Ursodeoxycholic Acid Influences the Expression of p27kip1 but Not FoxO1 in Patients with Non-Cirrhotic Primary Biliary Cirrhosis

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Malgorzata Milkiewicz

2014-01-01

Full Text Available Background. Enhanced expression of cell cycle inhibitor p27kip1 suppresses cell proliferation. Ursodeoxycholic acid (UDCA delays progression of primary biliary cirrhosis (PBC but its effect on p27kip1 expression is uncertain. Aims. To analyze the expression of p27kip1 and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. Materials and Methods. The examined human tissue included explanted livers from patients with cirrhotic PBC (n=23, primary sclerosing cholangitis (PSC; n=9, alcoholic liver disease (ALD; n=9, and routine liver biopsies from patients with non-cirrhotic PBC (n=26. Healthy liver samples served as controls (n=19. Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot. Results. p27kip1 expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls. FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P<0.05 versus control. UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27kip1 mRNA. Conclusion. PBC progression is characterized by a FoxO1-independent increase of p27kip1 expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism.

Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

NARCIS (Netherlands)

Georgitsi, Marianthi; Raitila, Anniina; Karhu, Auli; van der Luijt, Rob B.; Aalfs, Cora M.; Sane, Timo; Vierimaa, Outi; Mäkinen, Markus J.; Tuppurainen, Karoliina; Paschke, Ralph; Gimm, Oliver; Koch, Christian A.; Gündogdu, Sadi; Lucassen, Anneke; Tischkowitz, Marc; Izatt, Louise; Aylwin, Simon; Bano, Gul; Hodgson, Shirley; de Menis, Ernesto; Launonen, Virpi; Vahteristo, Pia; Aaltonen, Lauri A.

2007-01-01

Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two

Accelerated turnover of taste bud cells in mice deficient for the cyclin-dependent kinase inhibitor p27Kip1

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Perna Marla K

2011-04-01

Full Text Available Abstract Background Mammalian taste buds contain several specialized cell types that coordinately respond to tastants and communicate with sensory nerves. While it has long been appreciated that these cells undergo continual turnover, little is known concerning how adequate numbers of cells are generated and maintained. The cyclin-dependent kinase inhibitor p27Kip1 has been shown to influence cell number in several developing tissues, by coordinating cell cycle exit during cell differentiation. Here, we investigated its involvement in the control of taste cell replacement by examining adult mice with targeted ablation of the p27Kip1 gene. Results Histological and morphometric analyses of fungiform and circumvallate taste buds reveal no structural differences between wild-type and p27Kip1-null mice. However, when examined in functional assays, mutants show substantial proliferative changes. In BrdU incorporation experiments, more S-phase-labeled precursors appear within circumvallate taste buds at 1 day post-injection, the earliest time point examined. After 1 week, twice as many labeled intragemmal cells are present, but numbers return to wild-type levels by 2 weeks. Mutant taste buds also contain more TUNEL-labeled cells and 50% more apoptotic bodies than wild-type controls. In normal mice, p27 Kip1 is evident in a subset of receptor and presynaptic taste cells beginning about 3 days post-injection, correlating with the onset of taste cell maturation. Loss of gene function, however, does not alter the proportions of distinct immunohistochemically-identified cell types. Conclusions p27Kip1 participates in taste cell replacement by regulating the number of precursor cells available for entry into taste buds. This is consistent with a role for the protein in timing cell cycle withdrawal in progenitor cells. The equivalence of mutant and wild-type taste buds with regard to cell number, cell types and general structure contrasts with the hyperplasia

Salivary protein histatin 3 regulates cell proliferation by enhancing p27{sup Kip1} and heat shock cognate protein 70 ubiquitination

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Imamura, Yasuhiro, E-mail: yimamura@po.mdu.ac.jp [Department of Pharmacology, Matsumoto Dental University, Shiojiri, Nagano 399-0781 (Japan); Wang, Pao-Li [Department of Bacteriology, Osaka Dental University, Hirakata, Osaka 573-1121 (Japan); Masuno, Kazuya [Department of Dental Education Innovation, Osaka Dental University, Hirakata, Osaka 573-1121 (Japan); Sogawa, Norio [Department of Pharmacology, Matsumoto Dental University, Shiojiri, Nagano 399-0781 (Japan)

2016-02-05

Histatins are salivary proteins with antimicrobial activities. We previously reported that histatin 3 binds to heat shock cognate protein 70 (HSC70), which is constitutively expressed, and induces DNA synthesis stimulation and promotes human gingival fibroblast (HGF) survival. However, the underlying mechanisms of histatin 3 remain largely unknown. Here, we found that the KRHH sequence of histatin 3 at the amino acid positions 5–8 was essential for enhancing p27{sup Kip1} (a cyclin-dependent kinase inhibitor) binding to HSC70 that occurred in a dose-dependent manner; histatin 3 enhanced the binding between p27{sup Kip1} and HSC70 during the G{sub 1}/S transition of HGFs as opposed to histatin 3-M(5–8) (substitution of KRHH for EEDD in histatin 3). Histatin 3, but not histatin 3-M(5–8), stimulated DNA synthesis and promoted HGF survival. Histatin 3 dose-dependently enhanced both p27{sup Kip1} and HSC70 ubiquitination, whereas histatin 3-M(5–8) did not. These findings provide further evidence that histatin 3 may be involved in the regulation of cell proliferation, particularly during G{sub 1}/S transition, via the ubiquitin–proteasome system of p27{sup Kip1} and HSC70. - Highlights: • KRHH amino acid sequence was required in histatin 3 to bind HSC70. • Histatin 3 enhanced HSC70 binding to p27{sup Kip1} during the G{sub 1}/S transition in HGFs. • KRHH sequence stimulated DNA synthesis and promoted cell survival. • Histatin 3 dose-dependently enhanced both p27{sup Kip1} and HSC70 ubiquitination. • Histatin 3 stimulates cell proliferation via the ubiquitin–proteasome system.

Effect of X-irradiation on the protein expression of P57kip2 and TGF-β1 in lung cancer cell stain A549

International Nuclear Information System (INIS)

Zou Huawei; Tan Yonggang; Zhang Heying

2008-01-01

Objective: To analyze the effect of X-irradiation on the proteins expression of p57 kip2 and TGF-β1 in lung cancer cell stain A549 and its clinical significance. Methods: Lung cancer cell stain A549 was cultivated and cell, protein was extracted at 6,12,24,36 and 48 hours after X-irradiation by different doses(2,4, 8 and 12 Gy). The expression of p57 kip2 and TGF-β1 proteins were examined by Western blot. Results: The expression of p57 kip2 in lung cancer cell stain A549 was very low before X-irradiation, and increased significantly after irradiation with different doses and reached the peak level at 12 hours after irradiation (P kip2 and TGF-β1 proteins which increased with certain doses, p57 kip2 and TGF-β1 could be used to predict the damage degree of cancer cells by X-ray. (authors)

Time and flow-dependent changes in the p27(kip1) gene network drive maladaptive vascular remodeling.

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DeSart, Kenneth M; Butler, Khayree; O'Malley, Kerri A; Jiang, Zhihua; Berceli, Scott A

2015-11-01

Although clinical studies have identified that a single nucleotide polymorphism in the p27(kip1) gene is associated with success or failure after vein bypass grafting, the underlying mechanisms for this difference are not well defined. Using a high-throughput approach in a flow-dependent vein graft model, we explored the differences in p27(kip1)-related genes that drive the enhanced hyperplastic response under low-flow conditions. Bilateral rabbit carotid artery interposition grafts with jugular vein were placed with a unilateral distal outflow branch ligation to create differential flow states. Grafts were harvested at 2 hours and at 1, 3, 7, 14, and 28 days after implantation, measured for neointimal area, and assayed for cell proliferation. Whole-vessel messenger RNA was isolated and analyzed using an Affymetrix (Santa Clara, Calif) gene array platform. Ingenuity Pathway Analysis (Ingenuity, Redwood City, Calif) was used to identify the gene networks surrounding p27(kip1). This gene set was then analyzed for temporal expression changes after graft placement and for differential expression in the alternate flow conditions. Outflow branch ligation resulted in an eightfold difference in mean flow rates throughout the 28-day perfusion period (P Flow reduction led to a robust hyperplastic response, resulting in a significant increase in intimal area by 7 days (0.13 ± 0.04 mm(2) vs 0.014 ± 0.006 mm(2); P flow grafts demonstrated a burst of actively dividing intimal cells (36.4 ± 9.4 cells/mm(2) vs 11.5 ± 1.9 cells/mm(2); P = .04). Sixty-five unique genes within the microarray were identified as components of the p27(kip1) network. At a false discovery rate of 0.05, 26 genes demonstrated significant temporal changes, and two dominant patterns of expression were identified. Class comparison analysis identified differential expression of 11 genes at 2 hours and seven genes and 14 days between the high-flow and low-flow grafts (P flow and shear stress result in

p27kip1 overexpression regulates IL-1β in the microenvironment of stem cells and eutopic endometriosis co-cultures.

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Gonçalves, G A; Invitti, A L; Parreira, R M; Kopelman, A; Schor, E; Girão, M J B C

2017-01-01

Endometriosis is a gynecological benign chronic disease defined as the growth of endometrial glands and stroma in extra-uterine sites, most commonly implanted over visceral and peritoneal surfaces within the female pelvis causing inflammatory lesions. It affects around 10% of the female population and is often accompanied by chronic pelvic pain, adhesion formation and infertility. Therefore, endometriosis could be considered a "social disease", since it affects the quality of life, reproductivity and also has a socio-economic impact. The expression of cell cycle and inflammatory proteins is modified in the endometriotic tissues. Immunostaining of glandular and stromal cells in endometrial biopsies obtained from patients with endometriosis compared with those of healthy control demonstrated that endometriotic tissues have lower levels of p27 kip1 protein. Endometriosis endometrial cells cultures have also lower levels of p27 kip1 compared to health endometrial cells cultures and restore the cell cycle balance when transduced with an adenoviral vector carring the p27 kip1 coding gene (Adp27EGFP). The low levels of p27 kip1 are related to the S phase in the cell cycle, whereas higher levels lead to a G1 cell cycle arrest. The inflammatory cytokine IL-1β was recently identified as another key protein in the endometriosis proliferation. This cytokine has elevated levels during the proliferative and secretory phases of the menstrual cycle. In endometriosis endometrial cells cultures the IL-1β stimulates the production of IL-6 and IL-8, increasing the cell proliferation and reducing the apoptosis and Bax expression in these cells. According to these remarks, this work aims to evaluate the inflammatory effects in vitro, but more next to what happens in a woman's body, associating endometrial cells with stem cells, thus mimicking the endometrial microenvironment, with gene therapy using Adp27, notoriously known as controller cell cycle, apoptosis and potent modulator of

The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: persistent p27(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway.

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Li, Ao; Wang, Jun; Wu, Mingjun; Zhang, Xiaoxun; Zhang, Hongzhi

2015-01-15

Proliferation of hepatic stellate cells (HSCs) is vital for the development of fibrosis during liver injury. In this study, we describe that arctigenin (ATG), a major bioactive component of Fructus Arctii, exhibited selective cytotoxic activity via inhibiting platelet-derived growth factor-BB (PDGF-BB)-activated HSCs proliferation and arrested cell cycle at G0/G1 phase, which could not be observed in normal human hepatocytes in vitro. The cyclin-dependent kinase (CDK) 4/6 activities could be strongly inhibited by ATG through down-regulation of cyclin D1 and CDK4/6 expression in early G1 phase arrest. In the ATG-treated HSCs, the expression level of p27(Kip1) and the formation of CDK2-p27(Kip1) complex were also increased. p27(Kip1) silencing significantly attenuated the effect of ATG, including cell cycle arrest and suppression of proliferation in activated HSCs. We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a (FOXO3a), decreased binding of FOXO3a to 14-3-3 protein, and stimulated nuclear translocation of FOXO3a in activated HSCs. Furthermore, knockdown of FOXO3a expression by FOXO3a siRNA attenuated ATG-induced up-regulation of p27(Kip1) in activated HSCs. All the above findings suggested that ATG could increase the levels of p27(Kip1) protein through inhibition of Akt and improvement of FOXO3a activity, in turn inhibited the CDK2 kinase activity, and eventually caused an overall inhibition of HSCs proliferation. Copyright © 2014 Elsevier B.V. All rights reserved.

MIB-1 (KI-67) proliferation index and cyclin-dependent kinase inhibitor p27(Kip1) protein expression in nephroblastoma

NARCIS (Netherlands)

M.A.I. Ghanem (Mazen); Th.H. van der Kwast (Theo); M.K. Sudaryo; R.B. Mathoera (Rejiv); M.M. van den Heuvel-Eibrink (Marry); A.A. Al-Doray; R.J.M. Nijman (Rien); G.J. van Steenbrugge (Gert Jan)

2004-01-01

textabstractPURPOSE: A number of studies have indicated that the tumor proliferation marker MIB-1 and cell cycle inhibitor p27(Kip1) expression are of prognostic importance in a variety of cancers. The present study was performed to evaluate the prognostic value of these

The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development.

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Archana D Siddam

2018-03-01

Full Text Available Opacification of the ocular lens, termed cataract, is a common cause of blindness. To become transparent, lens fiber cells undergo degradation of their organelles, including their nuclei, presenting a fundamental question: does signaling/transcription sufficiently explain differentiation of cells progressing toward compromised transcriptional potential? We report that a conserved RNA-binding protein Celf1 post-transcriptionally controls key genes to regulate lens fiber cell differentiation. Celf1-targeted knockout mice and celf1-knockdown zebrafish and Xenopus morphants have severe eye defects/cataract. Celf1 spatiotemporally down-regulates the cyclin-dependent kinase (Cdk inhibitor p27Kip1 by interacting with its 5' UTR and mediating translation inhibition. Celf1 deficiency causes ectopic up-regulation of p21Cip1. Further, Celf1 directly binds to the mRNA of the nuclease Dnase2b to maintain its high levels. Together these events are necessary for Cdk1-mediated lamin A/C phosphorylation to initiate nuclear envelope breakdown and DNA degradation in fiber cells. Moreover, Celf1 controls alternative splicing of the membrane-organization factor beta-spectrin and regulates F-actin-crosslinking factor Actn2 mRNA levels, thereby controlling fiber cell morphology. Thus, we illustrate new Celf1-regulated molecular mechanisms in lens development, suggesting that post-transcriptional regulatory RNA-binding proteins have evolved conserved functions to control vertebrate oculogenesis.

Insect peptide CopA3-induced protein degradation of p27Kip1 stimulates proliferation and protects neuronal cells from apoptosis

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Nam, Seung Taek; Kim, Dae Hong; Lee, Min Bum; Nam, Hyo Jung; Kang, Jin Ku; Park, Mi Jung; Lee, Ik Hwan; Seok, Heon; Lee, Dong Gun; Hwang, Jae Sam; Kim, Ho

2013-01-01

Highlights: •CopA3 peptide isolated from the Korean dung beetle has antimicrobial activity. •Our study reported that CopA3 has anticancer and immunosuppressive effects. •We here demonstrated that CopA3 has neurotropic and neuroprotective effects. •CopA3 degrades p27Kip1 protein and this mediates effects of CopA3 on neuronal cells. -- Abstract: We recently demonstrated that the antibacterial peptide, CopA3 (a D-type disulfide dimer peptide, LLCIALRKK), inhibits LPS-induced macrophage activation and also has anticancer activity in leukemia cells. Here, we examined whether CopA3 could affect neuronal cell proliferation. We found that CopA3 time-dependently increased cell proliferation by up to 31 ± 2% in human neuroblastoma SH-SY5Y cells, and up to 29 ± 2% in neural stem cells isolated from neonatal mouse brains. In both cell types, CopA3 also significantly inhibited the apoptosis and viability losses caused by 6-hydroxy dopamine (a Parkinson disease-mimicking agent) and okadaic acid (an Alzheimer’s disease-mimicking agent). Immunoblotting revealed that the p27Kip1 protein (a negative regulator of cell cycle progression) was markedly degraded in CopA3-treated SH-SY5Y cells. Conversely, an adenovirus expressing p27Kip1 significantly inhibited the antiapoptotic effects of CopA3 against 6-hydroxy dopamine- and okadaic acid-induced apoptosis, and decreased the neurotropic effects of CopA3. These results collectively suggest that CopA3-mediated protein degradation of p27Kip1 may be the main mechanism through which CopA3 exerts neuroprotective and neurotropic effects

Insect peptide CopA3-induced protein degradation of p27Kip1 stimulates proliferation and protects neuronal cells from apoptosis

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Nam, Seung Taek; Kim, Dae Hong; Lee, Min Bum; Nam, Hyo Jung; Kang, Jin Ku; Park, Mi Jung; Lee, Ik Hwan [Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido 487-711 (Korea, Republic of); Seok, Heon [Department of Biomedical Science, Jungwon University, Goesan, Chungcheongbukdo 367-700 (Korea, Republic of); Lee, Dong Gun [School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Hwang, Jae Sam [Department of Agricultural Biology, National Academy of Agricultural Science, RDA, Suwon 441-707 (Korea, Republic of); Kim, Ho, E-mail: hokim@daejin.ac.kr [Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido 487-711 (Korea, Republic of)

2013-07-19

Highlights: •CopA3 peptide isolated from the Korean dung beetle has antimicrobial activity. •Our study reported that CopA3 has anticancer and immunosuppressive effects. •We here demonstrated that CopA3 has neurotropic and neuroprotective effects. •CopA3 degrades p27Kip1 protein and this mediates effects of CopA3 on neuronal cells. -- Abstract: We recently demonstrated that the antibacterial peptide, CopA3 (a D-type disulfide dimer peptide, LLCIALRKK), inhibits LPS-induced macrophage activation and also has anticancer activity in leukemia cells. Here, we examined whether CopA3 could affect neuronal cell proliferation. We found that CopA3 time-dependently increased cell proliferation by up to 31 ± 2% in human neuroblastoma SH-SY5Y cells, and up to 29 ± 2% in neural stem cells isolated from neonatal mouse brains. In both cell types, CopA3 also significantly inhibited the apoptosis and viability losses caused by 6-hydroxy dopamine (a Parkinson disease-mimicking agent) and okadaic acid (an Alzheimer’s disease-mimicking agent). Immunoblotting revealed that the p27Kip1 protein (a negative regulator of cell cycle progression) was markedly degraded in CopA3-treated SH-SY5Y cells. Conversely, an adenovirus expressing p27Kip1 significantly inhibited the antiapoptotic effects of CopA3 against 6-hydroxy dopamine- and okadaic acid-induced apoptosis, and decreased the neurotropic effects of CopA3. These results collectively suggest that CopA3-mediated protein degradation of p27Kip1 may be the main mechanism through which CopA3 exerts neuroprotective and neurotropic effects.

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

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Bradley J. Walters

2017-04-01

Full Text Available Summary: Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs declines abruptly after postnatal maturation. We find that combining p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration. : Auditory hair cells are nonregenerative, resulting in persistent hearing loss upon damage. Walters et al. find that manipulating two genes, p27Kip1 and Atoh1, induces the conversion of nonsensory cells to hair cells in adult mice. This effect is mediated by GATA3 and POU4F3, where POU4F3 alone was found to convert nonsensory cells. Keywords: regeneration, aging, differentiation, proliferation, development, cancer, sensory, cochlea, hearing

miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1.

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Galardi, Silvia; Mercatelli, Neri; Giorda, Ezio; Massalini, Simone; Frajese, Giovanni Vanni; Ciafrè, Silvia Anna; Farace, Maria Giulia

2007-08-10

MicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of several types of cancers. Here we show that miR-221 and miR-222, encoded in tandem on chromosome X, are overexpressed in the PC3 cellular model of aggressive prostate carcinoma, as compared with LNCaP and 22Rv1 cell line models of slowly growing carcinomas. In all cell lines tested, we show an inverse relationship between the expression of miR-221 and miR-222 and the cell cycle inhibitor p27(Kip1). We recognize two target sites for the microRNAs in the 3' untranslated region of p27 mRNA, and we show that miR-221/222 ectopic overexpression directly results in p27 down-regulation in LNCaP cells. In those cells, we demonstrate that the ectopic overexpression of miR-221/222 strongly affects their growth potential by inducing a G(1) to S shift in the cell cycle and is sufficient to induce a powerful enhancement of their colony-forming potential in soft agar. Consistently, miR-221 and miR-222 knock-down through antisense LNA oligonucleotides increases p27(Kip1) in PC3 cells and strongly reduces their clonogenicity in vitro. Our results suggest that miR-221/222 can be regarded as a new family of oncogenes, directly targeting the tumor suppressor p27(Kip1), and that their overexpression might be one of the factors contributing to the oncogenesis and progression of prostate carcinoma through p27(Kip1) down-regulation.

Rp58 and p27kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

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Clément, Olivier; Hemming, Isabel Anne; Gladwyn-Ng, Ivan Enghian; Qu, Zhengdong; Li, Shan Shan; Piper, Michael; Heng, Julian Ik-Tsen

2017-05-15

During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised. Here, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27 kip1 is important for E14.5-born cortical neurons to coordinate cell cycle exit and initiate their radial migration. Notably, we find that the impaired radial positioning of Rp58-deficient cortical neurons within the embryonic (E17.5) mouse cortex, as well as their multipolar to bipolar transition from the intermediate zone to the cortical plate can be restored by forced expression of p27 kip1 in concert with suppression of Rnd2, a downstream target gene of Rp58. Furthermore, the restorative effects of p27 kip1 and Rnd2 abrogation are reminiscent of suppressing RhoA signalling in Rp58-deficient cells. Our findings demonstrate functional interplay between a transcriptional regulator and a CDKI to mediate neuroprogenitor cell cycle exit, as well as to promote radial migration through a molecular mechanism consistent with suppression of RhoA signalling.

SKP2 siRNA inhibits the degradation of P27kip1 and down-regulates the expression of MRP in HL-60/A cells.

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Xiao, Jie; Yin, Songmei; Li, Yiqing; Xie, Shuangfeng; Nie, Danian; Ma, Liping; Wang, Xiuju; Wu, Yudan; Feng, Jianhong

2009-08-01

S-phase kinase-associated protein 2 (SKP2) gene is a tumor suppressor gene, and is involved in the ubiquitin-mediated degradation of P27kip1. SKP2 and P27kip1 affect the proceeding and prognosis of leukemia through regulating the proliferation, apoptosis and differentiation of leukemia cells. In this study, we explored the mechanism of reversing of HL-60/A drug resistance through SKP2 down-regulation. HL-60/A cells were nucleofected by Amaxa Nucleofector System with SKP2 siRNA. The gene and protein expression levels of Skp2, P27kip1, and multi-drug resistance associated protein (MRP) were determined by reverse transcription-polymerase chain reaction and western blot analysis, respectively. The cell cycle was analyzed by flow cytometry. The 50% inhibitory concentration value was calculated using cytotoxic analysis according to the death rate of these two kinds of cells under different concentrations of chemotherapeutics to compare the sensitivity of the cells. HL-60/A cells showed multi-drug resistance phenotype characteristic by cross-resistance to adriamycin, daunorubicin, and arabinosylcytosine, due to the expression of MRP. We found that the expression of SKP2 was higher in HL-60/A cells than in HL-60 cells, but the expression of P27kip1 was lower. The expression of SKP2 in HL-60/A cells nucleofected by SKP2 siRNA was down-regulated whereas the protein level of P27kip1 was up-regulated. Compared with the MRP expression level in the control group (nucleofected by control siRNA), the mRNA and protein expression levels of MRP in HL-60/A cells nucleofected by SKP2 siRNA were lower, and the latter cells were more sensitive to adriamycin, daunorubicin, and arabinosylcytosine. Down-regulating the SKP2 expression and arresting cells in the G0/G1 phase improve drug sensitivity of leukemia cells with down-regulated MRP expression.

P27Kip1, regulated by glycogen synthase kinase-3β, results in HMBA-induced differentiation of human gastric cancer cells

International Nuclear Information System (INIS)

Wei, Min; Gu, Qinlong; Wang, Zhiwei; Yao, Hongliang; Yang, Zhongyin; Zhang, Qing; Liu, Bingya; Yu, Yingyan; Su, Liping; Zhu, Zhenggang

2011-01-01

Gastric cancer is the second most common cause of global cancer-related mortality. Although dedifferentiation predicts poor prognosis in gastric cancer, the molecular mechanism underlying dedifferentiation, which could provide fundamental insights into tumor development and progression, has yet to be elucidated. Furthermore, the molecular mechanism underlying the effects of hexamethylene bisacetamide (HMBA), a recently discovered differentiation inducer, requires investigation and there are no reported studies concerning the effect of HMBA on gastric cancer. Based on the results of FACS analysis, the levels of proteins involved in the cell cycle or apoptosis were determined using western blotting after single treatments and sequential combinations of HMBA and LiCl. GSK-3β and proton pump were investigated by western blotting after up-regulating Akt expression by Ad-Akt infection. To investigate the effects of HMBA on protein localization and the activities of GSK-3β, CDK2 and CDK4, kinase assays, immunoprecipitation and western blotting were performed. In addition, northern blotting and RNase protection assays were carried out to determine the functional concentration of HMBA. HMBA increased p27Kip1 expression and induced cell cycle arrest associated with gastric epithelial cell differentiation. In addition, treating gastric-derived cells with HMBA induced G0/G1 arrest and up-regulation of the proton pump, a marker of gastric cancer differentiation. Moreover, treatment with HMBA increased the expression and activity of GSK-3β in the nucleus but not the cytosol. HMBA decreased CDK2 activity and induced p27Kip1 expression, which could be rescued by inhibition of GSK-3β. Furthermore, HMBA increased p27Kip1 binding to CDK2, and this was abolished by GSK-3β inhibition. The results presented herein suggest that GSK-3β functions by regulating p27Kip1 assembly with CDK2, thereby playing a critical role in G0/G1 arrest associated with HMBA-induced gastric epithelial

In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27Kip1 by dietary fish oil and butyrate in rats.

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Hong, Mee Young; Turner, Nancy D; Murphy, Mary E; Carroll, Raymond J; Chapkin, Robert S; Lupton, Joanne R

2015-11-01

We have shown that dietary fish oil is protective against experimentally induced colon cancer, and the protective effect is enhanced by coadministration of pectin. However, the underlying mechanisms have not been fully elucidated. We hypothesized that fish oil with butyrate, a pectin fermentation product, protects against colon cancer initiation by decreasing cell proliferation and increasing differentiation and apoptosis through a p27(Kip1)-mediated mechanism. Rats were provided diets of corn or fish oil, with/without butyrate, and terminated 12, 24, or 48 hours after azoxymethane (AOM) injection. Proliferation (Ki-67), differentiation (Dolichos Biflorus Agglutinin), apoptosis (TUNEL), and p27(Kip1) (cell-cycle mediator) were measured in the same cell within crypts in order to examine the coordination of cell cycle as a function of diet. DNA damage (N(7)-methylguanine) was determined by quantitative IHC analysis. Dietary fish oil decreased DNA damage by 19% (P = 0.001) and proliferation by 50% (P = 0.003) and increased differentiation by 56% (P = 0.039) compared with corn oil. When combined with butyrate, fish oil enhanced apoptosis 24 hours after AOM injection compared with a corn oil/butyrate diet (P = 0.039). There was an inverse relationship between crypt height and apoptosis in the fish oil/butyrate group (r = -0.53, P = 0.040). The corn oil/butyrate group showed a positive correlation between p27(Kip1) expression and proliferation (r = 0.61, P = 0.035). These results indicate the in vivo effect of butyrate on apoptosis and proliferation is dependent on dietary lipid source. These results demonstrate the presence of an early coordinated colonocyte response by which fish oil and butyrate protects against colon tumorigenesis. ©2015 American Association for Cancer Research.

CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer

International Nuclear Information System (INIS)

Larson, Pamela S; Schlechter, Benjamin L; King, Chia-Lin; Yang, Qiong; Glass, Chelsea N; Mack, Charline; Pistey, Robert; Morenas, Antonio de las; Rosenberg, Carol L

2008-01-01

CDKN1C (also known as p57 KIP2 ) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21 CIP1 and B/p27 KIP1 ) have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo. We determined rates of allele imbalance or loss of heterozygosity (AI/LOH) in CDKN1C, using an intronic polymorphism, and in the surrounding 11p15.5 region in 82 breast cancers. We examined the CDKN1C mRNA level in 10 cancers using quantitative real-time PCR (qPCR), and the CDKN1C protein level in 20 cancers using immunohistochemistry (IHC). All samples were obtained using laser microdissection. Data were analyzed using standard statistical tests. AI/LOH at 11p15.5 occurred in 28/73 (38%) informative cancers, but CDKN1C itself underwent AI/LOH in only 3/16 (19%) cancers (p = ns). In contrast, CDKN1C mRNA levels were reduced in 9/10 (90%) cancers (p < 0.0001), ranging from 2–60% of paired normal epithelium. Similarly, CDKN1C protein staining was seen in 19/20 (95%) cases' normal epithelium but in only 7/14 (50%) cases' CIS (p < 0.004) and 5/18 (28%) cases' IC (p < 0.00003). The reduction appears primarily due to loss of CDKN1C expression from myoepithelial layer cells, which stained intensely in 17/20 (85%) normal lobules, but in 0/14 (0%) CIS (p < 0.00001). In contrast, luminal cells displayed less intense, focal staining fairly consistently across histologies. Decreased CDKN1C was not clearly associated with tumor grade, histology, ER, PR or HER2 status. CDKN1C is expressed in normal epithelium of most breast cancer cases, mainly in the myothepithelial layer. This expression decreases, at both the mRNA and protein level, in the large majority of breast cancers, and does not appear to be mediated by AI/LOH at the gene. Thus, CDKN1C may be a breast cancer tumor suppressor

Development of mice without Cip/Kip CDK inhibitors

Energy Technology Data Exchange (ETDEWEB)

Tateishi, Yuki; Matsumoto, Akinobu; Kanie, Tomoharu [Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582 (Japan); CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan); Hara, Eiji [Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakayama, Keiko [Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 (Japan); Nakayama, Keiichi I., E-mail: nakayak1@bioreg.kyushu-u.ac.jp [Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582 (Japan); CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)

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 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{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

The cell cycle inhibitor p27Kip¹ controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist.

Science.gov (United States)

Menchón, Cristina; Edel, Michael J; Izpisua Belmonte, Juan Carlos

2011-05-01

The continued turn over of human embryonic stem cells (hESC) while maintaining an undifferentiated state is dependent on the regulation of the cell cycle. Here we asked the question if a single cell cycle gene could regulate the self-renewal or pluripotency properties of hESC. We identified that the protein expression of the p27(Kip)¹ cell cycle inhibitor is low in hESC cells and increased with differentiation. By adopting a gain and loss of function strategy we forced or reduced its expression in undifferentiating conditions to define its functional role in self-renewal and pluripotency. Using undifferentiation conditions, overexpression of p27(Kip)¹ in hESC lead to a G₁phase arrest with an enlarged and flattened hESC morphology and consequent loss of self-renewal ability. Loss of p27(Kip)¹ caused an elongated/scatter cell-like phenotype involving up-regulation of Brachyury and Twist gene expression. We demonstrate the novel finding that p27(Kip)¹ protein occupies the Twist1 gene promoter and manipulation of p27(Kip)¹ by gain and loss of function is associated with Twist gene expression changes. These results define p27(Kip)¹ expression levels as critical for self-renewal and pluripotency in hESC and suggest a role for p27(Kip)¹ in controlling an epithelial to mesenchymal transition (EMT) in hESC.

Motor imagery beyond the motor repertoire: Activity in the primary visual cortex during kinesthetic motor imagery of difficult whole body movements.

Science.gov (United States)

Mizuguchi, N; Nakata, H; Kanosue, K

2016-02-19

To elucidate the neural substrate associated with capabilities for kinesthetic motor imagery of difficult whole-body movements, we measured brain activity during a trial involving both kinesthetic motor imagery and action observation as well as during a trial with action observation alone. Brain activity was assessed with functional magnetic resonance imaging (fMRI). Nineteen participants imagined three types of whole-body movements with the horizontal bar: the giant swing, kip, and chin-up during action observation. No participant had previously tried to perform the giant swing. The vividness of kinesthetic motor imagery as assessed by questionnaire was highest for the chin-up, less for the kip and lowest for the giant swing. Activity in the primary visual cortex (V1) during kinesthetic motor imagery with action observation minus that during action observation alone was significantly greater in the giant swing condition than in the chin-up condition within participants. Across participants, V1 activity of kinesthetic motor imagery of the kip during action observation minus that during action observation alone was negatively correlated with vividness of the kip imagery. These results suggest that activity in V1 is dependent upon the capability of kinesthetic motor imagery for difficult whole-body movements. Since V1 activity is likely related to the creation of a visual image, we speculate that visual motor imagery is recruited unintentionally for the less vivid kinesthetic motor imagery of difficult whole-body movements. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

In vitro differentiation of HT-29 M6 mucus-secreting colon cancer cells involves a trychostatin A and p27(KIP1)-inducible transcriptional program of gene expression.

Science.gov (United States)

Mayo, Clara; Lloreta, Josep; Real, Francisco X; Mayol, Xavier

2007-07-01

Tumor cell dedifferentiation-such as the loss of cell-to-cell adhesion in epithelial tumors-is associated with tumor progression. To better understand the mechanisms that maintain carcinoma cells in a differentiated state, we have dissected in vitro differentiation pathways in the mucus-secretor HT-29 M6 colon cancer cell line, which spontaneously differentiates in postconfluent cultures. By lowering the extracellular calcium concentration to levels that prevent intercellular adhesion and epithelial polarization, our results reveal that differentiation is calcium-dependent and involves: (i) a process of cell cycle exit to G(0) and (ii) the induction of a transcriptional program of differentiation gene expression (i.e., mucins MUC1 and MUC5AC, and the apical membrane peptidase DPPIV). In calcium-deprived, non-differentiated postconfluent cultures, differentiation gene promoters are repressed by a trichostatin A (TSA)-sensitive mechanism, indicating that loss of gene expression by dedifferentiation is driven by histone deacetylases (HDAC). Since TSA treatment or extracellular calcium restoration allow gene promoter activation to similar levels, we suggest that induction of differentiation is one mechanism of HDAC inhibitor antitumor action. Moreover, transcriptional de-repression can also be induced in non-differentiating culture conditions by overexpressing the cyclin-dependent kinase inhibitor p27(KIP1), which is normally induced during spontaneous differentiation. Since p27(KIP1) downregulation in colon cancer is associated with poor prognosis independently of tumor cell division rates, we propose that p27 (KIP1) may prevent tumor progression by, at least in part, enhancing the expression of some differentiation genes. Therefore, the HT-29 M6 model allows the identification of some basic mechanisms of cancer cell differentiation control, so far revealing HDAC and p27(KIP1) as key regulatory factors of differentiation gene expression.

The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis.

Science.gov (United States)

Chou, Chu-Fang; Hsieh, Yu-Hua; Grubbs, Clinton J; Atigadda, Venkatram R; Mobley, James A; Dummer, Reinhard; Muccio, Donald D; Eto, Isao; Elmets, Craig A; Garvey, W Timothy; Chang, Pi-Ling

2018-06-01

Bexarotene (Targretin ® ) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC 50 ) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome. UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs. Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Dynamics of multiple nuclei in Ashbya gossypii hyphae depend on the control of cytoplasmic microtubules length by Bik1, Kip2, Kip3, and not on a capture/shrinkage mechanism.

