, little is known about the interactions and information flow between these two streams. We investigated these interactions within the network processing three-dimensional (3D) object information, comprising both the dorsal and ventral stream. Reversible inactivation of the macaque caudal intraparietal area (CIP) during functional magnetic resonance imaging (fMRI) reduced fMRI activations in posterior parietal cortex in the dorsal stream and, surprisingly, also in the inferotemporal cortex (ITC) in the ventral visual stream. Moreover, CIP inactivation caused a perceptual deficit in a depth-structure categorization task. CIP-microstimulation during fMRI further suggests that CIP projects via posterior parietal areas to the ITC in the ventral stream. To our knowledge, these results provide the first causal evidence for the flow of visual 3D information from the dorsal stream to the ventral stream, and identify CIP as a key area for depth-structure processing. Thus, combining reversible inactivation and electrical microstimulation during fMRI provides a detailed view of the functional interactions between the two visual processing streams.

Dependence of near field co-seismic ionospheric perturbations on surface deformations: A case study based on the April, 25 2015 Gorkha Nepal earthquake

NASA Astrophysics Data System (ADS)

Sunil, A. S.; Bagiya, Mala S.; Catherine, Joshi; Rolland, Lucie; Sharma, Nitin; Sunil, P. S.; Ramesh, D. S.

2017-03-01

Ionospheric response to the recent 25 April 2015 Gorkha, Nepal earthquake is studied in terms of Global Positioning System-Total Electron Content (GPS-TEC) from the viewpoints of source directivity, rupture propagation and associated surface deformations, over and near the fault plane. The azimuthal directivity of co-seismic ionospheric perturbations (CIP) amplitudes from near field exhibit excellent correlation with east-southeast propagation of earthquake rupture and associated surface deformations. In addition, the amplitude of CIP is observed to be very small in the opposite direction of the rupture movement. Conceptual explanations on the poleward directivity of CIP exist in literature, we show the observational evidences of additional equator ward directivity, interpreted in terms of rupture propagation direction. We also discuss the coupling between earthquake induced acoustic waves and local geomagnetic field and its effects on near field CIP amplitudes. We suggest that variability of near field CIP over and near the fault plane are the manifestations of the geomagnetic field-wave coupling in addition to crustal deformations that observed through GPS measurements and corroborated by Interferometric Synthetic Aperture Radar (InSAR) data sets.

Posterior Parietal Cortex Drives Inferotemporal Activations During Three-Dimensional Object Vision

PubMed Central

Van Dromme, Ilse C.; Premereur, Elsie; Verhoef, Bram-Ernst; Vanduffel, Wim; Janssen, Peter

2016-01-01

The primate visual system consists of a ventral stream, specialized for object recognition, and a dorsal visual stream, which is crucial for spatial vision and actions. However, little is known about the interactions and information flow between these two streams. We investigated these interactions within the network processing three-dimensional (3D) object information, comprising both the dorsal and ventral stream. Reversible inactivation of the macaque caudal intraparietal area (CIP) during functional magnetic resonance imaging (fMRI) reduced fMRI activations in posterior parietal cortex in the dorsal stream and, surprisingly, also in the inferotemporal cortex (ITC) in the ventral visual stream. Moreover, CIP inactivation caused a perceptual deficit in a depth-structure categorization task. CIP-microstimulation during fMRI further suggests that CIP projects via posterior parietal areas to the ITC in the ventral stream. To our knowledge, these results provide the first causal evidence for the flow of visual 3D information from the dorsal stream to the ventral stream, and identify CIP as a key area for depth-structure processing. Thus, combining reversible inactivation and electrical microstimulation during fMRI provides a detailed view of the functional interactions between the two visual processing streams. PMID:27082854

Carbonyl iron powder surface modification of magnetorheological elastomers for vibration absorbing application

NASA Astrophysics Data System (ADS)

Chen, Dong; Yu, Miao; Zhu, Mi; Qi, Song; Fu, Jie

2016-11-01

With excellent characteristic of magnetic-control stiffness, magnetorheological elastomer (MRE) is well suited as a spring element of vibration absorber. To improve the vibration attenuation performance of MRE vibration absorbers, this paper expects to improve the mechanical strength and reduce the loss factor of MRE by interface modification. The surface of carbonyl iron powder (CIP) was modified with silica coating by a simple and convenient approach. Several MRE samples, with different proportions of modified CIPs were fabricated under a constant magnetic field. The morphology and composition of modified CIP were characterized by scanning electron microscope and Fourier transform infrared spectra. The results indicated that the modified CIPs were coated with uniform and continuous silica, which can make a better combination between particle and matrix. The tensile strength, magnetorheological properties and the damping properties of the MRE samples were tested by material testing machine and rheometer. The experimental results demonstrated that the loss factor of the MRE which incorporated with modified CIPs decreased markedly, and the tensile strength of such material has been much improved, at the same time this kind of MRE kept high MR effect. It is expected that this MRE material will meet the requirements of vibration absorber.

Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase.