Science.gov (United States)

Grava, Sandrine; Philippsen, Peter

2010-11-01

Ashbya gossypii has a budding yeast-like genome but grows exclusively as multinucleated hyphae. In contrast to budding yeast where positioning of nuclei at the bud neck is a major function of cytoplasmic microtubules (cMTs), A. gossypii nuclei are constantly in motion and positioning is not an issue. To investigate the role of cMTs in nuclear oscillation and bypassing, we constructed mutants potentially affecting cMT lengths. Hyphae lacking the plus (+)end marker Bik1 or the kinesin Kip2 cannot polymerize long cMTs and lose wild-type nuclear movements. Interestingly, hyphae lacking the kinesin Kip3 display longer cMTs concomitant with increased nuclear oscillation and bypassing. Polymerization and depolymerization rates of cMTs are 3 times higher in A. gossypii than in budding yeast and cMT catastrophes are rare. Growing cMTs slide along the hyphal cortex and exert pulling forces on nuclei. Surprisingly, a capture/shrinkage mechanism seems to be absent in A. gossypii. cMTs reaching a hyphal tip do not shrink, and cMT +ends accumulate in hyphal tips. Thus, differences in cMT dynamics and length control between budding yeast and A. gossypii are key elements in the adaptation of the cMT cytoskeleton to much longer cells and much higher degrees of nuclear mobilities.

Herbal composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra prevents atherosclerosis by upregulating p27 (Kip1) expression.

Science.gov (United States)

Lee, Jung-Jin; Lee, Ji-Hye; Cho, Won-Kyung; Han, Joo-Hui; Ma, Jin Yeul

2016-07-28

Kiom-18 is a novel composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra. Curcuma longa and Glycyrrhiza glabra, which are traditional medicines in Asia, have been reported to demonstrate preventive effects against atherosclerosis; however, they have not yet been developed into functional atherosclerosis treatments. We therefore studied the anti-atherosclerotic effects and possible molecular mechanisms of Kiom-18 using vascular smooth muscle cells (VSMCs). To assess the anti-proliferative effect of Kiom-18 in vitro, we performed thymidine incorporation, cell cycle progression, immunoblotting and immunofluorescence assays in VSMCs stimulated by platelet derived-growth factor (PDGF)-BB. In addition, we used LDLr knockout mice to identify the effects of Kiom-18 as a preliminary result in an atherosclerosis animal model. Kiom-18 inhibited platelet-derived growth factor (PDGF)-BB-stimulated-VSMC proliferation and DNA synthesis. Additionally, Kiom-18 arrested the cell cycle transition of G0/G1 stimulated by PDGF-BB and its cell cycle-related proteins. Correspondingly, the level of p27(kip1) expression was upregulated in the presence of the Kiom-18 extract. Moreover, in an atherosclerosis animal model of LDLr knockout mice, Kiom-18 extract showed a preventive effect for the formation of atherosclerotic plaque and suppressed body weight, fat weight, food treatment efficiency, neutrophil count, and triglyceride level. These results indicate that Kiom-18 exerts anti-atherosclerotic effects by inhibiting VSMC proliferation via G0/G1 arrest, which upregulates p27(Kip1) expression.

A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.

Science.gov (United States)

Fero, M L; Rivkin, M; Tasch, M; Porter, P; Carow, C E; Firpo, E; Polyak, K; Tsai, L H; Broudy, V; Perlmutter, R M; Kaushansky, K; Roberts, J M

1996-05-31

Targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T lymphocyte proliferation, and T cells showed enhanced IL-2 responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia, suggesting that p27 and Rb function in the same regulatory pathway. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of secondary ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired.

p27kip1 expression distinguishes papillary hyperplasia in Graves' disease from papillary thyroid carcinoma.

Science.gov (United States)

Erickson, L A; Yousef, O M; Jin, L; Lohse, C M; Pankratz, V S; Lloyd, R V

2000-09-01

In most cases, the histopathologic and cytologic distinction between Graves' disease and papillary thyroid carcinoma is relatively easy, but on occasion Graves' disease may simulate a thyroid papillary carcinoma. For example, papillary fronds with fibrovascular cores may be present in both Graves' disease and papillary carcinoma. p27kip1 (p27) is a cyclin-dependent kinase inhibitory protein that has been shown to be an independent prognostic factor in a variety of human tumors. Our previous studies of p27 expression in hyperplastic and neoplastic endocrine lesions showed that the level of p27 was quite different in these two conditions. To determine if this distinction could also be made between Graves' disease and papillary carcinoma, we analyzed expression of p27 and other cell cycle proteins in a series of cases of Graves' disease with papillary hyperplasia and a series of papillary thyroid carcinomas. Formalin-fixed paraffin-embedded tissues from 61 randomly selected patients with thyroid disease, including 29 cases of Graves' disease with papillary architectural features and 32 cases of papillary carcinoma, were analyzed for expression of p27, Ki-67, and DNA topoisomerase II alpha (topo II alpha) by immunostaining. The distribution of immunoreactivity was analyzed by quantifying the percentage of positive nuclei that was expressed as the labeling index (LI) plus or minus the standard error of the mean. The papillary hyperplasia of Graves' disease had a p27 LI of 68.2 +/- 3.1 (range, 24 to 88), whereas papillary carcinomas had a LI of 25.6 +/- 2.5 (range, 12 to 70) (P hyperplasia in Graves' disease and papillary carcinoma. These results indicate that p27 protein expression is significantly higher in papillary hyperplasia of Graves' disease compared to papillary carcinoma, which may be diagnostically useful in difficult cases.

ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab

International Nuclear Information System (INIS)

Kurozumi, Sasagu; Inoue, Kenichi; Takei, Hiroyuki; Matsumoto, Hiroshi; Kurosumi, Masafumi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari

2015-01-01

Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27 Kip1 . We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27 Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1–2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27 Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). High-HG, low-ER, low-PgR, high-Ki67, and low-p27 Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals. The online version of this article (doi:10.1186/s12885-015-1641-y) contains supplementary material, which is available to authorized users

oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading.

Science.gov (United States)

Zhang, Chongxu; Adamos, Crystal; Oh, Myung-Jin; Baruah, Jugajyoti; Ayee, Manuela A A; Mehta, Dolly; Wary, Kishore K; Levitan, Irena

2017-09-01

Oxidized modifications of LDL (oxLDL) play a key role in the development of endothelial dysfunction and atherosclerosis. However, the underlying mechanisms of oxLDL-mediated cellular behavior are not completely understood. Here, we compared the effects of two major types of oxLDL, copper-oxidized LDL (Cu 2+ -oxLDL) and lipoxygenase-oxidized LDL (LPO-oxLDL), on proliferation of human aortic endothelial cells (HAECs). Cu 2+ -oxLDL enhanced HAECs' proliferation in a dose- and degree of oxidation-dependent manner. Similarly, LPO-oxLDL also enhanced HAEC proliferation. Mechanistically, both Cu 2+ -oxLDL and LPO-oxLDL enhance HAEC proliferation via activation of Rho, Akt phosphorylation, and a decrease in the expression of cyclin-dependent kinase inhibitor 1B (p27 kip1 ). Both Cu 2+ -oxLDL or LPO-oxLDL significantly increased Akt phosphorylation, whereas an Akt inhibitor, MK2206, blocked oxLDL-induced increase in HAEC proliferation. Blocking Rho with C3 or its downstream target ROCK with Y27632 significantly inhibited oxLDL-induced Akt phosphorylation and proliferation mediated by both Cu 2+ - and LPO-oxLDL. Activation of RhoA was blocked by Rho-GDI-1, which also abrogated oxLDL-induced Akt phosphorylation and HAEC proliferation. In contrast, blocking Rac1 in these cells had no effect on oxLDL-induced Akt phosphorylation or cell proliferation. Moreover, oxLDL-induced Rho/Akt signaling downregulated cell cycle inhibitor p27 kip1 Preloading these cells with cholesterol, however, prevented oxLDL-induced Akt phosphorylation and HAEC proliferation. These findings provide a new understanding of the effects of oxLDL on endothelial proliferation, which is essential for developing new treatments against neovascularization and progression of atherosclerosis. Copyright © 2017 the American Physiological Society.

Nuclear safety review for qualification of class 1E motor inside containment for nuclear power stations

International Nuclear Information System (INIS)

Li Shixin; Wu Qi; Zhang Yunbo; Wu Caixia

2013-01-01

In nuclear power plants with pressurized water reactors, the review for class 1E motor inside containment qualification process and documents is an important aspect of nuclear safety equipment review, and the reviewers should make evaluations for the qualification test results in terms of the compliance with standard and regulation, and the consistency with inside containment environment. Firstly, this paper introduces the qualification test of class 1E motor inside containment for nuclear power generating stations, such as aging test and design-basis-event test. Second, there is a discussion about typical problems of review. At last, comparison of IEEE334 with RCC-E is conducted and explored. (authors)

Downregulated CDKN1C/p57kip2 drives tumorigenesis and associates with poor overall survival in breast cancer.

Science.gov (United States)

Qiu, Zhu; Li, Yunhai; Zeng, Beilei; Guan, Xiaoqin; Li, Hongzhong

2018-02-26

CDKN1C, also known as p57 kip2 , is considered to be a potential tumor suppressor implicated in several kinds of human cancers. However, the current knowledge of CDKN1C in breast cancer remains obscure. In the present study, we demonstrated that CDKN1C was dramatically downregulated in breast cancer compared with normal tissues by using real-time quantitative polymerase chain reaction, western blot and two public data portals: The Cancer Genome Atlas (TCGA) and Oncomine datasets. Moreover, the expression of CDKN1C was correlated with age and tumor size in the TCGA cohort containing 708 cases of breast cancer. Low expression of CDKN1C was significantly associated with poor overall survival (OS) in the TCGA cohort and validated cohort composed of 1402 patients. Multivariate Cox regression analysis indicated that CDKN1C was an independent prognostic factor for worse OS (HR = 1.78, 95% CI: 1.09-2.89, p = 0.020). Furthermore, gene set enrichment analysis (GSEA) revealed that CDKN1C was significantly correlated with gene signatures involving DNA repair, cell cycle, glycolysis, adipogenesis, and two critical signaling pathways mTORC1 and PI3K/Akt/mTOR. In conclusion, our data suggested an essential role of CDKN1C in the tumorgenesis of breast cancer. Targeting CDKN1C may be a promising strategy for anticancer therapeutics. Copyright © 2018 Elsevier Inc. All rights reserved.

IEEE Std 649-1980: IEEE standard for qualifying Class 1E motor control centers for nuclear power generating stations

International Nuclear Information System (INIS)

Anon.

1992-01-01

This standard describes the basic principles, requirements, and methods for qualifying Class 1E motor control centers for outside containment applications in nuclear power generating stations. Qualification of motor control centers located inside containment in a nuclear power generating station is beyond the scope of this standard. The purpose of this standard is (1) to define specific qualification requirements for Class 1E motor control centers in accordance with the more general qualification requirements of IEEE Std 323-1974, IEE Standard for Qualifying Class 1E Equipment for Nuclear Power Generating Stations; (2) to provide guidance in establishing a qualification program for demonstrating the design adequacy of Class 1E motor control centers in nuclear power generating station applications

Mitochondrial ribosomal protein L41 mediates serum starvation-induced cell-cycle arrest through an increase of p21WAF1/CIP1

International Nuclear Information System (INIS)

Kim, Mi Jin; Yoo, Young A.; Kim, Hyung Jung; Kang, Seongman; Kim, Yong Geon; Kim, Jun Suk; Yoo, Young Do

2005-01-01

Ribosomal proteins not only act as components of the translation apparatus but also regulate cell proliferation and apoptosis. A previous study reported that MRPL41 plays an important role in p53-dependent apoptosis. It also showed that MRPL41 arrests the cell cycle by stabilizing p27 Kip1 in the absence of p53. This study found that MRPL41 mediates the p21 WAF1/CIP1 -mediated G1 arrest in response to serum starvation. The cells were released from serum starvation-induced G1 arrest via the siRNA-mediated blocking of MRPL41 expression. Overall, these results suggest that MRPL41 arrests the cell cycle by increasing the p21 WAF1/CIP1 and p27 Kip1 levels under the growth inhibitory conditions

Reliability program plan for the Kilowatt Isotope Power System (KIPS) technology verification phase

International Nuclear Information System (INIS)

1978-01-01

Ths document is an integral part of the Kilowatt Isotope Power System (KIPS) Program Plan. This document defines the KIPS Reliability Program Plan for the Technology Verification Phase. This document delineates the reliability assurance tasks that are to be accomplished by Sundstrand and its suppliers during the design, fabrication and testing of the KIPS

Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles.

Science.gov (United States)

Jang, Hoon; Na, Younghwa; Hong, Kwonho; Lee, Sangho; Moon, Sohyeon; Cho, Minha; Park, Miseon; Lee, Ok-Hee; Chang, Eun Mi; Lee, Dong Ryul; Ko, Jung Jae; Lee, Woo Sik; Choi, Youngsok

2017-10-01

Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27 Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27 Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

IEEE Std 649-1991: IEEE standard for qualifying Class 1E motor control centers for nuclear power generating stations

International Nuclear Information System (INIS)

Anon.

1993-01-01

The basic principles, requirements, and methods for qualifying Class 1E motor control centers for both harsh and mild environment applications in nuclear power generating stations are described. In addition to defining specific qualification requirements for Class 1E motor control centers and their components in accordance with the more general qualification requirements of IEEE Std 323-1983, this standard is intended to provide guidance in establishing a qualification program for demonstrating the adequacy of Class 1E motor control centers in nuclear power generating station applications

Inactivation of p27kip1 Promoted Nonspecific Inflammation by Enhancing Macrophage Proliferation in Islet Transplantation.

Science.gov (United States)

Li, Yang; Ding, Xiaoming; Fan, Ping; Guo, Jian; Tian, Xiaohui; Feng, Xinshun; Zheng, Jin; Tian, Puxun; Ding, Chenguang; Xue, Wujun

2016-11-01

Islet transplantation suffers from low efficiency caused by nonspecific inflammation-induced graft loss after transplantation. This study reports increased islet loss and enhanced inflammatory response in p27-deficient mice (p27-/-) and proposes a possible mechanism. Compared with wild type, p27-/- mice showed more severe functional injury of islet, with increased serum levels of inflammatory cytokines IL-1 and TNF-α, inducing macrophage proliferation. Furthermore, the increased number, proapoptotic proteins, and nuclear factor-kappa b (NF-κB) phosphorylation status of the infiltrating macrophages were accompanied by increased TNF-α mRNA level of islet graft site in p27-/- mice. Moreover, in vitro, we found that macrophages were still activated and cocultured with islet and promoted islet loss even blocking the direct effect of TNF-α on islets. Malondialdehyde (MDA, an end product of lipid peroxidation) in islet and media were increased after cocultured with macrophages. p27 deficiency also increased macrophage proliferation and islet injury. Therefore, p27 inactivation promotes injury islet graft loss via the elevation of proliferation and inflammatory cytokines secretion in infiltrating macrophages which induced nonspecific inflammation independent of TNF-α/nuclear factor-kappa b pathway. This potentially represents a promising therapeutic target in improving islet graft survival.

Improving motor reliability in nuclear power plants: Volume 1, Performance evaluation and maintenance practices

International Nuclear Information System (INIS)

Subudhi, M.; Gunther, W.E.; Taylor, J.H.; Sugarman, A.C.; Sheets, M.W.

1987-11-01

This report constitutes the first of the three volumes under this NUREG. The report presents recommendations for developing a cost-effective program for performance evaluation and maintenance of electric motors in nuclear power plants. These recommendations are based on current industry practices, available techniques for monitoring degradation in motor components, manufacturer's recommendations, operating experience, and results from two laboratory tests on aged motors. Two laboratory test reports on a small and a large motor are presented in separate volumes of this NUREG. These provide the basis for the various functional indicators recommended for maintenance programs in this report. The overall preventive maintenance program is separated into two broad areas of activity aimed at mitigating the potential effects of equipment aging: Performance Evaluation and Equipment Maintenance. The latter involves actually maintaining the condition of the equipment while the former involves those activities undertaken to monitor degradation due to aging. These monitoring methods are further categorized into periodic testing, surveillance testing, continuous monitoring and inspections. This study focuses on the methods and procedures for performing the above activities to maintain the motors operationally ready in a nuclear facility. This includes an assessment of various functional indicators to determine their suitability for trending to monitor motor component condition. The intrusiveness of test methods and the present state-of-the-art for using the test equipment in a plant environment are discussed. In conclusion, implementation of the information provided in this report, will improve motor reliability in nuclear power plants. The study indicates the kinds of tests to conduct, how and when to conduct them, and to which motors the tests should be applied. 44 refs., 12 figs., 13 tabs

EGCG-targeted p57/KIP2 reduces tumorigenicity of oral carcinoma cells: Role of c-Jun N-terminal kinase

International Nuclear Information System (INIS)

Yamamoto, Tetsuya; Digumarthi, Hari; Aranbayeva, Zina; Wataha, John; Lewis, Jill; Messer, Regina; Qin, Haiyan; Dickinson, Douglas; Osaki, Tokio; Schuster, George S.; Hsu, Stephen

2007-01-01

The green tea polyphenol epigallocatechin-3-gallate (EGCG) regulates gene expression differentially in tumor and normal cells. In normal human primary epidermal keratinocytes (NHEK), one of the key mediators of EGCG action is p57/KIP2, a cyclin-dependent kinase (CDK) inhibitor. EGCG potently induces p57 in NHEK, but not in epithelial cancer cells. In humans, reduced expression of p57 often is associated with advanced tumors, and tumor cells with inactivated p57 undergo apoptosis when exposed to EGCG. The mechanism of p57 induction by EGCG is not well understood. Here, we show that in NHEK, EGCG-induces p57 via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In p57-negative tumor cells, JNK signaling mediates EGCG-induced apoptosis, and exogenous expression of p57 suppresses EGCG-induced apoptosis via inhibition of c-Jun N-terminal kinase (JNK). We also found that restoration of p57 expression in tumor cells significantly reduced tumorigenicity in athymic mice. These results suggest that p57 expression may be an useful indicator for the clinical course of cancers, and could be potentially useful as a target for cancer therapies

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Directory of Open Access Journals (Sweden)

Christian M. Simon

2017-12-01

Full Text Available The hallmark of spinal muscular atrophy (SMA, an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.

Improving motor reliability in nuclear power plants: Volume 2, Functional indicator tests on a small electric motor subjected to accelerated aging

International Nuclear Information System (INIS)

Subudhi, M.; Taylor, J.H.; Lofaro, R.; Sugarman, A.C.; Sheets, M.W.; Skreiner, K.M.

1987-11-01

A ten horsepower electric motor was artificially aged by plug reverse cycling for test purposes. The motor was manufactured in 1967 and was in service at a commercial nuclear power plant for twelve years. Various tests were performed on the motor throughout the aging process. The motor failed after 3.79 million reversals (3 seconds per reversal) over seven months of testing. Each test parameter was trended to assess its suitability in monitoring aging and service wear degradation in motors. Results and conclusions are discussed relative to the applicability of the tests performed to nuclear power plant motor maintenance programs. 15 refs., 28 figs., 1 tab

The main pump motor remote visual check in the application of the domestic nuclear power plants

International Nuclear Information System (INIS)

Ge Lianwei; Yu Tao; Fang Jiang; Zhang Ting; Zhang Xingtian; Ding Youyuan

2014-01-01

In this paper, the Qinshan nuclear power station the first main pump motor to the successful implementation of remote visual inspection the main pump motor remote visual inspection applications. Qinshan Nuclear Power Plant Units 1 and 2 of the main pump motor inspection results show that the key components of the Qinshan Nuclear Power Plant Units 1 and 2 of the main pump rotor, stator end coils good condition, its problems for 10 years in the motor does not affect the normal use of the motor state disintegration overhaul problems tracking disintegration overhaul in 10 years. (authors)

Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27kip and sox2 in Supporting Cells.

Science.gov (United States)

Rubbini, Davide; Robert-Moreno, Àlex; Hoijman, Esteban; Alsina, Berta

2015-11-25

During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells

p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1.

Directory of Open Access Journals (Sweden)

Xiao-Su Zhao

Full Text Available Cyclin-dependent kinase 5 (Cdk5 is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC-interacting factor 1 (NIF-1, is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.

p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1).

Science.gov (United States)

Zhao, Xiao-Su; Fu, Wing-Yu; Chien, Winnie W Y; Li, Zhen; Fu, Amy K Y; Ip, Nancy Y

2014-01-01

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.

Qualification of electric motors class 1E for supply of motors and its repair

International Nuclear Information System (INIS)

Perez, E.; Gonzalez, J. J.; Fernandez, A.; Garcia, D.

2005-01-01

Different original suppliers of nuclear grade equipment have either disappeared or discontinued the manufacture of this kind equipment. Under this situation nuclear plants are experiencing difficulties when dealing with the substitution or maintenance of these equipment. Tecnatom and Cantarey have developed a new line of Class 1E qualified electric low voltage motors which can be used as an alternative to originally installed safety-related motors or for its repair and maintenance. (Author)

Qualification of electric motors class 1E for supply of motors and its repair; Calificacion de motores electricos clase 1E para el suministro de motores alternativos a los orginales y su reparacion

Energy Technology Data Exchange (ETDEWEB)

Perez, E.; Gonzalez, J. J.; Fernandez, A.; Garcia, D.

2005-07-01

Different original suppliers of nuclear grade equipment have either disappeared or discontinued the manufacture of this kind equipment. Under this situation nuclear plants are experiencing difficulties when dealing with the substitution or maintenance of these equipment. Tecnatom and Cantarey have developed a new line of Class 1E qualified electric low voltage motors which can be used as an alternative to originally installed safety-related motors or for its repair and maintenance. (Author)

Prolonged mechanical ventilation induces cell cycle arrest in newborn rat lung.

Directory of Open Access Journals (Sweden)

Andreas A Kroon

Full Text Available RATIONALE: The molecular mechanism(s by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown. OBJECTIVE: To determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats. METHODS: Seven-day old rats were ventilated with room air for 8, 12 and 24 h using relatively moderate tidal volumes (8.5 mL.kg⁻¹. MEASUREMENT AND MAIN RESULTS: Ventilation for 24 h (h decreased the number of elastin-positive secondary crests and increased the mean linear intercept, indicating arrest of alveolar development. Proliferation (assessed by BrdU incorporation was halved after 12 h of ventilation and completely arrested after 24 h. Cyclin D1 and E1 mRNA and protein levels were decreased after 8-24 h of ventilation, while that of p27(Kip1 was significantly increased. Mechanical ventilation for 24 h also increased levels of p57(Kip2, decreased that of p16(INK4a, while the levels of p21(Waf/Cip1 and p15(INK4b were unchanged. Increased p27(Kip1 expression coincided with reduced phosphorylation of p27(Kip1 at Thr¹⁵⁷, Thr¹⁸⁷ and Thr¹⁹⁸ (p<0.05, thereby promoting its nuclear localization. Similar -but more rapid- changes in cell cycle regulators were noted when 7-day rats were ventilated with high tidal volume (40 mL.kg⁻¹ and when fetal lung epithelial cells were subjected to a continuous (17% elongation cyclic stretch. CONCLUSION: This is the first demonstration that prolonged (24 h of mechanical ventilation causes cell cycle arrest in newborn rat lungs; the arrest occurs in G₁ and is caused by increased expression and nuclear localization of Cdk inhibitor proteins (p27(Kip1, p57(Kip2 from the Kip family.

Substance P signalling in primary motor cortex facilitates motor learning in rats.

Directory of Open Access Journals (Sweden)

Benjamin Hertler

Full Text Available Among the genes that are up-regulated in response to a reaching training in rats, Tachykinin 1 (Tac1-a gene that encodes the neuropeptide Substance P (Sub P-shows an especially strong expression. Using Real-Time RT-PCR, a detailed time-course of Tac1 expression could be defined: a significant peak occurs 7 hours after training ended at the first and second training session, whereas no up-regulation could be detected at a later time-point (sixth training session. To assess the physiological role of Sub P during movement acquisition, microinjections into the primary motor cortex (M1 contralateral to the trained paw were performed. When Sub P was injected before the first three sessions of a reaching training, effectiveness of motor learning became significantly increased. Injections at a time-point when rats already knew the task (i.e. training session ten and eleven had no effect on reaching performance. Sub P injections did not influence the improvement of performance within a single training session, but retention of performance between sessions became strengthened at a very early stage (i.e. between baseline-training and first training session. Thus, Sub P facilitates motor learning in the very early phase of skill acquisition by supporting memory consolidation. In line with these findings, learning related expression of the precursor Tac1 occurs at early but not at later time-points during reaching training.

Substance P signalling in primary motor cortex facilitates motor learning in rats.

Science.gov (United States)

Hertler, Benjamin; Hosp, Jonas Aurel; Blanco, Manuel Buitrago; Luft, Andreas Rüdiger

2017-01-01

Among the genes that are up-regulated in response to a reaching training in rats, Tachykinin 1 (Tac1)-a gene that encodes the neuropeptide Substance P (Sub P)-shows an especially strong expression. Using Real-Time RT-PCR, a detailed time-course of Tac1 expression could be defined: a significant peak occurs 7 hours after training ended at the first and second training session, whereas no up-regulation could be detected at a later time-point (sixth training session). To assess the physiological role of Sub P during movement acquisition, microinjections into the primary motor cortex (M1) contralateral to the trained paw were performed. When Sub P was injected before the first three sessions of a reaching training, effectiveness of motor learning became significantly increased. Injections at a time-point when rats already knew the task (i.e. training session ten and eleven) had no effect on reaching performance. Sub P injections did not influence the improvement of performance within a single training session, but retention of performance between sessions became strengthened at a very early stage (i.e. between baseline-training and first training session). Thus, Sub P facilitates motor learning in the very early phase of skill acquisition by supporting memory consolidation. In line with these findings, learning related expression of the precursor Tac1 occurs at early but not at later time-points during reaching training.

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models.

Science.gov (United States)

Yokoi, Fumiaki; Dang, Mai T; Yang, Guang; Li, Jindong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2012-02-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ɛ-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally inherited Sgce heterozygous knockout (Sgce KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since ɛ-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in Sgce KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of ɛ-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally inherited cerebellar Purkinje cell-specific Sgce conditional knockout (Sgce pKO) mice. Sgce pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that ɛ-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of ɛ-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits. Copyright © 2011 Elsevier B.V. All rights reserved.

Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models.

Science.gov (United States)

Yokoi, Fumiaki; Dang, Mai T; Zhou, Tong; Li, Yuqing

2012-02-15

DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ε-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ε-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ε-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ε-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.

Aging assessment of large electric motors in nuclear power plants

International Nuclear Information System (INIS)

Villaran, M.; Subudhi, M.

1996-03-01

Large electric motors serve as the prime movers to drive high capacity pumps, fans, compressors, and generators in a variety of nuclear plant systems. This study examined the stressors that cause degradation and aging in large electric motors operating in various plant locations and environments. The operating history of these machines in nuclear plant service was studied by review and analysis of failure reports in the NPRDS and LER databases. This was supplemented by a review of motor designs, and their nuclear and balance of plant applications, in order to characterize the failure mechanisms that cause degradation, aging, and failure in large electric motors. A generic failure modes and effects analysis for large squirrel cage induction motors was performed to identify the degradation and aging mechanisms affecting various components of these large motors, the failure modes that result, and their effects upon the function of the motor. The effects of large motor failures upon the systems in which they are operating, and on the plant as a whole, were analyzed from failure reports in the databases. The effectiveness of the industry's large motor maintenance programs was assessed based upon the failure reports in the databases and reviews of plant maintenance procedures and programs

Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models

Science.gov (United States)

Yokoi, Fumiaki; Dang, Mai T.; Zhou, Tong; Li, Yuqing

2012-01-01

DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ɛ-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ɛ-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ɛ-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ɛ-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients. PMID:22080833

Aging of electric motors in nuclear power plants

International Nuclear Information System (INIS)

Subudhi, M.; Taylor, J.H.

1987-06-01

Motor degradation due to aging and service wear decreases reliability and increases the potential for failure during nuclear plant accident and post accident conditions. The impact of motor failures on plant safety is an important concern among the nuclear utilities and the government agency regulating this industry. Economic impacts, relating to plant availability and safety, as well as corrective maintenance, have prompted utilities to improve their maintenance programs to mitigate such aging effects. 2 refs., 3 figs

Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1

Energy Technology Data Exchange (ETDEWEB)

Sakamaki, Jun-ichi; Daitoku, Hiroaki; Yoshimochi, Kenji [Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Miwa, Masanao [Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829 (Japan); Fukamizu, Akiyoshi, E-mail: akif@tara.tsukuba.ac.jp [Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan)

2009-05-08

Forkhead box O (FOXO) transcription factors play an important role in a wide range of biological processes, including cell cycle control, apoptosis, detoxification of reactive oxygen species, and gluconeogenesis through regulation of gene expression. In this study, we demonstrated that PARP-1 functions as a negative regulator of FOXO1. We showed that PARP-1 directly binds to and poly(ADP-ribosyl)ates FOXO1 protein. PARP-1 represses FOXO1-mediated expression of cell cycle inhibitor p27{sup Kip1} gene. Notably, poly(ADP-ribosyl)ation activity was not required for the repressive effect of PARP-1 on FOXO1 function. Furthermore, knockdown of PARP-1 led to a decrease in cell proliferation in a manner dependent on FOXO1 function. Chromatin immunoprecipitation experiments confirmed that PARP-1 is recruited to the p27{sup Kip1} gene promoter through a binding to FOXO1. These results suggest that PARP-1 acts as a corepressor for FOXO1, which could play an important role in proper cell proliferation by regulating p27{sup Kip1} gene expression.

An oral Na(V)1.8 blocker improves motor function in mice completely deficient of myelin protein P-0

DEFF Research Database (Denmark)

Rosberg, Mette R.; Alvarez Herrero, Susana; Krarup, Christian

2016-01-01

Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/−, a model of CMT......1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P0......-of-concept that treatment with oral subtype-selective NaV1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT....

Involvement of p27CIP/KIP in HSP25 or HSP70 Mediated Adaptive Response by Low Dose Radiation

International Nuclear Information System (INIS)

Seo, Hang Rhan; Lee, Yoon Jin; Lee, Su Jae; Bae, Sang woo; Lee, Yun Sil

2005-01-01

Adaptive responses that reduce the harmful effects of subsequent exposure to high-dose radiation have demonstrated in chromosome aberration, cell survival, sister chromatid exchanges, micronucleus induction, mutation and neoplastic transformation. The mechanisms and conditions for the adaptive response to radiation have not been clarified, although the continuous production of free radicals from radiation and other sources has stimulated cells to evolve a repair system for chromosome breaks. An alteration of the DNA molecule triggers the repair system, and frequent activation may increase the general repair capacity, irrespective of the cause of the damage. Besides, cell cycle regulation systems, antioxidant defense systems, molecular chaperone or stress-response systems. Our previous data showed that when cells were preirradiated with 1cGy, they showed the adaptive response. A reduction of apoptosis by low-dose preirradiation is another potential mechanism for this effect. We previously demonstrated that mouse RIF cells, which did not induce HSP25 and HSP70 did not exhibit a adaptive response after 1cGy preirradiation. whereas the thermoresistant TR cells, which expressed inducible HSP25 and HSP70 showed a response. Moreover, when HSP70 and HSP25 were transfected to RIF cells, the cells acquired adaptive response. In this study, to elucidate the mechanisms in induction of adaptiveresponse, we compared cell cycle distribution by low dose radiation after HSP25 or HSP70 transfected cells and p27CIP/KIP is responsible for the different induction of adaptive response

Millstone Unit 1 plant vulnerabilities during postulated severe nuclear accidents

International Nuclear Information System (INIS)

Khalil, Y.F.

1993-01-01

Generic Letter 88-20, Supplement No. 1 (Ref. 1), issued by the Nuclear Regulatory Commission (NRC) requested all licensees holding operating licenses and construction permits for nuclear power reactor facilities to perform Individual Plant Examinations (IPE) of their plant(s) for severe accident vulnerabilities and to submit the results to the Commission. This paper summarizes the major Front-End (Level-1 PRA) and Back-End (Level-2 PRA) insights gained from the Millstone Unit 1 (MP-1) IPE study. No major plant vulnerabilities have been identified from a Front-End perspective. The Back-End analysis, however, has identified two potential containment vulnerabilities during postulated events that progress beyond the Design Basis Accidents (DBAs), namely, (1) MP-1 is dominated by early source term releases that would occur within a six-hour time frame from time of accident initiation, or reactor trip, and (2) MP-1 containment is somewhat vulnerable to leak-type failure through the drywell head. As a result of the second finding, a recommendation currently under evaluation, has been made to increase the drywell head bolt's preload from 54 Kips to resist the containment design pressure value (62 psig)

ER-associated SNAREs and Sey1p mediate nuclear fusion at two distinct steps during yeast mating.

Science.gov (United States)

Rogers, Jason V; Arlow, Tim; Inkellis, Elizabeth R; Koo, Timothy S; Rose, Mark D

2013-12-01

During yeast mating, two haploid nuclei fuse membranes to form a single diploid nucleus. However, the known proteins required for nuclear fusion are unlikely to function as direct fusogens (i.e., they are unlikely to directly catalyze lipid bilayer fusion) based on their predicted structure and localization. Therefore we screened known fusogens from vesicle trafficking (soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]) and homotypic endoplasmic reticulum (ER) fusion (Sey1p) for additional roles in nuclear fusion. Here we demonstrate that the ER-localized SNAREs Sec20p, Ufe1p, Use1p, and Bos1p are required for efficient nuclear fusion. In contrast, Sey1p is required indirectly for nuclear fusion; sey1Δ zygotes accumulate ER at the zone of cell fusion, causing a block in nuclear congression. However, double mutants of Sey1p and Sec20p, Ufe1p, or Use1p, but not Bos1p, display extreme ER morphology defects, worse than either single mutant, suggesting that retrograde SNAREs fuse ER in the absence of Sey1p. Together these data demonstrate that SNAREs mediate nuclear fusion, ER fusion after cell fusion is necessary to complete nuclear congression, and there exists a SNARE-mediated, Sey1p-independent ER fusion pathway.

Necrosis related HIF-1α expression predicts prognosis in patients with endometrioid endometrial carcinoma

International Nuclear Information System (INIS)

Seeber, Laura MS; Horrée, Nicole; Groep, Petra van der; Wall, Elsken van der; Verheijen, René HM; Diest, Paul J van

2010-01-01

Hypoxia inducible factor 1α (HIF-1α) plays an essential role in the adaptive response of cells to hypoxia and is associated with aggressive tumour behaviour. We have shown p27 kip1 , which is generally reduced in endometrial cancer, to be re-expressed in hypoxic regions. This possibly contributes to survival of cancer cells. The aim of this study was to evaluate the prognostic value of HIF-1α and p27 kip expression in patients with endometrioid endometrial cancer. Expression levels of HIF-1α, CAIX, Glut-1, and p27 kip1 were analyzed by immunohistochemistry. Percentage of positive cells, staining pattern (perinecrotic, diffuse, or mixed) and presence of necrosis were noted. Necrosis was correlated with shortened disease free survival (DFS) (p = 0.008) and overall survival (OS) (p = 0.045). For DFS, perinecrotic HIF-1α expression was also prognostic (p = 0.044). Moreover, high p27 kip1 expression was an additional prognostic factor for these patients with perinecrotic HIF-1α expression. In multivariate Cox regression, perinecrotic HIF-expression emerged as an independent prognostic factor. Perinecrotic HIF-1α expression was significantly associated with CAIX and Glut-1 expression, pointing towards functional HIF-1. In patients with endometrioid endometrial cancer, necrosis and necrosis-related expression of HIF-1α are important prognostic factors. More aggressive adjuvant treatment might be necessary to improve the outcome of patients with these characteristics

Crystal structure of the Xpo1p nuclear export complex bound to the SxFG/PxFG repeats of the nucleoporin Nup42p.