PubMed

Villa, Fabrizio; Simon, Aline C; Ortiz Bazan, Maria Angeles; Kilkenny, Mairi L; Wirthensohn, David; Wightman, Mel; Matak-Vinkovíc, Dijana; Pellegrini, Luca; Labib, Karim

2016-08-04

Replisome assembly at eukaryotic replication forks connects the DNA helicase to DNA polymerases and many other factors. The helicase binds the leading-strand polymerase directly, but is connected to the Pol α lagging-strand polymerase by the trimeric adaptor Ctf4. Here, we identify new Ctf4 partners in addition to Pol α and helicase, all of which contain a "Ctf4-interacting-peptide" or CIP-box. Crystallographic analysis classifies CIP-boxes into two related groups that target different sites on Ctf4. Mutations in the CIP-box motifs of the Dna2 nuclease or the rDNA-associated protein Tof2 do not perturb DNA synthesis genome-wide, but instead lead to a dramatic shortening of chromosome 12 that contains the large array of rDNA repeats. Our data reveal unexpected complexity of Ctf4 function, as a hub that connects multiple accessory factors to the replisome. Most strikingly, Ctf4-dependent recruitment of CIP-box proteins couples other processes to DNA synthesis, including rDNA copy-number regulation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The Group B Streptococcus-Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways.

PubMed

Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla; Speziale, Pietro; Margarit, Immaculada

2016-01-01

The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. Copyright © 2015 by The American Association of Immunologists, Inc.

Isolated polypeptide having arabinofuranosidase activity

DOEpatents

Foreman, Pamela; Van Solingen, Pieter; Goedegebuur, Frits; Ward, Michael

2010-02-23

Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry. TABLE-US-00001 cip1 cDNA sequence (SEQ ID NO: 1) GACTAGTTCA TAATACAGTA GTTGAGTTCA TAGCAACTTC 50 ACTCTCTAGC TGAACAAATT ATCTGCGCAA ACATGGTTCG CCGGACTGCT 100 CTGCTGGCCC TTGGGGCTCT CTCAACGCTC TCTATGGCCC AAATCTCAGA 150 CGACTTCGAG TCGGGCTGGG ATCAGACTAA ATGGCCCATT TCGGCACCAG 200 ACTGTAACCA GGGCGGCACC GTCAGCCTCG ACACCACAGT AGCCCACAGC 250 GGCAGCAACT CCATGAAGGT CGTTGGTGGC CCCAATGGCT ACTGTGGACA 300 CATCTTCTTC GGCACTACCC AGGTGCCAAC TGGGGATGTA TATGTCAGAG 350 CTTGGATTCG GCTTCAGACT GCTCTCGGCA GCAACCACGT CACATTCATC 400 ATCATGCCAG ACACCGCTCA GGGAGGGAAG CACCTCCGAA TTGGTGGCCA 450 AAGCCAAGTT CTCGACTACA ACCGCGAGTC CGACGATGCC ACTCTTCCGG 500 ACCTGTCTCC CAACGGCATT GCCTCCACCG TCACTCTGCC TACCGGCGCG 550 TTCCAGTGCT TCGAGTACCA CCTGGGCACT GACGGAACCA TCGAGACGTG 600 GCTCAACGGC AGCCTCATCC CGGGCATGAC CGTGGGCCCT GGCGTCGACA 650 ATCCAAACGA CGCTGGCTGG ACGAGGGCCA GCTATATTCC GGAGATCACC 700 GGTGTCAACT TTGGCTGGGA GGCCTACAGC GGAGACGTCA ACACCGTCTG 750 GTTCGACGAC ATCTCGATTG CGTCGACCCG CGTGGGATGC GGCCCCGGCA 800 GCCCCGGCGG TCCTGGAAGC TCGACGACTG GGCGTAGCAG CACCTCGGGC 850 CCGACGAGCA CTTCGAGGCC AAGCACCACC ATTCCGCCAC CGACTTCCAG 900 GACAACGACC GCCACGGGTC CGACTCAGAC ACACTATGGC CAGTGCGGAG 1000 GGATTGGTTA CAGCGGGCCT ACGGTCTGCG CGAGCGGCAC GACCTGCCAG 1050 GTCCTGAACC CATACTACTC CCAGTGCTTA TAAGGGGATG AGCATGGAGT 1100 GAAGTGAAGT GAAGTGGAGA GAGTTGAAGT GGCATTGCGC TCGGCTGGGT 1150 AGATAAAAGT CAGCAGCTAT GAATACTCTA TGTGATGCTC ATTGGCGTGT 1200 ACGTTTTAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 1250 AAAAAAAAAA AAAAAAAAAG GGGGCGGCCG C 1271

78 FR 76986 - Version 5 Critical Infrastructure Protection Reliability Standards

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-20

...].'' The sentence as revised would thus read, ``NERC requests that the CIP version 5 Standards become... 16 is changed to ``[ninth].'' The sentence as revised would thus read, ``NERC requests that the CIP...

Numerical simulation of bubble deformation in magnetic fluids by finite volume method

NASA Astrophysics Data System (ADS)

Yamasaki, Haruhiko; Yamaguchi, Hiroshi

2017-06-01

Bubble deformation in magnetic fluids under magnetic field is investigated numerically by an interface capturing method. The numerical method consists of a coupled level-set and VOF (Volume of Fluid) method, combined with conservation CIP (Constrained Interpolation Profile) method with the self-correcting procedure. In the present study considering actual physical properties of magnetic fluid, bubble deformation under given uniform magnetic field is analyzed for internal magnetic field passing through a magnetic gaseous and liquid phase interface. The numerical results explain the mechanism of bubble deformation under presence of given magnetic field.

Distributed Wind Competitiveness Improvement Project

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

2016-05-01

The Competitiveness Improvement Project (CIP) is a periodic solicitation through the U.S. Department of Energy and its National Renewable Energy Laboratory. Manufacturers of small and medium wind turbines are awarded cost-shared grants via a competitive process to optimize their designs, develop advanced manufacturing processes, and perform turbine testing. The goals of the CIP are to make wind energy cost competitive with other distributed generation technology and increase the number of wind turbine designs certified to national testing standards. This fact sheet describes the CIP and funding awarded as part of the project.

A cost-effectiveness analysis of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis.

PubMed

Shen, Bo; Shermock, Kenneth M; Fazio, Victor W; Achkar, Jean-Paul; Brzezinski, Aaron; Bevins, Charles L; Bambrick, Marlene L; Remzi, Feza H; Lashner, Bret A

2003-11-01

Pouchitis is often diagnosed based on symptoms and empirically treated with antibiotics (treat-first strategy). However, symptom assessment alone is not reliable for diagnosis, and an initial evaluation with pouch endoscopy (test-first strategy) has been shown to be more accurate. Cost-effectiveness of these strategies has not been compared. The aim of this study was to compare cost-effectiveness of different clinical approaches for patients with symptoms suggestive of pouchitis. Pouchitis was defined as pouchitis disease activity index scores > or =7. The frequency of pouchitis in symptomatic patients with ileal pouch was estimated to be 51%; the efficacy for initial therapy with metronidazole (MTZ) and ciprofloxacin (CIP) was 75% and 85%, respectively. Cost estimates were obtained from Medicare reimbursement data. Six competing strategies (MTZ trial, CIP trial, MTZ-then-CIP trial, CIP-then-MTZ trial, pouch endoscopy with biopsy, and pouch endoscopy without biopsy) were modeled in a decision tree. Costs per correct diagnosis with appropriate treatment were $194 for MTZ trial, $279 for CIP trial, $208 for MTZ-then-CIP trial, $261 for CIP-then-MTZ trial, $352 for pouch endoscopy with biopsy, and $243 for pouch endoscopy without biopsy. Of the two strategies with the lowest cost, the pouch endoscopy without biopsy strategy costs $50 more per patient than the MTZ trial strategy but results in an additional 15 days for early diagnosis and thus initiation of appropriate treatment (incremental cost-effectiveness ratio $3 per additional day gained). The results of base-case analysis were robust in sensitivity analyses. Although the MTZ-trial strategy had the lowest cost, the pouch endoscopy without biopsy strategy was most cost-effective. Therefore, based on its relatively low cost and the avoidance of both diagnostic delay and adverse effects associated with unnecessary antibiotics, pouch endoscopy without biopsy is the recommended strategy among those tested for the diagnosis of pouchitis.

In vitro biopharmaceutical evaluation of ciprofloxacin/metal cation complexes for pulmonary administration.

PubMed

Brillault, J; Tewes, F; Couet, W; Olivier, J C

2017-01-15

Pulmonary delivery of fluoroquinolones (FQs) is an interesting approach to treat lung infections as it may lead to high local concentrations while minimizing systemic exposure. However, FQs have a rapid diffusion through the lung epithelium giving the pulmonary route no advantage compared to the oral route. Interactions between FQs and metal cations form complexes which limit the diffusion through the epithelial barrier and would reduce the absorption of FQs and maintain high concentrations in the lung. The effects of this complexation depend on the FQ and the metal cations and optimum partners should be selected through in vitro experiments prior to aerosol drug formulation. In this study, CIP was chosen as a representative FQ and 5 cations (Ca 2+ , Mg 2+ , Zn 2+ , Al 3+ , Cu 2+ ) were selected to study the complexation and its effects on permeability, antimicrobial efficacy and cell toxicity. The results showed that the apparent association constants between CIP and cations ranked with the descending order: Cu 2+ >Al 3+ >Zn 2+ >Mg 2+ >Ca 2+ . When a target of 80% complexation was reached with the adequate concentrations of cations, the CIP permeability through the Calu-3 lung epithelial cells was decreased of 50%. Toxicity of the CIP on the Calu-3 cells, with an EC50 evaluated at 7μM, was not significantly affected by the presence of the cations. The minimum inhibitory concentration of CIP for Pseudomonas aeruginosa was not affected or slightly increased in the range of cation concentrations tested, except for Mg 2+ . In conclusion, permeability was the main parameter that was affected by the metal cation complexation while cell toxicity and antimicrobial activity were not or slightly modified. Cu 2+ , with the highest apparent constant of association and with no effect on cell toxicity and antimicrobial activity of the CIP, appeared as a promising cation for the development of a controlled-permeability formulation of CIP for lung treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Taraxinic acid, a hydrolysate of sesquiterpene lactone glycoside from the Taraxacum coreanum NAKAI, induces the differentiation of human acute promyelocytic leukemia HL-60 cells.