Science.gov (United States)

Koyama, Masako; Hirano, Hidemi; Shirai, Natsuki; Matsuura, Yoshiyuki

2017-10-01

Xpo1p (yeast CRM1) is the major nuclear export receptor that carries a plethora of proteins and ribonucleoproteins from the nucleus to cytoplasm. The passage of the Xpo1p nuclear export complex through nuclear pore complexes (NPCs) is facilitated by interactions with nucleoporins (Nups) containing extensive repeats of phenylalanine-glycine (so-called FG repeats), although the precise role of each Nup in the nuclear export reaction remains incompletely understood. Here we report structural and biochemical characterization of the interactions between the Xpo1p nuclear export complex and the FG repeats of Nup42p, a nucleoporin localized at the cytoplasmic face of yeast NPCs and has characteristic SxFG/PxFG sequence repeat motif. The crystal structure of Xpo1p-PKI-Nup42p-Gsp1p-GTP complex identified three binding sites for the SxFG/PxFG repeats on HEAT repeats 14-20 of Xpo1p. Mutational analyses of Nup42p showed that the conserved serines and prolines in the SxFG/PxFG repeats contribute to Xpo1p-Nup42p binding. Our structural and biochemical data suggest that SxFG/PxFG-Nups such as Nup42p and Nup159p at the cytoplasmic face of NPCs provide high-affinity docking sites for the Xpo1p nuclear export complex in the terminal stage of NPC passage and that subsequent disassembly of the nuclear export complex facilitates recycling of free Xpo1p back to the nucleus. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

KIP THORNE: The Shaman of Space and Time.

Science.gov (United States)

Irion, R

2000-11-24

A generation of physicists probing the extremes of gravity can trace its scientific heritage to one man: Kip Thorne of the California Institute of Technology. A recent symposium to mark Thorne's 60th birthday brought together nearly 200 experts on gravity at its strongest and strangest: the domains of black holes, colliding neutron stars, and other exotic deep-space objects. Participants came to honor their mentor, who has led the way in converting Albert Einstein's General Theory of Relativity from a purely theoretical science into an astrophysical and observational one.

Heterogenic final cell cycle by chicken retinal Lim1 horizontal progenitor cells leads to heteroploid cells with a remaining replicated genome.

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Shahrzad Shirazi Fard

Full Text Available Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs exit the cell cycle. We have used markers for S- and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

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

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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

Motor life management at Gentilly 2 nuclear power plant

International Nuclear Information System (INIS)

Lazic, L.; Renaud, P.; Marcotte, P.

2002-01-01

Hydro Quebec's Gentilly 2 CANDU Nuclear Power Plant (NPP) located on the St. Lawrence River about 150 kms NE of Montreal Quebec Canada, is completing its second full decade of commercial operation. Since the original design life of 30 years is fast approaching, Hydro Quebec (HQ) is positioning itself proactively, to ensure plant operation for the original design life as well implementing a plant life management program to achieve a plant life extension to 50 years. All components in a nuclear plant are affected by ageing during the plant service life. This affects the availability, reliability, and safety of the plant operation and could affect the plant service life. However, if a life management program (LMP) is implemented; the ageing mechanisms can be understood and monitored, and their effects can be controlled and even mitigated. Among other vital equipment in the plant, the station motors are being examined to determine what has to be done to ensure that the motors do not contribute negatively to the plant operating plan. Gentilly 2 NPP has almost 900 motors of various configurations. Their size ranges from 0.1 HP to 9000 HP. A distribution of quantity at different horsepower levels is given. This paper will describe the plant's motor history, method of operation, and proposed future changes required to ensure effective life management of the motors. Up to the present time, Gentilly 2 NPP staff has had very good experience with plant motor operation and reliability. Nevertheless, indications from other industry motor experiences indicate that this favourable trend is unlikely to continue. A plant motor life management strategy as outlined in this paper, based on condition based maintenance in combination with traditional types of maintenance, can help to ensure protection against unexpected plant motor problems and help to ensure achievement of motor design life and beyond. Although nothing will ever replace a thorough visual inspection for discovering

Nitric oxide induces thioredoxin-1 nuclear translocation: Possible association with the p21Ras survival pathway

International Nuclear Information System (INIS)

Arai, Roberto J.; Masutani, H.; Yodoi, J.; Debbas, V.; Laurindo, Francisco R.; Stern, A.; Monteiro, Hugo P.

2006-01-01

One of the major redox-regulating molecules with thiol reducing activity is thioredoxin-1 (TRX-1). TRX-1 is a multifunctional protein that exists in the extracellular millieu, cytoplasm, and nucleus, and has a distinct role in each environment. It is well known that TRX-1 promptly migrates to the nuclear compartment in cells exposed to oxidants. However, the intracellular location of TRX-1 in cells exposed to nitrosothiols has not been investigated. Here, we demonstrated that the exposure of HeLa cells to increasing concentrations of the nitrosothiol S-nitroso-N-acetylpenicillamine (SNAP) promoted TRX-1 nuclear accumulation. The SNAP-induced TRX-1 translocation to the nucleus was inhibited by FPTIII, a selective inhibitor of p21Ras. Furthermore, TRX-1 migration was attenuated in cells stably transfected with NO insensitive p21Ras (p21 RasC118S ). Downstream to p21Ras, the MAP Kinases ERK1/2 were activated by SNAP under conditions that promote TRX-1 nuclear translocation. Inhibition of MEK prevented SNAP-stimulated ERK1/2 activation and TRX-1 nuclear migration. In addition, cells treated with p21Ras or MEK inhibitor showed increased susceptibility to cell death induced by SNAP. In conclusion, our observations suggest that the nuclear translocation of TRX-1 is induced by SNAP involving p21Ras survival pathway

Methodology to monitor and diagnostic vibrations of the motor-pumps used in the primary cooling system of IEAR-1 nuclear research reactor

International Nuclear Information System (INIS)

Benevenuti, Erion de Lima

2004-01-01

The objectives of this study are to establish a strategy to monitor and diagnose vibrations of the motor pumps used in the primary reactor cooling system of the IEA-R1 nuclear research reactor, to verify the possibility of using the existing installed monitoring vibration system and to implement such strategy in a continuous way. Four types of mechanical problems were considered: unbalancing, misalignment, gaps and faults in bearings. An adequate set of analysis tools, well established by the industry, was selected. These are: global measurements of vibration, velocity spectrum and acceleration envelope spectrum. Three sources of data and information were used; the data measured from the primary pumps, experimental results obtained with a Spectra Quest machine used to simulate mechanical defects and data from the literature. The results show that, for the specific case of the motor-pumps of IEA-R1 nuclear research reactor, although the technique using the envelope of acceleration, which is not available in the current system used to monitor the vibration of the motor pumps, is the one with best performance, the other techniques available in the system are sufficient to monitor the four types of mechanical problems mentioned. The proposed strategy is shown and detailed in this work. (author)

Phosphoinositide-3-kinases p110alpha and p110beta mediate S phase entry in astroglial cells in the marginal zone of rat neocortex

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Rabea eMüller

2013-03-01

Full Text Available In cells cultured from neocortex of newborn rats, phosphoinositide-3-kinases of class I regulate the DNA synthesis in a subgroup of astroglial cells. We have studied the location of these cells as well as the kinase isoforms which facilitate the S phase entry. Using dominant negative isoforms as well as selective pharmacological inhibitors we quantified S phase entry by nuclear labeling with bromodeoxyuridine. Only in astroglial cells harvested from the marginal zone of the neocortex inhibition of phosphoinositide-3-kinases reduced the nuclear labeling with bromodeoxyuridine, indicating that neocortical astroglial cells differ in the regulation of proliferation. The two kinase isoforms p110 and p110were essential for S phase entry. p110 diminished the level of the p27Kip1 which inactivates the complex of cyclin E and CDK2 necessary for entry into the S phase. p110phosphorylated and inhibited glycogen synthase kinase-3which can prevent S-phase entry. Taken together, both isoforms mediated S phase in a subgroup of neocortical astroglial cells and acted via distinct pathways.

Nuclear effects in protonium formation low-energy three-body reaction: p̄ + (pμ1s → (p̄pα + μ−: Strong p̄–p interaction in p̄ + (pμ1s

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Sultanov Renat A.

2016-01-01

Full Text Available A three-charge-particle system (p̄, μ−, p+ with an additional matter-antimatter, i.e. p̄–p+, nuclear interaction is the subject of this work. Specifically, we carry out a few-body computation of the following protonium formation reaction: p̄ + (p+μ−1s → (p̄p+1s + μ−, where p+ is a proton, p̄ is an antiproton, μ− is a muon, and a bound state of p+ and its counterpart p̄ is a protonium atom: Pn = (p̄p+. The low-energy cross sections and rates of the Pn formation reaction are computed in the framework of a Faddeev-like equation formalism. The strong p̄–p+ interaction is approximately included in this calculation.

Work-in-progress report on maintenance good practices for motors in nuclear power generating stations - Part 2

International Nuclear Information System (INIS)

Eckstein, E.R.; Hall, A.R.; Kasper, S.; Smith, P.R.; Subudhi, M.

1988-01-01

Motor maintenance is addressed by a variety of industry standards, utility procedures and manufacture's instructions, as well as by recently published assessments of nuclear and non-nuclear operating experience and motor reliability data. This experience supports the premise that motor failure rates are in large part related to application stress factors such as operating time, environmental factors and vibration. Due to the large number of critical motors installed in a nuclear generating station, additional considerations are necessary to effectively schedule their preventive maintenance activities. Therefore, in this part, a method for prioritizing motor maintenance based on application stresses experienced by the motors is presented

Development of method for detecting signs deterioration in insulator of high-voltage motors. 2. Test Results of a new on-line partial discharge monitor for high-voltage motors in nuclear power stations

International Nuclear Information System (INIS)

Tochio, Atsushi; Kaneda, Yoshiharu; Urakawa, Nobuo

2000-01-01

For the purpose of early detection of deterioration of insulators in high-voltage motors which are widely utilized in nuclear power stations, a new on-line partial discharge (PD) monitor was developed and was tested for sixteen motors which were practically running in nuclear power stations. From the test results, it is seen that (1) good signal to noise ratio is obtained by adopting a two frequency correlation method, (2) a resistance temperature detector (RTD) in a motor has sufficient sensitivity to detect PD, (3) when RTD is not installed or is unable to use for this purpose, a radio frequency current transformer (RFCT) can be utilized, although its sensitivity is about 1/10 of that of the RTD monitor. Finally we found a good correlation between the results of this on-line method and the conventional off-line method in which the insulator resistance of a concerned motor was measured during its shut-down, and thereby we demonstrated that this method could be applicable to the on-line test of high-voltage motors in nuclear power stations. (author)

Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.

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Ana Boulanger

Full Text Available Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment and received by the motor neuron (presynaptic compartment resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.

Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.

Science.gov (United States)

Boulanger, Ana; Farge, Morgane; Ramanoudjame, Christophe; Wharton, Kristi; Dura, Jean-Maurice

2012-01-01

Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor) triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment) and received by the motor neuron (presynaptic compartment) resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.

Posttranscriptional regulation of the karyogamy gene by Kem1p/Xrn1p exoribonuclease and Rok1p RNA helicase of Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Kim, Jaehee; Jeon, Soonmee; Yang, Yun-Seok; Kim, Jinmi

2004-01-01

The major biochemical activities ascribed to Kem1p/Xrn1p of Saccharomyces cerevisiae are 5'-3' exoribonuclease functioning in RNA turnover and a microtubule-binding protein. Mutational analysis has shown that Kem1p/Xrn1p participates in microtubule-related functions such as nuclear fusion (karyogamy) during mating, chromosome transmission, and spindle pole body duplication. Here, evidence is presented that Kem1p plays a specific role in nuclear fusion by affecting, at the posttranscriptional level, the pheromone induction of the karyogamy-specific transcription factor Kar4p and the expression of Rok1p, a putative RNA helicase. We found that Rok1p itself also affects the pheromone induction of Kar4p and thereby participates in nuclear fusion. Analysis of the active-site mutations, xrn1-D206A or D208A, shows that nuclear fusion as well as the Rok1p synthesis do not require the exoribonuclease activity of Kem1p. Our data provide an important insight into the gene-specific regulatory function mediated by the general RNA-modulating enzymes

Tensile tests of 2500-kip prestressing tendons for the PCRV

International Nuclear Information System (INIS)

Nicolayeff, V.

1978-05-01

A 2500-kip (11-MN) capacity prestressing tendon consisting of sixty 0.5-in. (12.7-mm) strands was designed and tested for General Atomic Company by VSL Corporation of Los Gatos, California. Results of the static tensile test described in this report, and of dynamic tensile tests conducted by VSL in 1968 and 1969, indicate that the tendon system satisfies the requirements of the ASME Boiler and Pressure Vessel Code, Section III, Division 2, and so can be used for prestressing concrete reactor vessels

Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice.

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Turner, Bradley J; Alfazema, Neza; Sheean, Rebecca K; Sleigh, James N; Davies, Kay E; Horne, Malcolm K; Talbot, Kevin

2014-04-01

Spinal muscular atrophy results from diminished levels of survival motor neuron (SMN) protein in spinal motor neurons. Low levels of SMN also occur in models of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1) and genetic reduction of SMN levels exacerbates the phenotype of transgenic SOD1(G93A) mice. Here, we demonstrate that SMN protein is significantly reduced in the spinal cords of patients with sporadic ALS. To test the potential of SMN as a modifier of ALS, we overexpressed SMN in 2 different strains of SOD1(G93A) mice. Neuronal overexpression of SMN significantly preserved locomotor function, rescued motor neurons, and attenuated astrogliosis in spinal cords of SOD1(G93A) mice. Despite this, survival was not prolonged, most likely resulting from SMN mislocalization and depletion of gems in motor neurons of symptomatic mice. Our results reveal that SMN upregulation slows locomotor deficit onset and motor neuron loss in this mouse model of ALS. However, disruption of SMN nuclear complexes by high levels of mutant SOD1, even in the presence of SMN overexpression, might limit its survival promoting effects in this specific mouse model. Studies in emerging mouse models of ALS are therefore warranted to further explore the potential of SMN as a modifier of ALS. Copyright © 2014 Elsevier Inc. All rights reserved.

FEATURES OF ELECTRIC MOTOR CHOICE FOR NUCLEAR POWER PLANT TECHNOLOGICAL OBJECTS

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V.V. Shevchenko

2013-06-01

Full Text Available Nuclear power plants remain the basic power generating enterprises for Ukraine. Execution of works on their reliability control and operating conditions optimization is therefore of current importance. Trouble-free nuclear power plant operation is a vital technical, economical, and ecological problem, a solution to which is largely specified by reliable operation of electric equipment, namely, electric motors of nuclear power plant technological process drives.

Association between physical activity and motor skills and coordination in Portuguese children. DOI: 10.5007/1980-0037.2011v13n1p15

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Beatriz Pereira

2011-01-01

Full Text Available Nowadays, there is growing evidence in literature that Health benefits from regular physical activity (PA. The variance in PA among children is caused by a number of factors including their motor abilities and coordination. The aim of the study was to analyse the relation between usual PA and gross motor abilities and motor coordination in children aged 6 to 7 years. The sample comprised 21 children, aged in average 6,38±0,50 years. Physical activity was accessed by accelerometry, gross motor abilities by using the Test of Gross Motor Development (TGMD-2 and motor coordination by using the Körperkoordination Test für Kinder (KTK. Subjects met the international recommendations for daily PA; in motor coordination 47,6% of children met normal coordination, nobody reach good or very good coordination, the majority (52,4% revelled disturbances or insufficiencies of coordination; in locomotion TGMD-2 76,2% of the children met percentile 50 or superior (P50, in object control TGMD-2 28,6% of the children reach P50 or superior, in total TGMD-2 38,1% of the children met P50 or superior. PA was positively correlated with TGMD-2 object control. Low performance attributed to the children in TGMD-2 and KTK tests could be an indicative of insufficient in the development of coordination and gross motor abilities; therefore we believe that this kind of intervention should be targeted at school children mainly in Physical Education classes.

Nuclear inner membrane fusion facilitated by yeast Jem1p is required for spindle pole body fusion but not for the first mitotic nuclear division during yeast mating.

Science.gov (United States)

Nishikawa, Shuh-ichi; Hirata, Aiko; Endo, Toshiya

2008-11-01

During mating of budding yeast, Saccharomyces cerevisiae, two haploid nuclei fuse to produce a diploid nucleus. The process of nuclear fusion requires two J proteins, Jem1p in the endoplasmic reticulum (ER) lumen and Sec63p, which forms a complex with Sec71p and Sec72p, in the ER membrane. Zygotes of mutants defective in the functions of Jem1p or Sec63p contain two haploid nuclei that were closely apposed but failed to fuse. Here we analyzed the ultrastructure of nuclei in jem1 Delta and sec71 Delta mutant zygotes using electron microscope with the freeze-substituted fixation method. Three-dimensional reconstitution of nuclear structures from electron microscope serial sections revealed that Jem1p facilitates nuclear inner-membrane fusion and spindle pole body (SPB) fusion while Sec71p facilitates nuclear outer-membrane fusion. Two haploid SPBs that failed to fuse could duplicate, and mitotic nuclear division of the unfused haploid nuclei started in jem1 Delta and sec71 Delta mutant zygotes. This observation suggests that nuclear inner-membrane fusion is required for SPB fusion, but not for SPB duplication in the first mitotic cell division.

ATP-binding motifs play key roles in Krp1p, kinesin-related protein 1, function for bi-polar growth control in fission yeast

International Nuclear Information System (INIS)

Rhee, Dong Keun; Cho, Bon A; Kim, Hyong Bai

2005-01-01

Kinesin is a microtubule-based motor protein with various functions related to the cell growth and division. It has been reported that Krp1p, kinesin-related protein 1, which belongs to the kinesin heavy chain superfamily, localizes on microtubules and may play an important role in cytokinesis. However, the function of Krp1p has not been fully elucidated. In this study, we overexpressed an intact form and three different mutant forms of Krp1p in fission yeast constructed by site-directed mutagenesis in two ATP-binding motifs or by truncation of the leucine zipper-like motif (LZiP). We observed hyper-extended microtubules and the aberrant nuclear shape in Krp1p-overexpressed fission yeast. As a functional consequence, a point mutation of ATP-binding domain 1 (G89E) in Krp1p reversed the effect of Krp1p overexpression in fission yeast, whereas the specific mutation in ATP-binding domain 2 (G238E) resulted in the altered cell polarity. Additionally, truncation of the leucine zipper-like domain (LZiP) at the C-terminal of Krp1p showed a normal nuclear division. Taken together, we suggest that krp1p is involved in regulation of cell-polarized growth through ATP-binding motifs in fission yeast

Procedure of qualification applied to motors driving auxiliaries in fossil fired and nuclear power plants

International Nuclear Information System (INIS)

Coperchini, C.; Fises, A.

1984-01-01

Twenty year operation have enabled EDF to better understand the factors improving the reliability of powerhouse auxiliary drive induction motors. Progress in the behaviour of such machines are mainly due to analysis and handling of full size test results achieved in the Saint-Denis Motor Test Laboratory. This work led to the printing of recommendations and technical specifications. Service and safety requirements of the nuclear plant new generation lead to examine again the procedures of qualification. The analysis made in this report let appear the justification to maintain the present EDF policy with some necessary adjustments, especially as far as the nuclear safety motors are concerned [fr

P2X1 receptors localized in lipid rafts mediate ATP motor responses in the human vas deferens longitudinal muscles.

Science.gov (United States)

Donoso, María Verónica; Norambuena, Andrés; Navarrete, Camilo; Poblete, Inés; Velasco, Alfredo; Huidobro-Toro, Juan Pablo

2014-02-01

To assess the role of the P2X1 receptors (P2X1R) in the longitudinal and circular layers of the human vas deferens, ex vivo-isolated strips or rings were prepared from tissue biopsies to record isometric contractions. To ascertain its membrane distribution, tissue extracts were analyzed by immunoblotting following sucrose gradient ultracentrifugation. ATP, alpha,beta-methylene ATP, or electrical field stimulation elicited robust contractions of the longitudinal layer but not of the circular layer which demonstrated inconsistent responses. Alpha,beta-methylene ATP generated stronger and more robust contractions than ATP. In parallel, prostatic segments of the rat vas deferens were examined. The motor responses in both species were not sustained but decayed within the first minute, showing desensitization to additional applications. Cross-desensitization was established between alpha,beta-methylene ATP or ATP-evoked contractions and electrical field stimulation-induced contractions. Full recovery of the desensitized motor responses required more than 30 min and showed a similar pattern in human and rat tissues. Immunoblot analysis of the human vas deferens extracts revealed a P2X1R oligomer of approximately 200 kDa under nonreducing conditions, whereas dithiothreitol-treated extracts showed a single band of approximately 70 kDa. The P2X1R was identified in ultracentrifugation fractions containing 15%-29% sucrose; the receptor localized in the same fractions as flotillin-1, indicating that it regionalized into smooth muscle lipid rafts. In conclusion, ATP plays a key role in human vas deferens contractile responses of the longitudinal smooth muscle layer, an effect mediated through P2X1Rs.

"3"1P Nuclear Magnetic Resonance of Charge-Density-Wave Transition in a Single Crystal of RuP

International Nuclear Information System (INIS)

Fan Guo-Zhi; Luo Jian-Lin; Chen Rong-Yan; Wang Nan-Lin

2015-01-01

We perform "3"1P nuclear magnetic resonance (NMR) measurements on a single crystal of RuP. The anomalies in resistivity at about T_A = 270 K and T_B = 330 K indicate that two phase transitions occur. The line shape of "3"1P NMR spectra in different temperature ranges is attributed to the charge density distribution. The Knight shift and spin-lattice relaxation rate 1/T_1T are measured from 10 K to 300 K. At about T_A = 270 K, they both decrease abruptly with the temperature reduction, which reveals the gap-opening behavior. Well below T_A, they act like the case of normal metal. Charge-density-wave phase transition is proposed to interpret the transition occurring at about T_A. (paper)

Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2.

Science.gov (United States)

Goyeneche, Alicia A; Seidel, Erin E; Telleria, Carlos M

2012-06-01

Antiprogestins have been largely utilized in reproductive medicine, yet their repositioning for oncologic use is rapidly emerging. In this study we investigated the molecular mediators of the anti-ovarian cancer activity of the structurally related antiprogestins RU-38486, ORG-31710 and CDB-2914. We studied the responses of wt p53 OV2008 and p53 null SK-OV-3 cells to varying doses of RU-38486, ORG-31710 and CDB-2914. The steroids inhibited the growth of both cell lines with a potency of RU-38486 > ORG-31710 > CDB-2914, and were cytostatic at lower doses but lethal at higher concentrations. Antiprogestin-induced lethality associated with morphological features of apoptosis, hypodiploid DNA content, DNA fragmentation, and cleavage of executer caspase substrate PARP. Cell death ensued despite RU-38486 caused transient up-regulation of anti-apoptotic Bcl-2, ORG-31710 induced transient up-regulation of inhibitor of apoptosis XIAP, and CDB-2914 up-regulated both XIAP and Bcl-2. The antiprogestins induced accumulation of Cdk inhibitors p21(cip1) and p27(kip1) and increased association of p21(cip1) and p27(kip1) with Cdk-2. They also promoted nuclear localization of p21(cip1) and p27(kip1), reduced the nuclear abundances of Cdk-2 and cyclin E, and blocked the activity of Cdk-2 in both nucleus and cytoplasm. The cytotoxic potency of the antiprogestins correlated with the magnitude of the inhibition of Cdk-2 activity, ranging from G1 cell cycle arrest towards cell death. Our results suggest that, as a consequence of their cytostatic and lethal effects, antiprogestin steroids of well-known contraceptive properties emerge as attractive new agents to be repositioned for ovarian cancer therapeutics.

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies.

Science.gov (United States)

Ehm, Patrick; Nalaskowski, Marcus M; Wundenberg, Torsten; Jücker, Manfred

2015-01-01

The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and leukemic haematopoietic cells. In addition, we report that ectopically expressed SHIP1 accumulates in nucleolar cavities and colocalizes with the tumor suppressor protein p53 and components of PML nuclear bodies (e.g. SP100, SUMO-1 and CK2). Moreover, SHIP1 also colocalizes in nucleolar cavities with components of the ubiquitin-proteasome pathway. By using confocal microscopy data, we generated 3D-models revealing the enormous extent of the SHIP1 aggresomes in the nucleolus. Furthermore, treatment of cells with the proteasome inhibitor MG132 causes an enlargement of nucleolar SHIP1 containing structures. Unexpectedly, this accumulation can be partially prevented by treatment with the inhibitor of nuclear protein export Leptomycin B. In recent years, several proteins aggregating in nucleolar cavities were shown to be key factors of neurodegenerative diseases and cancerogenesis. Our findings support current relevance of nuclear localized SHIP1.

Transportin-1-dependent YB-1 nuclear import

International Nuclear Information System (INIS)

Mordovkina, Daria A.; Kim, Ekaterina R.; Buldakov, Ilya A.; Sorokin, Alexey V.; Eliseeva, Irina A.; Lyabin, Dmitry N.; Ovchinnikov, Lev P.

2016-01-01

The DNA/RNA-binding protein YB-1 (Y-box binding protein 1) performs multiple functions both in the cytoplasm and the nucleus of the cell. Generally localized to the cytoplasm, under certain conditions YB-1 is translocated to the nucleus. Here we report for the first time a transport factor that mediates YB-1 nuclear import – transportin-1. The YB-1/transportin-1 complex can be isolated from HeLa cell extract. Nuclear import of YB-1 and its truncated form YB-1 (1-219) in in vitro transport assay was diminished in the presence of a competitor substrate and ceased in the presence of transportin-1 inhibitor M9M. Inhibitors of importin β1 had no effect on YB-1 transport. Furthermore, transport of YB-1 (P201A/Y202A) and YB-1 (1–219) (P201A/Y202A) bearing inactivating mutations in the transportin-1-dependent nuclear localization signal was practically abolished. Together, these results indicate that transportin-1 mediates YB-1 nuclear translocation. - Highlights: • Transportin-1 mediates YB-1 nuclear import. • YB-1 nuclear translocation is diminished in the presence of transportin-1 inhibitors. • Mutations in the PY motif of YB-1 NLS prevent its translocation to the nucleus.

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies

OpenAIRE

Ehm, Patrick; Nalaskowski, Marcus M; Wundenberg, Torsten; Jücker, Manfred

2015-01-01

The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and ...

Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function

Directory of Open Access Journals (Sweden)

Carola Dewitz

2018-02-01

Full Text Available Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, and afadin signaling. Our findings reveal that nuclear organization of motor neurons is dependent on inside-out positioning, orchestrated by N-cadherin, catenin, and afadin activities, controlling cell body layering on the medio-lateral axis. In addition to this lamination-like program, motor neurons undergo a secondary, independent phase of organization. This process results in segregation of motor neurons along the dorso-ventral axis of the spinal cord, does not require N-cadherin or afadin activity, and can proceed even when medio-lateral positioning is perturbed.

Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway*

Science.gov (United States)

Han, Sungwon; Bahmanyar, Shirin; Zhang, Peixiang; Grishin, Nick; Oegema, Karen; Crooke, Roseann; Graham, Mark; Reue, Karen; Dixon, Jack E.; Goodman, Joel M.

2012-01-01

Lipin-1 catalyzes the formation of diacylglycerol from phosphatidic acid. Lipin-1 mutations cause lipodystrophy in mice and acute myopathy in humans. It is heavily phosphorylated, and the yeast ortholog Pah1p becomes membrane-associated and active upon dephosphorylation by the Nem1p-Spo7p membrane complex. A mammalian ortholog of Nem1p is the C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly “dullard”), but its Spo7p-like partner is unknown, and the need for its existence is debated. Here, we identify the metazoan ortholog of Spo7p, TMEM188, renamed nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1). CTDNEP1 and NEP1-R1 together complement a nem1Δspo7Δ strain to block endoplasmic reticulum proliferation and restore triacylglycerol levels and lipid droplet number. The two human orthologs are in a complex in cells, and the amount of CTDNEP1 is increased in the presence of NEP1-R1. In the Caenorhabditis elegans embryo, expression of nematode CTDNEP1 and NEP1-R1, as well as lipin-1, is required for normal nuclear membrane breakdown after zygote formation. The expression pattern of NEP1-R1 and CTDNEP1 in human and mouse tissues closely mirrors that of lipin-1. CTDNEP1 can dephosphorylate lipins-1a, -1b, and -2 in human cells only in the presence of NEP1-R1. The nuclear fraction of lipin-1b is increased when CTDNEP1 and NEP1-R1 are co-expressed. Therefore, NEP1-R1 is functionally conserved from yeast to humans and functions in the lipin activation pathway. PMID:22134922

YB1/p32, a nuclear Y-box binding protein 1, is a novel regulator of myoblast differentiation that interacts with Msx1 homeoprotein

Energy Technology Data Exchange (ETDEWEB)

Song, Young Joon [Department of Biological Sciences, College of Natural Science, Inha University, 253 Yonghyun-dong, Nam-Gu, Incheon, Korea, 402-751 (Korea, Republic of); Lee, Hansol, E-mail: hlee@inha.ac.kr [Department of Biological Sciences, College of Natural Science, Inha University, 253 Yonghyun-dong, Nam-Gu, Incheon, Korea, 402-751 (Korea, Republic of)

2010-02-15

Precisely controlled cellular differentiation is essential for the proper development of vertebrate embryo and deregulated differentiation is a major cause of many human congenital diseases as well as cancer. Msx1 is a member of the homeoprotein family implicated in these processes, which inhibits the differentiation of skeletal muscle and other cell types, presumably by regulating transcription of target genes through interaction with other cellular factors. We presently show that YB1/p32, a nuclear Y-box binding protein 1, interacts with Msx1 homeoprotein and functions as a regulator of C2C12 myoblast differentiation. We demonstrate that YB1/p32 functionally interacts with Msx1 through its N-terminal region and colocalizes with Msx1 at the nuclear periphery. Moreover, we find that YB1/p32 is competent for inhibition of C2C12 myoblast differentiation, which is correlated with its activity as a negative regulator of MyoD gene expression and binding to the MyoD core enhancer region (CER). Furthermore, YB1/p32 cooperates with Msx1 in transcriptional repression and knocking down the expression of endogenous YB1 attenuates the effects of Msx1. Taken together, our study has uncovered a new function of YB1/p32, a regulator of skeletal muscle differentiation.

YB1/p32, a nuclear Y-box binding protein 1, is a novel regulator of myoblast differentiation that interacts with Msx1 homeoprotein

International Nuclear Information System (INIS)

Song, Young Joon; Lee, Hansol

2010-01-01

Precisely controlled cellular differentiation is essential for the proper development of vertebrate embryo and deregulated differentiation is a major cause of many human congenital diseases as well as cancer. Msx1 is a member of the homeoprotein family implicated in these processes, which inhibits the differentiation of skeletal muscle and other cell types, presumably by regulating transcription of target genes through interaction with other cellular factors. We presently show that YB1/p32, a nuclear Y-box binding protein 1, interacts with Msx1 homeoprotein and functions as a regulator of C2C12 myoblast differentiation. We demonstrate that YB1/p32 functionally interacts with Msx1 through its N-terminal region and colocalizes with Msx1 at the nuclear periphery. Moreover, we find that YB1/p32 is competent for inhibition of C2C12 myoblast differentiation, which is correlated with its activity as a negative regulator of MyoD gene expression and binding to the MyoD core enhancer region (CER). Furthermore, YB1/p32 cooperates with Msx1 in transcriptional repression and knocking down the expression of endogenous YB1 attenuates the effects of Msx1. Taken together, our study has uncovered a new function of YB1/p32, a regulator of skeletal muscle differentiation.

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P).

Science.gov (United States)

Campellone, Joseph V

2013-06-01

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disorder inherited in an autosomal dominant fashion. Patients present with slowly progressive proximal-predominant weakness, painful muscle cramps, fasciculations, large-fiber sensory loss, and areflexia. Electrodiagnostic (EDX) studies typically reveal abnormalities consistent with a sensorimotor neuronopathy. A patient with HMSN-P underwent EDX studies, revealing ongoing and chronic neurogenic denervation, motor unit instability, and neuromyotonic discharges, further defining the spectrum of EDX findings in HMSN-P. The clinical, pathological, and genetic features are also reviewed. The appearance of HMSN-P in the United States and elsewhere calls for clinicians in nonendemic regions to be familiar with this rare disorder, which has typically been geographically confined.

Conceptual design of stepper motor replacing servo motor for control rod controller

International Nuclear Information System (INIS)

Mohd Dzul Aiman Aslan; Mohd Idris Taib; Izhar Abu Hussin; Mohd Khairulezwan Abdul Manan; Mohd Sabri Minhat

2010-01-01

In PUSPATI TRIGA Reactor, current control rod controller are using servo motor to control the movement. Control rod is a very important safety element and measure in every nuclear reactor. So, precision is very important in measurement of security in the nuclear reactor. In this case, there are a few disadvantages when using the servo motor is measurement of the motor is not precise. One solution to overcome this is by shifting servo motor with stepper motor. A stepper motor (or step motor) is a brush less, synchronous electric motor that can divide a full rotation into a large number of steps. (author)

Prediction degradation trend of nuclear equipment based on GM (1, 1)-Markov chain

International Nuclear Information System (INIS)

Zhang Liming; Zhao Xinwen; Cai Qi; Wu Guangjiang

2010-01-01

The degradation trend prediction results are important references for nuclear equipment in-service inspection and maintenance plan. But it is difficult to predict the nuclear equipment degradation trend accurately by the traditional statistical probability due to the small samples, lack of degradation data and the wavy degradation locus. Therefore, a method of equipment degradation trend prediction based on GM (1, l)-Markov chain was proposed in this paper. The method which makes use of the advantages of both GM (1, 1) method and Markov chain could improve the prediction precision of nuclear equipment degradation trend. The paper collected degradation data as samples and accurately predicted the degradation trend of canned motor pump. Compared with the prediction results by GM (1, 1) method, the prediction precision by GM (1, l)-Markov chain is more accurate. (authors)

Human NTH1 physically interacts with p53 and proliferating cell nuclear antigen

International Nuclear Information System (INIS)

Oyama, Masaki; Wakasugi, Mitsuo; Hama, Takashi; Hashidume, Hatsuho; Iwakami, Yasutaka; Imai, Rika; Hoshino, Sanae; Morioka, Hiroshi; Ishigaki, Yasuhito; Nikaido, Osamu; Matsunaga, Tsukasa

2004-01-01

Thymine glycol (Tg) is one of predominant oxidative DNA lesions caused by ionizing radiation and other oxidative stresses. Human NTH1 is a bifunctional enzyme with DNA glycosylase and AP lyase activities and removes Tg as the first step of base excision repair (BER). We have searched for the factors interacting with NTH1 by using a pull-down assay and found that GST-NTH1 fusion protein precipitates proliferating cell nuclear antigen (PCNA) and p53 as well as XPG from human cell-free extracts. GST-NTH1 also bound to recombinant FLAG-tagged XPG, PCNA, and (His) 6 -tagged p53 proteins, indicating direct protein-protein interaction between those proteins. Furthermore, His-p53 and FLAG-XPG, but not PCNA, stimulated the Tg DNA glycosylase/AP lyase activity of GST-NTH1 or NTH1. These results provide an insight into the positive regulation of BER reaction and also suggest a possible linkage between BER of Tg and other cellular mechanisms

Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function.

Science.gov (United States)

Dewitz, Carola; Pimpinella, Sofia; Hackel, Patrick; Akalin, Altuna; Jessell, Thomas M; Zampieri, Niccolò

2018-02-13

Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, and afadin signaling. Our findings reveal that nuclear organization of motor neurons is dependent on inside-out positioning, orchestrated by N-cadherin, catenin, and afadin activities, controlling cell body layering on the medio-lateral axis. In addition to this lamination-like program, motor neurons undergo a secondary, independent phase of organization. This process results in segregation of motor neurons along the dorso-ventral axis of the spinal cord, does not require N-cadherin or afadin activity, and can proceed even when medio-lateral positioning is perturbed. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Mapping the involvement of BA 4a and 4p during Motor Imagery.

Science.gov (United States)

Sharma, Nikhil; Jones, P S; Carpenter, T A; Baron, Jean-Claude

2008-05-15

Motor Imagery (MI) is an attractive but intriguing means to access the motor network. There are marked inconsistencies in the functional imaging literature regarding the degree, extent and distribution of the primary motor cortex (BA 4) involvement during MI as compared to Executed Movement (EM), which may in part be related to the diverse role of BA 4 and its two subdivisions (i.e., 4a and 4p) in motor processes as well as to methodological issues. Here we used fMRI with monitoring of compliance to show that in healthy volunteers optimally screened for their ability to perform MI the contralateral BA 4 is involved during MI of a finger opposition sequence (2, 3, 4, 5; paced at 1 Hz), albeit less than during EM of the same sequence, and in a location sparing the hand area. Furthermore, both 4a and 4p subdivisions were found to be involved in MI, but the relative involvement of BA 4p appeared more robust and closer to that seen with EM. We suggest that during MI the role of BA 4 and its subdivisions may be non-executive, perhaps related to spatial encoding, though clearly further studies are needed. Finally, we report a similar hemispheric activation balance within BA 4 with both tasks, which extends the commonalities between EM and MI.

Improving motor reliability in nuclear power plants: Volume 3, Failure analysis and diagnostic tests on a naturally aged large electric motor

International Nuclear Information System (INIS)

Subudhi, M.; Taylor, J.H.; Sheets, M.W.

1987-11-01

Stator coils of a naturally failed 400 hp motor from the Brookhaven National Laboratory test reactor facility were tested for their dielectric integrities. The motor was used to drive the primary reactor coolant pump for the last 20 years. Maintenance activities on this motor during its entire service life were minimal, with the exception of meggering it periodically. The stator consisted of ninety individual coils which were separated for testing. Seven different dielectric tests were performed on the coils. Each set of data from the tested coils indicated a spectrum of variation depending on their aging conditions and characteristics. By comparing the test data to baseline data, the test methods were assessed for application to motor maintenance programs in nuclear power plants. Also included in this study are results of an investigation to determine the cause of this motor failure. Recommendations are provided on the aged condition of a second identical primary pump motor which is the same age and presently in operation. Recommendations are also presented relating to each of the dielectric test methods applicability to motor maintenance programs. 6 refs., 11 figs., 5 tabs

Motor Importance of motor assessment in school children: analysis of the reliability of the motor development scale doi: 10.5007/1980-0037.2010v12n6p422

Directory of Open Access Journals (Sweden)

Francisco Rosa Neto

2010-09-01

Full Text Available The objective of this study was to investigate the motor performance of school chil-dren aged 6 to 10 years without learning difficulties (n=101, and to analyze the reliability of the Motor Development Scale (MDS (Rosa Neto, 2002. Descriptive statistics with calculation of the mean, standard deviation, and range was used for data analysis. The internal consistency of the MDS was assessed using Cronbach’s alpha coefficient, and the correlation between variables was determined by Pearson’s linear correlation, with p<0.05. The results showed (1 that motor development was within normal limits in 96% of the children, and (2 a high correlation betwe-en chronological age and general motor age, indicating good internal consistency. These data demonstrate the logic and structured design of the MDS, confirming its reliability.

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

DEFF Research Database (Denmark)

Maddika, S; Ande, SR; Panigrahi, S

2007-01-01

)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted...... approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells....

Funtional MRI of cerebral motor cortex: comparison between 1.0 T and 1.5 T

International Nuclear Information System (INIS)

Jang, Hyun Jung; Yu, In Kyu; Song, In Chan; Han, Moon Hee; Lee, Heung Kyu; Chang, Kee Hyun

1997-01-01

To evaluate the feasibility of functional MR imaging(fMRI) with a 1.0 T scanner, fMRI of normal cerebral motor cortex at 1.0 T was compared with that at 1.5 T. FMRI of bilateral cerebral motor cortices (left, seven; right, six) was performed in seven healthy male volunteers aged 26-34 (mean 29) years,with BOLD contrast at both 1.0 T and 1.5 T units(Siemens MR scanners). Using both these systems,two-dimensional(2D) FLASH images were obtained with TR/TE of 90/56, flip angle of 40 deg, matrix size 128 * 128, slice thickness of 5mm, and FOV 23cm. A sequence consisting of five-image-off phase(rest phase) followed by five-image-on phase(activation with finger movement) was repeated four times without pause at a single plane. The same study was perfomed for the contralateral motor cortex in each volunteer. Using the z-test, activation images were obtained for the signal difference between on-and off-phases (p<0.05) and were then superimposed on 2D FLASH anatomic images at the same plane. Percentage changes of signal intensities(PCSIs) and numbers of activated pixels were compared, using the non-paramatric t-test, and periodicity of signal changes was compared, using the Mentel-Haenszel Chi-square test. Mean PCSIs at 1.5 T and 1.0 T in the left motor cortex were 3.13 ±1.20% and 1.43±0.56%, respectively(p=0.009),and in the right, 1.78±0.95% and 1.34±0.28%, respectively(p=0.32). The mean number of activated pixels at 1.5 T and 1.0 T in the left cortex was 21.14±10.67 and 19.86±11.36, respectively (p=0.83), and in the right, 22.5±6.47 and 16.8±8.47, respectively (p=0.22). At 1.5 T, periodicity of signal changes was seen in the left cortex in six of seven volunteers, and in the right cortex, in four of six. At 1.0 T, all showed periodicity (left:p=0.32;right:p=0.14). PCSIs in the dominant hemispheres were significantly higher at 1.5 T, but no other indicators showed significant differences between 1.0 T and 1.5 T. Acceptable fMRI can therefore be carried out with a 1

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

International Nuclear Information System (INIS)

Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng

2013-01-01

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 of 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 waf1 /cip1 and p57 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 waf1 /cip1 and p57 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 waf1/cip1 and p57 kip2

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

Energy Technology Data Exchange (ETDEWEB)

Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng, E-mail: zhanglf@cnilas.org

2013-10-15

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 of 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}.

P-shaped Coiled Stator Ultrasound Motor for Rotating Intravascular Surgery Device

Directory of Open Access Journals (Sweden)

Toshinobu ABE

2015-01-01

Full Text Available The primary focus of this paper is the development of an ultra-miniature ultrasound motor for use in the human blood vessel. Since the size of the drive source for rotating the atherectomy device and intravascular ultrasonography system are large currently in practical use, it is installed outside the body, and the rotational power for the atherectomy device and intravascular ultrasonography system are transmitted through the long tortuous blood vessel. Such systems suffer from the problem that the rotation becomes non-uniform, and the problem that the available time is limited. We have therefore developed a P-shaped coiled stator ultrasound motor as a miniature ultrasound motor for rotating the ultrasound sensor for use in blood vessels in order to solve these problems. In this paper, we describe measurement of the torque, revolution speed, output power, efficiency, and particle motion on acoustic waveguide of the P-shaped coiled stator ultrasound motor.

Tumor protein 53-induced nuclear protein 1 (TP53INP1 enhances p53 function and represses tumorigenesis

Directory of Open Access Journals (Sweden)

Jeyran eShahbazi

2013-05-01

Full Text Available Tumor protein 53-induced nuclear protein 1 (TP53INP1 is a stress-induced p53 target gene whose expression is modulated by transcription factors such as p53, p73 and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. When associated with homeodomain-interacting protein kinase-2 (HIPK2, TP53INP1 phosphorylates p53 protein at Serine 46, enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53 target genes such as p21, PIG-3 and MDM2, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis; while TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.

Regulation of p53 tetramerization and nuclear export by ARC.

Science.gov (United States)

Foo, Roger S-Y; Nam, Young-Jae; Ostreicher, Marc Jason; Metzl, Mark D; Whelan, Russell S; Peng, Chang-Fu; Ashton, Anthony W; Fu, Weimin; Mani, Kartik; Chin, Suet-Feung; Provenzano, Elena; Ellis, Ian; Figg, Nichola; Pinder, Sarah; Bennett, Martin R; Caldas, Carlos; Kitsis, Richard N

2007-12-26

Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.

Failure analysis of motor bearing of sea water pump in nuclear power plant

International Nuclear Information System (INIS)

Bian Chunhua; Zhang Wei

2015-01-01

The motor bearing of sea water pump in Qinshan Phase II Nuclear Power plant broke after only one year's using. This paper introduces failure analysis process of the motor bearing. Chemical composition analysis, metallic phase analysis, micrographic examination, and hardness analysis, dimension analysis of each part of the bearing, as well as the high temperature and low temperature performance analysis of lubricating grease are performed. According to the analysis above mentioned, the failure mode of the bearing is wearing, and the reason of wearing is inappropriate installation of the bearing. (authors)

Nuclear organization in the spinal cord depends on motor neuron lamination orchestrated by catenin and afadin function

OpenAIRE

Dewitz, C.; Pimpinella, S.; Hackel, P.; Akalin, A.; Jessell, T.M.; Zampieri, N.

2018-01-01

Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, a...

Myosin-1C uses a novel phosphoinositide-dependent pathway for nuclear localization.

Science.gov (United States)

Nevzorov, Ilja; Sidorenko, Ekaterina; Wang, Weihuan; Zhao, Hongxia; Vartiainen, Maria K

2018-02-01

Accurate control of macromolecule transport between nucleus and cytoplasm underlines several essential biological processes, including gene expression. According to the canonical model, nuclear import of soluble proteins is based on nuclear localization signals and transport factors. We challenge this view by showing that nuclear localization of the actin-dependent motor protein Myosin-1C (Myo1C) resembles the diffusion-retention mechanism utilized by inner nuclear membrane proteins. We show that Myo1C constantly shuttles in and out of the nucleus and that its nuclear localization does not require soluble factors, but is dependent on phosphoinositide binding. Nuclear import of Myo1C is preceded by its interaction with the endoplasmic reticulum, and phosphoinositide binding is specifically required for nuclear import, but not nuclear retention, of Myo1C. Our results therefore demonstrate, for the first time, that membrane association and binding to nuclear partners is sufficient to drive nuclear localization of also soluble proteins, opening new perspectives to evolution of cellular protein sorting mechanisms. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Performance analysis of samarium cobalt P.M. synchronous motor fed from PWM inverters

International Nuclear Information System (INIS)

Rahman, M.A.; Choudhury, M.A.

1985-01-01

This paper presents an analysis and performance of samarium cobalt permanent magnet (P.M.) synchronous motors fed from two types of voltage source pulse width modulated (PWM) inverters. The analysis and test results on the steady state performance of a P.M. motor fed from PWM inverters are presented. PWM inverters are used in variable voltage variable frequency applications to avoid a double conversion process of ordinary inverters. In drives, they are used for voltage and speed regulation of motors. Use of modulation technique in inverters also allow to eliminate or minimize selected harmonics from the inverter output voltage

Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor.

Science.gov (United States)

Salama, Asmaa; Kamel, Ahmad

2011-03-01

Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor. This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done. WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p=0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p<0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p=0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p=0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p=0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p=0.004). Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification. Copyright © 2011. Published by Elsevier B.V.

Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor

International Nuclear Information System (INIS)

Salama, A.; Kamel, A.

2011-01-01

Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor. Material and methods: This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done. Results: WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p = 0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p < 0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p = 0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p = 0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p = 0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p = 0.004). Conclusion: Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification

The Hog1p kinase regulates Aft1p transcription factor to control iron accumulation.

Science.gov (United States)

Martins, Telma S; Pereira, Clara; Canadell, David; Vilaça, Rita; Teixeira, Vítor; Moradas-Ferreira, Pedro; de Nadal, Eulàlia; Posas, Francesc; Costa, Vítor

2018-01-01

Iron acquisition systems have to be tightly regulated to assure a continuous supply of iron, since it is essential for survival, but simultaneously to prevent iron overload that is toxic to the cells. In budding yeast, the low‑iron sensing transcription factor Aft1p is a master regulator of the iron regulon. Our previous work revealed that bioactive sphingolipids modulate iron homeostasis as yeast cells lacking the sphingomyelinase Isc1p exhibit an upregulation of the iron regulon. In this study, we show that Isc1p impacts on iron accumulation and localization. Notably, Aft1p is activated in isc1Δ cells due to a decrease in its phosphorylation and an increase in its nuclear levels. Consistently, the expression of a phosphomimetic version of Aft1p-S210/S224 that favours its nuclear export abolished iron accumulation in isc1Δ cells. Notably, the Hog1p kinase, homologue of mammalian p38, interacts with and directly phosphorylates Aft1p at residues S210 and S224. However, Hog1p-Aft1p interaction decreases in isc1Δ cells, which likely contributes to Aft1p dephosphorylation and consequently to Aft1p activation and iron overload in isc1Δ cells. These results suggest that alterations in sphingolipid composition in isc1Δ cells may impact on iron homeostasis by disturbing the regulation of Aft1p by Hog1p. To our knowledge, Hog1p is the first kinase reported to directly regulate Aft1p, impacting on iron homeostasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Expression of p21 and p27 in gallbladder cancer

International Nuclear Information System (INIS)

Alsheyab, Fawzi M.; Ziadeh, Moroug T.; Bani-Hani, Kamal E.

2007-01-01

To investigate the expression of p21 and p27 factors in gallbladder cancer (GBC), and to correlate their expression with clinicopathological parameters: age, gender, stage, invasion and grade. Thirty-two surgically resected specimens were collected between 1994-2001 from different health centers in north Jordan. Tissues belong to 25 females and 7 males were examined immunohistochemically. The study took place in the Pathology Department, Jordan University of Science and Technology, Jordan. Levels of p21 were found in 75% and p27 in 25%. Furthermore, p21 was expressed in 50% of the specimens which belong to patients with ages 64 years have p 21WAF1/CIP1 expression (p=0.001). The expression of p21 between advanced stages (stages III and IV) was 89.5% and early stages (stages I and II) was 53.8% (p=0.031). The p27 expression was markedly decreased in GBC cases (25%) and there were no significant correlation between p27KIP1 expression and all clinicopathological parameters including gender, World health Organization grades, stages and invasion, whereas expression of p21 was 75% and there was a significant correlation between p21 and clinicopathological parameters including gender, stages and invasion. (author)

Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1

OpenAIRE

Lin, Hui-Ping; Lin, Ching-Yu; Huo, Chieh; Hsiao, Ping-Hsuan; Su, Liang-Cheng; Jiang, Shih Sheng; Chan, Tzu-Min; Chang, Chung-Ho; Chen, Li-Tzong; Kung, Hsing-Jien; Wang, Horng-Dar; Chuu, Chih-Pin

2015-01-01

Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1?3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4?2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAP...

Electric motors for use in radiation environments

International Nuclear Information System (INIS)

Aslam, T.U.D.; Mahmood, S.B.

1981-01-01

Requirements of electric motors for a nuclear plant and the effect of nuclear radiations on different parts of the motors are discussed. Feasibility of using locally-fabricated motors is also considered. (author)

Flood-proof motors

Energy Technology Data Exchange (ETDEWEB)

Schmitt, Marcus [AREVA NP GmbH, Erlangen (Germany)

2013-07-01

Even before the Fukushima event occurred some German nuclear power plants (NPP) have considered flooding scenarios. As a result of one of these studies, AREVA performed an upgrade project in NPP Isar 1 with flood-proof motors as a replacement of existing air-cooled low-voltage and high-voltage motors of the emergency cooling chain. After the Fukushima event, in which the cooling chains failed, the topic flood-proof equipment gets more and more into focus. This compact will introduce different kinds of flood-proof electrical motors which are currently installed or planned for installation into NPPs over the world. Moreover the process of qualification, as it was performed during the project in NPP Isar 1, will be shown. (orig.)

Flood-proof motors

International Nuclear Information System (INIS)

Schmitt, Marcus

2013-01-01

Even before the Fukushima event occurred some German nuclear power plants (NPP) have considered flooding scenarios. As a result of one of these studies, AREVA performed an upgrade project in NPP Isar 1 with flood-proof motors as a replacement of existing air-cooled low-voltage and high-voltage motors of the emergency cooling chain. After the Fukushima event, in which the cooling chains failed, the topic flood-proof equipment gets more and more into focus. This compact will introduce different kinds of flood-proof electrical motors which are currently installed or planned for installation into NPPs over the world. Moreover the process of qualification, as it was performed during the project in NPP Isar 1, will be shown. (orig.)

Nuclear transparency in 90 deg.c.m. quasielastic A(p,2p) reactions

International Nuclear Information System (INIS)

Aclander, J.; Alster, J.; Kosonovsky, I.; Malki, A.; Mardor, I.; Mardor, Y.; Navon, I.; Piasetzky, E.; Asryan, G.; Barton, D.S.; Buktoyarova, N.; Bunce, G.; Carroll, A.S.; Gushue, S.; Makdisi, Y.I.; Roser, T.; Tanaka, M.; Averiche, Y.; Panebratsev, Y.; Shimanskiy, S.

2004-01-01

We summarize the results of two experimental programs at the Alternating Gradient Synchrotron of BNL to measure the nuclear transparency of nuclei measured in the A(p,2p) quasielastic scattering process near 90 deg. in the pp center of mass. The incident momenta varied from 5.9 to 14.4 GeV/c, corresponding to 4.8 2 2 . Taking into account the motion of the target proton in the nucleus, the effective incident momenta extended from 5.0 to 15.8 GeV/c. First, we describe the measurements with the newer experiment, E850, which had more complete kinematic definition of quasielastic events. E850 covered a larger range of incident momenta, and thus provided more information regarding the nature of the energy dependence of the nuclear transparency. In E850 the angular dependence of the nuclear transparency near 90 deg. and the nuclear transparency deuterons were studied. Second, we review the techniques used in an earlier experiment, E834, and show that the two experiments are consistent for the carbon data. E834 also determines the nuclear transparencies for lithium, aluminum, copper, and lead nuclei as well as for carbon. A determination of the (π + ,π + p) transparencies is also reported. We find for both E850 and E834 that the A(p,2p) nuclear transparency, unlike that for A(e,e ' p) nuclear transparency, is incompatible with a constant value versus energy as predicted by Glauber calculations. The A(p,2p) nuclear transparency for carbon and aluminum increases by a factor of two between 5.9 and 9.5 GeV/c incident proton momentum. At its peak the A(p,2p) nuclear transparency is ∼80% of the constant A(e,e ' p) nuclear transparency. Then the nuclear transparency falls back to a value at least as small as that at 5.9 GeV/c, and is compatible with the Glauber level again. This oscillating behavior is generally interpreted as an interplay between two components of the pN scattering amplitude; one short ranged and perturbative, and the other long ranged and strongly absorbed

Motor circuit computer model based on studies of functional Nuclear Magnetic Resonance

International Nuclear Information System (INIS)

Garcia Ramo, Karla Batista; Rodriguez Rojas, Rafael; Carballo Barreda, Maylen

2012-01-01

The basal ganglia are a complex network of subcortical nuclei involved in motor control, sensorimotor integration, and cognitive processes. Their functioning and interaction with other cerebral structures remains as a subject of debate. The aim of the present work was to simulate the basal ganglia-thalamus-cortex circuitry interaction in motor program selection, supported by functional connectivity pattern obtained by functional nuclear magnetic resonance imaging. Determination of connections weights between neural populations by functional magnetic resonance imaging, contributed to a more realistic formulation of the model; and consequently to obtain similar results to clinical and experimental data. The network allowed to describe the participation of the basal ganglia in motor program selection and the changes in Parkinson disease. The simulation allowed to demonstrate that dopamine depletion above to 40 % leads to a loss of action selection capability, and to reflect the system adaptation ability to compensate dysfunction in Parkinson disease, coincident with experimental and clinical studies

Silencing p110β prevents rapid depletion of nuclear pAkt

International Nuclear Information System (INIS)

Ye, Zhi-wei; Ghalali, Aram; Högberg, Johan; Stenius, Ulla

2011-01-01

Highlights: ► p110β was essential for the statin- and ATP-induced depletion of nuclear pAkt and an associated inhibition of growth. ► p110β knock-out inhibited statin-induced changes in binding between FKBP51, pAkt and PTEN. ► Data supports the hypothesis that nuclear pAkt is important for anti-cancer effects of statins. -- Abstract: The p110β subunit in the class IA PI3K family may act as an oncogene and is critical for prostate tumor development in PTEN knockout mice. We tested the possible involvement of p110β in a recently described rapid depletion of phosphorylated Akt (pAkt) in the nucleus. Previous work showed that this down-regulation is induced by extracellular ATP or by statins and is mediated by the purinergic receptor P2X7. Here, we used p110β knock out mouse embryonic fibroblasts (MEFs) and siRNA-treated cancer cells. We found that p110β is essential for ATP- or statin-induced nuclear pAkt depletion in MEFs and in several cancer cell lines including prostate cancer cells. ATP, statin or the selective P2X7 agonist BzATP also inhibited cell growth, and this inhibition was not seen in p110β knock out cells. We also found that p110β was necessary for statin-induced changes in binding between FKBP51, pAkt and PTEN. Our data show that p110β is essential for the ATP- and statin-induced effects and support a role of nuclear pAkt in cancer development. They also provide support for a chemopreventive effect of statins mediated by depletion of nuclear pAkt.

Silencing p110{beta} prevents rapid depletion of nuclear pAkt

Energy Technology Data Exchange (ETDEWEB)

Ye, Zhi-wei; Ghalali, Aram; Hoegberg, Johan [Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm (Sweden); Stenius, Ulla, E-mail: ulla.stenius@ki.se [Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm (Sweden)

2011-12-02

Highlights: Black-Right-Pointing-Pointer p110{beta} was essential for the statin- and ATP-induced depletion of nuclear pAkt and an associated inhibition of growth. Black-Right-Pointing-Pointer p110{beta} knock-out inhibited statin-induced changes in binding between FKBP51, pAkt and PTEN. Black-Right-Pointing-Pointer Data supports the hypothesis that nuclear pAkt is important for anti-cancer effects of statins. -- Abstract: The p110{beta} subunit in the class IA PI3K family may act as an oncogene and is critical for prostate tumor development in PTEN knockout mice. We tested the possible involvement of p110{beta} in a recently described rapid depletion of phosphorylated Akt (pAkt) in the nucleus. Previous work showed that this down-regulation is induced by extracellular ATP or by statins and is mediated by the purinergic receptor P2X7. Here, we used p110{beta} knock out mouse embryonic fibroblasts (MEFs) and siRNA-treated cancer cells. We found that p110{beta} is essential for ATP- or statin-induced nuclear pAkt depletion in MEFs and in several cancer cell lines including prostate cancer cells. ATP, statin or the selective P2X7 agonist BzATP also inhibited cell growth, and this inhibition was not seen in p110{beta} knock out cells. We also found that p110{beta} was necessary for statin-induced changes in binding between FKBP51, pAkt and PTEN. Our data show that p110{beta} is essential for the ATP- and statin-induced effects and support a role of nuclear pAkt in cancer development. They also provide support for a chemopreventive effect of statins mediated by depletion of nuclear pAkt.

Bra.Di.P.O. and P.I.G.R.O.: Innovative Devices for Motor Learning Programs

Directory of Open Access Journals (Sweden)

Guido Belforte

2014-01-01

Full Text Available Two mechatronics prototypes, useful for robotic neurotreatments and new clinical trainings, are here presented. P.I.G.R.O. (pneumatic interactive gait rehabilitation orthosis is an active exoskeleton with an electropneumatic control. It imposes movements on lower limbs in order to produce in the patient’s brain proper motor cortex activation. Bra.Di.P.O. (brain discovery pneumatic orthosis is an MR-compatible device, designed to improve fMRI (functional magnetic resonance imaging analysis. The two devices are presented together because both are involved in the study of new robotic treatments of patients affected by ictus or brain stroke or in some motor learning experimental investigations carried out on healthy subjects.

Improving the Delivery of SOD1 Antisense Oligonucleotides to Motor Neurons Using Calcium Phosphate-Lipid Nanoparticles

Directory of Open Access Journals (Sweden)

Liyu Chen

2017-08-01

Full Text Available Amyotrophic Lateral Sclerosis (ALS is a fatal neurodegenerative disease affecting the upper and lower motor neurons in the motor cortex and spinal cord. Abnormal accumulation of mutant superoxide dismutase I (SOD1 in motor neurons is a pathological hallmark of some forms of the disease. We have shown that the orderly progression of the disease may be explained by misfolded SOD1 cell-to-cell propagation, which is reliant upon its active endogenous synthesis. Reducing the levels of SOD1 is therefore a promising therapeutic approach. Antisense oligonucleotides (ASOs can efficiently silence proteins with gain-of-function mutations. However, naked ASOs have a short circulation half-life and are unable to cross the blood brain barrier (BBB warranting the use of a drug carrier for effective delivery. In this study, calcium phosphate lipid coated nanoparticles (CaP-lipid NPs were developed for delivery of SOD1 ASO to motor neurons. The most promising nanoparticle formulation (Ca/P ratio of 100:1, had a uniform spherical core–shell morphology with an average size of 30 nm, and surface charge (ζ-potential of −4.86 mV. The encapsulation efficiency of ASO was 48% and stability studies found the particle to be stable over a period of 20 days. In vitro experiments demonstrated that the negatively charged ASO-loaded CaP-lipid NPs could effectively deliver SOD1-targeted ASO into a mouse motor neuron-like cell line (NSC-34 through endocytosis and significantly down-regulated SOD1 expression in HEK293 cells. The CaP-lipid NPs exhibited a pH-dependant dissociation, suggesting that that the acidification of lysosomes is the likely mechanism responsible for facilitating intracellular ASO release. To demonstrate tissue specific delivery and localization of these NPs we performed in vivo microinjections into zebrafish. Successful delivery of these NPs was confirmed for the zebrafish brain, the blood stream, and the spinal cord. These results suggest that CaP

Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells*

Science.gov (United States)

Gizard, Florence; Zhao, Yue; Findeisen, Hannes M.; Qing, Hua; Cohn, Dianne; Heywood, Elizabeth B.; Jones, Karrie L.; Nomiyama, Takashi; Bruemmer, Dennis

2011-01-01

Members of the NR4A subgroup of the nuclear hormone receptor superfamily have emerged as key transcriptional regulators of proliferation and inflammation. NOR1 constitutes a ligand-independent transcription factor of this subgroup and induces cell proliferation; however, the transcriptional mechanisms underlying this mitogenic role remain to be defined. Here, we demonstrate that the F-box protein SKP2 (S phase kinase-associated protein 2), the substrate-specific receptor of the ubiquitin ligase responsible for the degradation of p27KIP1 through the proteasome pathway, constitutes a direct transcriptional target for NOR1. Mitogen-induced Skp2 expression is silenced in vascular smooth muscle cells (VSMC) isolated from Nor1-deficient mice or transfected with Nor1 siRNA. Conversely, adenovirus-mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27. Transient transfection experiments establish that NOR1 transactivates the Skp2 promoter through a nerve growth factor-induced clone B response element (NBRE). Electrophoretic mobility shift and chromatin immunoprecipitation assays further revealed that NOR1 is recruited to this NBRE site in the Skp2 promoter in response to mitogenic stimulation. In vivo Skp2 expression is increased during the proliferative response underlying neointima formation, and this transcriptional induction depends on the expression of NOR1. Finally, we demonstrate that overexpression of Skp2 rescues the proliferative arrest of Nor1-deficient VSMC. Collectively, these results characterize Skp2 as a novel NOR1-regulated target gene and detail a previously unrecognized transcriptional cascade regulating mitogen-induced VSMC proliferation. PMID:21868379

Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK.

Science.gov (United States)

Rawashdeh, Oliver; Jilg, Antje; Maronde, Erik; Fahrenkrug, Jan; Stehle, Jörg H

2016-09-01

Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus

Nuclear NF-κB p65 in peripheral blood mononuclear cells correlates with urinary MCP-1, RANTES and the severity of type 2 diabetic nephropathy.

Directory of Open Access Journals (Sweden)

Bin Yi

Full Text Available AIMS: To investigate if nuclear NF-κB p65 expression in ex vivo isolated peripheral blood mononuclear cells correlates with urinary MCP-1 or RANTES and the severity of type 2 diabetic nephropathy. METHODS: According to their urinary albumin-to-creatinine ratio (uACR, 107 patients with type 2 diabetes (eGFR >60 ml/min were divided into normal albuminuria group (DN0 group, 38 cases, microalbuminuria group (DN1 group, 38 cases, and macroalbuminuria group (DN2 group, 31 cases, compared with matched healthy normal control group (NC group, 30 cases. Nuclear NF-κB p65 protein expression levels in peripheral blood mononuclear cells were detected by western blotting. Real-time quantitative polymerase chain reaction was used to detect NF-κB p65 mRNA expression and ELISA assay was used to detect the levels of urinary MCP-1 and RANTES. RESULTS: Nuclear NF-κB p65 protein and NF-κB p65 mRNA expression levels in peripheral blood mononuclear cells, urinary MCP-1/Cr and RANTES/Cr were all significantly higher in all diabetes groups as compared with NC group. In particular, the increase of nuclear NF-κB p65 protein and NF-κB p65 mRNA expressions, urinary MCP-1/Cr and RANTES/Cr all correlated with the severity of type 2 diabetic nephropathy as indicated by the increase in uACR. Pearson correlation analysis indicated that both urinary MCP-1/Cr and RANTES/Cr were positively correlated with nuclear NF-κB p65 protein or NF-κB p65 mRNA levels. Stepwise multiple regression analysis showed that nuclear NF-κB p65 protein or NF-κB p65 mRNA was an independent variable for urinary MCP-1/Cr, and MCP-1/Cr and RANTES/Cr were two independent variables for uACR. CONCLUSION: Our research demonstrates that nuclear NF-κB p65 protein and mRNA expressions in ex vivo isolated peripheral blood mononuclear cells well correlate with urinary MCP-1/Cr, RANTES/Cr and the severity of type 2 diabetic nephropathy.

Methodology to monitor and diagnostic vibrations of the motor-pumps used in the primary cooling system of IEAR-1 nuclear research reactor; Metodologia para monitoracao e diagnostico de vibracao das bombas moto-operadas do circuito primario de refrigeracao do Reator IEA-R1

Energy Technology Data Exchange (ETDEWEB)

Benevenuti, Erion de Lima

2004-07-01

The objectives of this study are to establish a strategy to monitor and diagnose vibrations of the motor pumps used in the primary reactor cooling system of the IEA-R1 nuclear research reactor, to verify the possibility of using the existing installed monitoring vibration system and to implement such strategy in a continuous way. Four types of mechanical problems were considered: unbalancing, misalignment, gaps and faults in bearings. An adequate set of analysis tools, well established by the industry, was selected. These are: global measurements of vibration, velocity spectrum and acceleration envelope spectrum. Three sources of data and information were used; the data measured from the primary pumps, experimental results obtained with a Spectra Quest machine used to simulate mechanical defects and data from the literature. The results show that, for the specific case of the motor-pumps of IEA-R1 nuclear research reactor, although the technique using the envelope of acceleration, which is not available in the current system used to monitor the vibration of the motor pumps, is the one with best performance, the other techniques available in the system are sufficient to monitor the four types of mechanical problems mentioned. The proposed strategy is shown and detailed in this work. (author)

Role of Acidophilic Methanotrophs in Long Term Natural Attenuation of cVOCs in Low pH Aquifers

Science.gov (United States)

2017-06-15

grow well only in dilute , oligtrophic media (Kip et al., 2011; Dedysh et al., 2002). It is likely that these organisms or similar ones may exist in...Carbon tetrachloride Cu – Copper cVOCs – Chlorinated volatile organic compounds 1,1-DCA – 1,2-Dichloroethane 1,2-DCA – 1,2-Dichloroethane DCM...the biodegradation of chlorinated volatile organic compounds (cVOCs) in low pH groundwater aquifers. Our objectives included (1) determining whether

Nuclear Trafficking of the Rabies Virus Interferon Antagonist P-Protein Is Regulated by an Importin-Binding Nuclear Localization Sequence in the C-Terminal Domain.

Directory of Open Access Journals (Sweden)

Caitlin L Rowe

Full Text Available Rabies virus P-protein is expressed as five isoforms (P1-P5 which undergo nucleocytoplasmic trafficking important to roles in immune evasion. Although nuclear import of P3 is known to be mediated by an importin (IMP-recognised nuclear localization sequence in the N-terminal region (N-NLS, the mechanisms underlying nuclear import of other P isoforms in which the N-NLS is inactive or has been deleted have remained unresolved. Based on the previous observation that mutation of basic residues K214/R260 of the P-protein C-terminal domain (P-CTD can result in nuclear exclusion of P3, we used live cell imaging, protein interaction analysis and in vitro nuclear transport assays to examine in detail the nuclear trafficking properties of this domain. We find that the effect of mutation of K214/R260 on P3 is largely dependent on nuclear export, suggesting that nuclear exclusion of mutated P3 involves the P-CTD-localized nuclear export sequence (C-NES. However, assays using cells in which nuclear export is pharmacologically inhibited indicate that these mutations significantly inhibit P3 nuclear accumulation and, importantly, prevent nuclear accumulation of P1, suggestive of effects on NLS-mediated import activity in these isoforms. Consistent with this, molecular binding and transport assays indicate that the P-CTD mediates IMPα2/IMPβ1-dependent nuclear import by conferring direct binding to the IMPα2/IMPβ1 heterodimer, as well as to a truncated form of IMPα2 lacking the IMPβ-binding autoinhibitory domain (ΔIBB-IMPα2, and IMPβ1 alone. These properties are all dependent on K214 and R260. This provides the first evidence that P-CTD contains a genuine IMP-binding NLS, and establishes the mechanism by which P-protein isoforms other than P3 can be imported to the nucleus. These data underpin a refined model for P-protein trafficking that involves the concerted action of multiple NESs and IMP-binding NLSs, and highlight the intricate regulation of P

Computer program /P1-GAS/ calculates the P-0 and P-1 transfer matrices for neutron moderation in a monatomic gas

Science.gov (United States)

Collier, G.; Gibson, G.

1968-01-01

FORTRAN 4 program /P1-GAS/ calculates the P-O and P-1 transfer matrices for neutron moderation in a monatomic gas. The equations used are based on the conditions that there is isotropic scattering in the center-of-mass coordinate system, the scattering cross section is constant, and the target nuclear velocities satisfy a Maxwellian distribution.

Role of polyamines at the G1/S boundary and G2/M phase of the cell cycle.

Science.gov (United States)

Yamashita, Tomoko; Nishimura, Kazuhiro; Saiki, Ryotaro; Okudaira, Hiroyuki; Tome, Mayuko; Higashi, Kyohei; Nakamura, Mizuho; Terui, Yusuke; Fujiwara, Kunio; Kashiwagi, Keiko; Igarashi, Kazuei

2013-06-01

The role of polyamines at the G1/S boundary and in the G2/M phase of the cell cycle was studied using synchronized HeLa cells treated with thymidine or with thymidine and aphidicolin. Synchronized cells were cultured in the absence or presence of α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, plus ethylglyoxal bis(guanylhydrazone) (EGBG), an inhibitor of S-adenosylmethionine decarboxylase. When polyamine content was reduced by treatment with DFMO and EGBG, the transition from G1 to S phase was delayed. In parallel, the level of p27(Kip1) was greatly increased, so its mechanism was studied in detail. Synthesis of p27(Kip1) was stimulated at the level of translation by a decrease in polyamine levels, because of the existence of long 5'-untranslated region (5'-UTR) in p27(Kip1) mRNA. Similarly, the transition from the G2/M to the G1 phase was delayed by a reduction in polyamine levels. In parallel, the number of multinucleate cells increased by 3-fold. This was parallel with the inhibition of cytokinesis due to an unusual distribution of actin and α-tubulin at the M phase. Since an association of polyamines with chromosomes was not observed by immunofluorescence microscopy at the M phase, polyamines may have only a minor role in structural changes of chromosomes at the M phase. In general, the involvement of polyamines at the G2/M phase was smaller than that at the G1/S boundary. Copyright © 2013 Elsevier Ltd. All rights reserved.

Non-viral gene therapy that targets motor neurons in vivo

Directory of Open Access Journals (Sweden)

Mary-Louise eRogers

2014-10-01

Full Text Available A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS. We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by ‘immunogene’ nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12 as DNA carrier was conjugated to an antibody (MLR2 to the neurotrophin receptor p75 (p75NTR. We used a plasmid (pVIVO2 designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP. MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0 % of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo.

Prognostic implications of the nuclear localization of Y-box-binding protein-1 and CXCR4 expression in ovarian cancer: their correlation with activated Akt, LRP/MVP and P-glycoprotein expression.