PubMed

Choi, Jung-Hye; Shin, Kyung-Min; Kim, Na-Young; Hong, Jung-Pyo; Lee, Yong Sup; Kim, Hyoung Ja; Park, Hee-Juhn; Lee, Kyung-Tae

2002-11-01

The present work was performed to elucidate the active moiety of a sesquiterpene lactone, taraxinic acid-1'-O-beta-D-glucopyranoside (1). from Taraxacum coreanum NAKAI on the cytotoxicity of various cancer cells. Based on enzymatic hydrolysis and MTT assay, the active moiety should be attributed to the aglycone taraxinic acid (1a). rather than the glycoside (1). Taraxinic acid exhibited potent antiproliferative activity against human leukemia-derived HL-60. In addition, this compound was found to be a potent inducer of HL-60 cell differentiation as assessed by a nitroblue tetrazolium reduction test, esterase activity assay, phagocytic activity assay, morphology change, and expression of CD 14 and CD 66 b surface antigens. These results suggest that taraxinic acid induces the differentiation of human leukemia cells to monocyte/macrophage lineage. Moreover, the expression level of c-myc was down-regulated during taraxinic acid-dependent HL-60 cell differentiation, whereas p21(CIP1) and p27(KIP1) were up-regulated. Taken together, our results suggest that taraxinic acid may have potential as a therapeutic agent in human leukemia.

12 CFR 952.3 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) of the Act (12 U.S.C. 1430(i)) (Community Investment Program (CIP)) and section 10(j) of the Act (12... CICA programs except for CIP programs, under which a Bank may only provide advances. [67 FR 12852, Mar...

Classification of Instructional Programs: 2000 Edition.

ERIC Educational Resources Information Center

Education Statistics Quarterly, 2002

2002-01-01

Describes the methods, processes, and procedures used to develop the Classification of Instructional Programs 2000 (CIP:2000), the National Center for Education Statistics taxonomy of instructional programs, and provides information on the CIP's structure, contents, and organization. (SLD)

12 CFR 952.3 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-01-01

...) of the Act (12 U.S.C. 1430(i)) (Community Investment Program (CIP)) and section 10(j) of the Act (12... CICA programs except for CIP programs, under which a Bank may only provide advances. [67 FR 12852, Mar...

12 CFR 952.3 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) of the Act (12 U.S.C. 1430(i)) (Community Investment Program (CIP)) and section 10(j) of the Act (12... CICA programs except for CIP programs, under which a Bank may only provide advances. [67 FR 12852, Mar...

12 CFR 952.3 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) of the Act (12 U.S.C. 1430(i)) (Community Investment Program (CIP)) and section 10(j) of the Act (12... CICA programs except for CIP programs, under which a Bank may only provide advances. [67 FR 12852, Mar...

HNP-3 enhanced the antimicrobial activity of CIP by promoting ATP efflux from P. aeruginosa cells.

PubMed

Wang, Hao; Dong, Birong; Lou, Li

2011-04-01

To establish a novel strategy of P. aeruginosa control, we acquired recombination HNP-3 by gene recombination. Then we examined HNP-3 bio-activities and the influences of antimicrobial peptide on the efflux of ATP. Consequently, we obtained target protein with a molecular mass of 3,000 D consistent with the Anticipation. FIC index of Ciprofloxacin added HNP-3 was less than 0.5 and HNP3 synergistically cooperated with CIP to suppress P. aeruginosa colony formation revealed that there was significant synergy. ATP efflux was however up-regulated by low concentrations of HNP-3, although CIP did not exert any influence on ATP efflux. Conclusively, recombination protein HNP-3 displayed antimicrobial and synergic effects. HNP-3 enhanced the antimicrobial activity of CIP by promoting ATP efflux from P. aeruginosa cells and decreasing efflux of the drugs, which could have useful clinical applications.

Scientific ways to study intercessory prayer as an intervention in clinical research.

PubMed

Rath, Linda L

2009-01-01

The purpose of this article is to share a "research journey" to study the somewhat controversial subject of Christian intercessory prayer (CIP) utilized as a clinical intervention, and the knowledge gained along the way. This article will explore the steps in the development and implementation of clinical research to scientifically examine a phenomenon that many say cannot--and should not--be studied. The sequential steps in developing this area of study are detailed and explained from the conception of the initial idea through utilization of concept analysis and literature review to develop the researchable topic. The subsequent development of both qualitative and quantitative pilot studies to investigate CIP in depth is presented to illustrate how the intervention of CIP can successfully be incorporated into clinical research. This article provides guidelines for future researchers who may want to utilize CIP as an intervention.

Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG

PubMed Central

Alvarez, Raymond A.; Maestre, Ana M.; Durham, Natasha D.; Barria, Maria Ines; Ishii-Watabe, Akiko; Tada, Minoru; Hotta, Mathew T.; Rodriguez-Caprio, Gabriela; Fierer, Daniel S.; Fernandez-Sesma, Ana; Simon, Viviana; Chen, Benjamin K.

2017-01-01

HIV-1 viremic controllers (VC) spontaneously control infection without antiretroviral treatment. Several studies indicate that IgG Abs from VCs induce enhanced responses from immune effector cells. Since signaling through Fc-γ receptors (FCGRs) modulate these Ab-driven responses, here we examine if enhanced FCGR activation is a common feature of IgG from VCs. Using an infected cell–based system, we observed that VC IgG stimulated greater FCGR2A and FCGR3A activation as compared with noncontrollers, independent of the magnitude of HIV-specific Ab binding or virus neutralization activities. Multivariate regression analysis showed that enhanced FCGR signaling was a significant predictor of VC status as compared with chronically infected patients (CIP) on highly active antiretroviral therapy (HAART). Unsupervised hierarchical clustering of patient IgG functions primarily grouped VC IgG profiles by enhanced FCGR2A, FCGR3A, or dual signaling activity. Our findings demonstrate that enhanced FCGR signaling is a common and significant predictive feature of VC IgG, with VCs displaying a distinct spectrum of FCGR activation profiles. Thus, profiling FCGR activation may provide a useful method for screening and distinguishing protective anti-HIV IgG responses in HIV-infected patients and in monitoring HIV vaccination regimens. PMID:28239647

75 FR 28663 - Government-Owned Inventions, Available for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-21

... Crack Arresting Barrier. NASA Case No. MFS-32605-1-CIP: Neutron Guides and Methods of Fabrication. NASA...-32697-1: Friction Modifier Using Adherent Metallic Multilayered or Mixed Element Layer Conversion...

Transient cocaine-associated behavioral symptoms rated with a new instrument, the scale for assessment of positive symptoms for cocaine-induced psychosis (SAPS-CIP).

PubMed

Tang, Yi-lang; Kranzler, Henry R; Gelernter, Joel; Farrer, Lindsay A; Pearson, Deborah; Cubells, Joseph F

2009-01-01

Chronic use of cocaine is associated with a variety of behavioral symptoms. The current report describes the assessment of cocaine-related behavioral symptoms (CRB) using the Scale for Assessment of Positive Symptoms of Cocaine-Induced Psychosis (SAPS-CIP). The CRB section, one of the three domains in the SAPS-CIP, consists of sub-domains, including Aggressive/Agitated Behavior, Repetitive/Stereotyped Behavior, and Unusual Social or Sexual Behavior. Severity scores are assigned according to operational criteria, and range from 0 (not present) to 5 (severe). We interviewed 261 unrelated cocaine-abusing adults using the SAPS-CIP, and 243 of them met criteria for inclusion in the study. The proportion of subjects endorsing different classes of CRBs varied across categories, with 109 of 243 (44.9%) subjects reporting aggressive and agitated behaviors, 180 subjects (74.1%) repetitive/stereotyped behaviors, and 192 (79.0%) unusual social/sexual behaviors. A substantial minority of the subjects (10.3-25.1%) reported that they experienced marked-to-severe behavioral symptoms associated with cocaine use. The proportions of subjects endorsing CRB did not differ by ethnic/racial group or by sex. Correlations among the different domains of CRB were strong, but behaviors rated in the CRB section were less well correlated with psychotic symptoms, which were rated in the hallucination and delusion sections of the instrument. A variety of CRBs are common in cocaine-dependent subjects, and many of these are highly intercorrelated. CRBs also correlate with hallucinations and delusions induced by cocaine, but to a lesser degree. Our findings suggest that there may be some common vulnerability factors that contribute to both cocaine-induced psychosis and CRBs.

Cold-induced aqueous acetonitrile phase separation: A salt-free way to begin quick, easy, cheap, effective, rugged, safe.

PubMed

Shao, Gang; Agar, Jeffrey; Giese, Roger W

2017-07-14

Cooling a 1:1 (v/v) solution of acetonitrile and water at -16° C is known to result in two clear phases. We will refer to this event as "cold-induced aqueous acetonitrile phase separation (CIPS)". On a molar basis, acetonitrile is 71.7% and 13.6% in the upper and lower phases, respectively, in our study. The phase separation proceeds as a descending cloud of microdroplets. At the convenient temperature (typical freezer) employed here the lower phase is rather resistant to solidification, although it emerges from the freezer as a solid if various insoluble matter is present at the outset. In a preliminary way, we replaced the initial (salting-out) step of a representative QuEChERS procedure with CIPS, applying this modified procedure ("CIPS-QuEChERS") to a homogenate of salmon (and partly to beef). Three phases resulted, where only the upper, acetonitrile-rich phase is a liquid (that is completely clear). The middle phase comprises ice and precipitated lipids, while the lower phase is the residual matrix of undissolved salmon or meat. Treating the upper phase from salmon, after isolation, with anhydrous MgSO 4 and C18-Si (typical QuEChERS dispersive solid phase extraction sorbents), and injecting into a GC-MS in a nontargeted mode, gives two-fold more preliminary hits for chemicals, and also number of spiked pesticides recovered, relative to that from a comparable QuEChERS method. In part, this is because of much higher background signals in the latter case. Further study of CIPS-QuEChERS is encouraged, including taking advantage of other QuERChERS conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1.