Science.gov (United States)

Oda, Yoshinao; Ohishi, Yoshihiro; Basaki, Yuji; Kobayashi, Hiroaki; Hirakawa, Toshio; Wake, Norio; Ono, Mayumi; Nishio, Kazuto; Kuwano, Michihiko; Tsuneyoshi, Masazumi

2007-07-01

The nuclear localization of Y-box-binding protein-1 (YB-1) is known to be a poor prognostic factor in several human malignancies, including ovarian carcinoma. Following on from our basic study dealing with microarray analyses of YB-1-associated gene expression in ovarian cancer cells, we examined whether nuclear localization of YB-1 is associated with the expression of CXCR4, a vault protein named lung resistance-related vault protein (LRP/MVP), phosphorylated Akt (p-Akt) or P-glycoprotein (P-gp) in human ovarian carcinoma. Fifty-three surgically resected ovarian carcinomas treated with paclitaxel and carboplatin were examined immunohistochemically for nuclear YB-1 expression and intrinsic expression of p-Akt, P-gp, LRP/MVP and CXCR4. Nuclear expression of YB-1 demonstrated significant correlation with p-Akt, P-gp and LRP expression, but no relationship with CXCR4 expression. By multivariate analysis, only YB-1 nuclear expression and CXCR4 expression were independent prognostic factors with regard to overall survival. These results indicate that YB-1 nuclear expression and CXCR4 expression are important prognostic factors in ovarian carcinoma.

Somato-motor haptic processing in posterior inner perisylvian region (SII/pIC of the macaque monkey.

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Hiroaki Ishida

Full Text Available The posterior inner perisylvian region including the secondary somatosensory cortex (area SII and the adjacent region of posterior insular cortex (pIC has been implicated in haptic processing by integrating somato-motor information during hand-manipulation, both in humans and in non-human primates. However, motor-related properties during hand-manipulation are still largely unknown. To investigate a motor-related activity in the hand region of SII/pIC, two macaque monkeys were trained to perform a hand-manipulation task, requiring 3 different grip types (precision grip, finger exploration, side grip both in light and in dark conditions. Our results showed that 70% (n = 33/48 of task related neurons within SII/pIC were only activated during monkeys' active hand-manipulation. Of those 33 neurons, 15 (45% began to discharge before hand-target contact, while the remaining neurons were tonically active after contact. Thirty-percent (n = 15/48 of studied neurons responded to both passive somatosensory stimulation and to the motor task. A consistent percentage of task-related neurons in SII/pIC was selectively activated during finger exploration (FE and precision grasping (PG execution, suggesting they play a pivotal role in control skilled finger movements. Furthermore, hand-manipulation-related neurons also responded when visual feedback was absent in the dark. Altogether, our results suggest that somato-motor neurons in SII/pIC likely contribute to haptic processing from the initial to the final phase of grasping and object manipulation. Such motor-related activity could also provide the somato-motor binding principle enabling the translation of diachronic somatosensory inputs into a coherent image of the explored object.

Nuclear export of human hepatitis B virus core protein and pregenomic RNA depends on the cellular NXF1-p15 machinery.

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Yang, Ching-Chun; Huang, Er-Yi; Li, Hung-Cheng; Su, Pei-Yi; Shih, Chiaho

2014-01-01

Hepatitis B virus (HBV) core protein (HBc) can shuttle between nucleus and cytoplasm. Cytoplasm-predominant HBc is clinically associated with severe liver inflammation. Previously, we found that HBc arginine-rich domain (ARD) can associate with a host factor NXF1 (TAP) by coimmunoprecipitation. It is well known that NXF1-p15 heterodimer can serve as a major export receptor of nuclear mRNA as a ribonucleoprotein complex (RNP). In the NXF1-p15 pathway, TREX (transcription/export) complex plays an important role in coupling nuclear pre-mRNA processing with mRNA export in mammalian cells. Here, we tested the hypothesis whether HBc and HBV specific RNA can be exported via the TREX and NXF1-p15 mediated pathway. We demonstrated here that HBc can physically and specifically associate with TREX components, and the NXF1-p15 export receptor by coimmunoprecipitation. Accumulation of HBc protein in the nucleus can be induced by the interference with TREX and NXF1-p15 mediated RNA export machinery. HBV transcripts encodes a non-spliced 3.5 kb pregenomic RNA (pgRNA) which can serve as a template for reverse transcription. Cytoplasmic HBV pgRNA appeared to be reduced by siRNA treatment specific for the NXF1-p15 complex by quantitative RT-qPCR and Northern blot analyses. This result suggests that the pgRNA was also exported via the NXF1-p15 machinery. We entertain the hypothesis that HBc protein can be exported as an RNP cargo via the mRNA export pathway by hijacking the TREX and NXF1-p15 complex. In our current and previous studies, HBc is not required for pgRNA accumulation in the cytoplasm. Furthermore, HBc ARD can mediate nuclear export of a chimeric protein containing HBc ARD in a pgRNA-independent manner. Taken together, it suggests that while both pgRNA and HBc protein exports are dependent on NXF1-p15, they are using the same export machinery in a manner independent of each other.

Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit.

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Asthana, Pallavi; Zhang, Ni; Kumar, Gajendra; Chine, Virendra Bhagawan; Singh, Kunal Kumar; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

2018-01-18

Consumption of fish containing ciguatera toxins or ciguatoxins (CTXs) causes ciguatera fish poisoning (CFP). In some patients, CFP recurrence occurs even years after exposure related to CTXs accumulation. Pacific CTX-1 (P-CTX-1) is one of the most potent natural substances known that causes predominantly neurological symptoms in patients; however, the underlying pathogenies of CFP remain unknown. Using clinically relevant neurobehavioral tests and electromyography (EMG) to assess effects of P-CTX-1 during the 4 months after exposure, recurrent motor strength deficit occurred in mice exposed to P-CTX-1. We detected irreversible motor strength deficits accompanied by reduced EMG activity, demyelination, and slowing of motor nerve conduction, whereas control unexposed mice fully recovered in 1 month after peripheral nerve injury. Finally, to uncover the mechanism underlying CFP, we detected reduction of spontaneous firing rate of motor cortical neurons even 6 months after exposure and increased number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Increased numbers of motor cortical neuron apoptosis were detected by dUTP-digoxigenin nick end labeling assay along with activation of caspase 3. Taken together, our study demonstrates that persistence of P-CTX-1 in the nervous system induces irreversible motor deficit that correlates well with excitotoxicity and neurodegeneration detected in the motor cortical neurons.

Influence of the p ¯ -p Nuclear Interaction on the Rate of the Low-Energy p ¯ + H μ → ( p ¯ p α + μ − Reaction

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Renat A. Sultanov

2018-04-01

Full Text Available The influence of an additional strong p ¯ -p nuclear interaction in a three-charge-particle system with arbitrary masses is investigated. Specifically, the system of p ¯ , μ − , and p is considered in this paper, where p ¯ is an antiproton, μ − is a muon and p is a proton. A numerical computation in the framework of a detailed few-body approach is carried out for the following protonium (antiprotonic hydrogen formation three-body reaction: p ¯ + H μ ( 1 s → ( p ¯ p α + μ − . Here, H μ ( 1 s is a ground state muonic hydrogen, i.e., a bound state of p and μ − . A bound state of p and its antimatter counterpart p ¯ is a protonium atom in a quantum atomic state α , i.e., P n = ( p ¯ p α . The low-energy cross sections and rates of the P n formation reaction are computed in the framework of coupled Faddeev-Hahn-type equations. The strong p ¯ -p interaction is included in these calculations within a first order approximation. It was found, that the inclusion of the nuclear interaction results in a quite significant correction to the rate of the three-body reaction.

Apparatus for facilitating the servicing of inverted canned pump motors having limited access space and restricted access time especially in nuclear power plants

International Nuclear Information System (INIS)

Matusz, J.M.

1991-01-01

This patent describes a service apparatus for one or more inverted canned motor pumps installed above a floor and beneath a steam generator in a nuclear or fossil power plant with limited access space and limited access time at least in the case of nuclear power plants, each of the canned motor pumps having a pump casing and a depending motor having a flange secured to a pump casing flange by tensioned studs with tightened nuts. It comprises a maintenance cart having a height greater than the height of the motor beneath the motor flange and further having a generally U-shaped frame means with an open vertical side that permits the cart to be moved horizontally such that the cart frame means can be moved under the pump casing to surround the depending motor; actuator means supported by the cart frame means and having translating arm means engageable with support means on the motor; means for operating the translating arm means to support, raise and lower the motor; means supported by the frame means to support the motor flange prior to raising the motor to its installed position and after the motor has been released from its installed position and lowered to the cart; work platform means provided on the cart frame means at an elevation beneath the motor flange elevation; and roller means provided on the bottom of the cart frame means to facilitate horizontal cart movement along the floor

Deletion of the nuclear localization sequences and C-terminus of PTHrP impairs embryonic mammary development but also inhibits PTHrP production.

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Kata Boras-Granic

Full Text Available Parathyroid hormone-related protein (PTHrP can be secreted from cells and interact with its receptor, the Type 1 PTH/PTHrP Receptor (PTHR1 in an autocrine, paracrine or endocrine fashion. PTHrP can also remain inside cells and be transported into the nucleus, where its functions are unclear, although recent experiments suggest that it may broadly regulate cell survival and senescence. Disruption of either the PTHrP or PTHR1 gene results in many abnormalities including a failure of embryonic mammary gland development in mice and in humans. In order to examine the potential functions of nuclear PTHrP in the breast, we examined mammary gland development in PTHrP (1-84 knock-in mice, which express a mutant form of PTHrP that lacks the C-terminus and nuclear localization signals and which can be secreted but cannot enter the nucleus. Interestingly, we found that PTHrP (1-84 knock-in mice had defects in mammary mesenchyme differentiation and mammary duct outgrowth that were nearly identical to those previously described in PTHrP-/- and PTHR1-/- mice. However, the mammary buds in PTHrP (1-84 knock-in mice had severe reductions in mutant PTHrP mRNA levels, suggesting that the developmental defects were due to insufficient production of PTHrP by mammary epithelial cells and not loss of PTHrP nuclear function. Examination of the effects of nuclear PTHrP in the mammary gland in vivo will require the development of alternative animal models.

Relationship between pain and motor and non-motor symptoms in Parkinson's disease.

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Defazio, G; Antonini, A; Tinazzi, M; Gigante, A F; Pietracupa, S; Pellicciari, R; Bloise, M; Bacchin, R; Marcante, A; Fabbrini, G; Berardelli, A

2017-07-01

Although female gender, depressive symptoms and medical conditions predisposing to pain are more common in patients with Parkinson's disease (PD) with pain, no study has yet explored the relationship between pain and other non-motor symptoms (NMS). A total of 321 consecutive patients with PD [190 men/131 women aged 68.3 (SD 9.2) years] attending four Italian movement disorder clinics were studied. Demographic/clinical data were obtained by a standardized interview and the NMS scale. The association of pain with motor and NMS was assessed by multivariable logistic regression models. At the time of the study, 180 patients with PD (56%) reported chronic pain that, in most cases, was described as being muscular or arthralgic pain. Pain preceded the onset of motor signs in 36/180 patients. In the main-effect model, factors independently associated with pain were female sex [odds ratio (OR), 2.1; P = 0.01], medical conditions predisposing to pain (OR, 2.9; P motor complications (OR, 4.7; P = 0.04) and NMS belonging to the sleep/fatigue (OR, 1.6; P = 0.04) and mood/cognition (OR, 1.6; P = 0.03) domains. Most explanatory variables in the multivariable analysis were similarly distributed in patients in whom pain may have been related to PD or to a cause other than PD. We confirm that pain in PD is more frequent in women and in subjects with medical conditions predisposing to painful symptoms. Moreover, this strengthens the association between pain and motor severity measures and NMS domains, particularly sleep and mood disturbances. © 2017 EAN.

Motor-pump unit provided with a lifting appliance of the motor

International Nuclear Information System (INIS)

Veronesi, Luciano; Francis, W.R.

1978-01-01

This invention relates to lifting appliances and particularly concerns a 'pump and motor set' or motor-pump unit fitted with a lifting appliance enabling the motor to be separated from the pump. In nuclear power stations the reactor discharges heat that is carried by the coolant to a distant point away from the reactor to generate steam and electricity conventionally. In order to cause the reactor coolant to flow through the system, coolant motor-pump units are provided in the cooling system. These units are generally of the vertical type with an electric motor fitted vertically on the pump by means of a cylindrical or conical structure called motor support [fr

Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene

DEFF Research Database (Denmark)

Rosberg, Mette Romer; Alvarez, Susana; Krarup, Christian

2013-01-01

Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate...... whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using...... threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated...

Comparative analysis between P1 and B1 equations for neutron moderation

International Nuclear Information System (INIS)

Martinez, Aquilino Senra; Silva, Fernando Carvalho da; Cardoso, Carlos Eduardo Santos

2000-01-01

In order to calculate the neutron flux in nuclear reactors, B1 or P1 equations are solved by numerical methods for several groups of energy. The neutron fluxes obtained from the solutions of the B1 and P1 equations are similar when they are applied to large nuclear power reactors. However, an important difference between the two fluxes is that the system of P1 equations uses one more approximation than the B1 system and then, its flux is less precise. The present work shows the relations between both equations and analyzes for what conditions the two equations systems are equivalent. Furthermore, this equations are numerically solved in 54 groups of energy for a quadrangular arrange. (author)

Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.

Science.gov (United States)

Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

2012-05-01

Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. Copyright © 2012 Elsevier B.V. All rights reserved.

Fleet wide motor asset management program

International Nuclear Information System (INIS)

Rosemeier, R.G.; Moxie, J.J.; Mendez, W.E.

2011-01-01

The Institute of Nuclear Power Operations (INPO) performed several studies concerning the effects of motor failures on US power production. Problems with aging and the lack of preventative maintenance were noted as major contributors to this production loss. Westinghouse has developed, and successfully utilized, a computer program to assist plants in the decision making process for maximizing the operational availability of their motor fleet. The program considers motors of a fleet as a single, critical to production asset, and aids the operator in decisions regarding the following: 1.) Purchase of spares. 2.) Rewind and refurbishment prioritization. 3.) Long-term budget forecasting. (author)

The influence of the level of lamina propria invasion and the prevalence of p53 nuclear accumulation on survival in stage T1 transitional cell bladder cancer

DEFF Research Database (Denmark)

Hermann, G G; Horn, T; Steven, K

1998-01-01

PURPOSE: We assessed the influence of the level of lamina propria invasion and the prevalence of p53 nuclear immunoreactivity on the survival of patients with stage T1 transitional cell bladder cancer. MATERIALS AND METHODS: All patients presenting with stage T1 bladder cancer were prospectively...... and routinely grouped according to the level of lamina propria invasion. Invasion of the tumor stalk was defined as stage T1a, invasion of the lamina propria proper superficial to the level of muscularis mucosa as stage T1b and into or deeper than the muscularis mucosa as stage T1c. The p53 nuclear...... related to age, level of lamina propria invasion and presence of p53 nuclear accumulation. For this subpopulation overall survival was 67%, and 79% for stage T1a, 70% for stage T1b and 57% for stage T1c (p

Finite nuclear size and Lamb shift of p-wave atomic states

International Nuclear Information System (INIS)

Milstein, A.I.; Sushkov, O.P.; Terekhov, I.S.

2003-01-01

We consider corrections to the Lamb shift of the p-wave atomic states due to the finite nuclear size (FNS). In other words, these are radiative corrections to the atomic isotope shift related to the FNS. It is shown that the structure of the corrections is qualitatively different to that for the s-wave states. The perturbation theory expansion for the relative correction for a p 1/2 state starts with a α ln(1/Zα) term, while for the s 1/2 states it starts with a Zα 2 term. Here, α is the fine-structure constant and Z is the nuclear charge. In the present work, we calculate the α terms for that 2p states, the result for the 2p 1/2 state reads (8α/9π){ln[1/(Zα) 2 ]+0.710}. Even more interesting are the p 3/2 states. In this case the 'correction' is several orders of magnitude larger than the 'leading' FNS shift. However, absolute values of energy shifts related to these corrections are very small

Dopaminergic mesocortical projections to M1: role in motor learning and motor cortex plasticity

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Jonas Aurel Hosp

2013-10-01

Full Text Available Although the architecture of a dopaminergic (DA system within the primary motorcortex (M1 was well characterized anatomically, its functional significance remainedobscure for a long time. Recent studies in rats revealed that the integrity ofdopaminergic fibers in M1 is a prerequisite for successful acquisition of motor skills.This essential contribution of DA for motor learning is plausible as it modulates M1circuitry at multiple levels thereby promoting plastic changes that are required forinformation storage: at the network level, DA increases cortical excitability andenhances the stability of motor maps. At the cellular level, DA induces the expressionof learning related genes via the transcription factor c-fos. At the level of synapses,DA is required for the formation of long-term potentiation (LTP, a mechanism thatlikely is a fingerprint of a motor memory trace within M1. Dopaminergic fibersinnervating M1 originate within the midbrain, precisely the ventral tegmental area(VTA and the medial portion of substantia nigra (SN. Thus, they could be part of themeso-cortico-limibic pathway – a network that provides information about saliencyand motivational value of an external stimulus and is commonly referred as

Isl1 is required for multiple aspects of motor neuron development.

Science.gov (United States)

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L; Evans, Sylvia M; Sun, Yunfu

2011-07-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Development of an integrated condition monitoring and diagnostic system for motor-operated valves used in nuclear power plant

International Nuclear Information System (INIS)

Carneiro, Alvaro Luiz Guimaraes

2003-01-01

The reliability question of the components, specifically of motor operated valves, became one of the most important issues to be investigated in nuclear power plants, considering security and life plant extension. Therefore, the necessity of improvements in monitoring and diagnosis methods started to be of extreme relevance in the maintenance predictive field, establishing as main goal the reliability and readiness of the system components. Specially in nuclear power plants, the predictive maintenance contributes in the security factor in order to diagnosis in advance the occurrence of a possible failure, preventing severe situations. It also presents a contribution on the economic side by establishing a better maintenance programming, and reducing unexpected shutdown. The development of non intrusive monitoring and diagnostic method makes it possible to identify malfunctions in plant components during normal plant operation. This dissertation presents the development of an integrated condition monitoring system for motor-operated valves used in nuclear power plants. The methodology used in this project is based on the electric motor power signatures analysis, during the closing and opening stroke time of the valve. Once the measurements baseline diagnostic of the motor-operated valve is taken, it is possible to detect long-term deviations during valve lifetime, detecting in advance valve failures. The system implements two parallel techniques for detection and categorization of anomalies: expert system using fuzzy logic based on rules and knowledge base, providing a systematic approach for decision making, and the Wavelet Transform Technique, where the main goal is to obtain more detailed information contained in the measured data, identifying and characterizing the transients phenomena in the time and frequency domains, correlating them to failures situations in the incipient stage. The conditioning monitoring and diagnostic system was designed and implemented at

Kilowatt Isotope Power System. Phase I. System test report. 78-KIPS-33

International Nuclear Information System (INIS)

1978-01-01

The KIPS Ground Demonstration System (GDS) was designed to simulate, as closely as possible, a Flight System Conceptual Design (FSCD). No radiator was incorporated and electric heat sources were used in place of isotope heat sources. To minimize air in-leakage and to simulate heat losses associated with space operation, the system was operated in a vacuum chamber. Initial testing was performed on the development system which did not incorporate a high performance turbine or non-condensing configuration of the cold liquid passages in certain regenerator vapor regions. After testing of the development system and retrofit to the GDS configuration, which included improvements in the above two items, the GDS was installed in the test chamber. Testing to date showed the GDS configuration has demonstrated a system efficiency of greater than 15%. Satisfactory heat balances have been calculated on most system components, permitting evaluation of component performance. Certain performance deficiencies currently exist which prevented the 18% efficiency goal being attained. These can be corrected with further development

Prm3p is a pheromone-induced peripheral nuclear envelope protein required for yeast nuclear fusion.

Science.gov (United States)

Shen, Shu; Tobery, Cynthia E; Rose, Mark D

2009-05-01

Nuclear membrane fusion is the last step in the mating pathway of the yeast Saccharomyces cerevisiae. We adapted a bioinformatics approach to identify putative pheromone-induced membrane proteins potentially required for nuclear membrane fusion. One protein, Prm3p, was found to be required for nuclear membrane fusion; disruption of PRM3 caused a strong bilateral defect, in which nuclear congression was completed but fusion did not occur. Prm3p was localized to the nuclear envelope in pheromone-responding cells, with significant colocalization with the spindle pole body in zygotes. A previous report, using a truncated protein, claimed that Prm3p is localized to the inner nuclear envelope. Based on biochemistry, immunoelectron microscopy and live cell microscopy, we find that functional Prm3p is a peripheral membrane protein exposed on the cytoplasmic face of the outer nuclear envelope. In support of this, mutations in a putative nuclear localization sequence had no effect on full-length protein function or localization. In contrast, point mutations and deletions in the highly conserved hydrophobic carboxy-terminal domain disrupted both protein function and localization. Genetic analysis, colocalization, and biochemical experiments indicate that Prm3p interacts directly with Kar5p, suggesting that nuclear membrane fusion is mediated by a protein complex.

Essential role of cofilin-1 in regulating thrombin-induced RelA/p65 nuclear translocation and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells.

Science.gov (United States)

Fazal, Fabeha; Bijli, Kaiser M; Minhajuddin, Mohd; Rein, Theo; Finkelstein, Jacob N; Rahman, Arshad

2009-07-31

Activation of RhoA/Rho-associated kinase (ROCK) pathway and the associated changes in actin cytoskeleton induced by thrombin are crucial for activation of NF-kappaB and expression of its target gene ICAM-1 in endothelial cells. However, the events acting downstream of RhoA/ROCK to mediate these responses remain unclear. Here, we show a central role of cofilin-1, an actin-binding protein that promotes actin depolymerization, in linking RhoA/ROCK pathway to dynamic alterations in actin cytoskeleton that are necessary for activation of NF-kappaB and thereby expression of ICAM-1 in these cells. Stimulation of human umbilical vein endothelial cells with thrombin resulted in Ser(3) phosphorylation/inactivation of cofilin and formation of actin stress fibers in a ROCK-dependent manner. RNA interference knockdown of cofilin-1 stabilized the actin filaments and inhibited thrombin- and RhoA-induced NF-kappaB activity. Similarly, constitutively inactive mutant of cofilin-1 (Cof1-S3D), known to stabilize the actin cytoskeleton, inhibited NF-kappaB activity by thrombin. Overexpression of wild type cofilin-1 or constitutively active cofilin-1 mutant (Cof1-S3A), known to destabilize the actin cytoskeleton, also impaired thrombin-induced NF-kappaB activity. Additionally, depletion of cofilin-1 was associated with a marked reduction in ICAM-1 expression induced by thrombin. The effect of cofilin-1 depletion on NF-kappaB activity and ICAM-1 expression occurred downstream of IkappaBalpha degradation and was a result of impaired RelA/p65 nuclear translocation and consequently, RelA/p65 binding to DNA. Together, these data show that cofilin-1 occupies a central position in RhoA-actin pathway mediating nuclear translocation of RelA/p65 and expression of ICAM-1 in endothelial cells.

Essential Role of Cofilin-1 in Regulating Thrombin-induced RelA/p65 Nuclear Translocation and Intercellular Adhesion Molecule 1 (ICAM-1) Expression in Endothelial Cells*

Science.gov (United States)

Fazal, Fabeha; Bijli, Kaiser M.; Minhajuddin, Mohd; Rein, Theo; Finkelstein, Jacob N.; Rahman, Arshad

2009-01-01

Activation of RhoA/Rho-associated kinase (ROCK) pathway and the associated changes in actin cytoskeleton induced by thrombin are crucial for activation of NF-κB and expression of its target gene ICAM-1 in endothelial cells. However, the events acting downstream of RhoA/ROCK to mediate these responses remain unclear. Here, we show a central role of cofilin-1, an actin-binding protein that promotes actin depolymerization, in linking RhoA/ROCK pathway to dynamic alterations in actin cytoskeleton that are necessary for activation of NF-κB and thereby expression of ICAM-1 in these cells. Stimulation of human umbilical vein endothelial cells with thrombin resulted in Ser3 phosphorylation/inactivation of cofilin and formation of actin stress fibers in a ROCK-dependent manner. RNA interference knockdown of cofilin-1 stabilized the actin filaments and inhibited thrombin- and RhoA-induced NF-κB activity. Similarly, constitutively inactive mutant of cofilin-1 (Cof1-S3D), known to stabilize the actin cytoskeleton, inhibited NF-κB activity by thrombin. Overexpression of wild type cofilin-1 or constitutively active cofilin-1 mutant (Cof1-S3A), known to destabilize the actin cytoskeleton, also impaired thrombin-induced NF-κB activity. Additionally, depletion of cofilin-1 was associated with a marked reduction in ICAM-1 expression induced by thrombin. The effect of cofilin-1 depletion on NF-κB activity and ICAM-1 expression occurred downstream of IκBα degradation and was a result of impaired RelA/p65 nuclear translocation and consequently, RelA/p65 binding to DNA. Together, these data show that cofilin-1 occupies a central position in RhoA-actin pathway mediating nuclear translocation of RelA/p65 and expression of ICAM-1 in endothelial cells. PMID:19483084

Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts

Energy Technology Data Exchange (ETDEWEB)

Gardner, Nicole M., E-mail: nicolegardner@creighton.edu [Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178 (United States); Riley, Ronald T.; Showker, Jency L.; Voss, Kenneth A. [USDA-ARS, Toxicology and Mycotoxin Research Unit, Athens, GA 30605 (United States); Sachs, Andrew J.; Maddox, Joyce R.; Gelineau-van Waes, Janee B. [Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178 (United States)

2016-05-01

Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Administration of FB1 to pregnant LM/Bc mice induces exencephaly in embryos, and ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs) in humans. FB1 inhibits ceramide synthase enzymes in sphingolipid biosynthesis, causing sphinganine (Sa) and bioactive sphinganine-1-phosphate (Sa1P) accumulation in blood, cells, and tissues. Sphingosine kinases (Sphk) phosphorylate Sa to form Sa1P. Upon activation, Sphk1 associates primarily with the plasma membrane, while Sphk2 is found predominantly in the nucleus. In cells over-expressing Sphk2, accumulation of Sa1P in the nuclear compartment inhibits histone deacetylase (HDAC) activity, causing increased acetylation of histone lysine residues. In this study, FB1 treatment in LM/Bc mouse embryonic fibroblasts (MEFs) resulted in significant accumulation of Sa1P in nuclear extracts relative to cytoplasmic extracts. Elevated nuclear Sa1P corresponded to decreased histone deacetylase (HDAC) activity and increased histone acetylation at H2BK12, H3K9, H3K18, and H3K23. Treatment of LM/Bc MEFs with a selective Sphk1 inhibitor, PF-543, or with ABC294640, a selective Sphk2 inhibitor, significantly reduced nuclear Sa1P accumulation after FB1, although Sa1P levels remained significantly increased relative to basal levels. Concurrent treatment with both PF-543 and ABC294640 prevented nuclear accumulation of Sa1P in response to FB1. Other HDAC inhibitors are known to cause NTDs, so these results suggest that FB1-induced disruption of sphingolipid metabolism leading to nuclear Sa1P accumulation, HDAC inhibition, and histone hyperacetylation is a potential mechanism for FB1-induced NTDs. - Highlights: • FB1 treatment results in accumulation of Sa1P primarily in the nucleus of MEFs. • FB1 treatment and elevated nuclear Sa1P are associated with HDAC inhibition. • Sphk2 inhibition alone

Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts

International Nuclear Information System (INIS)

Gardner, Nicole M.; Riley, Ronald T.; Showker, Jency L.; Voss, Kenneth A.; Sachs, Andrew J.; Maddox, Joyce R.; Gelineau-van Waes, Janee B.

2016-01-01

Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Administration of FB1 to pregnant LM/Bc mice induces exencephaly in embryos, and ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs) in humans. FB1 inhibits ceramide synthase enzymes in sphingolipid biosynthesis, causing sphinganine (Sa) and bioactive sphinganine-1-phosphate (Sa1P) accumulation in blood, cells, and tissues. Sphingosine kinases (Sphk) phosphorylate Sa to form Sa1P. Upon activation, Sphk1 associates primarily with the plasma membrane, while Sphk2 is found predominantly in the nucleus. In cells over-expressing Sphk2, accumulation of Sa1P in the nuclear compartment inhibits histone deacetylase (HDAC) activity, causing increased acetylation of histone lysine residues. In this study, FB1 treatment in LM/Bc mouse embryonic fibroblasts (MEFs) resulted in significant accumulation of Sa1P in nuclear extracts relative to cytoplasmic extracts. Elevated nuclear Sa1P corresponded to decreased histone deacetylase (HDAC) activity and increased histone acetylation at H2BK12, H3K9, H3K18, and H3K23. Treatment of LM/Bc MEFs with a selective Sphk1 inhibitor, PF-543, or with ABC294640, a selective Sphk2 inhibitor, significantly reduced nuclear Sa1P accumulation after FB1, although Sa1P levels remained significantly increased relative to basal levels. Concurrent treatment with both PF-543 and ABC294640 prevented nuclear accumulation of Sa1P in response to FB1. Other HDAC inhibitors are known to cause NTDs, so these results suggest that FB1-induced disruption of sphingolipid metabolism leading to nuclear Sa1P accumulation, HDAC inhibition, and histone hyperacetylation is a potential mechanism for FB1-induced NTDs. - Highlights: • FB1 treatment results in accumulation of Sa1P primarily in the nucleus of MEFs. • FB1 treatment and elevated nuclear Sa1P are associated with HDAC inhibition. • Sphk2 inhibition alone

41 CFR 109-38.301-1.53 - Responsibilities of motor vehicle operators.

Science.gov (United States)

2010-07-01

... motor vehicle operators. 109-38.301-1.53 Section 109-38.301-1.53 Public Contracts and Property... MANAGEMENT REGULATIONS AVIATION, TRANSPORTATION, AND MOTOR VEHICLES 38-MOTOR EQUIPMENT MANAGEMENT 38.3-Official Use of Government Motor Vehicles § 109-38.301-1.53 Responsibilities of motor vehicle operators...

Estimación de la característica de Inductancia de fase del Motor de Reluctancia Conmutada MFR 132.1 Estimation of phase inductance profile of MFR 132.1 switched reluctance motor

Directory of Open Access Journals (Sweden)

Javier Quintana Santos

2011-06-01

Full Text Available En el presente trabajo se enuncia la idea fundamental en la que se basan todos los métodos empleados para la estimación de los parámetros de fase de los motores de reluctancia conmutada. Se describe, además, un algoritmo de división con punto decimal fijo en lenguaje VHDL. El algoritmo descrito se utiliza posteriormente para la estimación de la inductancia de fase del motor de reluctancia conmutada MFR 132.1, mediante el empleo de la técnica invasiva de modulación de amplitud con señales de tensión pulsantes de tres estados. Se diseñó y construyó una instalación experimental sobre la base de un FPGA de Actel, de la familia ProASIC 3 modelo A3P250, para el procesamiento de las señales. Finalmente se exponen y comentan las características de inductancia de fase del motor de reluctancia MFR 132.1, obtenidas.  In the present work is enunciated the fundamental idea of all the methods used for the estimation of phase parameters in the switched reluctance motors. The fixed point division algorithm employed to estimate the inactive phase inductance profile of the MFR 132.1 switched reluctance motor, is described in VHDL programming language. The algorithm implements the intrusive estimation technique of amplitude modulation with three states pulsating signals. The structure of the experimental set up for the digital signal processing, which is based on the Actel FPGA ProAsic 3 A3P250 development kit, is depicted. Finally, the inactive phase’s inductance profiles, which were experimentally obtained, are shown for different voltage values in the Direct Current converter link.

1H and 31P nuclear magnetic resonance spectroscopy of erythrocyte extracts in myotonic muscular dystrophy

International Nuclear Information System (INIS)

Gadoth, N.; Grinblat, J.; Tel Aviv Univ.; Shvo, H.; Navon, G.

1984-01-01

Extracts freshly prepared from erythrocytes of patients with myotonic muscular dystrophy, their unaffected siblings, and normal control subjects were examined with both 1 H and 31 P nuclear magnetic resonance spectroscopy. A moderate variability was found in the relative amounts of various nonphosphorylated compounds among patients and control subjects; however, no significant differences were found between the groups. As for the phosphorylated compounds, the sum of ADP+ATP was found significantly elevated in the myotonic muscular dystrophy patients

Performance in complex motor tasks deteriorates in hyperthermic humans

DEFF Research Database (Denmark)

Piil, Jacob Feder; Lundbye-Jensen, Jesper; Trangmar, Steven J

2017-01-01

-motor tracking performance was reduced by 10.7 ± 6.5% following exercise-induced hyperthermia when integrated in the multipart protocol and 4.4 ± 5.7% when tested separately (bothP 1.3% (P math tasks...... of information or decision-making prior to responding. We hypothesized that divergences could relate to task complexity and developed a protocol consisting of 1) simple motor task [TARGET_pinch], 2) complex motor task [Visuo-motor tracking], 3) simple math task [MATH_type], 4) combined motor-math task [MATH...

Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase.

Science.gov (United States)

Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani; Zhao, Yutong; Natarajan, Viswanathan

2017-01-01

Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. . Copyright © 2016 Elsevier Ltd. All rights reserved.

The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear.

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Amy E Kiernan

2006-01-01

Full Text Available In mammals, six separate sensory regions in the inner ear are essential for hearing and balance function. Each sensory region is made up of hair cells, which are the sensory cells, and their associated supporting cells, both arising from a common progenitor. Little is known about the molecular mechanisms that govern the development of these sensory organs. Notch signaling plays a pivotal role in the differentiation of hair cells and supporting cells by mediating lateral inhibition via the ligands Delta-like 1 and Jagged (JAG 2. However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear. Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear. Cristae are completely lacking in Jag1-conditional knockout (cko mutant inner ears, whereas the cochlea and utricle show partial sensory development. The saccular macula is present but malformed. Using SOX2 and p27kip1 as molecular markers of the prosensory domain, we show that JAG1 is initially expressed in all the prosensory regions of the ear, but becomes down-regulated in the nascent organ of Corti by embryonic day 14.5, when the cells exit the cell cycle and differentiate. We also show that both SOX2 and p27kip1 are down-regulated in Jag1-cko inner ears. Taken together, these data demonstrate that JAG1 is expressed early in the prosensory domains of both the cochlear and vestibular regions, and is required to maintain the normal expression levels of both SOX2 and p27kip1. These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear.

Restauration of age related motor impairment: Role of IGF-1 based gene therapy and microglial activation.

Directory of Open Access Journals (Sweden)

Eugenia Falomir Lockhart

2015-05-01

In the current study we implemented ICV IGF-I gene therapy in very old rats (28 months and assessed the motor performance pre and 17-days after surgery. Glial immunoreactivity in striatum was evaluated by Iba1 and GFAP markers. Results: As we previously reported, IGF-I restored motor coordination and forelimb grip strength in aged rats (Sanchez et al., 2008. We found that microglia immunoreactivity (Iba-1+ was significantly increased for at least 17 days after treatment with IGF-I (Xm-senil-IGF-I=8.370±0.3297 vs Xm-senil-DsRed= 5.557±0.2553; p<0.0001, astrocytes (GFAP+ showed not changes. Our results identify a novel function of microglia in the maintenance of motor permormance and suggest an original approach for reversing age-associated motor and exploratory performance recorded in rats.