PubMed

Miyazaki, Junichiro; Ito, Keiichi; Fujita, Tomonobu; Matsuzaki, Yuriko; Asano, Takako; Hayakawa, Masamichi; Asano, Tomohiko; Kawakami, Yutaka

2017-04-01

Renal cell carcinoma (RCC) is the most lethal urological malignancy with high risk of recurrence; thus, new prognostic biomarkers are needed. In this study, a new RCC antigen, PTPL1 associated RhoGAP1 (PARG1), was identified by using serological identification of recombinant cDNA expression cloning with sera from RCC patients. PARG1 protein was found to be differentially expressed in RCC cells among patients. High PARG1 expression is significantly correlated with various clinicopathological factors relating to cancer cell proliferation and invasion, including G3 percentage (P = .0046), Ki-67 score (p expression is also correlated with high recurrence of N0M0 patients (P = .0084) and poor prognosis in RCC patients (P = .0345). Multivariate analysis has revealed that high PARG1 expression is an independent factor for recurrence (P = .0149) of N0M0 RCC patients. In in vitro studies, depletion of PARG1by siRNA in human RCC cell lines inhibited their proliferation through inducing G1 cell cycle arrest via upregulation of p53 and subsequent p21 Cip1/Waf1 , which are mediated by increased RhoA-ROCK activities. Similarly, PARG1 depletion cells inhibited invasion ability via increasing RhoA-ROCK activities in the RCC cell lines. Conversely, overexpression of PARG1 on human embryonic kidney cell line HEK293T promotes its cell proliferation and invasion. These results indicate that PARG1 plays crucial roles in progression of human RCC in increasing cell proliferation and invasion ability via inhibition of the RhoA-ROCK axis, and PARG1 is a poor prognostic marker, particularly for high recurrence of N0M0 RCC patients. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Enhancement of the electrical characteristics of metal-free phthalocyanine films using cold isostatic pressing

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

Matsushima, Toshinori, E-mail: tmatusim@opera.kyushu-u.ac.jp, E-mail: adachi@cstf.kyushu-u.ac.jp; Adachi, Chihaya, E-mail: tmatusim@opera.kyushu-u.ac.jp, E-mail: adachi@cstf.kyushu-u.ac.jp; Japan Science and Technology Agency

2014-12-15

Spatial gaps between grains and other grains, substrates, or electrodes in organic electronic devices are one of the causes of the reduction in the electrical characteristics. In this study, we demonstrate that cold isostatic pressing (CIP) is an effective method to crush the gaps and enhance the electrical characteristics. CIP of metal-free phthalocyanine (H{sub 2}PC) films induced a decrease in the film thickness by 34%–40% because of the gap crush. The connection of smaller grains into a larger grain and planarization of the film surface were also observed in the CIP film. The crystal axes of the H{sub 2}PC crystallitesmore » were rearranged from the a-axis to the c-axis of the α-phase crystal structure in a direction perpendicular to the substrate by CIP, indicating favorable hole injection and transport in this direction because of a better overlap of π orbitals. Thermally stimulated current measurements showed that deep hole traps disappeared and the total hole-trap density decreased after CIP. These CIP-induced changes of the film thicknesses, crystal axes and the hole traps lead to a marked increase in the hole mobility of the H{sub 2}PC films from 2.0 × 10{sup −7} to 4.0 × 10{sup −4} cm{sup 2}/V s by 2000 times in the perpendicular direction. We believe that these findings are important for unveiling the underlying carrier injection and transport mechanisms of organic films and for enhancing the performance of future organic electronic devices.« less

Evaluation of a self-equilibrium cutting strategy for the contour method of residual stress measurement

DOE PAGES

Muránsky, Ondrej; Hamelin, Cory J.; Hosseinzadeh, F.; ...