Relationship of striatal 99Tcm-TRODAT-1 specific uptake and motor's severity in patients with Parkinson's disease

International Nuclear Information System (INIS)

Bian Yanzhu; Liu Huang; Feng Jue; Wei Qiang; Li Jinfu; Liu Guozhang

2004-01-01

Objective: To investigate the relationship of striatal 99 Tc m -2β-((N, N'-bis (2-mercap-toethyl) ethylene diamino) methyl), 3β-(4-chlorophenyl) tropane, ( 99 Tc m -TRODAT-1) specific uptake values (SUVs) and motor's severity in patients with Parkinson's disease (PD). Methods: 35 patients with PD were examined by 99 Tc m -TRODAT-1 SPECT dopamine transporter brain imaging. The SUVs of the striatum and its subregions, including the putamen and caudate nucleus, were calculated by semi-quantity region of interest (ROI) technique with the radiation ratios of target/cerebellum. Motor's severity of PD was measured by Unified Parkinson's Disease Rating Scale (UPDRS). Motor UPDRS scores were divided into four subscales, bradykinesia scores, rigidity scores, postural instability scores and tremor scores. Results: SUVs of putamen correlated best with the motor UPDRS scores(r=-0.846, P<0.001), followed by that of striatum and caudate nucleus. Among the four major clinical signs of PD, the bradykinesia scores (X1) correlated best with SUVs of putamen(r=-0.858, P<0.001), followed by rigidity scores (X2) and postural instability scores. There was no significant correlation between tremor scores and SUVs of putamen (Y). A regression equation (Y=2.345-0.0418 X1-0.0580 X2) was founded by stepwise multiple linear regression analysis. Conclusions: The SUVs of striatum (especially SUVs of putamen) was a useful marker to evaluate the motor's severity of PD and monitor the progression of PD. (authors)

48 CFR 970.2307-1 - Motor vehicle fleet operations.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Motor vehicle fleet..., Renewable Energy Technologies, Occupational Safety and Drug-Free Work Place 970.2307-1 Motor vehicle fleet... that the Federal motor vehicle fleet will serve as an example and provide a leadership role in the...

IE Information No. 87-08: Degraded motor leads in Limitorque dc motor operators

International Nuclear Information System (INIS)

Jordan, E.L.

1992-01-01

On May 6, 1986 the NRC received from Portland General Electric Company a 10 CFR 21 report concerning a motor failure which occurred at its Trojan Nuclear Power Plant. The failure involved shorting of the motor leads inside a Limitorque motor operator connected to an auxiliary feedwater flow control valve. Upon inspection it was determined that the failure was the result of insulation degradation of the motor leads that had allowed two leads to short together. Recently, the NRC has also learned of a failure at the Turkey Point Nuclear Power Plant in which the steam supply valve for the auxiliary feedwater turbine failed to operate after a Limitorque motor operator experienced a similar motor lead short circuit. The Trojan and the Turkey Point Limitorque operators were found to contain motors manufactured with Nomex-Kapton insulated leads. On January 12--14, 1987, the NRC conducted an inspection at Peerless-Winsmith, Inc., manufacturer of dc motors for Limitorque Co. During this inspection it was determined that the failed Nomex-Kapton leads were different than the leads which were fitted to the motors, tested, and documented in Limitorque Qualification Report B-0009 for dc motor operators. The leads attached to the tested motors were insulated with Nomex plus an epoxy impregnated braided fiberglass sleeve. The NRC knows of no analysis or testing that has been performed to show the Nomex-Kapton leads are acceptable for use in an application requiring environmental qualification. Further, it should be noted that the failures cited above occurred under normal operating conditions, not under the harsh conditions which could occur in areas where environmental qualification is required

Analysis of ZDDP Content and Thermal Decomposition in Motor Oils Using NAA and NMR

Science.gov (United States)

Ferguson, S.; Johnson, J.; Gonzales, D.; Hobbs, C.; Allen, C.; Williams, S.

Zinc dialkyldithiophosphates (ZDDPs) are one of the most common anti-wear additives present in commercially-available motor oils. The ZDDP concentrations of motor oils are most commonly determined using inductively coupled plasma atomic emission spectroscopy (ICP-AES). As part of an undergraduate research project, we have determined the Zn concentrations of eight commercially-available motor oils and one oil additive using neutron activation analysis (NAA), which has potential for greater accuracy and less sensitivity to matrix effects as compared to ICP-AES. The 31P nuclear magnetic resonance (31P-NMR) spectra were also obtained for several oil additive samples which have been heated to various temperatures in order to study the thermal decomposition of ZDDPs.

Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity

International Nuclear Information System (INIS)

Qi, Wentao; Weber, Christopher R; Wasland, Kaarin; Savkovic, Suzana D

2011-01-01

Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells plays an important role in colon cancer progression and is mediated by loss of tumor suppressor FOXO3 activity. The aim of this study was to assess if genistein exerts anti-proliferative properties by attenuating the negative effect of EGF on FOXO3 activity. The effect of genistein on proliferation stimulated by EGF-mediated loss of FOXO3 was examined in human colonic cancer HT-29 cells. EGF-induced FOXO3 phosphorylation and translocation were assessed in the presence of genistein. EGF-mediated loss of FOXO3 interactions with p53 (co-immunoprecipitation) and promoter of p27kip1 (ChIP assay) were examined in presence of genistein in cells with mutated p53 (HT-29) and wild type p53 (HCT116). Silencing of p53 determined activity of FOXO3 when it is bound to p53. Genistein inhibited EGF-induced proliferation, while favoring dephosphorylation and nuclear retention of FOXO3 (active state) in colon cancer cells. Upstream of FOXO3, genistein acts via the PI3K/Akt pathway to inhibit EGF-stimulated FOXO3 phosphorylation (i.e. favors active state). Downstream, EGF-induced disassociation of FOXO3 from mutated tumor suppressor p53, but not wild type p53, is inhibited by genistein favoring FOXO3-p53(mut) interactions with the promoter of the cell cycle inhibitor p27kip1 in colon cancer cells. Thus, the FOXO3-p53(mut) complex leads to elevated p27kip1 expression and promotes cell cycle arrest. These novel anti-proliferative mechanisms of genistein suggest a possible role of combining genistein with other chemoreceptive agents for the treatment of colon cancer

Development of a smart type motor operated valve for nuclear power plants

Science.gov (United States)

Kim, Chang-Hwoi; Park, Joo-Hyun; Lee, Dong-young; Koo, In-Soo

2005-12-01

In this paper, the design concept of the smart type motor operator valve for nuclear power plant was described. The development objective of the smart valve is to achieve superior accuracy, long-term reliability, and ease of use. In this reasons, developed smart valve has fieldbus communication such as deviceNet and Profibus-DP, auto-tuning PID controller, self-diagnostics, and on-line calibration capabilities. And also, to achieve pressure, temperature, and flow control with internal PID controller, the pressure sensor and transmitter were included in this valve. And, temperature and flow signal acquisition port was prepared. The developed smart valve will be performed equipment qualification test such as environment, EMI/EMC, and vibration in Korea Test Lab. And, the valve performance is tested in a test loop which is located in Seoul National University Lab. To apply nuclear power plant, the software is being developed according to software life cycle. The developed software is verified by independent software V and V team. It is expected that the smart valve can be applied to an existing NPPs for replacing or to a new nuclear power plants. The design and fabrication of smart valve is now being processed.

Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα.

Science.gov (United States)

Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J; Paulsen, Janet L; Muth, Aaron; Bawadekar, Mandar; Li, Gang; Thompson, Paul R; Shelef, Miriam A; Schiffer, Celia A; Weerapana, Eranthie; Ho, I-Cheng

2017-06-09

Many citrullinated proteins are known autoantigens in rheumatoid arthritis, a disease mediated by inflammatory cytokines, such as tumor necrosis factor-α (TNFα). Citrullinated proteins are generated by converting peptidylarginine to peptidylcitrulline, a process catalyzed by the peptidylarginine deiminases (PADs), including PAD1 to PAD4 and PAD6. Several major risk factors for rheumatoid arthritis are associated with heightened citrullination. However, the physiological role of citrullination in immune cells is poorly understood. We report that suppression of PAD activity attenuates Toll-like receptor-induced expression of interleukin-1β (IL-1β) and TNFα by neutrophils in vivo and in vitro but not their global transcription activity. Mechanistically, PAD4 directly citrullinates nuclear factor κB (NF-κB) p65 and enhances the interaction of p65 with importin α3, which brings p65 into the nucleus. The citrullination-enhanced interaction of p65 with importin α3 and its nuclear translocation and transcriptional activity can be attributed to citrullination of four arginine residues located in the Rel homology domain of p65. Furthermore, a rheumatoid arthritis-prone variant of PAD4, carrying three missense mutations, is more efficient in interacting with p65 and enhancing NF-κB activity. Together, these data not only demonstrate a critical role of citrullination in an NF-κB-dependent expression of IL-1β and TNFα but also provide a molecular mechanism by which heightened citrullination propagates inflammation in rheumatoid arthritis. Accordingly, attenuating p65-mediated production of IL-1β and TNFα by blocking the citrullination of p65 has great therapeutic potential in rheumatoid arthritis. Copyright © 2017, American Association for the Advancement of Science.

Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK

DEFF Research Database (Denmark)

Rawashdeh, Oliver; Jilg, Antje; Maronde, Erik

2016-01-01

, the presence of PER1 in hippocampal neurons is a prerequisite for the time-of-day-dependent phosphorylation of CREB, as it regulates the shuttling of pP90RSK into the nucleus. Representative immunofluorescence images show a temporal difference in phosphorylated cAMP response element-binding protein (p...... activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility......CREB; green color) levels in all regions of the dorsal hippocampus between a wild-type C3H mouse (WT; left) and a Period1-knockout (Per1−/−; right) mouse. Images were taken 2 h after lights on, thus, when fluctuating levels of pCREB peak in WT mouse hippocampus. Insets show a representative hippocampal neuron...

Motor and non-motor symptoms in old-age onset Parkinson's disease patients.

Science.gov (United States)

Mendonça, Marcelo D; Lampreia, Tania; Miguel, Rita; Caetano, André; Barbosa, Raquel; Bugalho, Paulo

2017-07-01

Advancing age is a well-known risk factor for Parkinson's disease (PD). With population ageing it is expected that the total number of patients with PD onset at oldage increases. Information on the motor but particularly on non-motor phenotype of this late-onset population is lacking. We recruited 24 patients with PD onset at or over 75 years. Each patient was matched with 1 control patient with PD onset between the ages of 40 and 65 and matched for disease duration. Both groups were assessed with the UPDRS, the Non-motor symptoms scale (NMSS) and other scales to assess non-motor symptoms. Groups were compared with conditional logistic regression analysis. Old-age onset PD was, on average, 80 years at the time of PD onset while middle-age onset were 59. Disease duration was approximately 5 years in both groups. While no difference was observed in the total UPDRS-III scores, old-age onset PD was associated with higher axial symptoms (7.42 vs. 4.63, p = 0.011) and a higher frequency of dementia (7/24 vs. 0/24, p = 0.009). While no difference in the total number of non-motor symptoms was observed (6.79 vs. 6.22, p = 0.310), old-age onset patients had a higher prevalence of gastrointestinal symptoms (20/24 vs. 12/24, p = 0.037). For the same disease duration, older age onset is associated with worse axial motor dysfunction and dementia in PD patients. Beside gastrointestinal symptoms, non-motor symptoms are not associated with age.

MOTORIC STIMULATION RELATED TO FINE MOTORIC DEVELOPMENT ON CHILD

Directory of Open Access Journals (Sweden)

Mira Triharini

2017-07-01

Full Text Available Introduction: Motor developmental stimulation is an activity undertaken to stimulate the children basic skills and so they can grow and develop optimally. Children who obtain a direct stimulus will grow faster than who get less stimulus. Mother’s behavior of stimulation is very important for children, it is considering as the basic needs of children and it must be fulfilled. Providing good stimulation could optimize fine motor development in children. The purpose of this study was to analyze mother’s behavior about motor stimulation with fine motor development in toddler age 4-5 years old. Method: Design have been  used in this study was cross sectional. Population were mothers and their toddler in Group A of Dharma Wanita Persatuan Driyorejo Gresik Preschool. Sample were 51 respondents recruited by using purposive sampling technique according to inclusion and exclusion criteria. The independent variable was mother’s behavior about motor stimulation whereas dependent variable was fine motor development in toddler. The data were collected using questionnaire and conducting observation on fine motor development based on Denver Development Screening Test (DDST. Data then analyzed using Spearman Rho (r test to find relation between mother’s behaviors about stimulation motor on their toddler fine motor development. Result: Results  of this study showed that there were correlations between mother’s knowledge and fine motor development in toddler (p=0.000, between mother’s attitude and fine motor development in toddler (p=0.000, and between mother’s actions and fine motor development in toddler (p=0.000. Analysis: In sort study found that there were relation between fine motor development and mother’s behavior. Discussion: Therefore mother’s behavior needed to be improved. Further research about stimulation motor and fine motor development aspects in toddler is required.

[Two cases of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)].

Science.gov (United States)

Mori, Chiaki; Saito, Tomoko; Saito, Toshio; Fujimura, Harutoshi; Sakoda, Saburo

2015-01-01

We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place.

Molecular control of brain size: Regulators of neural stem cell life, death and beyond

International Nuclear Information System (INIS)

Joseph, Bertrand; Hermanson, Ola

2010-01-01

The proper development of the brain and other organs depends on multiple parameters, including strictly controlled expansion of specific progenitor pools. The regulation of such expansion events includes enzymatic activities that govern the correct number of specific cells to be generated via an orchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteins in turn exert direct control of these enzymatic activities and thus progenitor pool expansion and organ size. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators of cell cycle exit that interact with and inhibit the activity of cyclin-CDK complexes, whereas members of the p53/p63/p73 family are traditionally associated with regulation of cell death. It has however become clear that the roles for these proteins are not as clear-cut as initially thought. In this review, we discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cycle control, differentiation, and death of neural stem cells. We suggest that these proteins act as molecular interfaces, or 'pilots', to assure the correct assembly of protein complexes with enzymatic activities at the right place at the right time, thereby regulating essential decisions in multiple cellular events.

Molecular control of brain size: Regulators of neural stem cell life, death and beyond

Energy Technology Data Exchange (ETDEWEB)

Joseph, Bertrand [Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm (Sweden); Hermanson, Ola, E-mail: ola.hermanson@ki.se [Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm (Sweden)

2010-05-01

The proper development of the brain and other organs depends on multiple parameters, including strictly controlled expansion of specific progenitor pools. The regulation of such expansion events includes enzymatic activities that govern the correct number of specific cells to be generated via an orchestrated control of cell proliferation, cell cycle exit, differentiation, cell death etc. Certain proteins in turn exert direct control of these enzymatic activities and thus progenitor pool expansion and organ size. The members of the Cip/Kip family (p21Cip1/p27Kip1/p57Kip2) are well-known regulators of cell cycle exit that interact with and inhibit the activity of cyclin-CDK complexes, whereas members of the p53/p63/p73 family are traditionally associated with regulation of cell death. It has however become clear that the roles for these proteins are not as clear-cut as initially thought. In this review, we discuss the roles for proteins of the Cip/Kip and p53/p63/p73 families in the regulation of cell cycle control, differentiation, and death of neural stem cells. We suggest that these proteins act as molecular interfaces, or 'pilots', to assure the correct assembly of protein complexes with enzymatic activities at the right place at the right time, thereby regulating essential decisions in multiple cellular events.

Cell Cycle Inhibitors and Outcome after Radiotherapy in Bladder Cancer Patients

International Nuclear Information System (INIS)

Roetterud, Ranveig; Pettersen, Erik O.; Berner, Aasmund; Holm, Ruth; Olsen, Dag Rune; Fossaa, Sophie D.

2002-01-01

The aim of this study was to correlate the expression of cell cycle inhibitors with outcome of patients with muscle-invasive bladder cancer treated with preoperative radiotherapy (46 Gy/4-5 weeks or 20 Gy/1 week) and cystectomy. Patients with pT3b (n=42) or pT0 (n=17) were included in the study. Expression of p16INK4a and p27KIP1 was assessed immunohistochemically in pre-radiotherapy biopsies and cystectomy specimens. Previously reported results of p21CIP1 expression were also included. No difference in pretreatment protein expression was found between patients with pT0 and pT3b. Expression of p21CIP1 and p27KIP1 was lower in cystectomy specimens than in pretreatment biopsies. None of the proteins showed significant impact on survival when analysed separately. However, patients with tumours showing > 50% expression of p16INK4a, p21CIP1, or p27KIP1 displayed poorer cancer-specific survival rates compared with the remaining patients (p=0.025). This effect was more pronounced in patients receiving 46 Gy than in those receiving 20 Gy. In conclusion, low expression of cell cycle inhibitors is related to favourable survival after precystectomy radiotherapy

Comparative analysis between P1 and B1 equations for neutron moderation; Analise comparativa entre os metodos de obtencao e das solucoes das equacoes P1 e B1 para moderacao de neutrons

Energy Technology Data Exchange (ETDEWEB)

Martinez, Aquilino Senra; Silva, Fernando Carvalho da; Cardoso, Carlos Eduardo Santos [Universidade Federal, Rio de Janeiro, RJ (Brazil). Coordenacao dos Programas de Pos-graduacao de Engenharia. Programa de Engenharia Nuclear

2000-07-01

In order to calculate the neutron flux in nuclear reactors, B1 or P1 equations are solved by numerical methods for several groups of energy. The neutron fluxes obtained from the solutions of the B1 and P1 equations are similar when they are applied to large nuclear power reactors. However, an important difference between the two fluxes is that the system of P1 equations uses one more approximation than the B1 system and then, its flux is less precise. The present work shows the relations between both equations and analyzes for what conditions the two equations systems are equivalent. Furthermore, this equations are numerically solved in 54 groups of energy for a quadrangular arrange. (author)

Dual personality of Mad1: regulation of nuclear import by a spindle assembly checkpoint protein.

Science.gov (United States)

Cairo, Lucas V; Ptak, Christopher; Wozniak, Richard W

2013-01-01

Nuclear transport is a dynamic process that can be modulated in response to changes in cellular physiology. We recently reported that the transport activity of yeast nuclear pore complexes (NPCs) is altered in response to kinetochore-microtubule (KT-MT) interaction defects. Specifically, KT detachment from MTs activates a signaling pathway that prevents the nuclear import of cargos by the nuclear transport factor Kap121p. This loss of Kap121p-mediated import is thought to influence the nuclear environment, including the phosphorylation state of nuclear proteins. A key regulator of this process is the spindle assembly checkpoint protein Mad1p. In response to unattached KTs, Mad1p dynamically cycles between NPCs and KTs. This cycling appears to induce NPC molecular rearrangements that prevent the nuclear import of Kap121p-cargo complexes. Here, we discuss the underlying mechanisms and the physiological relevance of Mad1p cycling and the inhibition of Kap121p-mediated nuclear import, focusing on outstanding questions within the pathway.

Enhancement of motor learning by focal intermittent theta burst stimulation (iTBS) of either the primary motor (M1) or somatosensory area (S1) in healthy human subjects.

Science.gov (United States)

Platz, Thomas; Adler-Wiebe, Marija; Roschka, Sybille; Lotze, Martin

2018-01-01

Motor rehabilitation after brain damage relies on motor re-learning as induced by specific training. Non-invasive brain stimulation (NIBS) can alter cortical excitability and thereby has a potential to enhance subsequent training-induced learning. Knowledge about any priming effects of NIBS on motor learning in healthy subjects can help to design targeted therapeutic applications in brain-damaged subjects. To examine whether complex motor learning in healthy subjects can be enhanced by intermittent theta burst stimulation (iTBS) to primary motor or sensory cortical areas. Eighteen young healthy subjects trained eight different arm motor tasks (arm ability training, AAT) once a day for 5 days using their left non-dominant arm. Except for day 1 (baseline), training was performed after applying an excitatory form of repetitive transcranial magnetic stimulation (iTBS) to either (I) right M1 or (II) S1, or (III) sham stimulation to the right M1. Subjects were randomly assigned to conditions I, II, or III. A principal component analysis of the motor behaviour data suggested eight independent motor abilities corresponding to the 8 trained tasks. AAT induced substantial motor learning across abilities with generalisation to a non-trained test of finger dexterity (Nine-Hole-Peg-Test, NHPT). Participants receiving iTBS (to either M1 or S1) showed better performance with the AAT tasks over the period of training compared to sham stimulation as well as a bigger improvement with the generalisation task (NHPT) for the trained left hand after training completion. Priming with an excitatory repetitive transcranial magnetic stimulation as iTBS of either M1 or S1 can enhance motor learning across different sensorimotor abilities.

Energy Dependence of Nuclear Transparency in C (p,2p) Scattering

Science.gov (United States)

Leksanov, A.; Alster, J.; Asryan, G.; Averichev, Y.; Barton, D.; Baturin, V.; Bukhtoyarova, N.; Carroll, A.; Heppelmann, S.; Kawabata, T.; Makdisi, Y.; Malki, A.; Minina, E.; Navon, I.; Nicholson, H.; Ogawa, A.; Panebratsev, Yu.; Piasetzky, E.; Schetkovsky, A.; Shimanskiy, S.; Tang, A.; Watson, J. W.; Yoshida, H.; Zhalov, D.

2001-11-01

The transparency of carbon for (p,2p) quasielastic events was measured at beam momenta ranging from 5.9 to 14.5 GeV/c at 90° c.m. The four-momentum transfer squared (Q2) ranged from 4.7 to 12.7 (GeV/c)2. We present the observed beam momentum dependence of the ratio of the carbon to hydrogen cross sections. We also apply a model for the nuclear momentum distribution of carbon to obtain the nuclear transparency. We find a sharp rise in transparency as the beam momentum is increased to 9 GeV/c and a reduction to approximately the Glauber level at higher energies.

Interleaved localized 1H/31P nuclear magnetic resonance spectroscopy of skeletal muscle

International Nuclear Information System (INIS)

Meyerspeer, M.

2005-09-01

Nuclear magnetic resonance (NMR) has been used as a spectroscopic method in physics and chemistry before it was developed to become a diagnostic imaging tool in medicine. When NMR spectroscopy is applied to human tissue, metabolism can be studied in normal physiological and pathological states in vivo. Metabolite concentrations and rates can be monitored dynamically and with localization of a defined region of interest. The 'window' which is opened for observation, i.e. which quantities are measured, depends on the nucleus used for RF excitation. Mechanisms of adenosine tri-phosphate (ATP) resynthesis, as a direct source of energy for muscle contraction, are phosphocreatine (PCr) splitting, glycolysis, beta-oxidation and, finally, oxidative phosphorylation. Whilst the dependency of these processes' fractional contribution to muscular energy supply on exercise type and duration is well known, quantitative models of the regulating mechanisms involved are still subject of current research. A large fraction of the established knowledge about metabolism is based on biochemical analysis of tissue acquired invasively (e.g. microdialysis and open-flow microperfusion) or representing averaged metabolic concentrations for the whole body (via serum metabolites or gas exchange analysis). Localized NMR spectroscopy, however, is capable of non-invasively acquiring time-resolved data from a defined volume of interest, in vivo. In contrast to the vast majority of MRS studies investigating metabolism, where spectra of a single nucleus (commonly 1 H, 31 P or 13 C) were acquired or several MR spectra with different nuclei were measured in separate experiments, this work opens an additional 'window' on muscle metabolism by interleaved localized acquisition of 1 H and 31 P NMR spectra from human calf muscle in vivo, during rest, exercise and recovery, in a single experiment. Using this technique, the time courses of the concentrations of phosphocreatine, inorganic phosphate (Pi), ATP

Motor areas of the frontal cortex in patients with motor eloquent brain lesions.

Science.gov (United States)

Bulubas, Lucia; Sabih, Jamil; Wohlschlaeger, Afra; Sollmann, Nico; Hauck, Theresa; Ille, Sebastian; Ringel, Florian; Meyer, Bernhard; Krieg, Sandro M

2016-12-01

OBJECTIVE Because of its huge clinical potential, the importance of premotor areas for motor function itself and plastic reshaping due to tumors or ischemic brain lesions has received increased attention. Thus, in this study the authors used navigated transcranial magnetic stimulation (nTMS) to investigate whether tumorous brain lesions induce a change in motor cortex localization in the human brain. METHODS Between 2010 and 2013, nTMS motor mapping was performed in a prospective cohort of 100 patients with brain tumors in or adjacent to the rolandic cortex. Spatial data analysis was performed by normalization of the individual motor maps and creation of overlays according to tumor location. Analysis of motor evoked potential (MEP) latencies was performed regarding mean overall latencies and potentially polysynaptic latencies, defined as latencies longer than 1 SD above the mean value. Hemispheric dominance, lesion location, and motor-function deficits were also considered. RESULTS Graphical analysis showed that motor areas were not restricted to the precentral gyrus. Instead, they spread widely in the anterior-posterior direction. An analysis of MEP latency showed that mean MEP latencies were shortest in the precentral gyrus and longest in the superior and middle frontal gyri. The percentage of latencies longer than 1 SD differed widely across gyri. The dominant hemisphere showed a greater number of longer latencies than the nondominant hemisphere (p < 0.0001). Moreover, tumor location-dependent changes in distribution of polysynaptic latencies were observed (p = 0.0002). Motor-function deficit did not show any statistically significant effect. CONCLUSIONS The distribution of primary and polysynaptic motor areas changes in patients with brain tumors and highly depends on tumor location. Thus, these data should be considered for resection planning.

The (n,p) reaction as a probe of nuclear structure

International Nuclear Information System (INIS)

Jackson, K.P.; Celler, A.

1988-08-01

An account is given of some results of studies of the (n,p) reaction on nuclear targets at TRIUMF. The (n,p) reaction, inducing spin flip transitions in isospin space, appears to exhibit a unique sensitivity to certain aspects of nuclear structure. The TRIUMF facility is the first to exploit the (n,p) reaction as a detailed probe of nuclear structure at energies above 65 MeV. In the (n,p) reaction Fermi transitions are absent, but there is a dramatic impact on Gamow-Teller and other collective transactions. Some nuclear transition matrix elements can be estimated on the basis of (n,p) measurements. Experiments have been carried out at TRIUMF on Li 6 , Fe 5 4, and Zr 9 0 targets. The calibration of the (n,p) reaction as a probe of the Gamow-Teller strength B + GT has been achieved for three targets. (L.L.) (45 refs., 10 figs.)

Educational attainment and motor burden in advanced Parkinson's disease - The emerging role of education in motor reserve.

Science.gov (United States)

Blume, Josefine; Rothenfusser, Eva; Schlaier, Jürgen; Bogdahn, Ulrich; Lange, Max

2017-10-15

To explore the relationship of motor burden and educational attainment in patients with advanced stage PD. We included 102 consecutive patients who underwent a complete evaluation for DBS surgery, including detailed neuropsychological testing and UPDRSIII in a standardized Levodopa challenge. Years of education (YoE) were calculated as the highest grade attained in secondary school plus years for post-secondary training. The OFF medication UPDRS-III score was associated with YoE (p=0.006; t=-2.82) and age (p=0.007; t=-2.75) in our multivariable linear regression model even while including disease duration (p=0.8; t=0.21), presence of mild cognitive impairment (MCI) (p=0.9; t=0.16) or current IQ (p=0.2; t=1.25) as additional covariables. In a subgroup of 60 patients two years after DBS, the ON/ON UPDRS score was associated with YoE (p=0.01; t=-2.42) and diagnosis of PD dementia (p=0.05, t=1.95), while age (p=0.08, t=1.75), disease duration (p=0.6t=0.48) and LEDD (p=0.3; t=1.05) showed no significant association to ON/ON UPDRS score. We found an inverse correlation between years of education and lower (better) UPDRS -III motor score after adjusting for important covariables. Education may lead to an increased ability to compensate disturbances in basal ganglia circuits affecting not only for cognitive, but also for motor aspects of PD. Thus, educational attainment may play an important role in the concept of motor reserve. Copyright © 2017 Elsevier B.V. All rights reserved.

Rehearsal strategies during motor-sequence learning in old age : Execution vs motor imagery

NARCIS (Netherlands)

Stoter, Arjan J. R.; Scherder, Erik J. A.; Kamsma, Yvo P. T.; Mulder, Theo

Motor imagery and action-based rehearsal were compared during motor sequence-learning by young adults (M = 25 yr., SD = 3) and aged adults (M = 63 yr., SD = 7). General accuracy of aged adults was lower than that of young adults (F-1,F-28 = 7.37, p = .01) even though working-memory capacity was

A Novel Nuclear Trafficking Module Regulates the Nucleocytoplasmic Localization of the Rabies Virus Interferon Antagonist, P Protein*

Science.gov (United States)

Oksayan, Sibil; Wiltzer, Linda; Rowe, Caitlin L.; Blondel, Danielle; Jans, David A.; Moseley, Gregory W.

2012-01-01

Regulated nucleocytoplasmic transport of proteins is central to cellular function and dysfunction during processes such as viral infection. Active protein trafficking into and out of the nucleus is dependent on the presence within cargo proteins of intrinsic specific modular signals for nuclear import (nuclear localization signals, NLSs) and export (nuclear export signals, NESs). Rabies virus (RabV) phospho (P) protein, which is largely responsible for antagonising the host anti-viral response, is expressed as five isoforms (P1–P5). The subcellular trafficking of these isoforms is thought to depend on a balance between the activities of a dominant N-terminal NES (N-NES) and a distinct C-terminal NLS (C-NLS). Specifically, the N-NES-containing isoforms P1 and P2 are cytoplasmic, whereas the shorter P3–P5 isoforms, which lack the N-NES, are believed to be nuclear through the activity of the C-NLS. Here, we show for the first time that RabV P contains an additional strong NLS in the N-terminal region (N-NLS), which, intriguingly, overlaps with the N-NES. This arrangement represents a novel nuclear trafficking module where the N-NLS is inactive in P1 but becomes activated in P3, concomitant with truncation of the N-NES, to become the principal targeting signal conferring nuclear accumulation. Understanding this unique switch arrangement of overlapping, co-regulated NES/NLS sequences is vital to delineating the critical role of RabV P protein in viral infection. PMID:22700958

Motor-operated valve (MOV) actuator motor and gearbox testing

International Nuclear Information System (INIS)

DeWall, K.; Watkins, J.C.; Bramwell, D.

1997-07-01

Researchers at the Idaho National Engineering and Environmental Laboratory tested the performance of electric motors and actuator gearboxes typical of the equipment installed on motor-operated valves used in nuclear power plants. Using a test stand that simulates valve closure loads against flow and pressure, the authors tested five electric motors (four ac and one dc) and three gearboxes at conditions a motor might experience in a power plant, including such off-normal conditions as operation at high temperature and reduced voltage. They also monitored the efficiency of the actuator gearbox. All five motors operated at or above their rated starting torque during tests at normal voltages and temperatures. For all five motors, actual torque losses due to voltage degradation were greater than the losses calculated by methods typically used for predicting motor torque at degraded voltage conditions. For the dc motor the actual torque losses due to elevated operating temperatures were greater than the losses calculated by the typical predictive method. The actual efficiencies of the actuator gearboxes were generally lower than the running efficiencies published by the manufacturer and were generally nearer the published pull-out efficiencies. Operation of the gearbox at elevated temperature did not affect the operating efficiency

Motor Importance of motor assessment in school children: analysis of the reliability of the motor development scale

Directory of Open Access Journals (Sweden)

Kassandra Nunes Amaro

2010-09-01

Full Text Available The objective of this study was to investigate the motor performance of school chil-dren aged 6 to 10 years without learning difficulties (n=101, and to analyze the reliability of the Motor Development Scale (MDS (Rosa Neto, 2002. Descriptive statistics with calculation of the mean, standard deviation, and range was used for data analysis. The internal consistency of the MDS was assessed using Cronbach’s alpha coefficient, and the correlation between variables was determined by Pearson’s linear correlation, with p<0.05. The results showed (1 that motor development was within normal limits in 96% of the children, and (2 a high correlation betwe-en chronological age and general motor age, indicating good internal consistency. These data demonstrate the logic and structured design of the MDS, confirming its reliability.

77 FR 11598 - Thermal Overload Protection for Electric Motors on Motor-Operated Valves

Science.gov (United States)

2012-02-27

... application of thermal overload protection devices that are integral with the motor starter for electric... Research, U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001, telephone: 301-251-7455; email... Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. [FR Doc. 2012-4552 Filed 2...

Evaluation excitation functions for "2"8Si(n,p)"2"8Al, "3"1P(n,p)"3"1Si, and "1"1"3In(n,γ)"1"1"4"mIn reactions

International Nuclear Information System (INIS)

Zolotarev, K.I.

2014-10-01

Cross section data for "2"8Si(n,p)"2"8Al, "3"1P(n,p)"3"1Si and "1"1"3In(n,γ)"1"1"4"mIn reactions are needed for solving a wide spectrum of scientific and technical tasks. The excitation function of "2"8Si(n,p)"2"8Al reaction refers to the nuclear data involved in fusion reactor design calculations. The "2"8Si(n,p)"2"8Al reaction is interesting also as the monitor reaction for measurements at fusion facilities. Activation detectors on the basis of the 31P(n,p)31Si reaction are commonly used in the reactor dosimetry. The "1"1"3In(n,γ)"1"1"4"mIn reaction is promising regarding reactor dosimetry application for two reasons. First, due to the "1"1"4"mIn decay parameters which are rather suitable for activation measurements. Half-life of "1"1"4"mIn is equal to T_1/_2 = (49.51 ± 0.01) days and gamma spectrum accompanying decay has only one line with energy 190.27 keV and intensity (15.56 ± 0.15)%. Second, the "1"1"3In(n,γ)"1"1"4"mIn reaction rate may be measured by using one activation detector simultaneously with the "1"1"5In(n,γ)"1"1"6"mIn reaction. Preliminary analysis of existing evaluated excitation functions for "2"8Si(n,p)"2"8Al, "3"1P(n,p)"3"1Si and "1"1"3In(n,γ)"1"1"4"mIn reactions show that new evaluations are needed for all above mentioned reactions. This report is devoted to the preparation of the new evaluations of cross sections data and related covariance matrixes of uncertainties for the "2"8Si(n,p)"2"8Al, "3"1P(n,p)"3"1Si and "1"1"3In(n,γ)"1"1"4"mIn reactions.

Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Science.gov (United States)

Egawa, Junji; Schilling, Jan M; Cui, Weihua; Posadas, Edmund; Sawada, Atsushi; Alas, Basheer; Zemljic-Harpf, Alice E; Fannon-Pavlich, McKenzie J; Mandyam, Chitra D; Roth, David M; Patel, Hemal H; Patel, Piyush M; Head, Brian P

2017-08-01

Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1-overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma-associated maladaptive plasticity.-Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. © FASEB.

Dopamine D1 receptor activation maintains motor coordination and balance in rats.

Science.gov (United States)

Avila-Luna, Alberto; Gálvez-Rosas, Arturo; Durand-Rivera, Alfredo; Ramos-Languren, Laura-Elisa; Ríos, Camilo; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

2018-02-01

Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D 1 receptors (D 1 Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D 1 Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D 1 R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D 1 R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D 1 R agonist to prevent and reverse the effect of the D 1 R antagonist in beam-walking scores is an indicator that the function of D 1 Rs is necessary to maintain motor coordination and balance in rats. Our results support that D 1 Rs mediate the SCH-23390-induced deficit in motor coordination.

Aging Management Guideline for commercial nuclear power plants: Motor control centers

International Nuclear Information System (INIS)

Toman, G.; Gazdzinski, R.; O'Hearn, E.