2017-04-06

An assessment of cutting-induced plasticity (CIP) is performed, by finite element (FE) prediction of the plastic strain accumulation along the cut tip when the EDM wire sections the NeT TG4 weld benchmark specimen along two cutting directions. The first direction corresponds to a conventional (C) cutting strategy, whereby the EDM wire cuts through the thickness of the weld specimen and travels in a direction transverse to the weld. The second direction corresponds to a self-equilibrating cutting (SE) strategy, whereby the EDM wire cuts across the transverse direction of the weld specimens and travels through the thickness of the plate. Themore » cutting thus progresses simultaneously through the compression-tension-compression regions of present weld residual stress (WRS) field. This type of cutting strategy is believed to minimize the CIP by minimising residual stress redistribution during cutting, due to stress equilibration across the sectioned material. The simulated cutting procedures are conducted under a range of clamping conditions to assess whether mechanical restraint has a primary or secondary influence on CIP accumulation. Both predictions of CIP and the resultant back-calculated WRS demonstrate that (i) mechanical restraint is the primary variable influencing CIP development, and (ii) under no circumstance does a self-equilibrating cutting strategy perform significantly better than a conventional cutting approach. Furthermore, the reason that self-equilibrating cuts are not effective is illustrated by calculating the Mode I (K I) stress intensity factor (SIF) along the cut tip, and correlating trends in K I to CIP development.« less

Evaluation of a self-equilibrium cutting strategy for the contour method of residual stress measurement

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

Muránsky, Ondrej; Hamelin, Cory J.; Hosseinzadeh, F.

An assessment of cutting-induced plasticity (CIP) is performed, by finite element (FE) prediction of the plastic strain accumulation along the cut tip when the EDM wire sections the NeT TG4 weld benchmark specimen along two cutting directions. The first direction corresponds to a conventional (C) cutting strategy, whereby the EDM wire cuts through the thickness of the weld specimen and travels in a direction transverse to the weld. The second direction corresponds to a self-equilibrating cutting (SE) strategy, whereby the EDM wire cuts across the transverse direction of the weld specimens and travels through the thickness of the plate. Themore » cutting thus progresses simultaneously through the compression-tension-compression regions of present weld residual stress (WRS) field. This type of cutting strategy is believed to minimize the CIP by minimising residual stress redistribution during cutting, due to stress equilibration across the sectioned material. The simulated cutting procedures are conducted under a range of clamping conditions to assess whether mechanical restraint has a primary or secondary influence on CIP accumulation. Both predictions of CIP and the resultant back-calculated WRS demonstrate that (i) mechanical restraint is the primary variable influencing CIP development, and (ii) under no circumstance does a self-equilibrating cutting strategy perform significantly better than a conventional cutting approach. Furthermore, the reason that self-equilibrating cuts are not effective is illustrated by calculating the Mode I (K I) stress intensity factor (SIF) along the cut tip, and correlating trends in K I to CIP development.« less

Removal of mercury from its aqueous solution using charcoal-immobilized papain (CIP).

PubMed

Dutta, Susmita; Bhattacharyya, Aparupa; De, Parameswar; Ray, Parthasarathi; Basu, Srabanti

2009-12-30

In the present work mercury has been eradicated from its aqueous solution using papain, immobilized on activated charcoal by physical adsorption method. Operating parameters for adsorption of papain on activated charcoal like pH, amount of activated charcoal, initial concentration of papain in solution have been varied in a suitable manner for standardization of operating conditions for obtaining the best immobilized papain sample based on their specific enzymatic activity. The immobilized papain sample obtained at initial papain concentration 40.0 g/L, activated charcoal amount 0.5 g and pH 7 shows the best specific enzymatic activity. This sample has been designated as charcoal-immobilized papain (CIP) and used for further studies of mercury removal. Adsorption equilibrium data fit most satisfactorily with the Langmuir isotherm model for adsorption of papain on activated charcoal. Physicochemical characterization of CIP has been done. The removal of mercury from its simulated solution of mercuric chloride using CIP has been studied in a lab-scale batch contactor. The operating parameters viz., the initial concentration of mercury in solution, amount of CIP and pH have been varied in a prescribed manner. Maximum removal achieved in the batch study was about 99.4% at pH 7, when initial metal concentration and weight of CIP were 20.0mg/L and 0.03 g respectively. Finally, the study of desorption of mercury has been performed at different pH values for assessment of recovery process of mercury. The results thus obtained have been found to be satisfactory.

The role of cyclase activating (CAP) and cyclase inhibiting (CIP) parathormone fractions in the assessment of bone metabolism disturbances in women with hyperprolactinemia of various origin.

PubMed

Zadrozna-Sliwka, Beata; Bolanowski, Marek; Jawiarczyk, Aleksandra; Kaluzny, Marcin; Syrycka, Joanna

2008-02-01

Hyperprolactinemia could be one of possible causes of bone loss. The reason is thought to be connected with hypogonadism due to PRL excess and the role of other hormones like PTH and PTH-rP. There is no data on the influence of PTH fractions (CAP and CIP) on bone turnover and density in hyperprolactinemia. The aim of the study was to assess the influence of PTH and its fractions on bone metabolism in hyperprolactinemia of various origin. The study was carried out in 75 women. Group I consisted of 32 women with prolactinoma, group II consisted of 43 women with functional hyperprolactinemia. Both groups were subdivided in patients with hypogonadism and normal gonadal function. The control group consisted of 29 healthy women. In all subjects PRL, PTH and its fractions (CAP, CIP), and bone turnover markers (BAP, ICTP) were studied. BMD measurement was carried out using DXA. In patients with functional hyperprolactinemia i-PTH and CAP levels were lower than in controls. CIP concentrations were lower in patients than in controls. CAP/CIP ratio was higher in patients with prolactinoma than in patients with functional hyperprolactinemia and controls. Higher values of bone turnover markers (BAP, ICTP) in patients groups and subgroups were shown as compared to controls. Some correlations between PTH and its fractions, and BMD and bone turnover were observed. There is no direct benefit from the assessment of parathormone fractions and CAP/CIP ratio in the prognosis of bone metabolism changes in hyperprolactinemia of various origin.