1994-02-01

This Aging Management Guideline (AMG) provides recommended methods for effective detection and mitigation of age-related degradation mechanisms in Boiling Water Reactor (BWR) and Pressurized Water Reactor (PWR) commercial nuclear power plant motor control centers important to license renewal. The intent of this AMG is to assist plant maintenance and operations personnel in maximizing the safe, useful life of these components. It also supports the documentation of effective aging management programs required under the License Renewal Rule 10 CFR Part 54. This AMG is presented in a manner that allows personnel responsible for performance analysis and maintenance to compare their plant-specific aging mechanisms (expected or already experienced) and aging management program activities to the more generic results and recommendations presented herein

Desempenho motor de lactentes frequentadores de berçários em creches públicas Motor performance of infants attending the nurseries of public day care centers

Directory of Open Access Journals (Sweden)

Letícia Baltieri

2010-09-01

Full Text Available OBJETIVO: Analisar o desempenho motor axial, apendicular e global e sua correlação com as características neonatais, familiares e de tempo de exposição à creche em crianças com idade entre 12-24 meses, frequentadoras de creches públicas. MÉTODOS: Estudo transversal com 40 lactentes (idade média 14,3±2,4 meses frequentadores de creches públicas. Os participantes foram avaliados quanto ao desempenho motor com a Bayley Scales of Infant and Toddler Development-III, a qual possibilita análise do desempenho motor e comparação dos domínios motores axial e apendicular. Foram coletados dados neonatais, familiares e de exposição à creche e pesquisou-se a correlação destes fatores ao desempenho motor. Foi utilizado o teste t pareado para comparar médias e a correlação de Pearson. RESULTADOS: O desempenho motor do grupo esteve, em média, abaixo da referência, com 22,5% das crianças classificadas como suspeitas de atraso nos desempenhos axial e global, contrastando com nenhuma no domínio apendicular. A comparação axial e apendicular apontou diferença significativa, com desempenho axial aquém do apendicular, além de 35% do grupo ter apresentado discrepância significativa entre esses domínios. Não foi encontrada correlação linear entre os domínios motores avaliados e as variáveis neonatais, familiares e de exposição à creche. CONCLUSÕES: O desempenho motor global do grupo esteve abaixo da média de referência, com desempenho motor axial inferior ao apendicular e importante discrepância entre esses. Recomenda-se atenção às habilidades motoras axiais e às oportunidades de exploração que o ambiente em creches pode propiciar, especialmente no decorrer dos dois primeiros anos de vida.OBJECTIVE: To analyze gross, fine and global motor performance and its correlation with neonatal and familial variables and day care exposure among children between 12-24 months of age attending public day care centers. METHODS: This

IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice.

Science.gov (United States)

Tsai, Li-Kai; Chen, Yi-Chun; Cheng, Wei-Cheng; Ting, Chen-Hung; Dodge, James C; Hwu, Wuh-Liang; Cheng, Seng H; Passini, Marco A

2012-01-01

The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2 months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8 months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA. Copyright © 2011 Elsevier Inc. All rights reserved.

The nuclear receptor Tlx regulates motor, cognitive and anxiety-related behaviours during adolescence and adulthood.

Science.gov (United States)

O'Leary, James D; Kozareva, Danka A; Hueston, Cara M; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

2016-06-01

The nuclear receptor Tlx is a key regulator of embryonic and adult hippocampal neurogenesis and has been genetically linked to bipolar disorder. Mice lacking Tlx (Nr2e1(-/-)) display deficits in adult hippocampal neurogenesis and behavioural abnormalities. However, whether Tlx regulates behaviour during adolescence or in a sex-dependent manner remains unexplored. Therefore, we investigated the role of Tlx in a series of behavioural tasks in adolescent male and female mice with a spontaneous deletion of Tlx (Nr2e1(-/-) mice). Testing commenced at adolescence (postnatal day 28) and continued until adulthood (postnatal day 67). Adolescent male and female Nr2e1(-/-) mice were hyperactive in an open field, an effect that persisted in adulthood. Male but not female Nr2e1(-/-) mice exhibited reduced thigmotaxis during adolescence and adulthood. Impairments in rotarod motor performance developed in male and female Nr2e1(-/-) mice at the onset of adulthood. Spontaneous alternation in the Y-maze, a hippocampus-dependent task, was impaired in adolescent but not adult male and female Nr2e1(-/-) mice. Contextual fear conditioning was impaired in adolescent male Nr2e1(-/-) mice only, but both male and female adolescent Nr2e1(-/-) mice showed impaired cued fear conditioning, a hippocampal-amygdala dependent cognitive process. These deficits persisted into adulthood in males but not females. In conclusion, deletion of Tlx impairs motor, cognitive and anxiety-related behaviours during adolescence and adulthood in male and female mice with most effects occurring during adolescence rather than adulthood, independent of housing conditions. This suggests that Tlx has functions beyond regulation of adult hippocampal neurogenesis, and may be an important target in understanding neurobiological disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Motor development skills of 1- to 4-year-old Iranian children with early treated phenylketonuria.

Science.gov (United States)

Nazi, Sepideh; Rohani, Farzaneh; Sajedi, Firoozeh; Biglarian, Akbar; Setoodeh, Arya

2014-01-01

Objective : To gauge the gross and fine motor development of early treated phenylketonuria (ETPKU) in children in the age range of 1-4 years. Methods : A cross-sectional analytic study was conducted in PKU clinics (reference clinics for PKU follow-up), Tehran, Iran. Seventy children with ETPKU were selected as the case group for the study. ETPKU children were those with early and continuous treatment with a phenylalanine-restricted diet (the mean of blood phenylalanine level during the recent 6 months was 2-6 mg/dL or 120-360 μmol/L). Also, 100 healthy and normal children matched with the ETPKU group for age were randomly selected from 4 kindergartens in four parts of Tehran as a control group. The measurements consisted of a demographic questionnaire, Peabody Developmental Motor Scale-2 (PDMS-2), and pediatrician assessment. Motor quotients were determined by PDMS-2 and then compared in both groups by two independent samples t-test. Results : The mean ages in case and control group were 28.5 (± 11.6) and 29.7 (± 11.3) months, respectively. Comparison of the mean fine, gross, and total developmental motor quotients (DMQs) showed statistically significant differences between the two groups (p fine and total DMQs of ETPKU children were also correlated with age. In addition, there was a negative correlation between the phenylalanine level and fine (p motor development. It is recommended to plan programs for early detection and intervention of developmental delays in these children.

Progression of motor axon dysfunction and ectopic Na(v)1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

DEFF Research Database (Denmark)

Rosberg, Mette R.; Alvarez Herrero, Susana; Klein, Dennis

2016-01-01

Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months...... pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing...

RELIABILITAS DAN FEASIBILITAS PENGGUNAAN KARTU MENUJU SEHAT PERKEMBANGAN (KMS-P MOTOR MILESTONE ANAK UMUR 3-18 BULAN DI PUSKESMAS DAN POSYANDU

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Yayah K. Husaini

2012-11-01

Full Text Available RELIABILITAS DAN FEASIBILITAS PENGGUNAAN KARTU MENUJU SEHAT PERKEMBANGAN (KMS-P MOTOR MILESTONE ANAK UMUR 3-18 BULAN DI PUSKESMAS DAN POSYANDU.Background: To monitor growth and development of a child could use the Road to the Health Card of Under Five (KMS-Balita for growth and Road to the Health Card of Motor Development (KMS-Perkembangan for development. The KMS-Perkembangan (KMS-P has been developed based on a scientific research design following the WHO-procedure for the development of a reference. In order the KMS-P could be used at Posyandu and/or at Puskesmas, it needs to be examined the reability and the feasibility in the field condition.Objectives: To examine the reliability and the feasibility of using KMS-P for children aged 3-18 months underfield condition.Methods: The study was carried out in Bogor City and Sukabumi District A total of 10 Puskesmas and 74 Pusyandu located in 19 villages were included as the study sites. The crossectional study designed was implemented, and 872 mothers and their children aged 3-18 months, 75 village cadres and 37 health providers were included as the sample studied. Data on general characteristics and motor milestones, reability and feasibility of using the KMS-P included plotting, its interpretation, and evaluating the child motor development were collected.Results: The study reveals that under field condition, 100% of health providers, 74.7% of village cadres and 77.56% mothers of the children studied could use the KMS-P property. The KMS-P has been developed simple, practicable, and action oriented.Conclusions: The reliability and feasilility of using KMS-P under field condition is highly acceptable. The prospect of KMS-P is very encouraging.Keywords: reliability, feasibility, motor milestone, motor development.

Measurement of the nuclear modification factor for high-$p_\\mathrm{T}$ charged hadrons in p+Pb collisions with the ATLAS detector

CERN Document Server

Balek, Petr; The ATLAS collaboration

2016-01-01

The charged hadron spectra in p+Pb and pp collisions at $\\sqrt{s}=5.02$TeV are measured with the ATLAS experiment at the LHC. The measurements are performed with p+Pb data recorded in 2013 with an integrated luminosity of 25nb${}^{-1}$ and pp data recorded in 2015 with an integrated luminosity of 28pb${}^{-1}$. The p+Pb results are directly compared to pp spectra, as a ratio scaled by the number of binary nucleon-nucleon collisions, the nuclear modification factor $R_\\mathrm{pPb}$. The study of $R_\\mathrm{pPb}$ allows a detailed comparison of the collision systems in different centrality intervals and up to high transverse momentum. It is shown that the nuclear modification factor does not have any significant deviation from unity in the high transverse momentum region.

Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder?

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Haas-Lude, Karin; Heimgärtner, Magdalena; Winter, Sarah; Mautner, Victor-Felix; Krägeloh-Mann, Ingeborg; Lidzba, Karen

2018-01-01

Attention deficit and compromised motor skills are both prevalent in Neurofibromatosis type 1 (NF1), but the relationship is unclear. We investigated motor function in children with NF1 and in children with Attention Deficit/Hyperactivity Disorder (ADHD), and explored if, in patients with NF1, attention deficit influences motor performance. Motor performance was measured using the Movement Assessment Battery for Children (M-ABC) in 71 children (26 with NF1 plus ADHD, 14 with NF1 without ADHD, and 31 with ADHD without NF1) aged 6-12 years. There was a significant effect of group on motor performance. Both NF1 groups scored below children with ADHD without NF1. Attention performance mediated motor performance in children with ADHD without NF1, but not in children with NF1. Motor function is not mediated by attention performance in children with NF1. While in ADHD, attention deficit influences motor performance, motor problems in NF1 seem to be independent from attention deficit. This argues for different pathomechanisms in these two groups of developmental disorders. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Anti-Inflammatory Effect of ETAS®50 by Inhibiting Nuclear Factor-κB p65 Nuclear Import in Ultraviolet-B-Irradiated Normal Human Dermal Fibroblasts

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Ken Shirato

2018-01-01

Full Text Available Ultraviolet (UV irradiation induces proinflammatory responses in skin cells, including dermal fibroblasts, accelerating premature skin aging (photoaging. ETAS 50, a standardized extract from the Asparagus officinalis stem, is a novel and unique functional food that suppresses proinflammatory responses of hydrogen peroxide-stimulated skin fibroblasts and interleukin- (IL- 1β-stimulated hepatocytes. To elucidate its antiphotoaging potencies, we examined whether ETAS 50 treatment after UV-B irradiation attenuates proinflammatory responses of normal human dermal fibroblasts (NHDFs. UV-B-irradiated NHDFs showed reduced levels of the cytosolic inhibitor of nuclear factor-κB α (IκBα protein and increased levels of nuclear p65 protein. The nuclear factor-κB nuclear translocation inhibitor JSH-23 abolished UV-B irradiation-induced IL-1β mRNA expression, indicating that p65 regulates transcriptional induction. ETAS 50 also markedly suppressed UV-B irradiation-induced increases in IL-1β mRNA levels. Immunofluorescence analysis revealed that ETAS 50 retained p65 in the cytosol after UV-B irradiation. Western blotting also showed that ETAS 50 suppressed the UV-B irradiation-induced increases in nuclear p65 protein. Moreover, ETAS 50 clearly suppressed UV-B irradiation-induced distribution of importin-α protein levels in the nucleus without recovering cytosolic IκBα protein levels. These results suggest that ETAS 50 exerts anti-inflammatory effects on UV-B-irradiated NHDFs by suppressing the nuclear import machinery of p65. Therefore, ETAS 50 may prevent photoaging by suppressing UV irradiation-induced proinflammatory responses of dermal fibroblasts.

Complex formation of p65/RelA with nuclear Akt1 for enhanced transcriptional activation of NF-κB

International Nuclear Information System (INIS)

Kwon, Osong; Kim, Kyung A; He, Long; Jung, Mira; Jeong, Sook Jung; Ahn, Jong Seog; Kim, Bo Yeon

2008-01-01

Akt1 was revealed to interact with Ki-Ras in the cytoplasm of Ki-Ras-transformed human prostate epithelial cells, 267B1/K-ras. Moreover, p65/RelA in the nucleus was found to interact with both Ki-Ras and Akt1, suggesting the nuclear translocation of Akt1:Ki-Ras complex for NF- κB activation. In support of this, compared with wild type Akt1, the dominant negative Akt1 mutant was decreased in its nuclear expression, reducing the Ki-Ras-induced NF-κB transcriptional activation. Moreover, inhibitors of Ras (sulindac sulfide and farnesyltransferase inhibitor I) or PI3K/Akt (wortmannin), reduced the amounts of Akt1 and Ki-Ras in the nucleus as well as partial NF-κB activity. The complete inhibition of Ki-Ras-induced NF-κB activation, however, could only be obtained by combined treatment with wortmannin and proteasome inhibitor-1. Accordingly, clonogenic assay showed Akt1 contribution to IκBα-mediated NF-κB activation for oncogenic cell growth by Ki-Ras. Our data suggest a crucial role of Ki-Ras:Akt1 complex in NF-κB transcriptional activation and enhancement of cell survival

JNK1 Controls Dendritic Field Size in L2/3 and L5 of the Motor Cortex, Constrains Soma Size and Influences Fine Motor Coordination

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Emilia eKomulainen

2014-09-01

Full Text Available Genetic anomalies on the JNK pathway confer susceptibility to autism spectrum disorders, schizophrenia and intellectual disability. The mechanism whereby a gain or loss of function in JNK signaling predisposes to these prevalent dendrite disorders, with associated motor dysfunction, remains unclear. Here we find that JNK1 regulates the dendritic field of L2/3 and L5 pyramidal neurons of the mouse motor cortex (M1, the main excitatory pathway controlling voluntary movement. In Jnk1-/- mice, basal dendrite branching of L5 pyramidal neurons is increased in M1, as is cell soma size, whereas in L2/3, dendritic arborization is decreased. We show that JNK1 phosphorylates rat HMW-MAP2 on T1619, T1622 and T1625 (Uniprot P15146 corresponding to mouse T1617, T1620, T1623, to create a binding motif, that is critical for MAP2 interaction with and stabilization of microtubules, and dendrite growth control. Targeted expression in M1 of GFP-HMW-MAP2 that is pseudo-phosphorylated on T1619, T1622 and T1625 increases dendrite complexity in L2/3 indicating that JNK1 phosphorylation of HMW-MAP2 regulates the dendritic field. Consistent with the morphological changes observed in L2/3 and L5, Jnk1-/- mice exhibit deficits in limb placement and motor coordination, while stride length is reduced in older animals. In summary, JNK1 phosphorylates HMW-MAP2 to increase its stabilization of microtubules while at the same time controlling dendritic fields in the main excitatory pathway of M1. Moreover, JNK1 contributes to normal functioning of fine motor coordination. We report for the first time, a quantitative sholl analysis of dendrite architecture, and of motor behavior in Jnk1-/- mice. Our results illustrate the molecular and behavioral consequences of interrupted JNK1 signaling and provide new ground for mechanistic understanding of those prevalent neuropyschiatric disorders where genetic disruption of the JNK pathway is central.

Motor Skill Competence and Perceived Motor Competence: Which Best Predicts Physical Activity among Girls?

Science.gov (United States)

Khodaverdi, Zeinab; Bahram, Abbas; Khalaji, Hassan; Kazemnejad, Anoshirvan

2013-10-01

The main purpose of this study was to determine which correlate, perceived motor competence or motor skill competence, best predicts girls' physical activity behavior. A sample of 352 girls (mean age=8.7, SD=0.3 yr) participated in this study. To assess motor skill competence and perceived motor competence, each child completed the Test of Gross Motor Development-2 and Physical Ability sub-scale of Marsh's Self-Description Questionnaire. Children's physical activity was assessed by the Physical Activity Questionnaire for Older Children. Multiple linear regression model was used to determine whether perceived motor competence or motor skill competence best predicts moderate-to-vigorous self-report physical activity. Multiple regression analysis indicated that motor skill competence and perceived motor competence predicted 21% variance in physical activity (R(2)=0.21, F=48.9, P=0.001), and motor skill competence (R(2)=0.15, ᵝ=0.33, P= 0.001) resulted in more variance than perceived motor competence (R(2)=0.06, ᵝ=0.25, P=0.001) in physical activity. Results revealed motor skill competence had more influence in comparison with perceived motor competence on physical activity level. We suggest interventional programs based on motor skill competence and perceived motor competence should be administered or implemented to promote physical activity in young girls.

Nuclear Transparency with the gamma + n -> pi- + p Process in 4He

International Nuclear Information System (INIS)

Dipangkar Dutta; Feng Xiong; Lingyan Zhu; John Arrington; Todd Averett; Elizabeth Beise; John Calarco; Ting Chang; Jian-Ping Chen; Eugene Chudakov; Marius Coman; Benjamin Clasie; Christopher Crawford; Sonja Dieterich; Frank Dohrmann; Kevin Fissum; Salvatore Frullani; Haiyan Gao; Ronald Gilman; Charles Glashausser; Javier Gomez; Kawtar Hafidi; Jens-Ole Hansen; Douglas Higinbotham; Holt, R.J.; Cornelis De Jager; Xiaochao Zheng; Jiang, X.; Edward Kinney; Kevin Kramer; Gerfried Kumbartzki; John LeRose; Nilanga Liyanage; David Mack; Pete Markowitz; Kathy McCormick; Zein-Eddine Meziani; Robert Michaels; Mitchell, J.; Sirish Nanda; David Potterveld; Ronald Ransome; Paul Reimer; Bodo Reitz; Arunava Saha; Elaine Schulte; Charles Seely; Simon Sirca; Steffen Strauch; Vincent Sulkosky; Branislav Vlahovic; Lawrence Weinstein; Krishni Wijesooriya; Claude Williamson; Bogdan Wojtsekhowski; Hong XIANG; Wang Xu; Zeng, J.

2003-01-01

We have measured the nuclear transparency of the fundamental process γ n → π - p in 4 He. These measurements were performed at Jefferson Lab in the photon energy range of 1.6 to 4.5 GeV and at θ cm π = 70 o and 90 o . These measurements are the first of their kind in the study of nuclear transparency in photoreactions. They also provide a benchmark test of Glauber calculations based on traditional models of nuclear physics. The transparency results suggest deviations from the traditional nuclear physics picture. The momentum transfer dependence of the measured nuclear transparency is consistent with Glauber calculations which include the quantum chromodynamics phenomenon of color transparency

Motor Development Skills of 1- to 4-Year-Old Iranian Children with Early Treated Phenylketonuria

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Firouzeh Sajedi

2014-03-01

Full Text Available Objective: To gauge the gross and fine motor development of early treated phenylketonuria (ETPKU in children in the age range of 1–4 years. Materials & Methods: A cross-sectional analytic study was conducted in PKU clinics (reference clinics for PKU follow-up, Tehran, Iran. Seventy children with ETPKU were selected as the case group for the study. ETPKU children were those with early and continuous treatment with a phenylalaninerestricted diet (the mean of blood phenylalanine level during the recent 6 months was 2–6 mg/dL or 120–360 mmol/L. Also, 100 healthy and normal children matched with the ETPKU group for age were randomly selected from 4 kindergartens in four parts of Tehran as a control group. The measurements consisted of a demographic questionnaire, Peabody Developmental Motor Scale-2 (PDMS-2, and pediatrician assessment. Motor quotients were determined by PDMS-2 and then compared in both groups by two independent samples t-test. Results: The mean ages in case and control group were 28.5 (±11.6 and 29.7 (±11.3 months, respectively. Comparison of the mean fine, gross, and total developmental motor quotients (DMQs showed statistically significant differences between the two groups (P<0.05. The fine and total DMQs of ETPKU children were also correlated with age. In addition, there was a negative correlation between the phenylalanine level and fine (P<0.001 and total (P=0.001 DMQs. Conclusion: It seems that ETPKU Iranian children, regardless of following a phenylalanine-restricted diet or not, have lower motor development. It is recommended to plan programs for early detection and intervention of developmental delays in these children.

Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells

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Li, Ju; Han, Suhyoun; Cousin, Wendy; Conboy, Irina M.

2014-01-01

The regenerative capacity of muscle dramatically decreases with age because old muscle stem cells fail to proliferate in response to tissue damage. Here we uncover key age-specific differences underlying this proliferative decline: namely, the genetic loci of CDK inhibitors (CDKI) p21 and p16 are more epigenetically silenced in young muscle stem cells, as compared to old, both in quiescent cells and those responding to tissue injury. Interestingly, phosphorylated ERK (pERK) induced in these cells by ectopic FGF-2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells FGF-2/pERK silences p21 epigenetically and transcriptionally, which leads to reduced p21 protein levels and enhanced cell proliferation. In agreement with the epigenetic silencing of the loci, young muscle stem cells do not depend as much as old on ectopic FGF/pERK for their myogenic proliferation. In addition, other CDKIs, such asp15INK4B and p27KIP1, become elevated in satellite cells with age, confirming and explaining the profound regenerative defect of old muscle. This work enhances our understanding of tissue aging, promoting strategies for combating age-imposed tissue degeneration. PMID:25447026

APRENDIZAJE MOTOR Y SÍNDROME GENERAL DE ADAPTACIÓN

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F. J. Moreno

2010-09-01

Full Text Available <p> 

Genetically encoded pH-indicators reveal activity-dependent cytosolic acidification of Drosophila motor nerve termini in vivo

Science.gov (United States)

Rossano, Adam J; Chouhan, Amit K; Macleod, Gregory T

2013-01-01

All biochemical processes, including those underlying synaptic function and plasticity, are pH sensitive. Cytosolic pH (pHcyto) shifts are known to accompany nerve activity in situ, but technological limitations have prevented characterization of such shifts in vivo. Genetically encoded pH-indicators (GEpHIs) allow for tissue-specific in vivo measurement of pH. We expressed three different GEpHIs in the cytosol of Drosophila larval motor neurons and observed substantial presynaptic acidification in nerve termini during nerve stimulation in situ. SuperEcliptic pHluorin was the most useful GEpHI for studying pHcyto shifts in this model system. We determined the resting pH of the nerve terminal cytosol to be 7.30 ± 0.02, and observed a decrease of 0.16 ± 0.01 pH units when the axon was stimulated at 40 Hz for 4 s. Realkalinization occurred upon cessation of stimulation with a time course of 20.54 ± 1.05 s (τ). The chemical pH-indicator 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein corroborated these changes in pHcyto. Bicarbonate-derived buffering did not contribute to buffering of acid loads from short (≤4 s) trains of action potentials but did buffer slow (∼60 s) acid loads. The magnitude of cytosolic acid transients correlated with cytosolic Ca2+ increase upon stimulation, and partial inhibition of the plasma membrane Ca2+-ATPase, a Ca2+/H+ exchanger, attenuated pHcyto shifts. Repeated stimulus trains mimicking motor patterns generated greater cytosolic acidification (∼0.30 pH units). Imaging through the cuticle of intact larvae revealed spontaneous pHcyto shifts in presynaptic termini in vivo, similar to those seen in situ during fictive locomotion, indicating that presynaptic pHcyto shifts cannot be dismissed as artifacts of ex vivo preparations. PMID:23401611

Loss analysis of a 1 MW class HTS synchronous motor

International Nuclear Information System (INIS)

Baik, S K; Kwon, Y K; Kim, H M; Lee, J D; Kim, Y C; Park, H J; Kwon, W S; Park, G S

2009-01-01

The HTS (High-Temperature Superconducting) synchronous motor has advantages over the conventional synchronous motor such as smaller size and higher efficiency. Higher efficiency is due to smaller loss than the conventional motor, so it is important to do loss analysis in order to develop a machine with higher efficiency. This paper deals with machine losses those are dissipated in each part of a HTS synchronous motor. These losses are analyzed theoretically and compared with loss data obtained from experimental results of a 1 MW class HTS synchronous motor. Each machine loss is measured based on IEEE 115 standard and the results are analyzed and considered based on the manufacturing of the test machine.

Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia.

Science.gov (United States)

Kim, Yong-Sik; Harry, G Jean; Kang, Hong Soon; Goulding, David; Wine, Rob N; Kissling, Grace E; Liao, Grace; Jetten, Anton M

2010-09-01

Previously, deficiency in the expression of the nuclear orphan receptor TAK1 was found to be associated with delayed cerebellar granule cell migration and Purkinje cell maturation with a permanent deficit in foliation of lobules VI–VII, suggesting a role for TAK1 in cerebellum development. In this study, we confirm that TAK1-deficient (TAK1(−/−)) mice have a smaller cerebellum and exhibit a disruption of lobules VI–VII. We extended these studies and show that at postnatal day 7, TAK1(−/−) mice exhibit a delay in monolayer maturation of dysmorphic calbindin 28K-positive Purkinje cells. The astrocyte-specific glutamate transporter (GLAST) was expressed within Bergmann fibers and internal granule cell layer at significantly lower levels in the cerebellum of TAK1(−/−) mice. At PND21, Golgi-positive Purkinje cells in TAK1(−/−) mice displayed a smaller soma (18%) and shorter distance to first branch point (35%). Neuronal death was not observed in TAK1(−/−) mice at PND21; however, activated microglia were present in the cerebellum, suggestive of earlier cell death. These structural deficits in the cerebellum were not sufficient to alter motor strength, coordination, or activity levels; however, deficits in acoustic startle response, prepulse startle inhibition, and social interactions were observed. Reactions to a novel environment were inhibited in a light/dark chamber, open-field, and home-cage running wheel. TAK1(−/−) mice displayed a plateau in performance on the running wheel, suggesting a deficit in learning to coordinate performance on a motor task. These data indicate that TAK1 is an important transcriptional modulator of cerebellar development and neurodevelopmentally regulated behavior.

Early hypersynchrony in juvenile PINK1-/- motor cortex is rescued by antidromic stimulation

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Romain eCARRON

2014-05-01

Full Text Available In Parkinson’s disease, cortical networks show enhanced synchronized activity but whether this precedes motor signs is unknown. We investigated this question in PINK1-/- mice, a genetic rodent model of the PARK6 variant of familial Parkinson’s disease which shows impaired spontaneous locomotion at 16 months. We used two-photon calcium imaging and whole-cell patch clamp in slices from juvenile (P14-P21 wild-type or PINK1-/- mice. We designed a horizontal tilted cortico-subthalamic slice where the only connection between cortex and subthalamic nucleus (STN is the hyperdirect cortico-subthalamic pathway. We report excessive correlation and synchronization in PINK1-/- M1 cortical networks 15 months before motor impairment. The percentage of correlated pairs of neurons and their strength of correlation were higher in the PINK1-/- M1 than in the wild type network and the synchronized network events involved a higher percentage of neurons. Both features were independent of thalamo-cortical pathways, insensitive to chronic levodopa treatment of pups, but totally reversed by antidromic invasion of M1 pyramidal neurons by axonal spikes evoked by high frequency stimulation (HFS of the STN. Our study describes an early excess of synchronization in the PINK1-/- cortex and suggests a potential role of antidromic activation of cortical interneurons in network desynchronization. Such backward effect on interneurons activity may be of importance for HFS-induced network desynchronization.

Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression.

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Heidi Loponen

Full Text Available 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.

Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression.

Science.gov (United States)

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.

The relationship between CA repeat polymorphism of the IGF-1 gene and the structure of motor skills in young athletes.

Science.gov (United States)

Karpowicz, Krzysztof; Krych, Katarzyna; Karpowicz, Małgorzata; Nowak, Witold; Gronek, Piotr

2018-01-01

The map of candidate genes that can potentially affect physical fitness becomes larger every year, and they are associated with such aspects as respiratory and cardiovascular stability; body build and composition - especially muscle mass and strength; carbohydrate and lipid metabolism; response to training; and exercise intolerance.The aim of this study was to analyze the relationship between the CA repeat polymorphism of the P1 promoter of the IGF1 gene and the structure of motor skills in the two groups of Polish young athletes in 2007-2009. In this study, 350 young sportsmen representing different sports disciplines were examined (age = 15.5 ± 0.5 years), by genotyping the IGF1 gene and determining the structure of motor skills using the International Physical Fitness Test (IPFT) battery. The multiple stepwise regression was used to determine the impact of the investigated motor skills on the indicator of the overall physical fitness, measured by the total score of the International Physical Fitness Test (IPFT). The analysis showed some regularity related to the character of the IGF1 gene polymorphism. It can be concluded that the two groups of young boys athletes practicing various sports disciplines (kinds of physical exercise) displayed similar associations between CA repeat polymorphism of the P1 promoter of the IGF1 gene and the level of motor effects. Our results suggest that this polymorphism may be a genetic marker of the physical performance phenotype. We demonstrated that CA repeat polymorphism of the P1 promoter of the IGF1 gene was associated with strength predispositions in the homozygous and non-carriers groups. In the group who were heterozygous it was speed-strength aptitudes.

Motor unit recruitment in human biceps brachii during sustained voluntary contractions.

Science.gov (United States)

Riley, Zachary A; Maerz, Adam H; Litsey, Jane C; Enoka, Roger M

2008-04-15

The purpose of the study was to examine the influence of the difference between the recruitment threshold of a motor unit and the target force of the sustained contraction on the discharge of the motor unit at recruitment. The discharge characteristics of 53 motor units in biceps brachii were recorded after being recruited during a sustained contraction. Some motor units (n = 22) discharged action potentials tonically after being recruited, whereas others (n = 31) discharged intermittent trains of action potentials. The two groups of motor units were distinguished by the difference between the recruitment threshold of the motor unit and the target force for the sustained contraction: tonic, 5.9 +/- 2.5%; intermittent, 10.7 +/- 2.9%. Discharge rate for the tonic units decreased progressively (13.9 +/- 2.7 to 11.7 +/- 2.6 pulses s(-1); P = 0.04) during the 99 +/- 111 s contraction. Train rate, train duration and average discharge rate for the intermittent motor units did not change across 211 +/- 153 s of intermittent discharge. The initial discharge rate at recruitment during the sustained contraction was lower for the intermittent motor units (11.0 +/- 3.3 pulses s(-1)) than the tonic motor units (13.7 +/- 3.3 pulses s(-1); P = 0.005), and the coefficient of variation for interspike interval was higher for the intermittent motor units (34.6 +/- 12.3%) than the tonic motor units (21.2 +/- 9.4%) at recruitment (P = 0.001) and remained elevated for discharge duration (34.6 +/- 9.2% versus 19.1 +/- 11.7%, P motor units were recorded at two different target forces below recruitment threshold (5.7 +/- 1.9% and 10.5 +/- 2.4%). Each motor unit exhibited the two discharge patterns (tonic and intermittent) as observed for the 53 motor units. The results suggest that newly recruited motor units with recruitment thresholds closer to the target force experienced less synaptic noise at the time of recruitment that resulted in them discharging action potentials at more regular

Comparison the Impact of Spark Motor Program and Basketball Techniques on Improving Gross Motor Skills in Educable Intellectually Disabled Boys

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Hashem Faal Moghanlo

2014-09-01

Full Text Available Background & objectives : Different types of practises are known for improving motor skills in intellectually disabled boys. The purpose of this study was to compar e the impact of spark motor program and basketball on improving of gross motor skills in this people.   Methods: In this semi-experimental study , from 98 educable intellectually disabled students who studied in special school in Urmia, 30 children ( age range of 9 to 13 years and IQ mean 64.4 were selected objectively and divided in three groups (2 experimental and 1 control based on pre - test. BOTMP was used as a measurement of motor ability. Selected motor program (Spark motor program including strengthening training, games, sports and basketball techniques was performed for 24 sessions. T-tests (dependent and co-variance were used to comparison of results.   Results: In Spark group after 24 sessions, there were significant effects on balance (p= 0.000, bilateral coordination (p=0.000 and strength (p=0.001. There was no significant effect in agility and speed (p= 0.343 in basketball techniques group after 24 sessions, there were significant effects in agility and speed (p= 0.001, balance (p= 0.000, bilateral coordination (p= 0.013 and strength (p= 0.007.   Conclusion: Based on the results of this study, it can be claimed that the Spark program and basketball techniques improve gross motor skills in educable intellectually disabled students. We also found a significant difference between the Spark program and basketball techniques efficacy on the improved skills. Furthermore, the efficacy of Spark program was significantly higher than basketball techniques (p<0.05.

Motor-operated gearbox efficiency

International Nuclear Information System (INIS)

DeWall, K.G.; Watkins, J.C.; Bramwell, D.; Weidenhamer, G.H.

1996-01-01

Researchers at the Idaho National Engineering Laboratory recently conducted tests investigating the operating efficiency of the power train (gearbox) in motor-operators typically used in nuclear power plants to power motor-operated valves. Actual efficiency ratios were determined from in-line measurements of electric motor torque (input to the operator gearbox) and valve stem torque (output from the gearbox) while the operators were subjected to gradually increasing loads until the electric motor stalled. The testing included parametric studies under reduced voltage and elevated temperature conditions. As part of the analysis of the results, the authors compared efficiency values determined from testing to the values published by the operator manufacturer and typically used by the industry in calculations for estimating motor-operator capabilities. The operators they tested under load ran at efficiencies lower than the running efficiency (typically 50%) published by the operator manufacturer

Motor-operated gearbox efficiency

Energy Technology Data Exchange (ETDEWEB)

DeWall, K.G.; Watkins, J.C.; Bramwell, D. [Idaho National Engineering Lab., Idaho Falls, ID (United States); Weidenhamer, G.H.

1996-12-01

Researchers at the Idaho National Engineering Laboratory recently conducted tests investigating the operating efficiency of the power train (gearbox) in motor-operators typically used in nuclear power plants to power motor-operated valves. Actual efficiency ratios were determined from in-line measurements of electric motor torque (input to the operator gearbox) and valve stem torque (output from the gearbox) while the operators were subjected to gradually increasing loads until the electric motor stalled. The testing included parametric studies under reduced voltage and elevated temperature conditions. As part of the analysis of the results, the authors compared efficiency values determined from testing to the values published by the operator manufacturer and typically used by the industry in calculations for estimating motor-operator capabilities. The operators they tested under load ran at efficiencies lower than the running efficiency (typically 50%) published by the operator manufacturer.

Motor-operator gearbox efficiency

International Nuclear Information System (INIS)

DeWall, K.G.; Watkins, J.C.; Bramwell, D.

1996-01-01

Researchers at the Idaho National Engineering Laboratory recently conducted tests investigating the operating efficiency of the power train (gearbox) in motor-operators typically used in nuclear power plants to power motor-operated valves. Actual efficiency ratios were determined from in-line measurements of electric motor torque (input to the operator gearbox) and valve stem torque (output from the gearbox) while the operators were subjected to gradually increasing loads until the electric motor stalled. The testing included parametric studies under reduced voltage and elevated temperature conditions. As part of the analysis of the results, we compared efficiency values determined from testing to the values published by the operator manufacturer and typically used by the industry in calculations for estimating motor-operator capabilities. The operators we tested under load ran at efficiencies lower than the running efficiency (typically 50%) published by the operator manufacturer

Frequent alteration of MDM2 and p53 in the molecular progression of recurring non-Hodgkin's lymphoma

DEFF Research Database (Denmark)

Møller, Michael Boe; Nielsen, O; Pedersen, Niels Tinggaard

2002-01-01

-Hodgkin's lymphoma. METHODS AND RESULTS: We have analysed sequential biopsies from 42 non-Hodgkin's lymphoma patients immunohistochemically for p53 alterations (based on p53 and p21Waf1 expression), as well as for expression of MDM2, p27Kip1 and cyclin D3. Relapse of follicle centre lymphoma was associated with p53...... alterations as 5/6 (83%) follicle centre lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. Of these cases, three showed transformation to diffuse large B-cell lymphoma. p53 alteration was also associated with relapse of de novo diffuse large B-cell lymphoma and T-cell non......-Hodgkin's lymphoma, as 2/5 (40%) diffuse large B-cell lymphomas and 3/9 (33%) T-cell non-Hodgkin's lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. No indolent non-Hodgkin's lymphoma case showed MDM2 over-expression at diagnosis, whereas 4/5 (80%) transformed diffuse large B-cell lymphomas...