Status report on CIP/CUP progress

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

Larkin, W.J.

1975-01-01

Work on the Cascade Improvement Program (CIP) and the Cascade Uprating Program (CUP) continues basically on schedule. When completed the productive capability of the gaseous diffusion facilities at Paducah, Oak Ridge, and Portsmouth will be increased by 60 percent. (JGB)

Molecular imprinting-based separation methods for selective analysis of fluoroquinolones in soils.

PubMed

Turiel, Esther; Martín-Esteban, Antonio; Tadeo, José Luis

2007-11-23

Molecularly imprinted polymers (MIPs) for fluoroquinolone antibiotics (FQs) have been synthesised in one single preparative step by precipitation polymerisation using ciprofloxacin (CIP) as template. Combinations of methacrylic acid (MAA) or 4-vinylpyridine (VP) as functional monomers, ethylene glycol dimethacrylate as crosslinker and dichloromethane, methanol, acetonitrile or toluene as porogens were tested. The experiments carried out by molecularly imprinted solid-phase extraction (MISPE) in cartridges did not allow to detect any imprint effect in the VP-based polymers whereas it was clearly observed in the MAA-based polymers. Among them, the MIP prepared in methanol using MAA as monomer showed the best performance and was chosen for further experiments. The ability of the selected MIP for the selective recognition of other widely used FQs (enoxacin, norfloxacin, danofloxacin and enrofloxacin) and quinolones (Qs) (cinoxacin, flumequine, nalidixic acid and oxolinic acid) was evaluated. The obtained results revealed the high selectivity of the obtained polymer, which was able to distinguish between FQs, that were recognised and retained onto the MIP cartridge, and Qs, which were washed out during loading and washing steps. The MIP was then packed into a stainless steel column (50mmx4.6mm i.d.) and evaluated as chromatography column for screening of FQs in soil samples. The mobile phase composition, flow rate, and the elution profile were then optimised in order to improve peak shape without sacrifying imprinting factor. Finally, under optimised conditions, soil samples spiked with CIP or with a mixture of fluoroquinolones in concentration of 0.5microgg(-1) were successfully analysed by the developed MIP-based procedures.

Azithromycin-Ciprofloxacin-Impregnated Urinary Catheters Avert Bacterial Colonization, Biofilm Formation, and Inflammation in a Murine Model of Foreign-Body-Associated Urinary Tract Infections Caused by Pseudomonas aeruginosa.

PubMed

Saini, Hina; Vadekeetil, Anitha; Chhibber, Sanjay; Harjai, Kusum

2017-03-01

Pseudomonas aeruginosa is a multifaceted pathogen causing a variety of biofilm-mediated infections, including catheter-associated urinary tract infections (CAUTIs). The high prevalence of CAUTIs in hospitals, their clinical manifestations, such as urethritis, cystitis, pyelonephritis, meningitis, urosepsis, and death, and the associated economic challenges underscore the need for management of these infections. Biomaterial modification of urinary catheters with two drugs seems an interesting approach to combat CAUTIs by inhibiting biofilm. Previously, we demonstrated the in vitro efficacy of urinary catheters impregnated with azithromycin (AZM) and ciprofloxacin (CIP) against P. aeruginosa Here, we report how these coated catheters impact the course of CAUTI induced by P. aeruginosa in a murine model. CAUTI was established in female LACA mice with uncoated or AZM-CIP-coated silicone implants in the bladder, followed by transurethral inoculation of 10 8 CFU/ml of biofilm cells of P. aeruginosa PAO1. AZM-CIP-coated implants (i) prevented biofilm formation on the implant's surface ( P ≤ 0.01), (ii) restricted bacterial colonization in the bladder and kidney ( P < 0.0001), (iii) averted bacteriuria ( P < 0.0001), and (iv) exhibited no major histopathological changes for 28 days in comparison to uncoated implants, which showed persistent CAUTI. Antibiotic implants also overcame implant-mediated inflammation, as characterized by trivial levels of inflammatory markers such as malondialdehyde ( P < 0.001), myeloperoxidase ( P < 0.05), reactive oxygen species ( P ≤ 0.001), and reactive nitrogen intermediates ( P < 0.01) in comparison to those in uncoated implants. Further, AZM-CIP-coated implants showed immunomodulation by manipulating the release of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 to the benefit of the host. Overall, the study demonstrates long-term in vivo effectiveness of AZM-CIP-impregnated catheters, which may possibly be a key to success in preventing CAUTIs. Copyright © 2017 American Society for Microbiology.