Nuclear IL-33 is a transcriptional regulator of NF-{kappa}B p65 and induces endothelial cell activation

Energy Technology Data Exchange (ETDEWEB)

Choi, Yeon-Sook; Park, Jeong Ae; Kim, Jihye; Rho, Seung-Sik; Park, Hyojin [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Young-Myeong [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon (Korea, Republic of); Kwon, Young-Guen, E-mail: ygkwon@yonsei.ac.kr [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

2012-05-04

Highlights: Black-Right-Pointing-Pointer IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. Black-Right-Pointing-Pointer Nuclear IL-33 increased the transcription of NF-{kappa}B p65 by binding to the p65 promoter. Black-Right-Pointing-Pointer Nuclear IL-33 controls NF-{kappa}B-dependent inflammatory responses. -- Abstract: Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-{kappa}B complex and is involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-{alpha}-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-{kappa}B pathway; NF-{kappa}B p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-{kappa}B p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-{kappa}B p65.

The Epstein-Barr virus nuclear antigen-6 protein co-localizes with EBNA-3 and survival of motor neurons protein

International Nuclear Information System (INIS)

Krauer, Kenia G.; Buck, Marion; Belzer, Deanna K.; Flanagan, James; Chojnowski, Grace M.; Sculley, Tom B.

2004-01-01

The Epstein-Barr virus nuclear antigen (EBNA)-6 protein is essential for Epstein-Barr virus (EBV)-induced immortalization of primary human B-lymphocytes in vitro. In this study, fusion proteins of EBNA-6 with green fluorescent protein (GFP) have been used to characterize its nuclear localization and organization within the nucleus. EBNA-6 associates with nuclear structures and in immunofluorescence demonstrate a punctate staining pattern. Herein, we show that the association of EBNA-6 with these nuclear structures was maintained throughout the cell cycle and with the use of GFP-E6 deletion mutants, that the region amino acids 733-808 of EBNA-6 contains a domain that can influence the association of EBNA-6 with these nuclear structures. Co-immunofluorescence and confocal analyses demonstrated that EBNA-6 and EBNA-3 co-localize in the nucleus of cells. Expression of EBNA-6, but not EBNA-3, caused a redistribution of nuclear survival of motor neurons protein (SMN) to the EBNA-6 containing nuclear structures resulting in co-localization of SMN with EBNA-6

Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation.

Science.gov (United States)

Seven, Yasin B; Perim, Raphael R; Hobson, Orinda R; Simon, Alec K; Tadjalli, Arash; Mitchell, Gordon S

2018-04-15

Although adenosine 2A (A 2A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A 2A receptor siRNA injections. A 2A receptor siRNA injections selectively knocked down A 2A receptors in cholera toxin B-subunit-identified phrenic motor neurons, sparing cervical non-phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A 2A receptors relevant to A 2A receptor-induced phrenic motor facilitation. Upregulation of A 2A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A 2A receptors for pMF are unknown. This is an important question since the physiological outcome of A 2A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A 2A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A 2A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 ± 2%). Intrapleural siRNA injections were used to selectively knock down A 2A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A 2A receptor knock-down was verified by a ∼45% decrease in A 2A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, p

Human Cytomegalovirus Nuclear Capsids Associate with the Core Nuclear Egress Complex and the Viral Protein Kinase pUL97.

Science.gov (United States)

Milbradt, Jens; Sonntag, Eric; Wagner, Sabrina; Strojan, Hanife; Wangen, Christina; Lenac Rovis, Tihana; Lisnic, Berislav; Jonjic, Stipan; Sticht, Heinrich; Britt, William J; Schlötzer-Schrehardt, Ursula; Marschall, Manfred

2018-01-13

The nuclear phase of herpesvirus replication is regulated through the formation of regulatory multi-component protein complexes. Viral genomic replication is followed by nuclear capsid assembly, DNA encapsidation and nuclear egress. The latter has been studied intensely pointing to the formation of a viral core nuclear egress complex (NEC) that recruits a multimeric assembly of viral and cellular factors for the reorganization of the nuclear envelope. To date, the mechanism of the association of human cytomegalovirus (HCMV) capsids with the NEC, which in turn initiates the specific steps of nuclear capsid budding, remains undefined. Here, we provide electron microscopy-based data demonstrating the association of both nuclear capsids and NEC proteins at nuclear lamina budding sites. Specifically, immunogold labelling of the core NEC constituent pUL53 and NEC-associated viral kinase pUL97 suggested an intranuclear NEC-capsid interaction. Staining patterns with phospho-specific lamin A/C antibodies are compatible with earlier postulates of targeted capsid egress at lamina-depleted areas. Important data were provided by co-immunoprecipitation and in vitro kinase analyses using lysates from HCMV-infected cells, nuclear fractions, or infectious virions. Data strongly suggest that nuclear capsids interact with pUL53 and pUL97. Combined, the findings support a refined concept of HCMV nuclear trafficking and NEC-capsid interaction.

Human Cytomegalovirus Nuclear Capsids Associate with the Core Nuclear Egress Complex and the Viral Protein Kinase pUL97

Directory of Open Access Journals (Sweden)

Jens Milbradt

2018-01-01

Full Text Available The nuclear phase of herpesvirus replication is regulated through the formation of regulatory multi-component protein complexes. Viral genomic replication is followed by nuclear capsid assembly, DNA encapsidation and nuclear egress. The latter has been studied intensely pointing to the formation of a viral core nuclear egress complex (NEC that recruits a multimeric assembly of viral and cellular factors for the reorganization of the nuclear envelope. To date, the mechanism of the association of human cytomegalovirus (HCMV capsids with the NEC, which in turn initiates the specific steps of nuclear capsid budding, remains undefined. Here, we provide electron microscopy-based data demonstrating the association of both nuclear capsids and NEC proteins at nuclear lamina budding sites. Specifically, immunogold labelling of the core NEC constituent pUL53 and NEC-associated viral kinase pUL97 suggested an intranuclear NEC-capsid interaction. Staining patterns with phospho-specific lamin A/C antibodies are compatible with earlier postulates of targeted capsid egress at lamina-depleted areas. Important data were provided by co-immunoprecipitation and in vitro kinase analyses using lysates from HCMV-infected cells, nuclear fractions, or infectious virions. Data strongly suggest that nuclear capsids interact with pUL53 and pUL97. Combined, the findings support a refined concept of HCMV nuclear trafficking and NEC-capsid interaction.

Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior

Directory of Open Access Journals (Sweden)

Toru eNakamura

2014-07-01

Full Text Available Both D1R and D2R knock out (KO mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT mice. First, we examined spontaneous motor activity in the home cage environment for consecutive five days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT

Development of a field pole of 1 MW-class HTS motor

International Nuclear Information System (INIS)

Yuan, S; Kimura, Y; Miki, M; Felder, B; Tsuzuki, K; Izumi, M; Ida, T; Umemoto, K; Aizawa, K; Yokoyama, M

2010-01-01

We report a field-pole high-temperature superconductor (HTS) magnet designed for 1 MW-class motor for propulsion. The field pole is assembled to the rotor of the radial-type motor. Each field pole is composed of HTS-Bi2223 tape wound into coils which have been piled up as a double pancake coils. In the design concept of the motor, we employ field poles without iron core. We prepared the test field-pole coil, whose dimension is smaller than the designed one for 1 MW, and tested its performances after cooling under self-field and external magnetic field. We verified the operation with the minimum bend radius of the coils required in the motor design, while keeping an optimal current which is lower than the critical current of the field-pole coil. The test HTS field poles were successfully cooled down and operated under a magnetic field ranging up to 5 T. We report the results of the test field-pole coil and the manufacture of a practical racetrack coil with Bi2223 and discuss the adaptability to 1 MW-class motors.

Development of a field pole of 1 MW-class HTS motor

Science.gov (United States)

Yuan, S.; Kimura, Y.; Miki, M.; Felder, B.; Tsuzuki, K.; Ida, T.; Izumi, M.; Umemoto, K.; Aizawa, K.; Yokoyama, M.

2010-06-01

We report a field-pole high-temperature superconductor (HTS) magnet designed for 1 MW-class motor for propulsion. The field pole is assembled to the rotor of the radial-type motor. Each field pole is composed of HTS-Bi2223 tape wound into coils which have been piled up as a double pancake coils. In the design concept of the motor, we employ field poles without iron core. We prepared the test field-pole coil, whose dimension is smaller than the designed one for 1 MW, and tested its performances after cooling under self-field and external magnetic field. We verified the operation with the minimum bend radius of the coils required in the motor design, while keeping an optimal current which is lower than the critical current of the field-pole coil. The test HTS field poles were successfully cooled down and operated under a magnetic field ranging up to 5 T. We report the results of the test field-pole coil and the manufacture of a practical racetrack coil with Bi2223 and discuss the adaptability to 1 MW-class motors.

Different effects of antisense RelA p65 and NF-κB1 p50 oligonucleotides on the nuclear factor-κB mediated expression of ICAM-1 in human coronary endothelial and smooth muscle cells

Directory of Open Access Journals (Sweden)

Both Anton

2001-08-01

Full Text Available Abstract Background Activation of nuclear factor-κB (NF-κB is one of the key events in early atherosclerosis and restenosis. We hypothesized that tumor necrosis factor-α (TNF-α induced and NF-κB mediated expression of intercellular adhesion molecule-1 (ICAM-1 can be inhibited by antisense RelA p65 and NF-κB1 p50 oligonucleotides (RelA p65 and NF-κB1 p50. Results Smooth muscle cells (SMC from human coronary plaque material (HCPSMC, plaque material of 52 patients, SMC from the human coronary media (HCMSMC, human endothelial cells (EC from umbilical veins (HUVEC, and human coronary EC (HCAEC were successfully isolated (HCPSMC, HUVEC, identified and cultured (HCPSMC, HCMSMC, HUVEC, HCAEC. 12 hrs prior to TNF-α stimulus (20 ng/mL, 6 hrs RelA p65 and NF-κB1 p50 (1, 2, 4, 10, 20, and 30 μM and controls were added for a period of 18 hrs. In HUVEC and HCAEC there was a dose dependent inhibition of ICAM-1 expression after adding of both RelA p65 and NF-κB1 p50. No inhibitory effect was seen after incubation of HCMSMC with RelA p65 and NF-κB1 p50. A moderate inhibition of ICAM-1 expression was found after simultaneous addition of RelA p65 and NF-κB1 p50 to HCPSMC, no inhibitory effect was detected after individual addition of RelA p65 and NF-κB1 p50. Conclusions The data point out that differences exist in the NF-κB mediated expression of ICAM-1 between EC and SMC. Experimental antisense strategies directed against RelA p65 and NF-κB1 p50 in early atherosclerosis and restenosis are promising in HCAEC but will be confronted with redundant pathways in HCMSMC and HCPSMC.

The stochastic chemomechanics of the F(1)-ATPase molecular motor.

Science.gov (United States)

Gaspard, P; Gerritsma, E

2007-08-21

We report a theoretical study of the F(1)-ATPase molecular rotary motor experimentally studied by R. Yasuda, H. Noji, M. Yoshida, K. Kinosita Jr., H. Itoh [Nature 410 (2001) 898]. The motor is modeled as a stochastic process for the angle of its shaft and the chemical state of its catalytic sites. The stochastic process is ruled by six coupled Fokker-Planck equations for the biased diffusion of the angle and the random jumps between the chemical states. The model reproduces the experimental observations that the motor proceeds by substeps and the rotation rate saturates at high concentrations of adenosine triphosphate or at low values of the friction coefficient. Moreover, predictions are made about the dependence of the rotation rate on temperature, and about the behavior of the F(1) motor under the effect of an external torque, especially, in the regime of synthesis of adenosine triphosphate.

Single to Two Cluster State Transition of Primary Motor Cortex 4-posterior (MI-4p Activities in Humans

Directory of Open Access Journals (Sweden)

Kazunori Nakada

2015-11-01

Full Text Available The human primary motor cortex has dual representation of the digits, namely, area 4 anterior (MI-4a and area 4 posterior (MI-4p. We have previously demonstrated that activation of these two functional subunits can be identified independently by functional magnetic resonance imaging (fMRI using independent component-cross correlation-sequential epoch (ICS analysis. Subsequent studies in patients with hemiparesis due to subcortical lesions and monoparesis due to peripheral nerve injury demonstrated that MI-4p represents the initiation area of activation, whereas MI-4a is the secondarily activated motor cortex requiring a “long-loop” feedback input from secondary motor systems, likely the cerebellum. A dynamic model of hand motion based on the limit cycle oscillator predicts that the specific pattern of entrainment of neural firing may occur by applying appropriate periodic stimuli. Under normal conditions, such entrainment introduces a single phase-cluster. Under pathological conditions where entrainment stimuli have insufficient strength, the phase cluster splits into two clusters. Observable physiological phenomena of this shift from single cluster to two clusters are: doubling of firing rate of output neurons; or decay in group firing density of the system due to dampening of odd harmonics components. While the former is not testable in humans, the latter can be tested by appropriately designed fMRI experiments, the quantitative index of which is believed to reflect group behavior of neurons functionally localized, e.g., firing density in the dynamic theory. Accordingly, we performed dynamic analysis of MI-4p activation in normal volunteers and paretic patients. The results clearly indicated that MI-4p exhibits a transition from a single to a two phase-cluster state which coincided with loss of MI-4a activation. The study demonstrated that motor dysfunction (hemiparesis in patients with a subcortical infarct is not simply due to afferent

The Cell Cycle Inhibitor p27KIP1: A Key of G1 Arrest by Androgen Ablation and by Vitamin D3 Analog

National Research Council Canada - National Science Library

Slingerland, Joyce

2001-01-01

.... Effects of androgens and vDR activation by EB 1089 on p27 function were assayed. We demonstrated that physiologic concentrations of DHT and EB 1089 have synergistic effects to upregulate p27 and inhibit growth of prostate cancer cells...

Recruitment of rat diaphragm motor units across motor behaviors with different levels of diaphragm activation.

Science.gov (United States)

Seven, Yasin B; Mantilla, Carlos B; Sieck, Gary C

2014-12-01

Phrenic motor neurons are recruited across a range of motor behaviors to generate varying levels of diaphragm muscle (DIAm) force. We hypothesized that DIAm motor units are recruited in a fixed order across a range of motor behaviors of varying force levels, consistent with the Henneman Size Principle. Single motor unit action potentials and compound DIAm EMG activities were recorded in anesthetized, neurally intact rats across different motor behaviors, i.e., eupnea, hypoxia-hypercapnia (10% O2 and 5% CO2), deep breaths, sustained airway occlusion, and sneezing. Central drive [estimated by root-mean-squared (RMS) EMG value 75 ms after the onset of EMG activity (RMS75)], recruitment delay, and onset discharge frequencies were similar during eupnea and hypoxia-hypercapnia. Compared with eupnea, central drive increased (∼25%) during deep breaths, and motor units were recruited ∼12 ms earlier (P motor units were recruited ∼30 ms earlier (P motor unit onset discharge frequencies were significantly higher (P Recruitment order of motor unit pairs observed during eupnea was maintained for 98%, 87%, and 84% of the same pairs recorded during hypoxia-hypercapnia, deep breaths, and airway occlusion, respectively. Reversals in motor unit recruitment order were observed primarily if motor unit pairs were recruited motor unit recruitment order being determined primarily by the intrinsic size-dependent electrophysiological properties of phrenic motor neurons. Copyright © 2014 the American Physiological Society.

Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus.

Science.gov (United States)

Strebovsky, Julia; Walker, Patrick; Lang, Roland; Dalpke, Alexander H

2011-03-01

Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytoplasmic Janus kinases (Jak) and signal transducer and activator of transcription (STAT) signaling pathways. Previously the authors surprisingly observed that SOCS1 translocated into the nucleus, which was because of the presence of a nuclear localization sequence. This report now hypothesizes that SOCS1 mediates specific functions within the nuclear compartment because it is instantly transported into the nucleus, as shown by photoactivation and live cell imaging in human HEK293 cells. The NFκB component p65 is identified as an interaction partner for SOCS1 but not for other members of the SOCS family. SOCS1 bound to p65 only within the nucleus. By means of its SOCS box domain, SOCS1 operated as a ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of nuclear p65. Thus, SOCS1 limited prolonged p65 signaling and terminated expression of NFκB inducible genes. Using mutants that lack either nuclear translocation or a functional SOCS box, this report identifies genes that are regulated in a manner dependent on the nuclear availability of SOCS1. Data show that beyond its receptor-proximal function in Jak/STAT signaling, SOCS1 also regulates the duration of NFκB signaling within the cell nucleus, thus exerting a heretofore unrecognized function.

Calculation of static characteristics of linear step motors for control rod drives of nuclear reactors - an approximate approach

International Nuclear Information System (INIS)

Khan, S.H.; Ivanov, A.A.

1993-01-01

This paper describes an approximate method for calculating the static characteristics of linear step motors (LSM), being developed for control rod drives (CRD) in large nuclear reactors. The static characteristic of such an LSM which is given by the variation of electromagnetic force with armature displacement determines the motor performance in its standing and dynamic modes. The approximate method of calculation of these characteristics is based on the permeance analysis method applied to the phase magnetic circuit of LSM. This is a simple, fast and efficient analytical approach which gives satisfactory results for small stator currents and weak iron saturation, typical to the standing mode of operation of LSM. The method is validated by comparing theoretical results with experimental ones. (Author)

Motor problems in children with neurofibromatosis type 1

NARCIS (Netherlands)

A.B. Rietman (André); R. Oostenbrink (Rianne); Bongers, S. (Sanne); Gaukema, E. (Eddy); Van Abeelen, S. (Sandra); J.G.M. Hendriksen; C.W.N. Looman (Caspar); P.F.A. de Nijs (Pieter); M.C.Y. de Wit (Marie Claire)

2017-01-01

textabstractBackground: Children with the neurogenetic disorder neurofibromatosis type 1 (NF1) often have problems with learning and behaviour. In both parent reports and neuropsychological assessment, motor problems are reported in approximately one third to one half of the children with NF1.

Development of Quasi-3DOF upper limb rehabilitation system using ER brake: PLEMO-P1

International Nuclear Information System (INIS)

Kikuchi, T; Fukushima, K; Furusho, J; Ozawa, T

2009-01-01

In recent years, many researchers have studied the potential of using robotics technology to assist and quantify the motor functions for neuron-rehabilitation. Some kinds of haptic devices have been developed and evaluated its efficiency with clinical tests, for example, upper limb training for patients with spasticity after stroke. However, almost all the devices are active-type (motor-driven) haptic devices and they basically require high-cost safety system compared to passive-type (brake-based) devices. In this study, we developed a new practical haptic device 'PLEMO-P1'; this system adopted ER brakes as its force generators. In this paper, the mechanism of PLEMO-P1 and its software for a reaching rehabilitation are described.

Development of Quasi-3DOF upper limb rehabilitation system using ER brake: PLEMO-P1

Energy Technology Data Exchange (ETDEWEB)

Kikuchi, T; Fukushima, K; Furusho, J; Ozawa, T [Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)], E-mail: kikuchi@mech.eng.osaka-u.ac.jp

2009-02-01

In recent years, many researchers have studied the potential of using robotics technology to assist and quantify the motor functions for neuron-rehabilitation. Some kinds of haptic devices have been developed and evaluated its efficiency with clinical tests, for example, upper limb training for patients with spasticity after stroke. However, almost all the devices are active-type (motor-driven) haptic devices and they basically require high-cost safety system compared to passive-type (brake-based) devices. In this study, we developed a new practical haptic device 'PLEMO-P1'; this system adopted ER brakes as its force generators. In this paper, the mechanism of PLEMO-P1 and its software for a reaching rehabilitation are described.

Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.

Science.gov (United States)

Nichols, Nicole L; Craig, Taylor A; Tanner, Miles A

2017-08-16

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1 G93A ), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1 G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28days following bilateral intrapleural injections of: 1) CTB-SAP (25μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162±18%, n=8 vs. 63±3%; n=8; pSAP: 64±10%, n=10 vs. 60±13; n=8; p>0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Phosphorylation and nuclear accumulation are distinct events contributing to the activation of p53

International Nuclear Information System (INIS)

O'Hagan, Heather M.; Ljungman, Mats

2004-01-01

It has been recently shown that ionizing radiation (IR) and the mRNA synthesis inhibitor 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) act in synergy to induce p53-mediated transactivation of reporter plasmids in human cells [Oncogene 19 (2000) 3829]. We have extended these studies and show that ionizing radiation and DRB also act in synergy to induce ATM-mediated phosphorylation of the ser15 site of p53 and enhance the expression of endogenous p21 protein. Examination of the localization of p53 revealed that while DRB did not induce phosphorylation of the ser15 site of p53 but efficiently accumulated p53 in the nucleus, ionizing radiation induced phosphorylation of the ser15 site of p53 without prolonged nuclear accumulation. Importantly, the combination of DRB and IR resulted in a strong accumulation of phosphorylated p53 in the nucleus that was more persistent then p53 accumulation after IR alone. Furthermore, the nuclear export inhibitor leptomycin B showed a similar synergy with IR as did DRB regarding ser15 phosphorylation of p53 and p21 induction. These results suggest that the synergistic activation of the p53 response by the combination treatment is due to the activation of two distinct pathways where DRB causes the prolonged nuclear accumulation of p53 while ionizing radiation activates p53 by ATM-mediated phosphorylation

Around and beyond 53BP1 Nuclear Bodies.

Science.gov (United States)

Fernandez-Vidal, Anne; Vignard, Julien; Mirey, Gladys

2017-12-05

Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

Around and beyond 53BP1 Nuclear Bodies

Directory of Open Access Journals (Sweden)

Anne Fernandez-Vidal

2017-12-01

Full Text Available Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1, a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

Equivalent molecular mass of cytosolic and nuclear forms of Ah receptor from Hepa-1 cells determined by photoaffinity labeling with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin

International Nuclear Information System (INIS)

Prokipcak, R.D.; Okey, A.B.

1990-01-01

The structure of the Ah receptor previously has been extensively characterized by reversible binding of the high affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report the use of [ 3 H]2,3,7,8-tetrachlorodibenzo-p-dioxin as a photoaffinity ligand for Ah receptor from the mouse hepatoma cell line Hepa-1c1c9. Both cytosolic and nuclear forms of Ah receptor could be specifically photoaffinity-labeled, which allowed determination of molecular mass for the two forms under denaturing conditions. After analysis by fluorography of polyacrylamide gels run in the presence of sodium dodecyl sulfate, molecular mass for the cytosolic form of Ah receptor was estimated at 92,000 +/- 4,300 and that for the nuclear form was estimated at 93,500 +/- 3,400. Receptor in mixture of cytosol and nuclear extract (each labeled separately with [ 3 H]2,3,7,8-tetrachlorodibenzo-p-dioxin) migrated as a single band. These results are consistent with the presence of a common ligand-binding subunit of identical molecular mass in both cytosolic and nuclear complexes

Nuclear Modification Factor RpA of b jets in pPb collisions

CERN Document Server

CMS Collaboration

2014-01-01

We present a measurement of the nuclear modification factor $R_{\\mathrm{pA}}^{\\mathrm{PYTHIA}}$ of b jets in proton-lead collisions from CMS. Jets from b-quark fragmentations are found by exploiting the long lifetime of the b-quark through tagging methods using distributions of the secondary vertex displacement. From these, b-jet cross-sections are calculated and compared to a pp cross-section obtained from a PYTHIA simulation. The $R_{\\mathrm{pA}}^{\\mathrm{PYTHIA}}$ is consistent with unity within systematic uncertainties and may show slight enhancement due to cold nuclear matter effects for a wide range in pseudorapidity. These effects are qualitatively consistent with the observed value for the inclusive jet $R_{\\mathrm{pA}}$. We use 35 nb$^{-1}$ of proton-lead data collected during the 2013 heavy-ion run at the LHC.

Nuclear thioredoxin-1 is required to suppress cisplatin-mediated apoptosis of MCF-7 cells

International Nuclear Information System (INIS)

Chen, Xiao-Ping; Liu, Shou; Tang, Wen-Xin; Chen, Zheng-Wang

2007-01-01

Different cell line with increased thioredoxin-1 (Trx-1) showed a decreased or increased sensitivity to cell killing by cisplatin. Recently, several studies found that the subcellular localization of Trx-1 is closely associated with its functions. In this study, we explored the association of the nuclear Trx-1 with the cisplatin-mediated apoptosis of breast cancer cells MCF-7. Firstly, we found that higher total Trx-1 accompanied by no change of nuclear Trx-1 can not influence apoptosis induced by cisplatin in MCF-7 cells transferred with Trx-1 cDNA. Secondly, higher nuclear Trx-1 accompanied by no change of total Trx-1 can protect cells from apoptosis induced by cisplatin. Thirdly, high nuclear Trx-1 involves in the cisplatin-resistance in cisplatin-resistive cells. Meanwhile, we found that the mRNA level of p53 is closely correlated with the level of nuclear Trx-1. In summary, we concluded that the nuclear Trx-1 is required to resist apoptosis of MCF-7 cells induced by cisplatin, probably through up-regulating the anti-apoptotic gene, p53

Investigation of phosphorous in thin films using the {sup 31}P(α,p){sup 34}S nuclear reaction

Energy Technology Data Exchange (ETDEWEB)

Pitthan, E., E-mail: eduardo.pitthan@ufrgs.br [PGMICRO, UFRGS, 91509-900 Porto Alegre, RS (Brazil); Gobbi, A.L. [Laboratório Nacional de Nanotecnologia, 13083-100 Campinas, SP (Brazil); Stedile, F.C. [PGMICRO, UFRGS, 91509-900 Porto Alegre, RS (Brazil); Instituto de Química, UFRGS, 91509-900 Porto Alegre, RS (Brazil)

2016-03-15

Phosphorus detection and quantification were obtained, using the {sup 31}P(α,p){sup 34}S nuclear reaction and Rutherford Backscattering Spectrometry, in deposited silicon oxide films containing phosphorus and in carbon substrates implanted with phosphorus. It was possible to determine the total amount of phosphorus using the resonance at 3.640 MeV of the {sup 31}P(α,p){sup 34}S nuclear reaction in samples with phosphorus present in up to 23 nm depth. Phosphorous amounts as low as 4 × 10{sup 14} cm{sup −2} were detected. Results obtained by nuclear reaction were in good agreement with those from RBS measurements. Possible applications of phosphorus deposition routes used in this work are discussed.

Cervical spinal erythropoietin induces phrenic motor facilitation via ERK and Akt signaling

Science.gov (United States)

Dale, Erica A.; Satriotomo, Irawan; Mitchell, Gordon S.

2012-01-01

Erythropoietin (EPO) is typically known for its role in erythropoiesis, but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by Hypoxia-Inducible Factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Since EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague-Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min post-injection (63±12% baseline 90 min post-injection; pphrenic motor neurons; EPO also increased pAkt (1.6 fold vs controls; pphrenic motor neurons (p<0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Since EPO expression is hypoxia-sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen. PMID:22539857

Urinary Levels of IL-1β and GDNF in Preterm Neonates as Potential Biomarkers of Motor Development: A Prospective Study

Directory of Open Access Journals (Sweden)

Rafael Coelho Magalhães

2017-01-01

Full Text Available Objectives. To evaluate the association between inflammatory biomarkers, neurotrophic factors, birth conditions, and the presence of motor development abnormalities in preterm neonates. Methods. Plasma and urinary levels of cytokines (IL-1β, IL-6, IL-10, TNF, and IL-12p70, chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL9/MIG, and neurotrophic factors (BDNF and GDNF were evaluated in 40 preterm neonates born between 28 and 32 incomplete weeks of gestation, at four distinct time points: at birth (umbilical cord blood (T0, at 48 (T1, at 72 hours (T2, and at 3 weeks after birth (T3. Biomarkers levels were compared between different time points and then associated with Test of Infant Motor Performance (TIMP percentiles. Results. Maternal age, plasma, and urinary concentrations of inflammatory molecules and neurotrophic factors were significantly different between groups with normal versus lower than expected motor development. Higher levels of GDNF were found in the group with lower than expected motor development, while IL-1β and CXCL8/IL-8 values were higher in the group with typical motor development. Conclusion. Measurements of cytokines and neurotrophic factors in spot urine may be useful in the follow-up of motor development in preterm neonates.

Theoretical nuclear physics. Progress report, October 1, 1991--August 1, 1992

Energy Technology Data Exchange (ETDEWEB)

Rost, E.; Shephard, J.R.

1992-08-01

This report discusses the following topics: Exact 1-loop vacuum polarization effects in 1 + 1 dimensional QHD; exact 1-fermion loop contributions in 1 + 1 dimensional solitons; exact scalar 1-loop contributions in 1 + 3 dimensions; exact vacuum calculations in a hyper-spherical basis; relativistic nuclear matter with self- consistent correlation energy; consistent RHA-RPA for finite nuclei; transverse response functions in the {triangle}-resonance region; hadronic matter in a nontopological soliton model; scalar and vector contributions to {bar p}p {yields} {bar {Lambda} {Lambda}} reaction; 0+ and 2+ strengths in pion double-charge exchange to double giant-dipole resonances; and nucleons in a hybrid sigma model including a quantized pion field.

Motor impairment in children with Neurofibromatosis type 1: Effect of the comorbidity with language disorders.

Science.gov (United States)

Iannuzzi, Stéphanie; Albaret, Jean-Michel; Chignac, Céline; Faure-Marie, Nathalie; Barry, Isabelle; Karsenty, Caroline; Chaix, Yves

2016-02-01

There is a body of evidence demonstrating comorbidity of motor and cognitive deficit in «idiopathic» developmental disorders. These associations are also found in developmental disorders secondary to monogenic disorders as in Neurofibromatosis type 1 for which the principal complication during childhood is learning disabilities. The comparison of motor impairment between developmental disorders either idiopathic or secondary as in NF1 could help us to better understand the cause of the combined language/motor deficit in these populations. The aim of this current study was to investigate motor impairment in children with NF1 for which oral language had been specified and then to compare the motors skills of the NF1 group to motor performance of children with Specific Language Disorder (SLD). Two groups of 49 children between 5 and 12years old were included and compared, the NF1 group and the SLD (Specific Language Disorder) group. Each child completed evaluation involving cognitive, language and motor assessment. In NF1 group, motor impairment was more frequent and more severe and concerned specifically balance rather than manual dexterity or ball skills, compared to a group of children with SLD. This motor impairment was independent of language status in the NF1 group. These results as well as other studies on the same topic could suggest that in NF1 children, fine motor skills impairment would be dependent on the existence of comorbidity with language disorders. Also, that gross motor skills impairment, and more precisely the balance deficit would be characteristic of NF1. This issue encourages studies of procedural learning that can involve the fronto-striatal or the fronto-cerebellar loops according to the type of motor tasks and the stage of learning. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Nuclear power. Volume 1. Nuclear power plant design

International Nuclear Information System (INIS)

Pedersen, E.S.

1978-01-01

NUCLEAR POWER PLANT DESIGN is intended to be used as a working reference book for management, engineers and designers, and as a graduate-level text for engineering students. The book is designed to combine theory with practical nuclear power engineering and design experience, and to give the reader an up-to-date view of the status of nuclear power and a basic understanding of how nuclear power plants function. Volume 1 contains the following chapters; (1) nuclear reactor theory; (2) nuclear reactor design; (3) types of nuclear power plants; (4) licensing requirements; (5) shielding and personnel exposure; (6) containment and structural design; (7) main steam and turbine cycles; (8) plant electrical system; (9) plant instrumentation and control systems; (10) radioactive waste disposal (waste management) and (11) conclusion

Glycogen synthase kinase 3-{beta} phosphorylates novel S/T-P-S/T domains in Notch1 intracellular domain and induces its nuclear localization

Energy Technology Data Exchange (ETDEWEB)

Han, Xiangzi [Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of); Department of Preventive Medicine, Yanbian University College of Medicine, Yanji (China); Ju, Ji-hyun [Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of); Shin, Incheol, E-mail: incheol@hanyang.ac.kr [Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of)

2012-06-29

Highlights: Black-Right-Pointing-Pointer Novel S/T-P-S/T domains were identified in NICD. Black-Right-Pointing-Pointer Phosphorylation of NICD on the S/T-P-S/T domains induced nuclear localization. Black-Right-Pointing-Pointer GSK-3{beta} phosphorylated S and T residues in NICD S/T-P-S/T domains. -- Abstract: We identified two S/T-P-S/T domains (2122-2124, 2126-2128) inducing Notch intracellular domain (NICD) nuclear localization. The GFP-NICD (1963-2145) fusion protein deletion mutant without classical NLS was localized in the nucleus like the full length GFP-NICD. However, quadruple substitution mutant (T2122A T2124A S2126A T2128A) showed increased cytoplasmic localization. GSK-3{beta} enhanced nuclear localization and transcriptional activity of WT NICD but not of quadruple substitution mutant. In vitro kinase assays revealed that GSK-3{beta} phosphorylated S and T residues in NICD S/T-P-S/T domains. These results suggest that the novel S/T-P-S/T domain, phosphorylated by GSK-3{beta} is also involved in the nuclear localization of NICD as well as classical NLS.

Association with the origin recognition complex suggests a novel role for histone acetyltransferase Hat1p/Hat2p

Directory of Open Access Journals (Sweden)

Greenblatt Jack F

2007-09-01

Full Text Available Abstract Background Histone modifications have been implicated in the regulation of transcription and, more recently, in DNA replication and repair. In yeast, a major conserved histone acetyltransferase, Hat1p, preferentially acetylates lysine residues 5 and 12 on histone H4. Results Here, we report that a nuclear sub-complex consisting of Hat1p and its partner Hat2p interacts physically and functionally with the origin recognition complex (ORC. While mutational inactivation of the histone acetyltransferase (HAT gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2 exacerbates the growth defects of conditional orc-ts mutants. Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication. Additional genetic and biochemical evidence points to the existence of partly overlapping histone H3 acetyltransferase activities in addition to Hat1p/Hat2p for proper DNA replication efficiency. Furthermore, we demonstrated a dynamic association of Hat1p with chromatin during S-phase that suggests a role of this enzyme at the replication fork. Conclusion We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p. The participation of a distinct Hat1p/Hat2p sub-complex suggests a linkage of histone H4 modification with ORC-dependent DNA replication.

Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1G93A Model of Amyotrophic Lateral Sclerosis

Science.gov (United States)

Riancho, Javier; Ruiz-Soto, Maria; Villagrá, Nuria T.; Berciano, Jose; Berciano, Maria T.; Lafarga, Miguel

2014-01-01

We investigated neuronal self-defense mechanisms in a murine model of amyotrophic lateral sclerosis (ALS), the transgenic hSOD1G93A, during both the asymptomatic and symptomatic stages. This is an experimental model of endoplasmic reticulum (ER) stress with severe chromatolysis. As a compensatory response to translation inhibition, chromatolytic neurons tended to reorganize the protein synthesis machinery at the perinuclear region, preferentially at nuclear infolding domains enriched in nuclear pores. This organization could facilitate nucleo-cytoplasmic traffic of RNAs and proteins at translation sites. By electron microscopy analysis, we observed that the active euchromatin pattern and the reticulated nucleolar configuration of control motor neurons were preserved in ALS chromatolytic neurons. Moreover the 5′-fluorouridine (5′-FU) transcription assay, at the ultrastructural level, revealed high incorporation of the RNA precursor 5′-FU into nascent RNA. Immunogold particles of 5′-FU incorporation were distributed throughout the euchromatin and on the dense fibrillar component of the nucleolus in both control and ALS motor neurons. The high rate of rRNA transcription in ALS motor neurons could maintain ribosome biogenesis under conditions of severe dysfunction of proteostasis. Collectively, the perinuclear reorganization of protein synthesis machinery, the predominant euchromatin architecture, and the active nucleolar transcription could represent compensatory mechanisms in ALS motor neurons in response to the disturbance of ER proteostasis. In this scenario, epigenetic activation of chromatin and nucleolar transcription could have important therapeutic implications for neuroprotection in ALS and other neurodegenerative diseases. Although histone deacetylase inhibitors are currently used as therapeutic agents, we raise the untapped potential of the nucleolar transcription of ribosomal genes as an exciting new target for the therapy of some neurodegenerative